Perlapine

Originator

Hypnodin ,Takeda ,Japan ,1974

Uses

Sedative-hypnotic.

Uses

Perlapine exhibits antipsychotic activity and blocks dopamine and serotonin receptors. Perlapine is also a novel agonist of hM3Dq, a designer receptor exclusively activated by designer drugs (DREADD).

Manufacturing Process

The 5.6-dihydro-6-oxo-morphanthridine used as a starting material is usefully obtained in the following way. 30.2 grams of o-aminodiphenylmethane are dissolved in 65 ml of absolute toluene and, while stirring and at a temperature of between 0° and -10°C, 140 ml of 20% phosgene solution in toluene are added drop by drop. By bubbling phosgene slowly through it the milky mixture is heated within 30 minutes to reflux temperature, which is maintained during some 20 minutes. While stirring vigorously, dry nitrogen is passed into the boiling reaction mixture for 10 minutes. After evaporation of the solvent there are obtained by vacuum distillation 29.7 grams (86% of the theory of o-isocyanatodiphenylmethane of boiling point 169°C/12 mm Hg.
21.1 grams of aluminum chloride are heated in 110 ml of o-dichlorobenzene to 80°C and, while stirring, a solution of 29.7 grams of oisocyanatodiphenylmethane in 60 ml of o-dichlorobenzene is added drop by drop, whereupon the temperature of the mixture rises to 120°C. This temperature is maintained for one hour while stirring. After cooling the reaction mixture is poured into 200 ml of 2 N hydrochloric acid, whereupon a brown precipitate is formed. After steam distillation the residue is isolated by filtration and crystallized from acetone/water. There are obtained 28.6 grams (97% of the theory) of 5,6-dihydro-6-oxo-morphanthridine of melting point 201°-203°C.
A mixture of 4.9 grams of 5,6-dihydro-6-oxo-morphanthridine, 37 ml of phosphorus oxychloride and 1.5 ml of dimethylaniline is heated for 3 hours at reflux, The viscous oil, obtained by evaporation of the reaction mixture in vacuo at 60°C, is diluted with 20 ml of absolute dioxane and, after adding 30 nil of N-methylpiperazine, heated for 4 hours at reflux. The resulting clear solution is evaporated in vacuo at 60°C to dryness. The residue is distributed between ether and ammonia water. The ethereal solution is separated, washed with water and then extracted with 1 N acetic acid. The acetic acid extract is mixed with ammonia water and then extracted with ether. The ethereal solution is washed with water, dried over sodium sulfate, filtered through alumina and evaporated.
The residue is caused to crystallize from ether/petroleum ether, and recrystallized from acetone/petroleum ether. 6.0 grams (88% of the theory) of 6-(4-methyl-1-piperazinyl)-morphanthridine of melting point 138°-138.5°C are obtained.

Therapeutic Function

Hypnotic