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