反应详情

温度

80 °C

To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.1 eq) and 2-iodopropane (34 mg, 0.200 mmol, 1.4 eq). The vial was capped and purged with nitrogen gas, and the reaction was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progressed only 15%. To the reaction mixture was added another equivalent of 2-iodopropane and the solution was irradiated in the microwave at 160° C. for 30 min. Analysis by LC/MS displayed the reaction had progressed to 35% completion. The reaction mixture was subjected to several iterations of microwave conditions, increasing the reaction temperature and reaction time, until the final conditions of 180° C. for 3 h was reached. It was determined via analysis by LC/MS that the reaction had proceeded to 90% completion. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-65% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (18 mg, 27%). MS(ES)+ m/e 471.3 [M+H]+.

1. customThe vial was capped
2. custompurged with nitrogen gas
3. additionTo the reaction mixture was added another equivalent of 2-iodopropane
4. customthe solution was irradiated in the microwave at 160° C. for 30 min
5. temperatureincreasing
6. customthe reaction temperature and reaction time
7. waituntil the final conditions of 180° C. for 3 h was reached
8. customThe organic layer was separated
9. washThe aqueous layer was washed with dichloromethane
10. extractionThe organic extractions
11. washwashed 3× with a dilute brine solution
12. customThe organic layer was separated
13. dry with materialdried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-65% acetonitrile w/0.1% TFA/water w/0.1% TFA)
17. additionThe product fractions were neutralized with the addition of saturated aq sodium bicarbonate
18. extractionextracted with dichloromethane
19. dry with materialThe organic layer was dried over sodium sulfate
20. filtrationfiltered
21. concentrationconcentrated in vacuo