反应详情

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-amide (31.1 g, 52.0 mmol) in DCM (500 mL) was treated with 37% aqueous formaldehyde solution (21.3 mL, 286.2 mmol). On complete addition the reaction was cooled in an ice bath before the addition of sodium triacetoxyborohydride (44.1 g, 208.2 mmol) portionwise. The reaction mixture was warmed to room temperature and stirred for 1.5 hours, after which, the reaction was filtered and the filtrate diluted with methanol. The mixture was diluted with methanol and loaded onto a pad of Isolute® SCX-2 which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The basic fractions were combined and evaporated. The resultant residue was purified by flash column chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM. Appropriate fractions were combined and evaporated. The resultant residue was recrystallized from ethyl acetate to afford the title compound as a pale brown solid (30.7 g, 96%). LCMS (Method 5) [M+H]+=612.2, RT=2.84 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=7.0, 1.6 Hz), 8.70-8.67 (m, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.63 (dd, 1H, J=8.8, 2.7 Hz), 7.56 (d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=7.0, 4.2 Hz), 7.26 (t, 1H, J=73.4 Hz), 5.22-5.24 (m, 2H), 4.38 (d, 1H, J=12.9 Hz), 3.96 (d, 1H, J=13.5 Hz), 3.06 (t, 1H, J=12.7 Hz), 2.62-2.65 (m, 6H), 2.22 (s, 3H), 1.72 (d, 2H, J=11.9 Hz), 1.34-1.40 (m, 2H).

1. additionOn complete addition the reaction
2. filtrationafter which, the reaction was filtered
3. additionthe filtrate diluted with methanol
4. additionThe mixture was diluted with methanol
5. customAfter flushing with MeOH
6. washthe product was eluted with 2M ammonia in MeOH
7. customevaporated
8. customThe resultant residue was purified by flash column chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM
9. customevaporated
10. customThe resultant residue was recrystallized from ethyl acetate