ChemicalBook CAS DataBase List Clozapine

Clozapine synthesis

7synthesis methods

Product Name:Clozapine
CAS Number:5786-21-0
Molecular formula:C18H19ClN4
Molecular Weight:326.82

Clozapine, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e] [1,4]diazepine (6.5.7) is synthesized by two methods. According to the first, 4-chloro-2-nitroaniline in the presence of copper filings is acylated by the o-chlorobenzoic acid methyl ester, forming the corresponding diphenylamine (6.5.4). By reacting this with N-methyl piperazine, the ester group in the resulting polyfunctional diphenylamine is transformed into the amide (6.5.5). The nitro group in the resulting 4-chloro-2- nitro-2′-carb-(N′-methyl piperazino)amide (6.5.5) is further reduced into an amine group by hydrogen in the presence of Raney nickel. Reacting the resulting product (6.5.6) with phosphorous oxychloride yields in heterocyclization into the desired dibenzodiazepine, clozapine (6.5.7).

The other way of synthesis of clozapine is from 8-chloro-10,11-dihydro-5H-dibenzo[b,e]1, 4-diazepin-11-thione, which is alkylated at the sulfur atom of the dibenzodiazepine ring by 4-nitrobenzylchloride in the presence of potassium tert-butoxide, giving N-methyl derivative (6.5.8). Reaction of this with N-methylpiperazine gives the desired clozapine (6.5.7).

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Yield:5786-21-0 41%

Reaction Conditions:

Stage #1: 2-amino-4-chlorodiphenylamine-2'-carboxylic acid (4''-methyl)piperazidewith N,N-dimethyl-aniline;trichlorophosphate for 3 h;Heating / reflux;
Stage #2: with ammonia in water;

Steps:

1

7.4 grams of 2-amino-4-chlorodiphenylamine-2'-carboxylic acid (4 methyl)piperazide and 35 ml of phosphoroxychloride are heated up for 3 hours under reflux in the presence of 1.4 ml of N,N-dimethylaniline. Upon concentration of the reaction mixture in vacuo as far as possible, the residue is distributed between benzene and ammonia/ice water. The benzene solution is extracted with dilute acetic acid. The acid extract is clarified with charcoal and treated with concentrated ammonia water to precipitate the alkaline substance, which is dissolved in ether. The ethereal solution is washed with water and dried over sodium sulfate. The residue obtains yields, after recrystallization from ether/petroleum ether 2.9 g (41% of theoretical yield) of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e] [1,4] diazepine in the form of yellow grains of melting point 182° to 184° C. (from acetone/petroleum ether).

References:

US2007/92586,2007,A1 Location in patent:Page/Page column 13

109-01-3 Synthesis