反应详情

Amyl alcohol (5100 ml) and 918.35 g (9.17 moles) of N-methylpiperazine are charged into a 12 liter 3-necked reaction flask fitted with a Dean-Stark adapter. The solution is stirred under nitrogen atmosphere and 989 ml of 10N ethanolic hydrogen chloride solution are added rapidly. The reaction mixture is heated to reflux and the distillate is collected in the Dean-Stark adapter. When the temperature of the reaction mixture reaches 131° the Dean-Stark adapter is 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 are added. The mixture is heated at reflux under nitrogen atmosphere for 20 hours. Amyl alcohol is then removed under reduced pressure at a water bath temperature of 80°. The viscous residual oil is 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 is then extracted with 3×2,000 ml of 6N hydrochloric acid. The aqueous solution is back washed with 2×2,000 ml of dichloromethane, treated with 100 g of activated carbon and filtered. The clear filtrate is adjusted to pH 9-10 with 1,500 ml of ammonium hydroxide solution (29%). The oil which separates is extracted with 3×4,000 ml of dichloromethane, the extracts are dried over 1,000 g of sodium sulfate and the solvent removed at reduced pressure with a water bath temperatures of 60°. An oil is obtained which rapidly solidifies and after drying further (5 mm Hg/40°) yields crude product, m.p. 113°-120°. The crude product is dissolved in 8,000 ml of hot (60°-70°) isopropanol. The solution is decolorized with 200 g of activated carbon and filtered. To this solution is added a solution of 760.7 g (8.28 moles) of maleic acid in 2,500 ml of warm (30°) isopropanol and the meleate salt begins to precipitate. The suspension is stirred overnight at ambient temperature to complete crystallization and the solid is collected by filtration. The product is washed with 3×500 ml of cold isopropanol and dried (0.5 mm/50°). This is recrystallized from ethanol, the resulting product is 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 is heated
3. temperatureto reflux
4. distillationthe distillate is collected in the Dean-Stark adapter
5. customreaches 131°
6. customis removed
7. additionare added
8. temperatureThe mixture is heated
9. temperatureat reflux under nitrogen atmosphere for 20 hours
10. customAmyl alcohol is then removed under reduced pressure at a water bath temperature of 80°
11. dissolutionThe viscous residual oil is 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 is then extracted with 3×2,000 ml of 6N hydrochloric acid
14. washThe aqueous solution is back washed with 2×2,000 ml of dichloromethane
15. additiontreated with 100 g of activated carbon
16. filtrationfiltered
17. extractionThe oil which separates is extracted with 3×4,000 ml of dichloromethane
18. dry with materialthe extracts are dried over 1,000 g of sodium sulfate
19. customthe solvent removed at reduced pressure with a water bath temperatures of 60°
20. customAn oil is obtained which
21. customafter drying further (5 mm Hg/40°)
22. customyields crude product, m.p. 113°-120°
23. filtrationfiltered
24. customto precipitate
25. stirringThe suspension is stirred overnight at ambient temperature
26. customcrystallization
27. filtrationthe solid is collected by filtration
28. washThe product is washed with 3×500 ml of cold isopropanol
29. customdried (0.5 mm/50°)
30. customThis is recrystallized from ethanol
31. washthe resulting product is washed first with ethanol
32. dry with materialwith ether and then dried