2.1 ARY-CH2-C(O)-NH2 to ARY-CH2-CH2-NH2 by Asch

Query Query 1. Query

NH 2

ARY

NH 2

Results

Date

61 reactions in Reaxys

2017-08-15 23h:30m:19s (EST)

Search as: As drawn, No salts, No mixtures

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O NH 2

H 2N

Rx-ID: 4087959 View in Reaxys 1/61 Yield 68 %

Conditions & References With sodium tetrahydroborate, boron trifluoride diethyl etherate in tetrahydrofuran, Time= 14h, Heating Sengupta, Sreela; Sahu, Devi P; Chatterjee, Sunil K; Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry; vol. 33; (1994); p. 285 - 287 View in Reaxys

68 %

With sodium tetrahydroborate, boron trifluoride diethyl etherate in tetrahydrofuran, Time= 14h, Heating, other amides, lactams, diketopiperazines and pyrrolo<2,1-b>quinazolin-1-one; var. reaction time Sengupta, Sreela; Sahu, Devi P; Chatterjee, Sunil K; Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry; vol. 33; (1994); p. 285 - 287 View in Reaxys Reaction Steps: 2 1: 63 percent / dimer of p-methoxyphenylthionophosphine sulfide / toluene / 5 h / 85 - 110 °C 2: 1.) triethyloxonium tetrafluoroborate; 2.) NaBH4 / 1.) CH2Cl2, 25 deg C, 10-20 min; 2.) anhydrous methanol 4-5 h With Lawesson's reagent, sodium tetrahydroborate, triethyloxonium tetra-fluoroborate in toluene Raucher, Stanley; Klein, Peter; Tetrahedron Letters; vol. 21; nb. 42; (1980); p. 4061 - 4064 View in Reaxys Reaction Steps: 2 1: potassium sulfide; xylene; phosphorus pentasulfide / 70 - 80 °C 2: concentrated hydrochloric acid; alcohol / 25 - 30 °C / Electrolysis.an einer Zinkkathode With hydrogenchloride, diphosphorus pentasulfide, potassium sulphide, ethanol, xylene Kindler; Justus Liebigs Annalen der Chemie; vol. 431; (1923); p. 213; Chem. Zentralbl.; vol. 94; nb. II; (1923); p. 403 View in Reaxys

O NH 2

H 2N

Rx-ID: 2951129 View in Reaxys 2/61 Yield 2 %, 56 %

Conditions & References With samarium diiodide, lithium amide, water in tetrahydrofuran, methanol, Time= 0.0188889h, Ambient temperature Kamochi, Yasuko; Kudo, Tadahiro; Tetrahedron Letters; vol. 32; nb. 29; (1991); p. 3511 - 3514 View in Reaxys

H 2N

O NH 2

Rx-ID: 288145 View in Reaxys 3/61 Yield

Conditions & References With lithium aluminium tetrahydride Benington et al.; Journal of Organic Chemistry; vol. 23; (1958); p. 1979,1980 View in Reaxys

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H 2N

O NH 2

Rx-ID: 370339 View in Reaxys 4/61 Yield

Conditions & References With lithium aluminium tetrahydride Benington et al.; Journal of Organic Chemistry; vol. 23; (1958); p. 1979,1980 View in Reaxys

NH 2 NH 2

H 2N

O O

Rx-ID: 1105077 View in Reaxys 5/61 Yield

Conditions & References (i) B2H6, THF, (ii) H2, Pd, Multistep reaction Burdick,B.A. et al.; Journal of the American Chemical Society; vol. 99; (1977); p. 5716 - 5725 View in Reaxys (i) BH3, dioxane, (ii) H2, Pd-C, EtOH, Multistep reaction Jen,T. et al.; Journal of Medicinal Chemistry; vol. 16; (1973); p. 407 - 411 View in Reaxys OH

H 2N

O NH 2

Rx-ID: 28046266 View in Reaxys 6/61 Yield 66 %

Conditions & References 10 With dimethylsulfide borane complex in tetrahydrofuran Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS; WO2008/134474; (2008); (A2) English View in Reaxys

H 2N

O NH 2

Rx-ID: 458005 View in Reaxys 7/61 Yield

Conditions & References With tetrahydrofuran, lithium aluminium tetrahydride Childs; Forbes; Journal of the Chemical Society; (1959); p. 2024,2026 View in Reaxys

H 2N

O NH 2

Rx-ID: 4393569 View in Reaxys 8/61 Yield

Conditions & References With lithium aluminium tetrahydride

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Beasley,J.G.; Burger,A.; Journal of Medicinal Chemistry; vol. 7; (1964); p. 686 - 689 View in Reaxys Reaction Steps: 2 1: POCl3 / benzene 2: LiAlH4 With lithium aluminium tetrahydride, trichlorophosphate in benzene Beasley,J.G.; Burger,A.; Journal of Medicinal Chemistry; vol. 7; (1964); p. 686 - 689 View in Reaxys HO

H 2N

O NH 2

Rx-ID: 5197925 View in Reaxys 9/61 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

O NH 2

H 2N

Rx-ID: 463006 View in Reaxys 10/61 Yield

Conditions & References With lithium aluminium tetrahydride, diethyl ether, benzene Benington et al.; Journal of Organic Chemistry; vol. 22; (1957); p. 332 View in Reaxys

O NH 2

NH 2

Rx-ID: 4394078 View in Reaxys 11/61 Yield

Conditions & References With lithium aluminium tetrahydride Beasley,J.G.; Burger,A.; Journal of Medicinal Chemistry; vol. 7; (1964); p. 686 - 689 View in Reaxys O

NH 2

H 2N

O O

Rx-ID: 4126672 View in Reaxys 12/61 Yield

Conditions & References With borane in 1,4-dioxane Jen,T. et al.; Journal of Medicinal Chemistry; vol. 16; (1973); p. 407 - 411 View in Reaxys With borane Frontana-Uribe; Moinet; Toupet; European Journal of Organic Chemistry; nb. 2; (1999); p. 419 - 430

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View in Reaxys

H 2N NH 2

Rx-ID: 1061538 View in Reaxys 13/61 Yield

Conditions & References With lithium aluminium tetrahydride Pacheco,H.; Gaige,R.; Bulletin de la Societe Chimique de France; (1965); p. 861 - 868 View in Reaxys 7.a : Example 7.a. The intermediate 2-(1-naphthyl)ethylamine was prepared as follows. A suspension of 2-(1-napthyl)acetamide (1.85 g) in tetrahydrofuran (30 mL) was treated dropwise with lithium aluminum hydride (20 mL, 1.0M in THF). After gas evolution ceased, the mixture was heated to reflux for 2 hours, cooled to 0° C., treated dropwise with water (2.9 mL) and filtered. The liltrate was evaporated and purified by chromatography, eluding with chloroform:methanol:ammonium hydroxide (gradient, 100:0:0, 9:1:0, 9:1:0.1), to afford the product (0,240 g) as a semisolid; TLC: Rf =0.09, chloroform:methanol (95:5); MS: m/z=172(M+1). in tetrahydrofuran, water Patent; Zeneca Limited; US5532366; (1996); (A1) English View in Reaxys Cl

O NH 2

H 2N

Rx-ID: 29063396 View in Reaxys 14/61 Yield 16.2 %

Conditions & References 97.A :2-(2-chloro-4-fluorophenyl)acetamide (400 mg, 2.13 mmol) was diluted with THF (2 mL), placed under nitrogen and cooled to 00C. LAH (4264 μL, 4.26 mmol) was added dropwise and the reaction was refluxed for 3 hours. The reaction was cooled to 00C and quenched with 160 μL of water, 160 μL of 15percent NaOH, and 530 μL of water. After stirring for 30 minutes the reaction was filtered and concentrated. The material was purified using a biotage 25 column eluting with 2percent NH4OH/10percent methanol/DCM to yield 2-(2-chloro-4- fluorophenyl)ethanamine (60 mg, 0.346 mmol, 16.2 percent yield). Stage 1: With lithium aluminium tetrahydride in tetrahydrofuran, Time= 3h, Reflux, Inert atmosphere Stage 2: With sodium hydroxide in tetrahydrofuran, water, Time= 0.5h, T= 0 °C Patent; ARRAY BIOPHARMA INC.; WO2009/158426; (2009); (A1) English View in Reaxys

O H 2N

NH 2

Rx-ID: 8755172 View in Reaxys 15/61 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

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NH 2

O H 2N

Rx-ID: 468089 View in Reaxys 16/61 Yield

Conditions & References With lithium aluminium tetrahydride Benington et al.; Journal of Organic Chemistry; vol. 23; (1958); p. 1979,1980 View in Reaxys

O NH 2 H 2N

Rx-ID: 335324 View in Reaxys 17/61 Yield

Conditions & References With lithium aluminium tetrahydride, diethyl ether Benington et al.; Journal of Organic Chemistry; vol. 23; (1958); p. 1979,1980 View in Reaxys

NH 2 O

H 2N

O O

Rx-ID: 468049 View in Reaxys 18/61 Yield

Conditions & References With lithium aluminium tetrahydride, diethyl ether Lindenmann; Helvetica Chimica Acta; vol. 32; (1949); p. 69,75 View in Reaxys

O O

H 2N

NH 2

Rx-ID: 34782787 View in Reaxys 19/61 Yield

Conditions & References

67 %

Stage 1: With tri-ruthenium(0)dodecacarbonyl, (HSiMe2)2NH in toluene, Time= 24.17h, T= 20 - 70 °C , Inert atmosphere Stage 2: With hydrogenchloride in 1,4-dioxane, ethyl acetate, toluene, Time= 0.5h, T= 20 °C Reeves, Jonathan T.; Tan, Zhulin; Marsini, Maurice A.; Han, Zhengxu S.; Xu, Yibo; Reeves, Diana C.; Lee, Heewon; Lu, Bruce Z.; Senanayake, Chris H.; Advanced Synthesis and Catalysis; vol. 355; nb. 1; (2013); p. 47 52 View in Reaxys

NH 2

NH 2 O

Rx-ID: 1131399 View in Reaxys 20/61 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, benzene Benington,F. et al.; Journal of Organic Chemistry; vol. 25; (1960); p. 2066 - 2067

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View in Reaxys

O O

NH 2

Rx-ID: 29548489 View in Reaxys 21/61 Yield

Conditions & References 8.70.2 :To a solution of D (1 0 g, 4 8 mmol) in THF (5 mL) was slowly added 1 0 M borane-THF solution (15 mL) at room temperature, and the mixture was refluxed for 5 h The reaction mixture was concentrated, the residue cooled to room temperature and methanol (20 mL) was added The mixture was further refluxed overnight The reaction mixture was extracted with EtOAc and water, the organic layer was collected and concentrated to give 700 mg ofE. Stage 1: With borane-THF in tetrahydrofuran, Time= 5h, Reflux Stage 2: With methanol, Reflux Patent; CVI PHARMACEUTICALS LIMITED; LIU, Haiyan; LI, Gaoping; WANG, Junbo; LIU, Jingwen; WO2010/75469; (2010); (A1) English View in Reaxys 2.32 :D-->E; To a solution of D (1.0 g, 4.8 mmol) in THF (5 mL) was slowly added 1.0 M borane-THF solution (15 mL) at room temperature, and the mixture was refluxed for 5 h. The reaction mixture was concentrated, the residue cooled to room temperature and methanol (20 mL) was added. The mixture was further refluxed overnight. The reaction mixture was extracted with EtOAc and water, the organic layer was collected and concentrated to give 700 mg of E. Stage 1: With borane-THF in tetrahydrofuran, Time= 5h, Reflux Stage 2: With methanol, Reflux Patent; Liu, Haiyan; Li, Gaoping; Wang, Junbo; Liu, Jingwen; US2011/9628; (2011); (A1) English View in Reaxys

NH 2

H 2N NH 2

NH 2

Rx-ID: 4364697 View in Reaxys 22/61 Yield

Conditions & References With hydrogenchloride, borane, 1.) THF, reflux, 16 h, b.) THF, reflux, 4 h, Yield given. Multistep reaction Ma, Su; Lin, Lorrie; Raghavan, R.; Cohenour, Pat; Lin, Peter Y. T.; et al.; Journal of Medicinal Chemistry; vol. 38; nb. 20; (1995); p. 4087 - 4097 View in Reaxys

H 2N

NH 2

Rx-ID: 4308484 View in Reaxys 23/61 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether Sam; Shafik; Journal of pharmaceutical sciences; vol. 58; nb. 8; (1969); p. 952 - 955 View in Reaxys

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H 15 2 N

O 15NH

Rx-ID: 9274264 View in Reaxys 24/61 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

O H 2N O

NH 2

Rx-ID: 33206613 View in Reaxys 25/61 Yield

Conditions & References 5 :Example 5: Preparation of 2-(7-methoxynaphthalen-1 -yl) ethanamine hydrochloride (formula Vila)Borane-DMS (106 gm) was added to a stirred solution of 2-(7-methoxynaphthalen-1 - yl) acetamide (1 00 gm) and toluene (500 ml) at room temperature. The reaction mixture was heated and maintained at 80-85 °C until reaction completes. The reaction mixture was cooled to room temperature. The reaction mass was slowly quenched into 10percent HCI. Solvent was evaporated and Ethyl acetate (50 ml) was added. pH was adjusted to 12 using NaOH solution. The organic layer was separated and washed with water and dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure at 45°C to obtain 2-(7-methoxynaphthalen-1 -yl) ethanamine (oily mass). 10percent Ethyl acetate hydrogenchloride (18.7 ml) was added to a stirred solution of 2-(7-methoxynaphthalen-1 -yl) ethanamine in ethyl acetate (30 ml) at low temperature. The reaction mixture was stirred at room temperature for 2 hr, filtered and evaporated to dryness to obtain 2-(7- methoxynaphthalen-1 -yl) ethanamine hydrochloride (71 gm, 64.28percent yield). With dimethylsulfide borane complex in toluene, T= 80 - 85 °C , Product distribution / selectivity Patent; CADILA PHARMACEUTICALS LTD; KHAMAR, Bakulesh Mafatlal; BHUVA, Chirag Vithalbhai; MUGALE, Balaji Ram; KANANI, Ashok Ratilal; KAGATHARA, Nirav Keshavlal; BAPAT, Uday Rajaram; MODI, Indravadan Ambalal; WO2012/70025; (2012); (A1) English View in Reaxys Reaction Steps: 2 1: triethylamine; trifluoroacetic anhydride / tetrahydrofuran / 20 °C / Cooling with ice 2: hydrogen; ammonia / ethanol; water / 12 h / 60 °C / 228015 Torr / Autoclave With ammonia, hydrogen, triethylamine, trifluoroacetic anhydride in tetrahydrofuran, ethanol, water Patent; Tianjin Taipu Pharmaceutical Science and Technology Development Co., Ltd.; EP2474522; (2012); (A1) English View in Reaxys O

NH 2 Cl

NH 2

Rx-ID: 25764285 View in Reaxys 26/61 Yield

Conditions & References A17 :To a stirring solution of BH3-THF (3.5 ml, 3.5 mmol, 1.0M) was added a solution of 2-(3-nitrophenyl)acetamide (0.25 g, 1.4 mmol) in THF (7.0 mL) at RT. The resulting solution was stirred at RT until the gas evolution had subsided and then heated at 70 °C overnight. The cooled reaction was quenched carefully with 3M HCl (2 ml)and heated again at 70 °C to complete the quench. The reaction was cooled to RT and concentrated to a white solid, which was dissolved in 3M NaOH (pH 14) and extracted with CH2Cl2 (4x). The organics were dried (Na2SO4), filtered, and concentrated to provide 0.20 g (87percent yield) of crude product as an oil, which was purified by precipitation from

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CH2Cl2 and 3M HC1/EtOAc (0.26 ml, 0.78 mmol) to yield 2-(3-nitrophenyl)ethanamine as the HCl salt as an off-white solid (0.164 g). With borane-THF in tetrahydrofuran, T= 20 - 70 °C Patent; DECIPHERA PHARMACEUTICALS, LLC; WO2006/71940; (2006); (A2) English View in Reaxys

O NH 2

Cl NH 2

Rx-ID: 34938754 View in Reaxys 27/61 Yield

Conditions & References

54.2 g

4.b :[0193] Borane - tetrahydrofuran complex (1M in THF, 1.05 mol) was cooled to 0 - 10°C. 2-(4-Hydroxy-3-methoxyphenyl)acetamide 13 (39.7g, 0.219 mol) was added in small portions as a solid over 20 minutes while maintaining the temperature below 10°C. The reaction mixture was warmed to reflux and aged 8 hours. After cooling to room temperature, the reaction mixture was quenched with methanol (100 mL). Concentrated the reaction mixture to dryness in vacuo. Charged hydrochloric acid (37percent aq., 79 mL), then heated back to reflux for 3 hours. Cooled the mixture to 0°C. Vacuum filtered to afford the amine hydrochloride salt 14 as a tan solid (54.2 g, 122percent yield). lH NMR (DMSO-de) δ 8.10 (br, 3H), 6.85 - 6.64 (m, 3H), 3.79 (s, 3H), 2.99 (m, 2H), 2.81 (m, 2H). Without drying, the hydrochloride salt was dissolved in water (90 mL) at 60- 70°C. Ammonium hydroxide (17 mL, 0.127 mol) was added to the solution at 50°C until a pH of 9-10 was acheived. Cooled to 0°C, vacuum filtered and washed with cold water (2 x 20 mL). Dried at room temperature under nitrogen to afford the amine freebase 15 (21.5g, 59percent yield from 2-(4-hydroxy-3-methoxyphenyl)acetamide). lH NMR (MeCN-d3) δ 6.82 - 6.64 (m, 3H), 3.84 (s, 3H), 2.94 (br, 3H), 2.83 (t, 7=7.14 Hz, 2H), 2.62 (t, 7=6.96 Hz, 2H). Stage 1: With borane-THF in tetrahydrofuran, Time= 8h, T= 0 °C , Reflux Stage 2: With hydrogenchloride in water, Time= 3h, Reflux Patent; MILLER, James Jackson; PHILLIPS, Anthony George; LAPISH, Christopher Court; SAMMIS, Glenn Martin; WO2013/20229; (2013); (A1) English View in Reaxys

O F

NH 2

O F F

NH 2

Rx-ID: 23854099 View in Reaxys 28/61 Yield 29 %

Conditions & References 2-[4-(Trifluoromethoxy)phenyl]ethanamine; 2-[4-(Trifluoromethoxy)phenyl]acetamide (1.13 g, 5.156 mmol) was dissolved in THF (20 ml) and the reaction mixture was cooled in an ice-bath. Borane dimethyl sulfide complex (6.4 ml, 2M in THF) was added dropwise. After the addition, the cooling-bath was removed and the mixture was heated to reflux for 5 h and cooled down to rt. HCl (10 percent, 4 ml) was added, the mixture was stirred at rt overnight and then evaporated to remove THF. Water (15 ml) and diethyl ether (15 ml) were added into the residue. The two phases were separated andNaHCO3 (sat.) was added into the water phase. It was then extracted with EtOAc (20 ml x3). The extracts were combined and washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20g/70 ml), eluting with MeOH/DCM (1:99, 2:98, 5:95 then 10:90), to give 0.2 g desired product and 0.46 g mixture. The mixture was further purified by re-chromatography (ISOLUTE SI, 20g/70 ml), eluting with MeOH/EtOAc (2:98, 5:95, 10:90), to give 0.107g more of the desired product. In total (0.307g, 29percent) of the title compound was obtained. Mass Spectrum: M+H+206. 1H NMR (400 MHz, CD3OD): 6 2.95 (t, 2H), 3.12 (t, 2H), 7.23 (d, 2H), 7.38 (d, 2H). 13C NMR (100 MHz, CD3OD): 35.3, 42.5, 122.2 (q, J=250 Hz), 122.6, 131.7, 136.2, 149.7. Stage 1: With dimethylsulfane; compound with borane (1:1) in tetrahydrofuran, Time= 5h, T= 0 °C , Heating / reflux Stage 2: With hydrochlorid acid, water in tetrahydrofuran, T= 20 °C Stage 3: With sodium hydrogencarbonate in water Patent; ASTRAZENECA AB; WO2006/73366; (2006); (A1) English View in Reaxys

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NH 2 Cl

H 2N O

Rx-ID: 31323949 View in Reaxys 29/61 Yield

Conditions & References

89 %

General procedure for the reduction of primary amides into amines: General procedure: 2-(trifluoromethyl)-benzamide 1a. To a nitrogene purged screw-cap vial containing 1a (250 mg, 1.3 mmol, 1.0 equiv) and 2.0 ml of anhydrous toluene were added PMHS (320 μl, 5.4 mmol, 4.2 equiv) and Ti(OiPr)4 (400 μl, 1.3 mmol, 1.0 equiv) at rt. The mixture was stirred and heated at 100 °C until analysis by tlc showed complete consumption of the starting material (ca. overnight). The mixture was then diluted with Et2O (30.0 ml) and acidified using 2 M Et2O-HCl solution (2.0 ml, 3.0 equiv). The ammonium salt 4a was precipitated, filtered, and washed first with Et2O and then with pentane. The primary amine 4a was isolated as the hydrochloride salt in 89percent yield. Stage 1: With titanium(IV) isopropylate in toluene, T= 20 - 100 °C Stage 2: With hydrogenchloride in diethyl ether, toluene Laval, Stephane; Dayoub, Wissam; Pehlivan, Leyla; Metay, Estelle; Favre-Reguillon, Alain; Delbrayelle, Dominique; Mignani, Gerard; Lemaire, Marc; Tetrahedron Letters; vol. 52; nb. 32; (2011); p. 4072 - 4075 View in Reaxys

72 %

NH 2 O

NH 2

O O

Rx-ID: 379783 View in Reaxys 30/61 Yield

Conditions & References

76 %

With lithium aluminium tetrahydride in tetrahydrofuran, dichloromethane, Time= 36h, Heating Sintas, Jose A.; Vitale, Arturo A.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 41; nb. 1; (1998); p. 53 - 61 View in Reaxys With lithium aluminium tetrahydride Banholzer et al.; Helvetica Chimica Acta; vol. 35; (1952); p. 1577,1579 View in Reaxys Cl

Cl NH 2

O Cl

H 2N

Rx-ID: 4126731 View in Reaxys 31/61 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, benzene Hellot,J.-P. et al.; Chimica Therapeutica; vol. 5; (1970); p. 55 - 64

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View in Reaxys H N

sodium

NH 2

H 2N

Rx-ID: 5964721 View in Reaxys 32/61 Yield

Conditions & References Kindler; Justus Liebigs Annalen der Chemie; vol. 431; (1923); p. 213; Chem. Zentralbl.; vol. 94; nb. II; (1923); p. 403 View in Reaxys Cl

Cl NH 2

O NH 2

Rx-ID: 4126775 View in Reaxys 33/61 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, benzene Hellot,J.-P. et al.; Chimica Therapeutica; vol. 5; (1970); p. 55 - 64 View in Reaxys Cl

NH 2

NH 2 Br

Rx-ID: 41818551 View in Reaxys 34/61 Yield 72 %

Conditions & References Two batches were run in parallel under the following conditions, then combined for purification: Borane-THF complex (1.0 M in THF, 400 mL, 400 mmol) was added dropwise to a cooled (0° C.) suspension of 2-(2-bromo-5-chlorophenyl)acetamide (Cpd AA, 22.0 g, 88.5 mmol) in anhydrous THF (300 mL). The resulting clear solution was heated to 80° C. for two hours, then cooled again to 0° C. The mixture was quenched by sequential addition of water (45 mL) and conc. HCl (120 mL), causing significant gas evolution. Stirring was continued at 10-15° C. for 16 hours, after which the mixture was concentrated to remove THF. The aqueous residue was cooled to 0° C., then 12 N aqueous sodium hydroxide was added to bring the pH to 11. The basified solution was extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product (25 g) as a yellow oil. Two 25 g batches of this crude product were combined, treated with 4N HCl/MeOH (500 mL), and stirred at 10-15° C. for 16 hours. The mixture was concentrated, and the residue stirred in ethyl acetate (500 mL) for 30 minutes. The resulting white solid was collected by filtration, and the filter cake washed with ethyl acetate (3×100 mL). The solids were dissolved in water (500 mL), filtered to remove insolubles, and the filtrate extracted with ethyl acetate (2×500 mL). The aqueous layer was basified with solid NaOH to pH 10, then extracted with ethyl acetate (2×500 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(2-bromo-5-chlorophenyl)ethan-1-amine (Cpd BB, 30.0 g, 72percent combined yield for the two batches) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.07 (dd, J=2.4, 8.4 Hz, 1H), 2.98 (t, J=6.8 Hz, 2H), 2.86 (t, J=6.8 Hz, 2H), 1.28 (m, 2H). With borane-THF in tetrahydrofuran, Time= 2h, T= 0 - 80 °C Patent; PFIZER INC.; Collins, Michael Raymond; Kania, Robert Steven; Kumpf, Robert Arnold; Kung, Pei-Pei; Richter, Daniel Tyler; Sutton, Scott Channing; Wythes, Martin James; US2015/361067; (2015); (A1) English View in Reaxys

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H 2N O

NH 2

Rx-ID: 2205476 View in Reaxys 35/61 Yield

Conditions & References With tetrahydridoaluminate(1-) in diethyl ether Yous; Andrieux; Howell; Morgan; Renard; Pfeiffer; Lesieur; Guardiola-Lemaitre; Journal of Medicinal Chemistry; vol. 35; nb. 8; (1992); p. 1484 - 1486 View in Reaxys Reaction Steps: 2 1: (CF3CO)2O / tetrahydrofuran / 0 °C 2: H2, HCl / Ni Raney / diethyl ether With hydrogenchloride, hydrogen, trifluoroacetic anhydride, nickel in tetrahydrofuran, diethyl ether Yous; Andrieux; Howell; Morgan; Renard; Pfeiffer; Lesieur; Guardiola-Lemaitre; Journal of Medicinal Chemistry; vol. 35; nb. 8; (1992); p. 1484 - 1486 View in Reaxys Reaction Steps: 2 1: dimethylsulfide borane complex / toluene / 80 - 85 °C 2: hydrogenchloride / ethyl acetate / 2 h / 20 °C With hydrogenchloride, dimethylsulfide borane complex in ethyl acetate, toluene Patent; CADILA PHARMACEUTICALS LTD; KHAMAR, Bakulesh Mafatlal; BHUVA, Chirag Vithalbhai; MUGALE, Balaji Ram; KANANI, Ashok Ratilal; KAGATHARA, Nirav Keshavlal; BAPAT, Uday Rajaram; MODI, Indravadan Ambalal; WO2012/70025; (2012); (A1) English View in Reaxys Reaction Steps: 2 1.1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide / 2 h / 85 °C 2.1: sodium hydroxide; hydrogen / water; methanol; isopropyl alcohol / 25 - 30 °C / 7500.75 Torr 2.2: 1 h / 50 - 55 °C With hydrogen, sodium hydroxide, trichlorophosphate in methanol, dichloromethane, water, N,N-dimethyl-formamide, isopropyl alcohol Patent; ALEMBIC PHARMACEUTICALS LIMITED; JAYARAMAN, Venkat, Raman; PANCHASARA, Dineshkumar, Ramabhai; PATEL, Ilesh; PRAJAPATI, Bhavesh; PATEL, Ketan; PATWA, Mitul; SHAH, Ankit; WO2014/1939; (2014); (A1) English View in Reaxys

NH 2

methanolic hydrogen chloride O

H 2N

Rx-ID: 25120110 View in Reaxys 36/61 Yield

Conditions & References 83 : EXAMPLE 83 EXAMPLE 83 A mixture containing 17.9 g. of 6-methoxy-2-naphthaleneacetamide, 250 ml. of a 1 M solution of borane in tetrahydrofuran, and 350 ml. of tetrahydrofuran was heated under reflux for 36 hours. The mixture was cooled and treated dropwise with 30 ml. of methanol followed by 70 ml. of 4 N methanolic hydrogen chloride. The resulting mixture was stirred one hour at 0°-5° C., then ten hours at room temperature and finally one hour at the reflux temperature. Evaporation to dryness followed by recrystallization from methanol-ether afforded 11.5 g. of 6-methoxy-2-naphthaleneethylamine hydrochloride, m.p. 306°-308° C. With borane in tetrahydrofuran, methanol

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Patent; Sterling Drug Inc.; US4169108; (1979); (A1) English View in Reaxys Patent; Sterling Drug Inc.; US4327022; (1982); (A1) English View in Reaxys

H 2N NH 2

Rx-ID: 4727122 View in Reaxys 37/61 Yield

Conditions & References

91 %

With sodium tetrahydroborate, boron trifluoride diethyl etherate in tetrahydrofuran, Time= 1.5h, Heating Balakin; Korshun; Prokhorenko; Maleev; Kudelina; Gontarev; Berlin; Russian Journal of Bioorganic Chemistry; vol. 23; nb. 1; (1997); p. 28 - 36 View in Reaxys With sodium tetrahydroborate Korshun; Prokhorenko; Gontarev; Skorobogatyi; Balakin; Manasova; Malakhov; Berlin; Nucleosides and Nucleotides; vol. 16; nb. 7-9; (1997); p. 1461 - 1464 View in Reaxys

526 mg

With lithium aluminium tetrahydride in tetrahydrofuran, Time= 20h Dale, Trevor J.; Rebek Jr., Julius; Journal of the American Chemical Society; vol. 128; nb. 14; (2006); p. 4500 4501 View in Reaxys

O H 2N

O NH 2

Rx-ID: 9909287 View in Reaxys 38/61 Yield

Conditions & References

93 %

With tetrahydrofuran, borane in tetrahydrofuran, Time= 5h, Heating Lewin, Anita H.; Szewczyk, Jerzy; Wilson, Joseph W.; Carroll, F. Ivy; Tetrahedron; vol. 61; nb. 30; (2005); p. 7144 - 7152 View in Reaxys I

H 2N

O NH 2

Rx-ID: 4897434 View in Reaxys 39/61 Yield

Conditions & References With sodium tetrahydroborate, boron trifluoride diethyl etherate in tetrahydrofuran, T= 0 - 20 °C Hays, Sheryl J.; Caprathe, Bradley W.; Gilmore, John L.; Amin, Nilam; Emmerling, Mark R.; Michael, Walter; Nadimpalli, Ravi; Nath, Rathna; Raser, Kadee J.; Stafford, Daniel; Watson, Desiree; Wang, Kevin; Jaen, Juan C.; Journal of Medicinal Chemistry; vol. 41; nb. 7; (1998); p. 1060 - 1067 View in Reaxys Cl

Cl O

NH 2 NH 2

Rx-ID: 4126791 View in Reaxys 40/61

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Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, benzene Hellot,J.-P. et al.; Chimica Therapeutica; vol. 5; (1970); p. 55 - 64 View in Reaxys O

NH 2

Rx-ID: 24213284 View in Reaxys 41/61 Yield

Conditions & References P.51 : Synthesis of Ethyl 2-[3-(2-Aminoethyl)phenoxy]-2-methylpropionate Production Example 51 Synthesis of Ethyl 2-[3-(2-Aminoethyl)phenoxy]-2-methylpropionate Under nitrogen atmosphere, ethyl 2-(3-aminocarbonylmethylphenoxy)-2-methylpropionate (507 mg, 1.91 mmol) was dissolved in tetrahydrofuran. Subsequently, borane-tetrahydrofuran complex in tetrahydrofuran solution [1M BH3-THF in THF (19.1 mL, 19.1 mmol)] was added thereto, and the mixture was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, followed by addition of 1M hydrochloric acid at 0° C. and stirring at room temperature. The resultant mixture was made basic with sodium carbonate, followed by extraction with chloroform and drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained (261.8 mg, 1.04 mmol, 54.5percent) 1H NMR (400 MHz, CDCl ) δ 1.17 (t, J=7 Hz, 3H), 1.52 (s, 6H), 2.64 (t, J=7 Hz, 2H), 2.85 (t, J=7 Hz, 2H), 3.13 (br.s, 3 2H), 4.16 (q, J=7 Hz, 2H), 6.59 (d, J=8 Hz, 1H), 6.63 (s, 1H), 6.73 (d, J=8 Hz, 1H), 7.07 (t, J=8 Hz, 1H). With hydrogenchloride, BH3-THF in tetrahydrofuran Patent; Kowa Co., Ltd.; US6653334; (2003); (B1) English View in Reaxys

O O

NH 2

Rx-ID: 495501 View in Reaxys 42/61 Yield

Conditions & References With lithium aluminium tetrahydride Benington et al.; Journal of Organic Chemistry; vol. 23; (1958); p. 1979,1980 View in Reaxys H 15 2 N

O O

15NH

Rx-ID: 4963018 View in Reaxys 43/61 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, 1.) reflux, 4 h, 2.) r.t., 16 h, Yield given McDonald, Edward; Ramage, Robert; Woodhouse, Robert N.; Underbill, Edward W.; Wetter, Leslie R.; Battersby, Alan R.; Journal of the Chemical Society - Perkin Transactions 1; nb. 18; (1998); p. 2979 - 2987 View in Reaxys

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NH 2

O H

H B

(v5)

N N

NH 2

Rx-ID: 10741963 View in Reaxys 44/61 Yield

Conditions & References T : EXAMPLE T EXAMPLE T To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane-methylsulfide (18 mmol). The mixture was heated to reflux for 90 min. and cooled to RT, after which 6 N HCl was added and heated to reflux for 10 min. The mixture was basified with NaOH and extracted with EtOAc. The organic layer was dried (Na2SO4) filtered and concentrated in vacuo to yield 3-tert-butyl-1-[3-(2-aminoethyl)phenyl]-1H-pyrazol-5 amine (0.9 g). With hydrogenchloride in tetrahydrofuran Patent; Flynn, Daniel L.; Petillo, Peter A.; US2008/248548; (2008); (A1) English View in Reaxys T : Example T Example T To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane-methylsulfide (18 mmol). The mixture was heated to reflux for 90 min and cooled to RT, after which 6 N HCl was added and heated to reflux for 10 min. The mixture was basified with NaOH and extracted with EtOAc. The organic layer was dried (Na2SO4) filtered and concentrated in vacuo to yield 3-tert-butyl-1-[3-(2-aminoethyl)phenyl]-1H-pyrazol-5 amine (0.9 g). With hydrogenchloride in tetrahydrofuran Patent; Flynn, Daniel L.; Petillo, Peter A.; US2005/288286; (2005); (A1) English View in Reaxys Patent; Deciphera Pharmaceuticals, LLC; US7666895; (2010); (B2) English View in Reaxys

NH 2 O

H 2N

Rx-ID: 25125001 View in Reaxys 45/61 Yield

Conditions & References 56 : EXAMPLE 56 EXAMPLE 56 Following a procedure similar to that in Example 52 but using 10.0 g. of 6,7-diethoxy-2-naphthaleneacetamide and 115 ml. of a 1 M solution of borane in tetrahydrofuran, and isolating the product in the free-base form yielded 2.3 g. of 6,7-diethoxy-2-naphthaleneethylamine, m.p. 109°-111° C. (benzene-n-hexane). With borane in tetrahydrofuran Patent; Sterling Drug Inc.; US4327022; (1982); (A1) English View in Reaxys 56 : EXAMPLE 56 EXAMPLE 56 Following a procedure similar to that in Example 52 but using 10.0 g. of 6,7-diethoxy-2-naphthaleneacetamide and 115 ml. of a 1 M solution of borane in tetrahydrofuran, and isolating the product in the free-base form yielded 2.3 g. of 6,7-diethoxy-2-naphthalenethylamine, m.p. 109°-111° C. (benzene-n-hexane). With borane in tetrahydrofuran

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Patent; Sterling Drug Inc.; US4169108; (1979); (A1) English View in Reaxys NH 2

O O

NH 2 Cl

Rx-ID: 22442128 View in Reaxys 46/61 Yield

Conditions & References Reaction Steps: 2 1: P2O5 / 220 - 240 °C 2: LiAlH4, AlCl3 / diethyl ether With lithium aluminium tetrahydride, aluminium trichloride, phosphorus pentoxide in diethyl ether Sam; Aparajithan; Shafik; Journal of pharmaceutical sciences; vol. 57; nb. 4; (1968); p. 564 - 568 View in Reaxys Cl

O O

NH 2 NH 2

Rx-ID: 4126820 View in Reaxys 47/61 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, benzene Hellot,J.-P. et al.; Chimica Therapeutica; vol. 5; (1970); p. 55 - 64 View in Reaxys I

H 2N NH 2

Rx-ID: 10161645 View in Reaxys 48/61 Yield

Conditions & References With borane-THF in tetrahydrofuran, Time= 3h, Heating Wipf, Peter; Furegati, Markus; Organic Letters; vol. 8; nb. 9; (2006); p. 1901 - 1904 View in Reaxys NH 2

O O O

NH 2 O

Rx-ID: 23328638 View in Reaxys 49/61 Yield 61 %

Conditions & References 20 : Synthesis of tert-Butyl 2-[2-(2-aminoethyl)phenoxy]-2-methylpropionate Production Example 20 Synthesis of tert-Butyl 2-[2-(2-aminoethyl)phenoxy]-2-methylpropionate tert-Butyl 2-[2-(aminocarbonylmethyl)phenoxy]-2-methylpropionate (1.4 g, 4.87 mmol) was dissolved in tetrahydrofuran (5.0 mL). Subsequently, under nitrogen atmosphere, borane-THF complex in THF solution [1.0M BH3-THF in THF (14.6 mL, 14.6 mmol)] was added thereto, the mixture was stirred for three hours at 50° C. Thereafter, concentrated hydrochloric acid was gradually added thereto at 0° C. The resultant mixture was stirred for one hour at room temperature and made basic with an aqueous ethylamine solution. Ethyl acetate was added thereto. The mixture was sequentially washed with water and brine, followed by drying over sodium sulfate. The mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (830 mg, 2.97 mmol, 61percent). 1H-NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.65 (s, 6H), 2.09 (br s, 2H), 2.79 (t, J=7 Hz, 2H), 2.97 (t, J=7 Hz, 2H), 6.69 (d, J=8 Hz, 1H), 6.88 (t, J=7 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 7.14 (d, J=7 Hz, 1H).

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Stage 1: With borane-THF in tetrahydrofuran, Time= 3h, T= 50 °C Stage 2: With hydrogenchloride in tetrahydrofuran, water, Time= 1h, T= 0 - 20 °C Patent; KOWA CO., LTD.; US2005/101636; (2005); (A1) English View in Reaxys

O O

NH 2 O

NH 2

Rx-ID: 2458115 View in Reaxys 50/61 Yield

Conditions & References

70 %

With lithium aluminium tetrahydride in tetrahydrofuran, Time= 5h, Heating Martinez, Elena; Estevez, Juan C; Estevez, Ramon J; Castedo, Luis; Tetrahedron; vol. 57; nb. 10; (2001); p. 1973 - 1979 View in Reaxys With lithium aluminium tetrahydride in tetrahydrofuran, 1.) reflux, 2.) r.t. Estevez; Carmen Villaverde; Seijas; Castedo; Canadian Journal of Chemistry; vol. 68; nb. 6; (1990); p. 964 - 968 View in Reaxys

NH 2

H H 2N

Rx-ID: 25125000 View in Reaxys 51/61 Yield

Conditions & References 55 : EXAMPLE 55 EXAMPLE 55 Following a procedure similar to that in Example 52 but using 14.0 g. of 6,7-dimethoxy-8-methyl-2-naphthaleneacetamide and 175 ml. of a 1 M solution of borane in tetrahydrofuran, yielded 13.0 g. of 6,7-dimethoxy-8-methyl-2-naphthaleneethylamine hydrochloride, m.p. 205°-215° C. With borane in tetrahydrofuran Patent; Sterling Drug Inc.; US4169108; (1979); (A1) English View in Reaxys Patent; Sterling Drug Inc.; US4327022; (1982); (A1) English View in Reaxys

F F

H 2N

NH 2

Rx-ID: 27748890 View in Reaxys 52/61 Yield 37 %

Conditions & References 95 :Intermediate 95. {2-[4-(2,2-difluoro-2-phenylethoxy)-3-methylphenyl]ethyl}amine; To a solution of Intermediate 94 (0.43 g, 1.41 mmol) in tetrahydrofuran (15 mL) was added under nitrogen borane-methyl sulphide complex (2.01 mL, 21.17 mmol). The reaction mixture was stirred at reflux for 1 hour. After cooling, hydrochloric acid 1 N (3 mL) was added into the reaction mixture and the solution was basified with sodium hydroxide 5N, concentrated and extracted with ethyl acetate. The crude obtained was purified by column chromatography with silica gel, eluting with methylene chloride/methanol (from 98:1 to 9:1 ) to give the title compound as an oil (0.15 g, 37percent). Stage 1: With dimethylsulfide borane complex in tetrahydrofuran, Time= 1h, Heating / reflux Stage 2: With hydrogenchloride in tetrahydrofuran, water

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Stage 3: With sodium hydroxide in tetrahydrofuran, water Patent; LABORATORIOS ALMIRALL, S.A.; WO2008/46598; (2008); (A1) English View in Reaxys Cl

O O

NH 2 NH 2

Rx-ID: 4126869 View in Reaxys 53/61 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, benzene Hellot,J.-P. et al.; Chimica Therapeutica; vol. 5; (1970); p. 55 - 64 View in Reaxys

O O

Br 2 H NH 2

H 2N

NH 2

Rx-ID: 17945328 View in Reaxys 54/61 Yield

Conditions & References Reaction Steps: 2 1: 1.) BH3, 2.) 6M aq. HCl / 1.) THF, reflux, 16 h, b.) THF, reflux, 4 h 2: 75 percent / conc. aq. HBr / 12 h / Heating With hydrogenchloride, borane, hydrogen bromide Ma, Su; Lin, Lorrie; Raghavan, R.; Cohenour, Pat; Lin, Peter Y. T.; et al.; Journal of Medicinal Chemistry; vol. 38; nb. 20; (1995); p. 4087 - 4097 View in Reaxys

NH 2 O

NH 2

O O

Rx-ID: 16915738 View in Reaxys 55/61 Yield

Conditions & References Reaction Steps: 2 1: 76 percent / LiAlH4 / tetrahydrofuran; CH2Cl2 / 36 h / Heating 2: 1) Tl(CF3COO)2, 2) KI / 1) CH3CN, reflux, 4 h, 2) CH2Cl2, 0 deg C, 15 min With lithium aluminium tetrahydride, Tl(CF3COO)2, potassium iodide in tetrahydrofuran, dichloromethane Sintas, Jose A.; Vitale, Arturo A.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 41; nb. 1; (1998); p. 53 - 61 View in Reaxys

O O O

NH 2 O

NH 2

Rx-ID: 2461648 View in Reaxys 56/61 Yield 75 %

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 5h, Heating

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Martinez, Elena; Estevez, Juan C; Estevez, Ramon J; Castedo, Luis; Tetrahedron; vol. 57; nb. 10; (2001); p. 1973 - 1979 View in Reaxys With lithium aluminium tetrahydride in tetrahydrofuran, 1.) reflux, 5 h, 2.) r.t. Estevez; Carmen Villaverde; Seijas; Castedo; Canadian Journal of Chemistry; vol. 68; nb. 6; (1990); p. 964 - 968 View in Reaxys

O O

NH 2

NH 2 O

Rx-ID: 21777781 View in Reaxys 57/61 Yield

Conditions & References Reaction Steps: 2 1: 40 percent / iodine / diethyl ether / Ambient temperature; Irradiation 2: LAH / tetrahydrofuran / 1.) reflux, 5 h, 2.) r.t. With lithium aluminium tetrahydride, iodine in tetrahydrofuran, diethyl ether Estevez; Carmen Villaverde; Seijas; Castedo; Canadian Journal of Chemistry; vol. 68; nb. 6; (1990); p. 964 - 968 View in Reaxys

O S

NH 2 HCl

H 2N

Rx-ID: 24813689 View in Reaxys 58/61 Yield

Conditions & References

92.6 %

II.23.3 :A solution of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-acetamide (1.37 g, 4.13 mmol) in tetrahydrofuran (30 ml) was refluxed and then a solution of borane- dimethylsulfid complex (2M in tetrahydrofuran, 10.33 mmol) was added. The mixture was refluxed for 2 h. The mixture was allowed to cool down to room temperature and adjusted to pH = 1 with a solution of HCI in ethanol (2M). After stirring the mixture for 15 min the solvents were evaporated under reduce pressure. Diethyl ether was added to residue. A slurry of the resulting white powder in diethyl ether was stirred for 15 min. The remaining solid was collected, washed with diethyl ether, and dried in a vacuum oven to give white crystals of 2-[4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]- ethylamine x HCI (1.36 g, 92.6percent).MS (ESI) m/z: 318.15 [M+H]+ Stage 1: With dimethylsulfane; compound with borane (1:1) in tetrahydrofuran, Time= 2h, Heating / reflux Stage 2: With hydrochlorid acid in tetrahydrofuran, ethanol, Time= 0.25h, T= 20 °C , pH= 1 Patent; ABBOTT GMBH and CO. KG; WO2006/40179; (2006); (A1) English View in Reaxys

O F

NH 2

O S

O F F

O S

NH 2 HCl

F O

Rx-ID: 24813692 View in Reaxys 59/61 Yield 84.7 %

Conditions & References II.24.2 :A solution of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-acetamide (1.36 g, 3.64 mmol) in tetrahydrofuran (30 ml) was refluxed and a solution of borane- dimethylsulfid complex (2M in tetrahydrofuran, 9.11 mmol) was added. The mixture was refluxed for 2 h. The mixture was allowed to come to room temperature and was adjusted to pH = 1 using a solution of HCI in ethanol (2M). After stirring the mixture for 15 min the solvents were evaporated under reduced pressure. A slurry of the resultingM/45293 EPO <DP n="127"/>white powder in diethyl ether was stirred for 15 min. The remaining solid was collected, washed with diethyl ether, and dried in a vacuum oven to give

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white crystals of 2-[4-(4- trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethylamine x HCI (1.22 g, 84.7percent).MS (ESI) m/z:360.05 [M+H]+ Stage 1: With dimethylsulfane; compound with borane (1:1) in tetrahydrofuran, Time= 2h, Heating / reflux Stage 2: With hydrochlorid acid in tetrahydrofuran, ethanol, Time= 0.25h, T= 20 °C , pH= 1 Patent; ABBOTT GMBH and CO. KG; WO2006/40179; (2006); (A1) English View in Reaxys O O

O O

H 2N

H 2N O

Rx-ID: 45123451 View in Reaxys 60/61 Yield

Conditions & References 1.T : T. Standard Procedure for the Synthesis of Building Block S51 To a solution of 2-(2-hydroxyphenyl)acetamide (50-1, Fluorochem Cat. No. 375417, 50.0 mg, 0.331 mmol), Ph3P (104 mg, 0.397 mmol) and Fmoc-2- aminoethanol (Fmoc-S1, 122 mg, 0.430 mmol) in THF (4 mL) at rt was added DIAD (0.077 ml, 0.397 mmol) dropwise. The mixture was stirred at rt overnight, then evaporated in vacuo and the residue purified by flash chroatography. The intermediate amide 51-2 was then treated with borane-dimethyl sulfide at 0°C for 2 h, then quenched carefully with water, followed by dilute acid. The product Fmoc-S51 was isolated after standard work-up. Use of other appropriate nitrogen protecting groups on 2-aminoethanol provides alternative protected derivatives ofS51. With dimethylsulfide borane complex, Time= 2h, T= 0 °C Patent; CYCLENIUM PHARMA INC.; WAHHAB, Amal; THOMAS, Helmut; RICHARD, Luc; PETERSON, Mark L.; MACDONALD, Dwight; DUBÉ, Daniel; (324 pag.); WO2017/49383; (2017); (A1) English View in Reaxys OH

OH O

NH O

H 2N

NH 2

Rx-ID: 45123455 View in Reaxys 61/61 Yield

Conditions & References Reaction Steps: 2 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C 2: dimethylsulfide borane complex / 2 h / 0 °C With di-isopropyl azodicarboxylate, dimethylsulfide borane complex, triphenylphosphine in tetrahydrofuran, 1: |Mitsunobu Displacement Patent; CYCLENIUM PHARMA INC.; WAHHAB, Amal; THOMAS, Helmut; RICHARD, Luc; PETERSON, Mark L.; MACDONALD, Dwight; DUBÉ, Daniel; (324 pag.); WO2017/49383; (2017); (A1) English View in Reaxys

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