反应详情

Conversion of rel-N-[(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C42) to the free base of the product was carried out via the method described for synthesis of (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (4) in Example 4. In this case, purification was effected using silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane), affording an oil. This was dissolved in dichloromethane and treated with a 1 M solution of hydrogen chloride in diethyl ether; removal of volatiles under reduced pressure provided the product as a solid. Yield: 8.6 mg, 21 μmol, 58%. LCMS m/z 369.2 [M+H+]. 1H NMR, free base of 5: (400 MHz, CDCl3) δ 7.33 (ddd, J=9.0, 9.0, 6.6 Hz, 1H), 6.74-6.87 (m, 2H), 4.03 (dd, J=10.9, 2.3 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.58-3.65 (m, 1H), 3.32-3.39 (m, 2H), 3.30 (s, 3H), 2.79-2.87 (m, 2H), 1.63-1.74 (m, 1H), 1.50-1.57 (m, 1H), 0.91-1.04 (m, 1H), 0.47-0.61 (m, 2H), 0.38-0.46 (m, 1H), 0.19-0.27 (m, 1H).

1. customIn this case, purification
2. customaffording an oil
3. customremoval of volatiles under reduced pressure