反应详情

Amyl alcohol (5100 ml) and 918.35 g (9.17 moles) of N-methylpiperazine were charged into a 12 liter 3-necked reaction flask fitted with a Dean-Stark adapter. The solution was stirred under nitrogen atmosphere and 989 ml of 10N ethanolic hydrogen chloride solution were added rapidly. The reaction mixture was heated to reflux and the distillate was collected in the Dean-Stark adapter. When the temperature of the reaction mixture reached 131° the Dean-Stark adapter was removed and an additional 918.35 g (9.17 moles) of N-methylpiperazine followed by 1045.0 g (4.56 moles) of 5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine were added. The mixture was heated at reflux under nitrogen atmosphere for 20 hours. Amyl alcohol was then removed under reduced pressure at a water bath temperature of 80°. The viscous residual oil was dissolved in 10,000 ml of dichloromethane, washed with 3×4,000 ml of 4N sodium hydroxide and 6×4,000 ml of water. The dichloromethane solution was then extracted with 3×2,000 ml of 6N hydrochloric acid. The aqueous solution was back washed with 2×2,000 ml of dichloromethane, treated with 100 g of activated carbon and filtered. The clear filtrate was adjusted to pH 9-10 with 1,500 ml of ammonium hydroxide solution (29%). The oil which separated was extracted with 3×4,000 ml of dichloromethane, the extracts were dried over 1,000 g of sodium sulfate and the solvent removed at reduced pressure with a water bath temperature of 60°. An oil was obtained which rapidly solidified and after drying further (5 mm Hg/40°) yielded crude product, m.p. 113°-120°. The crude product was dissolved in 8,000 ml of hot (60°-70°) isopropanol. The solution was decolorized with 200 g of activated carbon and filtered. To this solution was added a solution of 760.7 g (8.28 moles) of maleic acid in 2,500 ml of warm (30°) isopropanol and the maleate salt began to precipitate. The suspension was stirred overnight at ambient temperature to complete crystallization and the solid was collected by filtration. The product was washed with 3×500 ml of cold isopropanol and dried (0.5 mm/50°). This was recrystallized from ethanol, the resulting product was washed first with ethanol and then with ether and then dried to give 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine monomaleate, m.p. 204°-205° (dec).

1. customfitted with a Dean-Stark adapter
2. temperatureThe reaction mixture was heated
3. temperatureto reflux
4. distillationthe distillate was collected in the Dean-Stark adapter
5. customreached 131°
6. customwas removed
7. additionwere added
8. temperatureThe mixture was heated
9. temperatureat reflux under nitrogen atmosphere for 20 hours
10. customAmyl alcohol was then removed under reduced pressure at a water bath temperature of 80°
11. dissolutionThe viscous residual oil was dissolved in 10,000 ml of dichloromethane
12. washwashed with 3×4,000 ml of 4N sodium hydroxide and 6×4,000 ml of water
13. extractionThe dichloromethane solution was then extracted with 3×2,000 ml of 6N hydrochloric acid
14. washThe aqueous solution was back washed with 2×2,000 ml of dichloromethane
15. additiontreated with 100 g of activated carbon
16. filtrationfiltered
17. customThe oil which separated
18. extractionwas extracted with 3×4,000 ml of dichloromethane
19. dry with materialthe extracts were dried over 1,000 g of sodium sulfate
20. customthe solvent removed at reduced pressure with a water bath temperature of 60°
21. customAn oil was obtained which
22. customafter drying further (5 mm Hg/40°)
23. customyielded crude product, m.p. 113°-120°
24. filtrationfiltered
25. customto precipitate
26. stirringThe suspension was stirred overnight at ambient temperature
27. customcrystallization
28. filtrationthe solid was collected by filtration
29. washThe product was washed with 3×500 ml of cold isopropanol
30. customdried (0.5 mm/50°)
31. customThis was recrystallized from ethanol
32. washthe resulting product was washed first with ethanol
33. dry with materialwith ether and then dried