benzyl N-[(1S)-1-[(2S)-oxiran-2-yl]-2-phenylethyl]carbamate

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

Procedure: A solution of potassium hydroxide (6.52 g. 0.116 mol. 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(s)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and washed with water, dried over anhyd MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-[N-(benzyloxycarbonyl) amino]-1,2(S)-epoxy-4-phenylbutane, mp 102-103° C., FAB MS: MH+=298. concentrated in vacuo to give a white solid washed with water dried over anhyd MgSO4 filtered concentrated in vacuo to give a white solid The solid was crystallized from hexanes and ethyl acetate

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

Procedure: A solution of potassium hydroxide (6.52 g, 0.116 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and washed with water, dried over anhyd MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-[N-(benzyloxycarbonyl) amino]-1,2(S)-epoxy-4-phenylbutane, mp 102-103° C., FAB MS: MH+=298. concentrated in vacuo to give a white solid washed with water dried over anhyd MgSO4 filtered concentrated in vacuo to give a white solid The solid was crystallized from hexanes and ethyl acetate

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

Procedure: To a solution of 1.2 equiv. of potassium hydroxide in 968 mL of absolute ethanol at room temperature, is added 0.097 mol of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. After stirring for fifteen minutes, the solvent is removed under reduced pressure and the solids are dissolved in methylene chloride. After washing with water, drying over magnesium sulfate, filtering and stripping, one obtains a white solid. Recrystallization from hot ethyl acetate and hexane will afford N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4- phenylbutane. the solvent is removed under reduced pressure the solids are dissolved in methylene chloride After washing with water drying over magnesium sulfate filtering one obtains a white solid Recrystallization from hot ethyl acetate and hexane

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

Procedure: To a suspension of 196.7 g of the N-benzyloxycarbonyl-3(S)-amino-2(R)-methanesulfonyloxy-4-phenyl-1-butanol obtained in the above Example 3 in 2,500 ml of methanol was added 90 g of potassium carbonate. The obtained mixture was then stirred at room temperature for 5 hours. The pH value of the reaction mixture was adjusted to 7 with a 10% aqueous solution of citric acid. Then the solvent was concentrated under reduced pressure. After adding water to the residue, it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. After adding anhydrous sodium sulfate and activated carbon, the mixture was filtered. Then the filtrate was concentrated and n-hexane was added thereto for crystallization. The crystals thus precipitated were filtered and dried. Thus the target N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane was obtained in the form of white crystals. The overall yield of Referential Example 2 and Example 3 through Example 4 was 72.3%. Then the solvent was concentrated under reduced pressure After adding water to the residue, it was extracted with ethyl acetate The organic layer was washed with a saturated aqueous solution of sodium chloride After adding anhydrous sodium sulfate and activated carbon the mixture was filtered Then the filtrate was concentrated n-hexane was added for crystallization The crystals thus precipitated were filtered dried

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 25.5 g of the crude N-benzyloxycarbonyl-3(S)-amino-2(R)-p-toluenesulfonyl-4-phenyl-1-butanol obtained in the above Example 1 was dissolved in 750 ml of methanol. Then 13.9 g of potassium carbonate was added thereto at 10° C. and the resulting mixture was stirred for 3 hours at 10° to 20° C. The pH value of the reaction mixture was adjusted to 7 to 7.5 by adding a 5% aqueous solution of citric acid. After distilling off the solvent under reduced pressure, 150 ml of water was added to the concentrate. Then it was extracted with 150 ml portions of ethyl acetate twice and the extract was washed with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate and distilling off the solvent under reduced pressure, 14.4 g of crude N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane was obtained. After distilling off the solvent under reduced pressure, 150 ml of water was added to the concentrate Then it was extracted with 150 ml portions of ethyl acetate twice the extract was washed with 50 ml of a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate After filtering off the sodium sulfate distilling off the solvent under reduced pressure

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

Procedure: A solution of N-benzyloxycarbonyl 3 (S)-amino-1,2-(S)-epoxy-4-phenylbutane (30.1 g, 0.10 mol) and 165mL of isoamylamine in 150 mL of isopropyl alcohol was heated to reflux for 2.5 hours. The solution was cooled to room temperature, concentrated in vacuo and then recrystallized. The product was isolated by filtration and from ethyl acetate/hexane to afford 31.7 g (81%) of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine. to reflux for 2.5 hours concentrated in vacuo recrystallized The product was isolated by filtration and from ethyl acetate/hexane

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

Procedure: A solution of potassium hydroxide (6.52 g, 0.116 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and washed with water, dried over anhyd MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-[N-(benzyloxycarbonyl) amino]-1,2(S)-epoxy-4-phenylbutane, mp 102-103° C., FAB MS: MH+ =298. concentrated in vacuo to give a white solid washed with water dried over anhyd MgSO4 filtered concentrated in vacuo to give a white solid The solid was crystallized from hexanes and ethyl acetate

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

Procedure: To a solution of 1.2 equiv. of potassium hydroxide in 968 mL of absolute ethanol at room temperature, is added 0.097 mol of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. After stirring for fifteen minutes, the solvent is removed under reduced pressure and the solids are dissolved in methylene chloride. After washing with water, drying over magnesium sulfate, filtering and stripping, one obtains a white solid. Recrystallization from hot ethyl acetate and hexane will afford N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane. the solvent is removed under reduced pressure the solids are dissolved in methylene chloride After washing with water drying over magnesium sulfate filtering one obtains a white solid Recrystallization from hot ethyl acetate and hexane

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

Procedure: From the reaction of (1.48 g, 5.0 mmol) of N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and (7.314 g, 100.0 mmol) of n-butylamine, one obtains 1.50 g (80%) of N-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-butylamine, mp 125-128° C., FAB MS, Spectrum: MH+=371.

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

Procedure: A solution of potassium hydroxide (6.52 g, 0.116 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(s)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 min and then concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and washed with water, dried over anhyd MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of N-benzyloxycarbonyl-3(S)-amino-1,2(S)epoxy-4-phenylbutane, mp 102-103° C., FAB MS: MH+=298. concentrated in vacuo to give a white solid washed with water dried over anhyd MgSO4 filtered concentrated in vacuo to give a white solid The solid was crystallized from hexanes and ethyl acetate

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

Procedure: A solution of potassium hydroxide (6.52 g. 0.116 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissovled in dichloromethane and washed with water, dried over anhyd MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-[N-(benzyloxycarbonyl) amino]-1,2(S)-epoxy-4-phenylbutane, mp 102-103° C., FAB MS: MH+=298. concentrated in vacuo to give a white solid washed with water dried over anhyd MgSO4 filtered concentrated in vacuo to give a white solid The solid was crystallized from hexanes and ethyl acetate

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

Procedure: 0.395 g of 4-(tert.butoxycarbonyl)-N-tert.butyl-2-piperazinecarboxamide was dissolved in 50 ml of dry isopropanol and treated with 0.413 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane. The mixture was stirred at room temperature for 72 hours. The solvent was removed by evaporation to give a brown semi-solid material which was purified by flash chromatography on silica gel using 5% methanol in dichloromethane for the elution. There was obtained 0.234 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-4-(tert.butoxycarbonyl)-N-tert.butyl-2(R or S)-piperazinecarboxamide as a mixture of diastereomers. The solvent was removed by evaporation to give a brown semi-solid material which was purified by flash chromatography on silica gel using 5% methanol in dichloromethane for the elution