(1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one

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

Procedure: 3-Fluoro phenyl acetonitrile (70 g) was dissolved in THF (500 ml), and NaHMDS (1000 ml, 1.06 M) was then added dropwise to the solution under cooling in an ice-salt bath. The obtained mixture was stirred for 1 hour, and R-(−)-epichlorohydrin (40.6 ml) was then added dropwise to the reaction solution (approximately 10 minutes, internal temperature<10° C.). The obtained mixture was stirred for 2 hours (wherein the internal temperature was maintained around 0° C.), and it was then stirred at room temperature for 14 hours. Thereafter, the reaction solution was cooled on ice, and a small amount of water was added dropwise thereto. The reaction solution was concentrated under reduced pressure, and thereafter, ethanol (700 ml) and a 1 N potassium hydroxide aqueous solution (1000 ml) were added to the residue. The obtained mixture was heated to reflux for 5 hours. Thereafter, the temperature of the reaction solution was returned to room temperature, and 5 N hydrochloric acid (400 ml) was then added to the solution. The obtained mixture was stirred at 60° C. for 1 hour. Thereafter, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrate to carry out liquid separation. The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The resultant organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (84.9 g). under cooling in an ice-salt bath The obtained mixture was stirred for 2 hours (wherein the internal temperature was then stirred at room temperature for 14 hours Thereafter, the reaction solution was cooled on ice The reaction solution was concentrated under reduced pressure ethanol (700 ml) and a 1 N potassium hydroxide aqueous solution (1000 ml) were added to the residue The obtained mixture was heated to reflux for 5 hours was returned to room temperature 5 N hydrochloric acid (400 ml) was then added to the solution The obtained mixture was stirred at 60° C. for 1 hour Thereafter, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrate liquid separation The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution The resultant organic layer was dried over magnesium sulfate the solvent was then concentrated under reduced pressure The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate)

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

Procedure: 3-Fluoro phenyl acetonitrile (70 g) was dissolved in THF (500 ml), and NaHMDS (1000 ml, 1.06 M) was then added dropwise to the solution under cooling in an ice-salt bath. The obtained mixture was stirred for 1 hour, and R-(−)-epichlorohydrin (40.6 ml) was then added dropwise to the reaction solution (approximately 10 minutes, internal temperature<10° C.). The obtained mixture was stirred for 2 hours (wherein the internal temperature was maintained around 0° C.), and it was then stirred at room temperature for 14 hours. Thereafter, the reaction solution was cooled on ice, and a small amount of water was added dropwise thereto. The reaction solution was concentrated under reduced pressure, and thereafter, ethanol (700 ml) and a 1 N potassium hydroxide aqueous solution (1000 ml) were added to the residue. The obtained mixture was heated to reflux for 5 hours. Thereafter, the temperature of the reaction solution was returned to room temperature, and 5 N hydrochloric acid (400 ml) was then added to the solution. The obtained mixture was stirred at 60° C. for 1 hour. Thereafter, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrate to carry out liquid separation. The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The resultant organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (84.9 g). under cooling in an ice-salt bath The obtained mixture was stirred for 2 hours (wherein the internal temperature was then stirred at room temperature for 14 hours Thereafter, the reaction solution was cooled on ice The reaction solution was concentrated under reduced pressure ethanol (700 ml) and a 1 N potassium hydroxide aqueous solution (1000 ml) were added to the residue The obtained mixture was heated to reflux for 5 hours was returned to room temperature 5 N hydrochloric acid (400 ml) was then added to the solution The obtained mixture was stirred at 60° C. for 1 hour Thereafter, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrate liquid separation The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution The resultant organic layer was dried over magnesium sulfate the solvent was then concentrated under reduced pressure The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate)

Conditions: temp:-7.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (4, 10.08 g, 0.052 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (75.60 mL) under nitrogen. The solution was cooled to −5 to −10° C., and 2.0 M Lithium tetrahydroborate in THF (39.34 mL, 0.079 mol, 1.5 equiv.) was added to the reaction mixture while maintaining the internal temperature below 0° C. The reaction was stirred at 20-25° C. for 14-16 hours and monitored by HPLC and TLC (EtOAc/Heptane=1/1). Once the reaction was completed, the reaction mixture was cooled to 0-5° C. and reverse quenched into a pre-cooled (0-5° C.) 20% aqueous citric acid solution (50.40 mL, 1.67 equiv.) at such a rate as to maintain the internal temperature below 5° C. Once the quench was complete, the reaction mixture was warmed to 20-25° C. and stirred for at least 20 min. The aqueous layer was back extracted once with 2-methyl-THF (50.40 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol; 5 (10.29 g). while maintaining the internal temperature below 0° C the reaction mixture was cooled to 0-5° C. reverse quenched into to maintain the internal temperature below 5° C the reaction mixture was warmed to 20-25° C. stirred for at least 20 min The aqueous layer was back extracted once with 2-methyl-THF (50.40 mL) washed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL) The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF