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

Thumbnail Image
McCarthy, Laura A.
Journal Title
Journal ISSN
Volume Title
University College Cork
Published Version
Research Projects
Organizational Units
Journal Issue
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.
Salbutamol , NCI , a-diazocarbonyl , Indazole , Aryne , [3+2]-Cycloaddition , Continuous processing
McCarthy, L. A. 2019. Innovative synthetic approaches to indazole derivatives and other compounds of pharmaceutical relevance. PhD Thesis, University College Cork.