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

Participants

Reaction Conditions

Reaction Steps

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)

Provenance & Evidence