Innovative synthetic approaches to indazole derivatives and other compounds of pharmaceutical relevance

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dc.contributor.advisor Maguire, Anita R. en
dc.contributor.advisor Collins, Stuart en McCarthy, Laura A. 2020-05-28T09:44:31Z 2020-05-28T09:44:31Z 2019-12-19 2019-12-19
dc.identifier.citation McCarthy, L. A. 2019. Innovative synthetic approaches to indazole derivatives and other compounds of pharmaceutical relevance. PhD Thesis, University College Cork. en
dc.identifier.endpage 369 en
dc.description.abstract Synthesis of pharmaceutically active compounds at scale requires a diverse toolkit of powerful synthetic methodologies which effect the necessary molecular transformations coupled with excellent efficiencies and selectivity patterns. The research described in this thesis is focussed on development of a number of synthetic methods, in particular a [3+2] cycloaddition process leading to indazoles which are key motifs in a number of Active Pharmaceutical Ingredients. Use of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazo-β-ketoesters, α-diazophosphonates, α-diazomalonates, and an α-diazosulfone has been explored leading to enhanced insight into this transformation. Chapter One contains a review on modern applications of cycloaddition chemistry in the synthesis of compounds of potential pharmaceutical relevance, with a particular focus on cycloadditions involving diazo compounds, both with and without retention of nitrogen. Chapter Two is focussed on the synthetically powerful [3+2] cycloaddition of arynes and α-diazocarbonyl compounds to form indazoles. The scope of this process has been expanded considerably, including the use of α-diazophosphonates to lead to indazole-3-phosphonates. Furthermore, the impact of alteration of the substrate and reaction conditions on the outcome of the cycloaddition has been explored in detail, with a view to optimising the formation of the N–H, N–Ac or N–Ph indazoles. The impact of the observed experimental outcomes on the mechanistic understanding of this process is discussed. A number of conditions for generation of the aryne were explored, including reaction of CsF or TBAF with an aryne precursor or via diazotisation and fragmentation of anthranilic acid. Having established conditions in which this could be achieved in a homogeneous reaction medium, extension to continuous flow processing was successfully achieved. Results of the biological evaluation of a number of the novel indazoles are discussed. Chapter Three summarises progress made in the optimisation of a key bromination step as part of a revised synthetic route to the API Salbutamol. Both the efficiency and ease of reagent handling were optimised relative to previous results. Chapter Four explores the potential use of novel synthetic approaches to α-aminoketones as model systems for Salbutamol and related compounds. Umpolung couplings utilising NHC or BAC mediated transformations were investigated, in addition to N–H insertion with an α-diazoketone. Chapter Five describes the scientific achievements of this work. The experimental details for the synthesis, including spectroscopic characterisation of all compounds synthesised in this work are provided at the end of each chapter. Full details of the biological testing results are included in the Appendix. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2019, Laura A. McCarthy en
dc.rights.uri en
dc.subject Salbutamol en
dc.subject NCI en
dc.subject a-diazocarbonyl en
dc.subject Indazole en
dc.subject Aryne en
dc.subject [3+2]-Cycloaddition en
dc.subject Continuous processing en
dc.title Innovative synthetic approaches to indazole derivatives and other compounds of pharmaceutical relevance en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD - Doctor of Philosophy en
dc.internal.availability Full text not available en
dc.description.version Accepted Version en
dc.contributor.funder Irish Research Council for Science, Engineering and Technology en
dc.contributor.funder GlaxoSmithKline en
dc.description.status Not peer reviewed en Chemistry en
dc.check.chapterOfThesis Chapter 3 and Chapter 5 to be redacted permanently 10 year embargo on entire thesis en
dc.internal.conferring Summer 2020 en
dc.internal.ricu Analytical and Biological Chemistry Research Facility en
dc.availability.bitstream embargoed 2030-05-06

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