Ethyl Acetate → (R)-3-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-5-methoxy-3-((S)-2-methyl-propane-2-sulfinylamino)-pentanoic acid ethyl ester

Participants

Reaction Steps

To a suspension of zinc (3.07 g, 47 mmol) and copper(I) chloride (233 mg, 2.349 mmol) in dry THF (90 ml) were added 4 drops of trimethylchlorosilane under nitrogen to activate the zinc. After 10 minutes ethyl 2-bromo-2,2-difluoroacetate (9.54 g, 47 mmol) was added slowly by syringe over a period of 20 minutes between 25° and 30° C. adjusted with an external cooling bath (exothermic). The reaction mixture was kept in an ultrasound bath for 30 minutes. This black fine suspension was added drop wise to a solution of (S)-2-methyl-propane-2-sulfinic acid [1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3-methoxy-prop-(E)-ylidene]-amide (7.51 g, 15.66 mmol) in dry THF (75 ml) at 0° C. under inert atmosphere. After 15 min the reaction mixture was kept at 50° C. for 2 h and was then added to a cold aq. ammonium chloride solution (5%). Ethyl acetate was added and the organic phase was washed with aq. citric acid (5% solution), water, sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude yellowish oil (9.77 g, roughly a 4:1 mixture of diastereoisomers) was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl acetate 85:15) to give the title compound as a yellow oil. 6.11 g yellow oil. (64.6% yield).

Provenance & Evidence