(S)-(-)-2-AMINO-3-METHYL-1,1-DIPHENYL-1-BUTANOL

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 37.17 g (145 mmol) of (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol in 180 ml of tetrahydrofuran is stirred at −40° C. and 285 ml of a 1M solution of borane-tetrahydrofuran complex (285 mmol) are slowly added. The mixture is stirred for three hours from −40° C. to ambient temperature and is then cooled to −10° C., and a solution of 17 g (57 mmol) of compound 3.1 is added. The reaction mixture is stirred for twenty hours at ambient temperature and is then cooled to −10° C., and 285 ml of 2N hydrochloric acid are added. The mixture is left to stir for twenty hours and then the tetrahydrofuran is evaporated under reduced pressure. An (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol hydrochloride precipitate is formed and is filtered off and rinsed with 1N hydrochloric acid. The combined acidic filtrates are washed with tert-butyl methyl ether, then cooled to 0° C. and basified slowly with a 35% aqueous sodium hydroxide solution. After extracting three times with dichloromethane, the combined organic phases are washed with water and then with water saturated with sodium chloride and dried over sodium sulphate, and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: 95/5 (v/v) dichloromethane/methanol). 7.2 g of amine are obtained in oily form. Yield 47%. ee>98%. The reaction mixture is stirred for twenty hours at ambient temperature is then cooled to −10° C. The mixture is left to stir for twenty hours the tetrahydrofuran is evaporated under reduced pressure

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 37.17 g (145 mmol) of (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol in 180 ml of tetrahydrofuran is stirred at −40° C. and 285 ml of a 1M solution of borane-tetrahydrofuran complex (285 mmol) are slowly added. The mixture is stirred for three hours from −40° C. to ambient temperature and is then cooled to −10° C., and a solution of 17 g (57 mmol) of compound 3.1 is added. The reaction mixture is stirred for twenty hours at ambient temperature and is then cooled to −10° C., and 285 ml of 2N hydrochloric acid are added. The mixture is left to stir for twenty hours and then the tetrahydrofuran is evaporated under reduced pressure. An (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol hydrochloride precipitate is formed and is filtered off and rinsed with 1N hydrochloric acid. The combined acidic filtrates are washed with tert-butyl methyl ether, then cooled to 0° C. and basified slowly with a 35% aqueous sodium hydroxide solution. After extracting three times with dichloromethane, the combined organic phases are washed with water and then with water saturated with sodium chloride and dried over sodium sulphate, and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: 95/5 (v/v) dichloromethane/methanol). 7.2 g of amine are obtained in oily form. Yield 47%. ee>98%. The reaction mixture is stirred for twenty hours at ambient temperature is then cooled to −10° C. The mixture is left to stir for twenty hours the tetrahydrofuran is evaporated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (4.75 g) in dry methylene chloride was cooled to -70° C. and treated with a solution of borane in THF (1.8M, 9.5 ml) over a 20 minute period under an atmosphere of dry nitrogen. The resulting solution was gradually warmed to 0° C. and allowed to stand overnight at 4° C. This mixture was treated with a solution of 1-(4-nitrophenyl)-4-methyl-7.8-methylenedioxy-5H-2,3-benzodiazepine (5.0 g) in dry methylene chloride (100 ml) at room temperature over a period of about 1 hour. The resulting solution was allowed to stand at room temperature for seven days. The reaction was quenched by the addition of 10% sodium carbonate (15 ml). The resulting phases were separated, and the organic layer washed with water (2×50 ml), dried ever sodium sulfate, and concentrated in vacuo to give a yellow crystalline solid. This solid was suspended in ethanol (50 ml), filtered, and dried to give 4.47 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows the product as 90:10 mixture of enantiomers. This material was dissolved in hot ethyl acetate (24 ml) and allowed to stand at room temperature overnight. The crystalline precipitate was separated by filtration, washed with ethyl acetate (3×5 ml), and dried to give 2.87 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows this material to have an enantiomeric purity of more than 98%. Melting point 171°-172.5° C. to stand at room temperature for seven days The reaction was quenched by the addition of 10% sodium carbonate (15 ml) The resulting phases were separated the organic layer washed with water (2×50 ml) dried ever sodium sulfate concentrated in vacuo to give a yellow crystalline solid filtered dried

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (4.75 g) in dry methylene chloride was cooled to -70° C. and treated with a solution of borane in THF (1.8M, 9.5 ml) over a 20 minute period under an atmosphere of dry nitrogen. The resulting solution was gradually warmed to 0° C. and allowed to stand overnight at 4° C. This mixture was treated with a solution of 1-(4-nitrophenyl)-4-methyl-7.8-methylenedioxy-5H-2,3-benzodiazepine (5.0 g) in dry methylene chloride (100 ml) at room temperature over a period of about 1 hour. The resulting solution was allowed to stand at room temperature for seven days. The reaction was quenched by the addition of 10% sodium carbonate (15 ml). The resulting phases were separated, and the organic layer washed with water (2×50 ml), dried ever sodium sulfate, and concentrated in vacuo to give a yellow crystalline solid. This solid was suspended in ethanol (50 ml), filtered, and dried to give 4.47 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows the product as 90:10 mixture of enantiomers. This material was dissolved in hot ethyl acetate (24 ml) and allowed to stand at room temperature overnight. The crystalline precipitate was separated by filtration, washed with ethyl acetate (3×5 ml), and dried to give 2.87 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows this material to have an enantiomeric purity of more than 98%. Melting point 171°-172.5° C. to stand at room temperature for seven days The reaction was quenched by the addition of 10% sodium carbonate (15 ml) The resulting phases were separated the organic layer washed with water (2×50 ml) dried ever sodium sulfate concentrated in vacuo to give a yellow crystalline solid filtered dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a nitrogen atmosphere, a solution of 0.230 g (0.90 mmole) of (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol in 2.5 ml of 1,2-dichloroethane was added dropwise at -78° C. to a solution comprising 1.29 ml (0.90 mmole) of 0.70M borane-tetrahydrofuran solution and 1 ml of 1,2-dichloroethane, and the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, a solution of 0.157 g (0.6 mmole, E/Z=99.9/0.1) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one in 2.5 ml of 1,2-dichloroethane was added dropwise to this solution, and stirring was carried out for 24 hours. The reaction product was decomposed with addition of 6 ml of 10% hydrochloric acid to the solution, and after removing (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol hydrochloride by filtration, the organic layer was washed with water and concentrated under reduced pressure to obtain crude (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours after removing (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol hydrochloride by filtration the organic layer was washed with water concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (4.75 g) in dry methylene chloride was cooled to -70° C. and treated with a solution of borane in THF (1.8 M, 9.5 ml) over a 20 minute period under an atmosphere of dry nitrogen. The resulting solution was gradually warmed to 0° C. and allowed to stand overnight at 4° C. This mixture was treated with a solution of 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (5.0 g) in dry methylene chloride (100 ml) at room temperature over a period of about 1 hour. The resulting solution was allowed to stand at room temperature for seven days. The reaction was quenched by the addition of 10% sodium carbonate (15 ml). The resulting phases were separated, and the organic layer washed with water (2×50 ml), dried over sodium sulfate, and concentrated in vacuo to give a yellow crystalline solid. This solid was suspended in ethanol (50 ml), filtered, and dried to give 4.47 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows the product as 90:10 mixture of enantiomers. This material was dissolved in hot ethyl acetate (24 ml) and allowed to stand at room temperature overnight.. The crystalline precipitate was separated by filtration, washed with ethyl acetate (3×5 ml), and dried to give 2.87 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows this material to have an enantiomeric purity of more than 98%. Melting point 171°-172.5° C. to stand at room temperature for seven days The reaction was quenched by the addition of 10% sodium carbonate (15 ml) The resulting phases were separated the organic layer washed with water (2×50 ml) dried over sodium sulfate concentrated in vacuo to give a yellow crystalline solid filtered dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Trichloromethyl chloroformate (2.71 g, 13.7 mmol) was added to a mixture of (S)-2-amino-3-methyl-1,1-diphenyl-1-butanol (2) (3.18 g, 12.45 mmol) and triethylamine (2.68 g, 26.52 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 2 h at the same temperature and then poured into a brine solution (250 ml). The aqueous layer was made basic with NaOH pellets and organic products were extracted into AcOEt (5×200 ml). Combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The resulting crude product was washed with diethyl ether to obtain the title compound (3) (3.03 g, 86%) as a white solid. m.p. 250–251° C. (liti 250–251° C.). [α]D25=−201.59° (c, 0.0252 in DMSO). δH (DMSO-d6) 0.51 (3H, d, 3J=6.60 Hz, CH3), 0.92 (3H, d, 3J=7.20 Hz, CH3), 1.86 (1H, ds, 3J=2.10 and 6.60 Hz, CH—Me2), 4.46 (1H, d, 3J=6.5 Hz, CH—NH2), 7.24–7.72 (10H, m, Ar—H), 8.14 (1H, s, NH). δC 15.2 and 20.9 (CH3), 29.8 (CH), 64.9 (CH—NHCO), 88.4 (C—O), 125.8, 126.2, 127.9, 128.4, 128.8 and 129.1 (Ar), 140.5 and 146.1 (α-Ar), 158.1 (C═O). Ir 3295 (NH2), 1765 and 1745 (C═O). m/e (CI—NH3) 282 (MH+, 25%), 299 (MNH4+, 8%), 238 (96%), 223 (100%), 72 (100%). were extracted into AcOEt (5×200 ml) Combined organic extracts were dried over MgSO4 concentrated under reduced pressure The resulting crude product was washed with diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: L-Valine methyl ester hydrochloride (9.9 g, 59.06 mmol) was added portionwise to a 1.0 M solution of phenylmagnesium bromide (108.8 g, 0.6 mol) in THF at 0° C. and heated at reflux for 20 h. After quenching with crushed ice and NH4Cl salt, the organic layer was separated, washed with brine and concentrated under reduced pressure. The resulting solid was treated with HCl (2.0 M, 100 ml) and then evaporated to dryness under reduced pressure. Impurities precipitated out as a white solid, when the amine hydrochloride salt was dissolved in hot MeOH and allowed to cool to room temperature. After removing the impurities by filtration, the filtrate was made basic with KOH (1.0 M) and the organics were extracted into diethyl ether (4×100 ml). Combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to obtain a crude product as a light brown solid. Purification over silica gel, eluting with a 1:4 and 1:1 mixture of ethyl acetate and petrol gave the title compound (2) (5.42 g, 36%) as a white solid. m.p. 90–92° C. (liti 94–95° C.). [α]D25=−107.92° (c, 0.0424 in CHCl3) (litii: −127.7° (c, 0.639 in CHCl3). δH 0.81 (3H, d, 3J=6.90 Hz, CH3), 0.85 (3H, d, 3J=7.20 Hz), 1.67 (1H, ds, 3J=1.80 and 6.90 Hz, CH-Me2), 3.76 (1H, d, 3J=2.10 Hz, CH—NH2), 7.04–7.58 (10H, m, Ar). δC 16.3 and 23.2 (CH3), 28.1 (CH—Me2), 60.4 (CH—NH2), 79.9 (C—OH), 125.7, 126.1, 126.5, 126.8, 128.2 and 128.6 (o-, m- and p-Ar), 145.1 and 148.2 (α-Ar. Anal. Calcld. for C17H21NO: C 79.96; H 8.29; N 5.48. Found: C 79.80; H 8.15; N 5.39. ir 3338 (OH and NH2). m/e (CI—CH4) 256 (MH+, 14%), 72 (100%). heated at reflux for 20 h After quenching with crushed ice and NH4Cl salt the organic layer was separated washed with brine concentrated under reduced pressure The resulting solid was treated with HCl (2.0 M, 100 ml) evaporated to dryness under reduced pressure Impurities precipitated out as a white solid, when the amine hydrochloride salt was dissolved in hot MeOH After removing the impurities by filtration the organics were extracted into diethyl ether (4×100 ml) Combined organic extracts were dried over MgSO4 concentrated under reduced pressure to obtain a crude product as a light brown solid Purification over silica gel eluting with a 1:4 and 1:1 mixture of ethyl acetate and petrol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a nitrogen atmosphere, a solution of 0.230 g (0.90 mmole) of (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol in 2.5 ml of 1,2-dichloroethane was added dropwise at -78° C. to a solution comprising 1.29 ml (0.90 mmole) of 0.70M borane-tetrahydrofuran solution and 1 ml of 1,2-dichloroethane, and the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, a solution of 0.157 g (0.6 mmole, E/Z=99.9/0.1) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one in 2.5 ml of 1,2-dichloroethane was added dropwise to this solution, and stirring was carried out for 24 hours. The reaction product was decomposed with addition of 6 ml of 10% hydrochloric acid to the solution, and after removing (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol hydrochloride by filtration, the organic layer was washed with water and concentrated under reduced pressure to obtain crude (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours after removing (S)-2-amino-1,1-diphenyl-3-methylbutan-1-ol hydrochloride by filtration the organic layer was washed with water concentrated under reduced pressure

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 37.17 g (145 mmol) of (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol in 180 ml of tetrahydrofuran is stirred at −40° C. and 285 ml of a 1M solution of borane-tetrahydrofuran complex (285 mmol) are slowly added. The mixture is stirred for three hours from −40° C. to ambient temperature and is then cooled to −10° C., and a solution of 17 g (57 mmol) of compound 3.1 is added. The reaction mixture is stirred for twenty hours at ambient temperature and is then cooled to −10° C., and 285 ml of 2N hydrochloric acid are added. The mixture is left to stir for twenty hours and then the tetrahydrofuran is evaporated under reduced pressure. An (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol hydrochloride precipitate is formed and is filtered off and rinsed with 1N hydrochloric acid. The combined acidic filtrates are washed with tert-butyl methyl ether, then cooled to 0° C. and basified slowly with a 35% aqueous sodium hydroxide solution. After extracting three times with dichloromethane, the combined organic phases are washed with water and then with water saturated with sodium chloride and dried over sodium sulphate, and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: 95/5 (v/v) dichloromethane/methanol). 7.2 g of amine are obtained in oily form. Yield 47%. ee>98%. The reaction mixture is stirred for twenty hours at ambient temperature is then cooled to −10° C. The mixture is left to stir for twenty hours the tetrahydrofuran is evaporated under reduced pressure