反应详情

温度

57.5 °C

2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (15.0 g, 50 mmol) was charged to a suitably sized reactor, followed by methanol (306 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate V (18.8 g, 75 mmol), N-methyl morpholine (10.2 g, 100 mmol) and trimethylorthoformate (53.1 g, 500 mmol). The slurry was heated to 55-60° C. and stirred for 4 hrs. 5-Ethyl-2-methylpyridine borane (8.7 g, 60.0 mmol) were slowly added and the solution was stirred for 2 h. The reaction mixture was partially concentrated under reduced pressure. Me-THF (350 mL) was added and the reaction mixture was concentrated under reduced pressure to an end volume of 300 mL. The mixture was cooled to 5° C. 3.3% Sulfuric acid in water (401 g) was added and pH 1.6 was reached. The organic phase was removed. The pH of the aqueous phase was adjusted to 7.9 with 10% aqueous sodium carbonate solution (300 g) at 0-5° C. The mixture was warmed to 25° C. and the organic phase was separated. The organic phase was concentrated under reduced pressure to 75 mL. The solution was warmed to 35° C. and seeded with 41 mg (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II. The suspension was cooled to 0° C. and n-heptane (200 g) was added. The resulting slurry was aged at −5° C., filtered and washed with n-heptane. The cake was dried at 70° 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 (17.8 g, 81% yield)

1. stirringthe solution was stirred for 2 h
2. concentrationThe reaction mixture was partially concentrated under reduced pressure
3. additionMe-THF (350 mL) was added
4. concentrationthe reaction mixture was concentrated under reduced pressure to an end volume of 300 mL
5. temperatureThe mixture was cooled to 5° C
6. addition3.3% Sulfuric acid in water (401 g) was added
7. customThe organic phase was removed
8. customwas adjusted to 7.9 with 10% aqueous sodium carbonate solution (300 g) at 0-5° C
9. temperatureThe mixture was warmed to 25° C.
10. customthe organic phase was separated
11. concentrationThe organic phase was concentrated under reduced pressure to 75 mL
12. temperatureThe solution was warmed to 35° C.
13. temperatureThe suspension was cooled to 0° C.
14. additionn-heptane (200 g) was added
15. customwas aged at −5° C.
16. filtrationfiltered
17. washwashed with n-heptane
18. customThe cake was dried at 70° C. under reduced pressure