Ammonium Chloride → 2-Bromo-1-(4,4-difluorocyclohexyl)-4,4-dimethylpentan-3-one

3-(4,4-Difluorocyclohexyl)propionic acid (330 mg, 1.72 mmol) obtained in step 3 was dissolved in thionyl chloride (3.0 mL), and the solution was stirred for 4 hours under heat and reflux. The solvent was then evaporated under reduced pressure. The residue was dissolved in THF (3.3 mL) under ice-cooled condition, and the mixture was stirred at room temperature for 30 minutes after adding copper chloride(I) (8.5 mg, 0.086 mmol) and tert-butyl magnesium chloride (2 mol/L-THF solution) (1.03 mL, 2.06 mmol). Under ice-cooled condition, a saturated ammonium chloride aqueous solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was dissolved in ethanol (4.0 mL), and the solution was stirred for 2 hours under heat and reflux after adding tetra-n-butylammonium tribromide (910 mg, 1.89 mmol). Under ice-cooled condition, a saturated sodium hydrogen carbonate aqueous solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3→90/10) to give 2-bromo-1-(4,4-difluorocyclohexyl)-4,4-dimethylpentan-3-one (433 mg, yield 81%).

1. temperatureunder heat
2. temperaturereflux
3. customThe solvent was then evaporated under reduced pressure
4. dissolutionThe residue was dissolved in THF (3.3 mL) under ice-
5. temperaturecooled condition
6. stirringthe mixture was stirred at room temperature for 30 minutes
7. temperatureUnder ice-cooled condition
8. extractionthe reaction mixture was extracted with ethyl acetate
9. washThe organic layer was washed with saturated brine
10. dry with materialdried over anhydrous magnesium sulfate
11. customThe solvent was then evaporated under reduced pressure
12. dissolutionThe residue was dissolved in ethanol (4.0 mL)
13. stirringthe solution was stirred for 2 hours
14. temperatureunder heat
15. temperaturereflux
16. temperatureUnder ice-cooled condition
17. extractionthe reaction mixture was extracted with ethyl acetate
18. washThe organic layer was washed with saturated brine
19. dry with materialdried over anhydrous magnesium sulfate
20. customThe solvent was then evaporated under reduced pressure
21. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3→90/10)

ORD record

ord-049a89fdb03c4cddb9298a90f871a627

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09000186B2