反应详情

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).

1. stirringstirred for 10 minutes
2. extractionThe aqueous layer was extracted twice with dichloromethane
3. washthe combined organic layers were washed with water until the pH of the
4. extractionaqueous extract
5. washwere washed twice with 0.2 N hydrochloric acid
6. dry with materialAfter being dried over sodium sulfate
7. filtrationthe organic layer was filtered
8. concentrationconcentrated in vacuo