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    Approaches to the synthesis of pentacyclic dibenzazepines and phenothiazines.

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    Author
    Dunbar, Philip Gordon.
    Issue Date
    1987
    Keywords
    Benzodiazepines.
    Tranquilizing drugs.
    Psychotropic drugs.
    Antidepressants.
    Advisor
    Martin, Arnold
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Rigid analogues of the tricyclic antidepressant imipramine and the phenothiazine tranquilizer promazine were designed and their syntheses were attempted. Conformational rigidity was expected to reduce the side effects of these drugs by limiting their binding to multiple receptors. Ortho-directed metalation followed by acylation provided synthetic intermediates for the formation of the desired pentacyclic congeners. The known dilithiation of phenothiazine and iminodibenzyl and n-butyllithium, followed by acylation with dimethylformamide, gave carboxaldehydes at the 1 and 4 positions respectively. Ortho-lithiated nicotinamides were acylated by these aldehydes exclusively at the 4 position to provide the key intermediate alcohol amides. Difficulties in amide hydrolysis are discussed. Catalytic hydrogenation over palladium-on-carbon in refluxing acetic acid yielded carboxylic acids, apparently via the gamma-lactones formed in situ. The lactones could not be isolated easily due to instability to oxidation. Pentacyclic lactams were formed by dehydration, and borane was used to reduce the carbonyl function. Only the iminodibenzyl lactam was reduced, and problems encountered in subsequent pyridine ring reduction are discussed. Cis and trans ring fusion isomers were identified by ¹³C nmr. Attempted one-pot synthesis of this pentacycle and a regioisomer by double acylation of 4,5-dilithioiminodibenzyl with 2,3-pyridinedicarboxylic anhydride, and 3,4-pyridinedicarboxylic anhydride failed. Mechanistic considerations are discussed regarding regiochemistry and reactivity of the nitrogen and carbon anions involved. Ortho-lithiation of 3-bromopyridine to form 3-pyridyne in the presence of the preformed N-lithioiminodibenzyl-4-carboxaldehyde was unsuccessful in providing a pentacyclic benzonaphthyridinobenzazepine. The resulting 2- and 4-lithiated 3-bromopyridines were trapped by the aldehyde instead. Both hydroxymethylbromopyridines were identified by their proton coupling patterns in the pyridine ring. These compounds are discussed as potential precursors to pentacyclic benzazepinopyridobenzazepines. Several other attempts at forming benzonaphthyridinobenzazepines and naphthyridinophenothiazines were unsuccessful. Intermediates were obtained by carbon acylation of the dilithiated iminodibenzyl and phenothiazine with arecoline esters, arecaidine, and pyridine-3-carboxaldehyde. Dibenzylic alcohol reduction is discussed, as is its labile oxidation. None of the resulting pyridylmethyl heterocycles could be cyclized.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Pharmaceutical Sciences
    Graduate College
    Degree Grantor
    University of Arizona
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    Dissertations

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