[DB] 1-'[H,C]'-2-(2,3,4,5,6-penta'GH'phenyl)propan-1-amine by Asch

Query Query

Results

Date

553 reactions in Reaxys

2018-08-17 22h:59m:04s (UTC)

GH GH

NH 2

1. Query

L GH

[H,C]

Search as: Product, As drawn, Ignore stereo, No salts, No mixtures, No isotopes, No charges, No radicals, No additional rings ))

1/236

2018-08-17 23:02:17

H NH 2

H 2N

Rx-ID: 436392 View in Reaxys 1/553 Yield

Conditions & References With D-Malic acid Brode; Raasch; Journal of the American Chemical Society; vol. 64; (1942); p. 1449,1450 View in Reaxys With l-tartaric acid Brode; Raasch; Journal of the American Chemical Society; vol. 64; (1942); p. 1449,1450 View in Reaxys With D-(+)-camphoric acid Brode; Raasch; Journal of the American Chemical Society; vol. 64; (1942); p. 1449,1450 View in Reaxys With MANDELIC ACID Jarowski; Hartung; Journal of Organic Chemistry; vol. 8; (1943); p. 564,566 View in Reaxys

H NH 2

H 2N

Rx-ID: 436393 View in Reaxys 2/553 Yield

Conditions & References With MANDELIC ACID Jarowski; Hartung; Journal of Organic Chemistry; vol. 8; (1943); p. 564,566 View in Reaxys With malic acid Brode; Raasch; Journal of the American Chemical Society; vol. 64; (1942); p. 1449,1450 View in Reaxys With l-tartaric acid Brode; Raasch; Journal of the American Chemical Society; vol. 64; (1942); p. 1449,1450 View in Reaxys With MANDELIC ACID Jarowski; Hartung; Journal of Organic Chemistry; vol. 8; (1943); p. 564,566 View in Reaxys

NH 2 N

Rx-ID: 436597 View in Reaxys 3/553

2/236

2018-08-17 23:02:17

Yield

Conditions & References

98 %

With samarium diiodide, water, triethylamine in tetrahydrofuran, Time= 0.0833333h, T= 20 °C , Inert atmosphere Szostak, Michal; Sautier, Brice; Spain, Malcolm; Procter, David J.; Organic Letters; vol. 16; nb. 4; (2014); p. 1092 - 1095 View in Reaxys With hydrogenchloride, ethanol, palladium, Hydrogenation Hartung; Munch; Journal of the American Chemical Society; vol. 53; (1931); p. 1875,1878 View in Reaxys With ethanol, ammonia, nickel, Hydrogenation Girault-Vexlearschi; Bulletin de la Societe Chimique de France; (1956); p. 589,596 View in Reaxys With lithium aluminium tetrahydride in diethyl ether Eiden; Iwan; Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft; vol. 303; nb. 7; (1970); p. 612 - 617 View in Reaxys Reaction Steps: 2 1: woollins’ reagent / toluene / 6 h / Inert atmosphere; Reflux 2: water; samarium diiodide / tetrahydrofuran / 20 °C / Inert atmosphere With samarium diiodide, water, woollins’ reagent in tetrahydrofuran, toluene Thurow, Samuel; Lenardo, Eder J.; Just-Baringo, Xavier; Procter, David J.; Organic Letters; vol. 19; nb. 1; (2017); p. 50 53 View in Reaxys

NH 2

O NH 2

Rx-ID: 437489 View in Reaxys 4/553 Yield

Conditions & References With lithium aluminium tetrahydride, diethyl ether Pettersson; Arkiv foer Kemi; vol. 10; (1957); p. 283,285, 286 View in Reaxys

NH 2 H 2N

Rx-ID: 746836 View in Reaxys 5/553 Yield

Conditions & References With aluminium trichloride Weston; Ruddy; Suter; Journal of the American Chemical Society; vol. 65; (1943); p. 675 View in Reaxys

3/236

2018-08-17 23:02:17

NH 2

Rx-ID: 802402 View in Reaxys 6/553 Yield

Conditions & References With benzene Bras; Doklady Akademii Nauk SSSR; vol. 87; (1952); p. 747,750; ; (1954); p. 569 View in Reaxys

NH 2

N HO

Rx-ID: 1059892 View in Reaxys 7/553 Yield

Conditions & References

73 %

With sodium tetrahydroborate, <CoPc>(-) in ethanol, Time= 48h, T= 20 Â°C Eckert, Heiner; Kiesel, Yvonne; Angewandte Chemie; vol. 93; nb. 5; (1981); p. 477 - 479 View in Reaxys (i) Na<AlH2(OCH2CH2OMe)2>, benzene, (ii) aq. H2SO4, Multistep reaction Cerny,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 34; nb. 3; (1969); p. 1033 - 1041 View in Reaxys

NH 2

Si N N N

Rx-ID: 1065942 View in Reaxys 8/553 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether Kyba,E.P.; John,A.M.; Tetrahedron Letters; (1977); p. 2737 - 2740 View in Reaxys

NH 2

O N O

Rx-ID: 2117202 View in Reaxys 9/553 Yield 96 %

Conditions & References 26 : Example 26 Under argon atmosphere, 121mg of optically active L-NITRO-2-PHENYLPROPANE (732 G MOL) were dissolved in 5mol of dry methanol and 50mg of palladium on charcoal (10percent) were added thereto. The obtained suspension was vigorously stirred under hydrogen atmosphere for 24 hours. The mixture was filtered and the solid was washed with methanol. The solvent was evaporated and the residue was dissolved in 2ML of benzene. The solvent was evaporated to give 95mg of an optically active LAMINO-2-PHENYLPROPANE as a colorless oil (703 G MOL). Yield: 96percent With hydrogen, 10% palladium on activated carbon; Degussa type in methanol, Time= 24h

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

4/236

2018-08-17 23:02:17

Patent; SUMITOMO CHEMICAL COMPANY, LIMITED; CARREIRA, Erick, M.; WO2004/103951; (2004); (A1) English View in Reaxys 41 %

With hydrogenchloride, iron in water, Heating Hansson, A.-T.; Nilsson, M.; Tetrahedron; vol. 38; nb. 3; (1982); p. 389 - 391 View in Reaxys

84 %Chromat.

With sodium hypophosphite monohydrate, Johnson & Matthey type 440, hypophosphorous acid in 2-methyltetrahydrofuran, water, Time= 0.25h, T= 60 °C , Sonication, Green chemistry Letort; Lejeune; Kardos; Métay; Popowycz; Lemaire; Draye; Green Chemistry; vol. 19; nb. 19; (2017); p. 4583 - 4590 View in Reaxys

O NH 2

H N O

H 2N

Rx-ID: 2117204 View in Reaxys 10/553 Yield

Conditions & References With lithium aluminium tetrahydride, Title compound not separated from byproducts Ohta, Hiromichi; Ozaki, Kazuhiko; Tsuchihashi, Gen-ichi; Chemistry Letters; (1987); p. 191 - 192 View in Reaxys

H N

NH 2

Rx-ID: 2167175 View in Reaxys 11/553 Yield 85 %

Conditions & References With (bicyclo<2.2.1>heptadiene) <(R)-trans-4,5-bis<(diphenylphosphino)methyl>-2,2-dimethyldioxolan>rhodium(I) tetrafluoroborate, hydrogen bromide, hydrogen in methanol, T= 20 °C , p= 760Torr , 1.) 12 h, 2.) H2O, 18 h Brown, John M.; Parker, David; Journal of Organic Chemistry; vol. 47; nb. 14; (1982); p. 2722 - 2730 View in Reaxys

H H

NH 2

Rx-ID: 2198213 View in Reaxys 12/553 Yield

Conditions & References With lithium aluminium tetrahydride Ruechardt, Christoph; Meier, Michael; Haaf, Klaus; Pakusch, Joachim; Wolber, Erwin K. A.; Mueller, Barbara; Angewandte Chemie; vol. 103; nb. 8; (1991); p. 907 - 915 View in Reaxys

5/236

2018-08-17 23:02:17

H N

NH 2

O HN

H 2N N O

Rx-ID: 2831108 View in Reaxys 13/553 Yield

Conditions & References With hydrogen, nickel in methanol, Time= 24h, T= 20 - 40 °C , p= 2625.2 - 2850.2Torr , Yield given. Yields of byproduct given Enders, Dieter; Schubert, Heinrich; Angewandte Chemie; vol. 96; nb. 5; (1984); p. 368 - 369 View in Reaxys

NH 2

H 2N

Rx-ID: 3191920 View in Reaxys 14/553 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, Yield given. Title compound not separated from byproducts Kirmse, Wolfgang; Guenther, Bernd-Rainer; Loosen, Karin; Chemische Berichte; vol. 113; nb. 6; (1980); p. 2140 - 2153 View in Reaxys

NH 2 B

Rx-ID: 3249553 View in Reaxys 15/553 Yield 56 %

Conditions & References With ammonium hydroxide, sodium hypochlorite in water, 1.) 0 deg C, 5-10 min, 2.) 0 deg C -> room temperature Kabalka, George W.; Wang, Zhe; Goudgaon, Nganna M.; Synthetic Communications; vol. 19; nb. 13-14; (1989); p. 2409 2414 View in Reaxys

NH 2

Rx-ID: 3923360 View in Reaxys 16/553 Yield 88 %

Conditions & References Stage 1: With Schwartz's reagent in tetrahydrofuran, T= 25 °C Stage 2: With hydroxylamine-O-sulfonic acid in tetrahydrofuran, Time= 0.5h, T= 25 °C Strom, Alexandra E.; Hartwig, John F.; Journal of Organic Chemistry; vol. 78; nb. 17; (2013); p. 8909 - 8914 View in Reaxys With borane-THF, hydroxylamine-O-sulfonic acid, 1) THF, 2) 3 h, reflux, Yield given. Multistep reaction

6/236

2018-08-17 23:02:17

Brown, Herbert C.; Kim, Kee-Won; Srebnik, Morris; Singaram, Bakthan; Tetrahedron; vol. 43; nb. 18; (1987); p. 4071 4078 View in Reaxys With methanol, borane-THF, trimethylsilylazide, 1.) reflux, 2.) reflux, 40 h, Yield given. Multistep reaction Kabalka, George W.; Goudgaon, Naganna M.; Liang, Yanhong; Synthetic Communications; vol. 18; nb. 12; (1988); p. 1363 - 1370 View in Reaxys

H N

NH 2

Rx-ID: 4798387 View in Reaxys 17/553 Yield

Conditions & References

66 %

With cyclohexene, palladium dihydroxide, Time= 24h, Heating Jullian, Valerie; Quirion, Jean-Charles; Husson, Henri-Philippe; Synthesis; nb. 9; (1997); p. 1091 - 1097 View in Reaxys

NH 2 Al

H 2N

Rx-ID: 5801210 View in Reaxys 18/553 Yield

Conditions & References analoge Reaktionen erfolgen mit Fluorbenzol und mit Toluol Weston; Ruddy; Suter; Journal of the American Chemical Society; vol. 65; (1943); p. 675 View in Reaxys Weston; Ruddy; Suter; Journal of the American Chemical Society; vol. 65; (1943); p. 675 View in Reaxys

NH 2

Rx-ID: 6330938 View in Reaxys 19/553 Yield

Conditions & References Mix; Trettin; Guelzow; Hoppe-Seyler's Zeitschrift fuer physiologische Chemie; vol. 343; nb. 1; (1965); p. 52 - 60 View in Reaxys Agrawal et al.; Journal of Medicinal Chemistry; vol. 19; (1976); p. 970 View in Reaxys Biere et al.; Journal of Medicinal Chemistry; vol. 17; (1974); p. 716,719 View in Reaxys Potapov et al.; Doklady Chemistry; vol. 202; (1972); p. 147; Dokl. Akad. Nauk SSSR Ser. Khim.; vol. 202; (1972); p. 1087 View in Reaxys Sugi; Mitsui; Bulletin of the Chemical Society of Japan; vol. 42; (1969); p. 2984,2988

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

7/236

2018-08-17 23:02:17

View in Reaxys Brown et al.; Journal of the American Chemical Society; vol. 86; (1964); p. 3565 View in Reaxys Redenilh et al.; Bulletin de la Societe Chimique de France; (1973); p. 2668,2670-2672 View in Reaxys Tamura et al.; Synthesis; (1974); p. 196 View in Reaxys Lamant; Cariou; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 257; (1963); p. 3942; ; nb. 27027; (1961) View in Reaxys Milstein; Journal of Heterocyclic Chemistry; vol. 5; (1968); p. 339 View in Reaxys Goodman; Chen; Macromolecules; vol. 3; (1970); p. 398,399,401 View in Reaxys

NH 2

α-phenyl-propionic acid nitrile

Rx-ID: 6330939 View in Reaxys 20/553 Yield

Conditions & References With ethanol, sodium Freund; Koenig; Chemische Berichte; vol. 26; (1893); p. 2871 View in Reaxys

NH 2

α-methyl-hydrocinnamic acid amide

Rx-ID: 6330940 View in Reaxys 21/553 Yield

Conditions & References With potassium hydroxide, bromine v. Braun; Grabowski; Kirschbaum; Chemische Berichte; vol. 46; (1913); p. 1280 View in Reaxys

H NH 2

(R)-2-phenyl-propionitrile

Rx-ID: 8094949 View in Reaxys 22/553 Yield

Conditions & References With acetic acid, platinum, Hydrogenation Levene; Mikeska; Passoth; Journal of Biological Chemistry; vol. 88; (1930); p. 27,57 View in Reaxys

NH 2

(+-)-2-phenyl-propyl chloride

Rx-ID: 8094950 View in Reaxys 23/553

8/236

2018-08-17 23:02:17

Yield

Conditions & References With ethanol, ammonia, T= 160 °C Patrick; McBee; Hass; Journal of the American Chemical Society; vol. 68; (1946); p. 1009 View in Reaxys

NH 2

(+-)-3-phenyl-butyramide

Rx-ID: 8094951 View in Reaxys 24/553 Yield

Conditions & References With alkaline aqueous sodium hypobromite Dey; Ramanathan; Proceedings of the National Institute of Sciences of India; vol. 9; (1943); p. 193,222 View in Reaxys Woodruff; Pierson; Journal of the American Chemical Society; vol. 60; (1938); p. 1075 View in Reaxys With alkaline aqueous sodium hypochlorite Dey; Ramanathan; Proceedings of the National Institute of Sciences of India; vol. 9; (1943); p. 193,222 View in Reaxys Woodruff; Pierson; Journal of the American Chemical Society; vol. 60; (1938); p. 1075 View in Reaxys

H OH

NH 2

N H

Rx-ID: 8265082 View in Reaxys 25/553 Yield

Conditions & References T= 80 - 90 °C Weston; Ruddy; Suter; Journal of the American Chemical Society; vol. 65; (1943); p. 675 View in Reaxys

NH 2

(+-)-2-phenyl-propyl bromide

Rx-ID: 8265086 View in Reaxys 26/553 Yield

Conditions & References With ethanol, ammonia Weston; Ruddy; Suter; Journal of the American Chemical Society; vol. 65; (1943); p. 675 View in Reaxys

NH 2

Rx-ID: 8519298 View in Reaxys 27/553

9/236

2018-08-17 23:02:17

Yield 82 %

Conditions & References With ammonia, hydrogen in tert-butyl alcohol, Time= 15h, T= 120 °C Jagadeesh, Rajenahally V.; Murugesan, Kathiravan; Alshammari, Ahmad S.; Neumann, Helfried; Pohl, Marga-Martina; Radnik, Jörg; Beller, Matthias; Science; vol. 358; nb. 6361; (2017); p. 326 - 332 View in Reaxys

7.2 g

Stage 1: With formamide, Time= 10h, Heating, Condensation, Leuckart reaction Stage 2: With sodium hydroxide, Time= 15h, Heating, Hydrolysis, Leuckart reaction Bocchinfuso, Ronald; Robinson, J. Barry; European Journal of Medicinal Chemistry; vol. 34; nb. 4; (1999); p. 293 - 300 View in Reaxys Reaction Steps: 2 1: ZnCl2 2: LiAlH4 / diethyl ether With lithium aluminium tetrahydride, zinc(II) chloride in diethyl ether Kyba,E.P.; John,A.M.; Tetrahedron Letters; (1977); p. 2737 - 2740 View in Reaxys Reaction Steps: 2 1: NH2OH*HCl, aq. NaOH 2: (i) Na<AlH2(OCH2CH2OMe)2>, benzene, (ii) aq. H2SO4 With sodium hydroxide, hydroxylamine hydrochloride Cerny,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 34; nb. 3; (1969); p. 1033 - 1041 View in Reaxys 2.9 Enzymatic reaction General procedure: The enzymatic reactions were carried out at 37°C in pH 8.0 potassium phosphate buffer 100mM and 15percent v/v purified enzyme solution corresponding to 0.89U/mL for the screening of the amino donors, and 0.71U/mL for the screening of the amino acceptor reactions. The reaction mixture contained 10mM enantiopure amino donor (20mM if racemic), 10mM amino acceptor and 0.05mg/mL of HEWT in a reaction volume of 200μL. For the determination of enantioselectivity, reactions were carried out at 37°C in pH 8.0 potassium phosphate buffer 100mM in 1mL, containing 20mM rac-1-phenylethylamine, 10mM pyruvate, 0.1mM PLP with 0.1mg/mL of HEWT. As a control, the reactions were set up as previously described but without the addition of HEWT, in which case only starting material was detected. The activity of the enzyme in the various reaction conditions was established employing (S)-(–)-1-phenylethylamine as amino donor and pyruvate as acceptor. One enzymatic unit was defined as the amount of enzyme that converts 1μmol of (S)-(–)-1-phenylethylamine in 1min. The initial rate was determined by monitoring the decrease of the concentration of (S)-(–)-1-phenylethylamine during the first three minutes. Frozen aliquots of the enzyme at −20°C were used. H. elongata α-transaminase was stable for several months without evident loss of activity. Data were obtained by averaging the measurements on three independent samples. With (S)-1-phenyl-ethylamine, Halomonas elongata α-transaminase in aq. phosphate buffer, T= 37 °C , pH= 8, Enzymatic reaction Cerioli, Lorenzo; Planchestainer, Matteo; Cassidy, Jennifer; Tessaro, Davide; Paradisi, Francesca; Journal of Molecular Catalysis B: Enzymatic; vol. 120; (2015); p. 141 - 150 View in Reaxys

H NH 2

H O

H 2N

Rx-ID: 8540854 View in Reaxys 28/553 Yield

Conditions & References Stage 1: With formamide, Time= 10h, Heating, Condensation, Leuckart reaction Stage 2: With sodium hydroxide, Time= 15h, Heating, Hydrolysis, Leuckart reaction, Title compound not separated from byproducts Bocchinfuso, Ronald; Robinson, J. Barry; European Journal of Medicinal Chemistry; vol. 34; nb. 4; (1999); p. 293 - 300

10/236

2018-08-17 23:02:17

View in Reaxys

NH 2

N OH N N

Rx-ID: 8589890 View in Reaxys 29/553 Yield

Conditions & References

79 %

With hydrogen, 10 wt. % palladium on activated carbon in ethanol, Time= 24h, Hydrogenolysis Chandrasekhar, Sosale; Sridhar, Malayalam; Tetrahedron Letters; vol. 41; nb. 23; (2000); p. 4685 - 4688 View in Reaxys

NH 2

N N N

Rx-ID: 8710588 View in Reaxys 30/553 Yield 16 % Chromat.

Conditions & References With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride, tri-n-butyl-tin hydride in tetrahydrofuran, Time= 0.5h, T= 0 °C , Reduction Malanga, Corrado; Mannucci, Serena; Lardicci, Luciano; Journal of Chemical Research, Miniprint; nb. 6; (2000); p. 701 715 View in Reaxys

O HN

NH 2

Rx-ID: 8842969 View in Reaxys 31/553 Yield 91 %

Conditions & References With caesium carbonate, thiophenol in N,N-dimethyl-formamide, Time= 0.5h, T= 20 °C Nihei; Kato; Yamane; Palma; Konno; Synlett; nb. 7; (2001); p. 1167 - 1169 View in Reaxys

11/236

2018-08-17 23:02:17

H O

O N

NH 2

O S O

N O

Rx-ID: 8845852 View in Reaxys 32/553 Yield

Conditions & References

85 %

With 2-hydroxyethanethiol in N,N-dimethyl-formamide, Time= 1h, T= 20 °C Nihei; Kato; Yamane; Palma; Konno; Synlett; nb. 7; (2001); p. 1167 - 1169 View in Reaxys

NH 2

N O

Rx-ID: 9536852 View in Reaxys 33/553 Yield

Conditions & References

96 %

With hydrogen, 10 wt. % palladium on activated carbon in methanol, T= 20 °C , p= 760Torr Czekelius, Constantin; Carreira, Erick M.; Angewandte Chemie - International Edition; vol. 42; nb. 39; (2003); p. 4793 4795 View in Reaxys

O N

O S

NH 2 HN

Rx-ID: 9824553 View in Reaxys 34/553 Yield 74 %

Conditions & References With magnesium in methanol Han, Hoon; Bae, Imhyuck; Eun, Jeong Yoo; Lee, Junseong; Do, Youngkyu; Chang, Sukbok; Organic Letters; vol. 6; nb. 22; (2004); p. 4109 - 4112 View in Reaxys

NH 2

[Rh(PEt3)2(μ-NH(p-tolyl))]2

Rx-ID: 13244883 View in Reaxys 35/553 Yield

Conditions & References Reaction Steps: 3 1: 84 percent / PhI(OAc)2; copper(II) trifluoroacetylacetonate / acetonitrile / 12 h / 25 °C 2: 66 percent / CuI / diethyl ether / 2 h / -78 °C 3: 74 percent / Mg / methanol

12/236

2018-08-17 23:02:17

With copper(l) iodide, copper(II) hexafluoro-2,4-pentanedionate, [bis(acetoxy)iodo]benzene, magnesium in methanol, diethyl ether, acetonitrile Han, Hoon; Bae, Imhyuck; Eun, Jeong Yoo; Lee, Junseong; Do, Youngkyu; Chang, Sukbok; Organic Letters; vol. 6; nb. 22; (2004); p. 4109 - 4112 View in Reaxys

O N

O S

NH 2 N

Rx-ID: 13273129 View in Reaxys 36/553 Yield

Conditions & References Reaction Steps: 2 1: 66 percent / CuI / diethyl ether / 2 h / -78 °C 2: 74 percent / Mg / methanol With copper(l) iodide, magnesium in methanol, diethyl ether Han, Hoon; Bae, Imhyuck; Eun, Jeong Yoo; Lee, Junseong; Do, Youngkyu; Chang, Sukbok; Organic Letters; vol. 6; nb. 22; (2004); p. 4109 - 4112 View in Reaxys

NH 2

Rx-ID: 15544579 View in Reaxys 37/553 Yield

Conditions & References Reaction Steps: 3 1: Et3N / CH2Cl2 / 12 h / -5 °C 2: 85 percent / dimethylformamide / 6 h / 60 °C 3: 16 percent Chromat. / TBTH; Ni(diphenylphosphinoethane)Cl2 / tetrahydrofuran / 0.5 h / 0 °C With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride, tri-n-butyl-tin hydride, triethylamine in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide, 1: sulfonylation / 2: Substitution / 3: Reduction Malanga, Corrado; Mannucci, Serena; Lardicci, Luciano; Journal of Chemical Research, Miniprint; nb. 6; (2000); p. 701 715 View in Reaxys

NH 2

O S

Rx-ID: 15562916 View in Reaxys 38/553 Yield

Conditions & References Reaction Steps: 2 1: 85 percent / dimethylformamide / 6 h / 60 °C 2: 16 percent Chromat. / TBTH; Ni(diphenylphosphinoethane)Cl2 / tetrahydrofuran / 0.5 h / 0 °C With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride, tri-n-butyl-tin hydride in tetrahydrofuran, N,N-dimethyl-formamide, 1: Substitution / 2: Reduction Malanga, Corrado; Mannucci, Serena; Lardicci, Luciano; Journal of Chemical Research, Miniprint; nb. 6; (2000); p. 701 715 View in Reaxys

13/236

2018-08-17 23:02:17

CH2=CH-CH2-Mg-Hlg O

NH 2

p-ClPhCH2NH-(acid sensitive methoxy benzaldehyde polystyrene)

Rx-ID: 15924045 View in Reaxys 39/553 Yield

Conditions & References Reaction Steps: 2 1: 72 percent / Mg; iodine / tetrahydrofuran / 1 h / 20 Â°C / ultrasound 2: 79 percent / H2 / Pd/C / ethanol / 24 h With hydrogen, iodine, magnesium, 10 wt. % palladium on activated carbon in tetrahydrofuran, ethanol, 1: Barbier reaction / 2: Hydrogenolysis Chandrasekhar, Sosale; Sridhar, Malayalam; Tetrahedron Letters; vol. 41; nb. 23; (2000); p. 4685 - 4688 View in Reaxys

H NH 2

O HO

Rx-ID: 17093749 View in Reaxys 40/553 Yield

Conditions & References Reaction Steps: 3 1: 1.) s-BuLi, LiCl / 1.) THF, hexane, -78 deg C, 1 h, 2.) THF, hexane, -23 deg C 2: 86 percent / LiALH4 / tetrahydrofuran / Heating 3: 66 percent / cyclohexene / Pd(OH)2/C / 24 h / Heating With lithium aluminium tetrahydride, sec.-butyllithium, lithium chloride, cyclohexene, palladium dihydroxide in tetrahydrofuran Jullian, Valerie; Quirion, Jean-Charles; Husson, Henri-Philippe; Synthesis; nb. 9; (1997); p. 1091 - 1097 View in Reaxys

H N

NH 2

Rx-ID: 17094447 View in Reaxys 41/553 Yield

Conditions & References Reaction Steps: 2 1: 86 percent / LiALH4 / tetrahydrofuran / Heating 2: 66 percent / cyclohexene / Pd(OH)2/C / 24 h / Heating With lithium aluminium tetrahydride, cyclohexene, palladium dihydroxide in tetrahydrofuran Jullian, Valerie; Quirion, Jean-Charles; Husson, Henri-Philippe; Synthesis; nb. 9; (1997); p. 1091 - 1097

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

14/236

2018-08-17 23:02:17

View in Reaxys

H NH 2

Rx-ID: 19969123 View in Reaxys 42/553 Yield

Conditions & References Reaction Steps: 3 1: pyridine 2: NaN3 / dimethylsulfoxide / 20 h / 80 °C 3: LiAlH4 / diethyl ether With lithium aluminium tetrahydride, sodium azide in pyridine, diethyl ether, dimethyl sulfoxide Kirmse, Wolfgang; Guenther, Bernd-Rainer; Loosen, Karin; Chemische Berichte; vol. 113; nb. 6; (1980); p. 2140 - 2153 View in Reaxys

H NH 2

Rx-ID: 19969124 View in Reaxys 43/553 Yield

NH 2

S O

Rx-ID: 19994777 View in Reaxys 44/553 Yield

Conditions & References Reaction Steps: 2 1: NaN3 / dimethylsulfoxide / 20 h / 80 °C 2: LiAlH4 / diethyl ether With lithium aluminium tetrahydride, sodium azide in diethyl ether, dimethyl sulfoxide Kirmse, Wolfgang; Guenther, Bernd-Rainer; Loosen, Karin; Chemische Berichte; vol. 113; nb. 6; (1980); p. 2140 - 2153 View in Reaxys

15/236

2018-08-17 23:02:17

H NH 2

O S O

Rx-ID: 19994778 View in Reaxys 45/553 Yield

H NH 2

H 2N

Rx-ID: 20515978 View in Reaxys 46/553 Yield

Conditions & References Reaction Steps: 2 1: 80 percent / pyridine / CH2Cl2 / 1 h / 0 °C 2: 85 percent / 1.) (bicyclo<2.2.1>heptadiene) <(R)-trans-4,5-bis<(diphenylphosphino)methyl>-2,2-dimethyldioxolan>rhodium(I) tetrafluoroborate, H2, 2.) HBr / methanol / 20 °C / 760 Torr / 1.) 12 h, 2.) H2O, 18 h With pyridine, (bicyclo<2.2.1>heptadiene) <(R)-trans-4,5-bis<(diphenylphosphino)methyl>-2,2-dimethyldioxolan>rhodium(I) tetrafluoroborate, hydrogen bromide, hydrogen in methanol, dichloromethane Brown, John M.; Parker, David; Journal of Organic Chemistry; vol. 47; nb. 14; (1982); p. 2722 - 2730 View in Reaxys

H NH 2

N H N

Rx-ID: 20625606 View in Reaxys 47/553 Yield

Conditions & References Reaction Steps: 2 1: CB / diethyl ether / 12 h / 0 deg C to r. t. 2: H2 / Raney-Ni / methanol / 24 h / 20 - 40 °C / 2625.2 - 2850.2 Torr With hydrogen, nickel in methanol, diethyl ether Enders, Dieter; Schubert, Heinrich; Angewandte Chemie; vol. 96; nb. 5; (1984); p. 368 - 369 View in Reaxys

16/236

2018-08-17 23:02:17

H NH 2

N H N

Rx-ID: 20625607 View in Reaxys 48/553 Yield

NH 2

O N O

Rx-ID: 20707327 View in Reaxys 49/553 Yield

Conditions & References Reaction Steps: 2 1: 1.) copper(I) iodide, 2.) LiI / 1.) ether, 0 deg C, 2.) ether, 0 deg C 2: 41 percent / metallic Fe, HCl / H2O / Heating With hydrogenchloride, copper(l) iodide, iron, lithium iodide in water Hansson, A.-T.; Nilsson, M.; Tetrahedron; vol. 38; nb. 3; (1982); p. 389 - 391 View in Reaxys

NH 2

Rx-ID: 22871539 View in Reaxys 50/553 Yield

Conditions & References With hydrogenchloride in water Patent; Yamakawa Chemical Industry Co., Ltd.; US6342636; (2002); (B1) English View in Reaxys

NH 2

H 2N

Rx-ID: 22889600 View in Reaxys 51/553

17/236

2018-08-17 23:02:17

Yield

Conditions & References 1 : EXAMPLE 1; Preparation of {(2R)-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine; Preparation of (2R)-2-phenylpropylamine Malate EXAMPLE 1 [0048] Preparation of {(2R)-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine. [CHEMMOL-00010] [0049] Preparation of 2-Phenyl-1-propylamine HCl. [CHEMMOL-00011] [0050] Scheme I, step A: To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5percent palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5percent starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to -400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitate solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2percent) as a white powder. [0051] 1H NMR analysis of the free base: 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). [0052] Preparation of (2R)-2-phenylpropylamine Malate. [CHEMMOL-00012] [0053] Scheme I, step B: To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The mixture was stirred for 1.6 hours, and the resulting milky white NaCl salts were filtered. An aliquot of the filtrate was analyzed by gas chromatography to provide the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles). A solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was added dropwise to the yellow filtrate and the solution was heated to 75° C. The solution was stirred at 75° C. for 30 minutes. The heat was removed and the solution was allowed to cool slowly. The resulting thick precipitate was allowed to stir overnight. The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5percent) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine) [0054] 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). [0055] A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2percent e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (-79.2° C.) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5° C.) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35° C. to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2percent recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, revealed 96.7percent e.e. enriched in the R-isomer. [0056] 1H NMR (CD3OD, 300 MHz) α 7.32 (m, 10H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1H, J=9.3, 15.3), 2.38 (dd, 1H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). [0057] Preparation of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]Amine. [CHEMMOL-00013] [0058] Scheme I, steps C and D: To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol) in CH2Cl2 (1000 mL) was added 1.0 N NaOH (1050 mL, 1.05 moles). The mixture was stirred at room temperature for 1 hour and the organic phase was separated and gravity filtered into a 3.0 L round-bottom flask with a CH2Cl2 rinse (200 mL). The resulting free base, (2R)-2-phenylpropylamine, was dried via azeotropic distillation. Accordingly, the clear filtrate was concentrated to 600 mL at atmospheric pressure via distillation through a simple distillation head. Heptane (1000 mL) was added and the solution was concentrated again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation. The final pot temperature was 109° C. [0059] The solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine. To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 mol), triethylamine (200 g, 1.98 moles), and CH2Cl2 (500 mL). The mixture was stirred at room temperature until a clear solution was obtained. This solution was cooled to 5° C. and a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH2Cl2 (250 mL) was added dropwise with stirring over 2 hrs. The mixture was allowed to warm gradually to room temperature over 16 h. GC analysis indicated complete consumption of the (2R)-2-phenylpropylamine starting material. [0060] The stirred mixture was cooled to 8° C. and 2 N HCl (500 mL) was added dropwise. The organic phase was separated and extracted with water (1.x.500 mL) and saturated NaHCO3 (1.x.500 mL). The organic phase was isolated, dried (Na2SO4), and gravity filtered. The filtrate was concentrated under reduced pressure to provide ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (230 g, 96percent) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) α 7.34 (m, 2H), 7.23 (m, 3H), 3.89 (br t, 1H, J=5.4), 3.36 (m, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.98 (m, 1H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9). [0061] Preparation of [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine. [CHEMMOL-00014] [0062] Scheme I, step E: A stirred room temperature solution of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (37.1 g, 0.154 mol) in glacial acetic acid (185 mL) was treated with concentrated H2SO4 (16.0 g, 0.163 mol), added dropwise in a slow stream, followed by a H2O rinse (37 mL). To this solution (30° C.) was added H5IO6 (8.29 g, 0.0369 mol), followed by iodine (17.9 g, 0.0707 mol). The resulting reaction mixture was heated and allowed to stir for 3 h at 60° C. After HPLC analysis verified the consumption of starting material, the reaction mixture was cooled to 30° C. and a 10percent aqueous solution of NaHSO3 (220 mL) was added dropwise while maintaining the temperature between 25° C. and 30° C. The mixture crystallized to a solid mass upon cooling to 0-5° C. [0063] The solids were suction filtered and rinsed with H2O to afford 61.7 g of crude solids that were redissolved into warm MTBE (500 mL). This solution was extracted with H2O (2.x.200 mL) and saturated NaHCO3 (1.x.200 mL) and the organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to -200 mL. Heptane (100 mL) was added dropwise to the product solution with slow stirring until crystallization commenced. An additional 100 mL of heptane was added and the resulting suspension was allowed to stir slowly overnight at room temperature. The mixture was then cooled (0°

18/236

2018-08-17 23:02:17

C.), filtered, and the collected solids were rinsed with heptane. The solids were then air-dried to afford the intermediate title compound, [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (33.7 g, 59.8percent) as a white powder. Chiral Chromatography of this lot indicated 100percent e.e. [0064] 1H NMR (CDCl3, 300 MHz) α 7.66 (d, 2H, J=8.1), 6.98 (d, 2H, J=8.4), 3.86 (br t, 1H, J=5.1), 3.33 (m, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.92 (m, 1H), 1.30 (d, 3H, J=6.6), 1.27 (d, 6H, J=6.6). [0065] Preparation of (methylsulfonyl)(2-phenylethyl)amine. [CHEMMOL-00015] [0066] Scheme II, step A: To a 10° C. solution of phenethylamine (12.1 g, 0.100 mol) and triethylamine (11.1 g, 0.110 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at room temperature for 1.5 h and was then washed with 1 N HCl (5.x.20 mL). The organic phase was directly concentrated to provide the intermediate title compound, (methylsulfonyl)(2phenylethyl)amine, (21.2 g, 93.3percent) as an oil. [0067] 1H NMR (CDCl3, 300 MHz) 67.32 (m, 2H), 7.23 (m, 3H), 4.30 (br s, 1H), 3.40 (t, 2H, J=3.9), 2.88 (t, 2H, J=4.2), 2.81 (s, 3H). [0068] Preparation of [2-(4-iodophenyl)ethyl](methylsulfonyl)amine. [CHEMMOL-00016] [0069] Scheme II, step B: To a stirring room temperature solution of (methylsulfonyl)(2-phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95percent sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and periodic acid (H5IO6, 45.6 g, 0.206 mol). The reaction mixture was warmed to 70-75° C. for 3 h. The heat was removed and the dark violet reaction mixture was allowed to proceed overnight at room temperature. Potassium hydroxide pellets (85percent, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension. The suspension was cooled to 15° C. and filtered. The filter cake was triturated thoroughly with water and was then dissolved in CH2Cl2 (1 L) and extracted with additional water (2.x.200 mL). The organic phase was concentrated under reduced pressure to provide the intermediate title compound, [2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2percent) as a white powder. [0070] 1H NMR (CDCl3, 300 MHz) α 7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1), 4.37 (br t, 1H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t, 2H, J=3.9). [0071] Preparation of (tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide. [CHEMMOL-00017] [0072] Scheme II, step C: A room temperature solution of [2-(4-iodophenyl)ethyl](methylsulfonyl)amine (201 g, 0.618 mol), 4-dimethylaminopyridine (3.8 g, 0.031 mol) and di-tert-butyl dicarbonate (162 g, 0.744 mol) in CH2Cl2 (1 L) was allowed to stir overnight. The reaction mixture was washed with water (2.x.400 mL) and the organic phase was concentrated to about 600 mL and hexanes (400 mL) was added. This combined solution was washed again with water (400 mL) and was concentrated to a solid that was suspended in hexanes (600 mL) and filtered. The collected solids were dried under reduced pressure to afford the intermediate title compound, (tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (241.5 g, 91.5percent) as a white solid. [0073] 1H NMR (CDCl3, 300 MHz) α 7.63 (d, 2H, J=7.8), 6.98 (d, 2H, J=7.8), 3.88 (t, 2H, J=6.9), 3.10 (s, 3H), 2.88 (t, 2H, J=6.9), 1.51 (s, 9H). [0074] Preparation of (tert-butoxy-N-(methylsulfonyl)-N-[2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl)phenyl]ethyl]carboxamide. [CHEMMOL-00018] [0075] Scheme II, step D: To a degassed solution of (tert-butoxy)-N-[2-(4iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (128 g, 0.300 mol), triethylamine (91.1 g, 0.900 mol), and 1,1'-bis(diphenylphosphino) ferrocenedichloropalladium (II)-CH2Cl2 complex (2.9 g, 0.0035 mol) in acetonitrile (600 mL) was added pinacolborane (50 g, 0.391 mol) dropwise. The mixture was stirred at 70-74° C. for 8 h and then was cooled to room temperature. The reaction mixture was concentrated to a fluid oil that was partitioned between MTBE (500 mL) and water (500 mL). The organic phase was separated and washed with water (2.x.200 mL) and concentrated to a residue that was partially dissolved with heptane (1 L). The heptane soluble fraction was filtered through Celite.(R). 521 and concentrated to an oil (95 g). The residue was dissolved in acetone (600 mL) and heptane (600 mL) and filtered through Celite.(R). 521. The combined filtrates were concentrated to 95 g of a mixture of a 3:1 molar ratio (1H NMR, 81.0percent by weight) of intermediate title compound, (tert-butoxy)-N(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide, (60.3percent potency corrected yield) and protio derivative. [0076] 1H NMR (CDCl3, 300 MHz) α 7.75 (d, 2H, J=7.8), 7.23 (d, 2H, J=8.1), 3.87 (t, 2H, J-8.1), 2.99 (s, 3H), 2.90 (t, 2H, J=7.5), 1.53 (s, 9H), 1.33 (s, 6H), 1.27 (s, 6H). [0077] Preparation of (Methylsulfonyl) {2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine. [CHEMMOL-00019] [0078] Scheme II, step E: To a 2 L flask charged with a stirring solution of (tert-butoxy)-N-(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl))phenyl]ethyl}carboxamide (98.7 g, 0.232 mol) in CH2Cl2 (500 mL) was added trifluoroacetic acid (82 mL, 121.4 g, 1.06 moles) dropwise from an addition funnel. No exotherm was observed and the reaction solution was allowed to stir at room temperature for 18 h. [0079] HPLC analysis indicated 98percent completion so the cooled (5° C.) reaction mixture was neutralized by the slow addition of 5N NaOH (175 mL). The pH of the aqueous phase was 10.5. The phases were separated and the aqueous phase was extracted with CH2Cl2 (50 mL). The combined CH2Cl2 phases were washed with brine (2.x.100 mL) and water (1.x.100 mL). The CH2Cl2 phase was diluted with heptane (300 mL) and was concentrated under reduced pressure to afford a suspension that was isolated by filtration. The collected solids were washed with pentane (2.x.100 mL) and dried under vacuum to provide the intermediate title compound, (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine, (69.0 g, 91.4percent) as a white powder. [0080] 1H NMR (CDCl3, 300 MHz) α 7.77 (d, 2H, J=8.1), 7.22 (d, 2H, J=7.8), 4.26 (br t, 1H, J-6), 3.40 (q, 2H, J=6.9), 2.89 (t, 2H, J=6.6), 2.82 (s, 3H), 1.34 (s, 12H). [0081] Preparation of 4-[2-[(methylsulfonyl)amino]ethyl]benzene Boronic Acid. [CHEMMOL-00020] [0082] Scheme II, step F: (Methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine (68.0 g, 0.209 mol) was placed into a 2L flask and combined with acetone (600 mL), 1N ammonium acetate (600 mL), and NaIO4 (168.1 g, 0.786 mol). This mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove insoluble matter to afford filtrate A. The collected solids were washed with acetone (2.x.100 mL) and this filtrate was combined with filtrate A. The combined filtrates were concentrated under reduced pressure to 600 mL to afford a precipitate that was recovered by filtration. The collected solids were air-dried to give 110 g of crude material. This crude material was suspended in water (100 mL) and 5N NaOH was added until the pH was 12.5. The resulting suspension was filtered and the filtrate was treated with decolorizing carbon (Darco 6-60). The mixture was filtered and

19/236

2018-08-17 23:02:17

the filtrate was diluted with 10N H2SO4 until the pH was 5.0 to precipitate the intermediate title compound. This precipitate was collected by filtration and dried under reduced pressure to provide the intermediate title compound, 4-{(2-[(methylsulfonyl)amino]ethyl}benzene boronic acid, (41.9 g, 82.5percent) as a white powder. [0083] 1H NMR (acetone-d6, 300 MHz) α 7.82 (d, 2H, J=8.4), 7.27 (d, 2H, J=7.8), 7.11 (s, 2H), 6.03 (m, 1H), 3.36 (m, 2H), 2.91 (m, 2H), 2.84 (s, 3H). [0084] Preparation of Final Title Compound. [0085] Scheme III: An aqueous solution of potassium formate was prepared in the following manner. To 15 mL of water was added KOH (85percent flakes, 6.73 g, 0.102 mol), then 98percent formic acid (4.70 g, 0.102 mol). Alternatively, one may use commercially available potassium formate. To this solution was then added K2CO3 (2.76 g, 0.0210 mol), 4-{2[(methylsulfonyl)amino]ethyl}benzene boronic acid (4.62 g, 0.190 mol), 1-propanol (100 mL), and [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (7.35 g, 0.200 With sodium hydroxide, ethanol, Time= 1.6h, Under nitrogen Patent; Arnold, Macklin Brian; Bleisch, Thomas John; Cuff, George William; Ornstein, Paul Leslie; Zimmerman, Dennis Michael; US2003/225163; (2003); (A1) English View in Reaxys

NH 2

H Cl

H 2N

Rx-ID: 22966002 View in Reaxys 52/553 Yield

Conditions & References 2 :Scheme I, step B: To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The mixture was stirred for 1.6 hours, and the resulting milky white NaCl salts were filtered. An aliquot of the filtrate was analyzed by gas chromatography to provide the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles). A solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was added dropwise to the yellow filtrate and the solution was heated to 75 C. The solution was stirred at 75 C. for 30 minutes. The heat was is removed and the solution was allowed to cool slowly. The resulting thick precipitate was allowed to stir overnight. The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5percent) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison, via chiral HPLC, with commercially available (R)-2-phenyl-1-propylamine). 1H NMR (CDCl3, 300 MHz) ? 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). A slurry of (2R)-2phenylpropylamine malate (147.1 g, 83.2percent e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (~79.2 C.) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5 C.) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35 C. to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2percent recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, revealed 96.7percent e.e. enriched in the R-isomer. 1H NMR (CD3OD, 300 MHz) ? 7.32 (m, 10 H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1H, J=9.3, 15.3), 2.38 (dd, 1H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). With sodium hydroxide in ethanol, Time= 1.6h Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys 1 : Preparation of (2R)-2-phenylpropylamine Malate. To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 ML).The mixture was stirred for 1.6 hours, and the resulting milky white NaCl salts were filtered.An aliquot of the filtrate was analyzed by gas chromatography to provide the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles).A solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 ML) was added dropwise to the yellow filtrate and the solution was heated to 75° C. The solution was stirred at 75° C. for 30 minutes.The heat was removed and the solution was allowed to cool slowly.The resulting thick precipitate was allowed to stir overnight.The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 ML) to afford the intermediate title compound, (2R)-2-phenylpropylamine malate, (147.6 g, 39.5percent) as a white crystalline solid.Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison, via chiral HPLC, with commercially available (R)-2-phenyl-1-propylamine). 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).

20/236

2018-08-17 23:02:17

A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2percent e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (79.2° C.) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5° C.) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35° C. to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2percent recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, revealed 96.7percent e.e. enriched in the R-isomer. 1H NMR (CD3OD, 300 MHz) α 7.32 (m, 10 H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1H, J=9.3, 15.3), 2.38 (dd, 1H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). With sodium hydroxide in ethanol, Time= 1.6h Patent; Bender, David Michael; Forman, Scott Louis; Jones, Winton Dennis; Smith, Daryl Lynn; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/225127; (2003); (A1) English View in Reaxys

NH 2

2 OH

Rx-ID: 22970881 View in Reaxys 53/553 Yield

Conditions & References 6 :Add 1.0 N NaOH (1050 mL, 1.05 moles) to a stirred slurry of (2R)-2- phenylpropylamine malate (200 g, 0.494 moles) in CH2CI2 (1000 mL). Stir the mixture at room temperature for 1 hour. Separate the organic phase and gravity filter into a 3.0 L round-bottom flask with a CH2CI2 rinse (200 mL). Dry the resulting free base, (2R)-2- phenylpropylamine via azeotropic distillation. Concentrate the clear filtrate to a volume <n="9"/>of 600 mL at atmospheric pressure via distillation through a simple distillation head. Add heptane (1000 mL), then concentrate the solution again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation, with a final pot temperature of 1090C. Cool the solution to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine. To this solution add 4dimethylaminopyridine (6.04 g, 0.0494 moles), triethylamine (200 g, 1.98 moles), and CH2CI2 (500 mL). Stir the mixture at room temperature until a clear solution is obtained. Cool the solution to 5 0C. While stirring, add a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH2CI2 (250 mL) dropwise over 2 hours. Allow the mixture to warm gradually to room temperature over 16 hours.Cool the stirred mixture to 8 0C, then add 2 N HCl (500 mL) dropwise. Separate the organic phase and extract with water (1 x 500 mL) and saturated NaHCα3 (1 x 500 mL). Isolate the organic phase, dry with (Na2SO4), and gravity filter. Concentrate the filtrate under reduced pressure to provide ((2R)-2- phenylpropyl)[(methylethyl)sulfonyl]amine (230g, 96percent) as a pale yellow oil. IH NMR (CDCl3, 300 MHz) α 7.34 (m, 2H), 7.23 (m, 3H), 3.89 (br t, IH, J=5.4), 3.36 (m, IH), 3.22 (m, IH), 3.05 (m, IH), 2.98 (m, IH), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9). With sodium hydroxide, water in dichloromethane, Time= 1h, T= 20 °C Patent; ELI LILLY AND COMPANY; WO2008/73789; (2008); (A1) English View in Reaxys 1 : Preparation of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine Preparation of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine. To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol) in CH2Cl2 (1000 ML) was added 1.0 N NaOH (1050 ML, 1.05 moles).The mixture was stirred at room temperature for 1 hour and the organic phase was separated and gravity filtered into a 3.0 L round-bottom flask with a CH2Cl2 rinse (200 ML).The resulting free base, (2R)-2-phenylpropylamine, was dried via azeotropic distillation.Accordingly, the clear filtrate was concentrated to 600 ML at atmospheric pressure via distillation through a simple distillation head.heptane (1000 ML) was added and the solution was concentrated again at atmospheric pressure to 600 ML using a nitrogen purge to increase the rate of distillation.The final pot temperature was 109° C. The solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 ML) of (2R)-2-phenylpropylamine.To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 mol), triethylamine (200 g, 1.98 moles), and CH2Cl2 (500 ML).The mixture was stirred at room temperature until a clear solution was obtained.This solution was cooled to 5° C. and a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH2Cl2 (250 ML) was added dropwise with stirring over 2 hrs.The mixture was allowed to warm gradually to room temperature over 16 h. GC analysis indicated complete consumption of the (2R)-2-phenylpropylamine starting material. The stirred mixture was cooled to 8° C. and 2 N HCl (500 ML) was added dropwise.The organic phase was separated and extracted with water (1*500 ML) and saturated NaHCO3 (1*500 ML).The organic phase was isolated, dried (Na2SO4), and gravity filtered.The filtrate was concentrated under reduced pressure to provide the intermediate title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (230 g, 96percent) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) α 7.34 (m, 2H), 7.23 (m,

21/236

2018-08-17 23:02:17

3H), 3.89 (br t, 1H, J=5.4), 3.36 (m, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.98 (m, 1H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9). With sodium hydroxide in dichloromethane, water, Time= 1h, T= 20 °C Patent; Bender, David Michael; Forman, Scott Louis; Jones, Winton Dennis; Smith, Daryl Lynn; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/225127; (2003); (A1) English View in Reaxys

OH NH 2

NH 2

O2 HO OH

Rx-ID: 23240476 View in Reaxys 54/553 Yield

Conditions & References 4 :Preparation of (2R)-2-phenylpropylamine To a stirred suspension of (2R)-2-phenylpropylamine malate (24.3 g, 0.0601 mol, prepared directly above) in CH2Cl2 (200 mL) was added 1.0 N NaOH dropwise at room temperature. The organic phase was isolated, extracted with brine (1*125 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give (2R)-2-phenylpropylamine (19 g) as a clear, colorless oil. With sodium hydroxide in dichloromethane, water Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys 2 :Scheme I, steps C and D: To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol) in CH2Cl2 (1000 mL) was added 1.0 N NaOH (1050 mL, 1.05 moles). The mixture was stirred at room temperature for 1 hour and the organic phase was separated and gravity filtered into a 3.0 L round-bottom flask with a CH2Cl2 rinse (200 mL). The resulting free base, (2R)-2-phenylpropylamine, was dried via azeotropic distillation. Accordingly, the clear filtrate was concentrated to 600 mL at atmospheric pressure via distillation through a simple distillation head. Heptane (1000 mL) was added and the solution was concentrated again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation. The final pot temperature was 109 C. The solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine. To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 mol), triethylamine (200 g, 1.98 moles), and CH2Cl2 (500 mL). The mixture was stirred at room temperature until a clear solution was obtained. This solution was cooled to 5 C. and a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH2Cl2 (250 mL) was added dropwise with stirring over 2 hrs. The mixture was allowed to warm gradually to room temperature over 16 h. GC analysis indicated complete consumption of the (2R)-2-phenylpropylamine starting material. The stirred mixture was cooled to 8 C. and 2 N HCl (500 mL) was added dropwise. The organic phase was separated and extracted with water (1500 mL) and saturated NaHCO3 (1500 mL). The organic phase was isolated, dried (Na2SO4), and gravity filtered. The filtrate was concentrated under reduced pressure to provide ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (230 g, 96percent) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) ? 7.34 (m, 2H), 7.23 (m, 3H), 3.89 (br t, 1H, J=5.4), 3.36 (m, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.98 (m, 1H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9). With sodium hydroxide in dichloromethane, water, Time= 1h, T= 20 °C Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys

O H

NH 2

Rx-ID: 23240479 View in Reaxys 55/553

22/236

2018-08-17 23:02:17

Yield 94.9 %

Conditions & References 5 : Preparation of (2R)-2-phenylpropylamine A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel is charged with 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione (11.54 g, 43.49 mmol), toluene (200.0 mL) and anhydrous hydrazine (2.73 mL, 86.99 mmol). Reaction is then stirred at room temperature for 3.0 hours and then heated at 90 C.-95 C. for 2.0 hours. Cooled the slurry to room temperature, filtered precipitates, then concentrated filtrate to provide the intermediate title compound, (2R)-2phenylpropylamine, (5.58 g, 94.9percent) an oil; 1H nmr (CDCl3, 300 MHz) ? 1.21 (d, 3H), 1.40-1.60 (b, 2H), 2.68-2.80 (m, 1H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H). With hydrazine in toluene, Time= 5h, T= 20 - 95 °C Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys

O H NH 2

Rx-ID: 24001476 View in Reaxys 56/553 Yield

Conditions & References Preparation of (2R)-2-phenylpropylamine. Preparation of (2R)-2-phenylpropylamine. A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel is charged with 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione (11.54 g, 43.49 mmol), toluene (200.0 mL) and anhydrous hydrazine (2.73 mL, 86.99 mmol). Reaction is then stirred at room temperature for 3.0 hours and then heated at 90° C.-95° C. for 2.0 hours. Cooled the slurry to room temperature, filtered precipitates, then concentrated filtrate to provide the intermediate title compound, (2R)-2-phenylpropylamine, (5.58 g, 94.9percent) an oil; 1H nmr (CDCl3) α 1.21 (d, 3H), 1.40-1.60 (b, 2H), 2.68-2.80 (m, 1H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H). With hydrazine in toluene Patent; Skolnick, Phil; US2003/92770; (2003); (A1) English View in Reaxys

H NH 2

H H 2N

H 2N

Rx-ID: 29884941 View in Reaxys 57/553 Yield

Conditions & References With Sepharose-4B-L-tyrosine-N-p-aminobenzoyl-L-glutamic acid-based column, pH= 6 - 8, Resolution of racemate, aq. phosphate buffer Yilmaz, Hayrullah; Topal, Giray; Cakmak, Resit; Hosgoren, Halil; Chirality; vol. 22; nb. 2; (2010); p. 252 - 257 View in Reaxys 35.16 :In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.|0132| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.|0133| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral

23/236

2018-08-17 23:02:17

analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 μL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.|0134| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2percent diethylamine (DEA). The gradient mobile phase composition was 5percent cosolvent hold during 0- 0.6 min, 5-60percent during 0.6-4.3 min, 60percent hold during 4.3-6.3 min, 60percent-5percent during 6.3-6.9 min, and 5percent hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 percent TFA or 0.1percent diethylamine). The flow rate was 3 mL/min.|0135| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode. With chiral stationary phase including isopropyl-functionalized CF6 in methanol, acetic acid, triethylamine, acetonitrile, T= 20 °C , Purification / work up Patent; BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM; ARMSTRONG, Daniel, W.; PING, Sun; BREITBACH, Zachary, S.; WANG, Chunlei; WO2010/148191; (2010); (A2) English View in Reaxys Cl

NH 2

Rx-ID: 33663776 View in Reaxys 58/553 Yield 72 %

Conditions & References Stage 1: With hydroxylamine-O-sulfonic acid in tetrahydrofuran, T= 60 °C , Inert atmosphere Stage 2: With hydrogenchloride in methanol, diethyl ether, water, T= 20 °C , Inert atmosphere Stage 3: With sodium hydroxide in methanol, diethyl ether, water, T= 0 °C , Inert atmosphere Malhotra, Sanjay V.; Brown, Herbert C.; Letters in Organic Chemistry; vol. 9; nb. 6; (2012); p. 383 - 385 View in Reaxys

H NH 2

Rx-ID: 38250168 View in Reaxys 59/553 Yield 8 %Chromat.

24/236

2018-08-17 23:02:17

2: (R)-7,7’-diphenylphosphino-1,1'-spirobiindane; di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate; hydrogen / tetrahydrofuran / 8 h / 25 °C / 15001.5 Torr / Autoclave 3: sulfuric acid / 48 h / 100 °C / Darkness With di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate, sulfuric acid, (R)-7,7’-diphenylphosphino-1,1'-spirobiindane, hydrogen, trifluoroacetic anhydride in tetrahydrofuran, dichloromethane Zhang, Jian; Liu, Chong; Wang, Xingguang; Chen, Jianzhong; Zhang, Zhenfeng; Zhang, Wanbin; Chemical Communications; vol. 54; nb. 47; (2018); p. 6024 - 6027 View in Reaxys Reaction Steps: 3 1: trifluoroacetic anhydride / dichloromethane / 20 °C 2: (R)-7,7’-diphenylphosphino-1,1'-spirobiindane; di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate; hydrogen / tetrahydrofuran / 8 h / 25 °C / 15001.5 Torr / Autoclave 3: sulfuric acid / 48 h / 100 °C / Darkness With di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate, sulfuric acid, (R)-7,7’-diphenylphosphino-1,1'-spirobiindane, hydrogen, trifluoroacetic anhydride in tetrahydrofuran, dichloromethane Zhang, Jian; Liu, Chong; Wang, Xingguang; Chen, Jianzhong; Zhang, Zhenfeng; Zhang, Wanbin; Chemical Communications; vol. 54; nb. 47; (2018); p. 6024 - 6027 View in Reaxys Reaction Steps: 3 1: trifluoroacetic anhydride / dichloromethane / 20 °C 2: (R)-7,7’-diphenylphosphino-1,1'-spirobiindane; di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate; hydrogen / toluene / 8 h / 25 °C / 15001.5 Torr / Autoclave 3: sulfuric acid / 48 h / 100 °C / Darkness With di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate, sulfuric acid, (R)-7,7’-diphenylphosphino-1,1'-spirobiindane, hydrogen, trifluoroacetic anhydride in dichloromethane, toluene Zhang, Jian; Liu, Chong; Wang, Xingguang; Chen, Jianzhong; Zhang, Zhenfeng; Zhang, Wanbin; Chemical Communications; vol. 54; nb. 47; (2018); p. 6024 - 6027 View in Reaxys

H NH 2

H O

H 2N

Rx-ID: 38250169 View in Reaxys 60/553 Yield 67 %Chromat., 6 %Chromat.

H NH 2

Rx-ID: 38250170 View in Reaxys 61/553 Yield 54 %Chromat., 19 %Chromat.

25/236

2018-08-17 23:02:17

Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

H NH 2

Rx-ID: 38250192 View in Reaxys 62/553 Yield

Conditions & References Reaction Steps: 2 1: dodecacarbonyltetrarhodium(0); hydrogen / toluene / 96 h / 40 °C / 7500.75 - 30003 Torr / Autoclave; Inert atmosphere 2: pyridoxal 5'-phosphate; α-transaminase form Pseudomonas pudita1; formate dehydrogenase from Candida boidinii; NADH; Lalanine dehydrogenase from Bacillus subtilis; ammonium formate; L-alanin / aq. phosphate buffer; 1,2-dimethoxyethane / 24 h / 30 °C / Resolution of racemate; Enzymatic reaction With dodecacarbonyltetrarhodium(0), L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'-phosphate, α-transaminase form Pseudomonas pudita1, hydrogen, ammonium formate, NADH in 1,2-dimethoxyethane, aq. phosphate buffer, toluene Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys Reaction Steps: 2 1: C50H65O4P; hydrogen; [Rh(CO)2acac]; (R,R)-1,2-bis(2,5-diphenylphospholanyl)ethane; di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate / toluene / 72 h / 25 °C / 750.08 Torr / Inert atmosphere; Schlenk technique; Molecular sieve 2: benzyl chloroformate; sodium carbonate; ammonium cerium (IV) nitrate / -15 °C With ammonium cerium (IV) nitrate, [Rh(CO)2acac], C50H65O4P, hydrogen, sodium carbonate, di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate, benzyl chloroformate, (R,R)-1,2-bis(2,5-diphenylphospholanyl)ethane in toluene Meng, Jing; Li, Xing-Han; Han, Zhi-Yong; Organic Letters; vol. 19; nb. 5; (2017); p. 1076 - 1079 View in Reaxys

H NH 2

H 2N

Rx-ID: 38250193 View in Reaxys 63/553 Yield

26/236

2018-08-17 23:02:17

NH 2

Rx-ID: 38250195 View in Reaxys 64/553 Yield

Conditions & References Reaction Steps: 3 1.1: dodecacarbonyltetrarhodium(0); hydrogen / toluene / 96 h / 40 °C / 7500.75 - 30003 Torr / Autoclave; Inert atmosphere 2.1: tetrahydrofuran / 0.42 h / Inert atmosphere 2.2: 3 h / 20 °C / Inert atmosphere 3.1: hydrogen; 10% palladium on activated carbon; Degussa type / tert-butyl methyl ether / 20 °C / 760.05 Torr With dodecacarbonyltetrarhodium(0), 10% palladium on activated carbon; Degussa type, hydrogen in tetrahydrofuran, tert-butyl methyl ether, toluene Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

H NH 2

Rx-ID: 38250196 View in Reaxys 65/553 Yield

NH 2

H N

Rx-ID: 38250220 View in Reaxys 66/553 Yield

Conditions & References Stage 1: With 10% palladium on activated carbon; Degussa type, hydrogen in tert-butyl methyl ether, T= 20 °C , p= 760.051Torr Stage 2: With hydrogenchloride in diethyl ether Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

27/236

2018-08-17 23:02:17

NH 2 H

H 2N

Rx-ID: 39265208 View in Reaxys 67/553 Yield 123 mg

Conditions & References 1 : Example 1 : Racemisation of optically active (R)-2-phenylpropan-1 -amine using potassium ie f-butoxide Starting material (R)-2-(3-chlorophenyl)propan-1 -amine {{R)-S, 1 mmol; 136 mg; > 98percent optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 1 .25 mmol) was added in two portions in 30 min intervals and the closed reaction system was stirred at 100 °C for 36 hours. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (123 mg) was analysed with chiral HPLC where 0 percent e.e. (full racemisation) was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 136; CI). With potassium tert-butylate in dimethyl sulfoxide, Time= 36h, T= 100 °C Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; CLUZEAU, Jerome; WO2015/7897; (2015); (A1) English View in Reaxys

H NH 2

Rx-ID: 41746847 View in Reaxys 68/553 Yield

Conditions & References Reaction Steps: 3 1: ammonium cerium (IV) nitrate; acetic acid; sodium nitrite / chloroform / Sealed tube; Sonication 2: bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S,S)-f-spiro-Phos; hydrogen / dichloromethane / 6 h / 50 °C / 15201 Torr / Autoclave 3: hydrogen; Johnson & Matthey type 440 / methanol / 5 h / 20 °C / 760.05 Torr With bis(1,5-cyclooctadiene)diiridium(I) dichloride, ammonium cerium (IV) nitrate, Johnson & Matthey type 440, (S,S)-f-spiroPhos, hydrogen, acetic acid, sodium nitrite in methanol, dichloromethane, chloroform Liu, Man; Kong, Duanyang; Li, Meina; Zi, Guofu; Hou, Guohua; Advanced Synthesis and Catalysis; vol. 357; nb. 18; (2015); p. 3875 - 3879 View in Reaxys With D-Glucose, ammonia, oxygen in aq. phosphate buffer, Time= 24h, T= 30 °C , Green chemistry, Reagent/catalyst, enantioselective reaction Wu, Shuke; Liu, Ji; Li, Zhi; ACS Catalysis; vol. 7; nb. 8; (2017); p. 5225 - 5233 View in Reaxys

O NH 2

N O

Rx-ID: 41746854 View in Reaxys 69/553 Yield

Conditions & References Reaction Steps: 2 1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S,S)-f-spiro-Phos; hydrogen / dichloromethane / 6 h / 50 °C / 15201 Torr / Autoclave 2: hydrogen; Johnson & Matthey type 440 / methanol / 5 h / 20 °C / 760.05 Torr

28/236

2018-08-17 23:02:17

With bis(1,5-cyclooctadiene)diiridium(I) dichloride, Johnson & Matthey type 440, (S,S)-f-spiro-Phos, hydrogen in methanol, dichloromethane Liu, Man; Kong, Duanyang; Li, Meina; Zi, Guofu; Hou, Guohua; Advanced Synthesis and Catalysis; vol. 357; nb. 18; (2015); p. 3875 - 3879 View in Reaxys

H NH 2

Rx-ID: 41746934 View in Reaxys 70/553 Yield

Conditions & References Reaction Steps: 4 1.1: potassium tert-butylate / tetrahydrofuran / 0.75 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C 2.1: ammonium cerium (IV) nitrate; acetic acid; sodium nitrite / chloroform / Sealed tube; Sonication 3.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S,S)-f-spiro-Phos; hydrogen / dichloromethane / 6 h / 50 °C / 15201 Torr / Autoclave 4.1: hydrogen; Johnson & Matthey type 440 / methanol / 5 h / 20 °C / 760.05 Torr With bis(1,5-cyclooctadiene)diiridium(I) dichloride, ammonium cerium (IV) nitrate, Johnson & Matthey type 440, (S,S)-f-spiroPhos, potassium tert-butylate, hydrogen, acetic acid, sodium nitrite in tetrahydrofuran, methanol, dichloromethane, chloroform Liu, Man; Kong, Duanyang; Li, Meina; Zi, Guofu; Hou, Guohua; Advanced Synthesis and Catalysis; vol. 357; nb. 18; (2015); p. 3875 - 3879 View in Reaxys

NH 2

N O

Rx-ID: 41747069 View in Reaxys 71/553 Yield 97 %

Conditions & References With Johnson & Matthey type 440, hydrogen in methanol, Time= 5h, T= 20 °C , p= 760.051Torr Liu, Man; Kong, Duanyang; Li, Meina; Zi, Guofu; Hou, Guohua; Advanced Synthesis and Catalysis; vol. 357; nb. 18; (2015); p. 3875 - 3879 View in Reaxys

H NH 2

N H

Rx-ID: 44766129 View in Reaxys 72/553 Yield 65 %

Conditions & References Stage 1: With ammonium cerium (IV) nitrate, sodium carbonate, benzyl chloroformate, T= -15 °C Stage 2: With 10% palladium on activated charcoal, hydrogen Meng, Jing; Li, Xing-Han; Han, Zhi-Yong; Organic Letters; vol. 19; nb. 5; (2017); p. 1076 - 1079 View in Reaxys

29/236

2018-08-17 23:02:17

H NH 2

H 2N

Rx-ID: 46012184 View in Reaxys 73/553 Yield

Conditions & References With D-Glucose, ammonia, oxygen in aq. phosphate buffer, Time= 24h, T= 30 °C , Green chemistry, Reagent/catalyst, enantioselective reaction Wu, Shuke; Liu, Ji; Li, Zhi; ACS Catalysis; vol. 7; nb. 8; (2017); p. 5225 - 5233 View in Reaxys

NH 2

Rx-ID: 46366929 View in Reaxys 74/553 Yield

Conditions & References Reaction Steps: 3 1: ammonium acetate / 5 h / Reflux; Inert atmosphere 2: tetrahydrofuran; diethyl ether / 3 h / -45 - 20 °C 3: sodium hypophosphite monohydrate; hypophosphorous acid; Johnson & Matthey type 440 / water; 2-methyltetrahydrofuran / 0.25 h / 60 °C / Sonication; Green chemistry With sodium hypophosphite monohydrate, Johnson & Matthey type 440, ammonium acetate, hypophosphorous acid in tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, water, 1: |Henry Nitro Aldol Condensation Letort; Lejeune; Kardos; Métay; Popowycz; Lemaire; Draye; Green Chemistry; vol. 19; nb. 19; (2017); p. 4583 - 4590 View in Reaxys

NH 2

O N O

Rx-ID: 46366930 View in Reaxys 75/553 Yield

Conditions & References Reaction Steps: 2 1: tetrahydrofuran; diethyl ether / 3 h / -45 - 20 °C 2: sodium hypophosphite monohydrate; hypophosphorous acid; Johnson & Matthey type 440 / water; 2-methyltetrahydrofuran / 0.25 h / 60 °C / Sonication; Green chemistry With sodium hypophosphite monohydrate, Johnson & Matthey type 440, hypophosphorous acid in tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, water Letort; Lejeune; Kardos; Métay; Popowycz; Lemaire; Draye; Green Chemistry; vol. 19; nb. 19; (2017); p. 4583 - 4590 View in Reaxys

NH 2

Rx-ID: 46763217 View in Reaxys 76/553 Yield 49 %

Conditions & References With samarium diiodide, water in tetrahydrofuran, T= 20 °C , Inert atmosphere

30/236

2018-08-17 23:02:17

Thurow, Samuel; Lenardo, Eder J.; Just-Baringo, Xavier; Procter, David J.; Organic Letters; vol. 19; nb. 1; (2017); p. 50 53 View in Reaxys O

N H

H NH 2

Rx-ID: 48264079 View in Reaxys 77/553 Yield

Conditions & References Reaction Steps: 2 1: (R)-7,7’-diphenylphosphino-1,1'-spirobiindane; di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate; hydrogen / tetrahydrofuran / 8 h / 25 °C / 15001.5 Torr / Autoclave 2: sulfuric acid / 48 h / 100 °C / Darkness With di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate, sulfuric acid, (R)-7,7’-diphenylphosphino-1,1'-spirobiindane, hydrogen in tetrahydrofuran Zhang, Jian; Liu, Chong; Wang, Xingguang; Chen, Jianzhong; Zhang, Zhenfeng; Zhang, Wanbin; Chemical Communications; vol. 54; nb. 47; (2018); p. 6024 - 6027 View in Reaxys Reaction Steps: 2 1: (R)-7,7’-diphenylphosphino-1,1'-spirobiindane; di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate; hydrogen / toluene / 8 h / 25 °C / 15001.5 Torr / Autoclave 2: sulfuric acid / 48 h / 100 °C / Darkness With di[(α-1,2,5,6)-1,5-cyclooctadiene] rhodium hexafluoroantimonate, sulfuric acid, (R)-7,7’-diphenylphosphino-1,1'-spirobiindane, hydrogen in toluene Zhang, Jian; Liu, Chong; Wang, Xingguang; Chen, Jianzhong; Zhang, Zhenfeng; Zhang, Wanbin; Chemical Communications; vol. 54; nb. 47; (2018); p. 6024 - 6027 View in Reaxys

H N

NH 2

Rx-ID: 48264093 View in Reaxys 78/553 Yield

31/236

2018-08-17 23:02:17

H N NH 2

Rx-ID: 48264096 View in Reaxys 79/553 Yield

Conditions & References With sulfuric acid, Time= 48h, T= 100 °C , Darkness Zhang, Jian; Liu, Chong; Wang, Xingguang; Chen, Jianzhong; Zhang, Zhenfeng; Zhang, Wanbin; Chemical Communications; vol. 54; nb. 47; (2018); p. 6024 - 6027 View in Reaxys

NH 2

sodium

HO NH 2

Rx-ID: 5807147 View in Reaxys 80/553 Yield

Conditions & References amide of/the/ optically inactive hydratropic acid Ramart; Amagat; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 184; (1927); p. 32; Annales de Chimie (Cachan, France); vol. <10>; nb. 8; (1927); p. 282 View in Reaxys

NH 2

α-phenyl-propionic acid amide HO

Rx-ID: 6674937 View in Reaxys 81/553 Yield

Conditions & References With ethanol, sodium Ramart; Amagat; Annales de Chimie (Cachan, France); vol. <10> 8; (1927); p. 286; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 184; (1927); p. 32 View in Reaxys

NH 2

hydratropic acid amide HO

Rx-ID: 7159163 View in Reaxys 82/553 Yield

Conditions & References With ethanol, sodium Ramart; Amagat; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 184; (1927); p. 32; Annales de Chimie (Cachan, France); vol. <10>; nb. 8; (1927); p. 282 View in Reaxys

32/236

2018-08-17 23:02:17

NH 2

Rx-ID: 317139 View in Reaxys 83/553 Yield

Conditions & References With nickel, Hydrogenation Gibson; Journal of the Chemical Society; (1956); p. 808,809 View in Reaxys H NH 2

Rx-ID: 436598 View in Reaxys 84/553 Yield

Conditions & References bei aufeinanderfolgender Umsetzung mit Methylmagnesiumbromid und mit LiAlH4 Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys

NH 2

H 2N H

Rx-ID: 436950 View in Reaxys 85/553 Yield

Conditions & References With l-tartaric acid Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys

H NH 2

H H

Rx-ID: 438786 View in Reaxys 86/553 Yield

Conditions & References With sodium azide, chloroform, sulfuric acid Patent; Haffner; Sommer; US2356582; (1939) View in Reaxys Patent; Chem. Fabr. Gruenau; DE747866; (1938); View in Reaxys beim Erwaermen des ueber das Saeurechlorid hergestellten Saeureazids in Benzol und anschliessenden Erhitzen mit wss. Salzsaeure McCoubrey; Mathieson; Journal of the Chemical Society; (1949); p. 696,699 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

33/236

2018-08-17 23:02:17

H 2N

NH 2

Rx-ID: 637791 View in Reaxys 87/553 Yield

Conditions & References anschliessend Kochen mit wss. NaOH Patent; Smith, Kline and French Labor.; US2394092; (1938) View in Reaxys Suter; Weston; Journal of the American Chemical Society; vol. 64; (1942); p. 533,535 View in Reaxys H H

H 2N

NH 2 H 2N

Rx-ID: 637792 View in Reaxys 88/553 Yield

Conditions & References T= 150 °C , beim Erwaermen des Reaktionsprodukts mit wss. Salzsaeure Patent; Smith, Kline and French Labor.; US2394092; (1938) View in Reaxys Suter; Weston; Journal of the American Chemical Society; vol. 64; (1942); p. 533,535 View in Reaxys Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys Crossley; Moore; Journal of Organic Chemistry; vol. 9; (1944); p. 529,533 View in Reaxys Ratschinskii; Winokurowa; Zhurnal Obshchei Khimii; vol. 24; (1954); p. 272,278; ; (1955); p. 4553 View in Reaxys

NH 2

H 2N

Rx-ID: 746800 View in Reaxys 89/553 Yield

Conditions & References With aluminium trichloride Weston; Ruddy; Suter; Journal of the American Chemical Society; vol. 65; (1943); p. 675 View in Reaxys

NH 2 O

Rx-ID: 1039411 View in Reaxys 90/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

34/236

2018-08-17 23:02:17

With ammonium acetate, sodium cyanoborohydride in methanol Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys H

H NH 2

HO H

Rx-ID: 1156600 View in Reaxys 91/553 Yield

Conditions & References (i) TsCl, Py, (ii) aq. NaN3, DMF, (iii) LiAlH4, Et2O, Multistep reaction Smissman,E.E.; Pazdernik,T.L.; Journal of Medicinal Chemistry; vol. 16; (1973); p. 14 - 18 View in Reaxys H

O H

NH 2

O H

Rx-ID: 1157266 View in Reaxys 92/553 Yield

Conditions & References (i) aq. NaN3, DMF, (ii) LiAlH4, Et2O, Multistep reaction Smissman,E.E.; Pazdernik,T.L.; Journal of Medicinal Chemistry; vol. 16; (1973); p. 14 - 18 View in Reaxys

H NH 2

O H

Rx-ID: 3037211 View in Reaxys 93/553 Yield 56 %

Conditions & References With diphenyl-phosphinic acid, triethylamine in benzene, 1 h, RT; 16 h, reflux Oppolzer, Wolfgang; Kingma, Arend J.; Poli, Giovanni; Tetrahedron; vol. 45; nb. 2; (1989); p. 479 - 488 View in Reaxys OH O

NH 2

platinum

Rx-ID: 7434384 View in Reaxys 94/553 Yield

Conditions & References Hydrogenation Witkop; Journal of the American Chemical Society; vol. 70; (1948); p. 1424,1427 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

35/236

2018-08-17 23:02:17

NH 2

Rx-ID: 7875016 View in Reaxys 95/553 Yield

Conditions & References entspr.Hydroxy-oxim, Na, A., Δ Jones; Journal of the Chemical Society; (1960); p. 1918,1923 View in Reaxys (yield)40percent Jones; Journal of the Chemical Society; (1960); p. 1918,1923 View in Reaxys

NH 2

Rx-ID: 7875141 View in Reaxys 96/553 Yield

Conditions & References 1-Phenyl-1-methylpropan-2-on-oxim, LiAlH4 Kotera,K. et al.; Tetrahedron; vol. 24; (1968); p. 3681 - 3696 View in Reaxys 3-Phenylbutan-2-on-oxim (syn-Isomer), LiAlH4 Alvernhe; Laurent; Bulletin de la Societe Chimique de France; (1970); p. 3003,3004,3007 View in Reaxys

H NH 2

Dg-threo-2-phenyl-3-<toluene-4-sulfonyloxy>-butane H

Rx-ID: 8095462 View in Reaxys 97/553 Yield

Conditions & References With 1,4-dioxane, ammonia Cram; McCarty; Journal of the American Chemical Society; vol. 79; (1957); p. 2866,2868 View in Reaxys

H NH 2

racemat of threo-1-methyl-2-phenyl-propylamine H

Rx-ID: 8095463 View in Reaxys 98/553 Yield

Conditions & References With malic acid Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743

36/236

2018-08-17 23:02:17

View in Reaxys

H NH 2

racemat of threo-1-methyl-2-phenyl-propyl-amine H

Rx-ID: 8095464 View in Reaxys 99/553 Yield

Conditions & References With l-tartaric acid Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys H NH 2

(+-)-threo-2-methyl-3-phenyl-butyramide

Rx-ID: 8095465 View in Reaxys 100/553 Yield

Conditions & References With alkali hypochlorite Patent; Chem. Fabr. Gruenau; DE747866; (1938); View in Reaxys H NH 2

(1RS,2SR)-1-methyl-2-phenyl-propylamine

Rx-ID: 8095466 View in Reaxys 101/553 Yield

Conditions & References With ethanol, ammonia, nickel, Hydrogenation.bei aufeinanderfolgender Umsetzung mit Methylmagnesiumbromid und mit LiAlH4 Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys H H

NH 2

(+-)-2-phenyl-butanone-(3)-oxime

H 2N

Rx-ID: 8095467 View in Reaxys 102/553 Yield

Conditions & References With ethanol, sodium Patent; Chem. Fabr. Gruenau; DE747866; (1938); View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

37/236

2018-08-17 23:02:17

NH 2

Rx-ID: 8619128 View in Reaxys 103/553 Yield

Conditions & References With ammonium acetate, sodium cyanoborohydride in methanol, T= 20 °C , reductive amination Kinbara, Kazushi; Harada, Yoshiko; Saigo, Kazuhiko; Journal of the Chemical Society. Perkin Transactions 2; nb. 7; (2000); p. 1339 - 1347 View in Reaxys

NH 2

H 2N

Rx-ID: 8619129 View in Reaxys 104/553 Yield

Conditions & References Stage 1: With ammonium acetate, sodium cyanoborohydride in methanol, T= 20 °C , reductive amination Stage 2:racemate resolution, Further stages. Kinbara, Kazushi; Harada, Yoshiko; Saigo, Kazuhiko; Journal of the Chemical Society. Perkin Transactions 2; nb. 7; (2000); p. 1339 - 1347 View in Reaxys With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Pseudomonas pudita1, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Solvent, Overall yield = 59 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

H NH 2

O N

Rx-ID: 8839491 View in Reaxys 105/553 Yield

Conditions & References With ammonium formate, 10 wt. % palladium on activated carbon in methanol, Time= 6h, T= 20 °C Kawai, Yasushi; Inaba, Yoshikazu; Tokitoh, Norihiro; Tetrahedron Asymmetry; vol. 12; nb. 2; (2001); p. 309 - 318 View in Reaxys

H NH 2

HO H

Rx-ID: 20674766 View in Reaxys 106/553

38/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 5 1: oxalyl chloride 2: 77 percent 3: 1.) CuI*PBu3 / 1.) hexane, toluene, -40 deg C, 30 min; 2.) toluene, 30 min, -80 deg C, -40 deg C, 16 h 4: 67 percent / LiOH*H2O / 120 h 5: 56 percent / Et3N, DPPA / benzene / 1 h, RT; 16 h, reflux With lithium hydroxide, oxalyl dichloride, CuI*P(n-Bu)3, diphenyl-phosphinic acid, triethylamine in benzene Oppolzer, Wolfgang; Kingma, Arend J.; Poli, Giovanni; Tetrahedron; vol. 45; nb. 2; (1989); p. 479 - 488 View in Reaxys

H NH 2

Rx-ID: 20686135 View in Reaxys 107/553 Yield

Conditions & References Reaction Steps: 4 1: 77 percent 2: 1.) CuI*PBu3 / 1.) hexane, toluene, -40 deg C, 30 min; 2.) toluene, 30 min, -80 deg C, -40 deg C, 16 h 3: 67 percent / LiOH*H2O / 120 h 4: 56 percent / Et3N, DPPA / benzene / 1 h, RT; 16 h, reflux With lithium hydroxide, CuI*P(n-Bu)3, diphenyl-phosphinic acid, triethylamine in benzene Oppolzer, Wolfgang; Kingma, Arend J.; Poli, Giovanni; Tetrahedron; vol. 45; nb. 2; (1989); p. 479 - 488 View in Reaxys

H NH 2

Li H

Rx-ID: 20690321 View in Reaxys 108/553 Yield

Conditions & References Reaction Steps: 3 1: 1.) Cu(I)thiocyanate / 1.) hexane, toluene, -40 deg C, 30 min; 2.) toluene, 30 min, -80 deg C, -40 deg C, 16 h 2: 67 percent / LiOH*H2O / 120 h 3: 56 percent / Et3N, DPPA / benzene / 1 h, RT; 16 h, reflux With lithium hydroxide, diphenyl-phosphinic acid, copper(I) thiocyanate, triethylamine in benzene Oppolzer, Wolfgang; Kingma, Arend J.; Poli, Giovanni; Tetrahedron; vol. 45; nb. 2; (1989); p. 479 - 488 View in Reaxys

H NH 2

N O

Rx-ID: 20692881 View in Reaxys 109/553 Yield

Conditions & References Reaction Steps: 3 1: 1.) CuI*PBu3 / 1.) hexane, toluene, -40 deg C, 30 min; 2.) toluene, 30 min, -80 deg C, -40 deg C, 16 h

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

39/236

2018-08-17 23:02:17

2: 67 percent / LiOH*H2O / 120 h 3: 56 percent / Et3N, DPPA / benzene / 1 h, RT; 16 h, reflux With lithium hydroxide, CuI*P(n-Bu)3, diphenyl-phosphinic acid, triethylamine in benzene Oppolzer, Wolfgang; Kingma, Arend J.; Poli, Giovanni; Tetrahedron; vol. 45; nb. 2; (1989); p. 479 - 488 View in Reaxys

H NH 2 H

O N S O

Rx-ID: 20702112 View in Reaxys 110/553 Yield

Conditions & References Reaction Steps: 2 1: 67 percent / LiOH*H2O / 120 h 2: 56 percent / Et3N, DPPA / benzene / 1 h, RT; 16 h, reflux With lithium hydroxide, diphenyl-phosphinic acid, triethylamine in benzene Oppolzer, Wolfgang; Kingma, Arend J.; Poli, Giovanni; Tetrahedron; vol. 45; nb. 2; (1989); p. 479 - 488 View in Reaxys

H NH 2

Rx-ID: 22034948 View in Reaxys 111/553 Yield

Conditions & References Reaction Steps: 2 1: 150 Â°C / beim Erwaermen des Reaktionsprodukts mit wss. Salzsaeure 2: Lg-tartaric acid With l-tartaric acid Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys Reaction Steps: 2 1: Raney nickel; ethanol; NH3 / Hydrogenation.bei aufeinanderfolgender Umsetzung mit Methylmagnesiumbromid und mit LiAlH4 2: Lg-tartaric acid With ethanol, l-tartaric acid, ammonia, nickel Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys

NH 2 H

Rx-ID: 22050158 View in Reaxys 112/553

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

40/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 2 1: aq.-ethanolic KOH-solution 2: beim Erwaermen des ueber das Saeurechlorid hergestellten Saeureazids in Benzol und anschliessenden Erhitzen mit wss. Salzsaeure With potassium hydroxide McCoubrey; Mathieson; Journal of the Chemical Society; (1949); p. 696,699 View in Reaxys

H NH 2

N H

Rx-ID: 22070624 View in Reaxys 113/553 Yield

Conditions & References Reaction Steps: 2 1: bei aufeinanderfolgender Umsetzung mit Methylmagnesiumbromid und mit LiAlH4 2: Lg-tartaric acid With l-tartaric acid Cram; McCarty; Journal of the American Chemical Society; vol. 76; (1954); p. 5740,5743 View in Reaxys NH 2

Rx-ID: 22113380 View in Reaxys 114/553 Yield

Conditions & References Reaction Steps: 2 1: KNH2; liquid NH3 / anschliessend Behandeln mit CH3I in Aether 2: Raney nickel / Hydrogenation With ammonia, nickel, potassium amide Gibson; Journal of the Chemical Society; (1956); p. 808,809 View in Reaxys H NH 2

potassium biphenylolate-(4)

Rx-ID: 22639148 View in Reaxys 115/553 Yield

Conditions & References Reaction Steps: 2 1: (i) Li, Et2O, (ii) /BRN= 79772/ 2: (i) TsCl, Py, (ii) aq. NaN3, DMF, (iii) LiAlH4, Et2O Smissman,E.E.; Pazdernik,T.L.; Journal of Medicinal Chemistry; vol. 16; (1973); p. 14 - 18 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

41/236

2018-08-17 23:02:17

NH 2

Rx-ID: 38250176 View in Reaxys 116/553 Yield

Conditions & References With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Aspergillus terreus, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = 91 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form hyphomonas neptunium, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = 8 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

NH 2

Rx-ID: 38250177 View in Reaxys 117/553 Yield 79 %Chromat.

NH 2

Rx-ID: 38250178 View in Reaxys 118/553 Yield 84 %Chromat.

42/236

2018-08-17 23:02:17

NH 2

Rx-ID: 38250183 View in Reaxys 119/553 Yield 31 %Chromat.

NH 2

Rx-ID: 38250184 View in Reaxys 120/553 Yield

Conditions & References With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Arthrobacter species S, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = 90 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Aspergillus terreus, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = 89 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

NH 2

Rx-ID: 38250185 View in Reaxys 121/553 Yield 87 %Chromat.

43/236

2018-08-17 23:02:17

View in Reaxys

NH 2

H 2N

Rx-ID: 38250197 View in Reaxys 122/553 Yield

NH 2

Rx-ID: 38250203 View in Reaxys 123/553 Yield

NH 2

Rx-ID: 38250204 View in Reaxys 124/553 Yield

44/236

2018-08-17 23:02:17

With dodecacarbonyltetrarhodium(0), L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'-phosphate, α-transaminase form Pseudomonas pudita1, hydrogen, ammonium formate, NADH in aq. phosphate buffer, toluene Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

NH 2

Rx-ID: 38250206 View in Reaxys 125/553 Yield

NH 2

Rx-ID: 38250211 View in Reaxys 126/553 Yield

45/236

2018-08-17 23:02:17

NH 2

Rx-ID: 38250212 View in Reaxys 127/553 Yield

NH 2

Rx-ID: 38250213 View in Reaxys 128/553 Yield

NH 2

H 2N

Rx-ID: 457791 View in Reaxys 129/553 Yield

Conditions & References With ammonia, nickel, T= 100 °C , p= 51485.6Torr , Hydrogenation Borovicka et al.; Chemicke Listy; vol. 49; (1955); p. 231,241; Collection of Czechoslovak Chemical Communications; vol. 20; (1955); p. 437,449; ; (1956); p. 1639,1640 View in Reaxys

46/236

2018-08-17 23:02:17

NH 2 N N

NH 2

Rx-ID: 923426 View in Reaxys 130/553 Yield

Conditions & References With hydrogen, nickel in methanol Elslager,E.F. et al.; Journal of Heterocyclic Chemistry; vol. 6; (1969); p. 491 - 495 View in Reaxys 21.1 : Step 1 Step 1 2-Amino-α-methylphenethylamine Reduction of 4-methyl-cinnoline (10 g, 69.5 mmol) in methanol (100 mL), using Raney nickel (3 g). The catalyst was removed and washed with methanol. The filtrate was treated with an excess of HCl in isopropanol; ether was then added and the solution cooled. The precipitate was filtered and dried; 9.4 g (60percent). With hydrogenchloride, aluminum nickel in methanol, isopropyl alcohol Patent; Warner-Lambert Company; US6300501; (2001); (B1) English View in Reaxys

NH 2

H 2N

Rx-ID: 7893076 View in Reaxys 131/553 Yield

Conditions & References Nitrophenylpropylamin, H2 Patent; BASF AG; DE2443342; (1974) View in Reaxys

O NH 2

N O N

H 2N

Rx-ID: 22160957 View in Reaxys 132/553 Yield 100 %

Conditions & References 17A :2-(4-Nitrophenyl)propionitrile (5.0 g, 28.38 mmoL) was dissolved in a 20percent NH3/methanol mixture (100 mL) and treated with Raney Nickel (24.79 g). It was then hydrogenated at 60 psi at room temperature for 4 hr. The reaction was then filtered through a nylon membrane. The filtrate was then concentrated in vacuo to give 4.26 g (100percent) of the title compound. It was used without further purification. 1H NMR (300 MHz, CDCl3) α ppm 7.00 (d, J=8.46 Hz, 2H) 6.66 (d, J=8.09 Hz, 2H) 3.58 (s, 2H) 2.71-2.85 (m, 2H) 2.56-2.70 (m, 1H) 1.20 (d, J=6.62 Hz, 3H). MS m/z (DCI) 151.0 (M+H)+. With ammonia, hydrogen, nickel in methanol, Time= 4h, T= 20 °C , p= 3102.97Torr Patent; Keyes, Robert F.; Gu, Yu gui; Sham, Hing L.; US2007/219258; (2007); (A1) English View in Reaxys Reaction Steps: 2 1: iron-powder; aq.-ethanolic HCl 2: Raney nickel; methanol.NH3 / 100 °C / 51485.6 Torr / Hydrogenation With hydrogenchloride, ammonia, iron, nickel

47/236

2018-08-17 23:02:17

Borovicka et al.; Chemicke Listy; vol. 49; (1955); p. 231,241; Collection of Czechoslovak Chemical Communications; vol. 20; (1955); p. 437,449; ; (1956); p. 1639,1640 View in Reaxys

NH 2 O H 2N

Rx-ID: 398147 View in Reaxys 133/553 Yield

Conditions & References With hydrogen iodide Gitschthaler; Klementschitz; Scientia Pharmaceutica; vol. 21; (1953); p. 237 View in Reaxys With hydrogenchloride, T= 160 °C Woodruff; Pierson; Journal of the American Chemical Society; vol. 60; (1938); p. 1075 View in Reaxys

H 2N

NH 2

Rx-ID: 398152 View in Reaxys 134/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Pierson; Journal of the American Chemical Society; vol. 60; (1938); p. 1075 View in Reaxys NH 2 O

H 2N

Rx-ID: 456563 View in Reaxys 135/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Pierson; Journal of the American Chemical Society; vol. 60; (1938); p. 1075 View in Reaxys

NH 2

Rx-ID: 7278532 View in Reaxys 136/553 Yield

Conditions & References aus X ueber XIa, XIIa (Chart 2) Kametani et al.; Journal of Heterocyclic Chemistry; vol. 7; (1970); p. 51 View in Reaxys aus 2-(3-Benzyloxy-phenyl)-propionitril (V) bei Hydrierung in A. an Raney-Ni

48/236

2018-08-17 23:02:17

Kametani et al.; Yakugaku Zasshi; vol. 89; (1969); p. 1212,1217; ; vol. 72; nb. 3192; (1970) View in Reaxys 2-(3-Hydroxyphenyl)-propionitril (XVII), H2 an Raney-Ni in NH3-gesaettigt. A. Kametani et al.; Yakugaku Zasshi; vol. 89; (1969); p. 1212,1217; ; vol. 72; nb. 3192; (1970) View in Reaxys

NH 2

O N HO

Rx-ID: 22009456 View in Reaxys 137/553 Yield

Conditions & References Reaction Steps: 2 1: sodium-amalgam 2: aqueous HI With sodium amalgam, hydrogen iodide Gitschthaler; Klementschitz; Scientia Pharmaceutica; vol. 21; (1953); p. 237 View in Reaxys

H 2N

NH 2

Rx-ID: 22045642 View in Reaxys 138/553 Yield

Conditions & References Reaction Steps: 2 1: alkaline aqueous sodium hypobromite / anschliessendes Erwaermen mit Natriumhydroxid 2: aqueous hydrochloric acid / 160 °C With hydrogenchloride, alkaline aqueous sodium hypobromite Woodruff; Pierson; Journal of the American Chemical Society; vol. 60; (1938); p. 1075 View in Reaxys NH 2

NH 2

Rx-ID: 22053740 View in Reaxys 139/553 Yield

49/236

2018-08-17 23:02:17

NH 2

4'-isopropylbenzoxazinorifamycin OH

Rx-ID: 25137735 View in Reaxys 140/553 Yield

Conditions & References 32 : [Synthesis of 4'-isopropylbenzoxazinorifamycin] To a solution of 5.07 g of 4-isopropyl-2-nitrophenol in 150 ml of ethanol was added 0.5 g of 10percent palladium carbon, to which hydrogen was introduced with stirring at room temperature for 4 hours. Palladium carbon was filtered off and the solvent was distilled away under a reduced pressure to give 4.87 g of a crude product of 2-amino-isopropylphenol. Patent; Kanegafuchi Kagaku Kogyo Kabushiki Kaisha; US4859661; (1989); (A) English View in Reaxys

NH 2

H 2N

Rx-ID: 746644 View in Reaxys 141/553 Yield

Conditions & References With aluminium trichloride Weston; Ruddy; Suter; Journal of the American Chemical Society; vol. 65; (1943); p. 675 View in Reaxys

NH 2

Rx-ID: 10816693 View in Reaxys 142/553 Yield 23 %

Conditions & References A.ii :Borane in THF (96 ml, 0.096 mol, 1M solution) was added dropwise to the solution of 1-Fluoro-4-isopropenyl-benzene from step (i) above (30 g, 0.24 mol) in THF (350 ml) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and hydroxylamine-O-sulphonic acid (27.72 g, 0.24 mol) was added portionwise. The reaction mixture was refluxed for overnight. Then the reaction mixture was quenched with water and concentrated, acidified with 1.5 N HCl. The reaction mixture was extracted with ethylacetate, aqueous layer was neutralized with 10percent sodium hydroxide solution and extracted with dichloromethane. The dichloromethane layer was washed with, water, brine and evaporated to give the title compound (8.5 g, 23percent) Stage 1: With borane-THF in tetrahydrofuran, Time= 3h, T= 0 - 20 °C Stage 2: With hydroxylamine-O-sulfonic acid in tetrahydrofuran, T= 0 °C , Heating / reflux Patent; ASTRAZENECA AB; US2008/15237; (2008); (A1) English View in Reaxys

NH 2

Rx-ID: 34338399 View in Reaxys 143/553

50/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 2 1: triphenylphosphine; diethylazodicarboxylate / toluene; tetrahydrofuran / 72 h 2: hydrazine / toluene / 0.5 h / 80 °C With triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, toluene Patent; Ashcraft, Luke W.; Bergnes, Gustave; Chuang, Chihyuan; Collibee, Scott; Lu, Pu-Ping; Morgan, Bradley; Muci, Alex; Qian, Xiangping; Warrington, Jeffrey; Yang, Zhe; US2012/289698; (2012); (A1) English View in Reaxys Reaction Steps: 2 1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 72 h 2: hydrazine hydrate / toluene / 0.5 h / 80 °C With hydrazine hydrate, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, toluene Patent; Cytokinetics, Inc.; Ashcraft, Luke W.; Bergnes, Gustave; Collibee, Scott; Chuang, Chihyuan; Gardina, Jeff; Morgan, Bradley P.; Muci, Alex R.; Qian, Xiangping; Romero, Antonio; Warrington, Jeffrey; Yang, Zhe; US9133123; (2015); (B2) English View in Reaxys

NH 2

O F N

Rx-ID: 34338405 View in Reaxys 144/553 Yield 99 %

Conditions & References 1 :(S)-2-(4-Fluorophenyl)propan-1-amine; To a room-temperature solution of (S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3dione (900 mg, 3.2 mmol, 1.0 equiv) in toluene (14 mL) was added hydrazine (1.4 mL, 45 mmol, 14 equiv) by syringe. The resulting mixture was heated to 80° C. for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with additional toluene. The combined organic layers were concentrated in vacuo to provide the title compound (491 mg, 99percent), which was used without further purification. m/ z=154.2 [M+H]+. With hydrazine in toluene, Time= 0.5h, T= 80 °C Patent; Ashcraft, Luke W.; Bergnes, Gustave; Chuang, Chihyuan; Collibee, Scott; Lu, Pu-Ping; Morgan, Bradley; Muci, Alex; Qian, Xiangping; Warrington, Jeffrey; Yang, Zhe; US2012/289698; (2012); (A1) English View in Reaxys

99 %

1 : (S)-2-(4-Fluorophenyl)propan-1-amine (S)-2-(4-Fluorophenyl)propan-1-amine To a room-temperature solution of (S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3-dione (900 mg, 3.2 mmol, 1.0 equiv) in toluene (14 mL) was added hydrazine hydrate (1.4 mL, 45 mmol, 14 equiv) by syringe. The resulting mixture was heated to 80° C. for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with additional toluene. The combined organic layers were combined and concentrated in vacuo to provide the title compound (491 mg, 99percent), which was used without further purification. With hydrazine hydrate in toluene, Time= 0.5h, T= 80 °C Patent; Cytokinetics, Inc.; Ashcraft, Luke W.; Bergnes, Gustave; Collibee, Scott; Chuang, Chihyuan; Gardina, Jeff; Morgan, Bradley P.; Muci, Alex R.; Qian, Xiangping; Romero, Antonio; Warrington, Jeffrey; Yang, Zhe; US9133123; (2015); (B2) English View in Reaxys

51/236

2018-08-17 23:02:17

NH 2

O F F

Rx-ID: 34348654 View in Reaxys 145/553 Yield

Conditions & References Reaction Steps: 5 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: 0.5 h 2.1: sodium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C 3.1: water; sodium tetrahydroborate / tetrahydrofuran / 3 h / 20 °C 4.1: triphenylphosphine; diethylazodicarboxylate / toluene; tetrahydrofuran / 72 h 5.1: hydrazine / toluene / 0.5 h / 80 °C With sodium tetrahydroborate, n-butyllithium, water, sodium hexamethyldisilazane, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, toluene Patent; Ashcraft, Luke W.; Bergnes, Gustave; Chuang, Chihyuan; Collibee, Scott; Lu, Pu-Ping; Morgan, Bradley; Muci, Alex; Qian, Xiangping; Warrington, Jeffrey; Yang, Zhe; US2012/289698; (2012); (A1) English View in Reaxys Reaction Steps: 5 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C 3.1: sodium tetrahydroborate; water / tetrahydrofuran / 3 h / 20 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 72 h 5.1: hydrazine hydrate / toluene / 0.5 h / 80 °C With sodium tetrahydroborate, n-butyllithium, water, sodium hexamethyldisilazane, hydrazine hydrate, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, hexane, toluene Patent; Cytokinetics, Inc.; Ashcraft, Luke W.; Bergnes, Gustave; Collibee, Scott; Chuang, Chihyuan; Gardina, Jeff; Morgan, Bradley P.; Muci, Alex R.; Qian, Xiangping; Romero, Antonio; Warrington, Jeffrey; Yang, Zhe; US9133123; (2015); (B2) English View in Reaxys

F NH 2

O F

O O

Rx-ID: 34348662 View in Reaxys 146/553 Yield

Conditions & References Reaction Steps: 4 1: sodium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C 2: water; sodium tetrahydroborate / tetrahydrofuran / 3 h / 20 °C 3: triphenylphosphine; diethylazodicarboxylate / toluene; tetrahydrofuran / 72 h 4: hydrazine / toluene / 0.5 h / 80 °C With sodium tetrahydroborate, water, sodium hexamethyldisilazane, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, toluene Patent; Ashcraft, Luke W.; Bergnes, Gustave; Chuang, Chihyuan; Collibee, Scott; Lu, Pu-Ping; Morgan, Bradley; Muci, Alex; Qian, Xiangping; Warrington, Jeffrey; Yang, Zhe; US2012/289698; (2012); (A1) English View in Reaxys Reaction Steps: 4

52/236

2018-08-17 23:02:17

1: sodium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C 2: sodium tetrahydroborate; water / tetrahydrofuran / 3 h / 20 °C 3: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 72 h 4: hydrazine hydrate / toluene / 0.5 h / 80 °C With sodium tetrahydroborate, water, sodium hexamethyldisilazane, hydrazine hydrate, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, toluene Patent; Cytokinetics, Inc.; Ashcraft, Luke W.; Bergnes, Gustave; Collibee, Scott; Chuang, Chihyuan; Gardina, Jeff; Morgan, Bradley P.; Muci, Alex R.; Qian, Xiangping; Romero, Antonio; Warrington, Jeffrey; Yang, Zhe; US9133123; (2015); (B2) English View in Reaxys

NH 2

Rx-ID: 34348678 View in Reaxys 147/553 Yield

Conditions & References Reaction Steps: 3 1: water; sodium tetrahydroborate / tetrahydrofuran / 3 h / 20 °C 2: triphenylphosphine; diethylazodicarboxylate / toluene; tetrahydrofuran / 72 h 3: hydrazine / toluene / 0.5 h / 80 °C With sodium tetrahydroborate, water, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, toluene Patent; Ashcraft, Luke W.; Bergnes, Gustave; Chuang, Chihyuan; Collibee, Scott; Lu, Pu-Ping; Morgan, Bradley; Muci, Alex; Qian, Xiangping; Warrington, Jeffrey; Yang, Zhe; US2012/289698; (2012); (A1) English View in Reaxys Reaction Steps: 3 1: sodium tetrahydroborate; water / tetrahydrofuran / 3 h / 20 °C 2: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 72 h 3: hydrazine hydrate / toluene / 0.5 h / 80 °C With sodium tetrahydroborate, water, hydrazine hydrate, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, toluene Patent; Cytokinetics, Inc.; Ashcraft, Luke W.; Bergnes, Gustave; Collibee, Scott; Chuang, Chihyuan; Gardina, Jeff; Morgan, Bradley P.; Muci, Alex R.; Qian, Xiangping; Romero, Antonio; Warrington, Jeffrey; Yang, Zhe; US9133123; (2015); (B2) English View in Reaxys O O H

NH NH 2

Rx-ID: 22879691 View in Reaxys 148/553 Yield 94.9 %

Conditions & References 3 : EXAMPLE 3; Alternative Preparation of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine; Preparation of (2R)-2phenylpropylamine

53/236

2018-08-17 23:02:17

EXAMPLE 3 [0101] Alternative Preparation of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine. [CHEMMOL-00022] [0102] Preparation of (2R)-2-phenylpropan-1-ol. [0103] An oven dried 500.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with 2.0 M solution of trimethylaluminum (65.6 mL, 131.2 mmol) and toluene (75.0 mL). Reaction solution was then chilled to -60° C. with dry ice/ acetone bath. To this solution was then added R-styrene oxide dissolved in 100.0 mL of toluene over a period of 50.0 minutes (reaction is quite exothermic and can be controlled by the rate of addition of substrate). After stirring at this temperature for 60.0 minutes, reaction was brought to room temperature and stirred for 4.0 hours. Reverse quenched reaction at room temperature into a slurry of THF (100.0 mL) and sodium sulfate decahydrate (46.0 g) very cautiously over a period of 90.0 minutes (quenching was quite exothermic with evolution of gas). Filtered the precipitate formed over hyflo, then concentrated filtrate to provide the intermediate title compound, (2R)-2-phenylpropan-1-ol, (11.03 g, 92.6percent) as an oil; 1H nmr (CDCl3) α 1.28-1.29 (d, 3H, J=6.9 Hz), 1.5 (b, 1H), 2.9-3.0 (m, 1H), 3.69-3.70 (d, 2H, J=6.64 Hz), 7.24-7.35 (aromatic); 13C nmr (CDCl3) α 18.31, 43.15, 69.40, 127.38, 128.20, 129.26144.39. [0104] Preparation of 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione [0105] An oven dried 250.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with (2R)-2-phenylpropan-1-ol (2.0 mL, 14.32 mmol), phthalimide (2.1 g, 14.32 mmol), triphenylphosphine (5.63 g, 21.48 mmol) and THF (70.0 mL). To this solution at room temperature was then added a solution of diethylazodicarboxylate (3.38 mL, 21.48 mmol) dissolved in THF (10.0 mL) over a period of 15-20 minutes (reaction exothermed slightly to 50° C. by the end of addition went from clear to reddish color). Stirred reaction to room temperature overnight). To the red solution was added water (50.0 mL) and the organic extracted with chloroform (140.0 mL). Dried the organic solution with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. To the oil was added heptane (150.0 mL) with stirring. Filtered of precipitates, then concentrated filtrate to an oil. Plug filtration of the oil over silica gel with 1:1 ethylacetate/hexane and concentrating product fractions afforded the intermediate title compound, 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione, (4.27 g, 96percent) as an oil which solidified on equilibrating to room temperature; 1H nmr (CDCl3) α 1.3 (d, 3H), 3.34.0 (m, 1H), 3.7-3.9 (m, 2H), 7.1-7.3 (aromat. m, 2H), 7.63-7.7 (aromat. m, 2H), 7.8-7.85 (aromat. m, 4H). [0106] Preparation of (2R)-2-phenylpropylamine. [0107] A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel is charged with 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione (11.54 g, 43.49 mmol), toluene (200.0 mL) and anhydrous hydrazine (2.73 mL, 86.99 mmol). Reaction is then stirred at room temperature for 3.0 hours and then heated at 90° C.-95° C. for 2.0 hours. Cooled the slurry to room temperature, filtered precipitates, then concentrated filtrate to provide the intermediate title compound, (2R)-2-phenylpropylamine, (5.58 g, 94.9percent) an oil; 1H nmr (CDCl3) α 1.21 (d, 3H), 1.40-1.60 (b, 2H), 2.68-2.80 (m, 1H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H). [0108] Preparation of Final Title Compound. [0109] To a solution of the (2R)-2-phenylpropylamine (1.2 g, 8.87 mmol) in hexane (16.0 mL) was added triethylamine (2.47 mL, 17.74 mmol) and dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5° C., then added a solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in methylene chloride (6.0 mL) over a period of 15.0 minutes. Stirred for 45.0 minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction with 1 N HCl (20.0 mL) and extracted organic with methylene chloride (25.0 mL). Dried organic layer with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide the final title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1percent) an oil; 1H nmr (CDCl3) α 1.25 (d, 3H, J=6.9 Hz), 1.29(d, 3H, J=6.9 Hz), 1.30 (d, 3H, J=7.2 Hz), 2.98 (m, 1H), 3.05 (m, 1H), 3.22 (m, 1H), 3.36 (m, 1H), 3.89 (b, 1H), 7.23 (m, 2H), 7.34 (m, 2H). With hydrazine in toluene, Time= 5h, T= 20 - 95 °C Patent; Arnold, Macklin Brian; Bleisch, Thomas John; Cuff, George William; Ornstein, Paul Leslie; Zimmerman, Dennis Michael; US2003/225163; (2003); (A1) English View in Reaxys

NH 2

H 2N

Rx-ID: 704801 View in Reaxys 149/553 Yield

Conditions & References With aluminium trichloride Patent; Sharp and Dohme Inc.; US2441518; (1945) View in Reaxys

54/236

2018-08-17 23:02:17

NH 2

H 2N

Rx-ID: 746714 View in Reaxys 150/553 Yield

Conditions & References With aluminium trichloride Patent; Sharp and Dohme Inc.; US2441518; (1945) View in Reaxys

NH 2

H 2N

Rx-ID: 746715 View in Reaxys 151/553 Yield

Conditions & References With aluminium trichloride, 1,2-dichloro-benzene Patent; Scharp and Dohme Inc.; US2441518; (1945) View in Reaxys NH 2

Rx-ID: 8028968 View in Reaxys 152/553 Yield

Conditions & References p-Xylol, Propylenimin, AlCl3 Milstein; Journal of Heterocyclic Chemistry; vol. 5; (1968); p. 339 View in Reaxys (yield)73percent Milstein; Journal of Heterocyclic Chemistry; vol. 5; (1968); p. 339 View in Reaxys

NH 2 H 2N

Rx-ID: 370849 View in Reaxys 153/553 Yield

Conditions & References With alkaline aqueous sodium hypobromite, anschliessendes Erwaermen mit Natriumhydroxid Woodruff; Pierson; Journal of the American Chemical Society; vol. 60; (1938); p. 1075 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

55/236

2018-08-17 23:02:17

NH 2 O N

Rx-ID: 438566 View in Reaxys 154/553 Yield

Conditions & References With sodium amalgam Gitschthaler; Klementschitz; Scientia Pharmaceutica; vol. 21; (1953); p. 237 View in Reaxys NH 2

NH 2

Rx-ID: 464527 View in Reaxys 155/553 Yield

NH 2 O

H 2N

Rx-ID: 657576 View in Reaxys 156/553 Yield

Conditions & References With aluminium trichloride Patent; Sharp and Dohme Inc.; US2441518; (1945) View in Reaxys

O N

NH 2

Rx-ID: 2831418 View in Reaxys 157/553 Yield 77.6 %

Conditions & References 118.2; 119.2; 120.2; 121.2 : 2-(3-methoxyphenyl)propan-1-amine To a solution of 1-methoxy-3-(1-methyl-2-nitro-ethyl)benzene (6.634 mmol, 1295 mg) in MeOH (26.5 mL) was added 10percent Pd/C (494 mg), followed by ammonium formate(2.09 g, 33.2 mmol). The mixture was stirred at room temperature for 4 h. The mix was filtered and concentrated. The residue was suspended in water with 1 mL of 25percent NaOH and chloroform. The layers were separated. The aqueous layer was saturated with NaC1, extracted with CHC13/iPrOH(3/1) twice. The combined organics were dried (Na2504), filtered and concentrated to give the title compound (850 mg, 77.6percent yield) as colorless oil. â&#x20AC;&#x2DC;H

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

56/236

2018-08-17 23:02:17

NMR (400MHz, Chloroform-d) ö 7.26 — 7.18 (m, 1H), 6.84 — 6.79 (m, 1H), 6.79 — 6.71 (m, 2H), 3.81(d, I = 0.5 Hz, 3H), 2.84 (d, I = 6.9 Hz, 2H), 2.72 (h, I = 6.9 Hz, 1H), 1.25 (dd, I = 6.9, 0.5 Hz, 3H). LCMS (ESI) mlz 166 [M+Hj. With 10% palladium on activated carbon; Degussa type, ammonium formate in methanol, Time= 4h, T= 20 °C Patent; F. HOFFMANN-LA ROCHE AG; GENENTECH, INC.; LABADIE, Sharada; LIANG, Jun; ORTWINE, Daniel Fred; WANG, Xiaojing; ZHANG, Birong; ZBIEG, Jason; VINOGRADOVA, Maia; WANG, Tao; (150 pag.); WO2017/174757; (2017); (A1) English View in Reaxys With ammonium formate, 10 wt. % palladium on activated carbon in methanol, Time= 10h, Ambient temperature Martinez, Silvio J.; Larsen, Lesley; Street, Janathan D.; Joule, John A.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1988); p. 1705 - 1710 View in Reaxys 1.56.B :Step B: Preparation of 2-(3-Methoxyphenyl)propan-l-amine. To a solution of l-methoxy-3-(l-nitropropan-2-yl)benzene (1.142 g, 5.85 mmol) in methanol (23.40 mL) was added palladium on carbon (10 percent) (0.436 g, 4.09 mmol) followed by ammonium formate (1.660 g, 26.3 mmol). The reaction was stirred at room temperature for 4 h, filtered and concentrated under reduced pressure. The residue was suspended in water with 0.5 mL of 50percent sodium hydroxide and chloroform. The phases were separated and the aqueous layer was saturated with sodium chloride and extracted twice with chloroform. The combined organic <n="92"/>layers were dried over sodium sulfate and filtered. The filtrate was treated with HCl (1 M in diethyl ether, 10 mL). The solvent removed under reduced pressure to give the title compound as a white solid (1.182 g). LCMS m/z = 166.1 [M +H]+; 1H NMR (400 MHz, Methanol-^) α ppm 1.30-1.36 (m, 3H), 3.00-3.07 (m, IH), 3.11-3.16 (m, 2H), 3.77-3.81 (m, 3H), 6.82-6.90 (m, 3H), 7.24-7.32 (m, IH). Stage 1: With ammonium formate, 10% palladium on activated carbon; Degussa type in methanol, Time= 4h, T= 20 °C Stage 2: With sodium hydroxide in chloroform, water Patent; ARENA PHARMACEUTICALS, INC.; WO2009/105206; (2009); (A1) English View in Reaxys

NH 2

Rx-ID: 7807975 View in Reaxys 158/553 Yield

Conditions & References Nitril III, Hydrierung, Ni/Cr2O3 Ovsepyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 26; (1973); p. 843,845, 846; ; vol. 80; nb. 70503s; (1974) View in Reaxys A.7.c : EXAMPLE A.7 c) A mixture of intermediate 17 (3.44 g) in methanol/ammonia (100 ml) was hydrogenated at RT, with Raney nickel (2.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off, and the filtrate was evaporated, yielding 3.6 g (quantitative yield) of (+-)-3-(cyclopropylemthoxy)-4-methoxy-α-methylbenzeneethanamine (interm. 18). Patent; Janssen Pharmaceutica, N.V.; US5994376; (1999); (A) English View in Reaxys

57/236

2018-08-17 23:02:17

NH 2

Rx-ID: 7807987 View in Reaxys 159/553 Yield

Conditions & References aus 2-(3-Methoxy-phenyl)-propionitril (1) bei Hydrierung an Raney-Ni in NH3-gesaettigtem A. Kametani et al.; Yakugaku Zasshi; vol. 89; (1969); p. 1212,1217; ; vol. 72; nb. 3192; (1970) View in Reaxys

NH 2

3-<3-methoxy-phenyl>-butyramide

Rx-ID: 7807988 View in Reaxys 160/553 Yield

NH 2 O

Rx-ID: 11255047 View in Reaxys 161/553 Yield

Conditions & References With borane-THF, Heating Jetter, Michele C.; Youngman, Mark A.; McNally, James J.; McDonnell, Mark E.; Zhang, Sui-Po; Dubin, Adrienne E.; Nasser, Nadia; Codd, Ellen E.; Flores, Christopher M.; Dax, Scott L.; Bioorganic and Medicinal Chemistry Letters; vol. 17; nb. 22; (2007); p. 6160 - 6163 View in Reaxys

O N

NH 2

Rx-ID: 20868604 View in Reaxys 162/553 Yield

Conditions & References Reaction Steps: 2 1: 76 percent / cuprous iodide / tetrahydrofuran; diethyl ether / 1.5 h / 0 °C 2: ammonium formate / 10percent palladium-charcoal / methanol / 10 h / Ambient temperature With copper(l) iodide, ammonium formate, 10 wt. % palladium on activated carbon in tetrahydrofuran, methanol, diethyl ether Martinez, Silvio J.; Larsen, Lesley; Street, Janathan D.; Joule, John A.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1988); p. 1705 - 1710 View in Reaxys Reaction Steps: 2 1: copper(l) iodide / tetrahydrofuran; diethyl ether / 3 h / 0 °C

58/236

2018-08-17 23:02:17

2: 10% palladium on activated carbon; Degussa type; ammonium formate / methanol / 4 h / 20 °C With copper(l) iodide, 10% palladium on activated carbon; Degussa type, ammonium formate in tetrahydrofuran, methanol, diethyl ether Patent; F. HOFFMANN-LA ROCHE AG; GENENTECH, INC.; LABADIE, Sharada; LIANG, Jun; ORTWINE, Daniel Fred; WANG, Xiaojing; ZHANG, Birong; ZBIEG, Jason; VINOGRADOVA, Maia; WANG, Tao; (150 pag.); WO2017/174757; (2017); (A1) English View in Reaxys

NH 2

Rx-ID: 25694794 View in Reaxys 163/553 Yield

Conditions & References

56 %

143 :To a solution of 2-(3-methoxyphenyl)propanenitrile (1.33 g, 8.26 mmol) in THF (10 mL) at room temperature was added lithium aluminum hydride (9.1 mL, 1M in THF, 9.1 mmol). The reaction was stirred overnight. More lithium aluminum hydride (0.5 mL) was added and the reaction was refluxed for 4 h. 1 N HCl was added carefully to quench the reaction. It was diluted with ether, washed with H2O. Aqueous layer was treated with NaOH and extracted with CH2Cl2. CH2Cl2 layer was washed with saturated NaCl, dried and concentrated to give 2-(3-methoxyphenyl)-propan-1-amine (761 g, 56percent yield) as a pale yellow oil. HPLC retention time (Method C)=1.59 min. LC/MS (ESI) (M+H)+=166.07. 1H NMR (CDCl3, 400 MHz) α ppm 1.24 (d, J=6.85 Hz, 3H), 2.65-2.77 (m, 1H), 2.85 (d, J=8 Hz, 2H), 3.80 (s, 3H), 6.71-6.84 (m, 3H), 7.20-7.26 (m, 1H). Stage 1: With lithium aluminium tetrahydride in tetrahydrofuran, T= 20 °C , Heating / reflux Stage 2: With hydrogenchloride, water in tetrahydrofuran Patent; Bristol-Myers Squibb Company; US2007/93523; (2007); (A1) English View in Reaxys NH 2 O

Rx-ID: 36353300 View in Reaxys 164/553 Yield

Conditions & References Reaction Steps: 4 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; cyclohexane / 1 h / -78 - 20 °C / Inert atmosphere 1.2: 18 h / -78 - 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 0 - 20 °C 3.1: triphenylphosphine / 0.25 h / 20 °C 3.2: 18 h 4.1: hydrazine / methanol / 18 h With lithium aluminium tetrahydride, n-butyllithium, diisopropylamine, triphenylphosphine, hydrazine in tetrahydrofuran, methanol, cyclohexane Patent; Charifson, Paul S.; Cottrell, Kevin Michael; Deng, Hongbo; Duffy, John P.; Gao, Huai; Giroux, Simon; Green, Jeremy; Jackson, Katrina Lee; Kennedy, Joseph M.; Lauffer, David J.; Ledeboer, Mark Willem; Li, Pan; Maxwell, John Patrick; Morris, Mark A.; Pierce, Albert Charles; Waal, Nathan D.; Xu, Jinwang; US2013/281431; (2013); (A1) English View in Reaxys

59/236

2018-08-17 23:02:17

NH 2 O HO

Rx-ID: 36353310 View in Reaxys 165/553 Yield

Conditions & References Reaction Steps: 3 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 0 - 20 °C 2.1: triphenylphosphine / 0.25 h / 20 °C 2.2: 18 h 3.1: hydrazine / methanol / 18 h With lithium aluminium tetrahydride, triphenylphosphine, hydrazine in tetrahydrofuran, methanol Patent; Charifson, Paul S.; Cottrell, Kevin Michael; Deng, Hongbo; Duffy, John P.; Gao, Huai; Giroux, Simon; Green, Jeremy; Jackson, Katrina Lee; Kennedy, Joseph M.; Lauffer, David J.; Ledeboer, Mark Willem; Li, Pan; Maxwell, John Patrick; Morris, Mark A.; Pierce, Albert Charles; Waal, Nathan D.; Xu, Jinwang; US2013/281431; (2013); (A1) English View in Reaxys NH 2 O

Rx-ID: 36353314 View in Reaxys 166/553 Yield

Conditions & References Reaction Steps: 2 1.1: triphenylphosphine / 0.25 h / 20 °C 1.2: 18 h 2.1: hydrazine / methanol / 18 h With triphenylphosphine, hydrazine in methanol Patent; Charifson, Paul S.; Cottrell, Kevin Michael; Deng, Hongbo; Duffy, John P.; Gao, Huai; Giroux, Simon; Green, Jeremy; Jackson, Katrina Lee; Kennedy, Joseph M.; Lauffer, David J.; Ledeboer, Mark Willem; Li, Pan; Maxwell, John Patrick; Morris, Mark A.; Pierce, Albert Charles; Waal, Nathan D.; Xu, Jinwang; US2013/281431; (2013); (A1) English View in Reaxys

NH 2

O N O

Rx-ID: 36353319 View in Reaxys 167/553 Yield 71 %

Conditions & References 4.iv : Example 4 Preparation (S)—N-(2-(2-Methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 32)

60/236

2018-08-17 23:02:17

As shown in step 4-iv of Scheme 4, to a stirred solution of 2-(2-(2-methoxyphenyl)propyl)isoindoline-1,3-dione (363 mg, 1.23 mmol) in MeOH (4.0 mL) was added hydrazine (39.4 mg, 38.6 μL, 1.23 mmol) and the reaction was stirred for 18 hours. The precipitate that had formed was filtered, washed with MeOH, and the filtrate concentrated under reduced pressure to give 2(methoxyphenyl)-1-propanamine as a light yellow oil (Compound 2011, 144 mg, 71percent yield): 1H NMR (CDCl3) α 7.27-7.13 (m, 2H), 6.95 (ddd, J=18.2, 12.3, 4.6 Hz, 2H), 3.84 (s, 3H), 3.39-3.18 (m, 1H), 2.86 (qd, J=12.7, 6.8 Hz, 2H), 1.44 (s, 2H), 1.24 (d, J=7.0 Hz, 3H). With hydrazine in methanol, Time= 18h Patent; Charifson, Paul S.; Cottrell, Kevin Michael; Deng, Hongbo; Duffy, John P.; Gao, Huai; Giroux, Simon; Green, Jeremy; Jackson, Katrina Lee; Kennedy, Joseph M.; Lauffer, David J.; Ledeboer, Mark Willem; Li, Pan; Maxwell, John Patrick; Morris, Mark A.; Pierce, Albert Charles; Waal, Nathan D.; Xu, Jinwang; US2013/281431; (2013); (A1) English View in Reaxys

NH 2

Rx-ID: 38250173 View in Reaxys 168/553 Yield

Conditions & References With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Arthrobacter species R, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Overall yield = 99 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Pseudomonas pudita1, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Overall yield = 94 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

NH 2

O O O

Rx-ID: 38250174 View in Reaxys 169/553 Yield 95 %Chromat.

61/236

2018-08-17 23:02:17

NH 2 O

NH 2

Rx-ID: 38250180 View in Reaxys 170/553 Yield

Conditions & References With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Arthrobacter species R, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = 99 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Pseudomonas pudita1, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = 97 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

NH 2

Rx-ID: 38250181 View in Reaxys 171/553 Yield > 99 %Chromat.

NH 2 O O

Rx-ID: 38250187 View in Reaxys 172/553 Yield 99 %Chromat.

62/236

2018-08-17 23:02:17

View in Reaxys

NH 2

O O O

Rx-ID: 38250188 View in Reaxys 173/553 Yield

Conditions & References With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Arthrobacter species R, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = > 99 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys With L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'phosphate, α-transaminase form Aspergillus terreus, ammonium formate, NADH in aq. phosphate buffer, Time= 24h, T= 30 °C , Resolution of racemate, Enzymatic reaction, Reagent/catalyst, Overall yield = > 99 percentChromat.; stereoselective reaction Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys NH 2 O

Rx-ID: 38250189 View in Reaxys 174/553 Yield

Conditions & References Reaction Steps: 2 1.1: tetrahydrofuran / 0.42 h / Inert atmosphere 1.2: 3 h / 20 °C / Inert atmosphere 2.1: hydrogen; 10% palladium on activated carbon; Degussa type / tert-butyl methyl ether / 20 °C / 760.05 Torr With 10% palladium on activated carbon; Degussa type, hydrogen in tetrahydrofuran, tert-butyl methyl ether Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

63/236

2018-08-17 23:02:17

NH 2 O O

Rx-ID: 38250190 View in Reaxys 175/553 Yield 95 %Chromat.

NH 2

O NH 2

Rx-ID: 38250199 View in Reaxys 176/553 Yield

NH 2

Rx-ID: 38250200 View in Reaxys 177/553 Yield

64/236

2018-08-17 23:02:17

NH 2

O O

Rx-ID: 38250208 View in Reaxys 178/553 Yield

NH 2

Rx-ID: 38250210 View in Reaxys 179/553 Yield

NH 2

Rx-ID: 38250215 View in Reaxys 180/553 Yield

Conditions & References Reaction Steps: 2

65/236

2018-08-17 23:02:17

1: dodecacarbonyltetrarhodium(0); hydrogen / toluene / 96 h / 40 °C / 7500.75 - 30003 Torr / Autoclave; Inert atmosphere 2: pyridoxal 5'-phosphate; α-transaminase form Pseudomonas pudita1; formate dehydrogenase from Candida boidinii; NADH; Lalanine dehydrogenase from Bacillus subtilis; ammonium formate; L-alanin / aq. phosphate buffer / 24 h / 30 °C / Resolution of racemate; Enzymatic reaction With dodecacarbonyltetrarhodium(0), L-alanin, formate dehydrogenase from Candida boidinii, L-alanine dehydrogenase from Bacillus subtilis, pyridoxal 5'-phosphate, α-transaminase form Pseudomonas pudita1, hydrogen, ammonium formate, NADH in aq. phosphate buffer, toluene Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

NH 2

Rx-ID: 38250216 View in Reaxys 181/553 Yield

Rx-ID: 38250217 View in Reaxys 182/553 Yield

66/236

2018-08-17 23:02:17

NH 2

Rx-ID: 38250219 View in Reaxys 183/553 Yield

Rx-ID: 38250226 View in Reaxys 184/553 Yield 60 mg

NH 2 O

O N

Rx-ID: 39772181 View in Reaxys 185/553 Yield

Conditions & References Reaction Steps: 2 1: cerium(III) chloride heptahydrate / tetrahydrofuran; diethyl ether / 0.17 h / -40 °C / Inert atmosphere 2: 10% palladium on activated carbon; Degussa type; hydrogen / ethyl acetate / 1.25 h / 2585.81 Torr / Inert atmosphere With cerium(III) chloride heptahydrate, 10% palladium on activated carbon; Degussa type, hydrogen in tetrahydrofuran, diethyl ether, ethyl acetate

67/236

2018-08-17 23:02:17

Patent; BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM; READY, Joseph M.; NIJHAWAN, Deepak; GONZALES, Stephen S.; THEODOROPOULOS, Pano; WO2015/35051; (2015); (A1) English View in Reaxys

NH 2 O

O N

Rx-ID: 39772183 View in Reaxys 186/553 Yield 48 %

Conditions & References Reduction of alkyl nitro Reduction of alkyl nitro 10percentPd/C (1.8 eq) was added to a solution of the alkyl nitro derivative (derived from aryl Grignard addition to the corresponding vinyl nitro compound in the presence of CeC13) (1 eq) in EtOAc (0.1 M). The reaction solution was N2 purged before adding H2 at 50 psi. The reaction mixture stirred for 1 h 15 min, then filtered through celite, and the filtrate was concentrated and dried to yield the desired product as a cream-colored solid in 48percent yield (42.5 mg) (GCMS m=165) and HNMR (sew- 192- 189-1) With 10% palladium on activated carbon; Degussa type, hydrogen in ethyl acetate, Time= 1.25h, p= 2585.81Torr , Inert atmosphere Patent; BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM; READY, Joseph M.; NIJHAWAN, Deepak; GONZALES, Stephen S.; THEODOROPOULOS, Pano; WO2015/35051; (2015); (A1) English View in Reaxys

NH 2

O N O

Rx-ID: 41958434 View in Reaxys 187/553 Yield

Conditions & References Reaction Steps: 2 1: D-glucose / water / 72 h / 20 °C / Microbiological reaction 2: nickel(II) chloride hexahydrate; sodium tetrahydroborate / water / 1 h With sodium tetrahydroborate, nickel(II) chloride hexahydrate, D-glucose in water Bertolotti, Mattia; Brenna, Elisabetta; Crotti, Michele; Gatti, Francesco G.; Monti, Daniela; Parmeggiani, Fabio; Santangelo, Sara; ChemCatChem; vol. 8; nb. 3; (2016); p. 577 - 583 View in Reaxys

NH 2

O N O

Rx-ID: 41958439 View in Reaxys 188/553 Yield 85 %

Conditions & References With sodium tetrahydroborate, nickel(II) chloride hexahydrate in water, Time= 1h Bertolotti, Mattia; Brenna, Elisabetta; Crotti, Michele; Gatti, Francesco G.; Monti, Daniela; Parmeggiani, Fabio; Santangelo, Sara; ChemCatChem; vol. 8; nb. 3; (2016); p. 577 - 583 View in Reaxys

68/236

2018-08-17 23:02:17

NH 2

O O O

Rx-ID: 41958472 View in Reaxys 189/553 Yield

Conditions & References Reaction Steps: 5 1: potassium tert-butylate / tetrahydrofuran 2: nitric acid / water 3: sodium hydroxide / water; dichloromethane 4: D-glucose / water / 72 h / 20 °C / Microbiological reaction 5: nickel(II) chloride hexahydrate; sodium tetrahydroborate / water / 1 h With sodium tetrahydroborate, nickel(II) chloride hexahydrate, D-glucose, potassium tert-butylate, nitric acid, sodium hydroxide in tetrahydrofuran, dichloromethane, water, 1: |Wittig Olefination Bertolotti, Mattia; Brenna, Elisabetta; Crotti, Michele; Gatti, Francesco G.; Monti, Daniela; Parmeggiani, Fabio; Santangelo, Sara; ChemCatChem; vol. 8; nb. 3; (2016); p. 577 - 583 View in Reaxys

NH 2

Rx-ID: 41958492 View in Reaxys 190/553 Yield

Conditions & References Reaction Steps: 4 1: nitric acid / water 2: sodium hydroxide / water; dichloromethane 3: D-glucose / water / 72 h / 20 °C / Microbiological reaction 4: nickel(II) chloride hexahydrate; sodium tetrahydroborate / water / 1 h With sodium tetrahydroborate, nickel(II) chloride hexahydrate, D-glucose, nitric acid, sodium hydroxide in dichloromethane, water Bertolotti, Mattia; Brenna, Elisabetta; Crotti, Michele; Gatti, Francesco G.; Monti, Daniela; Parmeggiani, Fabio; Santangelo, Sara; ChemCatChem; vol. 8; nb. 3; (2016); p. 577 - 583 View in Reaxys

O O

O NH 2

N O O

Rx-ID: 41958513 View in Reaxys 191/553 Yield

Conditions & References Reaction Steps: 3 1: sodium hydroxide / water; dichloromethane 2: D-glucose / water / 72 h / 20 °C / Microbiological reaction 3: nickel(II) chloride hexahydrate; sodium tetrahydroborate / water / 1 h With sodium tetrahydroborate, nickel(II) chloride hexahydrate, D-glucose, sodium hydroxide in dichloromethane, water

69/236

2018-08-17 23:02:17

Bertolotti, Mattia; Brenna, Elisabetta; Crotti, Michele; Gatti, Francesco G.; Monti, Daniela; Parmeggiani, Fabio; Santangelo, Sara; ChemCatChem; vol. 8; nb. 3; (2016); p. 577 - 583 View in Reaxys

NH 2

HO H 2N

Rx-ID: 394941 View in Reaxys 192/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

NH 2 O

OH H 2N

Rx-ID: 461625 View in Reaxys 193/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

NH 2

HO H 2N

Rx-ID: 461626 View in Reaxys 194/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys NH 2 O

H 2N

OH OH

Rx-ID: 461865 View in Reaxys 195/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

70/236

2018-08-17 23:02:17

NH 2 OH O

NH 2

Rx-ID: 464718 View in Reaxys 196/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys NH 2 O

H 2N O

Rx-ID: 464734 View in Reaxys 197/553 Yield

Conditions & References With hydrogenchloride, T= 160 °C Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

NH 2

HO H 2N

Rx-ID: 3378595 View in Reaxys 198/553 Yield

Conditions & References With hydrogen bromide, Time= 1h, Heating Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

NH 2

HO H 2N

Rx-ID: 3378596 View in Reaxys 199/553 Yield

71/236

2018-08-17 23:02:17

NH 2

O NH 2

Rx-ID: 5224710 View in Reaxys 200/553 Yield

Conditions & References With borane in tetrahydrofuran Ozaki, Yutaka; Quan, Zhe-Shan; Watabe, Kyouko; Kim, Sang-Won; Heterocycles; vol. 51; nb. 4; (1999); p. 727 - 731 View in Reaxys NH 2 O O

Rx-ID: 16323359 View in Reaxys 201/553 Yield

Conditions & References Reaction Steps: 2 1: 85 percent / NH3 / tetrahydrofuran 2: BH3 / tetrahydrofuran With borane, ammonia in tetrahydrofuran Ozaki, Yutaka; Quan, Zhe-Shan; Watabe, Kyouko; Kim, Sang-Won; Heterocycles; vol. 51; nb. 4; (1999); p. 727 - 731 View in Reaxys

NH 2

Rx-ID: 19395595 View in Reaxys 202/553 Yield

Conditions & References Reaction Steps: 6 1: 1.) LDA / 1.) THF, hexane, 25 deg C, 15 min, 2.) THF, hexane, overnight 2: SOCl2 / benzene / 3 h / Heating 3: pyridine / benzene / 0.25 h 4: 1 M BH3 / tetrahydrofuran / 72 h / 25 °C 5: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr 6: 48percent HBr / 1 h / Heating With pyridine, thionyl chloride, borane, hydrogen bromide, hydrogen, lithium diisopropyl amide, palladium dihydroxide in tetrahydrofuran, methanol, benzene Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

O HO

NH 2

O O HO

Rx-ID: 19404509 View in Reaxys 203/553

72/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 5 1: SOCl2 / benzene / 3 h / Heating 2: pyridine / benzene / 0.25 h 3: 1 M BH3 / tetrahydrofuran / 72 h / 25 °C 4: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr 5: 48percent HBr / 1 h / Heating With pyridine, thionyl chloride, borane, hydrogen bromide, hydrogen, palladium dihydroxide in tetrahydrofuran, methanol, benzene Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

H N

NH 2

S HO

Rx-ID: 19433194 View in Reaxys 204/553 Yield

Conditions & References Reaction Steps: 2 1: H2 / Pearlman's catalyst / methanol / 16 h / 2585.7 Torr 2: 48percent HBr / 1 h / Heating With hydrogen bromide, hydrogen, palladium dihydroxide in methanol Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

NH 2

O O

Rx-ID: 19433967 View in Reaxys 205/553 Yield

Conditions & References Reaction Steps: 4 1: pyridine / benzene / 0.25 h 2: 1 M BH3 / tetrahydrofuran / 72 h / 25 °C 3: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr 4: 48percent HBr / 1 h / Heating With pyridine, borane, hydrogen bromide, hydrogen, palladium dihydroxide in tetrahydrofuran, methanol, benzene Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

73/236

2018-08-17 23:02:17

H N

NH 2

Rx-ID: 19435193 View in Reaxys 206/553 Yield

Conditions & References Reaction Steps: 2 1: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr 2: 48percent HBr / 1 h / Heating With hydrogen bromide, hydrogen, palladium dihydroxide in methanol Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

H N

NH 2

Rx-ID: 19435576 View in Reaxys 207/553 Yield

Conditions & References Reaction Steps: 3 1: 1 M BH3 / tetrahydrofuran / 72 h / 25 °C 2: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr 3: 48percent HBr / 1 h / Heating With borane, hydrogen bromide, hydrogen, palladium dihydroxide in tetrahydrofuran, methanol Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys NH 2 O

HO H 2N

Rx-ID: 22054592 View in Reaxys 208/553 Yield

Conditions & References Reaction Steps: 2 1: alkaline aqueous sodium hypobromite 2: aqueous hydrochloric acid / 160 °C With hydrogenchloride, alkaline aqueous sodium hypobromite Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

74/236

2018-08-17 23:02:17

NH 2 NH 2

O O

OH OH

Rx-ID: 22055006 View in Reaxys 209/553 Yield

NH 2 O

HO H 2N

OH O

Rx-ID: 22055017 View in Reaxys 210/553 Yield

Conditions & References Reaction Steps: 2 1: sodium hypobromite 2: aqueous hydrochloric acid / 160 °C With hydrogenchloride, sodium hypobromide Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

HO H 2N

NH 2

HO O

Rx-ID: 22055018 View in Reaxys 211/553 Yield

NH 2

Rx-ID: 22055120 View in Reaxys 212/553

75/236

2018-08-17 23:02:17

Yield

HO H 2N

NH 2

HO O

Rx-ID: 22055127 View in Reaxys 213/553 Yield

NH 2

Rx-ID: 1061522 View in Reaxys 214/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 8029520 View in Reaxys 215/553 Yield

Conditions & References p-F-C6H4-CHMe-C(=NOH)Me in EtOH/EtNH2 (?), Hydrierung ueber Raney-Ni Patent; Science Union et Cie-Soc. Francaise de Recherches Medicales; BE609630; (1960); ; vol. 60; nb. 1647b; (1964) View in Reaxys F

F NH 2

Rx-ID: 22566955 View in Reaxys 216/553 Yield

Conditions & References Reaction Steps: 2

76/236

2018-08-17 23:02:17

1: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 2: HCONH2, HCO2H / 16 h / 170 - 180 °C With formic acid, formamide Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys O

NH 2

N O

Rx-ID: 22573973 View in Reaxys 217/553 Yield

Conditions & References Reaction Steps: 3 1: Fe, FeCl3, aq. HCl / 1 h / Heating 2: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 3: HCONH2, HCO2H / 16 h / 170 - 180 °C With hydrogenchloride, formic acid, iron(III) chloride, iron, formamide Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys F F

NH 2

Rx-ID: 22582593 View in Reaxys 218/553 Yield

Conditions & References Reaction Steps: 4 1: NH4OAc / acetic acid / 3 h / Heating 2: Fe, FeCl3, aq. HCl / 1 h / Heating 3: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 4: HCONH2, HCO2H / 16 h / 170 - 180 °C With hydrogenchloride, formic acid, ammonium acetate, iron(III) chloride, iron, formamide in acetic acid Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2 Cl Cl

Rx-ID: 317903 View in Reaxys 219/553 Yield

Conditions & References With ethanol, ammonia, T= 160 °C Patrick; McBee; Hass; Journal of the American Chemical Society; vol. 68; (1946); p. 1009 View in Reaxys

77/236

2018-08-17 23:02:17

NH 2

H 2N

Rx-ID: 713211 View in Reaxys 220/553 Yield

Conditions & References With aluminium trichloride Patent; Sharp and Dohme Inc.; US2441518; (1945) View in Reaxys

NH 2

Cl Cl

N H 2N

Rx-ID: 3193353 View in Reaxys 221/553 Yield

NH 2

(v2)

N H 2N

Rx-ID: 9782438 View in Reaxys 222/553 Yield

Conditions & References Stage 1: With 2-(diphenylphosphino)-L-Tle-L-Tyr(OBn)-NEt2, copper(II) bis(trifluoromethanesulfonate) in toluene, Time= 24h, T= 22 °C Stage 2: With hydrogen, 10 wt. % palladium on activated carbon in methanol, Time= 12h, T= 22 °C , p= 760Torr , Title compound not separated from byproducts Mampreian, Dawn M.; Hoveyda, Amir H.; Organic Letters; vol. 6; nb. 16; (2004); p. 2829 - 2832 View in Reaxys

NH 2 HO

S O

NH 2

Rx-ID: 10816695 View in Reaxys 223/553 Yield

Conditions & References B.ii :Borane in THF (124 ml, 1M solution) was added dropwise to the solution of 1-chloro-4-isopropenylbenzene from step (i) above (41.5 g, 0.272 mol) in THF (500 ml) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and hydroxylamine-O-sulphonic acid (30.76 g, 0.272 mol) was added portionwise. The reaction mixture was refluxed overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over anh. sodium sulphate and concentrated. The concentrated mass was dissolved in dry diethyl ether (20 ml) and stirred with saturated HCl in diethyl ether for 1/2 h. The solid salt was isolated by filtration, neutralized with sodium bicarbonate solution and free amine was extracted with diethyl ether. The diethyl ether layer was washed with brine, dried over anh.

78/236

2018-08-17 23:02:17

sodium sulphate and concentrated to give the title compound (18 g, 39percent) Stage 1: With borane-THF in tetrahydrofuran, Time= 3h, T= 0 - 20 °C Stage 2: in tetrahydrofuran, T= 0 °C , Heating / reflux, Product distribution / selectivity Patent; ASTRAZENECA AB; US2008/15237; (2008); (A1) English View in Reaxys

NH 2 Cl

HCl

H 2N

Rx-ID: 10816832 View in Reaxys 224/553 Yield

NH 2 Cl O

Rx-ID: 13299872 View in Reaxys 225/553 Yield

Conditions & References Reaction Steps: 2 1.1: 58 percent / aq. NaOH / methanol / 0.25 h / 0 °C 2.1: 2-(diphenylphosphino)-L-Tle-L-Tyr(OBn)-NEt2; Cu(OTf)2*PhH / toluene / 24 h / 22 °C 2.2: H2 / Pd/C / methanol / 12 h / 22 °C / 760 Torr With sodium hydroxide, 2-(diphenylphosphino)-L-Tle-L-Tyr(OBn)-NEt2, copper(II) bis(trifluoromethanesulfonate) in methanol, toluene Mampreian, Dawn M.; Hoveyda, Amir H.; Organic Letters; vol. 6; nb. 16; (2004); p. 2829 - 2832 View in Reaxys

NH 2

Cl O Cl

Rx-ID: 13299873 View in Reaxys 226/553 Yield

Conditions & References Reaction Steps: 2

79/236

2018-08-17 23:02:17

1.1: 58 percent / aq. NaOH / methanol / 0.25 h / 0 °C 2.1: 2-(diphenylphosphino)-L-Tle-L-Tyr(OBn)-NEt2; Cu(OTf)2*PhH / toluene / 24 h / 22 °C 2.2: H2 / Pd/C / methanol / 12 h / 22 °C / 760 Torr With sodium hydroxide, 2-(diphenylphosphino)-L-Tle-L-Tyr(OBn)-NEt2, copper(II) bis(trifluoromethanesulfonate) in methanol, toluene Mampreian, Dawn M.; Hoveyda, Amir H.; Organic Letters; vol. 6; nb. 16; (2004); p. 2829 - 2832 View in Reaxys NH 2

Rx-ID: 31698974 View in Reaxys 227/553 Yield 97 %

Conditions & References 651 :Example 651 2-(2-chlorophenyl)propan- 1 -amine To a solution of 2-(2-chlorophenyl) propanenitrile (14 g, 84.8 mmol) in tolune at 0 °C was added BFL/THF (127, 255 mmol) and the reaction was warmed to room temperature and heated at reflux for 4 h. The reaction mixture was cooled; queched with water, concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to obtain the desired product (13.9 g, 97percent) as a reddish oil: ESI MS m/z 170 [C9H12CIN + H]+. Stage 1: With borane-THF in toluene, Time= 4h, T= 0 °C , Reflux Stage 2: With water in toluene Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

NH 2

Rx-ID: 35684237 View in Reaxys 228/553 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 °C With lithium aluminium tetrahydride, sodium hydride in tetrahydrofuran, N,N-dimethyl-formamide, mineral oil Kang, Soosung; Cooper, Garry; Dunne, Sara Fernandez; Luan, Chi-Hao; Surmeier, D. James; Silverman, Richard B.; Journal of Medicinal Chemistry; vol. 56; nb. 11; (2013); p. 4786 - 4797 View in Reaxys Reaction Steps: 2 1: water; ethyl acetate; tetrahydrofuran 2: water; ethyl acetate; ethanol in tetrahydrofuran, ethanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

80/236

2018-08-17 23:02:17

NH 2

Rx-ID: 35684241 View in Reaxys 229/553 Yield 61 %

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 2h, T= 0 °C Kang, Soosung; Cooper, Garry; Dunne, Sara Fernandez; Luan, Chi-Hao; Surmeier, D. James; Silverman, Richard B.; Journal of Medicinal Chemistry; vol. 56; nb. 11; (2013); p. 4786 - 4797 View in Reaxys 16 : Preparation of 2-(3-chlorophenyl) propan-1-amine Example 16 Preparation of 2-(3-chlorophenyl) propan-1-amine AlCl3 (0.46 g) was added to the pre-cooled (5° C.) THF (15 mL) for 10 minutes and stirred for 40 minutes in a round bottom flask. THF (15 mL) and LiAlH4 (1.63 g) were charged into a separate round bottom flask under inert atmosphere and cooled to 0-5° C. AlCl3 mixture prepared above was added to the LiAlH4 mixture. 2-(3-chlorophenyl) propanenitrile (2.0 g) was added to the above mixture for 20 minutes at 2° C. and stirred at 25° C. till substantial completion of the reaction. The reaction mixture was cooled to 0-5° C. and water (1.2 mL) was added for 12 minutes. 20percent NaOH solution (8 mL) was added at 4° C. and stirred the reaction mass for 19 hours at 15-26° C. The reaction mass was filtered and washed with THF (15 mL). The filtrate was distilled under reduced pressure at 50° C. Ethyl acetate (20 mL) was charged and stirred the mixture for 15 minutes. Layers were separated. The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layer was dried over anhydrous sodium sulphate and distilled under reduced pressure at 50° C. to afford the title compound. Yield: 1.2 g in tetrahydrofuran, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys 18 : Preparation of 2-(3-chlorophenyl) propan-1-amine Example 18 Preparation of 2-(3-chlorophenyl) propan-1-amine 2-(3-chlorophenyl) propanenitrile (1.0 g) dissolved in methanol (10 mL) was passed through H2-Raney Nickel cartridge at 50° C. and 20 bar pressure. The reaction mass was collected in a separate reactor. The reaction mass was distilled under reduced pressure at 26° C. to afford the title compound. Yield: 0.8 g in methanol Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys 17 : Preparation of 2-(3-chlorophenyl) propan-1-amine Example 17 Preparation of 2-(3-chlorophenyl) propan-1-amine Raney nickel (0.25 g) and ethanol (5 mL) were charged into round bottom flask at 26° C. NaBH4 (0.5 g) was added slowly to the round bottom flask. 2-(3-chlorophenyl) propanenitrile (0.5 g) dissolved in ethanol (5 mL) was added to the above mixture for 10 minutes 26° C. The reaction mixture was maintained till substantial completion of the reaction. The reaction mass was filtered and washed with ethanol (5 mL).

81/236

2018-08-17 23:02:17

The filtrate was distilled under reduced pressure at 50° C. Water (5 ml) and ethyl acetate (5 mL) were charged to the distilled mass. The organic layer was separated and distilled under reduced pressure at 50° C. to afford the title compound. Yield: 0.25 g in ethanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

Cl Cl

NH 2

Rx-ID: 38003277 View in Reaxys 230/553 Yield

Conditions & References Reaction Steps: 3 1: ammonium chloride; sodium tetrahydroborate / methanol; water; ethyl acetate; tetrahydrofuran 3: sodium tetrahydroborate; ammonium formate / water; tetrahydrofuran With sodium tetrahydroborate, ammonium chloride, ammonium formate in tetrahydrofuran, methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Reaction Steps: 3 1: sodium hydroxide / water; ethyl acetate; ethanol 2: water; ethyl acetate; tetrahydrofuran; hexane 3: sodium tetrahydroborate; boron trifluoride diethyl etherate; hydrogenchloride; sodium hydrogencarbonate / ethyl acetate; tetrahydrofuran With hydrogenchloride, sodium hydroxide, sodium tetrahydroborate, boron trifluoride diethyl etherate, sodium hydrogencarbonate in tetrahydrofuran, ethanol, hexane, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Reaction Steps: 4 1: ammonium chloride; sodium tetrahydroborate / methanol; water; ethyl acetate; tetrahydrofuran 2: triethylamine / water 3: water 4: hydrazine hydrate / methanol; water; ethyl acetate With sodium tetrahydroborate, ammonium chloride, hydrazine hydrate, triethylamine in tetrahydrofuran, methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

82/236

2018-08-17 23:02:17

NH 2

Rx-ID: 38003281 View in Reaxys 231/553 Yield

Conditions & References Reaction Steps: 2 2: sodium tetrahydroborate; ammonium formate / water; tetrahydrofuran With sodium tetrahydroborate, ammonium formate in tetrahydrofuran, water Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Reaction Steps: 3 1: triethylamine / water 2: water 3: hydrazine hydrate / methanol; water; ethyl acetate With hydrazine hydrate, triethylamine in methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Cl

NH 2

O O

Rx-ID: 38003284 View in Reaxys 232/553 Yield

Conditions & References Reaction Steps: 2 1: water 2: hydrazine hydrate / methanol; water; ethyl acetate With hydrazine hydrate in methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

83/236

2018-08-17 23:02:17

O N

NH 2

Rx-ID: 38003287 View in Reaxys 233/553 Yield

Conditions & References 7 : Preparation of 2-(3-chlorophenyl) propan-1-amine Example 7 Preparation of 2-(3-chlorophenyl) propan-1-amine 2-(3-chlorophenyl)propylphthalimide (1.0 g), methanol (10 mL) and hydrazine hydrate (0.8 mL) were charged into the round bottom flask at 28° C. The contents were stirred and heated to reflux till substantial completion of the reaction. The reaction mass was cooled to 45° C. and distilled under reduced pressure at 45° C. Water (30 ml) and ethyl acetate (30 mL) were charged to the distilled mass at 25-30° C. and stirred. The organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layer was washed with water (20 mL). The solvent from the organic layer was distilled under reduced pressure at 45° C. to afford the title compound. Yield: 0.3 g. With hydrazine hydrate in methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

NH 2

Rx-ID: 38003288 View in Reaxys 234/553 Yield

Conditions & References 12 : Preparation of 2-(3-chlorophenyl) propan-1-amine Example 12 Preparation of 2-(3-chlorophenyl) propan-1-amine 2-(3-chlorophenyl) propanal (1.0 g) and ammonium formate (2.0 g) were charged into a round bottom flask and heated to 170° C. till substantial completion of the reaction. The reaction mass was cooled to 28° C. and THF (8 mL) was charged. NaBH4 (0.5 g) was slowly added to the reaction mass and stirred till substantial completion of the reaction. The reaction mass was cooled to 0° C. Water (2 mL) was charged at 0° C. and the aqueous layer was extracted with ethylacetate (2*25 mL) at 15° C. The combined organic layer was distilled under reduced pressure at 50° C. to afford the title compound. Yield: 0.3 g With sodium tetrahydroborate, ammonium formate in tetrahydrofuran, water Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

84/236

2018-08-17 23:02:17

NH 2

Rx-ID: 38003289 View in Reaxys 235/553 Yield

Conditions & References Reaction Steps: 2 1: water; ethyl acetate; tetrahydrofuran; hexane 2: sodium tetrahydroborate; boron trifluoride diethyl etherate; hydrogenchloride; sodium hydrogencarbonate / ethyl acetate; tetrahydrofuran With hydrogenchloride, sodium tetrahydroborate, boron trifluoride diethyl etherate, sodium hydrogencarbonate in tetrahydrofuran, hexane, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

O NH 2

NH 2

Rx-ID: 38003291 View in Reaxys 236/553 Yield

Conditions & References 13 : Preparation of 2-(3-chlorophenyl) propan-1-amine Example 13 Preparation of 2-(3-chlorophenyl) propan-1-amine 2-(3-chlorophenyl) propanamide (1.5 g) and THF (10 mL) were charged into a round bottom flask at 28° C. and stirred for 10 minutes. NaBH4 (1.0 g) was charged and heated to 73° C. BF3.Et2O (7 mL) dissolved in THF (7.0 mL) was added slowly to reaction mass for 2 hours and maintained the reaction till substantial completion of the reaction. The reaction mass was distilled under reduced pressure at 48° C. 5percent HCl solution (5 mL) was added to the distilled mass and stirred at 30° C. for 60 minutes. The contents were cooled to 20° C. and sodium bicarbonate solution (10 mL) was added. Stirred for 20 minutes and ethyl acetate (150 mL) was added. The aqueous and organic layers were separated. The aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layer was distilled under reduced pressure at 25° C. afford the title compound. Yield: 1.0 g With hydrogenchloride, sodium tetrahydroborate, boron trifluoride diethyl etherate, sodium hydrogencarbonate in tetrahydrofuran, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

NH 2

Rx-ID: 38003296 View in Reaxys 237/553 Yield

Conditions & References Reaction Steps: 5 1: sulfuric acid / methanol; water; ethyl acetate

85/236

2018-08-17 23:02:17

2: ammonium chloride / ethyl acetate; tetrahydrofuran 3: ammonium chloride; sodium tetrahydroborate / methanol; water; ethyl acetate; tetrahydrofuran 5: sodium tetrahydroborate; ammonium formate / water; tetrahydrofuran With sodium tetrahydroborate, sulfuric acid, ammonium chloride, ammonium formate in tetrahydrofuran, methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Reaction Steps: 5 1: sulfuric acid / methanol; water; ethyl acetate 2: ammonium chloride / ethyl acetate; tetrahydrofuran 3: sodium hydroxide / water; ethyl acetate; ethanol 4: water; ethyl acetate; tetrahydrofuran; hexane 5: sodium tetrahydroborate; boron trifluoride diethyl etherate; hydrogenchloride; sodium hydrogencarbonate / ethyl acetate; tetrahydrofuran With hydrogenchloride, sodium hydroxide, sodium tetrahydroborate, sulfuric acid, boron trifluoride diethyl etherate, ammonium chloride, sodium hydrogencarbonate in tetrahydrofuran, methanol, ethanol, hexane, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Reaction Steps: 6 1: sulfuric acid / methanol; water; ethyl acetate 2: ammonium chloride / ethyl acetate; tetrahydrofuran 3: ammonium chloride; sodium tetrahydroborate / methanol; water; ethyl acetate; tetrahydrofuran 4: triethylamine / water 5: water 6: hydrazine hydrate / methanol; water; ethyl acetate With sodium tetrahydroborate, sulfuric acid, ammonium chloride, hydrazine hydrate, triethylamine in tetrahydrofuran, methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

Cl Cl

NH 2

Rx-ID: 38003304 View in Reaxys 238/553 Yield

Conditions & References Reaction Steps: 4 1: ammonium chloride / ethyl acetate; tetrahydrofuran 2: ammonium chloride; sodium tetrahydroborate / methanol; water; ethyl acetate; tetrahydrofuran 4: sodium tetrahydroborate; ammonium formate / water; tetrahydrofuran With sodium tetrahydroborate, ammonium chloride, ammonium formate in tetrahydrofuran, methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Reaction Steps: 4 1: ammonium chloride / ethyl acetate; tetrahydrofuran 2: sodium hydroxide / water; ethyl acetate; ethanol

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

86/236

2018-08-17 23:02:17

3: water; ethyl acetate; tetrahydrofuran; hexane 4: sodium tetrahydroborate; boron trifluoride diethyl etherate; hydrogenchloride; sodium hydrogencarbonate / ethyl acetate; tetrahydrofuran With hydrogenchloride, sodium hydroxide, sodium tetrahydroborate, boron trifluoride diethyl etherate, ammonium chloride, sodium hydrogencarbonate in tetrahydrofuran, ethanol, hexane, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys Reaction Steps: 5 1: ammonium chloride / ethyl acetate; tetrahydrofuran 2: ammonium chloride; sodium tetrahydroborate / methanol; water; ethyl acetate; tetrahydrofuran 3: triethylamine / water 4: water 5: hydrazine hydrate / methanol; water; ethyl acetate With sodium tetrahydroborate, ammonium chloride, hydrazine hydrate, triethylamine in tetrahydrofuran, methanol, water, ethyl acetate Patent; DR. REDDY'S LABORATORIES LTD.; Boge, Rajesham; Tummala, Arjun Kumar; Peddy, Vishweshwar; Rangineni, Srinivasulu; Dahanukar, Vilas Hareshwar; Rakeshwar, Bandichhor; Srinivas, Areveli; Prabhakar, Macharla; Ganesh, Varanasi; US2014/187538; (2014); (A1) English View in Reaxys

N H

NH 2

Rx-ID: 39139799 View in Reaxys 239/553 Yield 78 %

Conditions & References 8 : Example 8: Deprotection of tert-butyl-(2-(3-chlorophenyl)propyl)carbamate (Ill-Boc) to 2-(3-chlorophenyl)propan-1amine (hId) Into a solution of tert-butyl-(2-(3-chlorophenyl)propyl)carbamate (hhl-Boc, 0.8 g, 3 mmol) in THF (6 mL) hydrochloric acid (10 mL, 6 M) was added and the reaction system was stirred for a few hours at 40-45°C. The solvent was evaporated, the organic residue was diluted with water, pH was adjusted to 9 using NaOH aqueous solution and then extracted with two portions of ethyl acetate (40 mL). The organic phase was dried over Na2SO4 and the solvent was evaporated to obtain an oily product (hId, 0.4 g, 78percent yield) which was confirmed with ‘H and ‘3C NMR analysis.‘H NMR (500 MHz, CDCI3, ppm) 8.25 (bs, NH2), 7.25-7.10 (m, 4ArH), 3.15 (m, 1H), 2.92 (m, 2H), 1.15 (d, J= 9 Hz, 3H);‘3C NMR (125 MHz, CDCI3, ppm) 147.4, 134.5, 130.0, 127.6, 126.9, 125.7, 49.4, 43.5, 19.4. With hydrogenchloride in tetrahydrofuran, water, T= 40 - 45 °C Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys

Cl N

NH 2

Rx-ID: 39147609 View in Reaxys 240/553 Yield

Conditions & References Reaction Steps: 3 1: bis-(dimethylamino)methane / 70 °C 2: saccharomyces cerevisiae baker’s yeast / Petroleum ether; water / 20 °C / Microbiological reaction 3: borane-THF / tetrahydrofuran; toluene / 4 h / 0 °C / Inert atmosphere; Reflux

87/236

2018-08-17 23:02:17

With borane-THF, bis-(dimethylamino)methane in tetrahydrofuran, water, toluene, Petroleum ether Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; GAZIC SMILOVIC, Ivana; CLUZEAU, Jerome; RICHTER, Frank; WO2014/202765; (2014); (A1) English View in Reaxys

Cl N

NH 2

Rx-ID: 39147612 View in Reaxys 241/553 Yield 80 %

Conditions & References 21 : Synthesis of (R)-2-(3-chlorophenyl)propan-1 -amine from (R)-2-(3-ch I oroph enyl )propa nen itri le Optical active starting material (R)-2-(3-chlorophenyl)propanenitrile (R)-ll-CN (1 .3 mmol; 0.22 g) was dissolved in toluene (5 mL) under nitrogen atmosphere and cooled down to 0 00 BH3-THF (4.3 mmol; 4.3 mL; 1M in THF) was slowly added to the solution and such reaction mixture was stirred under reflux for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (5 mL), dried over Mg504, filtered and the solvent was removed under reduced pressure. Colorless oily product was obtained (0.18 g; 80 percent yield; > 99 percent ee) and characterized with 1H and 130 NMR.1H NMR (500 MHz, CDCI3, ppm) 6 7.22 (m, 3H), 7.08 (d, 1H), 2.83 (m, 2H), 2.72 (m,1H), 1.23 (d, 3H), 1.08 (bs, NH);130 NMR (125 MHz, CDCI3, ppm) 6 145.5, 133.3, 130.5, 127.3, 126.9, 126.2, 44.6,37.3, 19.3. With borane-THF in tetrahydrofuran, toluene, Time= 4h, T= 0 °C , Inert atmosphere, Reflux Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; GAZIC SMILOVIC, Ivana; CLUZEAU, Jerome; RICHTER, Frank; WO2014/202765; (2014); (A1) English View in Reaxys

NH 2

Rx-ID: 39265209 View in Reaxys 242/553 Yield 81 mg

Conditions & References 5 : Example 5: Racemisation of optically active (S)-2-(3-chlorophenyl)propan-1 -amine using potassium ie f-butoxide Starting material (S)-2-(3-chlorophenyl)propan-1 -amine {(S)-5, 0.5 mmol; 85 mg; > 95percent optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 0.625 mmol) was added in three portions in 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted with nhexane (60 mL) for few times. The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (81 mg) was analysed with chiral HPLC where 0 percent e.e. (full racemisation) was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 169; CI) and 1H NMR. With potassium tert-butylate in dimethyl sulfoxide, T= 100 °C Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; CLUZEAU, Jerome; WO2015/7897; (2015); (A1) English View in Reaxys

Cl Cl

NH 2

Rx-ID: 44455423 View in Reaxys 243/553

88/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 4 1.1: n-butyllithium / diethyl ether / 1 h / Inert atmosphere 1.2: 24 h / 20 °C / Inert atmosphere 2.1: acetic acid; sodium nitrite; ammonium cerium (IV) nitrate / chloroform / Sealed tube; Sonication 3.1: di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate; 3-{(E)-[((1R,2R)-2-{[({(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethyl-propyl}amino)carbonothioyl]amino}cyclohexyl)imino]methyl}-5-(1,1-dimethylethyl)-4-hydroxyphenyl 2,2-dimethylpropanoate / toluene / 72 h / 40 °C 4.1: acetic acid; zinc / tetrahydrofuran; methanol / 0 - 20 °C With n-butyllithium, ammonium cerium (IV) nitrate, di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate, acetic acid, zinc, sodium nitrite, 3-{(E)-[((1R,2R)-2-{[({(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethyl-propyl}amino)carbonothioyl]amino}cyclohexyl)imino]methyl}-5-(1,1-dimethylethyl)-4-hydroxyphenyl 2,2-dimethylpropanoate in tetrahydrofuran, methanol, diethyl ether, chloroform, toluene Gini, Andrea; Bamberger, Julia; Luis-Barrera, Javier; Zurro, Mercedes; Mas-Ballesté, Rubén; Alemán, José; Mancheño, Olga García; Advanced Synthesis and Catalysis; vol. 358; nb. 24; (2016); p. 4049 - 4056 View in Reaxys

Cl Cl

NH 2

Rx-ID: 44455427 View in Reaxys 244/553 Yield

Conditions & References Reaction Steps: 3 1: acetic acid; sodium nitrite; ammonium cerium (IV) nitrate / chloroform / Sealed tube; Sonication 2: di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate; 3-{(E)-[((1R,2R)-2-{[({(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethyl-propyl}amino)carbonothioyl]amino}cyclohexyl)imino]methyl}-5-(1,1-dimethylethyl)-4-hydroxyphenyl 2,2-dimethylpropanoate / toluene / 72 h / 40 °C 3: acetic acid; zinc / tetrahydrofuran; methanol / 0 - 20 °C With ammonium cerium (IV) nitrate, di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate, acetic acid, zinc, sodium nitrite, 3-{(E)-[((1R,2R)-2-{[({(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethyl-propyl}amino)carbonothioyl]amino}cyclohexyl)imino]methyl}-5-(1,1-dimethylethyl)-4-hydroxyphenyl 2,2-dimethylpropanoate in tetrahydrofuran, methanol, chloroform, toluene Gini, Andrea; Bamberger, Julia; Luis-Barrera, Javier; Zurro, Mercedes; Mas-Ballesté, Rubén; Alemán, José; Mancheño, Olga García; Advanced Synthesis and Catalysis; vol. 358; nb. 24; (2016); p. 4049 - 4056 View in Reaxys O N O Cl

NH 2

Rx-ID: 44455431 View in Reaxys 245/553 Yield

Conditions & References Reaction Steps: 2 1: di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate; 3-{(E)-[((1R,2R)-2-{[({(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethyl-propyl}amino)carbonothioyl]amino}cyclohexyl)imino]methyl}-5-(1,1-dimethylethyl)-4-hydroxyphenyl 2,2-dimethylpropanoate / toluene / 72 h / 40 °C 2: acetic acid; zinc / tetrahydrofuran; methanol / 0 - 20 °C With di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate, acetic acid, zinc, 3-{(E)-[((1R,2R)-2-{[({(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethyl-propyl}amino)carbonothioyl]amino}cyclohexyl)imino]methyl}-5-(1,1-dimethylethyl)-4-hydroxyphenyl 2,2-dimethylpropanoate in tetrahydrofuran, methanol, toluene

89/236

2018-08-17 23:02:17

Gini, Andrea; Bamberger, Julia; Luis-Barrera, Javier; Zurro, Mercedes; Mas-Ballesté, Rubén; Alemán, José; Mancheño, Olga García; Advanced Synthesis and Catalysis; vol. 358; nb. 24; (2016); p. 4049 - 4056 View in Reaxys

O N O Cl

NH 2

Rx-ID: 44455435 View in Reaxys 246/553 Yield

Conditions & References With acetic acid, zinc in tetrahydrofuran, methanol, T= 0 - 20 °C Gini, Andrea; Bamberger, Julia; Luis-Barrera, Javier; Zurro, Mercedes; Mas-Ballesté, Rubén; Alemán, José; Mancheño, Olga García; Advanced Synthesis and Catalysis; vol. 358; nb. 24; (2016); p. 4049 - 4056 View in Reaxys

HCl Cl

NH 2

Rx-ID: 47902778 View in Reaxys 247/553 Yield

Conditions & References

91%

3.4 : 3.4 31 (R)-2-(3-Chlorophenyl)propan-1-amine (3) A solution of 1M 28 NaOH (5mL) was added to a solution of the hydrochloride 3-HCl (1.0g, 4.9mmol) in 27 H2O (30mL) and the mixture was extracted with EtOAc (1×50mL, 2×25mL). The combined extracts were dried over MgSO4, and the solvent was removed under reduced pressure to yield 0.75g (91percent) of a colourless liquid. 1H NMR (300MHz, DMSO-d6) α 1.16 (d, 3H), 1.9 (br s, 2H), 2.66 (m, 3H), 7.16–7.34 (m, 4H). 13C NMR (75MHz, DMSO-d6) α 18.7, 42.6, 49.0, 125.8, 125.9, 127.1, 130.0, 132.9, 148.5. IR (neat) α 2959, 2926, 1595, 1570, 1476, 1429, 1081, 780, 696cm–1. With sodium hydroxide in water Smilovic, Ivana Gazic; Cluzeau, Jerome; Richter, Frank; Nerdinger, Sven; Schreiner, Erwin; Laus, Gerhard; Schottenberger, Herwig; Bioorganic and Medicinal Chemistry; vol. 26; nb. 9; (2018); p. 2686 - 2690 View in Reaxys

Cl Cl

Mg NH 2

Rx-ID: 47902800 View in Reaxys 248/553 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether 2: hydrogenchloride / tetrahydrofuran; water / 3 h / 45 °C With hydrogenchloride in tetrahydrofuran, diethyl ether, water Smilovic, Ivana Gazic; Cluzeau, Jerome; Richter, Frank; Nerdinger, Sven; Schreiner, Erwin; Laus, Gerhard; Schottenberger, Herwig; Bioorganic and Medicinal Chemistry; vol. 26; nb. 9; (2018); p. 2686 - 2690 View in Reaxys

90/236

2018-08-17 23:02:17

N H

NH 2

Rx-ID: 47902812 View in Reaxys 249/553 Yield

Conditions & References 3.3 : 3.3 24 (R)-2-(3-Chlorophenyl)propan-1-amine hydrochloride (3-HCl) Hydrochloric acid (32mL, 6M) was added to a solution of the Boc derivative 6 2 (9.8mmol) in 26 THF (20mL). The emulsion was stirred at 45°C for 3h to give a clear solution. The solvent was evaporated, the residue dissolved in 27 H2O (65mL) made alkaline with 28 NaOH (1M). The mixture was extracted with EtOAc (1×60mL, 2×30mL). The combined extracts were dried over MgSO4, and the solvent was removed under reduced pressure to yield 1.60g of the crude base. Hydrogen chloride in 29 Et2O (12mL, 1M) was added dropwise to a solution of the base in Et2O (20mL). The precipitated hydrochloride was filtered, washed with Et2O (3×5mL) and dried in vacuum: 1.63g (81percent). With hydrogenchloride in tetrahydrofuran, water, Time= 3h, T= 45 °C Smilovic, Ivana Gazic; Cluzeau, Jerome; Richter, Frank; Nerdinger, Sven; Schreiner, Erwin; Laus, Gerhard; Schottenberger, Herwig; Bioorganic and Medicinal Chemistry; vol. 26; nb. 9; (2018); p. 2686 - 2690 View in Reaxys

H NH 2 Cl

Rx-ID: 9823283 View in Reaxys 250/553 Yield

Conditions & References With hydrogenchloride in ethanol, Time= 2h, Heating Kitamura, Mitsuru; Suga, Takahiro; Chiba, Shunsuke; Narasaka, Koichi; Organic Letters; vol. 6; nb. 24; (2004); p. 4619 4621 View in Reaxys

H NH 2 Cl Br

Rx-ID: 13255705 View in Reaxys 251/553 Yield

Conditions & References Reaction Steps: 2 1: CH2Cl2; diethyl ether / 0.5 h / 0 °C 2: aq. HCl / ethanol / 2 h / Heating With hydrogenchloride in diethyl ether, ethanol, dichloromethane Kitamura, Mitsuru; Suga, Takahiro; Chiba, Shunsuke; Narasaka, Koichi; Organic Letters; vol. 6; nb. 24; (2004); p. 4619 4621 View in Reaxys

91/236

2018-08-17 23:02:17

NH 2 Cl

Rx-ID: 22893573 View in Reaxys 252/553 Yield 76.2 %

Conditions & References 1 : EXAMPLE 1; Preparation of {(2R)-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine; Preparation of 2-Phenyl-1-propylamine HCl EXAMPLE 1 [0048] Preparation of {(2R)-2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine. [CHEMMOL-00010] [0049] Preparation of 2-Phenyl-1-propylamine HCl. [CHEMMOL-00011] [0050] Scheme I, step A: To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5percent palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5percent starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to -400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitate solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2percent) as a white powder. [0051] 1H NMR analysis of the free base: 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). [0052] Preparation of (2R)-2-phenylpropylamine Malate. [CHEMMOL-00012] [0053] Scheme I, step B: To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The mixture was stirred for 1.6 hours, and the resulting milky white NaCl salts were filtered. An aliquot of the filtrate was analyzed by gas chromatography to provide the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles). A solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was added dropwise to the yellow filtrate and the solution was heated to 75° C. The solution was stirred at 75° C. for 30 minutes. The heat was removed and the solution was allowed to cool slowly. The resulting thick precipitate was allowed to stir overnight. The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5percent) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine) [0054] 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). [0055] A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2percent e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (-79.2° C.) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5° C.) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35° C. to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2percent recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, revealed 96.7percent e.e. enriched in the R-isomer. [0056] 1H NMR (CD3OD, 300 MHz) α 7.32 (m, 10H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1H, J=9.3, 15.3), 2.38 (dd, 1H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). [0057] Preparation of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]Amine. [CHEMMOL-00013] [0058] Scheme I, steps C and D: To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol) in CH2Cl2 (1000 mL) was added 1.0 N NaOH (1050 mL, 1.05 moles). The mixture was stirred at room temperature for 1 hour and the organic phase was separated and gravity filtered into a 3.0 L round-bottom flask with a CH2Cl2 rinse (200 mL). The resulting free base, (2R)-2-phenylpropylamine, was dried via azeotropic distillation. Accordingly, the clear filtrate was concentrated to 600 mL at atmospheric pressure via distillation through a simple distillation head. Heptane (1000 mL) was added and the solution was concentrated again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation. The final pot temperature was 109° C. [0059] The solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine. To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 mol), triethylamine (200 g, 1.98 moles), and CH2Cl2 (500 mL). The mixture was stirred at room temperature until a clear solution was obtained. This solution was cooled to 5° C. and a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH2Cl2 (250 mL) was added dropwise with stirring over 2 hrs. The mixture was allowed to warm gradually to room temperature over 16 h. GC analysis indicated complete consumption of the (2R)-2-phenylpropylamine starting material. [0060] The stirred mixture was cooled to 8° C. and 2 N HCl (500 mL) was added dropwise. The organic phase was separated and extracted with water (1.x.500 mL) and saturated NaHCO3 (1.x.500 mL). The organic phase was isolated, dried (Na2SO4), and gravity filtered. The filtrate was concentrated under reduced pressure to provide ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (230 g, 96percent) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) α 7.34 (m, 2H), 7.23 (m, 3H), 3.89 (br t, 1H, J=5.4), 3.36 (m, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.98 (m, 1H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9). [0061] Preparation of [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine. [CHEMMOL-00014] [0062] Scheme I, step E: A stirred room temperature solution of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (37.1 g, 0.154 mol) in glacial acetic acid (185 mL) was treated with concentrated H2SO4 (16.0 g, 0.163 mol), added dropwise in a slow stream, followed by a H2O rinse (37 mL). To this solution (30° C.) was added H5IO6 (8.29 g, 0.0369 mol), followed by iodine (17.9 g, 0.0707 mol). The resulting reaction mixture was heated and allowed to stir for 3 h at 60° C. After HPLC analysis verified the consump-

92/236

2018-08-17 23:02:17

tion of starting material, the reaction mixture was cooled to 30° C. and a 10percent aqueous solution of NaHSO3 (220 mL) was added dropwise while maintaining the temperature between 25° C. and 30° C. The mixture crystallized to a solid mass upon cooling to 0-5° C. [0063] The solids were suction filtered and rinsed with H2O to afford 61.7 g of crude solids that were redissolved into warm MTBE (500 mL). This solution was extracted with H2O (2.x.200 mL) and saturated NaHCO3 (1.x.200 mL) and the organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to -200 mL. Heptane (100 mL) was added dropwise to the product solution with slow stirring until crystallization commenced. An additional 100 mL of heptane was added and the resulting suspension was allowed to stir slowly overnight at room temperature. The mixture was then cooled (0° C.), filtered, and the collected solids were rinsed with heptane. The solids were then air-dried to afford the intermediate title compound, [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (33.7 g, 59.8percent) as a white powder. Chiral Chromatography of this lot indicated 100percent e.e. [0064] 1H NMR (CDCl3, 300 MHz) α 7.66 (d, 2H, J=8.1), 6.98 (d, 2H, J=8.4), 3.86 (br t, 1H, J=5.1), 3.33 (m, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.92 (m, 1H), 1.30 (d, 3H, J=6.6), 1.27 (d, 6H, J=6.6). [0065] Preparation of (methylsulfonyl)(2-phenylethyl)amine. [CHEMMOL-00015] [0066] Scheme II, step A: To a 10° C. solution of phenethylamine (12.1 g, 0.100 mol) and triethylamine (11.1 g, 0.110 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at room temperature for 1.5 h and was then washed with 1 N HCl (5.x.20 mL). The organic phase was directly concentrated to provide the intermediate title compound, (methylsulfonyl)(2phenylethyl)amine, (21.2 g, 93.3percent) as an oil. [0067] 1H NMR (CDCl3, 300 MHz) 67.32 (m, 2H), 7.23 (m, 3H), 4.30 (br s, 1H), 3.40 (t, 2H, J=3.9), 2.88 (t, 2H, J=4.2), 2.81 (s, 3H). [0068] Preparation of [2-(4-iodophenyl)ethyl](methylsulfonyl)amine. [CHEMMOL-00016] [0069] Scheme II, step B: To a stirring room temperature solution of (methylsulfonyl)(2-phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95percent sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and periodic acid (H5IO6, 45.6 g, 0.206 mol). The reaction mixture was warmed to 70-75° C. for 3 h. The heat was removed and the dark violet reaction mixture was allowed to proceed overnight at room temperature. Potassium hydroxide pellets (85percent, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension. The suspension was cooled to 15° C. and filtered. The filter cake was triturated thoroughly with water and was then dissolved in CH2Cl2 (1 L) and extracted with additional water (2.x.200 mL). The organic phase was concentrated under reduced pressure to provide the intermediate title compound, [2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2percent) as a white powder. [0070] 1H NMR (CDCl3, 300 MHz) α 7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1), 4.37 (br t, 1H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t, 2H, J=3.9). [0071] Preparation of (tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide. [CHEMMOL-00017] [0072] Scheme II, step C: A room temperature solution of [2-(4-iodophenyl)ethyl](methylsulfonyl)amine (201 g, 0.618 mol), 4-dimethylaminopyridine (3.8 g, 0.031 mol) and di-tert-butyl dicarbonate (162 g, 0.744 mol) in CH2Cl2 (1 L) was allowed to stir overnight. The reaction mixture was washed with water (2.x.400 mL) and the organic phase was concentrated to about 600 mL and hexanes (400 mL) was added. This combined solution was washed again with water (400 mL) and was concentrated to a solid that was suspended in hexanes (600 mL) and filtered. The collected solids were dried under reduced pressure to afford the intermediate title compound, (tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (241.5 g, 91.5percent) as a white solid. [0073] 1H NMR (CDCl3, 300 MHz) α 7.63 (d, 2H, J=7.8), 6.98 (d, 2H, J=7.8), 3.88 (t, 2H, J=6.9), 3.10 (s, 3H), 2.88 (t, 2H, J=6.9), 1.51 (s, 9H). [0074] Preparation of (tert-butoxy-N-(methylsulfonyl)-N-[2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl)phenyl]ethyl]carboxamide. [CHEMMOL-00018] [0075] Scheme II, step D: To a degassed solution of (tert-butoxy)-N-[2-(4iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (128 g, 0.300 mol), triethylamine (91.1 g, 0.900 mol), and 1,1'-bis(diphenylphosphino) ferrocenedichloropalladium (II)-CH2Cl2 complex (2.9 g, 0.0035 mol) in acetonitrile (600 mL) was added pinacolborane (50 g, 0.391 mol) dropwise. The mixture was stirred at 70-74° C. for 8 h and then was cooled to room temperature. The reaction mixture was concentrated to a fluid oil that was partitioned between MTBE (500 mL) and water (500 mL). The organic phase was separated and washed with water (2.x.200 mL) and concentrated to a residue that was partially dissolved with heptane (1 L). The heptane soluble fraction was filtered through Celite.(R). 521 and concentrated to an oil (95 g). The residue was dissolved in acetone (600 mL) and heptane (600 mL) and filtered through Celite.(R). 521. The combined filtrates were concentrated to 95 g of a mixture of a 3:1 molar ratio (1H NMR, 81.0percent by weight) of intermediate title compound, (tert-butoxy)-N(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide, (60.3percent potency corrected yield) and protio derivative. [0076] 1H NMR (CDCl3, 300 MHz) α 7.75 (d, 2H, J=7.8), 7.23 (d, 2H, J=8.1), 3.87 (t, 2H, J-8.1), 2.99 (s, 3H), 2.90 (t, 2H, J=7.5), 1.53 (s, 9H), 1.33 (s, 6H), 1.27 (s, 6H). [0077] Preparation of (Methylsulfonyl) {2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine. [CHEMMOL-00019] [0078] Scheme II, step E: To a 2 L flask charged with a stirring solution of (tert-butoxy)-N-(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl))phenyl]ethyl}carboxamide (98.7 g, 0.232 mol) in CH2Cl2 (500 mL) was added trifluoroacetic acid (82 mL, 121.4 g, 1.06 moles) dropwise from an addition funnel. No exotherm was observed and the reaction solution was allowed to stir at room temperature for 18 h. [0079] HPLC analysis indicated 98percent completion so the cooled (5° C.) reaction mixture was neutralized by the slow addition of 5N NaOH (175 mL). The pH of the aqueous phase was 10.5. The phases were separated and the aqueous phase was extracted with CH2Cl2 (50 mL). The combined CH2Cl2 phases were washed with brine (2.x.100 mL) and water (1.x.100 mL). The CH2Cl2 phase was diluted with heptane (300 mL) and was concentrated under reduced pressure to afford a suspension that was isolated by filtration. The collected solids were washed with pentane (2.x.100 mL) and dried under vacuum to provide the intermediate title compound, (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine, (69.0 g, 91.4percent) as a white powder. [0080] 1H NMR (CDCl3, 300 MHz) α 7.77 (d, 2H, J=8.1), 7.22 (d, 2H, J=7.8), 4.26 (br t, 1H, J-6), 3.40 (q, 2H, J=6.9), 2.89 (t, 2H, J=6.6), 2.82 (s, 3H), 1.34 (s, 12H). [0081] Preparation of 4-[2-[(methylsulfonyl)amino]ethyl]benzene Boronic Acid. [CHEMMOL-00020] [0082] Scheme II, step F: (Methylsulfonyl){2-[4-(4,4,5,5-tetra-

93/236

2018-08-17 23:02:17

methyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine (68.0 g, 0.209 mol) was placed into a 2L flask and combined with acetone (600 mL), 1N ammonium acetate (600 mL), and NaIO4 (168.1 g, 0.786 mol). This mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove insoluble matter to afford filtrate A. The collected solids were washed with acetone (2.x.100 mL) and this filtrate was combined with filtrate A. The combined filtrates were concentrated under reduced pressure to 600 mL to afford a precipitate that was recovered by filtration. The collected solids were air-dried to give 110 g of crude material. This crude material was suspended in water (100 mL) and 5N NaOH was added until the pH was 12.5. The resulting suspension was filtered and the filtrate was treated with decolorizing carbon (Darco 6-60). The mixture was filtered and the filtrate was diluted with 10N H2SO4 until the pH was 5.0 to precipitate the intermediate title compound. This precipitate was collected by filtration and dried under reduced pressure to provide the intermediate title compound, 4-{(2-[(methylsulfonyl)amino]ethyl}benzene boronic acid, (41.9 g, 82.5percent) as a white powder. [0083] 1H NMR (acetone-d6, 300 MHz) α 7.82 (d, 2H, J=8.4), 7.27 (d, 2H, J=7.8), 7.11 (s, 2H), 6.03 (m, 1H), 3.36 (m, 2H), 2.91 (m, 2H), 2.84 (s, 3H). [0084] Preparation of Final Title Compound. [0085] Scheme III: An aqueous solution of potassium formate was prepared in the following manner. To 15 mL of water was added KOH (85percent flakes, 6.73 g, 0.102 mol), then 98percent formic acid (4.70 g, 0.102 mol). Alternatively, one may use commercially available potassium formate. To this solution was then added K2CO3 (2.76 g, 0.0210 mol), 4-{2[(methylsulfonyl)amino]ethyl}benzene boronic acid (4.62 g, 0.190 mol), 1-propanol (100 mL), and [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (7.35 g, 0.200 With hydrogenchloride, ethanol, hydrogen, water-wet 5% palladium on carbon in water, Time= 3h, T= 50 - 64 °C , p= 3878.71 4033.86Torr , Under nitrogen Patent; Arnold, Macklin Brian; Bleisch, Thomas John; Cuff, George William; Ornstein, Paul Leslie; Zimmerman, Dennis Michael; US2003/225163; (2003); (A1) English View in Reaxys

H NH 2 Cl

Rx-ID: 22986085 View in Reaxys 253/553 Yield 76.2 %

Conditions & References 4 :Charge to an autoclave hydrogenation apparatus under nitrogen water- wet 5percent palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613g, 5.6 mole). Stir the mixture rapidly and pressurize to 75 to 78 psi with hydrogen. Heat the mixture 50 0C to 64°C for 3 hours. Depressurize and filter the reaction mixture to afford two lots of filtrate. Concentrate filtrates under reduced pressure to approximately 400 mL each. Add methyl tert-butyl ether (MTBE) (2.2 L each) to each lot. Stir the precipitate overnight. Filter and wash solids with fresh MTBE (100 mL) and dry overnight. Combine the lots to afford 2- phenyl-1 -propylamine HCl (634.4 g, 76.2percent) as a white powder. IH NMR analysis of the free base: IH NMR (CDC13, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, IH), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). With hydrogenchloride, hydrogen, Johnson & Matthey type 440 in ethanol, water, Time= 3h, T= 50 - 64 °C , p= 3878.71 4033.86Torr Patent; ELI LILLY AND COMPANY; WO2008/73789; (2008); (A1) English View in Reaxys

76.2 %

2 :To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5percent palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5percent starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to ~400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitated solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2percent) as a white powder. 1H NMR analysis of the free base: 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). With hydrogenchloride, hydrogen, Johnson & Matthey type 440 in ethanol, water, Time= 3h, T= 50 - 64 °C , p= 3878.71 4033.86Torr

94/236

2018-08-17 23:02:17

Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys 76.2 %

1 : Preparation 1; Preparation of [(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine.; Preparation of 2-Phenyl-1-propylamine HCl. Preparation of 2-Phenyl-1-propylamine HCl. To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5percent palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole).The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen.The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5percent starting material.The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to ~400 ML each.To each lot was added methyl tertbutyl ether (MTBE) (2.2 L each) and the precipitated solids were allowed to stir overnight.Each lot was filtered and the collected solids were each washed with fresh MTBE (100 ML) and dried overnight.The lots were combined to afford the intermediate title compound, 2-phenyl-1-propylamine HCl, (634.4 g, 76.2percent) as a white powder. 1H NMR analysis of the free base: 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). With hydrogenchloride, hydrogen, 5% palladium-on-charcoal in ethanol, water, Time= 3h, T= 50 - 64 °C , p= 3878.71 4033.86Torr Patent; Bender, David Michael; Forman, Scott Louis; Jones, Winton Dennis; Smith, Daryl Lynn; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/225127; (2003); (A1) English View in Reaxys 38.1 :Step 1 : 2-Phenylpropan-l-amine hydrochloride; To a stirred suspension of lithium aluminum hydride (2.94 g, 77.4 mmol) in dry ether (100 mL) at RT was added, under nitrogen, alpha-methylbenzyl cyanide (6.4 mL, 48.4 mmol) in dry ether (50 mL) over a 30 min period. Then it was heated under reflux for 3 h, cooled to 0 °C and treated sequentially with water (2.3 mL), NaOH (5N, 2.3 mL) and water (6.9 mL). The mixture was then stirred at RT for 1.5 h, filtered and the filtrate dried over Na2SO4 the solids were removed by filtration. The solution was treated with IN HCl in ether (40 mL) and the white precipitated was separated by filtration to provide the title compound as a white solid. Stage 1: With lithium aluminium tetrahydride in diethyl ether, Time= 3.5h, T= 20 °C , Heating / reflux Stage 2: With sodium hydroxide, water in diethyl ether, Time= 1.5h, T= 0 - 20 °C Stage 3: With hydrogenchloride in diethyl ether Patent; AMGEN INC.; WO2009/73203; (2009); (A1) English View in Reaxys

H NH 2 Cl

N O

Rx-ID: 23994373 View in Reaxys 254/553 Yield 76.2%

Conditions & References 1.a : Preparation of 2-Phenyl-1-propylamine HCl. Preparation of 2-Phenyl-1-propylamine HCl. To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5percent palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5percent starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to ~400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitate solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2percent) as a white powder. 1H NMR analysis of the free base: 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).

95/236

2018-08-17 23:02:17

With hydrogenchloride, palladium in ethanol Patent; Skolnick, Phil; US2003/92770; (2003); (A1) English View in Reaxys 76.2%

1 : Preparation of 2-Phenyl-1-propylamine HCl. Preparation of 2-Phenyl-1-propylamine HCl. Scheme I, step A: To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5percent palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 89.7-92.7 psi (618.46-639.15 kPa) with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5percent starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to ~400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitate solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2percent) as a white powder. 1H NMR analysis of the free base: 1H NMR (CDCl , 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 3 (d, 3H, J=6.9), 1.02 (br s, 2H). With hydrogenchloride, palladium in ethanol Patent; Gardner, John Paul; Miller, William David; US2003/92947; (2003); (A1) English View in Reaxys

NH 2

Rx-ID: 7732879 View in Reaxys 255/553 Yield

Conditions & References Aus d. Amid, LiAlH4 Patent; Boots; Pure Drug; NL295860; (1965); ; vol. 63; nb. 14773g; (1965) View in Reaxys

NH 2

Rx-ID: 8029462 View in Reaxys 256/553 Yield

Conditions & References Propylenimin, Mesitylen, AlCl3; Ausb.57percent Milstein; Journal of Heterocyclic Chemistry; vol. 5; (1968); p. 339 View in Reaxys

NH 2

H 2N

2-mesitylene

Rx-ID: 8029463 View in Reaxys 257/553

96/236

2018-08-17 23:02:17

Yield

Conditions & References With aluminium trichloride Patent; Sharp and Dohme Inc.; US2441518; (1945) View in Reaxys

NH 2

O O O

Rx-ID: 1061985 View in Reaxys 258/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 1104345 View in Reaxys 259/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys NH 2 O

Rx-ID: 1112766 View in Reaxys 260/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

N N

Rx-ID: 3571985 View in Reaxys 261/553 Yield 71 %

Conditions & References With hydrogen, nickel in methanol, Time= 12h, p= 760Torr , Ambient temperature Habernegg, Renate; Severin, Theodor; Chemische Berichte; vol. 119; nb. 8; (1986); p. 2397 - 2413 View in Reaxys

97/236

2018-08-17 23:02:17

NH 2

Rx-ID: 7808977 View in Reaxys 262/553 Yield

Conditions & References Nitril III, Hydrierung, Ni/Cr2O3 Ovsepyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 26; (1973); p. 843,845, 846; ; vol. 80; nb. 70503s; (1974) View in Reaxys

NH 2

platinum HO

Rx-ID: 19063649 View in Reaxys 263/553 Yield

Conditions & References Reaction Steps: 2 1: 73 percent / Na-OEt / ethanol / 1.5 h / Heating 2: 71 percent / H2 / Raney-Ni / methanol / 12 h / 760 Torr / Ambient temperature With hydrogen, sodium ethanolate, nickel in methanol, ethanol Habernegg, Renate; Severin, Theodor; Chemische Berichte; vol. 119; nb. 8; (1986); p. 2397 - 2413 View in Reaxys

O N

NH 2

Rx-ID: 22565497 View in Reaxys 264/553 Yield

N O

Rx-ID: 22565611 View in Reaxys 265/553 Yield

Conditions & References Reaction Steps: 3 1: Fe, FeCl3, aq. HCl / 1 h / Heating 2: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/

98/236

2018-08-17 23:02:17

3: HCONH2, HCO2H / 16 h / 170 - 180 °C With hydrogenchloride, formic acid, iron(III) chloride, iron, formamide Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

O O O

Rx-ID: 22567007 View in Reaxys 266/553 Yield

Conditions & References Reaction Steps: 2 1: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 2: HCONH2, HCO2H / 16 h / 170 - 180 °C With formic acid, formamide Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 22567009 View in Reaxys 267/553 Yield

Rx-ID: 22573476 View in Reaxys 268/553 Yield

99/236

2018-08-17 23:02:17

NH 2 O O

6-amino-2-<2,4-dinitro-phenylhydrazono>-hexanoic acid hydrochloride O

Rx-ID: 22580794 View in Reaxys 269/553 Yield

Conditions & References Reaction Steps: 3 1: (i) nBuNH2, toluene, (ii) Fe, FeCl3, aq. HCl 2: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 3: HCONH2, HCO2H / 16 h / 170 - 180 °C With formic acid, formamide Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

triphenylbenzylphosphonium salt

Rx-ID: 22585701 View in Reaxys 270/553 Yield

Rx-ID: 22585840 View in Reaxys 271/553 Yield

100/236

2018-08-17 23:02:17

NH 2

O H 2N

N O

Rx-ID: 66006 View in Reaxys 272/553 Yield

Conditions & References With nitric acid, T= -15 °C Patrick; McBee; Hass; Journal of the American Chemical Society; vol. 68; (1946); p. 1153 View in Reaxys

NH 2

N N O

O N

Rx-ID: 9821841 View in Reaxys 273/553 Yield

Conditions & References

89 %

With water, triphenylphosphine in tetrahydrofuran, Time= 3h, T= 50 - 60 °C Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

O NH 2

N N

O O N

Rx-ID: 9829197 View in Reaxys 274/553 Yield

Conditions & References

95 %

With hydrazine in toluene, Time= 1h, T= 80 - 90 °C Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

NH 2

N HO

O N

Rx-ID: 13249358 View in Reaxys 275/553 Yield

Conditions & References Reaction Steps: 5 1: triethylamine / tetrahydrofuran / -78 - 5 °C 2: 24 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 - -20 °C 3: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 4: 88 percent / triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 18 h / 20 °C 5: 95 percent / hydrazine / toluene / 1 h / 80 - 90 °C

101/236

2018-08-17 23:02:17

With sodium tetrahydroborate, n-butyllithium, triphenylmethane, triethylamine, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene, 4: Mitsunobu reaction Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys Reaction Steps: 5 1: triethylamine / tetrahydrofuran / -78 - 5 °C 2: 24 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 - -20 °C 3: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 4: 93 percent / diethylazodicarboxylate; triphenylphosphine; hydrazoic acid / tetrahydrofuran; toluene / 16 h / 20 °C 5: 89 percent / triphenylphosphine; water / tetrahydrofuran / 3 h / 50 - 60 °C With sodium tetrahydroborate, n-butyllithium, hydrogen azide, triphenylmethane, water, triethylamine, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

NH 2

N HO

O N

Rx-ID: 13249987 View in Reaxys 276/553 Yield

Conditions & References Reaction Steps: 6 1: 96 percent / pyridine; cyanuric fluoride / acetonitrile / 3.5 h / 20 °C 2: 34 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3: 33 percent / sodium bis(trimethylsilyl)amide / tetrahydrofuran; toluene / -70 - 20 °C 4: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 5: 88 percent / triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 18 h / 20 °C 6: 95 percent / hydrazine / toluene / 1 h / 80 - 90 °C With pyridine, sodium tetrahydroborate, n-butyllithium, trifluoro-[1,3,5]triazine, triphenylmethane, sodium hexamethyldisilazane, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene, acetonitrile, 5: Mitsunobu reaction Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys Reaction Steps: 6 1: 96 percent / pyridine; cyanuric fluoride / acetonitrile / 3.5 h / 20 °C 2: 34 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3: 33 percent / sodium bis(trimethylsilyl)amide / tetrahydrofuran; toluene / -70 - 20 °C 4: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 5: 93 percent / diethylazodicarboxylate; triphenylphosphine; hydrazoic acid / tetrahydrofuran; toluene / 16 h / 20 °C 6: 89 percent / triphenylphosphine; water / tetrahydrofuran / 3 h / 50 - 60 °C With pyridine, sodium tetrahydroborate, n-butyllithium, hydrogen azide, trifluoro-[1,3,5]triazine, triphenylmethane, water, sodium hexamethyldisilazane, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene, acetonitrile Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

102/236

2018-08-17 23:02:17

O NH 2

N F

O N

Rx-ID: 13261166 View in Reaxys 277/553 Yield

Conditions & References Reaction Steps: 5 1: 34 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2: 33 percent / sodium bis(trimethylsilyl)amide / tetrahydrofuran; toluene / -70 - 20 °C 3: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 4: 88 percent / triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 18 h / 20 °C 5: 95 percent / hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, n-butyllithium, triphenylmethane, sodium hexamethyldisilazane, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene, 4: Mitsunobu reaction Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys Reaction Steps: 5 1: 34 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2: 33 percent / sodium bis(trimethylsilyl)amide / tetrahydrofuran; toluene / -70 - 20 °C 3: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 4: 93 percent / diethylazodicarboxylate; triphenylphosphine; hydrazoic acid / tetrahydrofuran; toluene / 16 h / 20 °C 5: 89 percent / triphenylphosphine; water / tetrahydrofuran / 3 h / 50 - 60 °C With sodium tetrahydroborate, n-butyllithium, hydrogen azide, triphenylmethane, water, sodium hexamethyldisilazane, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

NH 2

O N

O HO

N O

Rx-ID: 13270932 View in Reaxys 278/553 Yield

Conditions & References Reaction Steps: 2 1: 88 percent / triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 18 h / 20 °C 2: 95 percent / hydrazine / toluene / 1 h / 80 - 90 °C With triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, toluene, 1: Mitsunobu reaction Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys Reaction Steps: 2 1: 93 percent / diethylazodicarboxylate; triphenylphosphine; hydrazoic acid / tetrahydrofuran; toluene / 16 h / 20 °C 2: 89 percent / triphenylphosphine; water / tetrahydrofuran / 3 h / 50 - 60 °C With hydrogen azide, water, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, toluene Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

103/236

2018-08-17 23:02:17

O NH 2

O N

O O

Rx-ID: 13273133 View in Reaxys 279/553 Yield

Conditions & References Reaction Steps: 4 1: 24 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 - -20 °C 2: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 3: 88 percent / triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 18 h / 20 °C 4: 95 percent / hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, n-butyllithium, triphenylmethane, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene, 3: Mitsunobu reaction Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys Reaction Steps: 4 1: 24 percent / triphenylmethane; n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 - -20 °C 2: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 3: 93 percent / diethylazodicarboxylate; triphenylphosphine; hydrazoic acid / tetrahydrofuran; toluene / 16 h / 20 °C 4: 89 percent / triphenylphosphine; water / tetrahydrofuran / 3 h / 50 - 60 °C With sodium tetrahydroborate, n-butyllithium, hydrogen azide, triphenylmethane, water, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, hexane, water, toluene Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

O NH 2

N O O

Rx-ID: 13278680 View in Reaxys 280/553 Yield

Conditions & References Reaction Steps: 4 1: 33 percent / sodium bis(trimethylsilyl)amide / tetrahydrofuran; toluene / -70 - 20 °C 2: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 3: 88 percent / triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 18 h / 20 °C 4: 95 percent / hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, sodium hexamethyldisilazane, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, water, toluene, 3: Mitsunobu reaction Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys Reaction Steps: 4 1: 33 percent / sodium bis(trimethylsilyl)amide / tetrahydrofuran; toluene / -70 - 20 °C 2: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 3: 93 percent / diethylazodicarboxylate; triphenylphosphine; hydrazoic acid / tetrahydrofuran; toluene / 16 h / 20 °C 4: 89 percent / triphenylphosphine; water / tetrahydrofuran / 3 h / 50 - 60 °C

104/236

2018-08-17 23:02:17

With sodium tetrahydroborate, hydrogen azide, water, sodium hexamethyldisilazane, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, water, toluene Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

O N O NH 2

O N

O O

Rx-ID: 13279257 View in Reaxys 281/553 Yield

Conditions & References Reaction Steps: 3 1: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 2: 88 percent / triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 18 h / 20 °C 3: 95 percent / hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, triphenylphosphine, hydrazine, diethylazodicarboxylate in tetrahydrofuran, water, toluene, 2: Mitsunobu reaction Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys Reaction Steps: 3 1: 91 percent / sodium borohydride / tetrahydrofuran; H2O / 3 h / 20 °C 2: 93 percent / diethylazodicarboxylate; triphenylphosphine; hydrazoic acid / tetrahydrofuran; toluene / 16 h / 20 °C 3: 89 percent / triphenylphosphine; water / tetrahydrofuran / 3 h / 50 - 60 °C With sodium tetrahydroborate, hydrogen azide, water, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, water, toluene Czeskis, Boris A.; O'Bannon, Douglas D.; Wheeler, William J.; Clodfelter, Dean K.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 48; nb. 2; (2005); p. 85 - 100 View in Reaxys

NH 2

O N N

O O N

O O

Rx-ID: 23240478 View in Reaxys 282/553 Yield 97 %

Conditions & References 3 :Preparation of (2R)-2-(4-nitrophenyl)propylamine Scheme II, step E: A 250 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser and addition funnel is charged with 2-[(2R)-2-(4-nitrophenyl)propyl]isoindoline-1,3-dione (25.02 g, 80.6 mmol) and toluene (200.0 mL). To this solution at room temperature was added anhydrous hydrazine (7.08 mL, 226.0 mmol). Reaction exothermed slightly and was stirred for 45 minutes, heated at 90° C.-95° C. until the disappearance of starting material. A massive precipitate formed by the end of the reaction. Cooled to room temperature and chilled to 0° C. before filtration.

105/236

2018-08-17 23:02:17

Concentration of the filtrate afforded (2R)-2-(4-nitrophenyl)propylamine (14.11 g, 97percent) as an oil; 1H nmr (CDCl3, 300 MHz) α 1.01 (b, 1H), 1.27 (d, 3H, J=6.4 Hz), 2.87 (m, 2H), 7.36 (d, 2H), 8.14 (d, 2H); 13C nmr (CDCl3, 300 MHz) 819.03, 43.51, 49.21, 123.67, 128.09, 153.04. With hydrazine in toluene, Time= 0.75h, T= 20 - 95 °C Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys O N

NH 2

1-t-Butoxycarbonylamino-2-(3*nitrophenyl) propane

Rx-ID: 23858040 View in Reaxys 283/553 Yield

Conditions & References P.53 : 1-t-Butoxycarbonylamino-2-(3*nitrophenyl) propane Preparation Example 53 1-t-Butoxycarbonylamino-2-(3*nitrophenyl) propane A similar reaction to that in Preparation Example 35 was performed using 2-(3-nitrophenyl)propylamine obtained in Preparation Example 52. The resulting residue was purified by silica gel column, to give the title compound (2.626 g) as a yellow oil. 1H-NMR(CDCl ) α (ppm): 1.31 (3H, d, J=6.8 Hz), 1.40 (9H, s), 3.10 (1H, m), 3.26 (1H, m), 3.38 (1H, m), 7.49 (1H, dd, J=7.6, 3 8.4 Hz), 7.56 (1H, d, J=7.6 Hz), 8.08 (1H, s), 8.10 (1H, d, J=8.4 Hz). Patent; Haneda, Toru; Tsuruoka, Akihiko; Kamata, Junichi; Okabe, Tadashi; Takahashi, Keiko; Nara, Kazumasa; Hamaoka, Shinichi; Ueda, Norihiro; Wakabayashi, Toshiaki; Funahashi, Yasuhiro; Semba, Taro; Hata, Naoko; Yamamoto, Yuji; Ozawa, Yoichi; Tsukahara, Naoko; Owa, Takashi; US2003/144507; (2003); (A1) English View in Reaxys

NH 2

Rx-ID: 23914609 View in Reaxys 284/553 Yield

Conditions & References P.52 : 2-(3-Nitrophenyl)propylamine Preparation Example 52 2-(3-Nitrophenyl)propylamine The title compound was obtained as a yellow oil by the procedures of Preparation Examples 26 and 27, except using 2-(3-nitrophenyl)propan-1-ol (1.908 g, Preparation Example 51). Patent; Haneda, Toru; Tsuruoka, Akihiko; Kamata, Junichi; Okabe, Tadashi; Takahashi, Keiko; Nara, Kazumasa; Hamaoka, Shinichi; Ueda, Norihiro; Wakabayashi, Toshiaki; Funahashi, Yasuhiro; Semba, Taro; Hata, Naoko; Yamamoto, Yuji; Ozawa, Yoichi; Tsukahara, Naoko; Owa, Takashi; US2003/144507; (2003); (A1) English View in Reaxys P.52.b : Production Example 52b Production Example 52b 2-(3-Nitrophenyl)propylamine The title compound was obtained as a yellow oil by using 2-(3-nitrophenyl)propane-1-ol (1.908 g, Production Example 51b) in the same manner as in Production Examples 26b-27b. Patent; Eisai Co., Ltd.; EP1258252; (2002); (A1) English View in Reaxys P.52.b : 2-(3-Nitrophenyl)propylamine PRODUCTION EXAMPLE 52b

106/236

2018-08-17 23:02:17

2-(3-Nitrophenyl)propylamine The title compound was obtained as a yellow oil by using 2-(3-nitrophenyl)propane-1-ol (1.908 g, Production Example 51b) in the same manner as in Production Examples 26b-27b. Patent; Wakabayashi, Toshiaki; Funahashi, Yasuhiro; Hata, Naoko; Semba, Taro; Yamamoto, Yuji; Haneda, Toru; Owa, Takashi; Tsuruoka, Akihiko; Kamata, Junichi; Okabe, Tadashi; Takahashi, Keiko; Nara, Kazumasa; Hamaoka, Shinichi; Ueda, Norihiro; US2004/18192; (2004); (A1) English View in Reaxys

NH 2

O N O

Rx-ID: 24239546 View in Reaxys 285/553 Yield 8.5 g (71%)

Conditions & References 62 : 2-(4-nitrophenyl)propylamine CH2Cl2) to give 8.5 g (71percent) of the pure product. NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+=181. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

8.5 g (71%)

2 : 2-(4-nitrophenyl)propylamine CH2Cl2) to give 8.5 g (71percent) of the pure product. The NMR spectrum was consistent with the proposed title structure. Field Desorption Mass Spectrum:M+= 181. Patent; ELI LILLY AND COMPANY; EP994110; (2000); (A1) English View in Reaxys

HO H 2N

NH 2

O OH

Rx-ID: 133212 View in Reaxys 286/553 Yield

Conditions & References With hydrogen bromide, und Behandeln des Reaktionsprodukts mit aethanol.Ammoniak Patent; Kuelz; US2396580; (1941) View in Reaxys

NH 2 H

NH 2

H HO OH

Rx-ID: 4330846 View in Reaxys 287/553 Yield

Conditions & References With hydrogen, 10 wt. % palladium on activated carbon in methanol Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

107/236

2018-08-17 23:02:17

View in Reaxys

NH 2 H

NH 2

H HO OH

Rx-ID: 4330847 View in Reaxys 288/553 Yield

Conditions & References With hydrogen, 10 wt. % palladium on activated carbon in methanol Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys

NH 2

Rx-ID: 24821794 View in Reaxys 289/553 Yield 99%

Conditions & References 4 : Preparation 4 Preparation 4 The corresponding starting compounds are treated in the same manner as described in Preparation 3 to give 1- amino-2-(3-fluoro-4-methoxyphenyl)propane. Yield 99percent Patent; TANABE SEIYAKU CO., LTD.; EP255728; (1991); (B1) English View in Reaxys

99%

4 : Preparation 4 Preparation 4 The corresponding starting compounds are treated in the same manner as described in Preparation 3 to give 1-amino-2-(3-fluoro-4-methoxyphenyl)propane. Yield 99percent; IR max α neat (cm-1): 3270. Patent; Tanabe Seiyaku Co., Ltd.; US4866196; (1989); (A) English View in Reaxys 4.2 : Preparation 4 (2) 6 ml of Raney Nickel are added to an ethanol solution of 4.60 g of the product obtained above, and 10 g of hydrazine monohydrate are added dropwise thereto at a temperature below 50° C. After the reaction, the catalyst is filtered off, and the filtrate is evaporated. The residue is dissolved in chloroform, dried and evaporated to remove the solvent. 4.65 g of 1-amino-2-(3-fluoro-4-methoxyphenyl)propane are obtained as oil. neat IR vmax (cm-1): 3270 Patent; Tanabe Seiyaku Co., Ltd.; US4948810; (1990); (A) English View in Reaxys

108/236

2018-08-17 23:02:17

NH 2

Rx-ID: 36797727 View in Reaxys 290/553 Yield

Conditions & References 57 : Preparation Example 13 General procedure: A borane-THF complex (1 M THF solution, 21 mL) was added to a mixture of 1-(2-fluoro-5-methoxyphenyl)cyclopropanecarbonitrile (3.54 g) and THF (70 mL), followed by stirring for 5 hours under heating at an oil temperature of 80° C. After being left to cool to room temperature, the reaction liquid was concentrated under reduced pressure, methanol (30 mL) was added thereto, and the solvent was evaporated under reduced pressure. This operation was further repeated twice. 1 M hydrochloric acid (30 mL) was added to the residue, followed by stirring for 30 minutes under heating at an oil temperature of 60° C. and washing with diethyl ether. 1 M aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to about 9, and then extraction was performed with chloroform, followed by concentration under reduced pressure, thereby obtaining 1-[1-(2-fluoro-5-methoxyphenyl)cyclopropyl]methanamine (4.0 g). With borane-THF in tetrahydrofuran, Time= 5h, T= 80 °C Patent; Astellas Pharma Inc; HAMAGUCHI, Wataru; KINOYAMA, Isao; KOGANEMARU, Yohei; MIYAZAKI, Takehiro; KANEKO, Osamu; SEKIOKA, Ryuichi; WASHIO, Takuya; US2013/317010; (2013); (A1) English View in Reaxys

NH 2

Cl O

Rx-ID: 1061042 View in Reaxys 291/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys Cl

NH 2

Rx-ID: 1061523 View in Reaxys 292/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 1074027 View in Reaxys 293/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C

109/236

2018-08-17 23:02:17

Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 7732837 View in Reaxys 294/553 Yield

Conditions & References entspr.Keton: 1) Formamid, HCO2H 2) HCl Patent; Labor.Biosedra; FRM7432; (1968); ; vol. 76; nb. 99319; (1972) View in Reaxys

NH 2

N O

Rx-ID: 22565490 View in Reaxys 295/553 Yield

NH 2

Rx-ID: 22566956 View in Reaxys 296/553 Yield

NH 2

Rx-ID: 22566957 View in Reaxys 297/553 Yield

Conditions & References Reaction Steps: 2 1: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 2: HCONH2, HCO2H / 16 h / 170 - 180 °C With formic acid, formamide

110/236

2018-08-17 23:02:17

Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Cl N

Rx-ID: 22567394 View in Reaxys 298/553 Yield

O N

NH 2

Rx-ID: 22567434 View in Reaxys 299/553 Yield

NH 2

KMnO4

O Cl

Rx-ID: 22578996 View in Reaxys 300/553 Yield

111/236

2018-08-17 23:02:17

Cl Cl

NH 2

Rx-ID: 22579029 View in Reaxys 301/553 Yield

NH 2

Rx-ID: 22582573 View in Reaxys 302/553 Yield

NH 2

Rx-ID: 22593586 View in Reaxys 303/553 Yield

NH 2

N O

Rx-ID: 2806303 View in Reaxys 304/553

112/236

2018-08-17 23:02:17

Yield 86 %

Conditions & References With hydrogen, ammonium formate, 10 wt. % palladium on activated carbon in methanol Luening, Ulrich; Mueller, Michael; Angewandte Chemie; vol. 104; nb. 1; (1992); p. 99 - 102 View in Reaxys

NH 2

N O

Rx-ID: 20910396 View in Reaxys 305/553 Yield

Conditions & References Reaction Steps: 2 1: 1. potassium tert-butoxide; 2. buffer of 1,10-phenanthroline 6c, p-toluenesulfonic acid monohydrate / 1. <18>crown-6, EtOH, 15 h; 2. EtOH, 16 h, r.t. 2: 86 percent / H2, NH4 +HCOO- / Pd/C / methanol With buffer of 1,10-phenanthroline 6c, potassium tert-butylate, hydrogen, ammonium formate, toluene-4-sulfonic acid, 10 wt. % palladium on activated carbon in methanol Luening, Ulrich; Mueller, Michael; Angewandte Chemie; vol. 104; nb. 1; (1992); p. 99 - 102 View in Reaxys

NH 2 Cl

Rx-ID: 24220448 View in Reaxys 306/553 Yield

Conditions & References 31 : N-2-(4-Methylphenyl)propyl) 2-propanesulfonamide EXAMPLE 31 N-2-(4-Methylphenyl)propyl) 2-propanesulfonamide The title compound was prepared from the product of Preparation 33 as described in Example 13. Field Desorption Mass Spectrum: M=255.2. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2 Cl

N H

Rx-ID: 38250221 View in Reaxys 307/553 Yield 140 mg

Conditions & References Stage 1: With 10% palladium on activated carbon; Degussa type, hydrogen in tert-butyl methyl ether, T= 20 Â°C , p= 760.051Torr Stage 2: With hydrogenchloride in diethyl ether Fuchs, Christine S.; Hollauf, Manuel; Meissner, Maximilian; Simon, Robert C.; Besset, Tatiana; Reek, Joost N. H.; Riethorst, Waander; Zepeck, Ferdinand; Kroutil, Wolfgang; Advanced Synthesis and Catalysis; vol. 356; nb. 10; (2014); p. 2257 - 2265 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

113/236

2018-08-17 23:02:17

NH 2 HCl

H N

Rx-ID: 38250223 View in Reaxys 308/553 Yield 52 mg

NH 2

HCl N H

Rx-ID: 38250225 View in Reaxys 309/553 Yield 91 mg

NH 2

Rx-ID: 2142583 View in Reaxys 310/553 Yield

Conditions & References With sodium hydroxide, sodium tetrahydroborate, nickel in methanol, Time= 0.5h, T= 45 - 48 °C Glushkov, R. G.; Nikolaeva, L. A.; Dronova, L. N.; Kozlova, O. V.; Medvedev, B. A.; Mashkovskii, M. D.; Pharmaceutical Chemistry Journal; vol. 22; nb. 8; (1988); p. 623 - 627; Khimiko-Farmatsevticheskii Zhurnal; vol. 22; nb. 8; (1988); p. 951 - 955 View in Reaxys NH 2

O H 2N

Rx-ID: 8777984 View in Reaxys 311/553

114/236

2018-08-17 23:02:17

Yield

Conditions & References With borane-THF in tetrahydrofuran, T= 20 °C Ornstein; Zimmerman; Arnold; Bleisch; Cantrell; Simon; Zarrinmayeh; Baker; Gates; Tizzano; Bleakman; Mandelzys; Jarvie; Ho; Deverill; Kamboj; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4354 - 4358 View in Reaxys NH 2

OH O

Rx-ID: 15458197 View in Reaxys 312/553 Yield

Conditions & References Reaction Steps: 3 1: (ClCO)2 / CH2Cl2 / 2 h / 20 °C 2: NH4OH / methanol / 20 °C 3: BH3*THF / tetrahydrofuran / 20 °C With ammonium hydroxide, borane-THF, oxalyl dichloride in tetrahydrofuran, methanol, dichloromethane Ornstein; Zimmerman; Arnold; Bleisch; Cantrell; Simon; Zarrinmayeh; Baker; Gates; Tizzano; Bleakman; Mandelzys; Jarvie; Ho; Deverill; Kamboj; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4354 - 4358 View in Reaxys NH 2

O O

Rx-ID: 15458204 View in Reaxys 313/553 Yield

Conditions & References Reaction Steps: 5 1.1: LiN(SiMe3)2 / tetrahydrofuran / -78 °C 1.2: tetrahydrofuran / 2 h / -78 °C 2.1: LiOH / H2O; methanol; tetrahydrofuran / 20 °C 3.1: (ClCO)2 / CH2Cl2 / 2 h / 20 °C 4.1: NH4OH / methanol / 20 °C 5.1: BH3*THF / tetrahydrofuran / 20 °C With lithium hydroxide, ammonium hydroxide, borane-THF, oxalyl dichloride, lithium hexamethyldisilazane in tetrahydrofuran, methanol, dichloromethane, water Ornstein; Zimmerman; Arnold; Bleisch; Cantrell; Simon; Zarrinmayeh; Baker; Gates; Tizzano; Bleakman; Mandelzys; Jarvie; Ho; Deverill; Kamboj; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4354 - 4358 View in Reaxys NH 2

Cl O

Rx-ID: 15479326 View in Reaxys 314/553 Yield

Conditions & References Reaction Steps: 2

115/236

2018-08-17 23:02:17

1: NH4OH / methanol / 20 °C 2: BH3*THF / tetrahydrofuran / 20 °C With ammonium hydroxide, borane-THF in tetrahydrofuran, methanol Ornstein; Zimmerman; Arnold; Bleisch; Cantrell; Simon; Zarrinmayeh; Baker; Gates; Tizzano; Bleakman; Mandelzys; Jarvie; Ho; Deverill; Kamboj; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4354 - 4358 View in Reaxys NH 2

O O

Rx-ID: 15479328 View in Reaxys 315/553 Yield

Conditions & References Reaction Steps: 4 1: LiOH / H2O; methanol; tetrahydrofuran / 20 °C 2: (ClCO)2 / CH2Cl2 / 2 h / 20 °C 3: NH4OH / methanol / 20 °C 4: BH3*THF / tetrahydrofuran / 20 °C With lithium hydroxide, ammonium hydroxide, borane-THF, oxalyl dichloride in tetrahydrofuran, methanol, dichloromethane, water Ornstein; Zimmerman; Arnold; Bleisch; Cantrell; Simon; Zarrinmayeh; Baker; Gates; Tizzano; Bleakman; Mandelzys; Jarvie; Ho; Deverill; Kamboj; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4354 - 4358 View in Reaxys NH 2

Rx-ID: 24220445 View in Reaxys 316/553 Yield

Conditions & References 23 : 2-(4-t-butylphenyl)propylamine A saturated HCl/methanol solution (5 mL) was then added via a syringe at ambient temperature with severe foaming and the solution was then concentrated under reduced pressure. The resulting white solid was taken into 100 mL 1 N NaOH and the liberated free amine was extracted once with 200 ml diethyl ether. The organic layer was backwashed once with 200 mL H2O, dried over K2CO3, and concentrated under reduced pressure to yield 1.21 g of a brown oil. Chromatography (Chromatotron-2000 micron rotor) eluding with a gradient solvent of ethyl acetate/MeOH 9:1 to MeOH gave 856 mg (83percent). Mass Spectrum: M=191. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2

Rx-ID: 38450775 View in Reaxys 317/553

116/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 2 1: palladium diacetate; potassium phosphate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / 1,4-dioxane; water / 100 °C / Inert atmosphere 2: hydrogen / methanol / 25 °C / 1034.32 Torr With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane, potassium phosphate, hydrogen, palladium diacetate in 1,4-dioxane, methanol, water Georgsson, Jennie; Bergström, Fredrik; Nordqvist, Anneli; Watson, Martin J.; Blundell, Charles D.; Johansson, Magnus J.; Petersson, Annika U.; Yuan, Zhong-Qing; Zhou, Yiqun; Kristensson, Lisbeth; Kakol-Palm, Dorota; Tyrchan, Christian; Wellner, Eric; Bauer, Udo; Brodin, Peter; Svensson Henriksson, Anette; Journal of Medicinal Chemistry; vol. 57; nb. 14; (2014); p. 5935 - 5948 View in Reaxys

N N

NH 2

Rx-ID: 38450782 View in Reaxys 318/553 Yield 94 %

Conditions & References With hydrogen in methanol, T= 25 °C , p= 1034.32Torr Georgsson, Jennie; Bergström, Fredrik; Nordqvist, Anneli; Watson, Martin J.; Blundell, Charles D.; Johansson, Magnus J.; Petersson, Annika U.; Yuan, Zhong-Qing; Zhou, Yiqun; Kristensson, Lisbeth; Kakol-Palm, Dorota; Tyrchan, Christian; Wellner, Eric; Bauer, Udo; Brodin, Peter; Svensson Henriksson, Anette; Journal of Medicinal Chemistry; vol. 57; nb. 14; (2014); p. 5935 - 5948 View in Reaxys O

NH 2

H 2N OH HCl

Rx-ID: 28020481 View in Reaxys 319/553 Yield

Conditions & References 16.b :(b) methyl 3-(2-amino-1 -methyl -ethyl )-benzoate; 17.2 g (63.9 mmol, 80percent purity) 3-(2-amino-1-methyl-ethyl)-benzoic acid (as the hydrochloride salt) are dissolved in 100 ml of methanol and combined with 9 ml (124 mmol) thionyl chloride while cooling with an ice bath. The cooling bath is removed and the mixture is refluxed for three hours. Then the reaction mixture is evaporated to dryness i. vac. and combined with 2N sodium hydroxide solution and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. Rt value: 0.91 min (Method B) CH HI5NO2 (193.24) Mass spectrum: (M+H)+ = 194 Stage 1: With thionyl chloride, Time= 3h, T= 0 °C , Heating / reflux Stage 2: With sodium hydroxide, water in ethyl acetate Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; WO2008/135526; (2008); (A1) English View in Reaxys

NH 2

Rx-ID: 7809717 View in Reaxys 320/553

117/236

2018-08-17 23:02:17

Yield

Conditions & References Nitril III, Hydrierung, Ni/Cr2O3 Ovsepyan et al.; Armyanskii Khimicheskii Zhurnal; vol. 26; (1973); p. 843,845, 846; ; vol. 80; nb. 70503s; (1974) View in Reaxys

H H

NH 2

H N O

N O

Rx-ID: 417157 View in Reaxys 321/553 Yield

Conditions & References bei aufeinanderfolgender Umsetzung mit HNO3 und H2SO4 und mit wss. HCl Panizzi; Pepe; Annali di Chimica (Rome, Italy); vol. 43; (1953); p. 29,33 View in Reaxys NH 2 O

O H 2N

Rx-ID: 473482 View in Reaxys 322/553 Yield

Conditions & References With alkaline aqueous sodium hypobromite Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

NH 2

Rx-ID: 477989 View in Reaxys 323/553 Yield

Conditions & References With alkaline aqueous sodium hypobromite Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys NH 2

O O

H 2N O

Rx-ID: 478288 View in Reaxys 324/553 Yield

Conditions & References With sodium hypochlorite Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

118/236

2018-08-17 23:02:17

View in Reaxys Baltzly; Buck; Journal of the American Chemical Society; vol. 62; (1940); p. 164,166; Journal of the American Chemical Society; vol. 64; (1942); p. 3040 View in Reaxys With sodium hypobromide Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys Baltzly; Buck; Journal of the American Chemical Society; vol. 62; (1940); p. 164,166; Journal of the American Chemical Society; vol. 64; (1942); p. 3040 View in Reaxys

O O

NH 2 H 2N

O O

Rx-ID: 478289 View in Reaxys 325/553 Yield

Conditions & References With alkaline aqueous sodium hypobromite Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys NH 2 O

NH 2

Rx-ID: 479440 View in Reaxys 326/553 Yield

Conditions & References With alkaline aqueous sodium hypobromite Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys

H 2N

NH 2

O O

Rx-ID: 479526 View in Reaxys 327/553 Yield

Conditions & References With alkaline aqueous sodium hypobromite Woodruff; Journal of the American Chemical Society; vol. 64; (1942); p. 2859,2860 View in Reaxys With alkaline aqueous sodium hypochlorite

119/236

2018-08-17 23:02:17

Sugasawa; Sugimoto; Yakugaku Zasshi; vol. 61; (1941); p. 62,67; engl. Ref. S. 26, 29; Chem. Zentralbl.; vol. 112; nb. II; (1941); p. 1277 View in Reaxys

H N

NH 2

S HO

O O

Rx-ID: 3286621 View in Reaxys 328/553 Yield

Conditions & References With hydrogen, palladium dihydroxide in methanol, Time= 16h, p= 2585.7Torr Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

H N

NH 2

Rx-ID: 3406890 View in Reaxys 329/553 Yield

Conditions & References With hydrogen, palladium dihydroxide in methanol, Time= 24h, p= 2585.7Torr Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

NH 2

Rx-ID: 7790653 View in Reaxys 330/553 Yield

Conditions & References Methylhomoveratronitril, H2, Raney-Nickel, ammoniakal.Me., Parr-Bombe Wenkert; Haugwitz; Canadian Journal of Chemistry; vol. 46; (1968); p. 1160 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

120/236

2018-08-17 23:02:17

NH 2

Rx-ID: 19395596 View in Reaxys 331/553 Yield

Conditions & References Reaction Steps: 5 1: 1.) LDA / 1.) THF, hexane, 25 deg C, 15 min, 2.) THF, hexane, overnight 2: SOCl2 / benzene / 3 h / Heating 3: pyridine / benzene / 0.25 h 4: 1 M BH3 / tetrahydrofuran / 72 h / 25 °C 5: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr With pyridine, thionyl chloride, borane, hydrogen, lithium diisopropyl amide, palladium dihydroxide in tetrahydrofuran, methanol, benzene Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

NH 2

O O

Rx-ID: 19404510 View in Reaxys 332/553 Yield

Conditions & References Reaction Steps: 4 1: SOCl2 / benzene / 3 h / Heating 2: pyridine / benzene / 0.25 h 3: 1 M BH3 / tetrahydrofuran / 72 h / 25 °C 4: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr With pyridine, thionyl chloride, borane, hydrogen, palladium dihydroxide in tetrahydrofuran, methanol, benzene Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

NH 2

O O

Rx-ID: 19433968 View in Reaxys 333/553 Yield

Conditions & References Reaction Steps: 3 1: pyridine / benzene / 0.25 h 2: 1 M BH3 / tetrahydrofuran / 72 h / 25 °C 3: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr

121/236

2018-08-17 23:02:17

With pyridine, borane, hydrogen, palladium dihydroxide in tetrahydrofuran, methanol, benzene Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

H N

NH 2

O O

Rx-ID: 19435577 View in Reaxys 334/553 Yield

Conditions & References Reaction Steps: 2 1: 1 M BH3 / tetrahydrofuran / 72 h / 25 Â°C 2: H2 / Pearlman's catalyst / methanol / 24 h / 2585.7 Torr With borane, hydrogen, palladium dihydroxide in tetrahydrofuran, methanol Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

H N

NH 2

Rx-ID: 29885657 View in Reaxys 335/553 Yield 91 %

Conditions & References With 20 % Pd(OH)2/C, hydrogen Melchiorre, Michele; Del Lungo, Martina; Guandalini, Luca; Martini, Elisabetta; Dei, Silvia; Manetti, Dina; Scapecchi, Serena; Teodori, Elisabetta; Sartiani, Laura; Mugelli, Alessandro; Cerbai, Elisabetta; Romanelli, Maria Novella; Journal of Medicinal Chemistry; vol. 53; nb. 18; (2010); p. 6773 - 6777 View in Reaxys

H N

NH 2

Rx-ID: 29885658 View in Reaxys 336/553 Yield 72 %

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

122/236

2018-08-17 23:02:17

NH 2

O O

Rx-ID: 40707780 View in Reaxys 337/553 Yield

Conditions & References Reaction Steps: 5 1.1: N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -70 °C 1.2: 18 h / -78 - 20 °C 2.1: water; sodium hydroxide / methanol; tetrahydrofuran / 4 h / 20 °C 3.1: thionyl chloride / dichloromethane / 2.5 h / 0 - 20 °C / Reflux 4.1: ammonia / dichloromethane / 3 h / 0 - 20 °C 5.1: diborane / tetrahydrofuran / 12 h / Reflux 5.2: 2 h / Reflux With N,N,N,N,N,N-hexamethylphosphoric triamide, thionyl chloride, ammonia, water, sodium hydroxide, diborane, lithium diisopropyl amide in tetrahydrofuran, methanol, dichloromethane Patent; HOFFMANN-LA ROCHE INC.; Han, Xingchun; Javanbakht, Hassan; Jiang, Min; Liang, Chungen; Wang, Jianping; Wang, Yongguang; Wang, Zhanguo; Weikert, Robert James; Yang, Song; Zhou, Chengang; US2015/210682; (2015); (A1) English View in Reaxys Reaction Steps: 5 1.1: lithium diisopropyl amide; N,N,N,N,N,N-hexamethylphosphoric triamide / tetrahydrofuran / 0.5 h / -78 - -70 °C 1.2: 18 h / -70 - 20 °C 2.1: sodium hydroxide; water / methanol; tetrahydrofuran / 4 h / 20 °C 3.1: thionyl chloride / dichloromethane / 2.5 h / 0 °C / Reflux 4.1: ammonia / dichloromethane / 3 h / 0 - 20 °C 5.1: borane-THF / tetrahydrofuran / 12 h / Reflux With N,N,N,N,N,N-hexamethylphosphoric triamide, thionyl chloride, borane-THF, ammonia, water, sodium hydroxide, lithium diisopropyl amide in tetrahydrofuran, methanol, dichloromethane Patent; F. HOFFMANN-LA ROCHE AG; HOFFMANN-LA ROCHE INC.; HAN, Xingchun; JAVANBAKHT, Hassan; JIANG, Min; LIANG, Chungen; WANG, Jianping; WANG, Yongguang; WANG, Zhanguo; WEIKERT, Robert James; YANG, Song; ZHOU, Chengang; WO2015/113990; (2015); (A1) English View in Reaxys

NH 2

O O

Rx-ID: 40707786 View in Reaxys 338/553 Yield

Conditions & References Reaction Steps: 4 1.1: water; sodium hydroxide / methanol; tetrahydrofuran / 4 h / 20 °C 2.1: thionyl chloride / dichloromethane / 2.5 h / 0 - 20 °C / Reflux 3.1: ammonia / dichloromethane / 3 h / 0 - 20 °C 4.1: diborane / tetrahydrofuran / 12 h / Reflux 4.2: 2 h / Reflux With thionyl chloride, ammonia, water, sodium hydroxide, diborane in tetrahydrofuran, methanol, dichloromethane Patent; HOFFMANN-LA ROCHE INC.; Han, Xingchun; Javanbakht, Hassan; Jiang, Min; Liang, Chungen; Wang, Jianping; Wang, Yongguang; Wang, Zhanguo; Weikert, Robert James; Yang, Song; Zhou, Chengang; US2015/210682; (2015); (A1) English

123/236

2018-08-17 23:02:17

View in Reaxys Reaction Steps: 4 1: sodium hydroxide; water / methanol; tetrahydrofuran / 4 h / 20 °C 2: thionyl chloride / dichloromethane / 2.5 h / 0 °C / Reflux 3: ammonia / dichloromethane / 3 h / 0 - 20 °C 4: borane-THF / tetrahydrofuran / 12 h / Reflux With thionyl chloride, borane-THF, ammonia, water, sodium hydroxide in tetrahydrofuran, methanol, dichloromethane Patent; F. HOFFMANN-LA ROCHE AG; HOFFMANN-LA ROCHE INC.; HAN, Xingchun; JAVANBAKHT, Hassan; JIANG, Min; LIANG, Chungen; WANG, Jianping; WANG, Yongguang; WANG, Zhanguo; WEIKERT, Robert James; YANG, Song; ZHOU, Chengang; WO2015/113990; (2015); (A1) English View in Reaxys

NH 2

O O

Rx-ID: 40707791 View in Reaxys 339/553 Yield

Conditions & References Reaction Steps: 3 1.1: thionyl chloride / dichloromethane / 2.5 h / 0 - 20 °C / Reflux 2.1: ammonia / dichloromethane / 3 h / 0 - 20 °C 3.1: diborane / tetrahydrofuran / 12 h / Reflux 3.2: 2 h / Reflux With thionyl chloride, ammonia, diborane in tetrahydrofuran, dichloromethane Patent; HOFFMANN-LA ROCHE INC.; Han, Xingchun; Javanbakht, Hassan; Jiang, Min; Liang, Chungen; Wang, Jianping; Wang, Yongguang; Wang, Zhanguo; Weikert, Robert James; Yang, Song; Zhou, Chengang; US2015/210682; (2015); (A1) English View in Reaxys Reaction Steps: 3 1: thionyl chloride / dichloromethane / 2.5 h / 0 °C / Reflux 2: ammonia / dichloromethane / 3 h / 0 - 20 °C 3: borane-THF / tetrahydrofuran / 12 h / Reflux With thionyl chloride, borane-THF, ammonia in tetrahydrofuran, dichloromethane Patent; F. HOFFMANN-LA ROCHE AG; HOFFMANN-LA ROCHE INC.; HAN, Xingchun; JAVANBAKHT, Hassan; JIANG, Min; LIANG, Chungen; WANG, Jianping; WANG, Yongguang; WANG, Zhanguo; WEIKERT, Robert James; YANG, Song; ZHOU, Chengang; WO2015/113990; (2015); (A1) English View in Reaxys

O O

NH 2

O O

NH 2

Rx-ID: 40707795 View in Reaxys 340/553 Yield 7g

Conditions & References 69.4 : Preparation of 2-(3,4-dimethoxyphenyl)propan-1-amine In a three-neck round-bottom flask was added 2-(3,4-dimethoxyphenyl)propanamide (10.4 g, 50 mmol) and dry THF (250 mL). The mixture was heated to reflux. To the mixture was added a solution of BH3 in THF (1 M, 250 mL) dropwise. The resultant mixture was refluxed for 12 hours, and then cooled to 0° C. Methanol (150 mL) was added dropwise.

124/236

2018-08-17 23:02:17

The mixture was concentrated in vacuo, and the residue was dissolved in 1,4-dioxane (50 mL) and then followed by addition of hydrochloric acid (6 M, 175 mL). The resultant mixture was refluxed for 2 hours, and then cooled to room temperature, then diluted with water (200 mL) and extracted with DCM (200 mL). The aqueous layer was basified and then extracted with DCM (200 mL*3). The organic layers were combined, and then washed with water (200 mL), then dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to give 2-(3,4-dimethoxyphenyl)propan-1-amine (7 g) as light brown oil. Stage 1: With diborane in tetrahydrofuran, Time= 12h, Reflux Stage 2: With hydrogenchloride in tetrahydrofuran, 1,4-dioxane, methanol, Time= 2h, Reflux Patent; HOFFMANN-LA ROCHE INC.; Han, Xingchun; Javanbakht, Hassan; Jiang, Min; Liang, Chungen; Wang, Jianping; Wang, Yongguang; Wang, Zhanguo; Weikert, Robert James; Yang, Song; Zhou, Chengang; US2015/210682; (2015); (A1) English View in Reaxys 7g

69.4 : Step 4: Preparation of 2-(3,4-dimethoxypheny)propan-l -amine Step 4: Preparation of 2-(3,4-dimethoxypheny)propan-l -amine In a three-neck round-bottom flask was added 2-(3,4-dimethoxyphenyl)propanamide ( 1 0.4 g, 50 mmol ) and dry TH F (250 ml.). The mixture was heated to reflux. To the mixture was added a solution of Blh in THF (1 M, 250 ml. ) drop wise. The resultant mixture was re fluxed fo 12 hours, and then cooled to 0 °C. Methanol (150 ml. ) was added dropwise. The mixture was concentrated in vacuo, and the residue was dissolved in 1 ,4-dioxane (50 ml.) and then followed by addit ion of hydrochloric acid (6 M, 1 75 ml. ). The resultant mixture was re fluxed for 2 hours, and then cooled to room temperature, then diluted with water (200 ml.) and extracted with DCM (200 ml.). The aqueous layer was basified and then extracted with DCM (200 ml. x 3). The organic layers were combined, and then washed ith water (200 ml.), then dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography to give 2-(3,4dimethoxyphenyOpropan- 1 -amine (7 g) as light brown oil. With borane-THF in tetrahydrofuran, Time= 12h, Reflux Patent; F. HOFFMANN-LA ROCHE AG; HOFFMANN-LA ROCHE INC.; HAN, Xingchun; JAVANBAKHT, Hassan; JIANG, Min; LIANG, Chungen; WANG, Jianping; WANG, Yongguang; WANG, Zhanguo; WEIKERT, Robert James; YANG, Song; ZHOU, Chengang; WO2015/113990; (2015); (A1) English View in Reaxys

NH 2

O O

Rx-ID: 40707897 View in Reaxys 341/553 Yield

Conditions & References Reaction Steps: 2 1.1: ammonia / dichloromethane / 3 h / 0 - 20 °C 2.1: diborane / tetrahydrofuran / 12 h / Reflux 2.2: 2 h / Reflux With ammonia, diborane in tetrahydrofuran, dichloromethane Patent; HOFFMANN-LA ROCHE INC.; Han, Xingchun; Javanbakht, Hassan; Jiang, Min; Liang, Chungen; Wang, Jianping; Wang, Yongguang; Wang, Zhanguo; Weikert, Robert James; Yang, Song; Zhou, Chengang; US2015/210682; (2015); (A1) English View in Reaxys Reaction Steps: 2 1: ammonia / dichloromethane / 3 h / 0 - 20 °C 2: borane-THF / tetrahydrofuran / 12 h / Reflux With borane-THF, ammonia in tetrahydrofuran, dichloromethane

125/236

2018-08-17 23:02:17

Patent; F. HOFFMANN-LA ROCHE AG; HOFFMANN-LA ROCHE INC.; HAN, Xingchun; JAVANBAKHT, Hassan; JIANG, Min; LIANG, Chungen; WANG, Jianping; WANG, Yongguang; WANG, Zhanguo; WEIKERT, Robert James; YANG, Song; ZHOU, Chengang; WO2015/113990; (2015); (A1) English View in Reaxys

NH 2 Cl

Rx-ID: 24220439 View in Reaxys 342/553 Yield

Conditions & References 10 : 2-(4-Methoxyphenyl)propylamine hydrochloride Preparation 10 2-(4-Methoxyphenyl)propylamine hydrochloride Following the method of Preparation 8, but using the product of Preparation 9, 2.75 g (17.1 mmol), 2.77 g (81percent) of the title compound was obtained. Analysis for C10H16ClNO: Theory: C, 59.55; H, 8.00; N, 6.94. Found: C, 59.33; H, 7.89; N, 6.71. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2

Rx-ID: 38250222 View in Reaxys 343/553 Yield 35 mg

H N

NH 2

Rx-ID: 38250224 View in Reaxys 344/553 Yield 49 mg

126/236

2018-08-17 23:02:17

NH 2 F F

F F F

Rx-ID: 35683924 View in Reaxys 345/553 Yield

Conditions & References

61 %

With lithium aluminium tetrahydride in tetrahydrofuran, Time= 2h, T= 0 °C Kang, Soosung; Cooper, Garry; Dunne, Sara Fernandez; Luan, Chi-Hao; Surmeier, D. James; Silverman, Richard B.; Journal of Medicinal Chemistry; vol. 56; nb. 11; (2013); p. 4786 - 4797 View in Reaxys NH 2 F

F N

F F F

Rx-ID: 35684239 View in Reaxys 346/553 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 °C With lithium aluminium tetrahydride, sodium hydride in tetrahydrofuran, N,N-dimethyl-formamide, mineral oil Kang, Soosung; Cooper, Garry; Dunne, Sara Fernandez; Luan, Chi-Hao; Surmeier, D. James; Silverman, Richard B.; Journal of Medicinal Chemistry; vol. 56; nb. 11; (2013); p. 4786 - 4797 View in Reaxys NH 2

Cl Cl H 2N

O Cl Cl

Rx-ID: 23143257 View in Reaxys 347/553 Yield

Conditions & References 15 : Intermediate 15; [[1- (3. 5-DICHLORO-PHENVL)-ETHVLL-METHVLAMINE] Methylamine (2M solution in [MEOH-13] mL) was added to a solution of intermediate 14 (500 mg) in MeOH (26 mL) under a Nitrogen atmosphere. The mixture was stirred at r. t. for 18 hours, then it was cooled to [0°C] and sodium borohydride (98 mg) was added. The mixture was stirred at [0°C] for 2 hours, then it was quenched with water and extracted with DCM. The organic layer was dried and concentrated in vacuo to give the title compound (340 mg) as yellow oil. T. [I.] c.: CH/AcOEt 1: [1,] Rf=0.15. NMR [(CDCI3)] : 8 (ppm) 7.3 (m, 3H); 3.6 (q, [1 H)] ; 2.3 (s, 3H); 1.35 (d, 3H). MS (ES/+): m/z=204 [[M+HL+.] Stage 1: in methanol, Time= 18h, T= 20 °C Stage 2: With sodium tetrahydroborate in methanol, Time= 2h, T= 0 °C Patent; GLAXO GROUP LIMITED; WO2004/5255; (2004); (A1) English View in Reaxys

127/236

2018-08-17 23:02:17

NH 2 HCl

Cl H 2N

Rx-ID: 10816831 View in Reaxys 348/553 Yield

HCl

Rx-ID: 24219760 View in Reaxys 349/553 Yield

Conditions & References 32.2 : Step 2 Step 2 o-Chloro-α-methyl Phenethylamine Hydrochloride Reduction of the product from Step 1 was carried out in the presence of Raney nickel, in methanol/NH3. The catalyst was removed and washed with methanol. The filtrate was concentrated and diethyl ether (100 mL) was added to the residue. Concentrated HCl was added dropwise to precipitate the compound; 1.06 g (44percent). Patent; Warner-Lambert Company; US6300501; (2001); (B1) English View in Reaxys

NH 2 HCl

Rx-ID: 35460242 View in Reaxys 350/553 Yield 70 %

Conditions & References B : [B] 2-(3-Chloro-phenyl)-propylamine hydrochloride To a solution of 2-(3-chloro-phenyl)-propionitrile (5.0 g, 30.2 mmol) in THF (80 mL) was added borane-tetrahydrofuran complex solution (45 mL, 45.3 mmol). The reaction mixture was stirred at room temperature overnight. Ethanol (10 mL) was then added to the reaction mixture; after stirring at room temperature for 20 min, a solution of HCI in ether (2 M, 12.5 mL) was added. After stirring for another 1 hour, water was added to induce the precipitation of the product. The white solid was collected by filtration and dried in vacuo to give the title compound (3.6 g, 70percent). MS (for free amine): 170.1 (M+H+). Stage 1: With borane-THF in tetrahydrofuran, T= 20 °C , Inert atmosphere

128/236

2018-08-17 23:02:17

Stage 2: With hydrogenchloride in tetrahydrofuran, diethyl ether, ethanol, Time= 1.33333h, T= 20 °C Patent; F. HOFFMANN-LA ROCHE AG; AEBI, Johannes; AMREIN, Kurt; CHEN, Wenming; HORNSPERGER, Benoit; KUHN, Bernd; LIU, Yongfu; MAERKI, Hans P.; MAYWEG, Alexander V.; MOHR, Peter; TAN, Xuefei; WANG, Zhanguo; ZHOU, Mingwei; WO2013/79452; (2013); (A1) English View in Reaxys 70 %

20 : Example 20: Preparation of 2-(3-chlorophenyl)propan-1-amine from 2-(3- ch 10 ro ph en y I) propane nitrle To a solution of 2-(3-chlorophenyl)propanenitrile VIII (45.3 mmol; 7.5 g) in toluene (150 mL) under nitrogen atmosphere at 0 °C was added BH3.THF (135.8 mmol; 135.8 mL, 1M). The reaction mixture was stirred under reflux for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water (150 mL) followed by extraction with EtOAc (1x300 mL). The organic phase was dried over MgSO4, filtered and solvent was removed by evaporation. The pure product was isolated as a hydrochloride salt by treatment of residue with HCI (Et20 solution) in 70 percent yield (6.6 g).‘H NMR (500 MHz, CDCI3, ppm) 7.22 (m, 3H), 7.08 (d, 1H), 2.83 (m, 2H), 2.72 (m, 1H), 1.23 (d, 1H), 1.08 (bs, NH);‘3C NMR (125 MHz, CDCI3, ppm) 145.4, 133.2, 130.5, 127.2, 126.9, 126.1, 44.5, 37.1, 19.2. Stage 1: With borane-THF in toluene, Time= 4h, T= 0 °C , Inert atmosphere, Reflux Stage 2: With hydrogenchloride in diethyl ether, water Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys

NH 2 HCl

N H

Rx-ID: 39139857 View in Reaxys 351/553 Yield 71 %

Conditions & References 9 : Preparation of hydrochloride salt of (S) or (R)-2-(3- chlorophenyl)propan-1-amine ((R)-IIId or (S)-IIId) Into a cold solution of tert-butyl-(2-(3-chlorophenyl)propyl)carbamate ((R)Ill-Boc or (S)-III-Boc, 2.65 g, 9.8 mmol) in THF (20 mL) hydrochloric acid (32 mL, 6 M) was added and the reaction system was stirred for 3 hours at 45°C. The solvent was evaporated, the organic residue was diluted with water, pH was adjusted to 9 using NaOH aqueous solution and then extracted with two portions of ethyl acetate (50 mL). The organic phase was dried over Na2SO4 and the solvent was evaporated to obtain crude material which was then diluted in diethyl ether. Hydrochloric acid (1M, 12 mL) was then dropping for 1 hour into the reaction system at room temperature. Afterwards the reaction system was slowly cooled down where the salt started to precipitate. The resulting solid was filtered off, dried in vacuum ((R)-IIId or (S)-IIId, 1.42g, 71percent yield) and characterized with NMR spectroscopy and HPLC analysis. Stage 1: With hydrogenchloride in tetrahydrofuran, water, Time= 3h, T= 45 °C , Cooling with ice Stage 2: With hydrogenchloride in water, Time= 1h, T= 20 °C Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys

NH 2 HCl

Rx-ID: 39139943 View in Reaxys 352/553 Yield

Conditions & References Reaction Steps: 2 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 3 h / -78 - 20 °C 2.1: borane-THF / toluene / 4 h / 0 °C / Inert atmosphere; Reflux With borane-THF, lithium hexamethyldisilazane in tetrahydrofuran, toluene

129/236

2018-08-17 23:02:17

Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys

Cl Cl

NH 2 HCl

Rx-ID: 39147644 View in Reaxys 353/553 Yield

Conditions & References Reaction Steps: 3 1.1: sodium nitrite; ammonium cerium (IV) nitrate / chloroform / 0.25 h 1.2: 30 °C 2.1: D-glucose / ethanol; aq. phosphate buffer / 24 h / 35 °C / Microbiological reaction 3.1: zinc / tetrahydrofuran; methanol / 4 h / 0 - 30 °C With ammonium cerium (IV) nitrate, D-glucose, zinc, sodium nitrite in tetrahydrofuran, methanol, aq. phosphate buffer, ethanol, chloroform Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; GAZIC SMILOVIC, Ivana; CLUZEAU, Jerome; RICHTER, Frank; WO2014/202765; (2014); (A1) English View in Reaxys Reaction Steps: 3 1.1: sodium nitrite; ammonium cerium (IV) nitrate / chloroform / 0.25 h 1.2: 30 °C 2.1: 1-((S)-1-(N-benzyl-N-methylcarbamoyl)-2,2-dimethylpropyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea / toluene / 0.5 h / 30 °C / Inert atmosphere 2.2: 48 h / 40 °C / Inert atmosphere 3.1: zinc / tetrahydrofuran; methanol / 4 h / 0 - 30 °C With ammonium cerium (IV) nitrate, 1-((S)-1-(N-benzyl-N-methylcarbamoyl)-2,2-dimethylpropyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea, zinc, sodium nitrite in tetrahydrofuran, methanol, chloroform, toluene Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; GAZIC SMILOVIC, Ivana; CLUZEAU, Jerome; RICHTER, Frank; WO2014/202765; (2014); (A1) English View in Reaxys O N O

NH 2 HCl

Rx-ID: 39147647 View in Reaxys 354/553 Yield

Conditions & References Reaction Steps: 2 1.1: 1-((S)-1-(N-benzyl-N-methylcarbamoyl)-2,2-dimethylpropyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea / toluene / 0.5 h / 30 °C / Inert atmosphere 1.2: 48 h / 40 °C / Inert atmosphere 2.1: zinc / tetrahydrofuran; methanol / 4 h / 0 - 30 °C With 1-((S)-1-(N-benzyl-N-methylcarbamoyl)-2,2-dimethylpropyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea, zinc in tetrahydrofuran, methanol, toluene Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; GAZIC SMILOVIC, Ivana; CLUZEAU, Jerome; RICHTER, Frank; WO2014/202765; (2014); (A1) English View in Reaxys Reaction Steps: 2

130/236

2018-08-17 23:02:17

1: D-glucose / ethanol; aq. phosphate buffer / 24 h / 35 °C / Microbiological reaction 2: zinc / tetrahydrofuran; methanol / 4 h / 0 - 30 °C With D-glucose, zinc in tetrahydrofuran, methanol, aq. phosphate buffer, ethanol Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; GAZIC SMILOVIC, Ivana; CLUZEAU, Jerome; RICHTER, Frank; WO2014/202765; (2014); (A1) English View in Reaxys

O N O

NH 2 HCl

Rx-ID: 39147648 View in Reaxys 355/553 Yield

Conditions & References 3 : Reductive transformation of (R)-1 -chloro-3-(1 -nitropropan-2-yl) to (R)-2-(3- chlorophenyl)propan-2-amine hydrochloride salt Chiral 1-chloro-3-(1-nitropropan-2-yl)benzene lI-NO2 (180 mg) was dissolved in THF (4.5 mL) in a flask equipped with a magnetic stir bar and a rubber septum was placed and methanol (0.5 mL) was then added. The reaction system was cooled down to 0 00 and fine zinc powder was added followed by slow addition (30 mm) of acetic or hydrochloric acid (30 equiv. according to starting material). After addition, the reaction system was vigorously stirred for 4 hours at 30 00. The zinc powder was filtered off, the residue was diluted with water, the pH was adjusted to 11 and the aqueous phase was extracted then with two portions (100 mL) of EtOAc. The organic phases were washed with brine, dried over anhydrous Na2SO4 and the solvent was evaporated to afford crude liquid optical active product (105 mg; 78percent yield; 95percent optical purity). Hydrogen chloride solution in THF (2M, 1.5 mL) was added to the crude product at 0 00 and afterwards fine white crystals were filtered off, dried in vacuum and characterized with GO-MS analysis and NMR spectroscopy.1H NMR (500 MHz, DMSO, ppm) 6 8.30 (bs, 3H), 7.30-7.15 (m, 4ArH), 3.18 (m, 1H),2.96 (m, 2H), 1.24 (d, J = 9 Hz, 3H).130 NMR (125 MHz, DMSO, ppm) 6 145.4, 133.2, 130.5, 127.2, 126.9, 126.1, 44.5,37.1, 19.2. With zinc in tetrahydrofuran, methanol, Time= 4h, T= 0 - 30 °C Patent; LEK PHARMACEUTICALS D.D.; STAVBER, Gaj; GAZIC SMILOVIC, Ivana; CLUZEAU, Jerome; RICHTER, Frank; WO2014/202765; (2014); (A1) English View in Reaxys

NH 2

NH 2 HCl

Rx-ID: 47902788 View in Reaxys 356/553 Yield 1.63 g

Conditions & References 3.3 : 3.3 24 (R)-2-(3-Chlorophenyl)propan-1-amine hydrochloride (3-HCl) Hydrochloric acid (32mL, 6M) was added to a solution of the Boc derivative 6 2 (9.8mmol) in 26 THF (20mL). The emulsion was stirred at 45°C for 3h to give a clear solution. The solvent was evaporated, the residue dissolved in 27 H2O (65mL) made alkaline with 28 NaOH (1M). The mixture was extracted with EtOAc (1×60mL, 2×30mL). The combined extracts were dried over MgSO4, and the solvent was removed under reduced pressure to yield 1.60g of the crude base. Hydrogen chloride in 29 Et2O (12mL, 1M) was added dropwise to a solution of the base in Et2O (20mL). The precipitated hydrochloride was filtered, washed with Et2O (3×5mL) and dried in vacuum: 1.63g (81percent). M.p. 192°C. 1H NMR (300MHz, DMSO-d6) α 1.25 (d, J=6.9Hz, 3H), 2.98 (m, 2H), 3.12 (m, 1H), 7.26–7.40 (m, 4H), 8.16 (br, 3H). 13C NMR (75MHz, DMSO-d6) α 19.2, 37.2, 44.5, 126.1, 126.9, 127.2, 130.5, 133.2, 145.4. IR (neat) α 2967 (m), 2865 (s), 2819 (m), 1598 (m), 1507 (m), 1467 (m), 1435 (m), 1394 (m), 879 (m), 798 (m), 786 (s), 697 (s) cm−1. With hydrogenchloride in diethyl ether

131/236

2018-08-17 23:02:17

Smilovic, Ivana Gazic; Cluzeau, Jerome; Richter, Frank; Nerdinger, Sven; Schreiner, Erwin; Laus, Gerhard; Schottenberger, Herwig; Bioorganic and Medicinal Chemistry; vol. 26; nb. 9; (2018); p. 2686 - 2690 View in Reaxys NH 2

Rx-ID: 8030251 View in Reaxys 357/553 Yield

Conditions & References milde Hydrolyse von 1-(1-Cyanaethyl)-5-methoxy-2,3,4-trimethyl-benzol Kubota et al.; Tetrahedron Letters; (1967); p. 745 View in Reaxys NH 2

Rx-ID: 7808218 View in Reaxys 358/553 Yield

Conditions & References 2-(4-Trimethylsilyl-phenyl)-propionitril, LiAlH4, sd. Ae. Frankel et al.; Journal of the Chemical Society [Section] C: Organic; (1966); p. 379,381 View in Reaxys entspr.Nitril, LiAlH4 Patent; Yssum Res.Dev.Co.of the Hebrew Univ.Jerusalem; GB1108848; (1965); ; vol. 69; nb. 52283p; (1968) View in Reaxys

NH 2 O

NH 2

Rx-ID: 480562 View in Reaxys 359/553 Yield

Conditions & References With 1,4-dioxane, sodium hypochlorite, T= 70 °C Sugasawa; Sugimoto; Yakugaku Zasshi; vol. 61; (1941); p. 62,67; engl. Ref. S. 26, 29; Chem. Zentralbl.; vol. 112; nb. II; (1941); p. 1277 View in Reaxys

NH 2 O O

O O

Rx-ID: 1128362 View in Reaxys 360/553

132/236

2018-08-17 23:02:17

Yield

Conditions & References With lithium aluminium tetrahydride Aldous,F.A.B. et al.; Journal of Medicinal Chemistry; vol. 17; (1974); p. 1100 - 1111 View in Reaxys

NH 2

O N

O O

Rx-ID: 22650847 View in Reaxys 361/553 Yield

Conditions & References Reaction Steps: 2 1: (i) NaNH2, (ii) /BRN= 969135/ 2: LiAlH4 With lithium aluminium tetrahydride Aldous,F.A.B. et al.; Journal of Medicinal Chemistry; vol. 17; (1974); p. 1100 - 1111 View in Reaxys

O N

NH 2

O O

N O

Rx-ID: 47474222 View in Reaxys 362/553 Yield

Conditions & References Reaction Steps: 3 1: potassium tert-butylate / N,N-dimethyl-formamide / 1 h / -20 - 0 °C / Inert atmosphere 2: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 3: borane-THF / 2-methyltetrahydrofuran / 3 h / 60 °C With borane-THF, potassium tert-butylate, sodium hydride in 2-methyltetrahydrofuran, N,N-dimethyl-formamide Patent; GALDERMA RESEARCH & DEVELOPMENT; Fournier, Jean-Francois; Clary, Laurence; Thoreau, Etienne; (164 pag.); US2018/50992; (2018); (A1) English View in Reaxys

O N O

NH 2

O N O

Rx-ID: 47474223 View in Reaxys 363/553 Yield

Conditions & References Reaction Steps: 2 1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 2: borane-THF / 2-methyltetrahydrofuran / 3 h / 60 °C With borane-THF, sodium hydride in 2-methyltetrahydrofuran, N,N-dimethyl-formamide Patent; GALDERMA RESEARCH & DEVELOPMENT; Fournier, Jean-Francois; Clary, Laurence; Thoreau, Etienne; (164 pag.); US2018/50992; (2018); (A1) English

133/236

2018-08-17 23:02:17

View in Reaxys O N O

NH 2

O N O

Rx-ID: 47474262 View in Reaxys 364/553 Yield

Conditions & References 116.116.2 : 116.2: 2-(5-methoxy-2-nitrophenyl)-propylamine General procedure: 200 ml (200 mmol) of a complexed solution of borane-tetrahydrofuran is added to a solution containing 26 g (136 mmol) of (5-methoxy-2-nitrophenyl)-acetonitrile in 130 ml of 2-methyltetrahydrofuran at 60° C. After 3 hours, heating is stopped and 35 ml (863 mmol) of methanol is added slowly, as well as 200 ml of 1N aqueous solution of sodium hydroxide. The aqueous phase is then extracted with 250 ml of methyl-tetrahydrofuran. The organic phase is washed with water, dried over anhydrous sodium sulphate, filtered and concentrated partially. 400 ml of tert-butyl ether and 10 ml (175 mmol) of acetic acid are added. The mixture is cooled, left with stirring overnight and then concentrated and coevaporated with toluene. 40.6 g (100percent) of 2-(5-methoxy-2-nitrophenyl)-ethylamine acetate is obtained in the form of a brown oil. Similarly to example 115.2, starting from 663 mg (3.2 mmol) of 2-(5-methoxy-2-nitrophenyl)-propionitrile, 900 mg (104percent) of 2-(5-methoxy-2-nitrophenyl)-propylamine is obtained in the form of an oil. With borane-THF in 2-methyltetrahydrofuran, Time= 3h, T= 60 °C Patent; GALDERMA RESEARCH & DEVELOPMENT; Fournier, Jean-Francois; Clary, Laurence; Thoreau, Etienne; (164 pag.); US2018/50992; (2018); (A1) English View in Reaxys

NH 2 HCl

Rx-ID: 24220438 View in Reaxys 365/553 Yield

Conditions & References 33 : 2-(4-Methylphenyl)propylamine hydrochloride Preparation 33 2-(4-Methylphenyl)propylamine hydrochloride The title compound was prepared from the product of Preparation 32 as described in Preparation 8. Field Desorption Mass Spectrum: M=150 (M-HCl) Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2 HCl

Rx-ID: 24280193 View in Reaxys 366/553 Yield 1.76 g (73%)

Conditions & References 8 : 2-(4-Isopropylphenyl)propylamine hydrochloride Preparation 8 2-(4-Isopropylphenyl)propylamine hydrochloride

134/236

2018-08-17 23:02:17

In a 100 ml flask, fitted with a condenser, 2-(4-isopropylphenyl) propionitrile 1.90 g (11.0 mmol) was dissolved in tetrahydrofuran (70 ml) under a nitrogen atmosphere. Borane-methyl sulfide complex (10.0-10.2 M in tetrahydrofuran, 1.20 ml, 12.1 mmol) was added to the solution and the mixture heated to reflux for 3 hours. The solution was cooled to ambient temperature and a saturated solution of hydrochloric acid in methanol added slowly until a white precipitate formed. The solvent was removed in vacuo and the resulting white solid triturated (*4) with diethyl ether. Drying under vacuo gave 1.76 g (73percent) of the title compound. With hydrogenchloride in tetrahydrofuran, methanol Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2

Br Br

N H 2N

Rx-ID: 2204727 View in Reaxys 367/553 Yield

NH 2

Rx-ID: 8749883 View in Reaxys 368/553 Yield 86 %

Conditions & References With dimethylsulfide borane complex in tetrahydrofuran, Time= 18h, Heating Kendall, Jackie D.; Rewcastle, Gordon W.; Frederick, Raphael; Mawson, Claire; Denny, William A.; Marshall, Elaine S.; Baguley, Bruce C.; Chaussade, Claire; Jackson, Shaun P.; Shepherd, Peter R.; Bioorganic and Medicinal Chemistry; vol. 15; nb. 24; (2007); p. 7677 - 7687 View in Reaxys With dimethylsulfide borane complex in tetrahydrofuran, Heating Ornstein; Zimmerman; Arnold; Bleisch; Cantrell; Simon; Zarrinmayeh; Baker; Gates; Tizzano; Bleakman; Mandelzys; Jarvie; Ho; Deverill; Kamboj; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4354 - 4358 View in Reaxys 31 :Intermediate 31; 2-(4-Bromo-phenyl)-propylamine; A mixture of 3.00 g (14.3 mmol) 2-(4-bromo-phenyl)-propionitrile and 40 mL ammonia solution (7N in methanol) is charged with 0.30 g Raney nickel. The mixture is stirred under an atmosphere of hydrogen (50 psi) at r.t. for 34 h. The mixture is filtered and the solvent is removed in vacuo. The crude product is used without further purification.C9H12BrN (M=214.1 g/mol)ESI-MS: 214 [M+H]+ Rt (HPLC): 1.63 min (method E) With ammonia, hydrogen, Raney nickel in methanol, Time= 34h, T= 20 Â°C , p= 2585.81Torr Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2012/214785; (2012); (A1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

135/236

2018-08-17 23:02:17

NH 2

Rx-ID: 10203460 View in Reaxys 369/553 Yield

Conditions & References With lithium aluminium tetrahydride, aluminium trichloride in diethyl ether Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys

NH 2

N Br

Rx-ID: 11241290 View in Reaxys 370/553 Yield 94 %

981 mg

B : 2-(3-Bromophenyl)propan-1-amine (Intermediate 1H-b) Borane dimethyl sulfide complex (2M in THF, 7.29 mL, 14.57 mmol) was added to a solution of intermediate 1H-a (1.02 mL, 4.86 mmol) in dry THF (10 mL) at RT under argon, then heated at reflux for 5 h. The reaction was left to stand at RT overnight then quenched by dropwise addition of 6 M HCl (4 mL) and the mixture heated at reflux for 2 h. The reaction mixture was basified with 6 N NaOH then extracted three times with DCM. The organic phase was dried (Na2SO4), filtered and evaporated. The product was obtained as straw coloured liquid (981 mg). LCMS (Method 6): Rt=0.76 min, m/z 214.1/216.1 [M+H]+ With dimethylsulfide borane complex in tetrahydrofuran, Time= 5h, Inert atmosphere, Reflux Patent; CHIESI FARMACEUTISI S.p.A.; Accetta, Alessandro; Rancati, Fabio; Capelli, Anna Maria; Clark, David Edward; Tisselli, Patrizia; Edwards, Christine; Bhalay, Gurdip; (97 pag.); US2018/170939; (2018); (A1) English View in Reaxys

NH 2 N

1-nitro-cyclohexene-(1) Br

Rx-ID: 15457320 View in Reaxys 371/553 Yield

Conditions & References Reaction Steps: 2 1: K2CO3 / 16 h / 180 Â°C 2: BH3*SMe2 / tetrahydrofuran / Heating With dimethylsulfide borane complex, potassium carbonate in tetrahydrofuran Ornstein; Zimmerman; Arnold; Bleisch; Cantrell; Simon; Zarrinmayeh; Baker; Gates; Tizzano; Bleakman; Mandelzys; Jarvie; Ho; Deverill; Kamboj; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4354 - 4358 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

136/236

2018-08-17 23:02:17

NH 2

Rx-ID: 22989249 View in Reaxys 372/553 Yield 100 %

Conditions & References 19 Patent; Knobelsdorf, James Allen; Shepherd, Timothy Alan; Tromiczak, Eric George; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/229102; (2003); (A1) English View in Reaxys

NH 2

H 2N

Rx-ID: 23147244 View in Reaxys 373/553 Yield 23 %

Conditions & References 42.a : Example 42 2- (2, 5-Dioxoimidazolidin-4-yl)-N- [2- (4'-fluoro-1, 1'-biphenyl-4-yl) propyl]-acetamide; a)2- (4-Bromo-phenyl)-propylamine 2-Phenyl-propylamine (lg, 7.4mmol) was dissolved in n-hexane (30mL) and HBr/aq (5 drops) together with ZnBr on silica (1.75mmol/g,lg). Br2 (14.8mmol, 900RL) was slowly added and the slurry was stirred over night. The slurry was diluted with ethyl acetate (300mL) and washed with 2MNa2C03 (300mL). The organic phase was dried overNa2S04, filtered and evaporated to dryness. Purification and separation of regioisomers was done on semi prep-HPLCCl8-column (H2O : CH3CN, 1percent NH40Ac buffer, gradient 10percent to 60percent CH3CN,30 min). Yield 23percent With bromine, ZnBr2 on silica, hydrogen bromide in hexane, water Patent; ASTRAZENECA AB; WO2004/20415; (2004); (A1) English View in Reaxys

NH 2 N Br

Rx-ID: 33709943 View in Reaxys 374/553 Yield

Conditions & References Reaction Steps: 2 1: potassium carbonate / 16 h / 180 °C / autoclave 2: hydrogen; ammonia / Raney nickel / methanol / 34 h / 20 °C / 2585.81 Torr With ammonia, hydrogen, potassium carbonate, Raney nickel in methanol Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2012/214785; (2012); (A1) English View in Reaxys

NH 2

Rx-ID: 48311259 View in Reaxys 375/553 Yield

Conditions & References Reaction Steps: 2 1: potassium tert-butylate / tert-butyl alcohol; 1,2-dimethoxyethane / 10 - 20 °C / Inert atmosphere 2: dimethylsulfide borane complex / tetrahydrofuran / 5 h / Inert atmosphere; Reflux

137/236

2018-08-17 23:02:17

With dimethylsulfide borane complex, potassium tert-butylate in tetrahydrofuran, 1,2-dimethoxyethane, tert-butyl alcohol Patent; CHIESI FARMACEUTISI S.p.A.; Accetta, Alessandro; Rancati, Fabio; Capelli, Anna Maria; Clark, David Edward; Tisselli, Patrizia; Edwards, Christine; Bhalay, Gurdip; (97 pag.); US2018/170939; (2018); (A1) English View in Reaxys O

NH 2 OH

HCl

Rx-ID: 28020472 View in Reaxys 376/553 Yield

Conditions & References 16.a :(a) 3-(2-amino-1 -methyl-ethyl)-benzoic acid (as the hydrochloride salt); 14.5 g (82.8 mmol) 3-(cyano-methyl-methyl)benzoic acid are dissolved in a mixture of 200 ml THF and 140 ml of water, combined with 1.5 g palladium/charcoal and 82.7 ml (165.3 mmol) 2N hydrochloric acid and hydrogenated for four hours at 3 bar hydrogen and RT. Then the mixture is filtered to remove the catalyst and concentrated to dryness i. vac. Rt value: 0.81 min (Method B) C10H13NO2 x HCI (179.22) <n="69"/ >Mass spectrum: (M+H)+ = 180 With hydrogenchloride, hydrogen, 10 wt. % palladium on activated carbon in tetrahydrofuran, water, Time= 4h, T= 20 °C , p= 2250.23Torr Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; WO2008/135526; (2008); (A1) English View in Reaxys NH 2

F F F O

F F

Rx-ID: 1064937 View in Reaxys 377/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys NH 2 F

F O F

F F F

Rx-ID: 1064938 View in Reaxys 378/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

138/236

2018-08-17 23:02:17

NH 2 F F O F

F F F

Rx-ID: 22558161 View in Reaxys 379/553 Yield

F F O

Rx-ID: 22565596 View in Reaxys 380/553 Yield

O N O

F F F F

F F

Rx-ID: 22566021 View in Reaxys 381/553 Yield

139/236

2018-08-17 23:02:17

NH 2 F

F N F

F F F

Rx-ID: 22566023 View in Reaxys 382/553 Yield

Rx-ID: 22567101 View in Reaxys 383/553 Yield

F O F

F F F

Rx-ID: 22571671 View in Reaxys 384/553 Yield

140/236

2018-08-17 23:02:17

H H 2N

H 2N

H N

NH 2

Rx-ID: 9509255 View in Reaxys 385/553 Yield

Conditions & References With immobilized Candida antarctica lipase B (EC 3.1.1.1.), Time= 24h, T= 30 °C , p= 5Torr , Enzymatic reaction, Product distribution Irimescu, Roxana; Kato, Katsuya; Tetrahedron Letters; vol. 45; nb. 3; (2004); p. 523 - 525 View in Reaxys

NH 2

Rx-ID: 1062253 View in Reaxys 386/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 22565296 View in Reaxys 387/553 Yield

NH 2

O Cl

Rx-ID: 22587530 View in Reaxys 388/553 Yield

Conditions & References Reaction Steps: 3 1: (i) nBuNH2, toluene, (ii) Fe, FeCl3, aq. HCl 2: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 3: HCONH2, HCO2H / 16 h / 170 - 180 °C With formic acid, formamide

141/236

2018-08-17 23:02:17

Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

N N

Rx-ID: 23499175 View in Reaxys 389/553 Yield

Conditions & References

98.6 %

2.36.b :2.36.b 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propylamine 100 mg of Raney nickel are added to a solution of 400 mg (1.87 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile in 20 mL methanolic ammonia solution. The reaction mixture is stirred overnight at 50° C. and 5 bar hydrogen atmosphere. After the catalyst has been filtered off the solvent is eliminated using the rotary evaporator. The amine, which contains approx. 20percent of dimethylated compound, is further reacted without any more purification. Yield: 0.4 g (98.6percent of theory); C15H22N2 (M=218.345); calc.: molar peak (M+H)+: 219 fnd.: molar peak (M+H)+: 219; Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1). With hydrogen, nickel in methanol, ammonia, T= 50 °C , p= 3750.38Torr Patent; Boehringer Ingelheim International GmbH; US2004/242572; (2004); (A1) English View in Reaxys F NH 2 HCl O

Rx-ID: 25413452 View in Reaxys 390/553 Yield 75%

Conditions & References 3.2 : Preparation 3 (2) 15 ml of Raney Nickel are added to an ethanol solution of 5.05 g of the product obtained above, and 30 g of hydrazine monohydrate are added dropwise thereto at a temperature between 40 and 50 °C. After the reaction, the catalyst is filterd off, and the filtrate is evaporated. The residue is added to 15percent methanolic hydrochloric acid, and the mixture is evaporated to remove the solvent. The residue is recrystallized from a mixture of methanol and isopropylether, whereby 4.23 g of 1- amino-2-(2-fluoro-4-methoxyphenyl)propane hydrochloride are obtained as colorless crystals. Yield 75percent m.p. 147-149°C Patent; TANABE SEIYAKU CO., LTD.; EP255728; (1991); (B1) English View in Reaxys

75%

3.2 : Preparation 3 (2) 15 ml of Raney Nickel are added to an ethanol solution of 5.05 g of the product obtained above, and 30 g of hydrazine monohydrate are added dropwise thereto at a temperature between 40° and 50° C. After the reaction, the catalyst is filtered off, and the filtrate is evaporated. The residue is added to 15percent methanolic hydrochloric acid, and the mixture is evaporated to remove the solvent.

142/236

2018-08-17 23:02:17

The residue is recrystallized from a mixture of methanol and isopropylether, whereby 4.23 g of 1-amino-2-(2-fluoro-4-methoxyphenyl)propane hydrochloride are obtained as colorless crystals. Yield 75percent; m.p. 147°-149° C. Patent; Tanabe Seiyaku Co., Ltd.; US4866196; (1989); (A) English View in Reaxys

NH 2

O O

N O

Rx-ID: 1066096 View in Reaxys 391/553 Yield

Conditions & References With lithium aluminium tetrahydride Aldous,F.A.B. et al.; Journal of Medicinal Chemistry; vol. 17; (1974); p. 1100 - 1111 View in Reaxys N

NH 2

Rx-ID: 35701911 View in Reaxys 392/553 Yield

Conditions & References 15; 8.2 :General procedure: Scheme 8, Step 2. To a solution of 2-(3,4-diethoxyphenyl)propanenitrile ( 130 mg, 0.593 mmol) in THF (3 ml) was added slowly borane-methyl sulfide complex (0.593 ml, 1.186 mmol) (2.0M in THF). After the reaction mixture was refluxed for overnight, it was quenched with methanol and concentrated in vacuuo. The crude product was used in the next reaction without further purification. [0203] NMR (400 MHz, CHLOROFORM-d) α ppm 6.84 (d, J=8.22 Hz, 1 H), 6.70 - 6.76 (m, 2 H), 4.09 (dq, J=8.61 , 7.04 Hz, 4 H), 3.70 (br. s., 1 H), 2.77 - 2.85 (m, 2 H), 2.64 - 2.71 (m, 1 H), 1.66 - 1.72 (m, 1 H), 1.44 (td, J=6.95, 3.33 Hz, 6 H), 1.23 (d, J=7.04 Hz, 3 H). With dimethylsulfide borane complex in tetrahydrofuran, Reflux Patent; THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES; MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.; UNIVERSITY OF MARYLAND, BALTIMORE; BOXER, Matthew B.; BELLER, Mathias; TSCHAPALDA, Kirsten; SHEN, Min; LIU, Li; ZHANG, Yaqin; LI, Zhuyin; SZTALRYD, Carole; WO2013/78413; (2013); (A1) English View in Reaxys NH 2

O N

O O

Rx-ID: 35701912 View in Reaxys 393/553

143/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 2 1: potassium tert-butylate / tert-butyl alcohol / 4 h / 20 °C / Reflux 2: dimethylsulfide borane complex / tetrahydrofuran / Reflux With dimethylsulfide borane complex, potassium tert-butylate in tetrahydrofuran, tert-butyl alcohol Patent; THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES; MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.; UNIVERSITY OF MARYLAND, BALTIMORE; BOXER, Matthew B.; BELLER, Mathias; TSCHAPALDA, Kirsten; SHEN, Min; LIU, Li; ZHANG, Yaqin; LI, Zhuyin; SZTALRYD, Carole; WO2013/78413; (2013); (A1) English View in Reaxys F F

NH 2

F F

Rx-ID: 7819974 View in Reaxys 394/553 Yield

Conditions & References aus CN Petrova et al.; Siberian Chemistry Journal (English Translation); (1970); p. 401,403; ; nb. 3; p. 119 View in Reaxys

NH 2

Rx-ID: 1133660 View in Reaxys 395/553 Yield

Conditions & References With hydrogen, nickel Patent; Eli Lilly; FR2015728; (1970) French; ; vol. 75; nb. 48707; (1971) View in Reaxys

NH 2

Rx-ID: 22390399 View in Reaxys 396/553 Yield

Conditions & References Reaction Steps: 2 2: H2 / Raney-Ni With hydrogen, nickel Patent; Eli Lilly; FR2015728; (1970) French; ; vol. 75; nb. 48707; (1971) View in Reaxys

NH 2

Rx-ID: 22390969 View in Reaxys 397/553

144/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 4 1: NaBH4 2: PBr3 4: H2 / Raney-Ni With sodium tetrahydroborate, hydrogen, phosphorus tribromide, nickel Patent; Eli Lilly; FR2015728; (1970) French; ; vol. 75; nb. 48707; (1971) View in Reaxys

NH 2

Rx-ID: 22390993 View in Reaxys 398/553 Yield

Conditions & References Reaction Steps: 3 1: PBr3 3: H2 / Raney-Ni With hydrogen, phosphorus tribromide, nickel Patent; Eli Lilly; FR2015728; (1970) French; ; vol. 75; nb. 48707; (1971) View in Reaxys

NH 2

Rx-ID: 1061108 View in Reaxys 399/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys Br

NH 2

Rx-ID: 1061524 View in Reaxys 400/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Br O

Rx-ID: 1074028 View in Reaxys 401/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C

145/236

2018-08-17 23:02:17

Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 7732924 View in Reaxys 402/553 Yield

Conditions & References entspr.Keton: 1) Formamid, HCO2H 2) HCl Patent; Labor.Biosedra; FRM7432; (1968); ; vol. 76; nb. 99319; (1972) View in Reaxys Br

H 2N

NH 2

Rx-ID: 10200172 View in Reaxys 403/553 Yield 6 %, 29 %

Conditions & References With ammonium acetate, sodium cyanoborohydride in methanol, Time= 18h Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys Br

Br NH 2

Rx-ID: 14516597 View in Reaxys 404/553 Yield

Conditions & References Reaction Steps: 2 1: 98 percent / LDA / tetrahydrofuran / 1.5 h / -78 - 20 °C 2: 6 percent / NaBH3CN; NH4OAc / methanol / 18 h With ammonium acetate, sodium cyanoborohydride, lithium diisopropyl amide in tetrahydrofuran, methanol Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys Br

Br NH 2

Rx-ID: 14516598 View in Reaxys 405/553 Yield

Conditions & References Reaction Steps: 2 1: 98 percent / LDA / tetrahydrofuran / 1.5 h / -78 - 20 °C 2: 29 percent / NaBH3CN; NH4OAc / methanol / 18 h With ammonium acetate, sodium cyanoborohydride, lithium diisopropyl amide in tetrahydrofuran, methanol

146/236

2018-08-17 23:02:17

Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys Br

Br NH 2

Rx-ID: 14518269 View in Reaxys 406/553 Yield

Conditions & References Reaction Steps: 4 1.1: 100 percent / thionyl chloride / 2 h 2.1: CuI / diethyl ether; petroleum ether / 0.08 h / cooling 2.2: 79 percent / diethyl ether; petroleum ether / 0.5 h / -78 °C 3.1: 98 percent / LDA / tetrahydrofuran / 1.5 h / -78 - 20 °C 4.1: 6 percent / NaBH3CN; NH4OAc / methanol / 18 h With copper(l) iodide, thionyl chloride, ammonium acetate, sodium cyanoborohydride, lithium diisopropyl amide in tetrahydrofuran, methanol, diethyl ether, Petroleum ether Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys Br

Br NH 2

Rx-ID: 14518270 View in Reaxys 407/553 Yield

Conditions & References Reaction Steps: 4 1.1: 100 percent / thionyl chloride / 2 h 2.1: CuI / diethyl ether; petroleum ether / 0.08 h / cooling 2.2: 79 percent / diethyl ether; petroleum ether / 0.5 h / -78 °C 3.1: 98 percent / LDA / tetrahydrofuran / 1.5 h / -78 - 20 °C 4.1: 29 percent / NaBH3CN; NH4OAc / methanol / 18 h With copper(l) iodide, thionyl chloride, ammonium acetate, sodium cyanoborohydride, lithium diisopropyl amide in tetrahydrofuran, methanol, diethyl ether, Petroleum ether Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys Br

Br NH 2

Rx-ID: 14518935 View in Reaxys 408/553 Yield

Conditions & References Reaction Steps: 3 1.1: CuI / diethyl ether; petroleum ether / 0.08 h / cooling 1.2: 79 percent / diethyl ether; petroleum ether / 0.5 h / -78 °C 2.1: 98 percent / LDA / tetrahydrofuran / 1.5 h / -78 - 20 °C 3.1: 6 percent / NaBH3CN; NH4OAc / methanol / 18 h With copper(l) iodide, ammonium acetate, sodium cyanoborohydride, lithium diisopropyl amide in tetrahydrofuran, methanol, diethyl ether, Petroleum ether

147/236

2018-08-17 23:02:17

Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys Br

NH 2

Rx-ID: 14518936 View in Reaxys 409/553 Yield

Conditions & References Reaction Steps: 3 1.1: CuI / diethyl ether; petroleum ether / 0.08 h / cooling 1.2: 79 percent / diethyl ether; petroleum ether / 0.5 h / -78 °C 2.1: 98 percent / LDA / tetrahydrofuran / 1.5 h / -78 - 20 °C 3.1: 29 percent / NaBH3CN; NH4OAc / methanol / 18 h With copper(l) iodide, ammonium acetate, sodium cyanoborohydride, lithium diisopropyl amide in tetrahydrofuran, methanol, diethyl ether, Petroleum ether Viswanathan, Rajesh; Prabhakaran, Erode N.; Plotkin, Michael A.; Johnston, Jeffrey N.; Journal of the American Chemical Society; vol. 125; nb. 1; (2003); p. 163 - 168 View in Reaxys

NH 2

Rx-ID: 22558855 View in Reaxys 410/553 Yield

NH 2

Rx-ID: 22564980 View in Reaxys 411/553 Yield

148/236

2018-08-17 23:02:17

NH 2

Rx-ID: 22564982 View in Reaxys 412/553 Yield

NH 2

Rx-ID: 22566954 View in Reaxys 413/553 Yield

NH 2

Br N

Rx-ID: 22567404 View in Reaxys 414/553 Yield

Br NH 2

N O

Rx-ID: 22573975 View in Reaxys 415/553 Yield

Conditions & References Reaction Steps: 3 1: Fe, FeCl3, aq. HCl / 1 h / Heating 2: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 3: HCONH2, HCO2H / 16 h / 170 - 180 °C

149/236

2018-08-17 23:02:17

With hydrogenchloride, formic acid, iron(III) chloride, iron, formamide Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys O N

NH 2

Rx-ID: 22573977 View in Reaxys 416/553 Yield

NH 2

Br O Br

Rx-ID: 22582583 View in Reaxys 417/553 Yield

NH 2

Rx-ID: 22587515 View in Reaxys 418/553 Yield

150/236

2018-08-17 23:02:17

NH 2

NH S O

Rx-ID: 7815962 View in Reaxys 419/553 Yield

Conditions & References entspr. Acet-amino-Verb., HCl, W. Patent; Smith Kline and French Laboratories; US3487154; (1967); ; vol. 72; nb. 90059q; (1970) View in Reaxys H 2N O

HCl

Rx-ID: 28800851 View in Reaxys 420/553 Yield

Conditions & References Patent; Myriad Genetics, Incorporated; US2009/275583; (2009); (A1) English View in Reaxys

NH 2 HCl

O N

Rx-ID: 37629494 View in Reaxys 421/553 Yield

Conditions & References Reaction Steps: 2 1.1: N-ethyl-N,N-diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: 1.75 h / 0 - 78 °C 2.1: hydrogenchloride; hydrogen; 10% palladium on activated carbon; Degussa type / methanol; water With hydrogenchloride, n-butyllithium, 10% palladium on activated carbon; Degussa type, hydrogen, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, methanol, hexane, water Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He; Journal of Medicinal Chemistry; vol. 57; nb. 6; (2014); p. 2601 - 2610 View in Reaxys

NH 2 HCl

O N

Rx-ID: 37629495 View in Reaxys 422/553 Yield 1.21 g

Conditions & References With hydrogenchloride, 10% palladium on activated carbon; Degussa type, hydrogen in methanol, water

151/236

2018-08-17 23:02:17

Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He; Journal of Medicinal Chemistry; vol. 57; nb. 6; (2014); p. 2601 - 2610 View in Reaxys

H N

NH 2

O Cl

O O

Rx-ID: 3279797 View in Reaxys 423/553 Yield

Conditions & References

75.2 %

With hydrogen, 10 wt. % palladium on activated carbon in methanol, water, Time= 48h, p= 2585.7Torr Riggs, Robert M.; McKenzie, Ann T.; Byrn, Stephen R.; Nichols, David E.; Foreman, Mark M.; Truex, Lewis L.; Journal of Medicinal Chemistry; vol. 30; nb. 10; (1987); p. 1914 - 1918 View in Reaxys

NH 2

O Br

Rx-ID: 31698888 View in Reaxys 424/553 Yield

Conditions & References Reaction Steps: 6 1.1: triethylamine / toluene / 0.17 h / 0 °C 2.1: lithium hexamethyldisilazane / hexane; tetrahydrofuran / 0.17 h / -78 °C 2.2: 4 h / -78 - 20 °C 3.1: sodium hexamethyldisilazane / toluene; tetrahydrofuran / 3.75 h / -78 - 20 °C 4.1: water; sodium tetrahydroborate / tetrahydrofuran / 3 h / 20 °C 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h / 20 °C 6.1: hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, di-isopropyl azodicarboxylate, water, sodium hexamethyldisilazane, triethylamine, triphenylphosphine, lithium hexamethyldisilazane, hydrazine in tetrahydrofuran, hexane, toluene Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

F O

NH 2 O

Rx-ID: 31698960 View in Reaxys 425/553 Yield

Conditions & References Reaction Steps: 5 1.1: lithium hexamethyldisilazane / hexane; tetrahydrofuran / 0.17 h / -78 °C 1.2: 4 h / -78 - 20 °C

152/236

2018-08-17 23:02:17

2.1: sodium hexamethyldisilazane / toluene; tetrahydrofuran / 3.75 h / -78 - 20 °C 3.1: water; sodium tetrahydroborate / tetrahydrofuran / 3 h / 20 °C 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h / 20 °C 5.1: hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, di-isopropyl azodicarboxylate, water, sodium hexamethyldisilazane, triphenylphosphine, lithium hexamethyldisilazane, hydrazine in tetrahydrofuran, hexane, toluene Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

F NH 2 O O

Br O

Rx-ID: 31698964 View in Reaxys 426/553 Yield

Conditions & References Reaction Steps: 4 1: sodium hexamethyldisilazane / toluene; tetrahydrofuran / 3.75 h / -78 - 20 °C 2: water; sodium tetrahydroborate / tetrahydrofuran / 3 h / 20 °C 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h / 20 °C 4: hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, di-isopropyl azodicarboxylate, water, sodium hexamethyldisilazane, triphenylphosphine, hydrazine in tetrahydrofuran, toluene Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

F NH 2 O O

Br O

Rx-ID: 31698968 View in Reaxys 427/553 Yield

Conditions & References Reaction Steps: 3 1: water; sodium tetrahydroborate / tetrahydrofuran / 3 h / 20 °C

153/236

2018-08-17 23:02:17

2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h / 20 °C 3: hydrazine / toluene / 1 h / 80 - 90 °C With sodium tetrahydroborate, di-isopropyl azodicarboxylate, water, triphenylphosphine, hydrazine in tetrahydrofuran, toluene Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

F Br

NH 2

Rx-ID: 31698970 View in Reaxys 428/553 Yield

Conditions & References Reaction Steps: 2 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h / 20 °C 2: hydrazine / toluene / 1 h / 80 - 90 °C With di-isopropyl azodicarboxylate, triphenylphosphine, hydrazine in tetrahydrofuran, toluene Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

F O

NH 2

Br N

Br O

Rx-ID: 31698972 View in Reaxys 429/553 Yield

Conditions & References 635 :Example 635 (S)-tert-buty\\ 2-(2-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl) phenyl)propylcarbamateTo a solution of ((3/4)-2-(2-(4-bromo-2-fluorophenyl)propyl)isoindoline-l ,3-dione) (1.0 g, 2.8 mmol) in toluene (10 mL) was added hydrazine (1.3 mL, 41.5 mmol) dropwise. The reaction mixture was heated at 80-90 °C for 1 h and cooled to room temperature. The supernatant was decanted, and the residual solid was washed with toluene. The combined solution was evaporated under vacuum ,dissolved in DCM (10 mL) and cooled to 0 °C. Next, Boc20 (870 mg, 4 mmol) and Et3N (0.5 mL, 4 mmol) were added and the reaction mixture stirred for 30 min at room temperature. The reaction mixture diluted with DCM (20 mL) and washed with IN HC1 (1 xl O mL), water (1 x 20 mL) followed by brine (1 x 10 mL), dried over sodium sulfate, and evaporated under vacuum to afford the desire product (860 mg, 99percent) which was taken to next step without furthure purification. ESI MS m/z 333 [C|4Hi9BrFN02 + H]+The next step carried out following the procedure G (Scheme II): (S)-tert-bu\\y\\2-(4-bromo-2-fluorophenyl)propylcarbamate (860 mg, 2.66) was reacted with KOAc (833 mg, 8.5 mmol), Pd(dppf)Cl2 (200 mg, 0.26 mmol) and bis(pinacolato)diboron (863 mg, 3.4 mmol) to afford (S)-tert-bu y\\ 2-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl) propylcarbamate as a colourless paste (900 mg, 89percent): ESI MS m/z 380 [C20H3iBFNO4 + H]+ With hydrazine in toluene, Time= 1h, T= 80 - 90 °C Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

154/236

2018-08-17 23:02:17

H 2N

NH 2

HBr

Rx-ID: 25694795 View in Reaxys 430/553 Yield

Conditions & References 143 :2-(3-Methoxyphenyl)propan-1-amine (760 mg, 4.61 mmol) was added HBr solution(5.2 mL, 48percent solution in H2O 46.1 mmol). The reaction was heated at 100° C. for 4 h. It was cooled down to room temperature. Removal of solvents gave crude 3-(1-aminopropan-2-yl)phenol HBr salt as a greenish foam. HPLC retention time (Method C)=0.95 min. LC/MS (ESI) (M +H)+=152.18. 1H NMR (CDCl3, 400 MHz) α ppm 1.31 (d, J=6.59 Hz, 3H), 2.90-3.02 (m, 1H), 3.06-3.13 (m, 1H), 3.30 (s, 1H), 6.69-6.79 (m, 3H), 7.14-7.22 (m, 1H). With hydrogen bromide in water, Time= 4h, T= 100 °C Patent; Bristol-Myers Squibb Company; US2007/93523; (2007); (A1) English View in Reaxys NH 2

O O N

Rx-ID: 9097933 View in Reaxys 431/553 Yield

Conditions & References With ammonia, hydrogen, nickel in methanol, T= 20 °C Andres, J Ignacio; Alonso, Jose M; Diaz, Adolfo; Fernandez, Javier; Iturrino, Laura; Martinez, Pedro; Matesanz, Encarna; Freyne, Eddy J; Deroose, Frederik; Boeckx, Gustaaf; Petit, Davy; Diels, Gaston; Megens, Anton; Somers, Marijke; Van Wauwe, Jean; Stoppie, Paul; Cools, Marina; De Clerck, Fred; Peeters, Danielle; de Chaffoy, Didier; Bioorganic and medicinal chemistry letters; vol. 12; nb. 4; (2002); p. 653 - 658 View in Reaxys

NH 2

N N N

Rx-ID: 29049813 View in Reaxys 432/553 Yield 91 %

Conditions & References Stage 1: With triphenylphosphine in tetrahydrofuran, Time= 48h, T= 20 °C Stage 2: With water, sodium hydroxide in tetrahydrofuran Mahindroo, Neeraj; Connelly, Michele C.; Punchihewa, Chandanamali; Kimura, Hiromichi; Smeltzer, Matthew P.; Wu, Song; Fujii, Naoaki; Journal of Medicinal Chemistry; vol. 52; nb. 14; (2009); p. 4277 - 4287 View in Reaxys

155/236

2018-08-17 23:02:17

H 2N

F F F

HCl H N

F O

F F

Rx-ID: 31719294 View in Reaxys 433/553 Yield 94.5 %

Conditions & References Preparation of (R)-2-(3-trifluoromethyl-phenyl)-propyl-ammonium; chloride (7) A solution of 0.406 g (0.00134 mol) [(R)-2-(3-trifluoromethyl-phenyl)-propyl]-carbamic acid tert-butyl ester in 4.0 ml of a 2.26 M solution of hydrochloric acid in ethyl acetate was kept at room temperature for 4h. The solvent was evaporated and the residue was triturated with 4.0 ml heptane. The solid was collected by filtration and dried to constant weight to yield 0.303 g 7 (94.5percent) melting at 167-168 °C. 1H NMR (300 MHz, DMSOd6) α 8.33 (s, broad 3H), 7.60-7.40 (m, 4H), 3.46-3.33 (m, 1H), 3.35-3.20 (m, 1H), 3.15-3.00 (m, 2H), 1.41 (d, J=6.9 Hz, 3H) ppm; EA C10H12 F3NO2H.Cl.calculated (percent) C 50.12, H 5.47, N 5.84; found C 50.04, H 5.63, N 5.70 With hydrogenchloride in ethyl acetate, Time= 4h, T= 20 °C , Inert atmosphere Hebeisen, Paul; Weiss, Urs; Alker, Andre; Staempfli, Andreas; Tetrahedron Letters; vol. 52; nb. 41; (2011); p. 5229 - 5233 View in Reaxys

NH 2 HCl

N Cl

Rx-ID: 23762253 View in Reaxys 434/553 Yield 70 %

Conditions & References 5.B :B. 2-(3,4-Dichloro-phenyl)-propylamine hydrochloride. ; 2-(3,4-Dichloro-phenyl)-propionitrile (5.0 g, 25.0 mmol) was dissolved in THF (80 mL). BH3.THF (1 M in THF, 27.5 mL, 27.5 mmol) was added and the mixture was stirred overnight at rt. EtOH (10 mL) was added, the mixture was stirred for 20 min, and HCl in Et2O (2 M, 12.5 mL) was added. After stirring for 1 h, water was added, causing precipitation of the product. The product was collected by suction filtration and dried (4.2 g, 70percent). MS (ESI+): mass calcd. for C9H11Cl2N, 204.1; m/z found, 205 [M+H]++. 1H NMR (400 MHz, CD3OD): 7.45-7.42 (m, 2H), 7.17-7.15 (m, 1H), 3.05-3.02 (m, 2H), 2.98-2.96 (m, 1H), 1.24 (d, J=6.5, 3H). Stage 1: With borane-THF in tetrahydrofuran, T= 20 °C Stage 2: With hydrogenchloride in tetrahydrofuran, ethanol, Time= 1h Patent; Allison, Brett; Phuong, Victor K.; Pippel, Marna C.W.; Rabinowitz, Michael H.; Venkatesan, Hariharan; US2006/69286; (2006); (A1) English View in Reaxys

O N

NH 2

Rx-ID: 2931131 View in Reaxys 435/553 Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 1h, T= 60 °C Martinez, Silvio J.; Larsen, Lesley; Street, Janathan D.; Joule, John A.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1988); p. 1705 - 1710 View in Reaxys

156/236

2018-08-17 23:02:17

O O

NH 2

Rx-ID: 20870351 View in Reaxys 436/553 Yield

Conditions & References Reaction Steps: 2 1: 75 percent / cuprous iodide / tetrahydrofuran; diethyl ether / 1 h / 0 °C 2: lithium aluminium hydride / tetrahydrofuran / 1 h / 60 °C With copper(l) iodide, lithium aluminium tetrahydride in tetrahydrofuran, diethyl ether Martinez, Silvio J.; Larsen, Lesley; Street, Janathan D.; Joule, John A.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1988); p. 1705 - 1710 View in Reaxys

NH 2

H N

O O

Rx-ID: 39810637 View in Reaxys 437/553 Yield

Conditions & References 4-(2-Isothiocyanato-1-methylethyl)phenol (14) [43] was obtained from 4-(2-amino-1-methylethyl)phenol by Boc protection of the alcohol [44] followed by O-benzylation (benzyl bromide, potassium carbonate), N-deprotection (hydrochloric acid) and reaction with thiophosgene. Finally, debenzylation by reaction with triphenylphosphine hydrobromide in acetonitrile under microwave conditions [45], gave the required compound (14). With hydrogenchloride, water Spencer, Emma S.; Dale, Edward J.; Gommans, Aimée L.; Rutledge, Malcolm T.; Vo, Christine T.; Nakatani, Yoshio; Gamble, Allan B.; Smith, Robin A.J.; Wilbanks, Sigurd M.; Hampton, Mark B.; Tyndall, Joel D.A.; European Journal of Medicinal Chemistry; vol. 93; (2015); p. 501 - 510 View in Reaxys

NH 2

O OH Br

Rx-ID: 39810639 View in Reaxys 438/553 Yield

Conditions & References Reaction Steps: 2 1: potassium carbonate 2: hydrogenchloride; water With hydrogenchloride, water, potassium carbonate

157/236

2018-08-17 23:02:17

Spencer, Emma S.; Dale, Edward J.; Gommans, Aimée L.; Rutledge, Malcolm T.; Vo, Christine T.; Nakatani, Yoshio; Gamble, Allan B.; Smith, Robin A.J.; Wilbanks, Sigurd M.; Hampton, Mark B.; Tyndall, Joel D.A.; European Journal of Medicinal Chemistry; vol. 93; (2015); p. 501 - 510 View in Reaxys

NH 2

HCl

O O

Rx-ID: 24821792 View in Reaxys 439/553 Yield

Conditions & References 10.4 : Preparation 10 (4) The product obtained above is dissolved in 200 ml of 6N hydrochloric acid, and the solution is refluxed for 7.5 hours. After the reaction, the solvent is distilled off, and the residue is crystallized with tetrahydrofuran. 19 g of 4-(2-amino-1-methylethyl)phenoxyacetic acid hydrochloride are obtained as colorless solids. m.p. 220.5°-223° C. (decomp.) Patent; Tanabe Seiyaku Co., Ltd.; US4948810; (1990); (A) English View in Reaxys 52.2 : Example 52 (2) The product obtained above is dissolved in 200 ml of 6N-hydrochloric acid, and the solution is refluxed for 7.5 hours. After the reaction, the solvent is distilled off, and the residue is crystallized with tetrahydrofuran, whereby 19 g of (+-)-4-(2amino-1-methylethyl)phenoxyacetic acid hydrochloride are obtained as colorless solids. m.p. 220.5-223°C (decomp.) Mass (m/e):209(M+), 179 Patent; TANABE SEIYAKU CO., LTD.; EP255728; (1991); (B1) English View in Reaxys 52.2 : EXAMPLE 52 (2) The product obtained above is dissolved in 200 ml of 6N-hydrochloric acid, and the solution is refluxed for 7.5 hours. After the reaction, the solvent is distilled off, and the residue is crystallized with tetrahydrofuran, whereby 19 g of (+-)-4-(2amino-1-methylethyl)phenoxyacetic acid hydrochloride are obtained as colorless solids. m.p. 220.5°-223° C. (decomp.); Mass (m/e): 209 (M+), 179; IR αmax nujol (cm-1): 1730. Patent; Tanabe Seiyaku Co., Ltd.; US4866196; (1989); (A) English View in Reaxys NH 2 Cl Cl

H 2N

Rx-ID: 31698897 View in Reaxys 440/553 Yield

Conditions & References Reaction Steps: 2 1.1: dichloromethane / 1.5 h / 0 - 20 °C 1.2: 14 h / 0 °C 2.1: sodium hydroxide; methanol / 14 h / 20 °C

158/236

2018-08-17 23:02:17

With methanol, sodium hydroxide in dichloromethane Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys NH 2

Rx-ID: 31698976 View in Reaxys 441/553 Yield

Conditions & References Reaction Steps: 3 1.1: borane-THF / toluene / 4 h / 0 °C / Reflux 2.1: dichloromethane / 1.5 h / 0 - 20 °C 2.2: 14 h / 0 °C 3.1: sodium hydroxide; methanol / 14 h / 20 °C With methanol, borane-THF, sodium hydroxide in dichloromethane, toluene Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys NH 2

O F N H

Rx-ID: 31698978 View in Reaxys 442/553 Yield

Conditions & References 653 :Example 653 tert-butyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl) propylcarbamate A mixture of N-(2-(4-bromo-2-chlorophenyl)propyl)-2,2,2-trifluoroacetamide (14 g, 40.6 mmol), methanol (200 mL) and sodium hydroxide (2M, 200 mL, 81.2 mmol) was stirred at room temperature for 14 h. LCMS showed completion of the reaction. The solvent was removed, extraction with methylene chloride (200 mL) and concentrated to give an oil. The residue was dissolved in methylene chloride (100 mL) and cooled to 0 °C. Triethylamine (8.3 mL, 61.0 mmol) and di-tert-butyl dicarbonate (13.3 g, 61.0 mmol) and the reaction mixture stirred at room temperature for 18 h. The reaction mixture concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to obtain the desired product (13.8 g, 90percent) as white solid: ESI MS m/z 293 [Ci4H19BrClN02 - 56]+. With methanol, sodium hydroxide, Time= 14h, T= 20 °C Patent; ONCOTHERAPY SCIENCE, INC.; NAKAMURA, Yusuke; MATSUO, Yo; HISADA, Shoji; AHMED, Feryan; HUNTLEY, Raymond; SAJJADI-HASHEMI, Zohreh; JENKINS, David, M.; KARGBO, Robert B.; CUI, Wenge; GAUUAN, Polivina, Jolicia, F.; WALKER, Joel R.; DECORNEZ, Helene; GURRAM, Mahender; WO2011/123419; (2011); (A1) English View in Reaxys

159/236

2018-08-17 23:02:17

NH 2

O N O

O O

Rx-ID: 9098297 View in Reaxys 443/553 Yield

Conditions & References

100%

20.d : N-[2-(3-cyclopentyloxy-4-methoxyphenyl)propyl]oxamide (d) 2-(3-Cyclopentyloxy-4-methoxyphenyl)propylamine. To a solution of (3-cyclopentyloxy-4-methoxyphenyl)propionitrile (0.5 g, 2.0 mmol) in methanol (15 mL) was added 70percent perchloric acid (0.32 g, 2.2 mmol) and 10percent palladium on activated carbon (92 mg). The resulting mixture was hydrogenated at 50 psi hydrogen for 2 h and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was partitioned between methylene chloride and aqueous sodium carbonate and the methylene chloride layer was washed three times with water and dried (potassium carbonate). Solvent removal provided an oil (0.5 g, 100percent). With perchloric acid, hydrogen, palladium on activated carbon in methanol Patent; SmithKline Beecham Corporation; US5393788; (1995); (A) English View in Reaxys With ammonia, hydrogen, nickel in methanol, T= 20 °C Andres, J Ignacio; Alonso, Jose M; Diaz, Adolfo; Fernandez, Javier; Iturrino, Laura; Martinez, Pedro; Matesanz, Encarna; Freyne, Eddy J; Deroose, Frederik; Boeckx, Gustaaf; Petit, Davy; Diels, Gaston; Megens, Anton; Somers, Marijke; Van Wauwe, Jean; Stoppie, Paul; Cools, Marina; De Clerck, Fred; Peeters, Danielle; de Chaffoy, Didier; Bioorganic and medicinal chemistry letters; vol. 12; nb. 4; (2002); p. 653 - 658 View in Reaxys

NH 2

HBr

Rx-ID: 24831030 View in Reaxys 444/553 Yield

Conditions & References 4.3 : Preparation 4 (3) Hydrobromic acid is added to 4.55 g of the product obtained above, and the mixture is refluxed. Then, the reaction mixture is evaporated, and the residue is crystallized with a mixture of isopropyl alcohol and isopropyl ether. 5.25 g of 4-(2-amino-1-methylethyl)-2-fluorophenol hydrobromide are obtained as colorless crystals. m.p. 119°-121° C. Patent; Tanabe Seiyaku Co., Ltd.; US4948810; (1990); (A) English View in Reaxys F F

NH 2

Na +

HCl

HBr

O– H 2N

Rx-ID: 25457821 View in Reaxys 445/553

160/236

2018-08-17 23:02:17

Yield

Conditions & References

95%

10.1 : Preparation 10 (1) 4.19 g of 1-amino-2-(2-fluoro-4-methoxyphenyl)propane hydrochloride are neutralized with a mixture of chloroform and an aqueous sodium bicarbonate solution. The chloroform layer is separated therefrom and condensed to dryness. Hydrobromic acid is added to the residue, and the mixture is refluxed. Then, the reaction mixture is evaporated, and the residue is recrystallized from a mixture of isopropylacohol and isopropylether. 4.53 g of 3-fluoro-4-(2-amino-1-methylethyl)phenol hydrobromide are obtained. Yield 95percent m.p. 182-183.5°C With hydrogen bromide in chloroform Patent; TANABE SEIYAKU CO., LTD.; EP255728; (1991); (B1) English View in Reaxys

95%

10.1 : Preparation 10 (1) 4.19 g of 1-amino-2-(2-fluoro-4-methoxyphenyl)propane hydrochloride are neutralized with a mixture of chloroform and an aqueous sodium bicarbonate solution. The chloroform layer is separated therefrom and condensed to dryness. Hydrobromic acid is added to the residue, and the mixture is refluxed. Then, the reaction mixture is evaporated, and the residue is recrystallized from a mixture of isopropylalcohol and isopropylether. 4.53 g of 3-fluoro-4-(2-amino-1-methylethyl)phenol hydrobromide are obtained. Yield 95percent; m.p. 182°-183.5° C. With hydrogen bromide in chloroform Patent; Tanabe Seiyaku Co., Ltd.; US4866196; (1989); (A) English View in Reaxys

NH 2 HCl

Rx-ID: 24105628 View in Reaxys 446/553 Yield

Conditions & References 6 : N-2-(4-bromophenyl)propyl 2-propanesulfonamide PREPARATION 6 N-2-(4-bromophenyl)propyl 2-propanesulfonamide A solution of 15.0 g (59.9 mmol) of the material from Preparation 5 and 18.4 mL (131.8 mmol) of triethylamine in 150 mL of dichloromethane was stirred 20 min at room temperature, then cooled to 0° C. and treated dropwise over 5 min with 8.1 mL (71.9 mmol) of 2-propylsulfonyl chloride in 10 mL of dichloromethane. After stirring overnight at room temperature, the reaction was washed once with 200 mL of 10percent aqueous sodium bisulfate, the layers separated and the aqueous layer extracted twice with 100 mL each of dichloromethane. Patent; Eli Lilly and Company; US6358982; (2002); (B1) English View in Reaxys

31.2 g (74%)

2 : 2-(4-Bromophenyl)propylamine hydrochloride The resulting solid was suspended in ethyl ether, filtered, rinsed with ethyl ether and dried in vacuo to afford 31.2 g (74percent) of the title compound. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys 35 : 2-(4-Benzyloxyphenyl)propylamine hydrochloride Preparation 35 2-(4-Benzyloxyphenyl)propylamine hydrochloride

161/236

2018-08-17 23:02:17

The title compound was prepared from the product of Preparation 34 as described in Preparation 2. Analysis for C16H20ClNO: Theory: C, 59.55; H, 8.00; N, 6.94. Found: C, 59.33; H, 7.89; N, 6.71. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys 39 : N-2-(4-bromophenyl)propyl 2-propanesulfonamide Preparation 39 N-2-(4-bromophenyl)propyl 2-propanesulfonamide A solution of 15.0 g (59.9 mmol) of the material from Preparation 31 and 18.4 mL (131.8 mmol) of triethylamine in 150 mL of dichloromethane was stirred 20 min at room temperature, then cooled to 0Â° C. and treated dropwise over 5 min with 8.1 mL (71.9 mmol) of 2-propylsulfonyl chloride in 10 mL of dichloromethane. After stirring overnight at room temperature, the reaction was washed once with 200 mL of 10percent aqueous sodium bisulfate, the layers separated and the aqueous layer extracted twice with 100 mL each of dichloromethane. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

N N

NH 2 Cl

Br Br

Rx-ID: 24220466 View in Reaxys 447/553 Yield

Conditions & References

11.6 g (86%)

98 : (S)-(-)-2-(4-bromophenyl)propyl amine hydrochloride Preparation 98 (S)-(-)-2-(4-bromophenyl)propyl amine hydrochloride Following the procedure of Preparation 91 and using material from Preparation 97 instead of material from Preparation 90 afforded 11.6 g (86percent) of the title compound. Analysis calculated for C9H13BrClN: percentC, 43.14; percentH, 5.23; percentN, 5.59. Found: percentC, 43.36; percentH, 5.39; percentN, 5.64. Mass Spectrum: [M-HCl]=214. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2 Cl

Rx-ID: 24253950 View in Reaxys 448/553 Yield 11.9 g (94%)

Conditions & References 91 : (R)-(+)-2-(4-bromophenyl)propyl amine hydrochloride The mixture was diluted with 100 mL of ether and 50 mL of brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ether and to this was added 200 mL of hydrochloric acid saturated ether. Filtration of the resulting solid afforded 11.9 g (94percent) of the title compound. Analysis calculated for C9H13BrClN: percentC, 43.14; percentH, 5.23; percentN, 5.59. Found: percentC, 43.44; percentH, 5.23; percentN, 5.56. Mass Spectrum: [M-HCl]=214. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

162/236

2018-08-17 23:02:17

NH 2

O N O

O O

Rx-ID: 9098533 View in Reaxys 449/553 Yield

H N

NH 2

Rx-ID: 261561 View in Reaxys 450/553 Yield

Conditions & References With ethanol, nickel, T= 50 - 70 °C , p= 73550.8 - 110326Torr , Hydrogenation Keller; Helvetica Chimica Acta; vol. 20; (1937); p. 436,443 View in Reaxys N OH

nickel O

H N

NH 2

Rx-ID: 7052254 View in Reaxys 451/553 Yield

Conditions & References T= 50 - 70 °C , p= 73550.8 - 110326Torr , Hydrogenation Keller; Helvetica Chimica Acta; vol. 20; (1937); p. 436,443 View in Reaxys

NH 2

Rx-ID: 25439877 View in Reaxys 452/553

163/236

2018-08-17 23:02:17

Yield 79%

Conditions & References R.1.2 : Reference Example 1 (2) 5.36 g of the product are dissolved in 60 ml of methanol, and 2 ml of conc. hydrochloric acid are added thereto. The mixture is subjected to catalytic hydrogenation in the presence of 0.6 g of 10 percent palladium carbon at room temperature under an atmospheric pressure. After the reaction, the catalyst is filtered off, and the filtrate is evaporated under reduced pressure. The residue is recrystallized from a mixture of isopropylalchohol and ether, whereby 3.06 g of methyl (+-)-4-(2-amino-1-methylethyl)phenoxyacetate hydrochloride are obtained as colorless crystals. Yield 79percent m.p. 99-104°C Mass (m/e):223(M+) Patent; TANABE SEIYAKU CO., LTD.; EP255728; (1991); (B1) English View in Reaxys

79%

21.2 : EXAMPLE 21 (2) 5.36 g of the product are dissolved in 60 ml of methanol, and 2 ml of conc. hydrochloric acid are added thereto. The mixture is subjected to catalytic hydrogenation in the presence of 0.6 g of 10percent palladium carbon at room temperature under an atmospheric pressure. After the reaction, the catalyst is filtered off, and the filtrate is evaporated under reduced pessure. The residue is recrystallized from a mixture of isopropylalcohol and ether, whereby 3.06 g of methyl (+-)-4-(2-amino-1-methylethyl)phenoxyacetate hydrochloride are obtained as colorless crystals. Yield 79percent; m.p. 99°-104° C. Mass (m/e): 223 (M+); IR αmax nujol (cm-1): 2400-2800, 1732. Patent; Tanabe Seiyaku Co., Ltd.; US4866196; (1989); (A) English View in Reaxys NH 2

Rx-ID: 23935892 View in Reaxys 453/553 Yield

164/236

2018-08-17 23:02:17

, wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyi]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-]methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; ... Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

165/236

2018-08-17 23:02:17

Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys

166/236

2018-08-17 23:02:17

, wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys A combination according to claim 1, wherein the compound of formula I, or formula XXX, or pharmaceutically acceptable salt thereof, is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

167/236

2018-08-17 23:02:17

Patent; Pfizer Products Inc.; EP1260221; (2002); (A2) English View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys A compound or salt according to claim 1, wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys H 2N

NH O

HCl

Rx-ID: 11084846 View in Reaxys 454/553 Yield 93 %

Conditions & References With hydrogenchloride in ethyl acetate, T= 20 °C Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys

168/236

2018-08-17 23:02:17

H 2N

O Si

HCl

Rx-ID: 11530153 View in Reaxys 455/553 Yield

Conditions & References Reaction Steps: 6 1.1: LDA / tetrahydrofuran; heptane; ethylbenzene / -78 °C 1.2: 89 percent / tetrahydrofuran; heptane; ethylbenzene / 1 h / -78 °C 2.1: LiAlH4 / tetrahydrofuran / 24 h / Heating 3.1: 720 mg / aq. NaHCO3 / tetrahydrofuran / 20 °C 4.1: 91 percent / TBAF / tetrahydrofuran / 1 h / 0 °C 5.1: 41 percent / Cu(OAc)2; 4 Angstroem molecular sieves; pyridine / iPr2EtN / CH2Cl2 / 24 h / 20 °C 6.1: 93 percent / HCl / ethyl acetate / 20 °C With pyridine, hydrogenchloride, lithium aluminium tetrahydride, copper diacetate, 4 A molecular sieve, tetrabutyl ammonium fluoride, sodium hydrogencarbonate, lithium diisopropyl amide, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, n-heptane, dichloromethane, ethylbenzene, ethyl acetate Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys H 2N

HCl

Si O

Rx-ID: 11549475 View in Reaxys 456/553 Yield

Conditions & References Reaction Steps: 5 1: LiAlH4 / tetrahydrofuran / 24 h / Heating 2: 720 mg / aq. NaHCO3 / tetrahydrofuran / 20 °C 3: 91 percent / TBAF / tetrahydrofuran / 1 h / 0 °C 4: 41 percent / Cu(OAc)2; 4 Angstroem molecular sieves; pyridine / iPr2EtN / CH2Cl2 / 24 h / 20 °C 5: 93 percent / HCl / ethyl acetate / 20 °C With pyridine, hydrogenchloride, lithium aluminium tetrahydride, copper diacetate, 4 A molecular sieve, tetrabutyl ammonium fluoride, sodium hydrogencarbonate, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, dichloromethane, ethyl acetate Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys

169/236

2018-08-17 23:02:17

H 2N

HCl

NH 2

Rx-ID: 11549487 View in Reaxys 457/553 Yield

Conditions & References Reaction Steps: 4 1: 720 mg / aq. NaHCO3 / tetrahydrofuran / 20 °C 2: 91 percent / TBAF / tetrahydrofuran / 1 h / 0 °C 3: 41 percent / Cu(OAc)2; 4 Angstroem molecular sieves; pyridine / iPr2EtN / CH2Cl2 / 24 h / 20 °C 4: 93 percent / HCl / ethyl acetate / 20 °C With pyridine, hydrogenchloride, copper diacetate, 4 A molecular sieve, tetrabutyl ammonium fluoride, sodium hydrogencarbonate, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, dichloromethane, ethyl acetate Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys H 2N

HCl

O O

Rx-ID: 11549489 View in Reaxys 458/553 Yield

Conditions & References Reaction Steps: 3 1: 91 percent / TBAF / tetrahydrofuran / 1 h / 0 °C 2: 41 percent / Cu(OAc)2; 4 Angstroem molecular sieves; pyridine / iPr2EtN / CH2Cl2 / 24 h / 20 °C 3: 93 percent / HCl / ethyl acetate / 20 °C With pyridine, hydrogenchloride, copper diacetate, 4 A molecular sieve, tetrabutyl ammonium fluoride, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, dichloromethane, ethyl acetate Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys H 2N

NH OH

HCl

Rx-ID: 11549496 View in Reaxys 459/553

170/236

2018-08-17 23:02:17

Yield

Conditions & References Reaction Steps: 2 1: 41 percent / Cu(OAc)2; 4 Angstroem molecular sieves; pyridine / iPr2EtN / CH2Cl2 / 24 h / 20 °C 2: 93 percent / HCl / ethyl acetate / 20 °C With pyridine, hydrogenchloride, copper diacetate, 4 A molecular sieve, N-ethyl-N,N-diisopropylamine in dichloromethane, ethyl acetate Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys H 2N

HCl

O OH

Rx-ID: 11556317 View in Reaxys 460/553 Yield

Conditions & References Reaction Steps: 7 1.1: 84 percent / imidazole / CH2Cl2 / 24.5 h / 0 - 20 °C 2.1: LDA / tetrahydrofuran; heptane; ethylbenzene / -78 °C 2.2: 89 percent / tetrahydrofuran; heptane; ethylbenzene / 1 h / -78 °C 3.1: LiAlH4 / tetrahydrofuran / 24 h / Heating 4.1: 720 mg / aq. NaHCO3 / tetrahydrofuran / 20 °C 5.1: 91 percent / TBAF / tetrahydrofuran / 1 h / 0 °C 6.1: 41 percent / Cu(OAc)2; 4 Angstroem molecular sieves; pyridine / iPr2EtN / CH2Cl2 / 24 h / 20 °C 7.1: 93 percent / HCl / ethyl acetate / 20 °C With pyridine, 1H-imidazole, hydrogenchloride, lithium aluminium tetrahydride, copper diacetate, 4 A molecular sieve, tetrabutyl ammonium fluoride, sodium hydrogencarbonate, lithium diisopropyl amide, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, n-heptane, dichloromethane, ethylbenzene, ethyl acetate Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys H 2N

HO B

HCl

Rx-ID: 11573531 View in Reaxys 461/553 Yield

171/236

2018-08-17 23:02:17

Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys

NH 2 Cl

Rx-ID: 25226020 View in Reaxys 462/553 Yield

Conditions & References Representative compounds of the present invention include the following: ... 2-(3-Phenoxyphenyl)propionohydroxamic acid N-cyclopropylmethyl-2-(3-phenoxyphenyl)propylamine hydrochloride N-methyl-2-(3-phenoxyphenyl)propylamine sulfate N,n-dimethyl-2-(3-phenoxyphenyl)propylamine hydrochloride 2-(3-Phenoxyphenyl)propylamine hydrochloride 2-(3-Phenoxyphenyl)butylamine sulfate 3-(3-Phenoxyphenyl)butanol 3-(3-Phenoxyphenyl)butyl acetate ... Patent; Eli Lilly and Company; US3972934; (1976); (A) English View in Reaxys

NH 2

HBr O

Rx-ID: 24831027 View in Reaxys 463/553 Yield

Conditions & References 3.3 : Preparation 3 25percent hydrogen bromide-acetic acid solution are added dropwise to an acetic acid solution containing the product obtained above. After stirring the mixture, ether is added thereto, and the precipitated crystals are collected by filtration. 1.1 g of 1-amino-2-(3fluoro-4-methoxyphenyl)propane hydrobromide are obtained. Patent; Tanabe Seiyaku Co., Ltd.; US4948810; (1990); (A) English View in Reaxys 2 HCl NH 2

H H

N H 2N

Rx-ID: 23061602 View in Reaxys 464/553 Yield

Conditions & References 1 :Scheme I, step B: 2-[4-(Cyano-methyl-methyl)-phenyl]-propionitrile (3.25 g, 17.7 mmol) was dissolved in anhydrous THF (30 mL). The solution was heated to reflux and a 2M THF solution of borane-methyl sulfide complex (19.5 mL, 38.9 mmol) was added dropwise. Heating at reflux was continued for 30 minutes and then allowed to cool to room temperature. An HCl saturated solution of methanol (30 mL) was slowly added until pH=2. The mixture was concentrated in vacuo, redissolved in methanol and concentrated again to provide the intermediate title compound (4.5 g, 96percent). TLC and HPLC indicated the starting ma-

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

172/236

2018-08-17 23:02:17

terial had been consumed and produced a mixture of more polar products. This material was used crude in the next step without further characterization. Stage 1: With dimethylsulfide borane complex in tetrahydrofuran, Time= 0.5h, Heating / reflux Stage 2: With hydrogenchloride in tetrahydrofuran, methanol, pH= 2 Patent; Knobelsdorf, James Allen; Shepherd, Timothy Alan; Tromiczak, Eric George; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/229102; (2003); (A1) English View in Reaxys

NH 2 O

OH O

HO OH

Rx-ID: 23969457 View in Reaxys 465/553 Yield 39.5%

Conditions & References 1.a : Preparation of (2R)-2-phenylpropylamine Malate. Preparation of (2R)-2-phenylpropylamine Malate. To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The mixture was stirred for 1.6 hours, and the resulting milky white NaCl salts were filtered. An aliquot of the filtrate was analyzed by gas chromatography to provide the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles). A solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was added dropwise to the yellow filtrate and the solution was heated to 75° C. The solution was stirred at 75° C. for 30 minutes. The heat was removed and the solution was allowed to cool slowly. The resulting thick precipitate was allowed to stir overnight. The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5percent) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine) 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). Patent; Skolnick, Phil; US2003/92770; (2003); (A1) English View in Reaxys

39.5%

1 : Preparation of 2-Phenyl-1-propylamine HCl. Preparation of (2R)-2-phenylpropylamine Malate. Scheme I, step B: To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The mixture was stirred for 1.6 hours, and the resulting milky white NaCl salts were filtered. An aliquot of the filtrate was analyzed by gas chromatography to provide the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles). A solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was added dropwise to the yellow filtrate and the solution was heated to 75° C. The solution was stirred at 75° C. for 30 minutes. The heat was removed and the solution was allowed to cool slowly. The resulting thick precipitate was allowed to stir overnight. The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5percent) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine) 1H NMR (CDCl , 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). 3 Patent; Gardner, John Paul; Miller, William David; US2003/92947; (2003); (A1) English View in Reaxys

173/236

2018-08-17 23:02:17

F F

F NH 2

F F

Rx-ID: 36699549 View in Reaxys 466/553 Yield

Conditions & References A48 :General procedure: b) Preparation of intermediate 69 DIAD (1.5 mL, 7.62 mmol) was added to a stirred solution of intermediate 68 (1.67 g, 5.08 mmol), phtalimide (0.812 g, 5.6 mmol) and TPP (2 g, 7.62 mmol) in dry THF and under N2 at 0 °C. The mixture was stirred at r.t. for 4 h, then the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc/hexane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate 69 as an oil (1.41 g, 61percent). With di-isopropyl azodicarboxylate, triphenylphosphine in tetrahydrofuran, Time= 4h, T= 20 °C , Inert atmosphere Patent; JANSSEN PHARMACEUTICALS, INC.; ROMBOUTS, Frederik, Jan, Rita; TRABANCO-SUÁREZ, Andrés, Avelino; GIJSEN, Henricus, Jacobus, Maria; MACDONALD, Gregor, James; BISCHOFF, François Paul; ALONSO-de DIEGO, Sergio-Alvar; VELTER, Adriana, Ingrid; VAN ROOSBROECK, Yves, Emiel, Maria; WO2013/171712; (2013); (A1) English View in Reaxys NH 2

F F F

O O

Rx-ID: 9099499 View in Reaxys 467/553 Yield

NH 2

2-<4-benzyloxy-3-methoxy-phenyl>-propionaldehyde-oxime

Rx-ID: 8078098 View in Reaxys 468/553 Yield

Conditions & References With lithium aluminium tetrahydride, diethyl ether Sommers; Weston; Journal of the American Chemical Society; vol. 73; (1951); p. 5749,5750,5751 View in Reaxys

174/236

2018-08-17 23:02:17

NH 2

I O I

Rx-ID: 1061201 View in Reaxys 469/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

Rx-ID: 1061202 View in Reaxys 470/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys I

NH 2

Rx-ID: 1061525 View in Reaxys 471/553 Yield

Conditions & References With formic acid, formamide, Time= 16h, T= 170 - 180 °C Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

I O

NH 2

Rx-ID: 22562571 View in Reaxys 472/553 Yield

175/236

2018-08-17 23:02:17

I I

NH 2

Rx-ID: 22564743 View in Reaxys 473/553 Yield

NH 2

Rx-ID: 22564976 View in Reaxys 474/553 Yield

NH 2

Rx-ID: 22564981 View in Reaxys 475/553 Yield

I NH 2

Rx-ID: 22564983 View in Reaxys 476/553 Yield

Conditions & References Reaction Steps: 2 1: (i) NaOiPr, iPrOH, (ii) /BRN= 969135/ 2: HCONH2, HCO2H / 16 h / 170 - 180 °C

176/236

2018-08-17 23:02:17

With formic acid, formamide Binovic,K.; Vrancea,S.; Chimica Therapeutica; vol. 3; (1968); p. 313 - 320 View in Reaxys

NH 2

I N

Rx-ID: 22565345 View in Reaxys 477/553 Yield

O N

NH 2

Rx-ID: 22565464 View in Reaxys 478/553 Yield

I NH 2

N O

Rx-ID: 22565493 View in Reaxys 479/553 Yield

177/236

2018-08-17 23:02:17

NH 2 I O

Rx-ID: 22587511 View in Reaxys 480/553 Yield

O O

Rx-ID: 9099725 View in Reaxys 481/553 Yield

Rx-ID: 25318214 View in Reaxys 482/553 Yield 82%

Conditions & References 1.c : (c) The residue from the above evaporation step was taken up in 10 ml. of methylene chloride and was thoroughly mixed with 10 ml. of an aqueous solution of 0.1 N HBr. The aqueous phase was separated and evaporated under reduced pressure. The residue was recrystallized from ethanol to yield R(-)-1-amino-2-(3',4'-dimethoxyphenyl) propane hydrobromide, m.p. 250° C.; [α]D -17.5° (C 1, H2 O). The absolute configuration was shown to be R and the optical purity of the hydrobromide salt to be 82percent as determined by GLC of the N-trifluoracetyl-L-(S)-propyl (TPC) derivative. This configuration was confirmed by optical rotatory dispersion (ORD). Patent; Hoffmann-La Roche Inc.; US4129580; (1978); (A) English View in Reaxys

178/236

2018-08-17 23:02:17

NH 2

Rx-ID: 25291843 View in Reaxys 483/553 Yield

Conditions & References The products of structural formula (3) are illustrated by the following compounds. ... 1-(3,5-di tert.butyl-4-hydroxybenzyl)-1-aminopropane 1-(3,5-di tert.butyl-4-hydroxybenzyl)-1-aminobutane 2-(3,5-di tert.butyl-4-hydroxybenzyl)-2-aminobutane 1-(3,5-di tert.butyl-4-hydroxybenzyl)-1-aminohexane 1,2-dimethyl-2-(3,5-di tert.butyl-4-hydroxyphenyl)ethylamine 1,1,2-trimethyl-2-(3,5-di tert.butyl-4-hydroxyphenyl)ethylamine 1-methyl-2-ethyl-2-(3,5-di tert.butyl-4-hydroxyphenyl)ethylamine 1-methyl-2-[3,5-bis(1,1-dimethylbutyl)-4-hydroxyphenyl]ethylamine ... Patent; The Goodyear Tire and Rubber Company; US4097527; (1978); (A) English View in Reaxys NH 2

HCl O O O

Rx-ID: 24831032 View in Reaxys 484/553 Yield

Conditions & References 4.6 : Preparation 4 (6) 6.83 g of the product obtained above are dissolved in 100 ml of methanol and the mixture is subjected to catalytic hydrogenation in the presence of 0.7 g of 10percent palladium-carbon at room temperature under atmospheric pressure. After the reaction, the catalyst is filtered off, and the filtrate is evaporated under reduced pressure. 10 ml of 17percent hydrogen chloride-methanol solution are added to the residue and the solution is condensed to dryness. The residue is recrystallized from a mixture of isopropyl ether and methanol. 4.85 g of methyl 4-(2-amino-1-methylethyl)-2-fluoro-phenoxyacetate hydrochloride are obtained as colorless needles. m.p. 135.5°-136.5° C. Patent; Tanabe Seiyaku Co., Ltd.; US4948810; (1990); (A) English View in Reaxys

NH 2

HCl

Rx-ID: 24105630 View in Reaxys 485/553 Yield 1.6 g (86%)

Conditions & References 2 : 2-(4-Benzyloxyphenyl)propylamine hydrochloride

179/236

2018-08-17 23:02:17

The resulting white product was precipitated out of ether and collected by filtration to give 1.6 g (86percent) of the pure product. Electospray Mass Spectrum: 242 (M-HCl). Analysis calculated for C16H20ClNO: percent C, 69.30; percent H, 7.20; percent N, 5.10. Found: percent C, 68.60; percent H, 7.19; percent N, 4.80. Patent; Eli Lilly and Company; US6358982; (2002); (B1) English View in Reaxys 1.6 g (86%)

10 : 2-(4-Benzyloxyphenyl)propylamine hydrochloride The resulting white product was precipitated out of ether and collected by filtration to give 1.6 g (86percent) of the title compound. Electospray Mass Spectrum: 242 (M-HCl). Patent; ELI LILLY AND COMPANY; EP994110; (2000); (A1) English View in Reaxys NH 2

Rx-ID: 23935895 View in Reaxys 486/553 Yield

Conditions & References , wherein the compound of formula XXX, or pharmaceutically acceptable salt thereof, that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2003/130322; (2003); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-]methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

180/236

2018-08-17 23:02:17

Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4,5-dimethoxybenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

181/236

2018-08-17 23:02:17

[2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. 2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4,5-dimethoxybenzyl]-methylamine; ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

182/236

2018-08-17 23:02:17

Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4,5-dimethoxybenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine. [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy) phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys A combination according to claim 1, wherein the compound of formula I, or formula XXX, or pharmaceutically acceptable salt thereof, is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

183/236

2018-08-17 23:02:17

Patent; Pfizer Products Inc.; EP1260221; (2002); (A2) English View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys A compound or salt according to claim 1, wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylbenzyl]-dimethylamine; [4-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; [5-Bromo-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys O

O N

NH 2

H N

N O

Rx-ID: 25355645 View in Reaxys 487/553 Yield

Conditions & References P.53.b : Production Example 53b Production Example 53b 1-t-Butoxycarbonylamino-2-(3-nitrophenyl)propane The reaction was conducted using 2-(3-nitrophenyl)propylamine obtained in Production Example 52b in the same manner as in Production Example 35b. The resulting residue was purified by silica gel column, to give the title compound (2.626 g) as a yellow oil. 1H-NMR(CDCl ) α (ppm): 1.31 (3H, d, J = 6.8 Hz), 1.40 (9H, s), 3.10 (1H, m), 3.26 (1H, m), 3.38 (1H, m), 7.49 (1H, dd, J = 7.6, 3 8.4 Hz), 7.56 (1H, d, J = 7.6 Hz), 8.08 (1H, s), 8.10 (1H, d, J = 8.4 Hz). Patent; Eisai Co., Ltd.; EP1258252; (2002); (A1) English View in Reaxys P.53.b : 1-t-Butoxycarbonylamino-2-(3-nitrophenyl)propane PRODUCTION EXAMPLE 53b 1-t-Butoxycarbonylamino-2-(3-nitrophenyl)propane The reaction was conducted using 2-(3-nitrophenyl)propylamine obtained in Production Example 52b in the same manner as in Production Example 35b. The resulting residue was purified by silica gel column, to give the title compound (2.626 g) as a yellow oil. 1H-NMR(CDCl ) α (ppm): 1.31 (3H, d, J=6.8 Hz), 1.40 (9H, s), 3.10 (1H, m), 3.26 (1H, m), 3.38 (1H, m), 7.49 (1H, dd, J=7.6, 3 8.4 Hz), 7.56 (1H, d, J=7.6 Hz), 8.08 (1H, s), 8.10 (1H, d, J=8.4 Hz).

184/236

2018-08-17 23:02:17

Patent; Wakabayashi, Toshiaki; Funahashi, Yasuhiro; Hata, Naoko; Semba, Taro; Yamamoto, Yuji; Haneda, Toru; Owa, Takashi; Tsuruoka, Akihiko; Kamata, Junichi; Okabe, Tadashi; Takahashi, Keiko; Nara, Kazumasa; Hamaoka, Shinichi; Ueda, Norihiro; US2004/18192; (2004); (A1) English View in Reaxys

NH 2

HBr O

Rx-ID: 25413453 View in Reaxys 488/553 Yield 78%

Conditions & References 5.4 : Preparation 5 (4) 33 ml of an aqueous 25percent hydrobromide-acetic acid solution are added dropwise to an acetic acid solution containing 16.42 g of the product obtained above. After stirring the mixture, ether is added thereto, and the precipitated crystals are collected by filtration. 10.33 g of 1-amino-2-(3-chloro-4-methoxyphenyl)propane hydrobromide are obtained. Yield 78percent m.p. 163.5-165°C Patent; TANABE SEIYAKU CO., LTD.; EP255728; (1991); (B1) English View in Reaxys

78%

5.4 : Preparation 5 (4) 33 ml of an aqueous 25percent hydrobromide-acetic acid solution are added dropwise to an acetic acid solution containing 16.42 g of the product obtained above. After stirring the mixture, ether is added thereto, and the precipitated crystals are collected by filtration. 10.33 g of 1-amino-2-(3-chloro-4-methoxyphenyl)propane hydrobromide are obtained. Yield 78percent; m.p. 163.5°-165° C. Patent; Tanabe Seiyaku Co., Ltd.; US4866196; (1989); (A) English View in Reaxys 2 F

HCl

NH 2

H 2N N

Rx-ID: 23061157 View in Reaxys 489/553 Yield 78 %

Conditions & References 14 :Scheme Ia, step B: Into a 25 ML single neck flask was placed 2-[4-(cyanoethyl)-3-fluorophenyl]propanenitrile (545 mg, 2.7 mmol) in THF (10 ML).boron dimethylsulfide 2 M in THF (3 ML, 5.95 mmol) was added to the solution and the mixture was heated at reflux for 12 hours.The reaction mixture was cooled to RT and quenched with saturated solution of HCl in methanol (10 ML).diethyl ether (10 ML) was added to the reaction mixture and the mixture was cooled down to 0° C. The product was precipitated out of the solution as dihydrochloride salt.The salt was filtered and dried under vacuum to provide the intermediate title compound, 1-[4-(aminoethyl)-2-fluorophenyl]ethylamine dihydrochloride, (595 mg, 78percent) as a white solid crystal.Electron spray M.S. 211 (M*-2HCl) Stage 1: With dimethylsulfide borane complex in tetrahydrofuran, Time= 12h, Heating / reflux Stage 2: With hydrogenchloride in tetrahydrofuran, methanol, diethyl ether, T= 0 - 20 °C Patent; Knobelsdorf, James Allen; Shepherd, Timothy Alan; Tromiczak, Eric George; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/229102; (2003); (A1) English

185/236

2018-08-17 23:02:17

View in Reaxys F

NH 2

O F

N F

O O

Rx-ID: 9100491 View in Reaxys 490/553 Yield

NH 2

O O

O N HO

Rx-ID: 512462 View in Reaxys 491/553 Yield

Conditions & References With lithium aluminium tetrahydride, diethyl ether Sommers; Weston; Journal of the American Chemical Society; vol. 73; (1951); p. 5749,5750,5751 View in Reaxys

H N

NH 2

S O

Rx-ID: 24239547 View in Reaxys 492/553 Yield 8.9 g (68%)

Conditions & References 63 : N-2-(4-nitrophenyl)propyl 2-propanesulfonamide Preparation 63 N-2-(4-nitrophenyl)propyl 2-propanesulfonamide A 0° C. suspension of the material from Preparation 62 (8.2 g, 45.3 mmol) in dichloromethane (200 ml) was treated with 1,8diazabicyclo[5.4.0]undec-ene (7.6 g, 49.8 mmol) followed by 2-propylsulfonyl chloride (12 g, 49.8 mmol). The reaction mixture was stirred at 0 ° C. for 1 h and at room temperature for extra 12 h. The reaction was stopped by the addition of water (100 ml). Organic was extracted with dichloromethane (3*200 ml). The combined organic fraction was washed with water (3*200 ml), brine (100 ml), dried over potassium carbonate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (SiO2, 30percent EtOAc:Hexane) to give 8.9 g (68percent) of the pure product. NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+=287.

186/236

2018-08-17 23:02:17

Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys 8.9 g (68%)

3 : N-2-(4-nitrophenyl)propyl 2-propanesulfonamide Preparation 3 N-2-(4-nitrophenyl)propyl 2-propanesulfonamide A 0°C suspension of the material from Preparation 2 (8.2 g, 45.3 mmol) in dichloromethane (200 mL) was treated with 1,8diazabicyclo[5.4.0]undec-ene (7.6 g, 49.8 mmol) followed by 2-propylsulfonyl chloride (12 g, 49.8 mmol). The reaction mixture was stirred at 0 °C for 1 h and at room temperature for an extra 12 h. The reaction was stopped by the addition of water (100 mL). The organic layer was extracted with dichloromethane (3X200 mL). The combined organic fraction was washed with water (3X200 mL), brine (100 mL), dried over potassium carbonate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (SiO2, 30percent EtOAc: Hexane) to give 8.9 g (68percent) of the pure product. The NMR spectrum was consistent with the proposed title structure. Field Desorption Mass Spectrum:M+= 287. Patent; ELI LILLY AND COMPANY; EP994110; (2000); (A1) English View in Reaxys F

NH 2

F F

O AlNi F

O O O

Rx-ID: 24355835 View in Reaxys 493/553 Yield 3.66 g (98%)

Conditions & References A.2.b : Example A.2 b) A mixture of intermediate 9 (0.0129 mol) in CH3 OH/NH3 (100 ml) was hydrogenated at RT with Raney Nickel (3 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated, yielding 3.66 g (98percent) of (+-)-4-(difluoromethoxy)-α-methyl-3-[(tetrahydro-3-furanyl)oxy]benzeneethanamine (intermediate 10). With ammonia in CH3 Patent; Janssen Pharmaceutica, N.V.; US6051718; (2000); (A) English View in Reaxys NH 2

Cl Cl

Rx-ID: 23935891 View in Reaxys 494/553 Yield

187/236

2018-08-17 23:02:17

[2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US2003/130322; (2003); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-]methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethyl benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyi]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

188/236

2018-08-17 23:02:17

View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy) phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethyl benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

189/236

2018-08-17 23:02:17

[2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys A combination according to claim 1, wherein the compound of formula I, or formula XXX, or pharmaceutically acceptable salt thereof, is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Products Inc.; EP1260221; (2002); (A2) English

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

190/236

2018-08-17 23:02:17

View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; and ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys A compound or salt according to claim 1, wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys NH 2 N

O O

Rx-ID: 9100587 View in Reaxys 495/553 Yield

Conditions & References With ammonia, hydrogen, nickel in methanol, T= 20 Â°C Andres, J Ignacio; Alonso, Jose M; Diaz, Adolfo; Fernandez, Javier; Iturrino, Laura; Martinez, Pedro; Matesanz, Encarna; Freyne, Eddy J; Deroose, Frederik; Boeckx, Gustaaf; Petit, Davy; Diels, Gaston; Megens, Anton; Somers, Marijke; Van Wauwe, Jean; Stoppie, Paul; Cools, Marina; De Clerck, Fred; Peeters, Danielle; de Chaffoy, Didier; Bioorganic and medicinal chemistry letters; vol. 12; nb. 4; (2002); p. 653 - 658 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

191/236

2018-08-17 23:02:17

HCl

NH 2

H 2N F

Rx-ID: 22989245 View in Reaxys 496/553 Yield

Conditions & References

94 %

15 Patent; Knobelsdorf, James Allen; Shepherd, Timothy Alan; Tromiczak, Eric George; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/229102; (2003); (A1) English View in Reaxys

NH 2

O N

F O

O O

F F F

Rx-ID: 9101573 View in Reaxys 497/553 Yield

N Si O

Rx-ID: 11084836 View in Reaxys 498/553 Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 24h, Heating Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

192/236

2018-08-17 23:02:17

H 2N

O Si

Rx-ID: 11530145 View in Reaxys 499/553 Yield

Conditions & References Reaction Steps: 2 1.1: LDA / tetrahydrofuran; heptane; ethylbenzene / -78 °C 1.2: 89 percent / tetrahydrofuran; heptane; ethylbenzene / 1 h / -78 °C 2.1: LiAlH4 / tetrahydrofuran / 24 h / Heating With lithium aluminium tetrahydride, lithium diisopropyl amide in tetrahydrofuran, n-heptane, ethylbenzene Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys H 2N

Rx-ID: 11554779 View in Reaxys 500/553 Yield

Conditions & References Reaction Steps: 3 1.1: 84 percent / imidazole / CH2Cl2 / 24.5 h / 0 - 20 °C 2.1: LDA / tetrahydrofuran; heptane; ethylbenzene / -78 °C 2.2: 89 percent / tetrahydrofuran; heptane; ethylbenzene / 1 h / -78 °C 3.1: LiAlH4 / tetrahydrofuran / 24 h / Heating With 1H-imidazole, lithium aluminium tetrahydride, lithium diisopropyl amide in tetrahydrofuran, n-heptane, dichloromethane, ethylbenzene Tan, Edwin S.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David K.; Scanlan, Thomas S.; Journal of Medicinal Chemistry; vol. 50; nb. 12; (2007); p. 2787 - 2798 View in Reaxys

193/236

2018-08-17 23:02:17

H 2N

N OH

Rx-ID: 11556309 View in Reaxys 501/553 Yield

Cl Cl

Rx-ID: 23935890 View in Reaxys 502/553 Yield

Conditions & References , wherein the compound of formula XXX, or pharmaceutically acceptable salt thereof, that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US2003/130322; (2003); (A1) English View in Reaxys , wherein the compound of formula XXX, or pharmaceutically acceptable salt thereof, that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine;

194/236

2018-08-17 23:02:17

3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US2003/130322; (2003); (A1) English View in Reaxys , wherein the compound of formula XXX, or pharmaceutically acceptable salt thereof, that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US2003/130322; (2003); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl)-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifuoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyi]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl)-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifuoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyi]-methylamine; ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl-methylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

195/236

2018-08-17 23:02:17

{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-]methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethyl benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyi]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... 1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorophenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

196/236

2018-08-17 23:02:17

Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{[2-(3,4-Dichlorophenoxy)-5-fuorophenyl]-ethyl}-methylamine; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1 -[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1 -[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

197/236

2018-08-17 23:02:17

Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1 -[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1 -[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)4-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

198/236

2018-08-17 23:02:17

View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichorophenoxy)-5-trifuoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

199/236

2018-08-17 23:02:17

Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

200/236

2018-08-17 23:02:17

4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following: ... {1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethyl benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... 1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

201/236

2018-08-17 23:02:17

... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichorophenoxy)-5-trifuoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Preferred embodiments of formula I include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorophenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy) phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys A combination according to claim 1, wherein the compound of formula I, or formula XXX, or pharmaceutically acceptable salt thereof, is selected from the following compounds and their pharmaceutically acceptable salts: ... N-[4-(3,4-Dichlorophenoxy)-3-dimethylaminomethylphenyl]-acetamide; {1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

202/236

2018-08-17 23:02:17

Patent; Pfizer Products Inc.; EP1260221; (2002); (A2) English View in Reaxys A combination according to claim 1, wherein the compound of formula I, or formula XXX, or pharmaceutically acceptable salt thereof, is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Products Inc.; EP1260221; (2002); (A2) English View in Reaxys A combination according to claim 1, wherein the compound of formula I, or formula XXX, or pharmaceutically acceptable salt thereof, is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Pfizer Products Inc.; EP1260221; (2002); (A2) English View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

203/236

2018-08-17 23:02:17

[2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys A compound or salt according to claim 1, wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-dimethylamine; 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys A compound or salt according to claim 1, wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... 4-(3,4-Dichlorophenoxy)-3-methylaminomethyl-benzonitrile; [2-(3,4-Dichlorophenoxy)-4,5-dimethylbenzyl]-methylamine; 3-(3,4-Dichlorphenoxy)-4-methylaminomethyl-benzonitrile; (+)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; (-)-{1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-trifluoromethyl-benzyl]-methylamine; [2-(3,4-Dichlorophenoxy)-4-methoxybenzyl]-methylamine; [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys A compound or salt according to claim 1, wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ...

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

204/236

2018-08-17 23:02:17

{1-[2-(3,4-Dichlorophenoxy)phenyl]-ethyl}-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-4-trifluoromethylbenzyl]-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)phenyl}-ethyl}-methylamine; {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methoxybenzyl]-methylamine; ... Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys

NH 2

Cl N H

Rx-ID: 24253951 View in Reaxys 503/553 Yield

Conditions & References

5.9 g (94%)

99 : (S)-2-(4-bromophenyl)-N-(t-butoxycarbonyl)propyl amine Preparation 99 (S)-2-(4-bromophenyl)-N-(t-butoxycarbonyl)propyl amine Following the procedure of Preparation 92 and using material from Preparation 98 instead of material from Preparation 91 afforded 5.9 g (94percent) of the title compound. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2

H N

HCl O

O Br

Rx-ID: 24276758 View in Reaxys 504/553 Yield 16.5 g (95%)

Conditions & References 4 : 2-(4-bromophenyl)-N-(t-butoxycarbonyl)propylamine Preparation 4 2-(4-bromophenyl)-N-(t-butoxycarbonyl)propylamine To a solution of 11.8 g (55.0 mmol) of material from Preparation 2 in 100 mL of chloroform and 100 mL of saturated sodium bicarbonate was added 12.0 g (55.0 mmol) of di-tert-butyl dicarbonate. The solution was stirred at ambient temperature for 1 hour. The organic layer was separated and the aqueous layer was extracted three times with 30 mL each of chloroform. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford 16.5 g (95percent) of the title compound. With sodium hydrogencarbonate in chloroform Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

205/236

2018-08-17 23:02:17

NH 2

O O

N H

Rx-ID: 24276776 View in Reaxys 505/553 Yield

Conditions & References

6.2 g (100%)

92 : (R)-2-(4-bromophenyl)-N-(t-butoxycarbonyl)propyl amine Preparation 92 (R)-2-(4-bromophenyl)-N-(t-butoxycarbonyl)propyl amine To a solution of 5.0 g (20.0 mmol) of material from Preparation 91 in 30 mL of chloroform and 30 mL of saturated sodium bicarbonate was added 4.3 g (20.0 mmol) of di-tert-butyl dicarbonate. The solution was stirred at room temperature for 18 hr. The organic layer was separated and the aqueous layer was extracted three times with 10 mL each of chloroform. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford 6.2 g (100percent) of the title compound. With sodium hydrogencarbonate in chloroform Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

NH 2

Cl Cl

N H

Rx-ID: 39139808 View in Reaxys 506/553 Yield

Conditions & References Reaction Steps: 2 1: hydrogenchloride / tetrahydrofuran; water / 40 - 45 °C 2: ethanol / 20 - 70 °C With hydrogenchloride in tetrahydrofuran, ethanol, water Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys Cl

OH Cl

NH 2

O HO O

H 2N

Rx-ID: 39139832 View in Reaxys 507/553 Yield 0.19 g

Conditions & References 21 : Example 21: Optical resolution of 2-(3-chlorophenyl)propan-1-amine with (R)-(-)-2-phenylpropionic acid To a solution of 2-(3-chlorophenyl)propan-1-amine III (3.0 mmol; 0.5 g) in EtOH (3 mL) at 70 °C was added a solution of (R)(-)-2-phenylpropionic acid (1.5 mmol; 0.2 g) in EtOH (1 mL). The reaction mixture was stirred at 70 °C for 30 mm and then cooled to room temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with EtOH and dried under reduced pressure to give 0.29 g of salt 111-PP (Chiral HPLC: 74.1 percent ee, R-enantiomer).Recrystallization:0.28 g of obtained salts was dissolved in EtOH (3 mL) at 70 °C. The solution was stirred at 70 °C for 30 mm and then cooled to room

206/236

2018-08-17 23:02:17

temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with EtOH and dried under reduced pressure to give 0.19 g of salt (R)-III-PP (Chiral HPLC: 98.1 percent ee, R-enantiomer). in ethanol, T= 20 - 70 °C Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys

H N

NH 2 HCl

S O

Rx-ID: 24239684 View in Reaxys 508/553 Yield

Conditions & References

0.2 g (25%)

27 : N-2-(4-Bromophenyl)propyl 2-propylsulfonamide EXAMPLE 27 N-2-(4-Bromophenyl)propyl 2-propylsulfonamide To a suspension of 0.5 g (2.0 mmol) of the product of Preparation 31 in 5 mL of dichloromethane was added 0.6 mL (4.0 mmol) of triethylamine. The mixture was cooled to 0° C. and 0.2 mL (2.0 mmol) of isopropylsulfonyl chloride was added. After stirring at 0° C. for 20 min, the mixture was washed once with 10percent aqueous sodium bisulfate and the organic layer was separated. The aqueous layer was extracted three times with dichloromethane. The combined organic portions were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35percent ethyl acetate/hexane) afforded 0.2 g (25percent) of the title compound. Analysis calculated for C12H18NO2SBr: percentC, 45.01; percentH, 5.67; percentN, 4.37. Found: percentC, 45.30; percentH, 5.92; percentN,4.43. Field Desorption Mass Spectrum: M+1=321. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys

0.2 g (25%)

8 : N-2-(4-Bromophenyl)propyl 2-propylsulfonamide Preparation 8 N-2-(4-Bromophenyl)propyl 2-propylsulfonamide To a suspension of 0.5 g (2.0 mmol) of the product of Preparation 7 in 5 mL of dichloromethane was added 0.6 mL (4.0 mmol) of triethylamine. The mixture was cooled to 0 C and 0.2 mL (2.0 mmol) of isopropylsulfonyl chloride was added. After stirring at 0 C for 20 min, the mixture was washed once with 10percent aqueous sodium bisulfate and the organic layer was separated. The aqueous layer was extracted three times with dichloromethane. The combined organic portions were dried (Na2SO4), filtered and concentrated in vacuo.Chromatography on 50 g silica gel (35percent ethyl acetate/hexane) afforded 0.2 g (25percent) of the title compound. Analysis calculated for C12H18NO2SBr: percentC, 45.01; percentH, 5.67; percentN, 4.37. Found: percentC, 45.30; percentH, 5.92; percentN,4.43. Field Desorption Mass Spectrum: M+1 = 321 Patent; ELI LILLY AND COMPANY; EP994110; (2000); (A1) English View in Reaxys NH 2

F HN

S O

F O

Rx-ID: 24220446 View in Reaxys 509/553

207/236

2018-08-17 23:02:17

Yield

Conditions & References 17 : N-2-(4-t-butylphenyl)propyl trifluoromethanesulfonamide EXAMPLE 17 N-2-(4-t-butylphenyl)propyl trifluoromethanesulfonamide The title compound 70 mg (29percent) was prepared as an oil following the method of Example 16, starting from the product of Preparation 23 and using trifluoromethanesulfonyl chloride. Analysis calculated for C14H20NO2SF3: percent C, 52.00; percent H, 6.23; percent N, 4.33. Found percent C, 51.79; percent H, 6.20; percent N, 4.27. Mass Spectrum: M=323. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys NH 2

O O O

Rx-ID: 9102548 View in Reaxys 510/553 Yield

O O

Rx-ID: 9101809 View in Reaxys 511/553 Yield

208/236

2018-08-17 23:02:17

View in Reaxys NH 2 F

Rx-ID: 24005722 View in Reaxys 512/553 Yield

Conditions & References Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5fluoro-4-methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamine; 4-(3,4-Diclorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5-fluoro-4- methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)phenyl]-dimethylamine; [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]- methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl])-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts:

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

209/236

2018-08-17 23:02:17

... [2-(3,4-Dichlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

210/236

2018-08-17 23:02:17

[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Other embodiments of this invention include the following compounds and their pharmaceutically acceptable salts: ... [2-(3,4-Dichlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamine; [4-(3,4-Dichlorophenoxy)-3-(dimethylaminomethyl)-phenyl]-dimethylamine [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dimethylamine; [2-(4-Chlorophenoxy)-5-isopropylbenzyl]-methylamine; {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys NH 2

N N

Rx-ID: 8781944 View in Reaxys 513/553 Yield 100 %

Conditions & References With borane dimethyl sulphide complex Kronenberg, Ute B.; Drewes, Birte; Sihver, Wiebke; Coenen, Heinz H.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 50; nb. 13; (2007); p. 1169 - 1175 View in Reaxys

97 %

With dimethylsulfide borane complex in tetrahydrofuran, Time= 3h, Heating

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

211/236

2018-08-17 23:02:17

Zarrinmayeh; Bleakman; Gates; Yu; Zimmerman; Ornstein; McKennon; Arnold; Wheeler; Skolnick; Journal of medicinal chemistry; vol. 44; nb. 3; (2001); p. 302 - 304 View in Reaxys NH 2

N NH 2

Rx-ID: 15421965 View in Reaxys 514/553 Yield

Conditions & References Reaction Steps: 3 1.1: 76 percent / K2CO3; KI / dimethylformamide / 12 h / 20 °C 2.1: LiN(SiMe3)2 / tetrahydrofuran / 1 h / -78 °C 2.2: 95 percent / tetrahydrofuran / 13 h / -78 - 20 °C 3.1: 97 percent / BH3*DMS / tetrahydrofuran / 3 h / Heating With dimethylsulfide borane complex, potassium carbonate, potassium iodide, lithium hexamethyldisilazane in tetrahydrofuran, N,N-dimethyl-formamide Zarrinmayeh; Bleakman; Gates; Yu; Zimmerman; Ornstein; McKennon; Arnold; Wheeler; Skolnick; Journal of medicinal chemistry; vol. 44; nb. 3; (2001); p. 302 - 304 View in Reaxys

polymer-bound NMe3 (1+)*SCN(1-) Br

NH 2

Rx-ID: 15428461 View in Reaxys 515/553 Yield

212/236

2018-08-17 23:02:17

NH 2

Rx-ID: 15441420 View in Reaxys 516/553 Yield

Conditions & References Reaction Steps: 2 1.1: LiN(SiMe3)2 / tetrahydrofuran / 1 h / -78 °C 1.2: 95 percent / tetrahydrofuran / 13 h / -78 - 20 °C 2.1: 97 percent / BH3*DMS / tetrahydrofuran / 3 h / Heating With dimethylsulfide borane complex, lithium hexamethyldisilazane in tetrahydrofuran Zarrinmayeh; Bleakman; Gates; Yu; Zimmerman; Ornstein; McKennon; Arnold; Wheeler; Skolnick; Journal of medicinal chemistry; vol. 44; nb. 3; (2001); p. 302 - 304 View in Reaxys NH 2

O F

Rx-ID: 23703806 View in Reaxys 517/553 Yield

Conditions & References 41 Patent; Pfizer Inc; US2006/58361; (2006); (A1) English View in Reaxys

O Cl

NH 2

N H

O OH

Rx-ID: 39139811 View in Reaxys 518/553 Yield

Conditions & References Reaction Steps: 2 1: hydrogenchloride / tetrahydrofuran; water / 40 - 45 °C 2: toluene / 20 - 70 °C With hydrogenchloride in tetrahydrofuran, water, toluene Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys

213/236

2018-08-17 23:02:17

NH 2

H HO

H 2N

Rx-ID: 39139838 View in Reaxys 519/553 Yield

Conditions & References

0.23 g

22 : Example 22: Optical resolution of 2-(3-chlorophenyl)propan-1-amine with L-(-)-3-phenyllactic acid 69To a solution of 2-(3-chlorophenyl)propan-1-amine III (4.1 mmol; 0.7 g) in toluene (5 mL) at 70 °C was added L-(-)-3-phenyllactic acid (2.1 mmol; 0.3 g). The reaction mixture was stirred at 70 °C for 30 mm and then cooled to room temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with toluene and dried under reduced pressure to give 0.44 g of salt Ill-lact (Chiral HPLC: 80.5 percent ee, Renantiomer).Recrystallization:0.43 g of obtained salts was dissolved in i-PrOH (2 mL) at 70 °C. The solution was stirred at 70 °C for 30 mm and then cooled to room temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with i-PrOH and dried under reduced pressure to give 0.23 g of salt (R)-III-Iact (Chiral HPLC: 96.7 percent ee, Renantiomer).The lactic salt was optionally transformed to the base by washing ethyl acetate solution with aqueous Na2CO3 followed by removal of the solvent by evaporation. in toluene, T= 20 - 70 °C Patent; LEK PHARMACEUTICALS D.D.; GAJ, Stavber; CLUZEAU, Jerome; RICHTER, Frank; LAUS, Gerhard; GAZIC SMILOVIC, Ivana; WO2014/173928; (2014); (A1) English View in Reaxys

H 2N

Rx-ID: 22871523 View in Reaxys 520/553 Yield

Conditions & References

99 %

in ethanol, Time= 7h, T= 30 - 40 °C Patent; Yamakawa Chemical Industry Co., Ltd.; US6342636; (2002); (B1) English View in Reaxys NH 2 O N O

Cl Cl

Rx-ID: 24100501 View in Reaxys 521/553 Yield

Conditions & References 18.B : B. B. {1-[2-(3,4-Dichlorophenoxy)-5-nitrophenyl]ethyl}-methylamine A mixture of the preceding acetophenone resulting from step A (2.0 g, 6.1 mmol) and 2.0 M methylamine in methanol (6.1 mL, 12.2 mmol) in 25 mL of ethanol was stirred overnight at 25° C. Titanium (IV) isopropoxide (3.6 mL, 12.2 mmol) was added and the mixture was stirred another 24 hr.

214/236

2018-08-17 23:02:17

Sodium borohydride (0.346 g, 9.4 mmol) was then added and stirring was continued for another 24 hr, at which time a tic (10percent methanol: chloroform) indicated the reaction was complete. The reaction was quenched by adding 5 mL of 6N HCl, stirring for 20 min and then adding aqueous NaHCO3 until the pH was basic. The mixture was extracted with EtOAc and the combined extracts were washed with H2O, dried over NaSO4, filtered and concentrated to 1.7 g of colorless oil. The oil was flash chromatographed using 2percent MeOH in CHCl3, and the purified product was isolated as an oil, 1.37 g. Patent; Pfizer Inc.; US6410736; (2002); (B1) English View in Reaxys NH 2

Cl Cl

Rx-ID: 24005725 View in Reaxys 522/553 Yield

Conditions & References Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichloro-phenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine ... Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl])-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

215/236

2018-08-17 23:02:17

{1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichloro-phenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

216/236

2018-08-17 23:02:17

[2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-methylamine; ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichloro-phenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichloro-phenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichloro-phenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine ... Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine;

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

217/236

2018-08-17 23:02:17

[2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichloro-phenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Other embodiments of this invention include the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(4-Chlorophenoxy)-5-trifluoromethylphenyl]-ethyl}-methylamine; [2-(4-Chlorophenoxy)-4,5-dimethylbenzyl]-methylamine; {1-[5-Chloro-2(3,4-dichlorophenoxy)phenyl]-propyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamine; {1-[2-(3,4-Dichloro-phenoxy)-5-methylsulfanyl-phenyl]-1-methylethyl}-methylamine; [2-(3,4-Dichlorophenoxy)-5-methylsulfanyl-benzyl]-dimethylamine; [2-(3,4-Dichlorophenoxy)-5-methanesulfinyl-benzyl]-dimethylamine; ... Patent; Howard JR., Harry R.; Schmidt, Christopher J.; Seeger, Thomas F.; Elliott, Mark L.; US2002/143003; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US6677378; (2004); (B2) English View in Reaxys

NH 2

O O

HCl

HN S O O

Rx-ID: 24105631 View in Reaxys 523/553 Yield 7.3 g (54%)

Conditions & References 3 : N-2-(4-Benzyloxyphenyl)propyl 2-propanesulfonamide PREPARATION 3 N-2-(4-Benzyloxyphenyl)propyl 2-propanesulfonamide A 0° C. suspension of the material from Preparation 2 (10.8 g, 39 mmol) in dichloromethane (200 ml) was treated with 1,8diazabicyclo[5.4.0]undec-ene (14.4 mL, 116 mmol) followed by 2-propylsulfonyl chloride (4.8 mL, 43 mmol). The reaction mixture was stirred at 0° C. for 1 h and at ambient temperature for an extra 2 h. The reaction was stopped by the addition of water (100 ml). The organic material was extracted with dichloromethane (3*200 ml). The combined organic fraction was then washed with water (3*200 ml), brine (100 ml), dried over potassium carbonate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (SiO2, 20percent EtOAc: Hexane) to give 7.3 g (54percent) of the pure product. NMR was consistent with the proposed title structure.

218/236

2018-08-17 23:02:17

Electrospray Mass Spectrum:M+=346. Analysis calculated for C19H25NO3S: percent C, 65.68; percent H, 7.25; percent N, 4.03. Found: percent C, 65.63; percent H, 7.31; percent N, 4.07. Patent; Eli Lilly and Company; US6358982; (2002); (B1) English View in Reaxys OH N O

H O

NH 2

H O

Rx-ID: 4327338 View in Reaxys 524/553 Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys

OH N O

H O

NH 2

H O

Rx-ID: 4327339 View in Reaxys 525/553 Yield

Conditions & References With sodium bis(2-methoxyethoxy)aluminium dihydride in benzene Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

219/236

2018-08-17 23:02:17

O O

S O H

H O

NH 2 H

Rx-ID: 4327998 View in Reaxys 526/553 Yield

Conditions & References (i) aq. NaN3, DMF, (ii) LiAlH4, Et2O, Multistep reaction Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys

H OH

NH 2 H

Rx-ID: 22645489 View in Reaxys 527/553 Yield

Conditions & References Reaction Steps: 5 1: K2CO3 / acetone 2: (i) Et2O, (ii) MgSO4, benzene 3: (i) BF3-Et2O, NaBH4, diglyme, (ii) aq. H2O2, NaOH 4: Py 5: (i) aq. NaN3, DMF, (ii) LiAlH4, Et2O With pyridine, potassium carbonate in acetone Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys

220/236

2018-08-17 23:02:17

H O

O O

NH 2 H

Rx-ID: 22655374 View in Reaxys 528/553 Yield

Conditions & References Reaction Steps: 4 1: (i) Et2O, (ii) MgSO4, benzene 2: (i) BF3-Et2O, NaBH4, diglyme, (ii) aq. H2O2, NaOH 3: Py 4: (i) aq. NaN3, DMF, (ii) LiAlH4, Et2O With pyridine Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys

H O

NH 2

Rx-ID: 22655520 View in Reaxys 529/553 Yield

Conditions & References Reaction Steps: 3 1: (i) BF3-Et2O, NaBH4, diglyme, (ii) aq. H2O2, NaOH 2: Py 3: (i) aq. NaN3, DMF, (ii) LiAlH4, Et2O With pyridine Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys

221/236

2018-08-17 23:02:17

NH 2

H O

Rx-ID: 22678098 View in Reaxys 530/553 Yield

Conditions & References Reaction Steps: 2 1: Py 2: (i) aq. NaN3, DMF, (ii) LiAlH4, Et2O With pyridine Smissman; Borchardt; Journal of medicinal chemistry; vol. 14; nb. 8; (1971); p. 702 - 707 View in Reaxys NH 2

F F

F O

O O

Rx-ID: 9104073 View in Reaxys 531/553 Yield

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

222/236

2018-08-17 23:02:17

NH 2

N-2-(4-(N',N'-dibenzylamino)phenyl)propyl 2-propanesulfonamide

Rx-ID: 24219573 View in Reaxys 532/553 Yield

Conditions & References

10.32 g (63%)

57 : N-2-(4-(N',N'-dibenzylamino)phenyl)propyl 2-propanesulfonamide Preparation 57 N-2-(4-(N',N'-dibenzylamino)phenyl)propyl 2-propanesulfonamide A 0° C. suspension of the material from Preparation 56 (15.2 g, 37.7 mmol) in dichloromethane (125 ml) was treated with triethylamine (11.4 g, 113 mmol) followed by 2-propylsulfonyl chloride (9.2 g, 56.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 6 h. The reaction was stopped by the addition of water (100 ml). Organic was extracted with dichloromethane (3*200 ml). The combined organic fraction was washed with hydrochloric acid (0.2 M 100 ml), water (3*200 ml), brine (100 ml), dried over sodium sulfate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (SiO2, 30percent EtOAc:Hexane) to give 10.32 g (63percent) of the title compound. NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+=436. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys NH 2

Rx-ID: 24220453 View in Reaxys 533/553 Yield

Conditions & References

28.2 g (97%)

56 : 2-(4-(N,N-dibenzylamino)phenyl)propylamine hydrochloride The desired hydrochloric salt was dried under vacuo to give 28.2 g (97percent) of the pure product which was used in next step without any further purification. NMR was consistent with the proposed title structure. Patent; Eli Lilly and Company; US6303816; (2001); (B1) English View in Reaxys I

I H N

NH 2

O O

HCl

Rx-ID: 29270677 View in Reaxys 534/553 Yield 89 %

Conditions & References With hydrogenchloride in ethyl acetate, T= 0 - 20 °C , Inert atmosphere

223/236

2018-08-17 23:02:17

Stoffman, Elia J. L.; Clive, Derrick. L. J.; Organic and Biomolecular Chemistry; vol. 7; nb. 23; (2009); p. 4862 - 4870 View in Reaxys N

NH 2

HN S O

O O

Rx-ID: 23767564 View in Reaxys 535/553 Yield

Conditions & References 8.B :Step B: (2-{4-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl}propyl)amine 200 mg (5.25 mmol) of LiAlH4, in small portions, are added to a solution containing 485 mg (1.31 mmol) of the compound of Step A above in 15 ml of THF. After reacting for 3 hours, the excess hydride is hydrolyzed by dropwise addition of saturated aqueous NaCl solution. The reaction mixture is filtered, the solid is rinsed several times with THF and the filtrate is evaporated to yield a white meringue corresponding to the title compound. With lithium aluminium tetrahydride in tetrahydrofuran, Time= 3h Patent; Desos, Patrice; Cordi, Alexis; Lestage, Pierre; Danober, Laurence; US2006/128697; (2006); (A1) English View in Reaxys

NH 2

O OH

H OH

H 2N O

Rx-ID: 48565049 View in Reaxys 536/553 Yield

Conditions & References in acetone, T= 20 °C , Solvent Schlesinger, Carina; Tapmeyer, Lukas; Gumbert, Silke D.; Prill, Dragica; Bolte, Michael; Schmidt, Martin U.; Saal, Christoph; Angewandte Chemie - International Edition; vol. 57; nb. 29; (2018); p. 9150 - 9153; Angew. Chem.; vol. 130; nb. 29; (2018); p. 9289 - 9293,5 View in Reaxys

NH 2

O OH

H OH

H 2N O

Rx-ID: 48565051 View in Reaxys 537/553 Yield

Conditions & References in acetone, T= 20 °C Schlesinger, Carina; Tapmeyer, Lukas; Gumbert, Silke D.; Prill, Dragica; Bolte, Michael; Schmidt, Martin U.; Saal, Christoph; Angewandte Chemie - International Edition; vol. 57; nb. 29; (2018); p. 9150 - 9153; Angew. Chem.; vol. 130; nb. 29; (2018); p. 9289 - 9293,5 View in Reaxys

224/236

2018-08-17 23:02:17

NH 2 O

O S

Cl Cl

Rx-ID: 24034644 View in Reaxys 538/553 Yield

Conditions & References , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Diclorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; [2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-Dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorphenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sufonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Pfizer Inc.; US2002/183306; (2002); (A1) English View in Reaxys

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

225/236

2018-08-17 23:02:17

, wherein said compound or salt is selected from the following: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine; Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys Other embodiments of formula I include the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein the (SRI) anxiolytic agent or antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Pfizer Inc.; US2002/147206; (2002); (A1) English View in Reaxys , wherein the SRI antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Howard JR., Harry Ralph; US2002/99045; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]ethyl}methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine.

Copyright ÂŠ 2018 Elsevier Life Sciences IP Limited except certain content provided by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.

226/236

2018-08-17 23:02:17

Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/123490; (2002); (A1) English View in Reaxys Patent; Pfizer Inc.; US2002/165217; (2002); (A1) English View in Reaxys , wherein the antidepressant or pharmaceutically acceptable salt thereof that is employed in such method is selected from the following compounds and their pharmaceutically acceptable salts: ... {1-[2-(3,4-Dichlorophenoxy)-5fluorophenyl]-cyclopropyl}-dimethylamine; 2-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-1,5-dimethyl-pyrrolidine; 3-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-4-methyl-thiomorpholine; {1-[2-(3,4-Dichlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamine; {1-[2-(3,4-Dichlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamine; and [4-Chloro-2-(3,4-dichlorophenoxy)-5-methanesulfonyl-benzyl]-methylamine. Patent; Howard JR., Harry R.; US2002/107244; (2002); (A1) English View in Reaxys

NH 2

O H

2 OH

OH O

H 2N

Rx-ID: 22835128 View in Reaxys 539/553 Yield 38.2 %

227/236

2018-08-17 23:02:17

pylamine malate (147.6 g, 39.5percent) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine) [0054] 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). [0055] A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2percent e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (-79.2° C.) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5° C.) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35° C. to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2percent recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, revealed 96.7percent e.e. enriched in the R-isomer. [0056] 1H NMR (CD3OD, 300 MHz) α 7.32 (m, 10H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1H, J=9.3, 15.3), 2.38 (dd, 1H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). [0057] Preparation of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]Amine. [CHEMMOL-00013] [0058] Scheme I, steps C and D: To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol) in CH2Cl2 (1000 mL) was added 1.0 N NaOH (1050 mL, 1.05 moles). The mixture was stirred at room temperature for 1 hour and the organic phase was separated and gravity filtered into a 3.0 L round-bottom flask with a CH2Cl2 rinse (200 mL). The resulting free base, (2R)-2-phenylpropylamine, was dried via azeotropic distillation. Accordingly, the clear filtrate was concentrated to 600 mL at atmospheric pressure via distillation through a simple distillation head. Heptane (1000 mL) was added and the solution was concentrated again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation. The final pot temperature was 109° C. [0059] The solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine. To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 mol), triethylamine (200 g, 1.98 moles), and CH2Cl2 (500 mL). The mixture was stirred at room temperature until a clear solution was obtained. This solution was cooled to 5° C. and a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH2Cl2 (250 mL) was added dropwise with stirring over 2 hrs. The mixture was allowed to warm gradually to room temperature over 16 h. GC analysis indicated complete consumption of the (2R)-2-phenylpropylamine starting material. [0060] The stirred mixture was cooled to 8° C. and 2 N HCl (500 mL) was added dropwise. The organic phase was separated and extracted with water (1.x.500 mL) and saturated NaHCO3 (1.x.500 mL). The organic phase was isolated, dried (Na2SO4), and gravity filtered. The filtrate was concentrated under reduced pressure to provide ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (230 g, 96percent) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) α 7.34 (m, 2H), 7.23 (m, 3H), 3.89 (br t, 1H, J=5.4), 3.36 (m, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.98 (m, 1H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9). [0061] Preparation of [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine. [CHEMMOL-00014] [0062] Scheme I, step E: A stirred room temperature solution of ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (37.1 g, 0.154 mol) in glacial acetic acid (185 mL) was treated with concentrated H2SO4 (16.0 g, 0.163 mol), added dropwise in a slow stream, followed by a H2O rinse (37 mL). To this solution (30° C.) was added H5IO6 (8.29 g, 0.0369 mol), followed by iodine (17.9 g, 0.0707 mol). The resulting reaction mixture was heated and allowed to stir for 3 h at 60° C. After HPLC analysis verified the consumption of starting material, the reaction mixture was cooled to 30° C. and a 10percent aqueous solution of NaHSO3 (220 mL) was added dropwise while maintaining the temperature between 25° C. and 30° C. The mixture crystallized to a solid mass upon cooling to 0-5° C. [0063] The solids were suction filtered and rinsed with H2O to afford 61.7 g of crude solids that were redissolved into warm MTBE (500 mL). This solution was extracted with H2O (2.x.200 mL) and saturated NaHCO3 (1.x.200 mL) and the organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure to -200 mL. Heptane (100 mL) was added dropwise to the product solution with slow stirring until crystallization commenced. An additional 100 mL of heptane was added and the resulting suspension was allowed to stir slowly overnight at room temperature. The mixture was then cooled (0° C.), filtered, and the collected solids were rinsed with heptane. The solids were then air-dried to afford the intermediate title compound, [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (33.7 g, 59.8percent) as a white powder. Chiral Chromatography of this lot indicated 100percent e.e. [0064] 1H NMR (CDCl3, 300 MHz) α 7.66 (d, 2H, J=8.1), 6.98 (d, 2H, J=8.4), 3.86 (br t, 1H, J=5.1), 3.33 (m, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.92 (m, 1H), 1.30 (d, 3H, J=6.6), 1.27 (d, 6H, J=6.6). [0065] Preparation of (methylsulfonyl)(2-phenylethyl)amine. [CHEMMOL-00015] [0066] Scheme II, step A: To a 10° C. solution of phenethylamine (12.1 g, 0.100 mol) and triethylamine (11.1 g, 0.110 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at room temperature for 1.5 h and was then washed with 1 N HCl (5.x.20 mL). The organic phase was directly concentrated to provide the intermediate title compound, (methylsulfonyl)(2phenylethyl)amine, (21.2 g, 93.3percent) as an oil. [0067] 1H NMR (CDCl3, 300 MHz) 67.32 (m, 2H), 7.23 (m, 3H), 4.30 (br s, 1H), 3.40 (t, 2H, J=3.9), 2.88 (t, 2H, J=4.2), 2.81 (s, 3H). [0068] Preparation of [2-(4-iodophenyl)ethyl](methylsulfonyl)amine. [CHEMMOL-00016] [0069] Scheme II, step B: To a stirring room temperature solution of (methylsulfonyl)(2-phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95percent sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and periodic acid (H5IO6, 45.6 g, 0.206 mol). The reaction mixture was warmed to 70-75° C. for 3 h. The heat was removed and the dark violet reaction mixture was allowed to proceed overnight at room temperature. Potassium hydroxide pellets (85percent, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension. The suspension was cooled to 15° C. and filtered. The filter cake was triturated thoroughly with water and was then dissolved in CH2Cl2 (1 L) and extracted with additional water (2.x.200 mL). The organic phase was concentrated under reduced pressure to provide the intermediate title compound, [2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2percent) as a white powder. [0070] 1H NMR (CDCl3, 300 MHz) α 7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1), 4.37 (br t, 1H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t, 2H, J=3.9). [0071] Preparation of (tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide. [CHEMMOL-00017] [0072] Scheme II, step C: A room temperature solution of [2-(4-iodophenyl)ethyl](methylsulfonyl)amine (201 g, 0.618 mol), 4-dimethylamino-

228/236

2018-08-17 23:02:17

pyridine (3.8 g, 0.031 mol) and di-tert-butyl dicarbonate (162 g, 0.744 mol) in CH2Cl2 (1 L) was allowed to stir overnight. The reaction mixture was washed with water (2.x.400 mL) and the organic phase was concentrated to about 600 mL and hexanes (400 mL) was added. This combined solution was washed again with water (400 mL) and was concentrated to a solid that was suspended in hexanes (600 mL) and filtered. The collected solids were dried under reduced pressure to afford the intermediate title compound, (tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (241.5 g, 91.5percent) as a white solid. [0073] 1H NMR (CDCl3, 300 MHz) α 7.63 (d, 2H, J=7.8), 6.98 (d, 2H, J=7.8), 3.88 (t, 2H, J=6.9), 3.10 (s, 3H), 2.88 (t, 2H, J=6.9), 1.51 (s, 9H). [0074] Preparation of (tert-butoxy-N-(methylsulfonyl)-N-[2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl)phenyl]ethyl]carboxamide. [CHEMMOL-00018] [0075] Scheme II, step D: To a degassed solution of (tert-butoxy)-N-[2-(4iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (128 g, 0.300 mol), triethylamine (91.1 g, 0.900 mol), and 1,1'-bis(diphenylphosphino) ferrocenedichloropalladium (II)-CH2Cl2 complex (2.9 g, 0.0035 mol) in acetonitrile (600 mL) was added pinacolborane (50 g, 0.391 mol) dropwise. The mixture was stirred at 70-74° C. for 8 h and then was cooled to room temperature. The reaction mixture was concentrated to a fluid oil that was partitioned between MTBE (500 mL) and water (500 mL). The organic phase was separated and washed with water (2.x.200 mL) and concentrated to a residue that was partially dissolved with heptane (1 L). The heptane soluble fraction was filtered through Celite.(R). 521 and concentrated to an oil (95 g). The residue was dissolved in acetone (600 mL) and heptane (600 mL) and filtered through Celite.(R). 521. The combined filtrates were concentrated to 95 g of a mixture of a 3:1 molar ratio (1H NMR, 81.0percent by weight) of intermediate title compound, (tert-butoxy)-N(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide, (60.3percent potency corrected yield) and protio derivative. [0076] 1H NMR (CDCl3, 300 MHz) α 7.75 (d, 2H, J=7.8), 7.23 (d, 2H, J=8.1), 3.87 (t, 2H, J-8.1), 2.99 (s, 3H), 2.90 (t, 2H, J=7.5), 1.53 (s, 9H), 1.33 (s, 6H), 1.27 (s, 6H). [0077] Preparation of (Methylsulfonyl) {2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine. [CHEMMOL-00019] [0078] Scheme II, step E: To a 2 L flask charged with a stirring solution of (tert-butoxy)-N-(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl))phenyl]ethyl}carboxamide (98.7 g, 0.232 mol) in CH2Cl2 (500 mL) was added trifluoroacetic acid (82 mL, 121.4 g, 1.06 moles) dropwise from an addition funnel. No exotherm was observed and the reaction solution was allowed to stir at room temperature for 18 h. [0079] HPLC analysis indicated 98percent completion so the cooled (5° C.) reaction mixture was neutralized by the slow addition of 5N NaOH (175 mL). The pH of the aqueous phase was 10.5. The phases were separated and the aqueous phase was extracted with CH2Cl2 (50 mL). The combined CH2Cl2 phases were washed with brine (2.x.100 mL) and water (1.x.100 mL). The CH2Cl2 phase was diluted with heptane (300 mL) and was concentrated under reduced pressure to afford a suspension that was isolated by filtration. The collected solids were washed with pentane (2.x.100 mL) and dried under vacuum to provide the intermediate title compound, (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine, (69.0 g, 91.4percent) as a white powder. [0080] 1H NMR (CDCl3, 300 MHz) α 7.77 (d, 2H, J=8.1), 7.22 (d, 2H, J=7.8), 4.26 (br t, 1H, J-6), 3.40 (q, 2H, J=6.9), 2.89 (t, 2H, J=6.6), 2.82 (s, 3H), 1.34 (s, 12H). [0081] Preparation of 4-[2-[(methylsulfonyl)amino]ethyl]benzene Boronic Acid. [CHEMMOL-00020] [0082] Scheme II, step F: (Methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}amine (68.0 g, 0.209 mol) was placed into a 2L flask and combined with acetone (600 mL), 1N ammonium acetate (600 mL), and NaIO4 (168.1 g, 0.786 mol). This mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove insoluble matter to afford filtrate A. The collected solids were washed with acetone (2.x.100 mL) and this filtrate was combined with filtrate A. The combined filtrates were concentrated under reduced pressure to 600 mL to afford a precipitate that was recovered by filtration. The collected solids were air-dried to give 110 g of crude material. This crude material was suspended in water (100 mL) and 5N NaOH was added until the pH was 12.5. The resulting suspension was filtered and the filtrate was treated with decolorizing carbon (Darco 6-60). The mixture was filtered and the filtrate was diluted with 10N H2SO4 until the pH was 5.0 to precipitate the intermediate title compound. This precipitate was collected by filtration and dried under reduced pressure to provide the intermediate title compound, 4-{(2-[(methylsulfonyl)amino]ethyl}benzene boronic acid, (41.9 g, 82.5percent) as a white powder. [0083] 1H NMR (acetone-d6, 300 MHz) α 7.82 (d, 2H, J=8.4), 7.27 (d, 2H, J=7.8), 7.11 (s, 2H), 6.03 (m, 1H), 3.36 (m, 2H), 2.91 (m, 2H), 2.84 (s, 3H). [0084] Preparation of Final Title Compound. [0085] Scheme III: An aqueous solution of potassium formate was prepared in the following manner. To 15 mL of water was added KOH (85percent flakes, 6.73 g, 0.102 mol), then 98percent formic acid (4.70 g, 0.102 mol). Alternatively, one may use commercially available potassium formate. To this solution was then added K2CO3 (2.76 g, 0.0210 mol), 4-{2[(methylsulfonyl)amino]ethyl}benzene boronic acid (4.62 g, 0.190 mol), 1-propanol (100 mL), and [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (7.35 g, 0.200 in ethanol, Time= 0.5h, T= 75 °C Patent; Arnold, Macklin Brian; Bleisch, Thomas John; Cuff, George William; Ornstein, Paul Leslie; Zimmerman, Dennis Michael; US2003/225163; (2003); (A1) English View in Reaxys

229/236

2018-08-17 23:02:17

NH 2

O H

2 OH

HO OH

H 2N

Rx-ID: 22958696 View in Reaxys 540/553 Yield

Conditions & References 1 : Preparation of (2R)-2-phenylpropylamine Malate To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-1-propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 ML).The mixture was stirred for 1.6 hours, and the resulting milky white NaCl salts were filtered.An aliquot of the filtrate was analyzed by gas chromatography to provide the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles).A solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 ML) was added dropwise to the yellow filtrate and the solution was heated to 75° C. The solution was stirred at 75° C. for 30 minutes.The heat was removed and the solution was allowed to cool slowly.The resulting thick precipitate was allowed to stir overnight.The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 ML) to afford the intermediate title compound, (2R)-2-phenylpropylamine malate, (147.6 g, 39.5percent) as a white crystalline solid.Chiral GC analysis of the free base, 2-phenyl-1-propylamine revealed 83.2percent e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison, via chiral HPLC, with commercially available (R)-2-phenyl-1-propylamine). 1H NMR (CDCl3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2percent e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (79.2° C.) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5° C.) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35° C. to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2percent recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, revealed 96.7percent e.e. enriched in the R-isomer. 1H NMR (CD3OD, 300 MHz) α 7.32 (m, 10 H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1H, J=9.3, 15.3), 2.38 (dd, 1H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). in ethanol, Time= 0.5h, T= 75 °C Patent; Bender, David Michael; Forman, Scott Louis; Jones, Winton Dennis; Smith, Daryl Lynn; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/225127; (2003); (A1) English View in Reaxys

NH 2 O

HO OH H 2N

O2 HO

Rx-ID: 23234063 View in Reaxys 541/553 Yield 85.2 %

230/236

2018-08-17 23:02:17

free base, (2R)-2-phenylpropylamine, revealed 96.7percent e.e. enriched in the R-isomer. 1H NMR (CD3OD, 300 MHz) ? 7.32 (m, 10 H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1H, J=9.3, 15.3), 2.38 (dd, 1H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). in ethanol, Time= 0.5h, T= 75 °C Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys 32 %

4 :To a mechanically stirred solution of 2-phenyl-1-propylamine amine (50.0 g, 0.370 mol, can be prepared in a manner analogous to the procedure disclosed by A. W. Weston, et al., J. Am. Chem. Soc., 65, 674 (1943)) in 90percent ethanol/H2O (denatured with 0.5percent toluene) (450 mL) was added L-malic acid (24.8 g, 0.185 mol) portionwise at room temperature with a 90percent ethanol/H2O rinse (50 mL) to give a clear solution after a mild exotherm. This solution was allowed to cool and a white precipitate appeared after 30 min. The precipitation was allowed to proceed with slow stirring overnight. The resulting slurry was suction filtered (buchner funnel) and rinsed with 100percent ethanol (denatured with 0.5percent toluene) (2100 mL) to afford, after air-drying, 30 g of (2R)-2-phenylpropylamine malate as a white solid. Chiral chromatographic analysis of the isopropylsulfonamide derivative of the free base indicated 84percent ee. This (2R)-2-phenylpropylamine malate (30 g) was suspended in 90percent ethanol/H2O (300 mL) and heated to 78 C. with slow stirring to afford a clear colorless solution. The solution was allowed to cool slowly to room temperature overnight. Precipitation commenced at 60-65 C. The solids were filtered and rinsed at room temperature with 100percent ethanol (250 mL) to give (2R)-2-phenylpropylamine malate (24.3 g, 32percent) as a white crystalline solid. Chiral chromatographic analysis of the isopropylsulfonamide derivative of the free base indicated 96.5percent ee. in ethanol, water, toluene, T= 20 °C Patent; Aikins, James Abraham; Fray, Andrew Hendley; Miller, William David; Ornstein, Paul Leslie; Zarrinmayeh, Hamideh; Zimmerman, Dennis Michael; US2003/233015; (2003); (A1) English View in Reaxys

H Cl

H 2N

2 OH

OH O

NH 2

Rx-ID: 27803897 View in Reaxys 542/553 Yield 85.2 %

Conditions & References 5 :Charge 2 -phenyl- 1 -propylamine HCl (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) washed with additional ethanol (500 mL) to a dry 3 -L round bottom flask under nitrogen. Stir the mixture for 1.6 hours. Filter and add a solution of L-malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) dropwise to the yellow filtrate. Heat the solution to 75°C, then stir at 75°C for 30 minutes. Remove heat and allow the solution to cool slowly. Allow the resulting thick precipitate to stir overnight. Filter the precipitate, rinse with ethanol (325 mL) and dry under reduced pressure to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5percent) as a white crystalline solid. Chiral GC analysis of the free base, 2 phenyl- 1 -propylamine reveals 83.2percent e.e. enriched in the R-isomer. (Configuration is assigned via spectrometric comparison with commercial 2 -phenyl- 1 -propylamine.) IH NMR (CDCI3, 300 MHz) α 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, IH), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).Heat a slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2percent e.e.) in 1325 mL ethanol and 150 mL deionized water to reflux (approximately 79.2 0C) until the solids dissolve. Allow the homogeneous solution to slowly cool with stirring overnight. Cool the precipitate (0 0C to 5 0C) and filter. Collect solids, rinse with ethanol (150 mL), and dry at 35°C to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2percent recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, reveals 96.7percent e.e. enriched in the R-isomer. IH NMR (CD3OD, 300 MHz) α 7.32 (m, 10 H), 4.26 (dd, IH, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, IH, J=9.3, 15.3), 2.38 (dd, IH, J=9.3, 15.6), 1.33 (d, 6H, J=6.6). Stage 1: With sodium hydroxide in ethanol, Time= 1.6h Stage 2: in ethanol, Time= 0.5h, T= 75 °C Patent; ELI LILLY AND COMPANY; WO2008/73789; (2008); (A1) English View in Reaxys

231/236

2018-08-17 23:02:17

NH 2 O

O O

Rx-ID: 34023153 View in Reaxys 543/553 Yield

Conditions & References Reaction Steps: 4 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -40 °C 1.2: 4 h / -40 °C 2.1: pyridinium chlorochromate / dichloromethane / 20 °C 3.1: lithium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 4.1: diethyl ether With isopropylmagnesium chloride, pyridinium chlorochromate, lithium hydroxide in tetrahydrofuran, diethyl ether, dichloromethane, water Ma, Manling; Feng, Wei; Guo, Fang; Yang, Chao; Xia, Wujiong; Tetrahedron; vol. 68; nb. 43; (2012); p. 8875 - 8879 View in Reaxys

NH 2

OH O

O O

O OH

Rx-ID: 34023162 View in Reaxys 544/553 Yield

Conditions & References Reaction Steps: 3 1: pyridinium chlorochromate / dichloromethane / 20 °C 2: lithium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 3: diethyl ether With pyridinium chlorochromate, lithium hydroxide in tetrahydrofuran, diethyl ether, dichloromethane, water Ma, Manling; Feng, Wei; Guo, Fang; Yang, Chao; Xia, Wujiong; Tetrahedron; vol. 68; nb. 43; (2012); p. 8875 - 8879 View in Reaxys

NH 2

O O

O OH

Rx-ID: 34023169 View in Reaxys 545/553 Yield

Conditions & References Reaction Steps: 2 1: lithium hydroxide / tetrahydrofuran; water / 4 h / 20 °C

232/236

2018-08-17 23:02:17

2: diethyl ether With lithium hydroxide in tetrahydrofuran, diethyl ether, water Ma, Manling; Feng, Wei; Guo, Fang; Yang, Chao; Xia, Wujiong; Tetrahedron; vol. 68; nb. 43; (2012); p. 8875 - 8879 View in Reaxys

NH 2

H O

H 2N

Rx-ID: 34023176 View in Reaxys 546/553 Yield

Conditions & References 4 : General procedure for synthesis of salts 9 General procedure: To the solution of keto–acid 8 (100 mg, 0.36 mmol) in diethyl ether (5 mL) was added an equivalent of optically pure amine. Upon the addition, the precipitate formed immediately. The resulted suspension was filtered by suction to give the salt, which was then recrystallized from methanol. 3.2.4 (R)-(+)-2-Phenyl-1-propylamine salt of keto-acid 8 Mp 115-116 °C (Methanol). 1H NMR (400 MHz, CD OD): α 7.89 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.18 (m, 2H), 7.12 (m, 3H), 3.55 (m, 1H), 2.98 3 (d, J=7.0 Hz, 2H), 2.92 (m, 1H), 1.49 (m, 2H), 1.39 (m, 2H), 1.18 (d, J=6.8 Hz, 3H), 1.15 (m, 2H), 0.75 (d, J=6.5 Hz, 6H), 0.73 (d, J=6.5 Hz, 6H). 13C NMR (100 MHz, CD OD): α 206.8 (+), 174.0 (+), 143.5 (+), 143.4 (+), 140.0 (+), 130.5 (-), 130.1 (-), 128.8 (-), 128.5(-), 3 128.2 (-), 46.9 (+), 43.6 (-), 43.5 (+), 39.8 (-), 27.4 (-), 23.3 (-), 23.1 (-), 19.9 (-). IR (KBr) m α ax: 2961, 2698, 2198, 1674, 1582, 1532, 1385, 1209, 836, 794, 759, 732 cm-1. LRMS (ESI): 412 [M++1], 136, 105, 79. Anal. calcd for C26H37NO3: C, 75.87; H, 9.06; N, 3.40. Found: C, 76.10; H, 9.30; N, 3.45. in diethyl ether Ma, Manling; Feng, Wei; Guo, Fang; Yang, Chao; Xia, Wujiong; Tetrahedron; vol. 68; nb. 43; (2012); p. 8875 - 8879 View in Reaxys

NH 2 O

HO O

Rx-ID: 34023188 View in Reaxys 547/553 Yield

Conditions & References Reaction Steps: 5 1.1: pyridinium chlorochromate / dichloromethane / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -40 °C 2.2: 4 h / -40 °C 3.1: pyridinium chlorochromate / dichloromethane / 20 °C 4.1: lithium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 5.1: diethyl ether With isopropylmagnesium chloride, pyridinium chlorochromate, lithium hydroxide in tetrahydrofuran, diethyl ether, dichloromethane, water

233/236

2018-08-17 23:02:17

Ma, Manling; Feng, Wei; Guo, Fang; Yang, Chao; Xia, Wujiong; Tetrahedron; vol. 68; nb. 43; (2012); p. 8875 - 8879 View in Reaxys

O NH 2

OH O O

Rx-ID: 34023198 View in Reaxys 548/553 Yield

Conditions & References Reaction Steps: 7 1.1: lithium diisopropyl amide; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / tetrahydrofuran / -78 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran 3.1: pyridinium chlorochromate / dichloromethane / 20 °C 4.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -40 °C 4.2: 4 h / -40 °C 5.1: pyridinium chlorochromate / dichloromethane / 20 °C 6.1: lithium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 7.1: diethyl ether With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, lithium aluminium tetrahydride, isopropylmagnesium chloride, pyridinium chlorochromate, lithium hydroxide, lithium diisopropyl amide in tetrahydrofuran, diethyl ether, dichloromethane, water Ma, Manling; Feng, Wei; Guo, Fang; Yang, Chao; Xia, Wujiong; Tetrahedron; vol. 68; nb. 43; (2012); p. 8875 - 8879 View in Reaxys

NH 2 O

OH O

Rx-ID: 34023209 View in Reaxys 549/553 Yield

Conditions & References Reaction Steps: 6 1.1: lithium aluminium tetrahydride / tetrahydrofuran 2.1: pyridinium chlorochromate / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -40 °C 3.2: 4 h / -40 °C 4.1: pyridinium chlorochromate / dichloromethane / 20 °C 5.1: lithium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 6.1: diethyl ether With lithium aluminium tetrahydride, isopropylmagnesium chloride, pyridinium chlorochromate, lithium hydroxide in tetrahydrofuran, diethyl ether, dichloromethane, water Ma, Manling; Feng, Wei; Guo, Fang; Yang, Chao; Xia, Wujiong; Tetrahedron; vol. 68; nb. 43; (2012); p. 8875 - 8879 View in Reaxys

234/236

2018-08-17 23:02:17

O NH 2 N H

Rx-ID: 10887075 View in Reaxys 550/553 Yield

Conditions & References Patent; Millennium Pharmaceuticals, Inc.; US2008/64729; (2008); (A1) English View in Reaxys

NH 2

H 2N

Rx-ID: 29071767 View in Reaxys 551/553 Yield

Conditions & References 4 :PREPARATION 4; [00231] The acid of preparation (3) was resolved into its corresponding enantiomers, acid of Preparation (4a) and (4b) using chiral supercritical fluid chromatography (SFC) with the following conditions.Chiral-SFS Prep. Conditions: Preparative Column: Chiralcel OJ-H (3x25cm, 5μm)BPR pressure: 100 barsTemperature: 40 0CFlow rate: 70 mL/minMobile Phase: CO2MeOH (90/10) Detector Wavelength: 210 nmSeparation Program: Sequence injectionAnalytical HPLC (Column: OJH 250 X4.6 mm 5micron, Mobile phase: CO2MeOH, Flowrate: 90/10 2ml/min, BPR pressure: 00 Bar temperature: 40 0C Detection: UV220 nm) Retention times: Enantiomer A (4a): 5.27 min (ee >99.9 percent); Enantiomer B (4b): 7.25 min (ee 98.8 percent ). <n="65"/>[00232] In general, if the absolute stereochemistry of the two enantiomers are not yet defined. Isomer A designates the fast eluting enantiomer, and Isomer B the slow eluting enantiomer.[00233] A sample of the slow-eluting isomer (4b) co-crystallized with R-(+)-α- methyl phenethyl amine in MeCN.EtOH. An X-ray crystal structure determination of the crystalline material thus obtained has proved (4b) to be of (4R, 5R) configuration. The configuration of (4a), the antipode of (4b), thus was assigned as (4S, 5S). in ethanol, acetonitrile Patent; BRISTOL-MYERS SQUIBB COMPANY; WO2009/158380; (2009); (A1) English View in Reaxys

NH 2

N O

N O O

H 2N

Rx-ID: 24334254 View in Reaxys 552/553

235/236

2018-08-17 23:02:17

Yield

Conditions & References The compound of claim 6 which is selected from the group consisting of: ... cis-1,5-cyclooctylene bis{4-[2-(1-amidinopiperid-4-yl)ethylcarbamoyl]-1-piperazinecarboxylate}; cis-1,5-cyclooctylene bis[4-(trans-4-aminomethylcyclohexyl carbonyl)-1-piperidinecarboxylate]; cis-1,5-cyclooctylene bis{4-[4-(2-aminoethyl)phenylacetyl]-1-piperazinecarboxylate}; cis-1,5-cyclooctylene bis{4-[4-(2-aminoethyl)benzoyl[-1-piperazinecarboxylate}; cis-1,5-cyclooctylene bis{4-[4-(1-aminoprop-2-yl)benzoyl]-1-piperazinecarboxylate}; cis-1,5-cyclooctylene bis{4-[3-(1-amidinopiperid-4yl)propionoyl]-1-piperazinecarboxylate}; cis-1,5-cyclooctylene bis{4-[3-(4-amidinophenyl)propionoyl]-1-piperazinecarboxylate}; cis-1,5-cyclooctylene bis{4-[4-(2-aminoethyl)piperid-1-yl]-1-piperazinecarboxylate}; ... Patent; AXYS Pharmaceuticals, Inc.; US6022969; (2000); (A) English View in Reaxys

(v2)

– H O N N –Al3+ O– OH (v6) (v2) (v2)

H 2N

H+

–

(v2)

– H O

H H 2N

(v2)

N – 3+ –Al O OH (v6) (v2) (v2) –

(v2)

H+

– H O

NH 2

(v2)

N Al3+ O– O–H (v6) (v2) (v2) –O

(v2)

H+

Rx-ID: 41589499 View in Reaxys 553/553 Yield

Conditions & References in [D3]acetonitrile, T= 24.84 °C Seo, Min-Seob; Kim, Hyunwoo; Journal of the American Chemical Society; vol. 137; nb. 44; (2015); p. 14190 - 14195 View in Reaxys

236/236

2018-08-17 23:02:17