反应详情

温度

-3 °C

2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (3598 g, 11.89 mol) was dissolved in NMP (11.108 kg) and cooled to about −3° C. A 1 M solution of NaHMDS (11.919 kg, 1.1 eq.) was added over a period of 80 minutes maintaining the temperature below 4° C. Iodomethane (1.858 kg) was added over a period of 10 minutes maintaining the temperature below 35° C. The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred for 3 hours. A 1 M solution of NaHMDS (1.2 kg) was added at 23° C. followed by iodomethane (0.188 kg). The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred overnight. The temperature was adjusted to 10° C., concentrated aqueous hydrochloric acid (6.42 L), the THF was removed by distillation at reduced pressure, the temperature was adjusted to 20° C., and water (53.3 kg) was slowly added over about 60 minutes maintaining the temperature at about 23 to 25° C. The temperature was adjusted to about 10° followed by stirring overnight. The reaction mixture was filtered, the filter cake was washed with isopropyl alcohol/water (1:1, 2×2 L), and dried in by a stream of nitrogen. The filter cake was dissolved in isopropyl alcohol (4.17 kg) at 76° C., water (20.70 kg) was slowly added over about 85 minutes maintaining the temperature at about 73 to 76° C., after 20 minutes cooled to about 11° over about 3 hours and stir overnight. Collect the solid by filtration, rinse with isopropyl alcohol/water (1:1, 2×1.7 L), and dry under a stream of nitrogen, followed by drying in an oven for 4 days to give 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.

1. temperaturemaintaining the temperature below 4° C
2. temperaturemaintaining the temperature below 35° C
3. washThe addition funnel was washed with THF
4. customwas adjusted to 20 to 25° C.
5. additionA 1 M solution of NaHMDS (1.2 kg) was added at 23° C.
6. washThe addition funnel was washed with THF
7. customwas adjusted to 20 to 25° C.
8. stirringthe reaction mixture was stirred overnight
9. customwas adjusted to 10° C.
10. customconcentrated aqueous hydrochloric acid (6.42 L), the THF was removed by distillation at reduced pressure
11. customwas adjusted to 20° C.
12. additionwater (53.3 kg) was slowly added over about 60 minutes
13. temperaturemaintaining the temperature at about 23 to 25° C
14. customwas adjusted to about 10°
15. stirringby stirring overnight
16. filtrationThe reaction mixture was filtered
17. washthe filter cake was washed with isopropyl alcohol/water (1:1, 2×2 L)
18. customdried in by a stream of nitrogen
19. dissolutionThe filter cake was dissolved in isopropyl alcohol (4.17 kg) at 76° C.
20. additionwater (20.70 kg) was slowly added over about 85 minutes
21. temperaturemaintaining the temperature at about 73 to 76° C.
22. temperatureafter 20 minutes cooled to about 11° over about 3 hours
23. stirringstir overnight
24. customCollect the solid
25. filtrationby filtration
26. washrinse with isopropyl alcohol/water (1:1, 2×1.7 L)
27. customdry under a stream of nitrogen
28. customby drying in an oven for 4 days