反应详情

温度

26.5 °C

Charge 175 L of DMF and ethyl 2-(4,6-dichloropyrimidin-5-yl)acetate (25 kg) into a reactor at RT. Charge 17.55 Kg of DIPEA into the reactor over a period of 5-10 minutes while maintaining the temperature at 25-28° C. Cool the contents of the reactor to 10-15° C. and stir the reaction for 5-10 minutes. Charge 20.8 Kg of 2,4-Dimethoxybenzylamine into the reactor by while maintaining the temperature at 10-15° C. Heat the reaction slowly to a temperature of 60-65° C. and stir 3 hours. Cool the reaction slowly to 25-28° C. and add 250 L of water into the reactor while maintaining the temperature at 10-15° C. Stir the reaction mass for 10-15 minutes then heat the reaction to 25-28° C. Charge 125 L of DCM into the reaction, stir for 15 minutes and separate the layers. Wash the aqueous layer with 75 L of DCM. Wash the combined organic layers with 75 L of 1N HCl solution followed by water (100 L) and finally with 15% brine (100 L). Distill the organic layer under vacuum at 45-50° C. Charge 50 L of Hexane into the reaction at 45-50° C. and distill the reaction under vacuum at 45-50° C. (2×). Cool the reaction to 0-5° C. and stir for 30 minutes. Filter the resulting solid and wash the wet cake with 50 L of chilled n-Hexane (0-5° C.). Dry the resulting solids under vacuum at 40-45° C. Charge toluene (375 L) the dried solids and 1.025 Kg of para-Toluene to a reactor. Heat the reaction to 85-90° C. for 2 h. Cool the reaction to 80-85° C. and adjust the pH to 6.5-7.0 by adding 10% Sodium bicarbonate solution. Distill the reaction under vacuum at 45-50° C. Cool the contents of the reactor to 25-28° C., charge 3×L of Toluene into the reaction and heat to 85-90° C. Stir for 1 hour then cool the contents of the reactor to 25-28° C. Further cool to 0-5° C. and filter the solids. Wash the wet cake with 75 L of chilled Toluene (0-5° C.). Slurry the solids with 75 L of chilled water (0-5° C.) and filter. Wash the wet cake with 37.5 L of chilled water (0-5° C.) and dry the material under vacuum at 40-45° C. to afford 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (26.5 Kg, 73% yield, 98.89% purity by HPLC).

1. temperatureCool the contents of the reactor to 10-15° C.
2. customthe reaction for 5-10 minutes
3. temperaturewhile maintaining the temperature at 10-15° C
4. temperatureHeat
5. customthe reaction slowly to a temperature of 60-65° C.
6. stirringstir 3 hours
7. temperatureCool
8. customthe reaction slowly to 25-28° C.
9. temperaturewhile maintaining the temperature at 10-15° C
10. stirringStir the reaction mass for 10-15 minutes
11. temperaturethen heat
12. customthe reaction to 25-28° C
13. custominto the reaction
14. stirringstir for 15 minutes
15. customseparate the layers
16. washWash the aqueous layer with 75 L of DCM
17. washWash the combined organic layers with 75 L of 1N HCl solution
18. distillationDistill the organic layer under vacuum at 45-50° C
19. additionCharge 50 L of Hexane
20. custominto the reaction at 45-50° C.
21. distillationdistill
22. customthe reaction under vacuum at 45-50° C. (2×)
23. temperatureCool
24. customthe reaction to 0-5° C.
25. stirringstir for 30 minutes
26. filtrationFilter the resulting solid
27. washwash the wet cake with 50 L of chilled n-Hexane (0-5° C.)
28. customDry the resulting solids under vacuum at 40-45° C
29. temperatureHeat
30. customthe reaction to 85-90° C. for 2 h
31. temperatureCool
32. customthe reaction to 80-85° C.
33. distillationDistill
34. customthe reaction under vacuum at 45-50° C
35. temperatureCool the contents of the reactor to 25-28° C.
36. custominto the reaction
37. temperatureheat to 85-90° C
38. stirringStir for 1 hour
39. temperaturethen cool the contents of the reactor to 25-28° C
40. temperatureFurther cool to 0-5° C.
41. filtrationfilter the solids
42. washWash the wet cake with 75 L of chilled Toluene (0-5° C.)
43. customwith 75 L of chilled water (0-5° C.)
44. filtrationfilter
45. washWash the wet cake with 37.5 L of chilled water (0-5° C.)
46. customdry the material under vacuum at 40-45° C.