反应详情

温度

78.5 °C

On a larger scale, 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (1700.1 g) was suspended in EtOH (20.4 L) in a 50 L vessel then K2CO3 (1948.7 g) and N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (1731.4 g) added. EtOH (6.8 L) and purified water (5.1 L) were added to the mixture followed by the addition chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (37.3 g). The mixture was heated to reflux (77-80° C.) and stirred for 30 mins at reflux then cooled to 20° C. prior to being distilled under reduced pressure to a volume of 12.6 L. The batch was then cooled to 15-25° C. and purified water (19.9 L) added. The batch was stirred for 1 h 5 mins, filtered and the filter cake washed with purified water (3×3.7 L) then dried under vacuum at 40° C. to afford crude desired material (1978 g, 91.3%). The reaction was repeated on a similar scale to deliver a further 2084 g of crude material. The purification of the crude 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (2066.9 g) was carried out in 6 portions of 350 g or less. Crude 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (350.1 g) was charged to a 10 L flask with EtOH (7.7 L) and heated until a solution was formed (68-73° C.). Activated charcoal (35 g) was added and the solution stirred at 70-75° C. for 1 h. The hot solution was filtered using a porosity 3 sinter funnel through a celite pad (˜40 g) in small portions to ensure the product stayed in solution. The celite pad was washed with hot EtOH (2 L) to remove any residual product, on the celite and the initial filtrate charged to the vessel and the wash filtrate was stored in a carboy. This process was repeated with the remaining portions of crude material. After completion of the 6 hot titrations carried out over 2 days the filtrate in the vessel was distilled under reduced pressure until the remaining filtrate (held in a carboy) could be added. The batch was then heated until a solution was formed (69° C.) and the distillation was then continued until the volume in the vessel was equal to 5 volumes of the input material (maximum distillation batch temperature=55° C.). The distillation was stopped and the batch cooled to 5-15° C., filtered, washed with EtOH (2.3 L) and dried to give the pure desired product (1926 g, 93.2% yield).

1. customEtOH (6.8 L) and purified water (5.1 L)
2. additionwere added to the mixture
3. additionfollowed by the addition chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (37.3 g)
4. temperatureThe mixture was heated
5. temperatureat reflux
6. temperaturethen cooled to 20° C.
7. distillationto being distilled under reduced pressure to a volume of 12.6 L
8. temperatureThe batch was then cooled to 15-25° C.
9. custompurified water (19.9 L)
10. additionadded
11. stirringThe batch was stirred for 1 h 5 mins
12. filtrationfiltered
13. washthe filter cake washed with purified water (3×3.7 L)
14. customthen dried under vacuum at 40° C.
15. customto afford crude desired material (1978 g, 91.3%)
16. customThe purification of the crude 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (2066.9 g)
17. additionCrude 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (350.1 g) was charged to a 10 L flask with EtOH (7.7 L)
18. temperatureheated until a solution
19. customwas formed (68-73° C.)
20. stirringthe solution stirred at 70-75° C. for 1 h
21. filtrationThe hot solution was filtered
22. washThe celite pad was washed with hot EtOH (2 L)
23. customto remove any residual product
24. additionon the celite and the initial filtrate charged to the vessel
25. waitAfter completion of the 6 hot titrations carried out over 2 days
26. distillationthe filtrate in the vessel was distilled under reduced pressure until the remaining filtrate (
27. additioncould be added
28. temperatureThe batch was then heated until a solution
29. customwas formed (69° C.)
30. distillationthe distillation
31. customwas equal to 5 volumes of the input material (maximum distillation batch temperature=55° C.)
32. distillationThe distillation
33. temperaturethe batch cooled to 5-15° C.
34. filtrationfiltered
35. washwashed with EtOH (2.3 L)
36. customdried