Hydrochloric Acid → HCID 13344910, compound

Participants

Reaction Steps

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-11-H-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 temperature 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).

Provenance & Evidence