反应详情

A solution of (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 (889 mg, 3.97 mmol), 4-(2,2-difluorovinyl)pyrrolidin-2-one (643 mg, 4.37 mmol, 1.1 eq) and paratoluenesulfonic acid (76 mg, 0.40 mmol, 0.1 eq) in toluene (20 ml) is heated under reflux for 16 h. After cooling, the solvent is removed under reduced pressure, the crude product is dissolved in dichloromethane (100 ml). The organic layer is washed by water (150 ml). The aqueous layer is extracted by dichloromethane (100 ml). The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by preparative chromatography over silicagel (benzine/AcOEt: 60/40) to afford 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 62 after recristallization in diisopropylether.

1. temperatureunder reflux for 16 h
2. temperatureAfter cooling
3. customthe solvent is removed under reduced pressure
4. dissolutionthe crude product is dissolved in dichloromethane (100 ml)
5. washThe organic layer is washed by water (150 ml)
6. extractionThe aqueous layer is extracted by dichloromethane (100 ml)
7. dry with materialThe cumulated organic layers are dried over MgSO4
8. filtrationfiltered
9. customevaporated under reduced pressure
10. customThe residue is purified by preparative chromatography over silicagel (benzine/AcOEt: 60/40)