反应详情

To a suspension of 3-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.15 g, 0.00039 mol, obtained from step 1) in dichloromethane (5.0 mL) and dioxane (1.0 mL) is added NBS (0.075 g, 0.00042 mol). The resulting reaction mixture is stirred at room temperature for 1 hour and then concentrated to dryness. The residue is dried in a desiccator for 1 hour, dissolved in dimethylacetamide (2.5 mL), isobutylchloroformate (0.075 mL, 0.00058 mol) is added, N-methylmorpholine (0.14 mL, 0.0013 mol) is then added, and the reaction mixture is stirred at 0° C. for 5 min under argon. After stirring the reaction mixture at room temperature for 30 min, it is cooled to 0° C., a solution of ammonia in isopropanol (1.2 mL of 2M ammonia in isopropanol) is 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=464) are combined and concentrated to a small volume (˜25 mL), cooled, 5% NaHCO3 solution (5.0 mL) is added and then the mixture is extracted with dichloromethane (2×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the desired product (0.115 g, 77%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.95 (m 1H), 7.12 (d, 1H J=1.6 Hz), 7.62 (m 1H), 7.61 (m, 1H), 7.01 (m, 2H), 5.58 (m, 2H), 2.16 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 464.0436 (M+H calcd for C20H17N3O3F2Br requires 464.0416). 19F NMR(CD3OD/400 MHz) −111.85(m) and −115.92 (m).

1. customThe resulting reaction mixture
2. concentrationconcentrated to dryness
3. customThe residue is dried in a desiccator for 1 hour
4. dissolutiondissolved in dimethylacetamide (2.5 mL)
5. stirringthe reaction mixture is stirred at 0° C. for 5 min under argon
6. stirringAfter stirring the reaction mixture at room temperature for 30 min
7. temperatureit is cooled 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. addition5% NaHCO3 solution (5.0 mL) is added
16. extractionthe mixture is extracted with dichloromethane (2×20 mL)
17. dry with materialThe combined organic extracts are dried (Na2SO4)
18. filtrationfiltered
19. concentrationconcentrated to dryness