Methyl Acetate → methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate

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Reaction Steps

A solution of diisopropylamine (6.52 g, 9.19 ml, 64.5 mmol) in tetrahydrofuran (115 ml) was treated dropwise at −70° C. with n-butylithium (1.6 M in hexane) (40.3 ml, 64.5 mmol) and stirring was continued for 15 minutes at −70° C. The solution was treated with methyl acetate (4.77 g, 5.13 ml, 64.5 mmol) and after 30 minutes chlorotitanium triisopropoxide (0.85 M in tetrahydrofuran) (85.7 ml, 72.85 mmol) was added dropwise After stirring at −70° C. for 30 min., the mixture was treated with a solution of (S,E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (intermediate A2.9) (8.2 g, 23.0 mmol) in tetrahydrofuran (76.4 ml) and stirring was continued at −70° C. for 2 hours. For the workup, the mixture was quenched with a saturated aqueous solution of ammonium chloride (100 ml), diluted with ethyl acetate (200 ml). After filtration over Dicalite®, the organic layer was separated and washed with water and brine. The aqueous layers were re-extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and evaporated to give a yellow oil (11.5 g; 116%). The residue was purified by chromatography on 50 g silica gel using a gradient of ethyl acetate/heptane=0:100 to 50:50 as the eluent to give a 1:1 diastereomeric mixture of methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (7 g, 16.3 mmol, 70.7% yield) as a colorless oil. MS (ISP): m/z=430.2 [M+H]+ and 432.1 [M+2+H]+.

Provenance & Evidence