Dibenzodiazepines, Dibenzoxazepines, and a Dibenzothiazepine

The first step in one synthesis of the antipsychotic dmg clozapine (37-5) involves UUman coupling of anthranUic acid (37-1) with 2,4-dichloronitrobenzene (30-1) to give the substituted anthranilate (37-2). The carboxyl group is then converted to the A-methylpiperazinamide (37-3) via a suitably activated intermediate as, for example, the imidazohde obtained by reaction with carbonyidiimidazole (CDl). The nitro group is then reduced to amine (37-4) by means of catalytic hydrogenation. Intramolecular Schiff base formation catalyzed by toluenesulfonic acid then completes the synthesis of clozapine (37-5) [38]. 

Treatment of the product with phosphorus oxychloride leads to a cyclodehydration reaction possibly via the imino chloride. There is thus obtained the antipsychotic compound loxapine (38-7) [39]. 

The preparation of the A -desmethyl analogue, amoxapine (39-7), illustrates an alternate approach in which the oxygen ether linkage is formed last. Reaction of the imidazolide (39-2) from 2,4-dichlorobenzoic acid (39-1) and carbonyldiimidazole with ort/zo-aminophenol (39-3) gives the benzamide (39-4). This is then converted to its imino chloride (39-5) with the ubiquitous phosphorus oxychloride. Treatment of the product with piperazine leads to the amidine (39-6), probably by an addition-elimination sequence. Copper catalyzed displacement of chlorine by phenoxide closes the ring there is thus obtained amoxapine (39-7) [40]. 

Yet another approach to these compounds consists of substituting the piperazine ring onto the preformed heterocyclic moiety. Ullman condensation of the substituted thiosalyciclic acid (40-1) with ort/zo-chloronitrobenzene results in the displacement of chlorine by thiophenoxide and the formation of the thioether (40-2). The nitro group in this last intermediate is then reduced to an aniline (40-3) the resulting amino acid is then cyclized thermally to the lactam (40-4). Treatment of that with phosphorus oxychloride gives the imino chloride (40-5). Reaction with N-methylpiperazine leads to the replacement of chlorine by nitrogen and the formation of clothiapine (40-6) [39]. 

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