tert-butyl N-[(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethyl]carbamate

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

Procedure: A solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added over the course of 15 min at from 0° to 5° C. to a solution of 1.45 g of N-Boc-1-phenyl-3-buten-2(S)-amine in 20 ml of methylene chloride. The batch is stirred for 18 h at that same temperature and is then stirred for a further 8 h, with heating to RT, to complete the reaction and poured onto ice-cold 10% sodium carbonate solution. The aqueous phase is extracted three times with ether. The combined organic phases are washed in succession three times with 10% sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and with brine and dried over sodium sulfate. After concentrating the solvents, the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) and recrystallised from hexane. M.p. 51°-52° C.; TLC Rf (C)=0.33; FAB-MS (M+H)+=264. is then stirred for a further 8 h the reaction poured onto ice-cold 10% sodium carbonate solution The aqueous phase is extracted three times with ether The combined organic phases are washed in succession three times with 10% sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and with brine dried over sodium sulfate After concentrating the solvents the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) recrystallised from hexane

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

Procedure: A solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added over the course of 15 min at from 0° to 5° C. to a solution of 1.45 g of N-Boc-1-phenyl-3-buten-2(S)-amine in 20 ml of methylene chloride. The batch is stirred for 18 h at that same temperature and is then stirred for a further 8 h, with heating to RT, to complete the reaction and poured onto ice-cold 10% sodium carbonate solution. The aqueous phase is extracted three times with ether. The combined organic phases are washed in succession three times with 10% sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and with brine and dried over sodium sulfate. After concentrating the solvents, the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) and recrystallised from hexane. M.p. 51°-52° C.; TLC Rf (C)=0.33; FAB-MS (M+H)+=264. is then stirred for a further 8 h the reaction poured onto ice-cold 10% sodium carbonate solution The aqueous phase is extracted three times with ether The combined organic phases are washed in succession three times with 10% sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and with brine dried over sodium sulfate After concentrating the solvents the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) recrystallised from hexane

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suitable reactor was added 5 (2 g, 4.98 mmol), THF (20 mL), MeOH (20 mL), and K2CO3 (1.5 g, 10.96 mmol) at 20-30° C. under N2. The mixture was stirred at 20-30° C. for 15 hr. The mixture was filtered, and the filtrate was concentrated at 40-50° C. under reduced pressure to yield a pale yellow oil. After being purified by flash column chromatography, 6 was obtained as a white solid in 90% yield. The mixture was filtered the filtrate was concentrated at 40-50° C. under reduced pressure to yield a pale yellow oil After being purified by flash column chromatography 6 was obtained as a white solid in 90% yield

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suitable reactor was added 5 (2 g, 4.98 mmol), THF (20 mL), MeOH (20 mL), and K2CO3 (1.5 g, 10.96 mmol) at 20-30° C. under N2. The mixture was stirred at 20-30° C. for 15 hr. The mixture was filtered, and the filtrate was concentrated at 40-50° C. under reduced pressure to yield a pale yellow oil. After being purified by flash column chromatography, 6 was obtained as a white solid in 90% yield. The mixture was filtered the filtrate was concentrated at 40-50° C. under reduced pressure to yield a pale yellow oil After being purified by flash column chromatography 6 was obtained as a white solid in 90% yield

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methanesulfonyloxybutane(the 2-hydroxy-1-sulfonate compound:the 1-hydroxy-2-sulfonate compound:the diol compound:the 1,2-disulfonate compound=97.1:0.1:0.4:2.3 according to the HPLC area ratio) 50 g dissolved in ethyl acetate 510 ml was added 28% sodium methylate methanol solution 58.2 g under ice-cooling and stirred for 10 min. The reaction solution was diluted with water and adjusted with 6N-HCl to pH7 to separate an organic phase, which was distilled to remove the solvent. The concentrated residue was mixed with n-heptane, stirred at the ambient temperature for 1 hr to deposit crystals, which were filtered to remove. The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 2 g, stirred at the ambient temperature for 1 hr and filtered to remove charcoal. The filtrate was cooled down to −20° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenylbutane(98.5% according to the HPLC area ratio) 28.8 g. The diol compound and the 1,2-disulfonate compound contained in a concentration of 0.5% or less in the crystals according to the HPLC area ratio respectively. cooling to separate an organic phase, which was distilled to remove the solvent The concentrated residue was mixed with n-heptane stirred at the ambient temperature for 1 hr were filtered to remove The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 2 g stirred at the ambient temperature for 1 hr filtered to remove charcoal were filtered dried in vacuum

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

Procedure: A solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added over the course of 15 min at from 0° to 5° C. to a solution of 1.45 g of N-Boc-1-phenyl-3-buten-2(S)-amine in 20 ml of methylene chloride. The batch is stirred for 18 h at that same temperature and is then stirred for a further 8 h, with heating to RT, to complete the reaction and poured onto ice-cold 10% sodium carbonate solution. The aqueous phase is extracted three times with ether. The combined organic phases are washed in succession three times with 10% sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and with brine and dried over sodium sulfate. After concentrating the solvents, the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) and recrystallised from hexane. M.p. 51°-52° C.; TLC Rf (C)=0.33; FAB-MS (M+H)+=264. is then stirred for a further 8 h the reaction poured onto ice-cold 10% sodium carbonate solution The aqueous phase is extracted three times with ether The combined organic phases are washed in succession three times with 10% sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and with brine dried over sodium sulfate After concentrating the solvents the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) recrystallised from hexane

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

Procedure: 2-Propanol (12.9 ml) and aqueous 6.08 mol/l sodium hydroxide solution (2.94 g) were added to a solution containing (2R, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane obtained in Example 17 {(2R, 3S) content of 2.79 g; (2S, 3S) content of 83.9 mg}, for agitation at 4° C. for 15 hours. The resulting solution was analyzed by HPLC, which indicates that the objective (2R, 3S) compound was at 94.0% (HPLC area ratio). After the reaction was quenched by the addition of aqueous 4.4% citric acid solution (20.9 g), the reaction solution was cooled from 25° C. to −10° C. over 2.3 hours; then, the seed crystal was added, followed by addition of water (19.2 ml) for overnight agitation, to crystallize (2R, 3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. By filtration of the resulting slurry, the crystal of the objective (2R, 3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was obtained {(2R, 3S) yield: 2.4 g (96.2%)}. The dried crystal was then analyzed by HPLC. (2R, 3S): (2S, 3S)=97.9:2.1. Additionally, the purity of (2R, 3S) was at 95.4% (HPLC area ratio). After the reaction was quenched by the addition of aqueous 4.4% citric acid solution (20.9 g) the reaction solution was cooled from 25° C. to −10° C. over 2.3 hours then, the seed crystal was added followed by addition of water (19.2 ml) for overnight agitation to crystallize (2R, 3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane By filtration of the resulting slurry

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

Procedure: To the mixture of (2R,3S)-3-(t-butoxycarbonyl)amino-4-phenyl-butane-1,2-diol (44 g) and 400 ml of pyridine, 60 g (2 equivalents) of p-TsCl was added and the solution was stirred at 0° C. for 4 hours. After pH of the solution was adjusted 10 with 25% NaOH and it was stirred at 0° C. for 3 hours. 400 ml of methylene chloride was added to the solution and it was washed by 400 ml of 1N HCl, 400 ml of 5% aq.NaHCO3 and 400 ml of water and was distillated under reduced pressure. A white crystal compound of (2R,3S)-3-(t-butoxycarbonyl)amino-1,2-epoxy-4-phenylbutane was obtained using a column chromatography. was added was stirred at 0° C. for 3 hours was washed by 400 ml of 1N HCl, 400 ml of 5% aq

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

Procedure: A solution of 58.7 g (197 mmol) of N1 -(tert-butoxycarbonyl)-N2 -(4-biphenylylmethyl)hydrazine and 51.8 g (197 mmol) of N-(tert-butoxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxybutane (=(2R,3S)-1-[3-Boc-amino-2-phenylethyl]-oxirane) in 700 ml of absolute methanol is heated to reflux temperature during 16 h. The mixture is then cooled to 0° C. and diluted with 1.5 l of water. The solid is filtered and dried at 70° C. for 6 h to give the title compound: to reflux temperature during 16 h The solid is filtered dried at 70° C. for 6 h

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methanesulfonyloxybutane(the 2-hydroxy-1-sulfonate compound: the 1-hydroxy-2-sulfonate compound: the diol compound: the 1,2-disulfonate compund=97.1:0.1:0.4:2.3 according to the HPLC area ratio) 50 g dissolved in ethyl acetate 510 ml was added 28% sodium methylate methanol solution 58.2 g under ice-cooling and stirred for 10 min. The reaction solution was diluted with water and adjusted with 6N-HCl to pH7 to separate an organic phase, which was distilled to remove the solvent. The concentrated residue was mixed with n-heptane, stirred at the ambient temperature for 1 hr to deposit crystals, which were filtered to remove. The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 2 g, stirred at the ambient temperature for 1 hr and filtered to remove charcoal. The filtrate was cooled down to −20° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenylbutane(98.5% according to the HPLC area ratio) 28.8 g. The diol compound and the 1,2-disulfonate compound contained in a concentration of 0.5% or less in the crystals according to the HPLC area ratio respectively. cooling to separate an organic phase, which was distilled to remove the solvent The concentrated residue was mixed with n-heptane stirred at the ambient temperature for 1 hr were filtered to remove The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 2 g stirred at the ambient temperature for 1 hr filtered to remove charcoal were filtered dried in vacuum

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 450 g of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate was treated with 1.1 equivalents of diethyl malonate and 1.05 equivalents of sodium ethoxide in 1200 mL of ethanol at 5° C. for 0.5 hr, then at 25° C. for 5 hrs. The reaction mixture was quenched with acetic acid till the pH of the mixture was about 6. The reaction mixture was extracted with ethyl acetate (4 L) and the isolated organic phase was washed sequentially with 25% brine (4 L), 5% NaHCO3 (5L), and 25% brine (4 L), dried over NaSO4, filtered, concentrated and chased with 2 L of methyl tert-butyl ether to dryness. The oil was dissolved in 950 mL of methyl tert-butyl ether and warmed to 45° C., added heptane (4L) and cooled to −5° C. The solid was isolated by filtration to provide tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate. A mixture of the tert-butyl (1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate (400 g, 1.028 mol), the product of Example 111-7 (321 g, 1.08 mol, 1.05 equivalents) in absolute ethanol (3.35 L) was cooled to 5° C. was treated with a solution of sodium ethoxide (77.5 g sodium ethoxide in 0.65 L of absolute ethanol, 1.05 equivalents) over 1 hour. The reaction mixture was stirred at 3° C. for 3 hours. Lithium hydroxide monohydrate (215.6 g, 5.138 mol, 5 equivalents) was added all at once and the temperature rose to 10° C. The mixture was stirred at 10° C. for 2 hours, treated with acetic acid (308.6 gm, 5.138 mol, 5 eq) and stirred at 60° C. for 17 hours. The reaction mixture was treated with distilled water (4 L) over 20 minutes while maintaining the internal temperature >55° C. The slurry was cooled slowly to 14° C. over 2.5 hours, filtered, washed with 1:1 ethanol:water (total volume=2 L), heptanes (2 L) and dried at 55° C. vacuum oven under N2 for 40 hours to give the title compound (451.9 g, 91% yield). 1H NMR (CDCl3): δ 8.65(m, 1H), 7.90(m, 2H), 7.65-7.75 (m, 2H), 7.17-7.30(m, 8H), 4.63(m, 1H), 4.32(m, 1H), 3.95(m, 1H), 3.32(m, 1H), 2.7-3.0(m, 4H), 2.10 (m, 1H), 1.74(m, 1H), 1.36 (s, 9H). The reaction mixture was quenched with acetic acid till the pH of the mixture The reaction mixture was extracted with ethyl acetate (4 L) the isolated organic phase was washed sequentially with 25% brine (4 L), 5% NaHCO3 (5L), and 25% brine (4 L) dried over NaSO4 filtered concentrated The oil was dissolved in 950 mL of methyl tert-butyl ether added heptane (4L) cooled to −5° C The solid was isolated by filtration

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-Butyl(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. was treated with a solution of NaOEt (13.5 mL, 21% in ethanol) over 10 minutes. The reaction was warmed to 25° C. and stirred for 18 hours. The reaction was re-cooled to 0° C. and treated with a solution of 4-bromobenzyl bromide (9.5 g, 38.0 mmol) in ethanol (40 mL), stirred at 50° C. for 3 hours, cooled to 0° C. and adjusted to neutral pH by addition of 4N HCl. The ethanol was removed under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (22.4 g), which was used without further purification. The reaction was re-cooled to 0° C. stirred at 50° C. for 3 hours cooled to 0° C. The ethanol was removed under reduced pressure the residue was partitioned between chloroform and water The organic phase was washed with brine dried over MgSO4 filtered concentrated