methyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.25 g (36.7 mmol) of N-(t-butyloxycarbonyl)phenylalanine methyl ester in 60 ml of toluene was cooled to -78° C. under inert atmosphere and treated dropwise over a period of 45 min with 35 ml (52.5 mmol) of diisobutylaluminum hydride in toluene. The resulting solution was stirred for 5 min, treated with 200 ml (200 mmol) of vinylmagnesium bromide, and allowed to warm to 0° C. for 16 h. The solution was subsequently quenched cautiously with methanol, treated with-aqueous Rochelle salts, stirred for a few min, and filtered. The residue was digested several times with ethyl acetate and filtered; and the combined filtrates were washed with saturated brine, dried over MgSO4, and concentrated. Silica gel chromatography using 20% ethyl acetate in hexane gave 5.46 g (54%) of the pure desired compound as a mixture of diastereomers. The solution was subsequently quenched cautiously with methanol treated with-aqueous Rochelle salts stirred for a few min filtered filtered and the combined filtrates were washed with saturated brine dried over MgSO4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester (10 g, 35.8 mmole) dissolved in a mixture of tetrahydrofuran (190 ml) and absolute ethanol (190 ml) is added lithium chloride (6.09 g, 143.2 mmole). The resulting homogeneous solution is treated with sodium borohydride (5.42 g, 143.2 mmole) and the reaction is stirred at room temperature under argon for 24 hours. The reaction mixture is next filtered using ether (~700 ml) to rinse the filter cake. The resulting filtrate is rinsed with water (3×200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated in vacuo to give 9 g of crude product. Recrystallization from ether/hexane gives 7.59 g of the title D compound,; m.p. 94°-96°. The reaction mixture is next filtered to rinse the filter cake The resulting filtrate is rinsed with water (3×200 ml) and brine (200 ml) dried over magnesium sulfate concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution containing N-[(1,1-dimethylethoxy)carbonyl]phenylalanine (10 g, 37.7 mmole) in dimethylformamide (40 ml) is added solid sodium bicarbonate (4.75 g, 56.6 mmole) and iodometbane (16 g, 113 mmole). The mixture is heated at 40° under argon for 12 hours, the cooled and the reaction mixture partitioned between water (150 ml) and ether (250 ml). The organic layer is rinsed with 2% aqueous sodium bicarbonate (2×100 ml), 2% aqueous sodium bisulfite (100 ml), water (2×100 ml), and brine, dried over magnesium sulfate, and concentrated in vacuo to give 10.5 g of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester as an oil. The mixture is heated at 40° under argon for 12 hours the cooled the reaction mixture partitioned between water (150 ml) and ether (250 ml) The organic layer is rinsed with 2% aqueous sodium bicarbonate (2×100 ml), 2% aqueous sodium bisulfite (100 ml), water (2×100 ml), and brine dried over magnesium sulfate concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (Aldrich, 300 mg, 1.07 mmol) in MeOH (5.4 mL) was added hydrazine hydrate (170 μL, 3.44 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated with hexanes (2×) and then from a minimal amount of 2:3 hexanes/MeOH (2×) to give the title compound (195 mg, 65%) as a white solid. 1H NMR (CDCl3) δ 7.41-7.25 (m, 3H), 7.20 (d, J=6.8 Hz, 2H), 4.39-4.21 (m, 1H), 3.07 (d, J=7.0 Hz, 2H), 1.42 (s, 9H); MS (ESI+) m/z 280.3 (M+H)+. concentrated in vacuo The residue was triturated with hexanes (2×)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.25 g (36.7 mmol) of N-(t-butyloxycarbonyl)phenylalanine methyl ester in 60 ml of toluene was cooled to -78° C. under inert atmosphere and treated dropwise over a period of 45 min with 35 ml (52.5 mmol) of diisobutylaluminum hydride in toluene. The resulting solution was stirred for 5 min, treated with 200 ml (200 mmol) of vinylmagnesium bromide, and allowed to warm to 0° C. for 16 h. The solution was subsequently quenched cautiously with methanol, treated with aqueous Rochelle salts, stirred for a few min, and filtered. The residue was digested several times with ethyl acetate and filtered; and the combined filtrates were washed with saturated brine, dried over MgSO4, and concentrated. Silica gel chromatography using 20% ethyl acetate in hexane gave 5.46 g (54%) of the pure desired compound as a mixture of diastereomers. The solution was subsequently quenched cautiously with methanol treated with aqueous Rochelle salts stirred for a few min filtered filtered and the combined filtrates were washed with saturated brine dried over MgSO4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8.8 g(0.0344 mol) of N-t-butoxycarbonylphenylalanine in 50 ml of dichloromethane were successively added 5.25 ml of triethylamine solution, and 3 ml of chloromethylformate at 0° C. 50 mg of 4-dimethylaminopyridine was added to catalyze the reaction. After the reaction was completed the reaction mixture was extracted with dichloromethane and distilled under a reduced pressure to give the title compound quantitatively. at 0° C the reaction was extracted with dichloromethane distilled under a reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-t-Butoxycarbonyl-L-phenylalanine methyl ester (250 g., 0.90 mol) was dried by addition and removal at reduced pressure of 1.0 l dry toluene, and dissolved in dry toluene (3 l.) in a 12 l flask equipped with septum, nitrogen inlet, overhead stirrer, and thermometer. The solution was cooled to -78° C. and a solution of diisobutylaluminum hydride was added via cannula over a period of 0.5 hour so that the temperature was maintained below -70° C. After being stirred an additional 15 minutes, absolute methanol (250 ml.) was added (dropwise at first until vigorous effervescence subsided) at -78° C. followed 20 minutes later by 3.0 l of 50% Rochelle salt solution (also slowly at first). Diethyl ether (2 l) was added to the mixture, and the temperature was raised to 20° C. On standing the layers separated, and the aqueous was extracted with ether (2×1.5 l). The organic phase was washed with brine, dried sodium sulfate and concentrated to give crude N-t-butoxycarbonyl-L-phenylalaninal which was used immediately without purification. equipped with septum, nitrogen inlet, overhead stirrer was maintained below -70° C at -78° C. the temperature was raised to 20° C separated the aqueous was extracted with ether (2×1.5 l) The organic phase was washed with brine, dried sodium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8.8 g(0.0344 mol) of N-t-butoxycarbonylphenylalanine in 50 ml of dichloromethane were successively added 5.25 ml of triethylamine solution, and 3 ml of chloromethylformate at 0° C. 50 mg of 4-dimethylaminopyridine was added to catalyze the reaction. After the reaction was completed the reaction mixture was extracted with dichloromethane and distilled under a reduced pressure to give the title compound quantitatively. at 0° C the reaction was extracted with dichloromethane distilled under a reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: [(S)-1-(1H-imidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester: To (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester (100.0 g, 0.35 mol) in toluene (1 L) at −78° C. was added DIBAL-H (2M solution in toluene, 322 mL, 0.64 mol) dropwise and the reaction stirred at −78° C. for 30 min. The reaction was quenched with methanol (40 mL) and the mixture was stirred with NH4Cl (350 g in 100 mL of water) for 10 min. The solution was filtered through Celite® and the aluminum salts were washed with cold ethyl acetate and water. The filtrate layers were separated and the organic layer was dried over sodium sulfate and concentrated at a temperature below 35° C. to provide ((S)-1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (93 g). To this intermediate (93 g, 0.37 mol) in methanol (1 L) was added glyoxal trimeric dihydrate (39.2 g, 0.18 mol), followed by 2M NH3 in methanol (838 mL) and the reaction mixture was stirred at rt for 48 h. The reaction mixture was evaporated and the crude was purified by column chromatography followed by crystallization from hexane to provide 92C as a grey solid (23 g, 23%). 1HNMR (CDCl3, 400 MHz) δ: 9.8 (bs, 1H), 7.27 (m, 3H), 7.21 (m, 2H), 6.95 (d, 2H), 5.32, 4.91 (2d, 2H), 3.32 (d, 2H), 1.3 (s, 9H). LCMS m/z 287 (M+H)+. The reaction was quenched with methanol (40 mL) the mixture was stirred with NH4Cl (350 g in 100 mL of water) for 10 min The solution was filtered through Celite® the aluminum salts were washed with cold ethyl acetate and water The filtrate layers were separated the organic layer was dried over sodium sulfate concentrated at a temperature below 35° C.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: [(S)-1-(1H-imidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester: To (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester (100.0 g, 0.35 mol) in toluene (1 L) at −78° C. was added DIBAL-H (2M solution in toluene, 322 mL, 0.64 mol) dropwise and the reaction stirred at −78° C. for 30 min. The reaction was quenched with methanol (40 mL) and the mixture was stirred with NH4Cl (350 g in 100 mL of water) for 10 min. The solution was filtered through Celite® and the aluminum salts were washed with cold ethyl acetate and water. The filtrate layers were separated and the organic layer was dried over sodium sulfate and concentrated at a temperature below 35° C. to provide ((S)-1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (93 g). To this intermediate (93 g, 0.37 mol) in methanol (1 L) was added glyoxal trimeric dihydrate (39.2 g, 0.18 mol), followed by 2M NH3 in methanol (838 mL) and the reaction mixture was stirred at rt for 48 h. The reaction mixture was evaporated and the crude was purified by column chromatography followed by crystallization from hexane to provide 92C as a grey solid (23 g, 23%). 1HNMR (CDCl3, 400 MHz) δ: 9.8 (bs, 1H), 7.27 (m, 3H), 7.21 (m, 2H), 6.95 (d, 2H), 5.32, 4.91 (2d, 2H), 3.32 (d, 2H), 1.3 (s, 9H). LCMS m/z 287 (M+H)+. The reaction was quenched with methanol (40 mL) the mixture was stirred with NH4Cl (350 g in 100 mL of water) for 10 min The solution was filtered through Celite® the aluminum salts were washed with cold ethyl acetate and water The filtrate layers were separated the organic layer was dried over sodium sulfate concentrated at a temperature below 35° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.25 g (36.7 mmol) of N-(t-butyloxycarbonyl)phenylalanine methyl ester in 60 ml of toluene was cooled to -78° C. under inert atmosphere and treated dropwise over a period of 45 min with 35 ml (52.5 mmol) of diisobutylaluminum hydride in toluene. The resulting solution was stirred for 5 min, treated with 200 ml (200 mmol) of vinylmagnesium bromide, and allowed to warm to 0° C. for 16 h. The solution was subsequently quenched cautiously with methanol, treated with aqueous Rochelle salts, stirred for a few min, and filtered. The residue was digested several times with ethyl acetate and filtered; and the combined filtrates were washed with saturated brine, dried over MgSo4, and concentrated. Silica gel chromatography using 20% ethyl acetate in hexane gave 5.46 g (54%) of the pure desired compound. The solution was subsequently quenched cautiously with methanol treated with aqueous Rochelle salts stirred for a few min filtered filtered and the combined filtrates were washed with saturated brine dried over MgSo4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 315.3 g (1.28 mmol) of t-butoxycarbonyl-L-phenylalanine methyl ester are hydrogenated in the presence of 5% rhodium on aluminium oxide at room temperature and 440 kPa according to the method described by J. Boger et al. in J. Med. Chem., 28, 1779 (1985), whereby there are obtained 315.3 g of methyl 2-t-butoxycarbonylamino-3-cyclohexylpropionate as an oil which is used directly in the next step.