反应详情

Triethylamine (15.3 μL) was added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (E:Z=1:3 mixture) (32.9 mg) in methylene chloride (1 mL) at room temperature, and acetyl chloride (7.8 μL) was added under ice-cooling, after which the mixture was stirred under ice-cooling for 30 minutes. Triethylamine (15.3 μL) and acetyl chloride (7.8 μL) were added under ice-cooling and the mixture was stirred under ice-cooling for further 30 minutes. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. Acetonitrile (329 μL) and 48% hydrobromic acid (329 μL) were added to the resulting residue, and the mixture was stirred at 50° C. for one hour. Separately, triethylamine (121 μL) and acetyl chloride (61.6 μL) were added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (E:Z=1:3 mixture) (190 mg) in methylene chloride (2 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. Acetonitrile (1.9 mL) and 48% hydrobromic acid (1.9 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. The reaction solutions were neutralized respectively with saturated aqueous sodium bicarbonate at room temperature, combined and extracted with ethyl acetate. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate:methanol=4:1) to give a yellow oil. This was powdered with acetonitrile, and filtration operation gave the title compound as a colorless solid (49 mg, 23%).

1. temperaturecooling
2. temperaturecooling for 30 minutes
3. temperaturecooling
4. stirringthe mixture was stirred under ice-
5. temperaturecooling for further 30 minutes
6. extractionfollowed by extraction with methylene chloride
7. filtrationThe organic layer was filtered through diatomaceous earth
8. concentrationthe solvent was concentrated under reduced pressure
9. additionAcetonitrile (329 μL) and 48% hydrobromic acid (329 μL) were added to the resulting residue
10. stirringthe mixture was stirred at 50° C. for one hour
11. additionSeparately, triethylamine (121 μL) and acetyl chloride (61.6 μL) were added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (E:Z=1:3 mixture) (190 mg) in methylene chloride (2 mL) under ice-
12. temperaturecooling
13. stirringthe mixture was stirred under ice-
14. temperaturecooling for 30 minutes
15. additionWater was added to the reaction solution
16. extractionfollowed by extraction with methylene chloride
17. filtrationThe organic layer was filtered through diatomaceous earth
18. concentrationthe solvent was concentrated under reduced pressure
19. additionAcetonitrile (1.9 mL) and 48% hydrobromic acid (1.9 mL) were added to the resulting residue
20. stirringthe mixture was stirred at room temperature for 30 minutes
21. customwere neutralized respectively with saturated aqueous sodium bicarbonate at room temperature
22. extractionextracted with ethyl acetate
23. filtrationThe organic layer was filtered through diatomaceous earth
24. concentrationthe solvent was concentrated under reduced pressure
25. customThe resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate:methanol=4:1)
26. customto give a yellow oil
27. filtrationThis was powdered with acetonitrile, and filtration operation