Dimethyl Sulfoxide → N-[(4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

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Reaction Steps

Triethylamine (75.9 mL, 545 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (19 g, 45 mmol) in dichloromethane (908 mL) in an ambient temperature water bath. After 5 minutes, dimethyl sulfoxide (45.2 mL, 636 mmol) was rapidly added, immediately followed by sulfur trioxide pyridine complex (98%, 59.0 g, 363 mmol) in a single portion. The resulting solution was stirred at room temperature for 4 hours, whereupon it was diluted with a 1:1 mixture of saturated aqueous sodium chloride solution and water, and stirred for 10 minutes. The aqueous layer was extracted twice with dichloromethane; the combined organic layers were washed with water until the pH of the aqueous extract was pH 6-7, then were washed twice with 0.2 N hydrochloric acid, and once with saturated aqueous sodium chloride solution. After being dried over sodium sulfate, the organic layer was filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a pale yellow solid. Yield: 13.27 g, 31.86 mmol, 71%. 1H NMR (400 MHz, CDCl3) δ 9.71 (br s, 1H), 8.16-8.24 (m, 2H), 7.50-7.56 (m, 1H), 7.36-7.48 (m, 3H), 6.87-6.98 (m, 2H), 4.23 (dd, J=12.2, 1.6 Hz, 1H), 4.09-4.15 (m, 1H), 3.94 (d, J=12.1 Hz, 1H), 3.13-3.22 (m, 1H), 3.04 (dd, J=13.1, 4.0 Hz, 1H), 2.69 (dd, J=13.0, 2.9 Hz, 1H), 2.02-2.15 (m, 1H), 1.92-1.99 (m, 1H).

Provenance & Evidence