反应详情

温度

120 °C

5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-ol (62.2 g, 199 mmol), potassium carbonate (35.83 g, 259 mmol) and butyl acetate (435.4 mL) were charged to a 2 L multi-neck flask and stirred/heated to 42° C. p-Toluenesulfonyl chloride (41.83 g, 219 mmol) was then added in portions over 50 minutes, maintaining the temperature at ≦45° C. The reaction was stirred at this temp for 2.5 hours, at which point LCMS showed only the desired intermediate (MH+=467) present. Potassium carbonate (41.25 g, 299 mmol) and butyl acetate (186.6 mL) were then added and reaction heated to 120° C. Once at this temperature N-methylmethanesulfonamide (28.21 g, 259 mmol) was added over 30 mins. The reaction was held at this temperature for 18 hours, then butyl acetate (330 mL) and water (412 mL) were added, reducing the reaction temperature to 75° C. Stirring was continued at this temperature for 20 minutes, then the reaction mixture was transferred to a separating funnel, and allowed to stand for 10 mins to separate. The aqueous layer was separated off and re-extracted with butyl acetate (250 mL) by stirring at 60° C. for 15 mins. The organic layers were combined and 1 M aqueous NaOH (330 mL) added. This mixture was stirred at 60° C. for 20 minutes, then the lower aqueous phase separated off. The organic layer was concentrated in vacuo to 20% original volume, then allowed to cool and crystallize. The crude solid was isolated by filtration (50.5 g slightly damp), and this material recrystallized from methanol (500 mL), filtered and dried at 50° C. to constant weight to give the title compound (30.54 g, 38% yield) as a white crystalline solid.

1. additionwas then added in portions over 50 minutes
2. temperaturemaintaining the temperature at ≦45° C
3. customreaction
4. waitThe reaction was held at this temperature for 18 hours
5. customto 75° C
6. stirringStirring
7. waitwas continued at this temperature for 20 minutes
8. customthe reaction mixture was transferred to a separating funnel
9. waitto stand for 10 mins
10. customto separate
11. customThe aqueous layer was separated off
12. extractionre-extracted with butyl acetate (250 mL)
13. stirringby stirring at 60° C. for 15 mins
14. addition1 M aqueous NaOH (330 mL) added
15. stirringThis mixture was stirred at 60° C. for 20 minutes
16. customthe lower aqueous phase separated off
17. concentrationThe organic layer was concentrated in vacuo to 20% original volume
18. temperatureto cool
19. customcrystallize
20. customThe crude solid was isolated by filtration (50.5 g slightly damp), and this material
21. customrecrystallized from methanol (500 mL)
22. filtrationfiltered
23. customdried at 50° C. to constant weight