反应详情

温度

50 °C

Add a solution of 4-chloro-7-(4-methoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (18.11 g; 1.05 equiv; 62.52 mmol) in NMP (156.50 mL; 1.62 mol) at RT to 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (31.30 g; 1.00 equiv; 59.54 mmol) and DIPEA (51.92 mL; 297.71 mmol) and stir overnight at 50° C. Quench the reaction with water (900 mL) and EA (200 mL) and adjust the pH of the mixture to 1-2 with H3PO4 [85% aqueous (aq.)]. Stir for 15 min and separate the phases. Extract the organic phase with a H3PO4 solution (15% aq. 3×100 mL). Wash the combined aqueous phases with EA/tert-butylmethyl ether (tBuOMe) (4/1) (3×150 mL). Adjust the pH of the aqueous phase to 9 with solid K2CO3 and extract with EA (3×15 mL). Wash the combined organic phases with brine, decolor with charcoal, and filter over Celite®. Combine the filtrates and evaporate. Crystallize the residue from EA/tBuOMe to obtain the title compound (17.00 g; 26.66 mmol; 44.77% yield) as pale rose solid. 1H NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.91-7.83 (m, 2H), 7.43-7.40 (m, 2H), 7.17-7.11 (m, 2H), 6.86-6.81 (m, 2H), 4.87 (s, 2H), 4.56 (d, J=13.4 Hz, 2H), 4.13-4.07 (m, 2H), 3.77 (s, 3H), 3.63 (s, 2H), 3.40-3.36 (m, 2H), 3.21-3.05 (m, 3H), 2.74 (t, J=6.6 Hz, 2H), 2.40-2.35 (m, 6H), 2.09-1.99 (m, 2H).

1. customQuench
2. customthe reaction with water (900 mL) and EA (200 mL)
3. stirringStir for 15 min
4. customseparate the phases
5. extractionExtract the organic phase with a H3PO4 solution (15% aq. 3×100 mL)
6. washWash the combined aqueous phases with EA/tert-butylmethyl ether (tBuOMe) (4/1) (3×150 mL)
7. extractionextract with EA (3×15 mL)
8. washWash the combined organic phases with brine, decolor with charcoal
9. filtrationfilter over Celite®
10. customCombine the filtrates and evaporate
11. customCrystallize the residue from EA/tBuOMe