Tetrahydrofuran → 1-(4-Chloro-3-fluorophenyl)cyclobutanol

Temperature

-78 °C

To a cold (−78° C.) solution of 4-bromo-1-chloro-2-fluorobenzene (2.99 g, 14.27 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (5.71 mL, 14.27 mmol, 2.5 m in hexane) over 5 minutes. The reaction was stirred at −78° C. for 15 min, and cybutanone (1.0 g, 14.27 mmol) was added dropwise. After 15 minutes, the reaction mixture was quenched by the addition of saturated aqueous of NH4Cl (50 mL) and diethyl ether (50 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (2×50 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid Chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) to provide the title compound as a solid. MS (ESI) m/z 201[M+H]+.

1. additioncybutanone (1.0 g, 14.27 mmol) was added dropwise
2. waitAfter 15 minutes
3. customthe reaction mixture was quenched by the addition of saturated aqueous of NH4Cl (50 mL) and diethyl ether (50 mL)
4. customThe layers were separated
5. extractionthe aqueous was extracted with additional diethyl ether (2×50 mL)
6. dry with materialThe combined organic layers were dried with anhydrous Na2SO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid Chromatography)
10. customanalyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min)

ORD record

ord-f24799ce21ab4b5a8e8beb18f24652f3

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08242139B2