反应详情

1.56 g of 4-(diphenylmethoxy)-1-piperidinebutanamine and 617 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 185° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.52 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration. The residue was dissolved in 4 ml of ethanol; 4 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 4 hours; 1 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by stirring at 50° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 4.5 by the addition of 4 N hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was powdered by the addition of ethyl acetate, collected by filtration and dried to yield 271 mg of the title compound.

1. temperatureAfter cooling
2. extractionfollowed by extraction with ethyl acetate
3. washthe extract was washed with saturated saline
4. dry with materialdried over magnesium sulfate
5. concentrationconcentrated under reduced pressure
6. washeluted with ethyl acetate:methanol:triethylamine (50:5:1)
7. customThe desired fraction was collected
8. concentrationconcentrated under reduced pressure
9. dissolutiondissolved in 5 ml of ethyl acetate
10. addition0.52 ml of a 4 N hydrogen chloride solution in ethyl acetate was added
11. concentrationfollowed by concentration
12. dissolutionThe residue was dissolved in 4 ml of ethanol
13. addition4 ml of a 1 N aqueous solution of sodium hydroxide was added
14. addition1 ml of a 2 N aqueous solution of sodium hydroxide was added
15. stirringby stirring at 50° C. for 16 hours
16. concentrationThe mixture was concentrated under reduced pressure
17. additionThe residue was diluted with water
18. washwashed with ethyl acetate
19. additionthe water layer was adjusted to pH 4.5 by the addition of 4 N hydrochloric acid
20. extractionextracted with ethyl acetate-tetrahydrofuran (1:1)
21. washthe extract was washed with saturated saline
22. dry with materialdried over magnesium sulfate
23. concentrationconcentrated under reduced pressure
24. additionThe residue was powdered by the addition of ethyl acetate
25. filtrationcollected by filtration
26. customdried