2.1 Single Br– (C2–C6) by Asch

Query Query

Results

Date

89 reactions in Reaxys

2016-06-12 06h:57m:28s (EST)

ALH

1. Query

* Br

HN ALH

Search as: As drawn, No mixtures, No charges, No radicals

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H 2N

Rx-ID: 23234286 View in Reaxys 1/89 Yield 97 %

Conditions & References 7 :A suspension of LiAlH4 (3.04 g, 80 mmole) in dry THF ( 100 ml) was cooled to -5 0C. Concentrated H2SO4 (3.9 g, 40 mmole) was added dropwise, and the resulting mixture was stirred at -5 0C for 1 hour. A solution of 3-bromobenzenacetontrile (9.80 g, 50 mmole) in THF (5 ml) was added dropwise, and the reaction was allowed to warm to room temperature when the addition was complete. The reaction was stirred at room temperature for 1 hour, and then cooled back to 0 0C and quenched by the addition of a 1 : 1 THF: H2O mixture (12.4 ml). Et2O was added (50 ml), followed by a 3.6 M solution of NaOH (24.4 ml). The mixture was filtered through Celite, and the solids were washed well with additional Et2O. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound (9.7 g, 97percent). The crude compound was used in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 7.38-7.30 (m, 2H), 7.20-7.10 (m, 2H), 2.96 (t, 2H), 2.72 (t, 2H), 1.35 (br s, 2H). MS (ESI) m/z: Calculated: 199; Observed: 200/202 (M++.). With lithium aluminium tetrahydride, sulfuric acid in tetrahydrofuran, Time= 2h, T= -5 - 20 °C Patent; PREDIX PHARMACEUTICALS HOLDINGS, INC.; WO2007/61458; (2007); (A2) English View in Reaxys

96 %

6 : Compound 6b: 3-bromo-benzeneethanamine A suspension of LIALH4 (1.24 g, 32.7 mmol) in dry THF (50 mL) was cooled to 0 °C. Concentrated H2SO4 (1.6 g, 16.3 mmol) was added dropwise, and the resulting mixture was stirred at 0 °C for 30 min. A solution of 3-bromobenzeneacetonitrile (4.01 g, 20.4 mmol) in THF (5 mL) was added dropwise, and the reaction was allowed to warm to room temperature when the addition was complete. The reaction was stirred at room temperature for lh, and then cooled back to 0 °C and quenched by the addition of a 1: 1 THF: H20 mixture (5 mL). Et2O was added (20 mL), followed by a 3.6 M solution OF NAOH (10 mL). The mixture was filtered through Celite, and the solids were washed well with additional ET2O. The organic phase was dried over NA2S04, filtered, and concentrated in vacuo to provide the title compound (3.91 g, 96percent). The crude compound was used in subsequent STEPS. 1H- NMR (CDC13); 8 7.38-7. 30 (overlapping s at 7.35 and d, J=7. 2 Hz for d, 2H), 7.20- 7.10 (m, 2H), 2. 96 (t,. J=6. 8 Hz, 2H), 2.72 (t, J=6. 4 Hz, 2H), 1. 35 (br s, 2H). MS (ESI) (M+H) += 200/202. With lithium aluminium tetrahydride, sulfuric acid in tetrahydrofuran, Time= 1h, T= 0 - 20 °C Patent; ASTRAZENECA AB; WO2004/60882; (2004); (A1) English View in Reaxys

93 %

286 :A suspension of LiAH4 (2.5 g, 66 mmol, 1.6 eq) in dry THF (100 mL) was cooled to -5° C. and concentrated H2SO4 (3.2 g, 33 mmol, 0.8 eq) was added drop wise while the temperature was maintained below 3° C. The reaction mixture was stirred at 5° C. for 40 minutes and a solution of intermediate I-59 (8.0 g, 41 mmol, 1.0 eq) in THF was added drop wise. The reaction mixture was warmed to room temperature and stirred for additional 60 minutes. The reaction mixture was cooled to 0° C. and quenched by adding a mixture of THF (5 mL) and water (5 mL). Ether was added followed by a solution of sodium hydroxide (20 mL, 3.6M in water) and the crude reaction mixture was filtered through short plug of Celite. The combined organic layers were dried over anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give intermediate I-60 (8.0 g, 93percent). MS (ESI): m/z 200 (M+H+). With lithium aluminium tetrahydride, sulfuric acid in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Chytil, Milan; Engel, Sharon R.; Fang, Qun Kevin; Spear, Kerry L.; US2010/204214; (2010); (A1) English View in Reaxys

92%

1.1 :Step 1: 2-(3-bromophenyl)ethanamine To a solution of 2M LAH (31 mL) in THF (37 mL) at 0° C. was added sulfuric acid (1.6 mL) dropwise. This mixture was allowed to stir for 30 min and then (3-bromophenyl)-acetonitrile (30.6 mmol) in THF (7.5 mL) was slowly added. The reaction mixture was allowed to warm to rt and stir for 1 hr. The reaction was cooled to 0° C. and then a 1:1 v:v mixture of THF:water (20 mL) was added, followed by diethyl ether (40 mL).

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A precipitate formed. 4N NaOH was added until the solution reached pH=9. The mixture was filtered and the solid was washed with ether. The solution was dried over Na2SO4 and concentrated to give 2-(3-bromophenyl)ethanamine (28.1 mmol, 92percent) as an oil, which was used without further purification. Stage 1: With lithium aluminium tetrahydride, sulfuric acid in tetrahydrofuran, Time= 1h, T= 20 °C Stage 2: With sodium hydroxide, water in tetrahydrofuran, diethyl ether, pH= 9 Patent; Millennium Pharmaceuticals, Inc.; US2008/171754; (2008); (A1) English View in Reaxys 73 %

2-(3-Bromophenyl) ethylamine To a solution of 3-bromophenyl acetonitrile (9.8 g, 50 mmol) in THF (20 mL) is added a solution of borane (.1 M in THF, 150 mL) under a nitrogen atmosphere. The reaction mixture is refluxed overnight. It is cooled to room temperature and treated with 6 N HCl (150 mL). The resulting mixture is washed with ethyl acetate and ethyl acetate is discarded. The aqueous layer is basifed with sodium carbonate and then extracted with ethyl acetate several times. The combined organic layer is washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure to obtain colorless viscous oil without further purification (7.3 g, 73percent). Stage 1: With BH3*THF in tetrahydrofuran, Heating / reflux Stage 2: With hydrochlorid acid, water in tetrahydrofuran, T= 20 °C Patent; NOVARTIS AG; WO2008/76954; (2008); (A2) English View in Reaxys

58 %

With BH3*THF in tetrahydrofuran, Time= 7h, Inert atmosphere, Reflux Pesnot, Thomas; Gershater, Markus C.; Ward, John M.; Hailes, Helen C.; Advanced Synthesis and Catalysis; vol. 354; nb. 16; (2012); p. 2997 - 3008 View in Reaxys

H 2N

Rx-ID: 268698 View in Reaxys 2/89 Yield 85 %

Conditions & References With sodium tetrahydroborate, {[κ3-(1-pz)2HB(N=CHCH3)]Ru(cymene)}+ TfO-, sodium t-butanolate in methanol, Time= 14h, T= 70 °C Lu, Zhiyao; Williams, Travis J.; Chemical Communications; vol. 50; nb. 40; (2014); p. 5391 - 5393 View in Reaxys

83 %

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

78 %

To a solution of 4-bromophenyl acetonitrile (20 g, 102 mmol) in THF (20 mL) is added a solution of borane (1 M in THF, 300 mL) under a nitrogen atmosphere. The reaction mixture is stirred at 75 C overnight. It is cooled to room temperature and treated with 6 N <n="52"/>HCl (500 mL) drop-wise and stirred further at room temperature for 5 h. The resulting mixture is washed with ethyl acetate and ethyl acetate is discarded. The aqueous layer is basified with sodium carbonate and then extracted with ethyl acetate several times. The combined organic layer is washed with water, dried (Na2SO4), and the solvent was removed under reduced pressure to obtain pale yellow oil without further purification (16 g, 78percent). Stage 1: With borane-THF, 5-bromoisoindoline in tetrahydrofuran, T= 75 °C Stage 2: With hydrogenchloride, water in tetrahydrofuran, T= 20 °C Patent; NOVARTIS AG; WO2008/76954; (2008); (A2) English View in Reaxys With lithium aluminium tetrahydride, diethyl ether

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Benington et al.; Journal of Organic Chemistry; vol. 23; (1958); p. 1979,1980 View in Reaxys With lithium aluminium tetrahydride Deles,J. et al.; Polish Journal of Chemistry; vol. 53; (1979); p. 1025 - 1032 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 With borane-THF in tetrahydrofuran, Time= 8h, Reflux Runyon, Scott P.; Mosier, Philip D.; Roth, Bryan L.; Glennon, Richard A.; Westkaemper, Richard B.; Journal of Medicinal Chemistry; vol. 51; nb. 21; (2008); p. 6808 - 6828 View in Reaxys

H 2N

Rx-ID: 29510962 View in Reaxys 3/89 Yield

Conditions & References 49.1 :Step 1: l-(4-bromophenyl)propan-2~amine; To a mixture of 2.0 M of ammonia in ethanol (1 17 niL, 235 mmol, Aldrich, Cat. No. 392685) and titanium tetraisopropoxide (27.7 mL, 93.9 mmol, Aidrich, Cat. No. 377996) was added l-(4- bromophenyl)acetone (10.0 g, 46.9 mmol, Alfa Aesar, Cat. No. A 19028). The reaction mixture was stirred at r.t. under nitrogen overnight. Sodium tetrahydroborate (2.66 g, 70.4 mmol) was added. The mixture was stirred at r.t. for additional 3 h. The reaction mixture was quenched with 2M ammonia in water, and filtered. The solid was washed with AcOEt. The filtrate was concentrated to remove most ethanol, and then was washed with AcOEt twices. The combined organic layers were extracted with IN HCI aqueous solution (twice). The aqueous HCI solutions were combined, and adjusted with ammonia aqueous solution to pH =10. The result solution was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z = 214.2. Stage 1: With titanium(IV) isopropylate, ammonia in ethanol, T= 20 °C , Inert atmosphere Stage 2: With sodium tetrahydroborate, ethanol, Time= 3h, T= 20 °C Patent; INCYTE CORPORATION; ZHANG, Colin; QIAN, Ding-quan; ZHUO, Jincong; YAO, Wenqing; WO2010/75270; (2010); (A1) English View in Reaxys I29.1 :Intermediate 29; Example I29.1; General Route; 1-(4-Bromophenyl)propane-2-amine; A mixture of 25.0 g (0.12 mol) 4-bromophenylacetone and 400 mL 7N ammonia in MeOH is charged with 1.20 g Raney nickel. The mixture is stirred in an hydrogen atmosphere (15 psi) at r.t. over night. Again 0.6 g Raney nickel are added and the mixture is stirred again for 3.5 h. After complete reaction, the mixture is filtrated. The residue is washed with MeOH and the solvent of the filtrate is removed in vacuo. The crude product is used without further purification.C9H12BrN (M=214.1 g/mol)ESI-MS: 214 [M+H]+ Rf (TLC): 0.3 (silica gel, DCM/MeOH 9/1) With ammonia, hydrogen, Raney nickel in methanol, T= 20 °C , p= 775.743Torr Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2012/214785; (2012); (A1) English View in Reaxys I.1 : Example 1.1 (General Route) 1-(4-Bromophenyl)propane-2-amine Example 1.1 (General Route) 1-(4-Bromophenyl)propane-2-amine 1-(4-Bromophenyl)propane-2-amine A mixture of 25.0 g (0.12 mol) 4-bromophenylacetone and 400 mL 7N ammonia in MeOH is charged with 1.20 g Raney nickel. The mixture is stirred in an hydrogen atmosphere (15 psi) at r.t. over night. Again 0.6 g Raney nickel are added and the mixture is stirred again for 3.5 h. After complete reaction, the mixture is filtrated. The residue is washed with MeOH and the solvent of the filtrate is removed in vacuo.

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The crude product is used without further purification. C9H12BrN (M=214.1 g/mol) ESI-MS: 214 [M+H]+Rf (TLC): 0.3 (silica gel, DCM/MeOH 9/1) With ammonia, hydrogen in methanol, T= 20 °C , p= 775.743Torr Patent; FLECK, Martin; NOSSE, Bernd; ROTH, Gerald Juergen; US2013/172316; (2013); (A1) English View in Reaxys I.1 : Example I. Example I.1 (general route) 1-(4-bromophenyl)propane-2-amine A mixture of 25.0 g (0.12 mol) 4-bromophenylacetone and 400 mL 7N ammonia in MeOH is charged with 1 .20 g Raney nickel. The mixture is stirred in an hydrogen atmosphere (15 psi) at r.t. over night. Again 0.6 g Raney nickel are added and the mixture is stirred again for 3.5 h. After complete reaction, the mixture is filtrated. The residue is washed with MeOH and the solvent of the filtrate is removed in vacuo. The crude product is used without further purification. C9Hi2BrN (M= 214.1 g/mol) ESI-MS: 214 [M+H]+ Rf (TLC): 0.3 (silica gel, DCM/MeOH 9/1 ) With ammonia, hydrogen in methanol, T= 20 °C , p= 775.743Torr Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; FLECK, Martin; NOSSE, Bernd; ROTH, Gerald, Juergen; WO2013/98375; (2013); (A1) English View in Reaxys Br

H 2N N

Rx-ID: 4161043 View in Reaxys 4/89 Yield 94 %

Conditions & References Stage 1: With complex boron hydride with tetrahydrofurane in tetrahydrofuran, Time= 24h, Reflux Stage 2: With methanol, sulfuric acid in tetrahydrofuran, water, Time= 1h, T= 20 °C Stage 3: With sodium hydroxide in tetrahydrofuran, water Jarboe, Stephen G.; Terrazas, Michael S.; Beak, Peter; Journal of Organic Chemistry; vol. 73; nb. 24; (2008); p. 9627 - 9632 View in Reaxys

93%

10.a : (3'-Methoxybiphenyl-2-ylethyl)dimethylamine Hydrochloride 1st Stage 2-(2-Bromo-phenyl)-ethylamine 10.0 g (51.0 mmol) 2-bromophenylacetonitrile were dissolved in 80 ml ether and the solution was added dropwise to 5.81 g (153 mol) lithium aluminium hydride in 230 ml ether. The mixture was heated under reflux for three hours, while stirring, and, after cooling, 80 ml potassium hydroxide solution (10 wt. percent) were slowly added dropwise, with vigorous stirring. After stirring overnight, the supernatant was decanted off, the residue was rinsed twice with 100 ml ether each time, the combined organic phases were dried over anhydrous magnesium sulfate and filtered and the filtrate was concentrated on a rotary evaporator (500-10 mbar). 9.48 g 2-(2-bromo-phenyl)-ethylamine (93percent of theory) were obtained in this manner. With potassium hydroxide Patent; Sundermann, Bernd; Koegel, Babette-Yvonne; Buschmann, Helmut; US2002/198251; (2002); (A1) English View in Reaxys

90 %

With lithium aluminium tetrahydride, aluminium trichloride in diethyl ether, Time= 18h Wolfe, John P.; Rennels, Roger A.; Buchwald, Stephen L.; Tetrahedron; vol. 52; nb. 21; (1996); p. 7525 - 7546 View in Reaxys

87 %

With lithium aluminium tetrahydride, aluminium trichloride in diethyl ether, 1.) 0 deg C, 10 min, 2.) room temp., 2 h McClure, Cynthia K.; Kiessling, Anthony J.; Link, Jeffrey S.; Tetrahedron; vol. 54; nb. 25; (1998); p. 7121 - 7126 View in Reaxys

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87 %

With sodium tetrahydroborate in water, Time= 12h, T= 100 °C , pH= 5.5 Nabid, Mohammad Reza; Bide, Yasamin; Niknezhad, Mahvash; ChemCatChem; vol. 6; nb. 2; (2014); p. 538 546 View in Reaxys

85 %

With lithium aluminium tetrahydride, aluminium trichloride in diethyl ether Reimann, Eberhard; Ettmayr, Christian; Monatshefte fur Chemie; vol. 135; nb. 9; (2004); p. 1143 - 1155 View in Reaxys

82 %

With lithium aluminium tetrahydride Tomaszewski, Miroslaw J.; Warkentin, John; Werstiuk, Nick H.; Australian Journal of Chemistry; vol. 48; nb. 2; (1995); p. 291 - 322 View in Reaxys

80 %

With lithium borohydride, tBuCH2CH2B(H)NiPr2 in tetrahydrofuran, Time= 18h, Reflux Haddenham, Dustin; Pasumansky, Lubov; DeSoto, Jamie; Eagon, Scott; Singaram, Bakthan; Journal of Organic Chemistry; vol. 74; nb. 5; (2009); p. 1964 - 1970 View in Reaxys

50 %

67.1 :Into a 500-mL 3 -necked round-bottom flask, was placed 2-(2- bromophenyl)acetonitrile (9.8 g, 49.99 mmol, 1.00 equiv), tetrahydrofuran (50 mL). This was followed by the addition of BH3 solution (250 mL, IN in tetrahydrofuran) dropwise with stirring at 0°C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H20. The pH value of the aqueous solution was adjusted to 2 with aq. hydrogen chloride (5 N). The aqueous solution was washed with 3x20 mL of EA and adjusted to pH to 11 with sodium hydroxide. The resulting aqueous solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 5 g (50percent) of 2-(2- bromophenyl)ethanamine as brown oil.LC-MS : (ES , m/z) : 200 [M+H] + With borane-THF in tetrahydrofuran, T= 0 - 20 °C Patent; BIOENERGENIX; MCCALL, John, M.; MCKEARN, John; ROMERO, Donnal, L.; CLAIR, Michael; WO2011/28947; (2011); (A2) English View in Reaxys With lithium aluminium tetrahydride Yang, Bryant H.; Buchwald, Stephen L.; Organic Letters; vol. 1; nb. 1; (1999); p. 35 - 37 View in Reaxys

600 mg (55%)

6 : Synthesis of N-Boc-protected 3-[2-(aminoethyl)phenyl]-2-propenoic acid STR28 A solution of lithium aluminum hydride (15 mmol) in THF (30 ml) was cooled to 0° C. and nitrile 19 was added as a THF solution (25 ml). After being stirred for 4 hours, the reaction mixture was quenched by the addition of 10 ml of water followed by 20 ml of 2N NaOH. The mixture was filtered through Celite to remove solids and the filter cake was washed with 2*100 ml of ethyl acetate. The layers were separated and the organic phase was washed with 2*50 ml of water, dried and concentrated to obtain 600 mg (55percent) of oily product 2-bromophenethylamine 20, 1 H NMR (CDCl3): δ 2.79 (t, 2H); 2.85 (t, 2H); 7.21 (m, 4H). With sodium hydroxide in tetrahydrofuran, water, ethyl acetate Patent; Scios Nova, Inc.; US5444048; (1995); (A1) English View in Reaxys

600 mg (55%)

6 : Synthesis of N-Boc-protected 3-[2-(aminoethyl)phenyl]-2-propenoic acid STR35 A solution of lithium aluminum hydride (15 mmol) in THF (30 ml) was cooled to 0° C. and nitrile 19 was added as a THF solution (25 ml). After being stirred for 4 hours, the reaction mixture was quenched by the addition of 10 ml of water followed by 20 ml of 2N NaOH.

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The mixture was filtered through Celite to remove solids and the filter cake was washed with 2*100 ml of ethyl acetate. The layers were separated and the organic phase was washed with 2*50 ml of water, dried and concentrated to obtain 600 mg (55percent) of oily product 2-bromophenethylamine 20, 1 H NMR (CDCl3): δ2.79 (t, 2H); 2.85 (t, 2H); 7.21 (m, 4H). With sodium hydroxide in tetrahydrofuran, water, ethyl acetate Patent; Scios Nova Inc.; US5541286; (1996); (A1) English View in Reaxys With AlCl3, aluminium chloride, lithium aluminium tetrahydride in diethyl ether, Time= 3h, T= 0 °C , Inert atmosphere Kubo, Tetsuji; Katoh, Chiharu; Yamada, Ken; Okano, Kentaro; Tokuyama, Hidetoshi; Fukuyama, Tohru; Tetrahedron; vol. 64; nb. 49; (2008); p. 11230 - 11236 View in Reaxys With sodium tetrahydroborate, nickel dichloride Kawai, Nobuyuki; Abe, Ryuzou; Uenishi, Jun'Ichi; Tetrahedron Letters; vol. 50; nb. 47; (2009); p. 6580 - 6583 View in Reaxys With sodium tetrahydroborate, NiII chloride hexahydrate in methanol, Time= 1.5h, T= 0 - 20 °C He, Gang; Lu, Chengxi; Zhao, Yingsheng; Nack, William A.; Chen, Gong; Organic Letters; vol. 14; nb. 12; (2012); p. 2944 - 2947 View in Reaxys

H 2N

Rx-ID: 29043655 View in Reaxys 5/89 Yield 96 %

Conditions & References Stage 1: With titanium(IV) isopropylate, 1,1,3,3-tetramethyldisiloxane in toluene, Time= 24h, T= 60 °C , Inert atmosphere Stage 2: With hydrogenchloride in water, T= 20 °C Laval, Stephane; Dayoub, Wissam; Favre-Reguillon, Alain; Berthod, Mikael; Demonchaux, Patrice; Mignani, Gerard; Lemaire, Marc; Tetrahedron Letters; vol. 50; nb. 50; (2009); p. 7005 - 7007 View in Reaxys

92 %

4.2. General procedure for the reduction of nitriles General procedure: To a nitrogen purged screw-caped vial containing 1a (1.0 g, 5.1 mmol, 1.0 equiv) in 6.0 mL of toluene were added TMDS (900 μL, 5.1 mmol, 1.0 equiv) or PMHS (610 μL, 10.2 mmol, 2.0 equiv) and Ti(Oi-Pr)4 (1.5 mL, 5.1 mmol, 1.0 equiv) at rt. The mixture was then heated at 60 °C for 24 h (the colorless solution turned into black and the conversion of the substrate can be followed up by TLC and/or 1H NMR). After cooling to rt, the clear solution was acidified using aqueous 1 M HCl (7.7 mL, 1.5 equiv) and the crude mixture was concentrated under reduced pressure. The resulting solid was filtered, washed with pentane (3*50 mL), and dissolved in ethanol. The filtrate was finally concentrated under reduced pressure affording the amine 2a as a hydrochloride salt. 1H NMR (300 MHz, MeOD) δ 2.94 (t, 2H, J=7.1 Hz, CH2CH2NH2), 3.17 (t, 2H, J=7.1 Hz, CH2CH2NH2), 7.22 (d, 2H, J=8.1 Hz, 2*CHAr), 7.49 (d, 2H, J=8.1 Hz, 2*CHAr). 13C NMR (100 MHz, MeOD) δ 33.9, 41.6, 122.0, 131.8, 133.0, 137.2. MS (CI, NH3) m/z=200 (MH)+. Stage 1: With C46H178O41Si42, titanium (IV) isopropoxide in toluene, Time= 24h, T= 60 °C , Inert atmosphere Stage 2: With hydrogenchloride, water in toluene, T= 20 °C , Inert atmosphere, Reagent/catalyst, Temperature, Concentration Laval, Stephane; Dayoub, Wissam; Pehlivan, Leyla; Metay, Estelle; Favre-Reguillon, Alain; Delbrayelle, Dominique; Mignani, Gerard; Lemaire, Marc; Tetrahedron; vol. 70; nb. 4; (2014); p. 975 - 983 View in Reaxys

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H 2N

H N

Rx-ID: 27796164 View in Reaxys 6/89 Yield 75 %

Conditions & References A : [2-(3-Bromo-phenyl)-ethyl]-methyl-amine 2-(3-Bromo-phenyl)-ethylamine (0.5 mmol) and formaldehyde (0.42 mmol) were mixed in 3 ml of 1,2-dichloroethane in a process vial, which was sealed with a septum. Sodium triacetoxyborohydride (0.84 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover.(R). equipped with a CEM Explorer. (R). automated reaction handling module). The reaction mixture was heated for 5 min at 90°C and then cooled. The crude was evaporated to dryness and then suspended in aqueous NaHCO3. The product was extracted with CH2Cl2 and washed with aqueous NaHCO3. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product [2-(3-bromo-phenyl)-ethyl]-methyl-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion.(TM). system to yield the title compound (75percent) as colourless oil. With sodium tris(acetoxy)borohydride in 1,2-DICHLOROETHANE, Time= 0.0833333h, T= 90 °C , Microwave irradiation Patent; Laboratorios del Dr. Esteve S.A.; EP1935886; (2008); (A1) English View in Reaxys

75%

1.A :2-(3-Bromo-phenyl)-ethylamine (0.5 mmol) and formaldehyde (0.42 mmol) were mixed in 3 ml of 1,2-dichloroethane in a process vial, which was sealed with a septum. Sodium triacetoxyborohydride (0.84 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover.(R). equipped with a CEM Explorer. (R). automated reaction handling module). The reaction mixture was heated for 5 min at 90°C and then cooled. The crude was evaporated to dryness and then suspended in aqueous NaHCO3. The product was extracted with CH2Cl2 and washed with aqueous NaHCO3. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product [2-(3-bromo-phenyl)-ethyl]-methyl-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion.(TM). system to yield the title compound (75percent) as colourless oil. With sodium tris(acetoxy)borohydride in 1,2-DICHLOROETHANE, Time= 0.0833333h, T= 90 °C , Microwave irradiation, Sealed Patent; Laboratorios del Dr. Esteve S.A.; EP1997493; (2008); (A1) English View in Reaxys

O O

Br H 2N

Rx-ID: 2087646 View in Reaxys 7/89 Yield 80 %

Conditions & References With lithium aluminium tetrahydride in diethyl ether, Time= 5h, T= 0 - 5 °C Mestichelli, Paola; Scott, Matthew J.; Galloway, Warren R. J. D.; Selwyn, Jamie; Parker, Jeremy S.; Spring, David R.; Organic Letters; vol. 15; nb. 21; (2013); p. 5448 - 5451 View in Reaxys

56 %

Stage 1: With lithium aluminium tetrahydride in tetrahydrofuran, T= 0 - 20 °C , Inert atmosphere Stage 2: With water in tetrahydrofuran

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Chang, Chia-Fu; Huang, Chu-Yun; Huang, Yu-Chao; Lin, Kuan-Yu; Lee, Yean-Jang; Wang, Chau-Jong; Synthetic Communications; vol. 40; nb. 23; (2010); p. 3452 - 3466 View in Reaxys With lithium aluminium tetrahydride Mori,M. et al.; Journal of Organic Chemistry; vol. 43; nb. 9; (1978); p. 1684 - 1687 View in Reaxys With lithium aluminium tetrahydride in diethyl ether, Time= 5h, T= 0 - 5 °C , Yield given Bradsher, Charles K.; Hunt, David A.; Journal of Organic Chemistry; vol. 46; nb. 2; (1981); p. 327 - 330 View in Reaxys Martinez, Elena; Estevez, Juan C; Estevez, Ramon J; Castedo, Luis; Tetrahedron; vol. 57; nb. 10; (2001); p. 1981 - 1986 View in Reaxys With lithium aluminium tetrahydride in tetrahydrofuran, Time= 5h, T= 0 °C , Inert atmosphere Kenwright, Jayne L.; Galloway, Warren R. J. D.; Blackwell, David T.; Isidro-Llobet, Albert; Hodgkinson, James; Wortmann, Lars; Bowden, Steven D.; Welch, Martin; Spring, David R.; Chemistry - A European Journal; vol. 17; nb. 10; (2011); p. 2981 - 2986 View in Reaxys

Br Cl

H 2N

Rx-ID: 41474905 View in Reaxys 8/89 Yield 47 %

Conditions & References General Decarboxylation Procedure General procedure: Ten mL of 2M HCl was then added in a one-pot fashion, and, in all cases but threonine, the reaction vessel was heated to 190°Cover 5 min with stirring and then allowed to cool. In the case of the temperaturesensitive threonine, soxhlet extraction with toluene was performed at 80°C to remove R-carvone from the reaction mixture. The aqueous reaction mixture was washed three times with 25 mL of ether, and then water solvent was distilled off from the hydrochloride salt. The hydrochloride salt was transferred to a vacuum oven and dried overnight at 150 °C and 10 Torr. With hydrochlorid acid in propan-1-ol, Time= 0.0833333h, T= 190 °C , Microwave irradiation, Green chemistry Jackson, Douglas M.; Ashley, Robert L.; Brownfield, Callan B.; Morrison, Daniel R.; Morrison, Richard W.; Synthetic Communications; vol. 45; nb. 23; (2015); p. 2691 - 2700 View in Reaxys

H 2N

Rx-ID: 2070993 View in Reaxys 9/89 Yield 85 %

Conditions & References With sodium tetrahydroborate, borane-THF in tetrahydrofuran, Time= 144h, T= 25 °C Kabalka, George W.; Laila Guindi; Varma, Rajender S.; Tetrahedron; vol. 46; nb. 21; (1990); p. 7443 - 7457 View in Reaxys

80 %

With lithium aluminium tetrahydride in diethyl ether, Time= 3h, Inert atmosphere, Reflux

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Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys With hydrogenchloride, sodium hydroxide, sodium tetrahydroborate, borane-THF, 1.) 25 deg C, 6 days, 2.) 60 -65 deg C, 2 h, 3.) NaOH, Yield given. Multistep reaction Mourad, M. Soubei; Varma, Rajender S.; Kabalka, George W.; Synthetic Communications; vol. 14; nb. 12; (1984); p. 1099 - 1104 View in Reaxys With hydrogenchloride, sodium tetrahydroborate, boron trifluoride diethyl etherate, 1.) THF, reflux, 5.5 h, 2.) heating, 2 h, Yield given. Multistep reaction Varma, Rajender S.; Kabalka, George W.; Synthetic Communications; vol. 15; nb. 9; (1985); p. 843 - 848 View in Reaxys With lithium aluminium tetrahydride in diethyl ether, 1.) reflux, 6 h, 2.) RT, 16 h Glennon, Richard A.; Raghupathi, Reva; Bartyzel, Piotr; Teitler, Milt; Leonhardt, Sigrun; Journal of Medicinal Chemistry; vol. 35; nb. 4; (1992); p. 734 - 740 View in Reaxys O O

H 2N

Rx-ID: 23511479 View in Reaxys 10/89 Yield

Conditions & References 19 :[2- (3-Bromo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester: To a stirring solution of lithium aluminum hydride (24 mL of 1 M in tetrahydrofuran (THF), 24 mmol) at 0 °C under an atmosphere of nitrogen was added sulfuric acid (0.61 mL, 12.0 mmol) in tetrahydrofuran (10 mL) dropwise. Then a solution of 1-bromo-3- (2-nitro-propenyl)benzene (1.17 g, 4.8 mmol) in THF was added dropwise via an addition funnel. Reaction warmed to room temperature overnight. Reaction chilled to 0 °C, and a saturated solution of potassium sodium tartrate tetrahydrate added to the reaction dropwise. Once a cake formed, the organic phase was reduced to an oil under vacuum. This residue was then dissolved in dichloromethane and dried over magnesium sulfate. Di-tert-butyldicarbonate (1.05 g, 4.8 mmol) added and solution stirred overnight at room temperature. Reaction reduced to an oil under vacuum and isolated as a white solid after purification on silica. M+1=314/316. Stage 1: With lithium aluminium tetrahydride, sulfuric acid in tetrahydrofuran, T= 0 - 20 °C Stage 2: With water, Sodium potassium tartrate, T= 0 °C Patent; AMGEN INC.; WO2005/70932; (2005); (A2) English View in Reaxys Preparation of 1-(3-bromophenyl)propan-2-amine To a solution of 1-bromo-3-[2-nitroprop-1-enyl]benzene (10 g, 41.3 mmol) in THF (100 mL) was added LiAlH4 (4.7 g, 123.9 mmol) in portions at 0° C., then the reaction was slowly warmed to 60° C. and stirred for 1 hour. After 1-bromo-3-[2-nitroprop-1-enyl]benzene was consumed completely, the reaction was cooled to room temperature and then quenched with water and aqueous NaOH (10percent). The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude 1-(3-bromophenyl)propan-2-amine (5.7 g). With lithium aluminium tetrahydride in tetrahydrofuran, Time= 1h, T= 0 - 60 °C 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 59.2; 60.2 : Step 2: Preparation of l-(3-bromo henyl)propan-2-arnine Step 2: Preparation of l-(3-bromo henyl)propan-2-arnine To a solution of l-bromo-3-[2-nitroprop-l -enyljbenzene (10 g, 41.3 mmol) in TH F (100 mL) was added LiAlH4 (4.7 g, 123.9 mmol ) in portions at 0 °C, then the reaction was slowly warmed to 60 °C and st irred for 1 hour. After 1 -bromo-3-[ 2-nitroprop- 1 -enyljbenzene was consumed completely,

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the reaction was cooled to room temperature and then quenched with water and aqueous NaOH (10percent). The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude l-(3-bromophenyl)propan-2-amine (5.7 g). With lithium aluminium tetrahydride in tetrahydrofuran, Time= 1h, T= 0 - 60 °C 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

Br Cl

H 2N

Rx-ID: 29632404 View in Reaxys 11/89 Yield

Conditions & References

23 %

293 :To a stirred suspension of LiAlH4 (7.7 g, 203 mmol, 3.5 eq.) in THF (40 mL) was added drop wise a solution of intermediate I-67 (13 g, 59 mmol, 1.0 eq.) in THF (40 mL) and the reaction mixture was stirred at room temperature for 2 hours and quenched by adding a solution of NaOH (30percent in water). Ethyl acetate (100 mL) was added and the crude reaction mixture was stirred for another 30 minutes. The organic layer was separated and dried over anhydrous Na2SO4. Gaseous HCl was bubbled through the ethyl acetate solution at 0° C. and the white precipitate was collected by filtration to give intermediate I-68 (3.2 g, 23percent). 1H-NMR (400 MHz, DMSO-d6) δ: 7.52 (m, 2H), 7.24 (m, 2H), 3.18 (m, 2H), 2.95 (m, 2H). MS (ESI): m/z 198.1, 200.1 (M+H+). Stage 1: With lithium aluminium tetrahydride in tetrahydrofuran, Time= 2h, T= 20 °C Stage 2: With hydrogenchloride in ethyl acetate Patent; Chytil, Milan; Engel, Sharon R.; Fang, Qun Kevin; Spear, Kerry L.; US2010/204214; (2010); (A1) English View in Reaxys

H 2N

H N

Rx-ID: 39264876 View in Reaxys 12/89 Yield 18.32 %

Conditions & References 13.13A : Example 1 3A: 2-(3-Bromophenyl)-N-methylethanamine Example 1 3A: 2-(3-Bromophenyl)-N-methylethanamine j00279j 2-(3-Bromophenyl)ethanamine (0.500 g, 2.499 mmol) was dissolved in ethylformate (20.19 mL, 250 mmol) and formic acid (9.58 .iL, 0.250 mmol) was added. Thereaction was heated to reflux for 45 mm. Reaction was concentrated under reduced pressure. The residue was dissolved in THF (10 mL) and cooled to 0 °C. BH3.THF (10.00 mL, 10.00 mmol) was added and the reaction was brought to reflux and stirred forlh. The material was cooled to 0 °C and diluted with water, then 1 N NaOH. Thismixture was allowed to stir for 30 minutes, then extracted thrice with EtOAc. Theorganic layer was washed with iN HC1. The combined aqueous layer was then neutalized with iN NaOH. Upon neutalization, the aqueous layer was washed with 3 x EtOAc. The combined organic layer was washed with brine, dried with sodium sulfate, and concentrated to yield Example 13A (98 mg, 0.458 mmol, 18.32 percent yield) as acolorless oil. MS (ESI) m/z: 216.7 (M+H). Stage 1: With formic acid ethyl ester, Time= 0.75h, Reflux Stage 2: With borane-THF in tetrahydrofuran, Time= 1h, T= 0 °C , Reflux Patent; BRISTOL-MYERS SQUIBB COMPANY; RICHTER, Jeremy; BATES, J. Alex; CHENEY, Daniel L.; WO2014/201073; (2014); (A1) English View in Reaxys

NH 2Cl

H N

HCl Br

Rx-ID: 24276477 View in Reaxys 13/89

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Yield

Conditions & References

58%

3.B : B. B. [2-(4-Bromophenyl)-1-methylethyl]ethylamine hydrochloride A mixture of 1-(4-bromophenyl)propan-2-one (5 grams, 23.5 mmole), ethylamine hydrochloride (19 grams, 0.23 mole) and sodium cyanoborohydride (2.22 grams, 0.035 mole) in methanol (100 ml) was stirred at 22° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between 1.0N sodium hydroxide (25 ml) and ethyl ether (60 ml). The organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The oily base was converted to the hydrochloride salt and recrystallized from ethanol/ethyl ether to give [2-(4-bromophenyl)-1-methylethyl]ethylamine hydrochloride (3.8 grams, 58percent), m.p. 175-176° C. With sodium cyanoborohydride in methanol Patent; Syntex (U.S.A.) LLC; US6319920; (2001); (B1) English View in Reaxys

O O

H 2N

Rx-ID: 34846038 View in Reaxys 14/89 Yield

Conditions & References A suspension of Intermediate Bl (350 mg, 15.21 mmol) and zinc powder (300mg, 4.56 mmol) in methanol (50.0 mL) and 2N HCl (50.0 mL) was stirred at 65 °C for 1 hour. The reaction mixture was filtered, and the cake was washed with methanol (3 χ lOmL). The combined filtrates were concentrated under reduced pressure, and the residue was dissolved in dichloromethane, dried over anhydrous Na2S04, and the solvent was removed to afford the crude Intermediate BJ (lg, crude), which was used in the next step without further purification. With hydrogenchloride, zinc in methanol, water, Time= 1h, T= 65 °C Patent; HERCULES TECHNOLOGY MANAGEMENT CO V, INC.; BLAGG, Julian; WO2011/47156; (2011); (A1) English View in Reaxys Br O

H N

Rx-ID: 28191747 View in Reaxys 15/89 Yield

Conditions & References

85 %

Stage 1: With trifluoroacetic acid in dichloromethane, Time= 12h, T= 20 °C Stage 2: With sodium hydroxide in dichloromethane, water, T= 20 °C Jarboe, Stephen G.; Terrazas, Michael S.; Beak, Peter; Journal of Organic Chemistry; vol. 73; nb. 24; (2008); p. 9627 - 9632 View in Reaxys

Br H 2N

H N

Rx-ID: 29561474 View in Reaxys 16/89 Yield

Conditions & References 2.1.1 : 2.1.1: N-[2-(2-Bromophenyl)ethyl]heptan-4-amine 2.1.1: N-[2-(2-Bromophenyl)ethyl]heptan-4-amine

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10 g of 2-bromophenethylamine and 5.71 g of 4-heptanone are dissolved in 250 cm3 of 1,2-dichloroethane at a temperature close to 20° C. 14.84 g of sodium triacetoxyborohydride and 2.9 cm3 of glacial acetic acid are added to the reaction medium. Stirring is continued for 20 h. 300 cm3 of 1M sodium hydroxide are added to the reaction medium. The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate. The organic phases are combined and washed with 4 lots of 100 cm3 of water then 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated using a rotary evaporator under reduced pressure (5 kPa). The yellow liquid obtained is purified by flash chromatography over silica (column: 400 g; particle size: 20-40 μm, spherical; flow rate: 30 cm3/min; eluent: 100percent heptane to 70percent ethyl acetate/30percent heptane gradient). After concentrating the fractions under reduced pressure, 17.33 g of N-[2-(2-bromophenyl)ethyl]heptan-4-amine are obtained. LC-MS-DAD-ELSD: 298(+)(79Br)=(M+H)(+) With sodium tris(acetoxy)borohydride, acetic acid in 1,2-dichloro-ethane, Time= 20h, T= 20 °C Patent; SANOFI-AVENTIS; US2010/197725; (2010); (A1) English View in Reaxys Br O S

H N

H 2N

Rx-ID: 29561482 View in Reaxys 17/89 Yield

Conditions & References 6.1.1 : 6.1.1: N-[2-(2-bromophenyl)ethyl]pentan-1-amine 6.1.1: N-[2-(2-bromophenyl)ethyl]pentan-1-amine 7 g of 2-(2-bromophenyl)ethyl methanesulfonate, 14.5 cm3 of 1-pentanamine, 17.33 g of potassium carbonate and 200 cm3 of tetrahydrofuran are stirred at a temperature between 65° C. and 70° C. under an inert atmosphere for 72 h. The reaction mixture is brought to 30° C. in order to be poured over a mixture of water, ice and ethyl acetate. The phases are stirred for 5 min, then are separated. The aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 6.6 g of oil obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 95percent dichloromethane/5percent methanol to 90percent dichloromethane/10percent methanol gradient). After concentrating the fractions under reduced pressure, 4.56 g of N-[2-(2-bromophenyl)ethyl]pentan-1-amine are obtained in the form of a white oil. NMR: 0.86 (t, J=7.0 Hz, 3H) 1.21-1.32 (m, 4H) 1.41 (m, 2H) 2.55 (t, J=7.3 Hz, 2H) 2.74 (m, 2H) 2.84 (m, 2H) 3.14 (broad unresolved m, 1H) 7.14 (td, J=7.7, 2.0 Hz, 1H) 7.22-7.39 (m, 2H) 7.56 (dd, J=7.7, 2.0 Hz, 1H) ES: m/z=270 (79Br)=MH+ With potassium carbonate in tetrahydrofuran, Time= 72h, T= 65 - 70 °C , Inert atmosphere Patent; SANOFI-AVENTIS; US2010/197725; (2010); (A1) English View in Reaxys Br

Br O

H 2N

Rx-ID: 10200037 View in Reaxys 18/89 Yield 72 %

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

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View in Reaxys 2H 2H

Br N

H NH

O O

Rx-ID: 28191748 View in Reaxys 19/89 Yield

Conditions & References

72 %

Stage 1: With trifluoroacetic acid in dichloromethane, Time= 16h, T= 20 °C Stage 2: With sodium hydroxide in dichloromethane, water, T= 20 °C Jarboe, Stephen G.; Terrazas, Michael S.; Beak, Peter; Journal of Organic Chemistry; vol. 73; nb. 24; (2008); p. 9627 - 9632 View in Reaxys

H N

H 2N

Rx-ID: 33728784 View in Reaxys 20/89 Yield

Conditions & References

12 %

4.2.2. 2-(3-Bromophenyl)-N-methylethanamine (2) To a solution of 3-bromophenethylbromide (1 g, 3.83 mmol) in DMF (10 mL) was added 40percent aqueous methylamine (2.97 mL, 38.3 mmol), followed by Cs2CO3 (1.625 g, 5 mmol). After the reaction mixture was refluxed for 1 h, it was cooled to room temperature and the solvent was removed. The residue was dissolved in ethyl acetate (30 mL), and the organic layer was washed with water (3 .x. 20 mL) and dried over Na2SO4. The solvent was removed in vacuo, and the oily residue was further purified using flash column chromatography (CHCl3/MeOH 5:2) yielding in 2 (100 mg, 12percent) as a colorless liquid. 1H NMR (300 MHz, CDCl3): δ 7.26-7.23 (m, 2H, ArH), 7.06-7.04 (m, 2H, ArH), 2.78-2.74 (m, 4H), 2.30 (s, 3H, NCH3); TLC Rf: 0.2 (CHCl3/MeOH 5:2); GC-MS (EI) m/z (percent rel Int.): 214 (100.0 [M]+), rt: 7.240 min (full analytical data are reported in27). With caesium carbonate in water, N,N-dimethyl-formamide, Time= 1h, Reflux Herth, Matthias M.; Hansen, Hanne D.; Ettrup, Anders; Dyssegaard, Agnete; Lehel, Szabolcs; Kristensen, Jesper; Knudsen, Gitte M.; Bioorganic and Medicinal Chemistry; vol. 20; nb. 14; (2012); p. 4574 - 4581 View in Reaxys

H N

Br HCl

Rx-ID: 24282068 View in Reaxys 21/89 Yield

Conditions & References 29.a : a a [2-(3-Bromophenyl)ethyl]methylamine hydrochloride Borane in tetrahydrofuran (1.0M, 26.3 ml) was added dropwise to a tetrahydrofuran solution of 2-(3-bromophenyl)-Nmethyl-acetamide (1.5 g, Example 12a)) at 0° C. Once addition was complete the solution was refluxed at 90° C. for 20 hours. The solution was cooled to room temperature, acidified with 6M hydrochloric acid (10 ml) and refluxed for a further hour. The solution was cooled to room temperature and extracted with diethyl ether. The aqueous layer was basified with 10percent sodium hydroxide and extracted with ethyl acetate. The extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to the hydrochloride salt by treatment with a 4M solution of hydrochloric acid in dioxan to give the sub-title compound as a solid (0.727 g). m.p. 135-136° C. MS (APCI) 214/216[(M-HCl)+H]+

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NMR(DMSO) 9.00(1H, s); 7.51(1H, s); 7.50-7.45(1H, m); 7.35-7.25(2H, m); 3.20-3.05(2H, m); 3.00-2.90(2H, m); 2.55(3H, s). With hydrochlorid acid, borane in tetrahydrofuran, 1,4-dioxane

Patent; AstraZeneca AB; US6300352; (2001); (B1) English View in Reaxys H N

H N HCl

Rx-ID: 24289089 View in Reaxys 22/89 Yield

Conditions & References 30.a : a a [2-(4-Bromophenyl)ethyl]-N-methylamine hydrochloride Prepared according to the method described in Example 29a) from borane (1.0M solution in tetrahydrofuran, 35 ml), 4-bromophenyl acetic acid methylamide (2.0 g, Example 24a)) in dry tetrahydrofuran (60 ml) to afford the sub-title compound as a solid (0.45 g). m.p. 198-200° C. MS (APCI) 214 (M+H)+ 1H NMR (CDCl ) 7.43(2H, d); 7.12(2H, d); 3.25-3.09(4H, m); 2.72(3H, s). 3 With borane in tetrahydrofuran Patent; AstraZeneca AB; US6300352; (2001); (B1) English View in Reaxys

H N

Li+

B–

Rx-ID: 2086972 View in Reaxys 23/89 Yield 56 %

Conditions & References With borane-THF in tetrahydrofuran, T= 60 - 70 °C Kabalka, George W.; Laila Guindi; Varma, Rajender S.; Tetrahedron; vol. 46; nb. 21; (1990); p. 7443 - 7457 View in Reaxys

H 2N

O H

OH – Na +

Rx-ID: 28438506 View in Reaxys 24/89 Yield

Conditions & References 7 :Example 7: Synthesis of 4'-{2-[(2-butoxy-5-chlorobenzoyl)amino]propyl}biphenyl-4- carboxylic acid (Compound 95); 7.21; To a solution of 4-bromophenylacetone (2 g, 9.4 mmol) in methanol (50 mL) is added ammonium acetate (10.8 g, 140 mmol) followed by Na(CN)BH3 (3g, 48 mmol). The mixture <n="74"/>is heated to 70 0C (reflux) overnight. After cooling to 0 0C, H2O (100 niL) is added. 50percent NaOH solution is then added to the mixture to adjust pH to -10. The mixture is then stirred at room temperature for 2 hours, extracted with DCM (10OmL x 3), dried with Na2SO4 and concentrated to give 2.37 g of the crude reductive amination product as a yellowish oil. Stage 1: With methanol, ammonium acetate, sodium cyanoborohydride, T= 70 °C Stage 2:, Time= 2h, T= 0 - 20 °C , pH= ~ 10 Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; BOEHRINGER INGELHEIM PHARMA GMBH and CO. KG; WO2009/52078; (2009); (A1) English View in Reaxys

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H N

O Cl

H 2N

Rx-ID: 9037836 View in Reaxys 25/89 Yield

Conditions & References

88 %

With indium, ammonium chloride in ethanol, Time= 3h, Heating Mineno, Tomoko; Choi, Seoung-Ryoung; Avery, Mitchell A.; Synlett; nb. 6; (2002); p. 883 - 886 View in Reaxys

H 2N

NH 2

H N

NH 2

O O

Rx-ID: 32451797 View in Reaxys 26/89 Yield

Conditions & References

45 %

With Candida antartica lipase B, triethylamine in n-heptane, Time= 2.7h, T= 35 °C , Inert atmosphere, Enzymatic reaction, optical yield given as percent ee Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys Br

H 2N

Rx-ID: 456144 View in Reaxys 27/89 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

H 2N

Rx-ID: 457010 View in Reaxys 28/89 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 Br

H 15 2 N

O 15

NH 2

Rx-ID: 9274264 View in Reaxys 29/89 Yield

Conditions & References With borane in tetrahydrofuran, Time= 3h, Heating Reich, Hans J.; Goldenberg, Wayne S.; Sanders, Aaron W.; Jantzi, Kevin L.; Tzschucke, C. Christoph; Journal of the American Chemical Society; vol. 125; nb. 12; (2003); p. 3509 - 3521 View in Reaxys

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H N

O S

Rx-ID: 11130054 View in Reaxys 30/89 Yield

Conditions & References

1.930 g

Stage 1: in toluene, Time= 12h, Heating Stage 2: With hydrogenchloride in toluene, Time= 1h, T= 20 °C , Further stages. Donets, Pavel A.; Van Der Eycken, Erik V.; Organic Letters; vol. 9; nb. 16; (2007); p. 3017 - 3020 View in Reaxys Br

H 2N

HO O

Rx-ID: 14518268 View in Reaxys 31/89 Yield

Conditions & References Reaction Steps: 3 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: 72 percent / NaBH3CN; NH4OAc / methanol / 18 h With copper(l) iodide, thionyl chloride, ammonium acetate, sodium cyanoborohydride in 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

H 2N

Cl O

Rx-ID: 14518934 View in Reaxys 32/89 Yield

Conditions & References Reaction Steps: 2 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: 72 percent / NaBH3CN; NH4OAc / methanol / 18 h With copper(l) iodide, ammonium acetate, sodium cyanoborohydride in 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

O N

Br H 2N

Rx-ID: 9652762 View in Reaxys 33/89 Yield 22 %

Conditions & References With samarium diiodide, water, isopropylamine in tetrahydrofuran Ankner, Tobias; Hilmersson, Goeran; Tetrahedron Letters; vol. 48; nb. 32; (2007); p. 5707 - 5710 View in Reaxys With lithium aluminium tetrahydride in tetrahydrofuran, Time= 6h, T= 65 °C

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Batra, Sanjay; Sabnis, Yogesh A.; Rosenthal, Philip J.; Avery, Mitchell A.; Bioorganic and Medicinal Chemistry; vol. 11; nb. 10; (2003); p. 2293 - 2299 View in Reaxys

H 2N

Rx-ID: 11133980 View in Reaxys 34/89 Yield 60 %

H 2N Br O

Rx-ID: 21021563 View in Reaxys 35/89 Yield

Conditions & References Reaction Steps: 2 1: ammonium acetate / 1.) reflux, 8 h, 2.) RT, 60 h 2: LiAlH4 / diethyl ether / 1.) reflux, 6 h, 2.) RT, 16 h With ammonium acetate, lithium aluminium tetrahydride in diethyl ether Glennon, Richard A.; Raghupathi, Reva; Bartyzel, Piotr; Teitler, Milt; Leonhardt, Sigrun; Journal of Medicinal Chemistry; vol. 35; nb. 4; (1992); p. 734 - 740 View in Reaxys Reaction Steps: 2 1: 82 percent / NH4OAc 2: 94 percent / BH3,NaBH4 / Heating With sodium tetrahydroborate, borane, ammonium acetate Kabalka, George W.; Varma, Rajender S.; Gai, Yuan-Zhu; Baldwin, Ronald M.; Tetrahedron Letters; vol. 27; nb. 33; (1986); p. 3843 - 3844 View in Reaxys Reaction Steps: 2 1: ammonium acetate / Reflux 2: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux With lithium aluminium tetrahydride, ammonium acetate in diethyl ether, 1: Henry reaction Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys

H 2N Br

HCl

Rx-ID: 31374484 View in Reaxys 36/89 Yield 36 %

Conditions & References Stage 1: With sodium cyanoborohydride, acetic acid in methanol, T= 20 °C Stage 2: With hydrogenchloride in diethyl ether, T= 5 °C Taniguchi, Masashi; Yamamoto, Yoshio; Nishi, Katsuji; Journal of Mass Spectrometry; vol. 45; nb. 12; (2010); p. 1473 - 1476 View in Reaxys

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H 2N

NH 2 Br

Rx-ID: 32451906 View in Reaxys 37/89 Yield

Conditions & References

52 %

With methoxy acetic acid ethyl ester, Candida antartica lipase B, triethylamine, T= 35 °C , Enzymatic reaction, optical yield given as percent ee Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys H N

H 2N

Br I

Rx-ID: 32585303 View in Reaxys 38/89 Yield

Conditions & References

90 %

in tetrahydrofuran, water, Time= 3h, T= 20 °C Chan, Daniel Shiu-Hin; Yang, Hui; Kwan, Maria Hiu-Tung; Cheng, Zhen; Lee, Paul; Bai, Li-Ping; Jiang, ZhiHong; Wong, Chun-Yuen; Fong, Wang-Fun; Leung, Chung-Hang; Ma, Dik-Lung; Biochimie; vol. 93; nb. 6; (2011); p. 1055 - 1064 View in Reaxys

O NH 2

H N

Rx-ID: 2851463 View in Reaxys 39/89 Yield 80.4 %

Conditions & References in ethanol, Time= 4h, Heating Hardy, George W.; Lowe, Lawrence A.; Mills, Gail; Sang, Pang Yih; Simpkin, Dean S. A.; et al.; Journal of Medicinal Chemistry; vol. 32; nb. 5; (1989); p. 1108 - 1118 View in Reaxys

Br H 2N

Rx-ID: 22500150 View in Reaxys 40/89 Yield

Conditions & References Reaction Steps: 2 1: aq. NaOH 2: LiAlH4 With sodium hydroxide, lithium aluminium tetrahydride Mori,M. et al.; Journal of Organic Chemistry; vol. 43; nb. 9; (1978); p. 1684 - 1687 View in Reaxys Reaction Steps: 2 1: acetic acid; ammonium acetate / 4 h / 120 °C 2: lithium aluminium tetrahydride / diethyl ether / 5 h / 0 - 5 °C With lithium aluminium tetrahydride, ammonium acetate, acetic acid in diethyl ether Mestichelli, Paola; Scott, Matthew J.; Galloway, Warren R. J. D.; Selwyn, Jamie; Parker, Jeremy S.; Spring, David R.; Organic Letters; vol. 15; nb. 21; (2013); p. 5448 - 5451 View in Reaxys

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O N

H 2N

Rx-ID: 2153009 View in Reaxys 41/89 Yield

Conditions & References

94 %

With sodium tetrahydroborate, borane, Heating Kabalka, George W.; Varma, Rajender S.; Gai, Yuan-Zhu; Baldwin, Ronald M.; Tetrahedron Letters; vol. 27; nb. 33; (1986); p. 3843 - 3844 View in Reaxys

H 2N

H N

Rx-ID: 3524477 View in Reaxys 42/89 Yield

Conditions & References

86 %

With sodium cyanoborohydride Kabalka, George W.; Varma, Rajender S.; Gai, Yuan-Zhu; Baldwin, Ronald M.; Tetrahedron Letters; vol. 27; nb. 33; (1986); p. 3843 - 3844 View in Reaxys Br N NH Br

Rx-ID: 11130069 View in Reaxys 43/89 Yield

Conditions & References

847 mg

With sodium tris(acetoxy)borohydride in 1,2-dichloro-ethane Donets, Pavel A.; Van Der Eycken, Erik V.; Organic Letters; vol. 9; nb. 16; (2007); p. 3017 - 3020 View in Reaxys Br

H 2N NH Br

Rx-ID: 11465332 View in Reaxys 44/89 Yield

Conditions & References Reaction Steps: 2 1: CD2Cl2 / 2 h / 20 °C 2: 847 mg / NaBH(OAc)3 / 1,2-dichloro-ethane With sodium tris(acetoxy)borohydride in dichloromethane-d2, 1,2-dichloro-ethane Donets, Pavel A.; Van Der Eycken, Erik V.; Organic Letters; vol. 9; nb. 16; (2007); p. 3017 - 3020 View in Reaxys

H N

NH 2

O O

Rx-ID: 32451763 View in Reaxys 45/89 Yield 73 %

Conditions & References With water, potassium hydroxide, Reflux, optical yield given as percent ee Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177

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View in Reaxys H N Cl

Br HO

Rx-ID: 18983496 View in Reaxys 46/89 Yield

Conditions & References Reaction Steps: 2 1: 92 percent / NEt3 / CH2Cl2 / 1 h / 0 °C 2: 80.4 percent / ethanol / 4 h / Heating With triethylamine in ethanol, dichloromethane Hardy, George W.; Lowe, Lawrence A.; Mills, Gail; Sang, Pang Yih; Simpkin, Dean S. A.; et al.; Journal of Medicinal Chemistry; vol. 32; nb. 5; (1989); p. 1108 - 1118 View in Reaxys Br H 2N

Rx-ID: 22115864 View in Reaxys 47/89 Yield

Conditions & References Reaction Steps: 2 1: FeCl3 / -21 - -16 °C 2: ethanol; ammonia / 160 °C With ethanol, ammonia, iron(III) chloride Patrick; McBee; Hass; Journal of the American Chemical Society; vol. 68; (1946); p. 1009 View in Reaxys

H 2N Br

Rx-ID: 22115869 View in Reaxys 48/89 Yield

H N O

Rx-ID: 24067469 View in Reaxys 49/89 Yield

Conditions & References 43 : [2-(4-Bromo-phenyl)-ethyl]-heptyl-amine: EXAMPLE 43 [2-(4-Bromo-phenyl)-ethyl]-heptyl-amine: Synthesised from 2-(4-bromo-phenyl)-N-heptyl-acetamide using a procedure analogous to that used for Example 3 to give [2-(4-bromo-phenyl)-ethyl]-heptyl-amine as a crude oil. The clear crude oil was used in the next step without purification. (32.7 g, 95percent) 1H NMR δ (CDCl ):7.39 (m, 2H); 7.07 (m, 2H); 2.95-2.75 (m, 4H); 2.70-2.56 (m, 2H); 1.56-1.44 (m, 2H); 1.32-1.15 3 (m, 8H); 0.85 (t, 3H)

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Patent; Hayward, Cheryl M.; Perry, David A.; US2002/165282; (2002); (A1) English View in Reaxys

Br Cl

Br H 2N

H 2N

Rx-ID: 28703575 View in Reaxys 50/89 Yield

Conditions & References

1.20 g

With hydrogenchloride in water, Time= 0.5h, Reflux Runyon, Scott P.; Mosier, Philip D.; Roth, Bryan L.; Glennon, Richard A.; Westkaemper, Richard B.; Journal of Medicinal Chemistry; vol. 51; nb. 21; (2008); p. 6808 - 6828 View in Reaxys Br

H 2N

Rx-ID: 21438332 View in Reaxys 51/89 Yield

Conditions & References Reaction Steps: 2 1: 83 percent / dimethylformamide / 15 h / 90 °C 2: 1.) hydrazine hydrate 2.)concentrated HCl / 1.) methanol, reflux, 1h; 2.) reflux, 1.5 h With hydrogenchloride, hydrazine hydrate in N,N-dimethyl-formamide Bradsher, Charles K.; Hunt, David A.; Journal of Organic Chemistry; vol. 46; nb. 2; (1981); p. 327 - 330 View in Reaxys

NH 2

Br N

Rx-ID: 32451826 View in Reaxys 52/89 Yield

Conditions & References Reaction Steps: 2 1: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 2: Candida antartica lipase B; triethylamine / n-heptane / 2.7 h / 35 °C / Inert atmosphere; Enzymatic reaction With lithium aluminium tetrahydride, Candida antartica lipase B, triethylamine in diethyl ether, n-heptane Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys Reaction Steps: 3 1: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 2: Candida antartica lipase B; triethylamine / n-heptane / 2.7 h / 35 °C / Inert atmosphere; Enzymatic reaction 3: water; potassium hydroxide / Reflux With lithium aluminium tetrahydride, Candida antartica lipase B, water, triethylamine, potassium hydroxide in diethyl ether, n-heptane Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys

NH 2

Br N

Rx-ID: 32451827 View in Reaxys 53/89

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Yield

Conditions & References Reaction Steps: 2 1: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 2: Candida antartica lipase B; methoxy acetic acid ethyl ester; triethylamine / 35 °C / Enzymatic reaction With lithium aluminium tetrahydride, methoxy acetic acid ethyl ester, Candida antartica lipase B, triethylamine in diethyl ether Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys Reaction Steps: 2 1: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 2: Candida antartica lipase B; triethylamine / n-heptane / 2.7 h / 35 °C / Inert atmosphere; Enzymatic reaction With lithium aluminium tetrahydride, Candida antartica lipase B, triethylamine in diethyl ether, n-heptane Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys

NH 2

Br O

Rx-ID: 32451942 View in Reaxys 54/89 Yield

Conditions & References Reaction Steps: 3 1: ammonium acetate / Reflux 2: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 3: Candida antartica lipase B; triethylamine / n-heptane / 2.7 h / 35 °C / Inert atmosphere; Enzymatic reaction With lithium aluminium tetrahydride, Candida antartica lipase B, ammonium acetate, triethylamine in diethyl ether, nheptane, 1: Henry reaction Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys Reaction Steps: 4 1: ammonium acetate / Reflux 2: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 3: Candida antartica lipase B; triethylamine / n-heptane / 2.7 h / 35 °C / Inert atmosphere; Enzymatic reaction 4: water; potassium hydroxide / Reflux With lithium aluminium tetrahydride, Candida antartica lipase B, ammonium acetate, water, triethylamine, potassium hydroxide in diethyl ether, n-heptane, 1: Henry reaction Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys

NH 2

Br O

Rx-ID: 32451943 View in Reaxys 55/89 Yield

Conditions & References Reaction Steps: 3 1: ammonium acetate / Reflux 2: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 3: Candida antartica lipase B; methoxy acetic acid ethyl ester; triethylamine / 35 °C / Enzymatic reaction With lithium aluminium tetrahydride, methoxy acetic acid ethyl ester, Candida antartica lipase B, ammonium acetate, triethylamine in diethyl ether, 1: Henry reaction

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Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys Reaction Steps: 3 1: ammonium acetate / Reflux 2: lithium aluminium tetrahydride / diethyl ether / 3 h / Inert atmosphere; Reflux 3: Candida antartica lipase B; triethylamine / n-heptane / 2.7 h / 35 °C / Inert atmosphere; Enzymatic reaction With lithium aluminium tetrahydride, Candida antartica lipase B, ammonium acetate, triethylamine in diethyl ether, nheptane, 1: Henry reaction Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys

(v3)

OH 2

O O

(v2) –

HO (v4) N Cu 2+ O– N (v6)

O Br

O H 2N

(v2)

(v4)

OH 2 (v3)

O -1

2 (v3)

OH 2

O O

(v2) – O

HO (v4) N Cu 2+ O– (v6) (v2)

(v4)

H 2N O O

OH 2 (v3)

Rx-ID: 28608545 View in Reaxys 56/89 Yield

Conditions & References in acetone, amine, 0.5 equiv of Cu-complex Chen, Chun-Long; Beatty, Alicia M.; Journal of the American Chemical Society; vol. 130; nb. 51; (2008); p. 17222 - 17223 ; (from Gmelin) View in Reaxys

H 2N

NH 2 Br

Rx-ID: 32451905 View in Reaxys 57/89 Yield

Conditions & References Reaction Steps: 2 1: Candida antartica lipase B; triethylamine / n-heptane / 2.7 h / 35 °C / Inert atmosphere; Enzymatic reaction 2: water; potassium hydroxide / Reflux With Candida antartica lipase B, water, triethylamine, potassium hydroxide in n-heptane Munoz, Lourdes; Rodriguez, Anna M.; Rosell, Gloria; Bosch, M. Pilar; Guerrero, Angel; Organic and Biomolecular Chemistry; vol. 9; nb. 23; (2011); p. 8171 - 8177 View in Reaxys

(S)-(Fmoc-amino)-(4-fluoro-phenyl)-acetic acid on Wang resin

Br H 2N

Rx-ID: 13524706 View in Reaxys 58/89 Yield

Conditions & References Reaction Steps: 2 1: ammonium acetate; nitromethane; acetic acid / 3 h / 20 °C / sonication 2: LiAlH4 / tetrahydrofuran / 6 h / 65 °C With ammonium acetate, lithium aluminium tetrahydride, nitromethane, acetic acid in tetrahydrofuran, 1: Henry reaction

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Batra, Sanjay; Sabnis, Yogesh A.; Rosenthal, Philip J.; Avery, Mitchell A.; Bioorganic and Medicinal Chemistry; vol. 11; nb. 10; (2003); p. 2293 - 2299 View in Reaxys

H N

Rx-ID: 27978142 View in Reaxys 59/89 Yield

Conditions & References With borane-THF in tetrahydrofuran, Heating Lewin, Anita H.; Navarro, Hernan A.; Wayne Mascarella; Bioorganic and Medicinal Chemistry; vol. 16; nb. 15; (2008); p. 7415 - 7423 View in Reaxys H N

H N

Rx-ID: 27978143 View in Reaxys 60/89 Yield

H N

Rx-ID: 27978144 View in Reaxys 61/89 Yield

H 2N

Rx-ID: 40430129 View in Reaxys 62/89 Yield

Conditions & References Reaction Steps: 2 1: ammonium acetate / 3 h / 130 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 - 60 °C With lithium aluminium tetrahydride, ammonium acetate in tetrahydrofuran 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: ammonium acetate / 3 h / 130 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 - 60 °C With lithium aluminium tetrahydride, ammonium acetate in tetrahydrofuran

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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 Br

H N

H 2N

Rx-ID: 11465335 View in Reaxys 63/89 Yield

Conditions & References Reaction Steps: 2 1.1: toluene / 4 h / Heating 2.1: toluene / 12 h / Heating 2.2: 1.930 g / aq. HCl / toluene / 1 h / 20 °C in toluene Donets, Pavel A.; Van Der Eycken, Erik V.; Organic Letters; vol. 9; nb. 16; (2007); p. 3017 - 3020 View in Reaxys

O N

Br H 2N

Rx-ID: 1034975 View in Reaxys 64/89 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether Pritzkow,W. et al.; Journal fuer Praktische Chemie (Leipzig); vol. 29; (1965); p. 123 - 141 View in Reaxys

Br H 2N

Rx-ID: 22423274 View in Reaxys 65/89 Yield

Conditions & References Reaction Steps: 3 1: NOCl, HCl / diethyl ether 2: Et3N / diethyl ether 3: LiAlH4 / diethyl ether With hydrogenchloride, lithium aluminium tetrahydride, nitrosyl chloride, triethylamine in diethyl ether Pritzkow,W. et al.; Journal fuer Praktische Chemie (Leipzig); vol. 29; (1965); p. 123 - 141 View in Reaxys

O N Cl

Br H 2N

Rx-ID: 22454718 View in Reaxys 66/89 Yield

Conditions & References Reaction Steps: 2 1: Et3N / diethyl ether 2: LiAlH4 / diethyl ether With lithium aluminium tetrahydride, triethylamine in diethyl ether Pritzkow,W. et al.; Journal fuer Praktische Chemie (Leipzig); vol. 29; (1965); p. 123 - 141

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View in Reaxys

H 2N

Rx-ID: 34845916 View in Reaxys 67/89 Yield

Conditions & References Reaction Steps: 3 1: ammonium acetate / ethanol / 1 h / 90 °C 2: sodium tetrahydroborate / methanol / 1.25 h / 0 - 10 °C 3: hydrogenchloride; zinc / water; methanol / 1 h / 65 °C With hydrogenchloride, sodium tetrahydroborate, ammonium acetate, zinc in methanol, ethanol, water Patent; HERCULES TECHNOLOGY MANAGEMENT CO V, INC.; BLAGG, Julian; WO2011/47156; (2011); (A1) English View in Reaxys Br

H 2N

N O

Rx-ID: 2575098 View in Reaxys 68/89 Yield

Conditions & References With hydrogenchloride, hydrazine hydrate, 1.) methanol, reflux, 1h; 2.) reflux, 1.5 h, Yield given. Multistep reaction Bradsher, Charles K.; Hunt, David A.; Journal of Organic Chemistry; vol. 46; nb. 2; (1981); p. 327 - 330 View in Reaxys Br

H N

Rx-ID: 3089289 View in Reaxys 69/89 Yield

Conditions & References With lithium aluminium tetrahydride, Time= 24h, Heating Sielecki, Thais M.; Meyers, A. I.; Journal of Organic Chemistry; vol. 57; nb. 13; (1992); p. 3673 - 3676 View in Reaxys Br

H N

Rx-ID: 20260844 View in Reaxys 70/89 Yield

Conditions & References Reaction Steps: 2 2: LiAlH4 / 24 h / Heating With lithium aluminium tetrahydride Sielecki, Thais M.; Meyers, A. I.; Journal of Organic Chemistry; vol. 57; nb. 13; (1992); p. 3673 - 3676 View in Reaxys H N

O N O

Br Br

Rx-ID: 21443190 View in Reaxys 71/89

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Yield

Conditions & References Reaction Steps: 2 1: 94 percent / BH3,NaBH4 / Heating 2: 86 percent / NaBH3CN With sodium tetrahydroborate, borane, sodium cyanoborohydride Kabalka, George W.; Varma, Rajender S.; Gai, Yuan-Zhu; Baldwin, Ronald M.; Tetrahedron Letters; vol. 27; nb. 33; (1986); p. 3843 - 3844 View in Reaxys H N

Br O

Rx-ID: 21471844 View in Reaxys 72/89 Yield

Conditions & References Reaction Steps: 3 1: 82 percent / NH4OAc 2: 94 percent / BH3,NaBH4 / Heating 3: 86 percent / NaBH3CN With sodium tetrahydroborate, borane, ammonium acetate, sodium cyanoborohydride Kabalka, George W.; Varma, Rajender S.; Gai, Yuan-Zhu; Baldwin, Ronald M.; Tetrahedron Letters; vol. 27; nb. 33; (1986); p. 3843 - 3844 View in Reaxys H N

H 2N Br

Rx-ID: 10542545 View in Reaxys 73/89 Yield

Conditions & References With sodium cyanoborohydride Nakahara, Yuji; Hanajiri, Ruri; Life Sciences; vol. 66; nb. 7; (2000); p. 563 - 574 View in Reaxys

O O

H 2N

Rx-ID: 318533 View in Reaxys 74/89 Yield

Conditions & References Electrolysis Kondo; Ishiwata; Chemische Berichte; vol. 64; (1931); p. 1533,1537; Yakugaku Zasshi; vol. 51; (1931); p. 755,765 View in Reaxys bei der elektrochemischen Reduktion Ishiwata; Yakugaku Zasshi; vol. 51; (1931); p. 755,765 View in Reaxys Kondo; Ishiwata; Chemische Berichte; vol. 64; (1931); p. 1533,1537; Yakugaku Zasshi; vol. 51; (1931); p. 755,765 View in Reaxys Reaction Steps: 2 1: sodium tetrahydroborate / methanol / 1.25 h / 0 - 10 °C 2: hydrogenchloride; zinc / water; methanol / 1 h / 65 °C With hydrogenchloride, sodium tetrahydroborate, zinc in methanol, water

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Patent; HERCULES TECHNOLOGY MANAGEMENT CO V, INC.; BLAGG, Julian; WO2011/47156; (2011); (A1) English View in Reaxys Br

H 2N

AcX

Rx-ID: 15351700 View in Reaxys 75/89 Yield

Conditions & References Reaction Steps: 2 Martinez, Elena; Estevez, Juan C; Estevez, Ramon J; Castedo, Luis; Tetrahedron; vol. 57; nb. 10; (2001); p. 1981 - 1986 View in Reaxys H N

H N

(+)-enantiomer

Rx-ID: 4346233 View in Reaxys 76/89 Yield

Conditions & References Acs, Maria; Kozma, David; Fogassy, Elemer; ACH - Models in Chemistry; vol. 132; nb. 3; (1995); p. 475 - 478 View in Reaxys H N

H N

(-)-enantiomer

Rx-ID: 4346234 View in Reaxys 77/89 Yield

Conditions & References Acs, Maria; Kozma, David; Fogassy, Elemer; ACH - Models in Chemistry; vol. 132; nb. 3; (1995); p. 475 - 478 View in Reaxys

N H

H N

Rx-ID: 3304865 View in Reaxys 78/89 Yield

Conditions & References Irradiation, Yield given Tomioka, Hideo; Tabayashi, Kazuo; Izava, Yasuji; Journal of the Chemical Society, Chemical Communications; nb. 13; (1985); p. 906 - 907 View in Reaxys

Br H 2N

Rx-ID: 25148027 View in Reaxys 79/89 Yield

Conditions & References When an effective antiemetic amount of one of the following Formula I compounds (sources provided above): ...

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D-4-fluorophenylalanine, L-4-fluorophenylalanine, D-4-iodophenylalanine, DL-4- chloroamphetamine hydrochloride, 4-bromophenethylamine, 2-(2-chlorophenyl)ethylamine, 2-(4-chlorophenyl)ethylamine, 4-fluorophenethylamine hydrochloride, ... Patent; A. H. Robins Company, Incorporated; US4857553; (1989); (A1) English View in Reaxys When an effective antiemetic amount of one of the following Formula I compounds (sources provided above): ... D-4-fluorophenylalanine, L-4-fluorophenylalanine, D-4-iodophenylalanine, DL-4-chloroamphetamine hydrochloride, 4-bromophenethylamine, 2-(2-chlorophenyl)ethylamine, 2-(4-chlorophenyl)ethylamine, 4-fluorophenethylamine hydrochloride, ... Patent; A. H. Robins Company, Incorporated; US4857553; (1989); (A1) English View in Reaxys When an effective antiemetic amount of one of the following Formula I compounds (sources provided above): ... D-4-fluorophenylalanine, L-4-fluorophenylalanine, D-4-iodophenylalanine, DL-4-chloroamphetamine hydrochloride, 4-bromophenethylamine, 2-(2-chlorophenyl)ethylamine, 2-(4-chlorophenyl)ethylamine, 4-fluorophenethylamine hydrochloride, 2-(3-chlorophenyl)ethylamine, ... Patent; A. H. Robins Company, Incorporated; US4857553; (1989); (A1) English View in Reaxys When an effective antiemetic amount of one of the following Formula I compounds (sources provided above): ... D-4-fluorophenylalanine, L-4-fluorophenylalanine, jD-4-iodophenylalanine, DL-4-chloroamphetamine hydrochloride, 4-bromophenethylamine, 2-(2-chlorophenyl)ethylamine, 2-(4-chlorophenyl)ethylamine, 4-fluorophenethylamine hydrochloride, ... Patent; A. H. Robins Company, Incorporated; US4857553; (1989); (A1) English View in Reaxys 3.2 Patent; NOVARTIS AG; BOCK, Mark G.; GAUL, Christoph; GUMMADI, Venkateshwar Rao; MOEBITZ, Henrik; SENGUPTA, Saumitra; WO2012/35078; (2012); (A1) English View in Reaxys

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3.2 : Preparation of Intermediate 2-(4-Chloro-phenyl)-ethylamine (I-1b) General procedure: Step 2: Preparation of Intermediate 2-(4-Chloro-phenyl)-ethylamine (I-1b) 1-Chloro-4-(2-nitro-vinyl)-benzene (I-1a: 3.4 g, 0.0185 mmol) dissolved in dry THF (50 mL) was added dropwise to a stirred suspension of LAH (1.3 g, 0.03707 mmol) in dry THF (50 mL) over a period of 20 minutes at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 45° C. for 3 hours. The reaction was monitored by TLC (10percent ethylacetate in hexane). The reaction mixture was cooled to room temperature, quenched with 10percent NaOH solution (3 mL), and filtered through Celite® bed. The filtrate was washed with ethylacetate and concentrated under reduced pressure to afford 2.6 g of the crude product which was used in the next step without further purification. 1H NMR (CDCl , 300 MHz): δ 7.49-7.00 (m, 6H), 2.9 (t, 2H), 2.6 (t, 2H) 3 With lithium aluminium tetrahydride in tetrahydrofuran, Time= 3.33h, T= 0 - 45 °C , Inert atmosphere Patent; NOVARTIS AG; Bock, Mark Gary; Gaul, Christoph; Gummadi, Venkateshwar Rao; Moebitz, Henrik; Sengupta, Saumitra; US2014/45872; (2014); (A1) English View in Reaxys

N H

H N

Rx-ID: 3304864 View in Reaxys 80/89 Yield

Conditions & References Irradiation, Product distribution Tomioka, Hideo; Tabayashi, Kazuo; Izava, Yasuji; Journal of the Chemical Society, Chemical Communications; nb. 13; (1985); p. 906 - 907 View in Reaxys Br H 2N

Rx-ID: 7788463 View in Reaxys 81/89 Yield

Conditions & References Patent; Sahyun Laboratories; US3089826; (1963); ; vol. 59; nb. 12706s; (1963) View in Reaxys 9.2 : Step 2 Step 2 2-Bromo Phenethylamine To the styrene of Step 1 (0.310 g, 1.3 mmol) in 5 mL of THF was added 1 M LiAlH4 solution in THF (5.2 mL, 5.2 mmol) at 0° C. The solution was stirred for 1 hour. A concentrated KHSO4 solution was added dropwise to destroy the excess of LiAlH4. The solution was filtered over celite and the filtrate concentrated in vacuo to give a yellow oil; 150 mg (58percent). Patent; Warner-Lambert Company; US6300501; (2001); (B1) English View in Reaxys

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Br H 2N

Rx-ID: 25144006 View in Reaxys 82/89 Yield

Conditions & References When an effective antiemetic amount of one of the following Formula I compounds (sources provided above): ... 1-(p-trifluoromethylphenyl)-2-aminopropane hydrochloride, p-trifluoromethylphenylethylamine, o-trifluoromethylphenylethylamine, o-trifluoromethylphenylethylamine acetate, DL-2-bromoamphetamine, DL-3-bromoamphetamine, DL-4-bromoamphetamine, DL-2-chloroamphetamine, ... Patent; A. H. Robins Company, Incorporated; US4857553; (1989); (A1) English View in Reaxys

H 2N

Rx-ID: 25144007 View in Reaxys 83/89 Yield

Conditions & References When an effective antiemetic amount of one of the following Formula I compounds (sources provided above): ... p-trifluoromethylphenylethylamine, o-trifluoromethylphenylethylamine, o-trifluoromethylphenylethylamine acetate, DL-2-bromoamphetamine, DL-3-bromoamphetamine, DL-4-bromoamphetamine, DL-2-chloroamphetamine, DL-3-chloroamphetamine, ... Patent; A. H. Robins Company, Incorporated; US4857553; (1989); (A1) English View in Reaxys

H 2N

Rx-ID: 25144008 View in Reaxys 84/89 Yield

Conditions & References When an effective antiemetic amount of one of the following Formula I compounds (sources provided above): ... o-trifluoromethylphenylethylamine, o-trifluoromethylphenylethylamine acetate, DL-2-bromoamphetamine, DL-3-bromoamphetamine, DL-4-bromoamphetamine, DL-2-chloroamphetamine, DL-3-chloroamphetamine, DL-4-chloroamphetamine, ... Patent; A. H. Robins Company, Incorporated; US4857553; (1989); (A1) English

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View in Reaxys H N

Rx-ID: 25700302 View in Reaxys 85/89 Yield

Conditions & References

97 %

23B Patent; BRISTOL-MYERS SQUIBB COMPANY; WO2007/76431; (2007); (A1) English View in Reaxys

46 %

215 Patent; PETER MACCALLUM CANCER INSTITUTE; SPICER, Julie Ann; HUTTUNEN, Kristiina Maria; LYONS, Dani Michelle; TRAPANI, Joseph Albert; SMYTH, Mark John; DENNY, William Alexander; WO2011/75784; (2011); (A1) English View in Reaxys H N

Rx-ID: 31185025 View in Reaxys 86/89 Yield

Conditions & References

68 %

222 Patent; PETER MACCALLUM CANCER INSTITUTE; SPICER, Julie Ann; HUTTUNEN, Kristiina Maria; LYONS, Dani Michelle; TRAPANI, Joseph Albert; SMYTH, Mark John; DENNY, William Alexander; WO2011/75784; (2011); (A1) English View in Reaxys

H N

Rx-ID: 7732345 View in Reaxys 87/89 Yield

Conditions & References 1-(o-Aminophenyl)-2-methylaminopropan, 1) HBr, NaNO2, 2) KBr, Cu-Pulver, CuSO4, Δ Patent; Chinoin Gyogyszer-es Vegyeszeti Termekek Gyara Rt.; GB1142981; (1969); ; vol. 70; nb. 67866; (1969) View in Reaxys 1-(o-Aminophenyl)-2-methylaminopropan, KBr, Cu-Pulver/CuSO4, Δ Patent; Chinoin Gyogyszer-es Vegyeszeti Termekek Gyara Rt.; GB1142981; (1969); ; vol. 70; nb. 67866; (1969) View in Reaxys o-Amino-phenyl-isopropyl-methylamin mittels Sandmeyer-Rk. Patent; Chinoin; FRAD94906 View in Reaxys o-Br-C6H4CH2CH(CH3)-Cl, H2N-CH3 Patent; Chinoin Gyog. es Veg. Termekek Gyara Rt; AT271436; (1965); ; vol. 71; nb. 80910a; (1969) View in Reaxys RN2+, HBr Patent; Chinoin; NL6605956; (1966); ; vol. 67; nb. 21611; (1967) View in Reaxys

33/34

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H N

Rx-ID: 7732985 View in Reaxys 88/89 Yield

Conditions & References p-Br-C6H4CH2CH(CH3)-Cl, H2N-CH3 Patent; Chinoin Gyog. es Veg. Termekek Gyara Rt; AT271436; (1965); ; vol. 71; nb. 80910a; (1969) View in Reaxys p-Amino-phenyl-isopropyl-methylamin mittels Sandmeyer-Rk. Patent; Chinoin; FRAD94906 View in Reaxys aus dem Racemat Patent; Chinoin Gy.es Veg.Term.Gyara Rt.; HU12209; (1974); ; vol. 85; nb. 192336p; (1976) View in Reaxys

H 2N

Rx-ID: 7731707 View in Reaxys 89/89 Yield

Conditions & References aus entspr. Nitril Gittos et al.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1976); p. 33,34,37 View in Reaxys

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