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Title: Investigations of new synthetic routes to imidazo[4,5-b]pyridinone derivatives
Author: Weaver, George William
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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This thesis is concerned with the development of three new synthetic routes to highly functionaliscd imidazo[4,5-b]pyridinone derivatives of biological interest as purine antagonists. The first synthetic route developed was based on the construction of 5-nitro-6-methylthiopyridine derivatives by annulation of readily available l-amino-l-methylthio-2-nitroethenes with 1,3-bis-clectrophiles (e.g. mal-onyl dichloride). Although this new type of ring formation was successful, the yields of the new pyridine derivatives obtained were disappointingly low and studies to improve the efficiency of the cyclisation met with little success. Subsequent displacement of the methylthio group in the new pyridine derivatives with benzylamines, and base catalysed cyclisation of the resulting amino-nitropyridines provided an efficient new route to otherwise inaccessible and usefully functionaliscd imidazo[4,5-b]pyridinone derivatives. The second new synthetic route to imidazo[4,5-b)pyridinone derivatives investigated was concerned with reductive cyclisation reactions of 4-nitro-imidazol-5-ylcarbonylmethine derivatives accessible by the previously un-described acylation reactions of activated mcthylene compounds with 4-nitroimidazole-5-carbonyl chlorides. This synthetic approach was largely successful and allowed the efficient general synthesis of highly function-alised and otherwise unavailable imidazo[4,5-b]pyridinone derivatives. The chemistry of the novel compounds thereby made available was also studied and their utility as starting materials for the synthesis of other imidazopyridine derivatives by functional group manipulation, investigated. The third synthetic pathway to imidazo[4,5-b]pyridinone derivatives explored, involved as a key step, the successful displacement of the halogen atom in 5-chloro-4-nitroimidazoles by anions derived from activated methylene compounds. The resulting 4-nitroimidazol-5-ylacetate derivatives were converted smoothly on heating into 3-substituted imidazo[4,5-c] isoxazoles in high yield. Reductive opening of the isoxazole ring in these compounds provided a viable high yielding method for the synthesis of 4-amino-5-ethoxalylimidazole derivatives. The latter were in turn successfully converted into usefully functionaliscd imidazo[4,5-b]-pyridinone derivatives in moderate to good yield by cyclisation with activated methylene compounds in high boiling solvents. This method complements the second route developed in the present studies by allowing the synthesis of 6-substituted derivatives as distinct from the 5-and 7-substituted imidazo[4,5-b]pyridinones available through imidazolyl-carbonylmethine precursors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available