Sodium Hydroxide → Petesicatib

Participants

Reaction Conditions

Reaction Steps

(2S,4R)-4-[4-(1-Methyl-1H-pyrazol-4-yl)-2-trifluoromethyl-phenylsulfanyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (crude product, 97.6% purity, 64.0 g, 109 mmol) was dissolved in acetonitrile (480 mL) and magnesium monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) was added. The resulting white suspension was stirred for 5 h at 50° C. After that, a suspension of magnesium monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) in acetonitrile (150 mL) was added and the mixture was stirred for further 16 h at 50° C. After cooling to 20° C., water (480 mL) and a solution of sodium metabisulfite in water (40% w/w, 56.8 mL, 109 mmol) were added. The mixture was basified to pH 8 by addition of an aqueous sodium hydroxide solution (3 M, ca. 290 mL), extracted with dichloromethane (1 L), the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (1 L) and concentrated in vacuo. The residue was dissolved in dichloromethane (300 mL) and filtered to remove solid impurities. The solvent of the filtrate was exchanged to ethanol by continuous distillation while keeping the volume constant (ca. 750 mL ethanol used). The desired product started to crystallize. The resulting suspension was stirred for 12 h at 0° C., filtered, the precipitate was washed with cold ethanol (50 mL) and dried in vacuo at 45° C. to obtain the title compound as white crystals (50.0 g, 74.9%). MS (ESI & APCI): m/z=604.1 [M+H]+, 621.1 [M+NH4]+. 1H NMR (CDCl3, 600 MHz): δ 1.10-1.22 (m, 2H), 1.30-1.35 (m, 1H), 1.35-1.41 (m, 1H), 1.45-1.59 (m, 4H), 2.22-2.28 (m, 1H), 2.84 (ddd, J=5.9 Hz, 8.0 Hz, 14.3 Hz, 1H), 3.84 (dd, J=7.1 Hz, 13.2 Hz, 1H), 4.00 (s, 3H), 4.08-4.14 (m, 1H), 4.81 (d, J=13.3 Hz, 1H), 4.86 (dd, J=5.8 Hz, 8.6 Hz, 1H), 7.65 (bs, 1H), 7.80-7.83 (m, 2H), 7.89 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H).

Provenance & Evidence