反应详情

温度

52.5 °C

In a reaction flask, guanidine HCl (35.1 g) was dissolved in water (268 ml) and 50% NaOH (114.6 g). The acetonitrile/5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl chloride mixture of Example 4, was added in three equal portions to the flask containing the guanidine solution while maintaining the reaction temperature below 15° C. throughout the addition. The reaction mixture was brought to room temperature and stirred under nitrogen atmosphere for two hours. The reaction was confirmed to be complete by HPLC. A distillation head and condensor were then attached to the reaction vessel. The product mixture was atmospherically distilled at 85° C. resulting in a slurry having a volume of 400-450 ml. Tetrahydrofuran (THF) (720 ml) was added to the reaction flask and the mixture was warmed to 50-55° C. for 45 minutes and until all all contents had entered solution resulting in an orange biphasic mixture. The mixture was transferred to a separatory funnel and the layers were allowed to separate. The layers were separated and the aqueous layer was extracted with an additional 300 ml of THF. The resulting organic THF layers were combined. Darco® KB-B (5 g) (NORIT Americas Inc., Atlanta, Ga.) and Celite® (5 g) (Celite Corp., Lompoc, Calif.) were added to the THF layers and stirred at room temperature for one hour. The black mixture was vacuum filtered through a #2 Whatman paper filter (Whatman Inc., Clifton, N.J.) and the carbon cake was rinsed with THF. The filtrate was then collected, transferred to a clean flask. and atmospherically distilled at 70° C. to a volume of 450 ml. Ethanol (500 mL) was added to the flask and the mixture was atmospherically distilled at 85° C. to 450 ml. The addition of ethanol and subsequent distillation was repeated three more times. The resulting slurry was cooled to room temperature and allowed to granulate while stirring for three hours. The slurry was then filtered onto a #2 Whatman filter paper and rinsed with THF. The resulting white crystalline solid was allowed to dry for about 48 hours in a vacuum oven at 45 to 50° C. resulting in 52.2 g of N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.

1. temperaturewhile maintaining the reaction temperature below 15° C.
2. additionthroughout the addition
3. customwas brought to room temperature
4. distillationThe product mixture was atmospherically distilled at 85° C.
5. customresulting in a slurry
6. customresulting in an orange biphasic mixture
7. customThe mixture was transferred to a separatory funnel
8. customto separate
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with an additional 300 ml of THF
11. additionDarco® KB-B (5 g) (NORIT Americas Inc., Atlanta, Ga.) and Celite® (5 g) (Celite Corp., Lompoc, Calif.) were added to the THF layers
12. stirringstirred at room temperature for one hour
13. filtrationfiltered through a #2 Whatman paper
14. filtrationfilter (Whatman Inc., Clifton, N.J.)
15. washthe carbon cake was rinsed with THF
16. customThe filtrate was then collected
17. customtransferred to a clean flask
18. distillationand atmospherically distilled at 70° C. to a volume of 450 ml
19. additionEthanol (500 mL) was added to the flask
20. distillationthe mixture was atmospherically distilled at 85° C. to 450 ml
21. additionThe addition of ethanol and subsequent distillation
22. temperatureThe resulting slurry was cooled to room temperature
23. stirringwhile stirring for three hours
24. filtrationThe slurry was then filtered onto a #2 Whatman
25. filtrationfilter paper
26. washrinsed with THF
27. customto dry for about 48 hours in a vacuum oven at 45 to 50° C.
28. customresulting in 52.2 g of N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine