反应详情

温度

70 °C

Ammonium formate (99 g, 1568.94 mmol) was added to 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (81.2 g, 156.89 mmol) and 10% palladium on carbon (8.35 g, 7.84 mmol) in EtOH (810 mL) under nitrogen. The resulting mixture was stirred at 70° C. for 6 hours, then ammonium formate (50 g) was added. The mixture was stirred at 70° C. for 2 hours then further portions of 10% palladium on carbon (8.35 g, 7.84 mmol) and ammonium formate (50 g) were added and stirring continued at 70° C. for a further 10 hours. Ammonium formate (50 g) was added and the reaction mixture was stirred at 70° C. for 24 hours then cooled to room temperature. The catalyst was removed by filtration and the reaction charged with further 10% palladium on carbon (8.35 g, 7.84 mmol) and stirred at 70° C. for 16 hours. Further ammonium formate (50 g) was added and the stirring continued for 5 hours. The reaction mixture was cooled to room temperature and a further portion of 10% palladium on carbon (8.35 g, 7.84 mmol) was added. The mixture was heated to 70° C. for a 30 hours, cooled to room temperature and the catalyst removed by filtration and washed with EtOH. The solvent was evaporated and the residue dissolved in DCM (500 mL) and the solution washed with water (500 mL). The aqueous layer was re-extracted with DCM (500 mL), then EtOAc (500 mL×2). The combined extracts were dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford a gum, which was slurried with ether (300 mL) and re-evaporated. Methyl tert-butyl ether (250 mL) was added and the mixture was stirred vigorously for 3 days. The solid was collected by filtration and dried to afford 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (60.8 g, 75%) as a solid.

1. stirringThe mixture was stirred at 70° C. for 2 hours
2. stirringstirring
3. waitcontinued at 70° C. for a further 10 hours
4. stirringthe reaction mixture was stirred at 70° C. for 24 hours
5. temperaturethen cooled to room temperature
6. customThe catalyst was removed by filtration
7. stirringstirred at 70° C. for 16 hours
8. waitthe stirring continued for 5 hours
9. temperatureThe reaction mixture was cooled to room temperature
10. temperatureThe mixture was heated to 70° C. for a 30 hours
11. temperaturecooled to room temperature
12. customthe catalyst removed by filtration
13. washwashed with EtOH
14. customThe solvent was evaporated
15. dissolutionthe residue dissolved in DCM (500 mL)
16. washthe solution washed with water (500 mL)
17. extractionThe aqueous layer was re-extracted with DCM (500 mL)
18. dry with materialThe combined extracts were dried over MgSO4
19. filtrationfiltered
20. customevaporated
21. customto give crude product
22. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM
23. customPure fractions were evaporated to dryness
24. customto afford a gum, which
25. customre-evaporated
26. additionMethyl tert-butyl ether (250 mL) was added
27. stirringthe mixture was stirred vigorously for 3 days
28. filtrationThe solid was collected by filtration
29. customdried