Sodium hydride → HCID 90087815, compound

A suspension of sodium hydride (0.298 g, 7.46 mmol) in THF (10 mL) was cooled to 0° C. tert-Butyl diethylphosphonoacetate (1.751 mL, 7.46 mmol) diluted with THF (10 mL) was added dropwise. The reaction mixture was removed from the cooling bath and stirred at room temperature for 30 min. The reaction mixture was then cooled to 0° C. and 4,4-difluorocyclohexanone (1 g, 7.46 mmol) diluted with THF (2 mL) was added. The reaction mixture was stirred at room temperature under nitrogen over night. The reaction was quenched with sat NH4Cl (50 mL). The aqueous phase was extracted with diethyl ether (3×25 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 50% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 40 g). Concentration of the appropriate fractions provided Intermediate S-3A (1.43 g, 83%). 1H NMR (400 MHz, chloroform-d) δ 5.68 (s, 1H), 3.02 (td, J=6.7, 0.9 Hz, 2H), 2.43-2.36 (m, 2H), 2.12-1.97 (m, 4H), 1.51 (s, 9H).

1. additionwas added dropwise
2. customThe reaction mixture was removed from the cooling bath
3. temperatureThe reaction mixture was then cooled to 0° C.
4. additionwas added
5. stirringThe reaction mixture was stirred at room temperature under nitrogen over night
6. customThe reaction was quenched with sat NH4Cl (50 mL)
7. extractionThe aqueous phase was extracted with diethyl ether (3×25 mL)
8. dry with materialThe combined organic layers were dried with Na2SO4
9. filtrationfiltered
10. concentrationconcentrated
11. customThe crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 50% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 40 g)
12. customConcentration of the appropriate fractions provided Intermediate S-3A (1.43 g, 83%)

ORD record

ord-93563212c45e48d8a0131f6db932b703

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09427442B2