反应详情

6-Ethyl-2-methylimidazo[1,2-b]pyridazine (2.70 g, 16.7 mmol) was dissolved in 1,2-dichloroethane (30 ml), and chlorosulfonic acid (1.27 g, 18.5 mmol) was added thereto under stirring at room temperature, and the mixture was stirred for 5 hours under reflux with heating. Then, the reaction solution was cooled to about 70° C., and triethylamine (2.38 g, 23.5 mmol) was added dropwise thereto over 1 minute. After dropping, the reaction solution was stirred for 20 minutes under reflux with heating. Thereafter, the reaction solution was cooled to about 70° C., and phosphorus oxychloride (3.86 g, 25.2 mmol) was added dropwise thereto over 1 minute. After dropping, the mixture was stirred for 2 hours under reflux with heating. The reaction solution was left to cool to about 50° C., and poured into 50 ml warm water (about 50° C.). The reaction mixture was stirred for 5 minutes, and the organic layer was separated. The aqueous layer was extracted with chloroform (50 ml×2). The organic layers were combined, washed with water, dried over magnesium sulfate, and concentrated. The residues were dissolved in acetonitrile (40 ml), and 14 N ammonia water (7 ml) was added thereto under stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured onto ice-cold water (150 ml) and adjusted to about pH 4 with concentrated hydrochloric acid, to form crystals which were then collected by filtration, washed with water and dried under reduced pressure. Thereafter, the crystals were purified by silica gel column chromatography (chloroform:acetone=9:1→4:1). The title compound was obtained as white crystals. The yield was 1.8 g (44.7%).

1. stirringthe mixture was stirred for 5 hours
2. temperatureunder reflux
3. temperaturewith heating
4. temperatureThen, the reaction solution was cooled to about 70° C.
5. stirringthe reaction solution was stirred for 20 minutes
6. temperatureunder reflux
7. temperaturewith heating
8. temperatureThereafter, the reaction solution was cooled to about 70° C.
9. waitover 1 minute
10. stirringthe mixture was stirred for 2 hours
11. temperatureunder reflux
12. temperaturewith heating
13. waitThe reaction solution was left
14. temperatureto cool to about 50° C.
15. additionpoured into 50 ml
16. stirringThe reaction mixture was stirred for 5 minutes
17. customthe organic layer was separated
18. extractionThe aqueous layer was extracted with chloroform (50 ml×2)
19. washwashed with water
20. dry with materialdried over magnesium sulfate
21. concentrationconcentrated
22. dissolutionThe residues were dissolved in acetonitrile (40 ml)
23. addition14 N ammonia water (7 ml) was added
24. stirringunder stirring at room temperature
25. stirringthe mixture was stirred at room temperature for 2 hours
26. additionthe reaction solution was poured onto ice-cold water (150 ml)
27. customto form crystals which
28. filtrationwere then collected by filtration
29. washwashed with water
30. customdried under reduced pressure
31. customThereafter, the crystals were purified by silica gel column chromatography (chloroform:acetone=9:1→4:1)