反应详情

温度

20 °C

Prepare an anhydrous HCl solution by slow addition of acetyl chloride (193.14 mL; 2.71 moles, 4.00 eq) to methanol (1160 mL) over 45 minutes at <5° C. Add the resulting solution to a separate flask containing a solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (290 g; 678.46 mmoles) in methanol (2320 mL) over 90 minutes at 20° C. Stir the reaction mixture at 20° C. overnight. Concentrate the reaction mixture under vacuum at 30° C. Add dimethyl sulfoxide (1080 mL; 15.20 moles; 1.08 L; 1.19 kg) and the distillation continues until the internal temperature reaches 50° C. at a pressure of 20 mm Hg. Add DMSO until the total volume is 2030 mL. Then add triethylamine (473 mL; 3.39 moles, 5 eq) via addition funnel over 30 minutes. Charge solid 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (110.29 g; 713.58 mmoles, 1.05 eq) in equal portions equally spaced over 30 minutes. Stir the resulting slurry at 20° C. overnight. Heat the slurry to 80° C. Add water (229 mL) to afford a clear solution. Seed the reaction and add more water (1273 mL) slowly over 4 hours to fully crystallize the product. Cool the slurry to 50° C. and filter the solid. Wash the cake with 30% water in DMSO (2×290 mL), then water (290 mL). Dry the solids under vacuum at 60° C. to afford 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (301 g, 99%) as an off white solid.

1. additionAdd the resulting solution to a separate flask
2. concentrationConcentrate the reaction mixture under vacuum at 30° C
3. customreaches 50° C. at a pressure of 20 mm Hg
4. waitequally spaced over 30 minutes
5. stirringStir the resulting slurry at 20° C. overnight
6. temperatureHeat the slurry to 80° C
7. customthe reaction
8. customto fully crystallize the product
9. temperatureCool the slurry to 50° C.
10. filtrationfilter the solid
11. washWash the cake with 30% water in DMSO (2×290 mL)
12. customDry the solids under vacuum at 60° C.