Acetyl bromide → 5-[(1S,6S)-4,4-Difluoro-7-oxabicyclo[4.1.0]hept-1-yl]-1-methyl-1H-pyrazole

A solution of the crude (1S,2R)-4,4-difluoro-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol prepared in Example 102a, trimethyl orthoacetate (1.60 mL, 12.6 mmol) and p-toluenesulfonic acid (48 mg, 0.25 mmol) in dichloromethane (25 mL) was stirred for 45 hours. The reaction solution was concentrated and diluted with acetonitrile (15 mL). Lithium bromide (220 mg, 2.53 mmol) and acetyl bromide (0.93 mL, 12.6 mmol) were added thereto with cooling on ice, and the reaction solution was stirred for 6 hours with cooling on ice. The reaction solution was concentrated and then diluted with methanol (20 mL). Potassium carbonate (1.75 g, 12.7 mmol) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (752 mg, 70%, 2 steps) as a colorless solid.

1. concentrationThe reaction solution was concentrated
2. additiondiluted with acetonitrile (15 mL)
3. temperaturewith cooling on ice
4. temperaturewith cooling on ice
5. concentrationThe reaction solution was concentrated
6. additiondiluted with methanol (20 mL)
7. stirringthe reaction solution was stirred at room temperature for 2 hours
8. extractionfollowed by extraction with ethyl acetate (100 mL)
9. dry with materialThe thus obtained organic layer was dried over anhydrous sodium sulfate
10. concentrationAfter vacuum concentration
11. customthe residue was purified with silica gel chromatography

ORD record

ord-c39fd0fdf55e4abf91baaadd830c11ae

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08889741B2