Acetonitrile → 3-(3,5-Difluorophenyl)-3-oxopropanenitrile

Temperature

-20 °C

Diisopropylamine (10.6 mL, 76 mmol) was dissolved in dry THF (10 mL) and the solution cooled to −20° C. A solution of n-butyllithium (2.5N in hexanes, 30.5 mL, 76 mmol) was added slowly at such a rate as to keep the internal temperature below 0° C. After stirring for 5 min, the solution was cooled to −20° C. and added to a solution of acetonitrile (2.37 mL, 45.3 mmol) and ethyl 3,5-difluorobenzoate (6.23 g, 36.2 mmol) in dry THF (18 mL) at such a rate as to keep the temperature below −40° C. A further 10 mL of dry THF was used to transfer the remaining lithium diisopropylamide to the reaction. The reaction was allowed to warm to ambient over 2 h before being quenched with saturated aqueous ammonium chloride solution. The reaction was extracted with ethyl acetate (×2) and the extracts discarded. The aqueous was acidified with 2N HCl and extracted with ethyl acetate. The organic extract was washed with 2N HCl and brine before being dried over MgSO4, filtered and evaporated. Purification using chromatography (silica gel, gradient 5 to 100% ethyl acetate/isohexane) gave 3-(3,5-difluorophenyl)-3-oxopropanenitrile as a yellow solid (2.82 g).

1. customthe internal temperature below 0° C
2. temperaturethe solution was cooled to −20° C.
3. customthe temperature below −40° C
4. customto the reaction
5. temperatureto warm
6. waitto ambient over 2 h
7. custombefore being quenched with saturated aqueous ammonium chloride solution
8. extractionThe reaction was extracted with ethyl acetate (×2)
9. extractionextracted with ethyl acetate
10. extractionThe organic extract
11. washwas washed with 2N HCl and brine
12. dry with materialbefore being dried over MgSO4
13. filtrationfiltered
14. customevaporated
15. customPurification

ORD record

ord-ab1f577d4a4b42c4a419e91170a0094c

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09260381B2