Acetonitrile → 3-(2,2-Difluorocyclopropyl)-3-oxopropanenitrile

Temperature

-78 °C

To a solution of MeCN (1.1 g, 16.8 mmol) in THF (60 mL) was added dropwise n-BuLi in THF (11.2 mL, 40.3 mmol) at −78° C., and the reaction mixture was stirred at −78° C. under N2 for 30 min. Butyl 2,2-difluorocyclopropanecarboxylate (3.0 g, 16.8 mmol) was added at −78° C., and the reaction mixture was allowed to warm to RT over 3 h. The reaction mixture was quenched with water and adjusted to pH 7 with 1N HCl. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile. A mixture of crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile and hydrazine (2.0 g, 50.4 mmol, 85% pure) in EtOH (30 mL) was stirred at reflux for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by chromatography eluting with an EtOAc/petroleum ether gradient (12.5 to 100% EtOAc) to afford 2.1 g (78.5%) of 45 as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 11.40 (br s, 1H), 5.26 (s, 1H), 4.80 (br s, 2H), 2.78-2.66 (m, 1H), 2.04-1.75 (m, 1H), 1.73-1.21 (m, 1H); MS (ESI+) m/z=160.1 [M+1]+.

1. temperatureto warm to RT over 3 h
2. customThe reaction mixture was quenched with water
3. extractionThe mixture was extracted with EtOAc
4. washthe organic layer was washed with brine
5. dry with materialdried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated in vacuo

ORD record

ord-8cefc6f334a5496d8ad1e607f0dad3be

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08637537B2