ethyl (3R)-4-bromo-3-hydroxybutanoate

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

Procedure: To a 50 gallon reactor containing a solution of 2.2 kg (44 mol) of sodium cyanide dissolved in 40 L of demineralized water was added 7 kg (33 mol) of (S)-4-bromo-3-hydroxybutyric acid, ethyl ester (Example 3) dissolved in 8 L of ethanol. The reaction mixture was stirred for 16 hours at room temperature. Ethyl acetate (65 L) was added, the mixture agitated, and the layers were allowed to separate. The lower aqueous layer was transferred to a 50 gallon vessel containing 2.5 kg of sodium chloride and 65 L of ethyl acetate, the mixture was agitated and the layers allowed to separate, and the lower aqueous layer was cut off. The organic layers were combined and concentrated in vacuo. The residue was distilled to afford 3.1 kg of the title compound; bp 110-125° C. 0.5 mm Hg; optical rotation [α]D25 =33.1° (C=1.08, chloroform); the mixture agitated to separate The lower aqueous layer was transferred to a 50 gallon vessel containing 2.5 kg of sodium chloride and 65 L of ethyl acetate the mixture was agitated to separate concentrated in vacuo The residue was distilled

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

Procedure: To a 50 mL round bottom flask equipped with a magnetic stirring bar and nitrogen (N2) inlet was charged 2.13 g (S)-3-hydroxybutyrolactone (Example 2) (95.7% pure by VPC) and 5.0 mL acetic acid. The flask was cooled using an ice bath and 9.0 mL of 33% hydrogen bromide (HBr) in acetic acid was charged dropwise over several minutes upon which the ice bath was removed and the mixture allowed to warm to room temperature and stirred overnight under N2. An additional 1.0 mL of 33% HBr in acetic acid was added when VPC indicated that the reaction was not complete, and the mixture was stirred overnight at room temperature. The reaction was quenched by pouring into ethyl alcohol (85 mL) and heated at reflux until the reaction was complete (8 hours). The solvent was removed and the residue taken up in ethyl acetate (100 mL), washed with dilute aqueous sodium bicarbonate (NaHCO3) solution (25 mL), water (25 mL), and brine (25 mL). The organic layer was distilled and the residue purified by silica gel chromatography to yield 1.74 g (41.5%) of the title compound. To a 50 mL round bottom flask equipped with a magnetic stirring bar and nitrogen (N2) inlet The flask was cooled was removed An additional 1.0 mL of 33% HBr in acetic acid was added when VPC the mixture was stirred overnight at room temperature The reaction was quenched by pouring into ethyl alcohol (85 mL) heated at reflux until the reaction (8 hours) The solvent was removed washed with dilute aqueous sodium bicarbonate (NaHCO3) solution (25 mL), water (25 mL), and brine (25 mL) The organic layer was distilled the residue purified by silica gel chromatography

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

Procedure: To a 50 mL round bottom flask equipped with a magnetic stirring bar and nitrogen (N2) inlet was charged 2.13 g (S)-3-hydroxybutyrolactone (Example 2) (95.7% pure by VPC) and 5.0 mL acetic acid. The flask was cooled using an ice bath and 9.0 mL of 33% hydrogen bromide (HBr) in acetic acid was charged dropwise over several minutes upon which the ice bath was removed and the mixture allowed to warm to room temperature and stirred overnight under N2. An additional 1.0 mL of 33% HBr in acetic acid was added when VPC indicated that the reaction was not complete, and the mixture was stirred overnight at room temperature. The reaction was quenched by pouring into ethyl alcohol (85 mL) and heated at reflux until the reaction was complete (8 hours). The solvent was removed and the residue taken up in ethyl acetate (100 mL), washed with dilute aqueous sodium bicarbonate (NaHCO3) solution (25 mL), water (25 mL), and brine (25 mL). The organic layer was distilled and the residue purified by silica gel chromatography to yield 1.74 g (41.5%) of the title compound. To a 50 mL round bottom flask equipped with a magnetic stirring bar and nitrogen (N2) inlet The flask was cooled was removed An additional 1.0 mL of 33% HBr in acetic acid was added when VPC the mixture was stirred overnight at room temperature The reaction was quenched by pouring into ethyl alcohol (85 mL) heated at reflux until the reaction (8 hours) The solvent was removed washed with dilute aqueous sodium bicarbonate (NaHCO3) solution (25 mL), water (25 mL), and brine (25 mL) The organic layer was distilled the residue purified by silica gel chromatography

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

Procedure: Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-bromo-3-hydroxybutyrate (1%, w/v) was used as a reactant and novozyme 435 lipase was used as a biocatalyst. After reaction for 1 hour 40 minutes, ethyl (R)-4-bromo-3-hydroxybutyrate (99% e.e) was obtained at 88.3% conversion. After reaction for 1 hour 40 minutes

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

Procedure: To a 50 gallon reactor containing a solution of 2.2 kg (44 mol) of sodium cyanide dissolved in 40 L of demineralized water was added 7 kg (33 mol) of (S)-4-bromo-3-hydroxybutyric acid, ethyl ester (Example 3) dissolved in 8 L of ethanol. The reaction mixture was stirred for 16 hours at room temperature. Ethyl acetate (65 L) was added, the mixture agitated, and the layers were allowed to separate. The lower aqueous layer was transferred to a 50 gallon vessel containing 2.5 kg of sodium chloride and 65 L of ethyl acetate, the mixture was agitated and the layers allowed to separate, and the lower aqueous layer was cut off. The organic layers were combined and concentrated in vacuo. The residue was distilled to afford 3.1 kg of the title compound; bp 110-125° C. 0.5 mm Hg; optical rotation [α]D25 =33.1° (C=1.08, chloroform); the mixture agitated to separate The lower aqueous layer was transferred to a 50 gallon vessel containing 2.5 kg of sodium chloride and 65 L of ethyl acetate the mixture was agitated to separate concentrated in vacuo The residue was distilled

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

Procedure: To a 50 mL round bottom flask equipped with a magnetic stirring bar and nitrogen (N2) inlet was charged 2.13 g (S)-3-hydroxybutyrolactone (Example 2) (95.7% pure by VPC) and 5.0 mL acetic acid. The flask was cooled using an ice bath and 9.0 mL of 33% hydrogen bromide (HBr) in acetic acid was charged dropwise over several minutes upon which the ice bath was removed and the mixture allowed to warm to room temperature and stirred overnight under N2. An additional 1.0 mL of 33% HBr in acetic acid was added when VPC indicated that the reaction was not complete, and the mixture was stirred overnight at room temperature. The reaction was quenched by pouring into ethyl alcohol (85 mL) and heated at reflux until the reaction was complete (8 hours). The solvent was removed and the residue taken up in ethyl acetate (100 mL), washed with dilute aqueous sodium bicarbonate (NaHCO3) solution (25 mL), water (25 mL), and brine (25 mL). The organic layer was distilled and the residue purified by silica gel chromatography to yield 1.74 g (41.5%) of the title compound. To a 50 mL round bottom flask equipped with a magnetic stirring bar and nitrogen (N2) inlet The flask was cooled was removed An additional 1.0 mL of 33% HBr in acetic acid was added when VPC the mixture was stirred overnight at room temperature The reaction was quenched by pouring into ethyl alcohol (85 mL) heated at reflux until the reaction (8 hours) The solvent was removed washed with dilute aqueous sodium bicarbonate (NaHCO3) solution (25 mL), water (25 mL), and brine (25 mL) The organic layer was distilled the residue purified by silica gel chromatography