ethyl (2R)-2-hydroxy-4-phenylbutanoate

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

Procedure: A 3 L three-neck, round-bottom flask equipped with a mechanical stirrer, an electrode connected to a pH control unit and an addition tube connected to a peristaltic pump, was charged with 450 ml of deionized water, 50 ml of 0.05M aqueous phosphate buffer (pH 7.0) and 52.0 g of racemic ethyl 2-hydroxy-4-phenylbutanoate. The mixture was stirred for a few minutes to make certain that the pH remained constant at 7.0. Then, 1.0 g (30,000 units) of Pseudomonas lipase enzyme (P-30, Amano International) was added and the hydrolysis was allowed to proceed at pH 7.0 and room temperature, with stirring. The pH was kept constant by adding 1.0N aqueous sodium hydroxide solution via the paristaltic pump, which was activated by the pH control unit. The reaction was discontinued at 55% conversion when 137.5 ml of 1.0N aqueous sodium hydroxide solution had been added (at the 25 hour mark). The reaction mixture was then extracted with 3×200 ml (600 ml total) of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. under 70 mm Hg of vacuum to provide 22.4 g of ethyl (2R)-2-hydroxy-4-phenylbutanoate (43% yield; 96% of theory), which was 99% enantiomerically pure (α)D25 -8.4° (c 1.15, EtOH). The aqueous layer was acidified to pH 2 with 3N hydrochloric acid and extracted with 3×200 ml of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. and 70 mm Hg to give 22.7 g of (2S)-2-hydroxy-4-phenylbutanoic acid (50% yield; 91% of theory), which was 73% enantiomerically pure. (α)D25 +5.7°, m.p. 109°-110° C. A 3 L three-neck, round-bottom flask equipped with a mechanical stirrer Then, 1.0 g (30,000 units) of Pseudomonas lipase enzyme (P-30, Amano International) was added to proceed at pH 7.0 and room temperature with stirring had been added (at the 25 hour mark) The reaction mixture was then extracted with 3×200 ml (600 ml total) of diethyl ether The combined organic layers were dried over anhydrous sodium sulfate the solvent was removed at 45° C. under 70 mm Hg of vacuum

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

Procedure: A 3 L three-neck, round-bottom flask equipped with a mechanical stirrer, an electrode connected to a pH control unit and an addition tube connected to a peristaltic pump, was charged with 450 ml of deionized water, 50 ml of 0.05M aqueous phosphate buffer (pH 7.0) and 52.0 g of racemic ethyl 2-hydroxy-4-phenylbutanoate. The mixture was stirred for several minutes to make certain that the pH remained constant at 7.0. Then, 0.67 g (20,000 units) of Pseudomonas lipase enzyme (P-30, Amano International Enzyme Co., Inc., Troy, Va.) was added and the hydrolysis was allowed to proceed at pH 7.0 and room temperature, with stirring. The pH was kept constant by adding 1.0N aqueous sodium hydroxide solution via the peristaltic pump, which was activated by the pH control unit. The reaction was discontinued at 50% conversion when 125 ml of 1.0N aqueous sodium hydroxide solution had been added (at the 24 hour mark). The reaction mixture was then extracted with 3 portions of 200 ml (600 ml total) of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. under 70 mm Hg of vacuum, to provide 25.3 g of ethyl (2R)-2-hydroxy-4-phenylbutanoate (48.5% yield; 97% of theory), which was 91% enantiomerically pure (α)D25 -7.8° (c 1.0, EtOH). The aqueous layer was acidified to pH 2 with 3N hydrochloric acid and extracted with 3×200 ml of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed at 45° C. and 70 mm Hg to give 20.8 g of (2S)-2-hydroxy-4-phenylbutanoic acid (46% yield; 92% of theory), which was 90.8% enantiomerically pure. (α)D25 +7.6° (c 1.0, EtOH), m.p. 109°-110° C. A 3 L three-neck, round-bottom flask equipped with a mechanical stirrer Then, 0.67 g (20,000 units) of Pseudomonas lipase enzyme (P-30, Amano International Enzyme Co., Inc., Troy, Va.) was added to proceed at pH 7.0 and room temperature with stirring had been added (at the 24 hour mark) The reaction mixture was then extracted with 3 portions of 200 ml (600 ml total) of diethyl ether The combined organic layers were dried over anhydrous sodium sulfate the solvent was removed at 45° C. under 70 mm Hg of vacuum

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

Procedure: NaBH4 (1.82 g) was added portionwise to an ice cooled solution of ethyl (R)-2-hydroxy-4-phenylbutyrate (2.0 g) in methanol (40 ml). After the addition was completed, the reaction mixture was stirred at room temperature for 45 minutes. Water (20 ml) was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave (R)-4-phenylbutane-1,2-diol (1.63 g) as a colorless oil. This material was used for the next reaction without further purification. After the addition the resulting mixture was stirred for several minutes evaporated under reduced pressure The residue was extracted with ethyl acetate The extract was washed with brine dried over magnesium sulfate Evaporation of the solvent under reduced pressure

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

Procedure: NaBH4 (1.82 g) was added portionwise to an ice cooled solution of ethyl (R)-2-hydroxy-4-phenylbutyrate (2.0 g) in methanol (40 ml). After the addition was completed, the reaction mixture was stirred at room temperature for 45 minutes. Water (20 ml) was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave (R)-4-phenylbutane-1,2-diol (1.63 g) as a colorless oil. This material was used for the next reaction without further purification. After the addition the resulting mixture was stirred for several minutes evaporated under reduced pressure The residue was extracted with ethyl acetate The extract was washed with brine dried over magnesium sulfate Evaporation of the solvent under reduced pressure

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

Procedure: Triethylamine (583 mg) was added dropwise to a stirred mixture of ethyl (R)-2-hydroxy-4-phenylbutyrate (1.0 g) and methanesulfonyl chloride (660 mg) in dichloromethane (10 ml) at ice-bath temperature. After 40 minutes, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give ethyl (R)-2-methylsulfonyloxy-4-phenylbutyrate (1.37 g) as an oil. This material was used immediately without further purification. NaH (60% in mineral oil, 192 mg) was added to a solution of 4-imidazolecarboxamide (534 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred for 30 minutes. The methanesulfonate prepared above was added and the resulting mixture was stirred for 3 hours at 60° C. the reaction mixture was partitioned between dichloromethane and water The organic layer was washed with brine dried over magnesium sulfate concentrated in vacuo

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

Procedure: Triethylamine (583 mg) was added dropwise to a stirred mixture of ethyl (R)-2-hydroxy-4-phenylbutyrate (1.0 g) and methanesulfonyl chloride (660 mg) in dichloromethane (10 ml) at ice-bath temperature. After 40 minutes, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give ethyl (R)-2-methylsulfonyloxy-4-phenylbutyrate (1.37 g) as an oil. This material was used immediately without further purification. NaH (60% in mineral oil, 192 mg) was added to a solution of 4-imidazolecarboxamide (534 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred for 30 minutes. The methanesulfonate prepared above was added and the resulting mixture was stirred for 3 hours at 60° C. the reaction mixture was partitioned between dichloromethane and water The organic layer was washed with brine dried over magnesium sulfate concentrated in vacuo

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

Procedure: Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2×). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C. saturate with sodium chloride extract with ethyl acetate (3×25 mL) Combine the organic phases, dry (MgSO4) evaporate the solvent in vacuo Stir overnight wash with saturated sodium hydrogen carbonate (2×) Dry (MgSO4) evaporate the solvent in vacuo recrystallize (methylene chloride/hexane

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

Procedure: Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2×). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C. saturate with sodium chloride extract with ethyl acetate (3×25 mL) Combine the organic phases, dry (MgSO4) evaporate the solvent in vacuo Stir overnight wash with saturated sodium hydrogen carbonate (2×) Dry (MgSO4) evaporate the solvent in vacuo recrystallize (methylene chloride/hexane

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

Procedure: Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2×). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C. saturate with sodium chloride extract with ethyl acetate (3×25 mL) Combine the organic phases, dry (MgSO4) evaporate the solvent in vacuo Stir overnight wash with saturated sodium hydrogen carbonate (2×) Dry (MgSO4) evaporate the solvent in vacuo recrystallize (methylene chloride/hexane

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

Procedure: Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2×). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C. saturate with sodium chloride extract with ethyl acetate (3×25 mL) Combine the organic phases, dry (MgSO4) evaporate the solvent in vacuo Stir overnight wash with saturated sodium hydrogen carbonate (2×) Dry (MgSO4) evaporate the solvent in vacuo recrystallize (methylene chloride/hexane

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

Procedure: Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2X). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C. saturate with sodium chloride extract with ethyl acetate (3×25mL) Combine the organic phases, dry (MgSO4) evaporate the solvent in vacuo Stir overnight wash with saturated sodium hydrogen carbonate (2X) Dry (MgSO4) evaporate the solvent in vacuo recrystallize (methylene chloride/hexane

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

Procedure: Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2X). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C. saturate with sodium chloride extract with ethyl acetate (3×25mL) Combine the organic phases, dry (MgSO4) evaporate the solvent in vacuo Stir overnight wash with saturated sodium hydrogen carbonate (2X) Dry (MgSO4) evaporate the solvent in vacuo recrystallize (methylene chloride/hexane