反应详情

To a suspension of 4-{[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]methyl}benzoic acid (0.18 g, 0.00047 mol, from step 4) in dichloromethane (3.0 mL) and dioxane (1.0 mL) is added NBS (0.09 g, 0.0005 mol). The resulting reaction mixture is stirred at room temperature for 3 hours, concentrated to dryness, and the residue is then dried in a desiccator for 2 h. This residue is dissolved in dimethylacetamide (2.5 mL), isobutylchloroformate (0.08 mL, 0.00062 mol) is added, N-methylmorpholine (0.0.08 mL, 0.00073 mol) is then added, and the reaction mixture is stirred at 0° C. for 5 min under argon. The reaction mixture is then stirred at room temperature for 30 min, it is recooled to 0° C., a solution of N-methylamine in THF (1.1 mL of 2M in THF) is then added, and the resulting reaction mixture is stirred at 0° C. for 30 min. The resulting mixture is concentrated to dryness under reduced pressure 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=478) are combined and concentrated to a small volume (˜25 mL), cooled added 5% NaHCO3 solution (5.0 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts are dried (Na2SO4), filtered and concentrated to dryness to afford the title compound (0.14 g, 64%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.77 (d 2H, J=8.4 Hz), 7.58 (m, 1H), 7.26 (d, 2H, J=8.4 Hz), 7.01 (m, 2H), 5.49 (s, 2H), 5.42 (s, 2H), 2.89 (s, 3H), and 2.48 (s, 3H); ES-HRMS m/z 478.0596 (M+H calcd for C21H19N3O3F2Br requires 478.0572). 19F NMR(CD3OD/400 MHz) −111.99 (m) and −115.99 (m).

1. customThe resulting reaction mixture
2. concentrationconcentrated to dryness
3. customthe residue is then dried in a desiccator for 2 h
4. dissolutionThis residue is dissolved in dimethylacetamide (2.5 mL)
5. stirringthe reaction mixture is stirred at 0° C. for 5 min under argon
6. stirringThe reaction mixture is then stirred at room temperature for 30 min
7. customis recooled to 0° C.
8. customthe resulting reaction mixture
9. stirringis stirred at 0° C. for 30 min
10. concentrationThe resulting mixture is concentrated to dryness under reduced pressure
11. customthe residue is purified by reverse-phase
12. custom10–90% CH3CN/Water gradient (40 min)
13. concentrationconcentrated to a small volume (˜25 mL)
14. temperaturecooled
15. additionadded 5% NaHCO3 solution (5.0 mL)
16. extractionextracted with dichloromethane (2×20 mL)
17. dry with materialThe combined organic extracts are dried (Na2SO4)
18. filtrationfiltered
19. concentrationconcentrated to dryness