Sodium borohydride → 3-Cyclopropyl-2,2-difluoropropan-1-ol

Temperature

5 °C

A solution of ethyl 3-cyclopropyl-2,2-difluoropropanoate (43.5 g, 0.244 mol), prepared as in Example 1, in absolute ethanol (100 mL) was added drop wise to a stirred slurry of sodium borohydride (9.45 g, 0.25 mol) in absolute ethanol (150 mL). The temperature of the mixture was allowed to rise to 35° C., whereupon cooling (ice/acetone bath) was applied and the temperature was maintained at 5° C. by controlling the rate of addition of the ester over 2 hours. The mixture then was stirred in an ice bath for 3 hours and then for 17 hours at room temperature. The reaction was quenched at 0° C. with 2M hydrochloric acid (180 mL) and the mixture was stirred for 30 minutes. The resulting homogenous mixture was poured into water (1000 mL) and extracted with diethyl ether (4×300 mL). The combined extracts were washed with 2M hydrochloric acid, water, 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure. Distillation of the residue under reduced pressure gave 3-cyclopropyl-2,2-difluoro-1-propanol (28.3 g, 85% over 2 steps), as a colorless oil, b.p. 48-50° C./5 mbar. 1H-NMR (400 MHz, CDCl3): δ=6:15-0.23 (m, 2H), 0.49-0.60 (m, 2H), 0.77-0.90 (m, 1H), 1.77 (bs, 1H), 1.80-1.90 (m, 2H), 3.83 (t, J=14 Hz, 2H); 1H-NMR (400 MHz, CD3SOCD3): δ=0.08-0.28 (m, 2H), 0.39-0.55 (m, 2H), 0.70-0.86 (m, 1H), 1.70-1.87 (m, 2H), 3.53-3.73 (m, 2H), 5.36 (t, J=4 Hz, 1H).

1. customto rise to 35° C.
2. waitfor 17 hours at room temperature
3. customThe reaction was quenched at 0° C. with 2M hydrochloric acid (180 mL)
4. stirringthe mixture was stirred for 30 minutes
5. additionThe resulting homogenous mixture was poured into water (1000 mL)
6. extractionextracted with diethyl ether (4×300 mL)
7. washThe combined extracts were washed with 2M hydrochloric acid, water, 10% aqueous sodium bicarbonate and brine
8. dry with materialdried over magnesium sulfate
9. filtrationfiltered
10. customThe solvent was removed from the filtrate under reduced pressure
11. distillationDistillation of the residue under reduced pressure

ORD record

ord-7e0331e08ae04cab91dd19c8d222645c

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08324417B2