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Title: The synthesis of benzimidazoles of medicinial interest.
Author: Wathey, William B.
ISNI:       0000 0001 3563 954X
Awarding Body: University of Wales, College of Cardiff,
Current Institution: Cardiff University
Date of Award: 1989
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The aim of this programme was to design and synthesize triazinobenzimidazoles that are analogous to the antihypertensive agents, hydralazine and dihydralazine. Retrosynthetic analysis of these analogues showed that the key intermediates in the synthesis were the novel [1,2,4]triazino[4,5-a]benzimidazol-l-ones and the related 1,4-diones. Existing routes to this tricyclic ring system were either limited in scope or needed expensive starting materials. Therefore, a new synthetic route to these compounds was developed using the readily available 2-acylbenzimidazoles as starting materials. These acyl derivatives were converted to hydrazones, ethoxycarbonylhydrazones and benzimidazole-2-carboxylic acid ethoxycarbonylhydrazides. The substituted hydrazines were cyclized to the desired tricyclic lactam intermediates either thermally, or acylatively using ethyl chloroformate in pyridine. The versatility of these cyclization methods has been demonstrated by the synthesis of a variety of novel N-2 substituted [1,2,4]triazino[4,5-a]benzimidazol- 1-ones which may or may not have a substituent at C-4. In addition, it has been shown that these types of cyclizations provide a better route to existing triazinobenzimidazoles. Although attempts to chlorinate or thiate these lactams were unsuccessful, use of the dithio analogue of ethyl carbazate, methyl dithiocarbazate, afforded sulphur-containing hydrazones which were cyclized to the desired [1,2,4]triazino[4,5-a]benzimi dazole-1-thiones. Displacement of the enolized 1-thione by hydrazine produced the desired target molecules, 1-hydrazino- [1,2,4]triazino[4,5-a]benzimidazoles. In preliminary screening, these compounds exhibited in vivo vasodilatory activity. In an attempt to vary the 4-substituent of the tricyclic system further, the synthesis of a variety of modified 2-acylbenzimidazoles was undertaken. In particular, the structure and reactions of one of these modified ketones, 2-bromoacetylbenzimidazole, was investigated in an attempt to explain its bromination pattern. Other workers have suggested that the unusual bromination pattern of 2-acetyl and 2-bromoacetylbenzimidazole may arise from the influence of intramolecular hydrogen bonding between the imine proton and the carbonyl group. However, a computer-aided reinvestigation of this reaction has shown that a more plausible intermediate is an intramolecularly hydrogen bonded enol of the ketone. The synthesis of two novel triazepinobenzimidazole ring systems has been examined. The acylative-cyclization (ethyl chloroformate-pyridine) developed for the preparation of the novel triazines has been extended to the synthesis of the hitherto unknown [1,2,4]triazepino[4,5-a]benzimidazole ring system. A series of new 1,2-diacylbenzimidazoles were prepared as precursors to [1,2,5]triazepino[5,4-a]benzimidazoles. However, attempts to add hydrazine across the dicarbonyl groups gave only novel benzimidazole hydrazine or hydrazide derivatives instead of the desired triazepinobenzimidazoles. Many of the compounds described in this thesis have been screened for possible pharmacological activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry Pharmacology Chemistry, Organic