反应详情

A mixture of methyl 4-methyl-3-(2-methyl-4,6-dioxo-5,6-dihydropyrimidin-1(4H)-yl)benzoate (0.1 g, 0.00036 mol, from Step 2), K2CO3 (0.075 g, 0.00054 mol) and 2,4 difluorobenzylbromide (0.075 g, 0.00036 mol) in DMF (2.0 mL) containing 18-crown-6 (0.005 g) is stirred at room temperature for 1 h under argon atmosphere. DMF is distilled in vacuo and the residue is purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=401) are combined and concentrated to a small volume (˜20 mL). After cooling, 5% NaHCO3 solution (10 mL) is added and the solution is extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.12 g, 82%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.16 Hz), 7.55 (m, 2H), 7.00 (m, 2H), 5.79 (s, 1H), 5.38 (s, 2H), 3.89 (s, 3H), 2.14 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 401.1346 (M+H calcd for C21H19N2O4F2 requires 401.1307).

1. distillationDMF is distilled in vacuo
2. customthe residue is purified by reverse-phase
3. custom10-90% CH3CN/Water gradient (40 min)
4. concentrationconcentrated to a small volume (˜20 mL)
5. temperatureAfter cooling
6. addition5% NaHCO3 solution (10 mL) is added
7. extractionthe solution is extracted with dichloromethane (3×20 mL)
8. dry with materialThe combined organic extracts are dried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated to dryness