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

Temperature

0 °C

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).

1. temperatureunder cooling in an ice-salt bath
2. stirringThe obtained mixture was stirred for 2 hours (wherein the internal temperature
3. stirringwas then stirred at room temperature for 14 hours
4. temperatureThereafter, the reaction solution was cooled on ice
5. concentrationThe reaction solution was concentrated under reduced pressure
6. additionethanol (700 ml) and a 1 N potassium hydroxide aqueous solution (1000 ml) were added to the residue
7. temperatureThe obtained mixture was heated
8. temperatureto reflux for 5 hours
9. customwas returned to room temperature
10. addition5 N hydrochloric acid (400 ml) was then added to the solution
11. stirringThe obtained mixture was stirred at 60° C. for 1 hour
12. concentrationThereafter, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water
13. additionwere added to the
14. concentrationconcentrate
15. customliquid separation
16. washThe organic layer was successively washed with a saturated sodium bicarbonate aqueous solution
17. dry with materialThe resultant organic layer was dried over magnesium sulfate
18. concentrationthe solvent was then concentrated under reduced pressure
19. customThe residue was purified by silica gel column chromatography (n-heptane:ethyl acetate)

ORD record

ord-214ec1ce7c89499280f8fa84aa4f057a

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08268848B2