Pyridine → (R)-N-{2-Chloro-3-methylphenyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide

Participants

Reaction Steps

A solution of (S)-3,3,3-trifluoro-2-trimethylsilyoxy-2-methylpropanoyl chloride (prepared from (R)-(+)-2-Hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 3) as described in J Med. Chem., 1999, 42, 2741-2746)(17.4 g, 70 mmol) in DCM (50 ml) was added to a stirred mixture of 2-chloro-3-methyl-aniline (WO 9741846; 8.25 g, 141.6 mmol) and pyridine (7.1 ml, 87.5 mmol) in DCM (100 ml). The resultant mixture was stirred at ambient temperature for 24 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (150 ml), treated with 2 M hydrochloric acid (130 ml) and the mixture stirred at ambient temperature for 18 hour. The methanol was evaporated, the aqueous layer was extracted with EtOAc (2×75 ml), the EtOAc extracts were combined and washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with DCM as eluent to give the title compound as a solid (13.6 g, 48.4 mmol). NMR (CDCl3): 1.75 (s, 3H), 2.4 (s, 3H), 3.75 (s, 1H), 7.05 (d, 1H), 7.2 (dd, 1H), 8.2 (d, 1H), 8.85 (brs, 1H); m/z 280.

Provenance & Evidence