(S)-3,3,3-trifluoro-2-trimethylsilyloxy-2-methylpropanoyl chloride → (R)-N-(3-Acetamido-2-Chloro-4-{4-fluorophenylsulphanyl}phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide

Participants

Reaction Steps

A solution of (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (1.179 g) in DCM (10 ml) was added dropwise to a stirred and ice-cooled suspension of 3-acetamido-2-chloro-4-(4-fluorophenylsulphanyl)aniline (Method 18) (1.315 g) in DCM (20 ml) and triethylamine (1.72 ml). The mixture was allowed to warm to ambient temperature overnight. More triethylamine (0.8 ml) followed by (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (0.6 g) in DCM (5 ml) was added. After a further 6 hours the mixture was concentrated by evaporation. MeOH (50 ml) and 2M aqueous HCl (5 ml) were added, the mixture was stirred overnight, and then diluted with water (20 ml). The MeOH was removed by evaporation and 2M aqueous HCl (30 ml) was added. The mixture was then extracted with ether (2×80 ml). The extracts were washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a Biotage cartridge (40 g silica), eluting with 50% EtOAc/isohexane to give the title compound (1.104 g) as a foam. NMR: 1.6 (s, 3H), 2.05 (s, 3H), 7.0 (d, 1H), 7.26 (t, 2H), 7.38-7.48 (m, 2H), 7.8-7.9 (m, 2H), 9.76 (brs, 1H), 9.9 (brs, 1H); m/z: 449.

Provenance & Evidence