反应详情

温度

57.5 °C

2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (14.9 g, 50.0 mmol.) was charged to a suitably sized reactor, followed by methanol (298 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate V (18.6 g, 74.9 mmol), sodium acetate (12.3 g, 150 mmol), glacial acetic acid (3.0 g, 50.0 mmol) and trimethylorthoformate (53.1 g, 500 mmol). The slurry was heated to 55-60° C. and stirred for 4 hr. A 30% solution of 2-picoline-borane in THF (21.4 g, 60.0 mmol) was slowly added and the slurry was stirred for 1-2 h. The reaction mixture was partially concentrated under reduced pressure. Toluene (230 mL) was added and the reaction mixture was concentrated under reduced pressure. Toluene (114 mL) was added and the reaction mixture was again partially concentrated under reduced pressure. To the residue was added toluene (218 mL) and the mixture was cooled to 20-30° C. Water (431 mL) was added and the pH was adjusted to 7.5-8.5 with 10% aqueous sodium carbonate solution (162 mL). The organic phase was separated, cooled to 0-5° C. and extracted with a mixture of water (180 mL) and 96% sulfuric acid (6.1 g). The aqueous phase was separated and toluene (118 mL) was added. The pH was adjusted to 7.5-8.5 with 10% aqueous sodium carbonate solution (110 mL) at 0-5° C. The mixture was warmed to 20° C. and the organic phase was separated. The organic phase was diluted with toluene (100 mL) and concentrated under reduced pressure to its original volume (approximately 150 mL). The solution was warmed to 53-57° C., and n-heptane (26 mL) was added. The solution was seeded with (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II and the suspension was stirred at 53-57° C. for 30 min. Heptane (82 mL) was slowly added and the resulting slurry was cooled to 0-5° C., filtered and washed with a mixture of toluene and n-heptane and subsequently with n-heptane. The cake was dried at 30-45° C. under reduced pressure to afford (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (18.6 g, 84% yield)

1. stirringthe slurry was stirred for 1-2 h
2. concentrationThe reaction mixture was partially concentrated under reduced pressure
3. additionToluene (230 mL) was added
4. concentrationthe reaction mixture was concentrated under reduced pressure
5. additionToluene (114 mL) was added
6. concentrationthe reaction mixture was again partially concentrated under reduced pressure
7. additionTo the residue was added toluene (218 mL)
8. temperaturethe mixture was cooled to 20-30° C
9. additionWater (431 mL) was added
10. customThe organic phase was separated
11. temperaturecooled to 0-5° C.
12. extractionextracted with a mixture of water (180 mL) and 96% sulfuric acid (6.1 g)
13. customThe aqueous phase was separated
14. additiontoluene (118 mL) was added
15. customwas adjusted to 7.5-8.5 with 10% aqueous sodium carbonate solution (110 mL) at 0-5° C
16. temperatureThe mixture was warmed to 20° C.
17. customthe organic phase was separated
18. additionThe organic phase was diluted with toluene (100 mL)
19. concentrationconcentrated under reduced pressure to its original volume (approximately 150 mL)
20. temperatureThe solution was warmed to 53-57° C.
21. additionn-heptane (26 mL) was added
22. stirringthe suspension was stirred at 53-57° C. for 30 min
23. additionHeptane (82 mL) was slowly added
24. temperaturethe resulting slurry was cooled to 0-5° C.
25. filtrationfiltered
26. washwashed with a mixture of toluene and n-heptane and subsequently with n-heptane
27. customThe cake was dried at 30-45° C. under reduced pressure