Acetic Acid → (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one

Temperature

80 °C

2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (68.9 g, 231 mmol) was charged to a suitably sized reactor, followed by acetonitrile (870 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate (V) (86.2 g, 347 mmol), sodium acetate (57.0 g, 695 mmol) and glacial acetic acid (6.90 g, 115 mmol). Molecular sieve 3 Å powder (75 g) was added to the reactor, and the slurry was heated to 80° C. and stirred for a minimum of 2 h. The mixture was cooled to 40° C. and sodium triacetoxyborohydride (59.0 g, 278 mmol) was added. After being stirred for 2 h, water (690 mL) and CELITE® (35 g) were slowly added and the mixture was heated to 50° C. and stirred for 1 h, filtered and rinsed with acetonitrile (210 mL). The filtrate was concentrated under reduced pressure to remove acetonitrile. Toluene (689 mL) was added and the pH was adjusted to 7.5-8.0 with 10% aqueous sodium carbonate solution. The organic phase was separated, extracted with a mixture of water and sulfuric acid. The aqueous phase was separated and toluene (483 mL) was added. The pH was adjusted to 7.5-8.0 with 10% aqueous sodium carbonate solution. The mixture was warmed to 20° C. and the organic phase was separated, concentrated under reduced pressure to remove acetonitrile, flushed with toluene and the resulting mixture was cooled to 0-5° C. n-Heptane (344 mL) was slowly added and the resulting slurry was filtered and rinsed a mixture of toluene and n-heptane. The cake was dried 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 (76.3 g, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 4.84 (d, J=6.80 Hz, 1H), 4.37-4.47 (m, 1H), 3.79-3.97 (m, 4H), 3.65-3.78 (m, 4H) 3.35-3.64 (m, 4H), 3.30 (s, 2H), 2.33-2.64 (m, 4H), 2.24 (s, 3H), 1.17 (d, J=6.80 Hz, 3H)

1. temperatureThe mixture was cooled to 40° C.
2. stirringAfter being stirred for 2 h
3. temperaturethe mixture was heated to 50° C.
4. stirringstirred for 1 h
5. filtrationfiltered
6. washrinsed with acetonitrile (210 mL)
7. concentrationThe filtrate was concentrated under reduced pressure
8. customto remove acetonitrile
9. additionToluene (689 mL) was added
10. customThe organic phase was separated
11. extractionextracted with a mixture of water and sulfuric acid
12. customThe aqueous phase was separated
13. additiontoluene (483 mL) was added
14. temperatureThe mixture was warmed to 20° C.
15. customthe organic phase was separated
16. concentrationconcentrated under reduced pressure
17. customto remove acetonitrile
18. customflushed with toluene
19. temperaturethe resulting mixture was cooled to 0-5° C. n-Heptane (344 mL)
20. additionwas slowly added
21. filtrationthe resulting slurry was filtered
22. washrinsed
23. additiona mixture of toluene and n-heptane
24. customThe cake was dried under reduced pressure

ORD record

ord-f291d3b4f4bb46d795a813c3ad290164

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08895729B2