4-Methoxybenzenesulfonyl chloride → N-[(1S)-1-(2',4-difluoro-1,1'-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide

Participants

Reaction Steps

A stirred suspension of (1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethanaminium (4R)-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphinan-2-olate 2-oxide (2.53 g, 5.0 mmol) in acetonitrile (50 mL) was treated sequentially with triethylamine (1.39 mL, 10 mmol) and 4-methoxybenzenesulfonyl chloride (1.04 g, 5.05 mmol). The progress of the reaction was monitored by LCMS. After eight hours, approximately 5% of the starting amine was still present. An additional aliquot of 4-methoxybenzenesulfonyl chloride (52 mg, 0.25 mmol, 5 mole %) was added, and the reaction was stirred at ambient temperature for an additional 16 hours. Monitoring by LCMS indicated complete formation of a single product. The solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with a 5% aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with a 2 N hydrochloric acid solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a residue. The residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butylether in hexane, to afford N-[(1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (1.8 g, 89%, 99.2% ee), m.p. 133-135° C.;

Provenance & Evidence