反应详情

Tetrapropylammonium perruthenate (1.09 g, 3.10 mmol) was added to a mixture 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) (13.0 g, 31.1 mmol) and 4-methylmorpholine N-oxide monohydrate (25.2 g, 186 mmol) in acetonitrile (207 mL), and the reaction mixture was stirred for 90 minutes at room temperature. After addition of 2-propanol (100 mL), it was stirred for an additional 2 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was extracted twice with 0.5 M aqueous sodium hydroxide solution, and the combined aqueous layers were acidified to a pH of approximately 1 with 2 M aqueous hydrochloric acid, then extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure; the residue was dissolved in dichloromethane, washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Gradient: 0% to 20% methanol in dichloromethane) provided the product as a reddish solid. Yield: 12.36 g, 28.58 mmol, 92%. LCMS m/z 433.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.09-8.13 (m, 2H), 7.52-7.57 (m, 1H), 7.43-7.51 (m, 3H), 7.03-7.11 (m, 2H), 4.35 (dd, J=11.2, 3.4 Hz, 1H), 4.19 (dd, J=12.0, 1.4 Hz, 1H), 3.97 (d, J=12.1 Hz, 1H), 3.20-3.27 (m, 1H), 2.96 (dd, half of ABX pattern, J=13.1, 4.0 Hz, 1H), 2.78 (dd, half of ABX pattern, J=13.2, 2.8 Hz, 1H), 2.03-2.15 (m, 2H).

1. stirringwas stirred for an additional 2 hours
2. concentrationconcentrated in vacuo
3. customThe residue was partitioned between ethyl acetate and 0.5 M aqueous sodium hydroxide solution
4. extractionThe organic layer was extracted twice with 0.5 M aqueous sodium hydroxide solution
5. extractionextracted three times with ethyl acetate
6. dry with materialThe combined ethyl acetate layers were dried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. dissolutionthe residue was dissolved in dichloromethane
10. washwashed with water and with saturated aqueous sodium chloride solution
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customPurification via chromatography on silica gel (Gradient: 0% to 20% methanol in dichloromethane)