Hydrochloric Acid → Serazapine

Participants

Reaction Steps

A mixture of methyl 1,3,4,16b-tetrahydro-2-methyl-1,4-dioxo-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate (1.48 kg) in tetrahydrofuran (52 L) is heated to reflux under an atmosphere of nitrogen and then a solution of diborane in tetrahydrofuran (1M, 9.47 L) is added over a period of one hour. The reaction mixture is maintained at reflux for 20 hours, at which time it is treated sequentially with methanol (4 L) (slow, cautious addition) and a solution of hydrogen chloride in methanol (7.5N, 1.6 L). The mixture is stirred, refluxed for 2 hours and evaporated in vacuo, and the solid residue obtained is triturated with acetone (4 L) for 1 hour, collected, washed with acetone (4×500 ml) and dried (18 hours, 50°/0.5 mm Hg) to yiled methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate hydrochloride, mp 272°-273° . This salt is suspended in dichloromethane and sufficient ammonium hydroxide (28%) in water is added to liberate the free base. The basic mixture is stirred for 45 minutes, the aqueous layer is removed and discarded and the organic layer is washed with water. The dichloromethane is evaporated in vacuo and the residual foam dissolved in boiling 2-propanol. The solution is filtered to remove a small amount of insolubles, then allowed to cool overnight for complete crystallization. The obtained solid is purified by recrystallization from 2-propanol. The solution is allowed to cool gradually while stirring overnight. The resulting crystals are collected by filtration, washed with 2-propanol and dried (16 hours, 80°/3 mm Hg) to yield methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate, mp 157°-159°, the compound of formula I wherein R1 is methyl, R2 and R3 are hydrogen and R4 is methoxycarbonyl.

Provenance & Evidence