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

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dc.availability.bitstreamembargoed
dc.check.chapterOfThesisChapter 3 and Chapter 5 to be redacted permanently 10 year embargo on entire thesisen
dc.check.date2030-05-06
dc.contributor.advisorMaguire, Anita R.en
dc.contributor.advisorCollins, Stuarten
dc.contributor.authorMcCarthy, Laura A.
dc.contributor.funderIrish Research Council for Science, Engineering and Technologyen
dc.contributor.funderGlaxoSmithKlineen
dc.date.accessioned2020-05-28T09:44:31Z
dc.date.available2020-05-28T09:44:31Z
dc.date.issued2019-12-19
dc.date.submitted2019-12-19
dc.description.abstractSynthesis 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.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMcCarthy, L. A. 2019. Innovative synthetic approaches to indazole derivatives and other compounds of pharmaceutical relevance. PhD Thesis, University College Cork.en
dc.identifier.endpage369en
dc.identifier.urihttps://hdl.handle.net/10468/10072
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2019, Laura A. McCarthyen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectSalbutamolen
dc.subjectNCIen
dc.subjecta-diazocarbonylen
dc.subjectIndazoleen
dc.subjectAryneen
dc.subject[3+2]-Cycloadditionen
dc.subjectContinuous processingen
dc.titleInnovative synthetic approaches to indazole derivatives and other compounds of pharmaceutical relevanceen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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