(1S,2S)-[3-Chloro-2-hydroxy-1-(phenylmethyl)-propyl]carbamic acid, 1,1-dimethylethyl ether

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl acetate (4.2 ml) and ethanol (16.7 ml) were added to (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g). Sodium borohydride (133 mg) was added in portions to the obtained mixture at −10° C., and they were stirred for 1 hour 40 minutes. Acetic acid (0.40 ml) was added to the reaction mixture to terminate the reaction. The reaction mixture was slowly heated to 60° C. for the duration of 1 hour and then stirred at 60° C. for 30 minutes. The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes and then stirred at −10° C. for 6 hours. The crystals thus formed were taken by the filtration, washed with 0° C. water and dried under reduced pressure to obtain intended (2S, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g). to terminate the reaction stirred at 60° C. for 30 minutes The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes stirred at −10° C. for 6 hours The crystals thus formed were taken by the filtration washed with 0° C. water dried under reduced pressure

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (22.9 g, (2S,3S):(2R,3S)=99.2:0.8) obtained in the same manner as in Reference Example 1 were added 2-propanol (115 ml) and water (9.6 ml). Furthermore, 4N aqueous sodium hydroxide solution (28.6 ml) was added, and the mixture was stirred at 4° C. for 3 hr. After the completion of the reaction, to the reaction mixture was added citric acid (2.45 g) dissolved in water (134 ml). The reaction mixture was once heated to 27° C. and cooled to −10° C. over 5 hr. The reaction mixture was stirred at −10° C. for 10 hr and crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration. The wet crystals were analyzed by HPLC and confirmed to be (2S,3S):(2R,3S)=100:0. Acetonitrile (113 ml) was added to the obtained wet crystals, and then a solution of citric acid (14.7 g) in water (56 ml) was added. The mixture was stirred at 70° C. for 2 hr. The reaction mixture was cooled to room temperature and adjusted to pH=7.0 with 8N potassium hydroxide solution. To this solution were added sodium hydrogencarbonate (16.0 g) and TEMPO (0.115 g), and 12% aqueous sodium hypochrolite solution (189 g) was added dropwise at room temperature over 2 hr. After the completion of the dropwise addition, the mixture was stirred for 30 min, and potassium bromide (10.9 g) was added. The mixture was stirred for 13 hr and the 12% aqueous sodium hypochlorite solution (23.6 g) was further added. The mixture was stirred for 1 hr and sodium hydrogensulfite (3.80 g) was added to the reaction mixture. To the solution was added 8N aqueous potassium hydroxide solution (28.6 ml) and the mixture was stirred at 90° C. for 6 hr. The 8N aqueous potassium hydroxide solution (9.6 ml) was further added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was cooled to room temperature and adjusted to pH=10 with 6N aqueous hydrochloric acid solution. A solution of di-tert-butoxycarbonate (16.7 g) in acetonitrile (20 ml) was added and the mixture was stirred at 40° C. for 2 hr. The reaction mixture was adjusted to pH=2.0 with 6N aqueous hydrochloric acid solution and the organic layer and aqueous layer were partitioned. The aqueous layer was extracted twice with ethyl acetate (100 ml, 50 ml) and the ethyl acetate layer and the organic layer partitioned earlier were combined. The organic layer was back extracted three times with 1N aqueous sodium hydroxide solution (100 ml, 50 ml, 50 ml). The aqueous layer was then adjusted to pH=1.5 with 6N aqueous hydrochloric acid solution and extracted twice with ethyl acetate (100 ml, 100 ml). This ethyl acetate solution was analyzed by HPLC, and as a result, it was confirmed that (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (19.4 g, yield 86%) was obtained. The solvent of this solution was removed under reduced pressure. Methanol (60 ml) and water (60 ml) were added, and while stirring at 0° C., water (90 ml) was added over 30 min. The temperature was once raised to 20° C. and cooled to −3° C. over 2 hr. The mixture was stirred at −3° C. for 2 hr, and the obtained crystals were collected by filtration. The crystals were dried under reduced pressure to give the objective (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (16.0 g, yield 71%). After the completion of the reaction The reaction mixture was once heated to 27° C. cooled to −10° C. over 5 hr The reaction mixture was stirred at −10° C. for 10 hr crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration Acetonitrile (113 ml) was added to the obtained wet crystals a solution of citric acid (14.7 g) in water (56 ml) was added The mixture was stirred at 70° C. for 2 hr The reaction mixture was cooled to room temperature To this solution were added sodium hydrogencarbonate (16.0 g) and TEMPO (0.115 g), and 12% aqueous sodium hypochrolite solution (189 g) was added dropwise at room temperature over 2 hr After the completion of the dropwise addition the mixture was stirred for 30 min potassium bromide (10.9 g) was added The mixture was stirred for 13 hr the 12% aqueous sodium hypochlorite solution (23.6 g) was further added The mixture was stirred for 1 hr sodium hydrogensulfite (3.80 g) was added to the reaction mixture To the solution was added 8N aqueous potassium hydroxide solution (28.6 ml) the mixture was stirred at 90° C. for 6 hr The 8N aqueous potassium hydroxide solution (9.6 ml) was further added the mixture was stirred at 90° C. for 16 hr The reaction mixture was cooled to room temperature A solution of di-tert-butoxycarbonate (16.7 g) in acetonitrile (20 ml) was added the mixture was stirred at 40° C. for 2 hr the organic layer and aqueous layer were partitioned The aqueous layer was extracted twice with ethyl acetate (100 ml, 50 ml) the ethyl acetate layer and the organic layer partitioned earlier The organic layer was back extracted three times with 1N aqueous sodium hydroxide solution (100 ml, 50 ml, 50 ml) extracted twice with ethyl acetate (100 ml, 100 ml)

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (4.91 g, (2S,3S):(2R,3S)=99.2:0.8) obtained in the same manner as in Reference Example 1 were added 2-propanol (24.6 ml) and water (2.0 ml). 4N Aqueous sodium hydroxide solution (6.1 ml) was then added, and the mixture was stirred at 4° C. for 3 hr. After the completion of the reaction, citric acid (0.525 g) dissolved in water (28.7 ml) was added. The reaction mixture was once heated to 27° C. and cooled to −10° C. over 5 hr. The mixture was stirred at −10° C. for 10 hr, and crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration. The wet crystals were analyzed by HPLC and found to be (2S,3S):(2R,3S)=100:0. To the obtained wet crystals was added acetonitrile (3.0 ml) and then a solution of citric acid (3.15 g) in water (2.5 ml) was added. The mixture was stirred at 70° C. for 2 hr. The mixture was cooled to room temperature and adjusted to pH=7.0 with 8N potassium hydroxide solution. To this solution were added sodium hydrogencarbonate (3.44 g), TEMPO (0.0246 g) and potassium bromide (4.88 g) and 12% aqueous sodium hypochlorite solution (25.4 g) was added dropwise at room temperature over 1 hr. After the completion of the dropwise addition, the mixture was stirred for 3 hr and sodium hydrogensulfite (0.853 g) was added to the reaction mixture. To this solution was added 8N aqueous potassium hydroxide solution (8.2 ml) and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was cooled to room temperature and analyzed by HPLC, and as a result, it was confirmed that (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid (3.02 g, yield 94%) was obtained. The reaction mixture was then cooled to 0° C. and adjusted to pH=5.5 with 6N aqueous hydrochloric acid solution. The mixture was stirred at 0° C. for 1 hr and the resulting crystals were collected by filtration. The crystals were dried under reduced pressure to give (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid as crystals (2.41 g, yield 75%). was added The reaction mixture was once heated to 27° C. cooled to −10° C. over 5 hr The mixture was stirred at −10° C. for 10 hr crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration To the obtained wet crystals was added acetonitrile (3.0 ml) a solution of citric acid (3.15 g) in water (2.5 ml) was added The mixture was stirred at 70° C. for 2 hr The mixture was cooled to room temperature To this solution were added sodium hydrogencarbonate (3.44 g), TEMPO (0.0246 g) and potassium bromide (4.88 g) and 12% aqueous sodium hypochlorite solution (25.4 g) was added dropwise at room temperature over 1 hr After the completion of the dropwise addition the mixture was stirred for 3 hr sodium hydrogensulfite (0.853 g) was added to the reaction mixture To this solution was added 8N aqueous potassium hydroxide solution (8.2 ml) the mixture was stirred at 90° C. for 18 hr The reaction mixture was cooled to room temperature

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g) were added toluene (4.2 ml) and ethanol (16.7 ml). Sodium borohydride (133 mg) was added by portions at −10° C. and the mixture was stirred for 1 hr and 40 min. The reaction was quenched by adding acetic acid (0.40 ml). The reaction mixture was warmed to 60° C. over 1 hr and further stirred 60° C. for 30 min. The reaction mixture was then cooled to −10° C. over 1 hr and 50 min and further stirred at −10° C. for 6 hr. The obtained crystals were collected by filtration, washed with toluene (10.4 ml) and water of 0° C., and dried under reduced pressure to give the objective (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g, yield 83%). The obtained dry crystals were analyzed by HPLC and found to be (2S,3S):(2R,3S)=99.2:0.8 crystals. The reaction was quenched by adding acetic acid (0.40 ml) The reaction mixture was then cooled to −10° C. over 1 hr and 50 min further stirred at −10° C. for 6 hr The obtained crystals were collected by filtration washed with toluene (10.4 ml) and water of 0° C. dried under reduced pressure

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Propanol (2.4 ml) was added to (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (300 mg). After cooling to 4° C., 4 mol/l aqueous sodium hydroxide solution (0.375 ml) and water (0.225 ml) were added to the obtained mixture, and they were stirred at 4° C. for 7 hours. 13.7% aqueous citric acid solution (695 mg) was added to the reaction mixture. After the extraction with tert-butyl methyl ether, the obtained organic layer was washed with water and analyzed by HPLC to find that intended (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (230 mg)was obtained in an yield of 87%. After the extraction with tert-butyl methyl ether the obtained organic layer was washed with water was obtained in an yield of 87%

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl acetate (4.2 ml) and ethanol (16.7 ml) were added to (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g). Sodium borohydride (133 mg) was added in portions to the obtained mixture at −10° C., and they were stirred for 1 hour 40 minutes. Acetic acid (0.40 ml) was added to the reaction mixture to terminate the reaction. The reaction mixture was slowly heated to 60° C. for the duration of 1 hour and then stirred at 60° C. for 30 minutes. The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes and then stirred at −10° C. for 6 hours. The crystals thus formed were taken by the filtration, washed with 0° C. water and dried under reduced pressure to obtain intended (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g). to terminate the reaction stirred at 60° C. for 30 minutes The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes stirred at −10° C. for 6 hours The crystals thus formed were taken by the filtration washed with 0° C. water dried under reduced pressure

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

Procedure: A mixture composed of 2.0 mmol (0.599 g) of (2S,3S)-3-(t-butoxycarbonylamino)-1-chloro-2-hydroxy-4-phenylbutane, 0.1 mmol (0.032 g) of tetrabutylammoniumbromide, 5.0 mmol (0.49 g) of potassium acetate and 10 ml of acetonitrile was stirred under reflux for 50 hours. Thereafter, the solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. Quantitative analysis was curried out by high performance liquid chromatography using ethylbenzene as an internal standard. Thus was obtained 0.289 g (45%) of the title compound. under reflux for 50 hours Thereafter, the solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added the organic layer was separated dried over sodium sulfate filtered concentrated under reduced pressure to give a crude product

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

Procedure: A mixture composed of 2.0 mmol (0.599 g) of (2S,3S)-3-(t-butoxycarbonylamino)-1-chloro-2-hydroxy-4-phenylbutane, 0.1 mmol (0.032 g) of tetrabutylammoniumbromide, 5.0 mmol (0.49 g) of potassium acetate and 10 ml of acetonitrile was stirred under reflux for 50 hours. Thereafter, the solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. Quantitative analysis was curried out by high performance liquid chromatography using ethylbenzene as an internal standard. Thus was obtained 0.289 g (45%) of the title compound. under reflux for 50 hours Thereafter, the solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added the organic layer was separated dried over sodium sulfate filtered concentrated under reduced pressure to give a crude product

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl acetate (4.2 ml) and ethanol (16.7 ml) were added to (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g). Sodium borohydride (133 mg) was added in portions to the obtained mixture at −10° C., and they were stirred for 1 hour 40 minutes. Acetic acid (0.40 ml) was added to the reaction mixture to terminate the reaction. The reaction mixture was slowly heated to 60° C. for the duration of 1 hour and then stirred at 60° C. for 30 minutes. The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes and then stirred at −10° C. for 6 hours. The crystals thus formed were taken by the filtration, washed with 0° C. water and dried under reduced pressure to obtain intended (2S, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g). to terminate the reaction stirred at 60° C. for 30 minutes The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes stirred at −10° C. for 6 hours The crystals thus formed were taken by the filtration washed with 0° C. water dried under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl acetate (4.2 ml) and ethanol (16.7 ml) were added to (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g). Sodium borohydride (133 mg) was added in portions to the obtained mixture at −10° C., and they were stirred for 1 hour 40 minutes. Acetic acid (0.40 ml) was added to the reaction mixture to terminate the reaction. The reaction mixture was slowly heated to 60° C. for the duration of 1 hour and then stirred at 60° C. for 30 minutes. The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes and then stirred at −10° C. for 6 hours. The crystals thus formed were taken by the filtration, washed with 0° C. water and dried under reduced pressure to obtain intended (2S, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g). to terminate the reaction stirred at 60° C. for 30 minutes The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes stirred at −10° C. for 6 hours The crystals thus formed were taken by the filtration washed with 0° C. water dried under reduced pressure

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (22.9 g, (2S,3S):(2R,3S)=99.2:0.8) obtained in the same manner as in Reference Example 1 were added 2-propanol (115 ml) and water (9.6 ml). Furthermore, 4N aqueous sodium hydroxide solution (28.6 ml) was added, and the mixture was stirred at 4° C. for 3 hr. After the completion of the reaction, to the reaction mixture was added citric acid (2.45 g) dissolved in water (134 ml). The reaction mixture was once heated to 27° C. and cooled to −10° C. over 5 hr. The reaction mixture was stirred at −10° C. for 10 hr and crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration. The wet crystals were analyzed by HPLC and confirmed to be (2S,3S):(2R,3S)=100:0. Acetonitrile (113 ml) was added to the obtained wet crystals, and then a solution of citric acid (14.7 g) in water (56 ml) was added. The mixture was stirred at 70° C. for 2 hr. The reaction mixture was cooled to room temperature and adjusted to pH=7.0 with 8N potassium hydroxide solution. To this solution were added sodium hydrogencarbonate (16.0 g) and TEMPO (0.115 g), and 12% aqueous sodium hypochrolite solution (189 g) was added dropwise at room temperature over 2 hr. After the completion of the dropwise addition, the mixture was stirred for 30 min, and potassium bromide (10.9 g) was added. The mixture was stirred for 13 hr and the 12% aqueous sodium hypochlorite solution (23.6 g) was further added. The mixture was stirred for 1 hr and sodium hydrogensulfite (3.80 g) was added to the reaction mixture. To the solution was added 8N aqueous potassium hydroxide solution (28.6 ml) and the mixture was stirred at 90° C. for 6 hr. The 8N aqueous potassium hydroxide solution (9.6 ml) was further added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was cooled to room temperature and adjusted to pH=10 with 6N aqueous hydrochloric acid solution. A solution of di-tert-butoxycarbonate (16.7 g) in acetonitrile (20 ml) was added and the mixture was stirred at 40° C. for 2 hr. The reaction mixture was adjusted to pH=2.0 with 6N aqueous hydrochloric acid solution and the organic layer and aqueous layer were partitioned. The aqueous layer was extracted twice with ethyl acetate (100 ml, 50 ml) and the ethyl acetate layer and the organic layer partitioned earlier were combined. The organic layer was back extracted three times with 1N aqueous sodium hydroxide solution (100 ml, 50 ml, 50 ml). The aqueous layer was then adjusted to pH=1.5 with 6N aqueous hydrochloric acid solution and extracted twice with ethyl acetate (100 ml, 100 ml). This ethyl acetate solution was analyzed by HPLC, and as a result, it was confirmed that (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (19.4 g, yield 86%) was obtained. The solvent of this solution was removed under reduced pressure. Methanol (60 ml) and water (60 ml) were added, and while stirring at 0° C., water (90 ml) was added over 30 min. The temperature was once raised to 20° C. and cooled to −3° C. over 2 hr. The mixture was stirred at −3° C. for 2 hr, and the obtained crystals were collected by filtration. The crystals were dried under reduced pressure to give the objective (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (16.0 g, yield 71%). After the completion of the reaction The reaction mixture was once heated to 27° C. cooled to −10° C. over 5 hr The reaction mixture was stirred at −10° C. for 10 hr crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration Acetonitrile (113 ml) was added to the obtained wet crystals a solution of citric acid (14.7 g) in water (56 ml) was added The mixture was stirred at 70° C. for 2 hr The reaction mixture was cooled to room temperature To this solution were added sodium hydrogencarbonate (16.0 g) and TEMPO (0.115 g), and 12% aqueous sodium hypochrolite solution (189 g) was added dropwise at room temperature over 2 hr After the completion of the dropwise addition the mixture was stirred for 30 min potassium bromide (10.9 g) was added The mixture was stirred for 13 hr the 12% aqueous sodium hypochlorite solution (23.6 g) was further added The mixture was stirred for 1 hr sodium hydrogensulfite (3.80 g) was added to the reaction mixture To the solution was added 8N aqueous potassium hydroxide solution (28.6 ml) the mixture was stirred at 90° C. for 6 hr The 8N aqueous potassium hydroxide solution (9.6 ml) was further added the mixture was stirred at 90° C. for 16 hr The reaction mixture was cooled to room temperature A solution of di-tert-butoxycarbonate (16.7 g) in acetonitrile (20 ml) was added the mixture was stirred at 40° C. for 2 hr the organic layer and aqueous layer were partitioned The aqueous layer was extracted twice with ethyl acetate (100 ml, 50 ml) the ethyl acetate layer and the organic layer partitioned earlier The organic layer was back extracted three times with 1N aqueous sodium hydroxide solution (100 ml, 50 ml, 50 ml) extracted twice with ethyl acetate (100 ml, 100 ml)

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (22.9 g, (2S,3S):(2R,3S)=99.2:0.8) obtained in the same manner as in Reference Example 1 were added 2-propanol (115 ml) and water (9.6 ml). Furthermore, 4N aqueous sodium hydroxide solution (28.6 ml) was added, and the mixture was stirred at 4° C. for 3 hr. After the completion of the reaction, to the reaction mixture was added citric acid (2.45 g) dissolved in water (134 ml). The reaction mixture was once heated to 27° C. and cooled to −10° C. over 5 hr. The reaction mixture was stirred at −10° C. for 10 hr and crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration. The wet crystals were analyzed by HPLC and confirmed to be (2S,3S):(2R,3S)=100:0. Acetonitrile (113 ml) was added to the obtained wet crystals, and then a solution of citric acid (14.7 g) in water (56 ml) was added. The mixture was stirred at 70° C. for 2 hr. The reaction mixture was cooled to room temperature and adjusted to pH=7.0 with 8N potassium hydroxide solution. To this solution were added sodium hydrogencarbonate (16.0 g) and TEMPO (0.115 g), and 12% aqueous sodium hypochrolite solution (189 g) was added dropwise at room temperature over 2 hr. After the completion of the dropwise addition, the mixture was stirred for 30 min, and potassium bromide (10.9 g) was added. The mixture was stirred for 13 hr and the 12% aqueous sodium hypochlorite solution (23.6 g) was further added. The mixture was stirred for 1 hr and sodium hydrogensulfite (3.80 g) was added to the reaction mixture. To the solution was added 8N aqueous potassium hydroxide solution (28.6 ml) and the mixture was stirred at 90° C. for 6 hr. The 8N aqueous potassium hydroxide solution (9.6 ml) was further added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was cooled to room temperature and adjusted to pH=10 with 6N aqueous hydrochloric acid solution. A solution of di-tert-butoxycarbonate (16.7 g) in acetonitrile (20 ml) was added and the mixture was stirred at 40° C. for 2 hr. The reaction mixture was adjusted to pH=2.0 with 6N aqueous hydrochloric acid solution and the organic layer and aqueous layer were partitioned. The aqueous layer was extracted twice with ethyl acetate (100 ml, 50 ml) and the ethyl acetate layer and the organic layer partitioned earlier were combined. The organic layer was back extracted three times with 1N aqueous sodium hydroxide solution (100 ml, 50 ml, 50 ml). The aqueous layer was then adjusted to pH=1.5 with 6N aqueous hydrochloric acid solution and extracted twice with ethyl acetate (100 ml, 100 ml). This ethyl acetate solution was analyzed by HPLC, and as a result, it was confirmed that (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (19.4 g, yield 86%) was obtained. The solvent of this solution was removed under reduced pressure. Methanol (60 ml) and water (60 ml) were added, and while stirring at 0° C., water (90 ml) was added over 30 min. The temperature was once raised to 20° C. and cooled to −3° C. over 2 hr. The mixture was stirred at −3° C. for 2 hr, and the obtained crystals were collected by filtration. The crystals were dried under reduced pressure to give the objective (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (16.0 g, yield 71%). After the completion of the reaction The reaction mixture was once heated to 27° C. cooled to −10° C. over 5 hr The reaction mixture was stirred at −10° C. for 10 hr crystals of (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were collected by filtration Acetonitrile (113 ml) was added to the obtained wet crystals a solution of citric acid (14.7 g) in water (56 ml) was added The mixture was stirred at 70° C. for 2 hr The reaction mixture was cooled to room temperature To this solution were added sodium hydrogencarbonate (16.0 g) and TEMPO (0.115 g), and 12% aqueous sodium hypochrolite solution (189 g) was added dropwise at room temperature over 2 hr After the completion of the dropwise addition the mixture was stirred for 30 min potassium bromide (10.9 g) was added The mixture was stirred for 13 hr the 12% aqueous sodium hypochlorite solution (23.6 g) was further added The mixture was stirred for 1 hr sodium hydrogensulfite (3.80 g) was added to the reaction mixture To the solution was added 8N aqueous potassium hydroxide solution (28.6 ml) the mixture was stirred at 90° C. for 6 hr The 8N aqueous potassium hydroxide solution (9.6 ml) was further added the mixture was stirred at 90° C. for 16 hr The reaction mixture was cooled to room temperature A solution of di-tert-butoxycarbonate (16.7 g) in acetonitrile (20 ml) was added the mixture was stirred at 40° C. for 2 hr the organic layer and aqueous layer were partitioned The aqueous layer was extracted twice with ethyl acetate (100 ml, 50 ml) the ethyl acetate layer and the organic layer partitioned earlier The organic layer was back extracted three times with 1N aqueous sodium hydroxide solution (100 ml, 50 ml, 50 ml) extracted twice with ethyl acetate (100 ml, 100 ml)