反应详情

温度

110 °C

800 g of solid Compound VI (4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1) equipped with a temperature probe, mechanical stirrer and a dropping funnel. 1.5 liter (9.31 mol) Diethylaniline was charged over 30 min to 1 h keeping the temperature at or below 25° C. The internal temperature was brought up to 105-110° C. and 0.68 equiv. (868 ml, 34% of the total) of phosphorus oxychloride was added into the reactor (reactor 1) over 5-10 min. When the inside temperature began to decrease, the internal temperature was maintained at 110° C. and addition of the remaining POCl3 (1.32 equiv. or 66% of the total) resumed over a period of 30-40 min. The internal temperature was adjusted to 105-110° C. and the mixture was stirred for 18-24 h or until complete (HPLC analysis). The mixture was cooled to 45° C. and THF (400 mL) was charged at 45° C. The above crude mixture was placed into a secondary dry vessel or reactor (vessel or reactor 2). 4.8 l of water was charged into the reactor 1 and cooled to 5° C. The crude reaction mixture (in reactor or vessel 2) is then slowly charged into reactor 1 containing water keeping the temperature at 5-10° C. The mixture was stirred at 5° C. for 30 min to 1 h and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 l per rinse) and the cake was air dried in the funnel for 6-8 h to afford 964 g (92% w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) is charged into a 10 L reactor. Crude Compound VII and activated carbon (46.2 g) were charged into the reactor, the mixture is heated to 40° C. and stirred for 20 min. The resulting solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed with dichloromethane twice (175 ml per rinse). The solution was concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether. Additional petroleum ether (1.3 l) was charged into the reactor, the mixture was cooled to 10° C. and stirred for 1 hr. The resulting solid was collected by filtration and the cake was rinsed with petroleum ether twice (150 ml per rinse). The cake was air dried in the funnel (suction) until it appeared dry. The resulting solid Compound VII was transferred to a suitable tared container and dried in an oven at 50° C. for 6 hr to get final product: 1H NMR (400 MHz, DMSO-d6) • 3.45-3.56 (m, 4H); 13C NMR (400 MHz, DMSO-d6) • 29.3, 36.5, 134.8, 151.0, 154.1, 175.9.

1. customdry jacketed reactor (reactor 1)
2. customequipped with a temperature probe, mechanical stirrer and a dropping funnel
3. custombelow 25° C
4. customwas brought up to 105-110° C.
5. customwas adjusted to 105-110° C.
6. temperatureThe mixture was cooled to 45° C.
7. customThe above crude mixture was placed into a secondary dry vessel or reactor
8. temperaturecooled to 5° C
9. customThe crude reaction mixture (in reactor or vessel 2)
10. stirringThe mixture was stirred at 5° C. for 30 min to 1 h
11. filtrationthe resulting solid was collected by filtration
12. washThe cake was rinsed with water twice (1.6 l per rinse)
13. customdried in the funnel for 6-8 h
14. customto afford 964 g (92% w/w; 88% yield) of crude Compound VII
15. temperaturethe mixture is heated to 40° C.
16. stirringstirred for 20 min
17. filtrationThe resulting solution was collected by filtration through a filter media
18. customto remove charcoal
19. washThe cake was rinsed with dichloromethane twice (175 ml per rinse)
20. concentrationThe solution was concentrated under reduced pressure to a minimum stirrable volume
21. distillationthe remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether
22. additionAdditional petroleum ether (1.3 l) was charged into the reactor
23. temperaturethe mixture was cooled to 10° C.
24. stirringstirred for 1 hr
25. filtrationThe resulting solid was collected by filtration
26. washthe cake was rinsed with petroleum ether twice (150 ml per rinse)
27. customdried in the funnel (suction) until it
28. customappeared dry
29. customdried in an oven at 50° C. for 6 hr