Acetyl chloride → 1-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

Participants

Reaction Steps

A 10-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate B) (85.95 mg, 0.131 mmol) and DMF (1.3 mL) to give a clear, light-yellow solution. Sodium hydride (60% in mineral oil) (7.88 mg, 0.197 mmol) was added, and the resulting mixture was stirred for 15 min. Acetic anhydride (24.77 μl, 0.263 mmol) was added dropwise to give a thick slurry. After 15 min of stirring, the mixture was diluted with water, EtOAc, and a small amount of brine. The layers were separated, and the aq. layer was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL) and treated dropwise with acetyl chloride (46.7 μl, 0.656 mmol) for 1.5 h. The reaction mixture was concentrated in vacuo, and the residue was suspended in DCM (2 mL) and triethylamine (0.5 mL). The resulting solution was again concentrated, and the crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (48.77 mg, 0.089 mmol, 68.0% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.82 (dd, J=0.5, 1.7 Hz, 1 H), 8.42 (s, 1 H), 8.06-7.97 (m, 1 H), 7.93-7.85 (m, 3 H), 7.60 (dd, J=1.8, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 7.33 (s, 1 H), 6.31 (d, J=1.9 Hz, 1 H), 3.43 (s, 3 H), 2.59 (s, 3 H). m/z (ESI) 547.2 (M+H)+.

Provenance & Evidence