The application of flow chemistry to the synthesis of pharmaceutically privileged heterocycles

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2019
Thesis identifier
  • T15961
Person Identifier (Local)
  • 201590023
Qualification Level
Qualification Name
Department, School or Faculty
  • This thesis describes the development and use of flow methods in the synthesis of medicinally privileged heterocycles. As a developing technology, advances in the understanding and technological hardware involved within flow chemistry have resulted in its widespread employment throughout the chemical sector. Specifically, factors including the ease of in-line analysis and streamlining of multi-step syntheses, as well as benefits offered in safety control, heating efficiency, reagent addition control, uniformity of performance and facile upscaling, and the reduced footprint of reactors in comparison to traditional batch methods have appreciably added to the value and applicability of this technique, especially in large scale synthetic procedures. Despite this, the majority of early-stage research and discovery chemistry still relies on the use of batch reactions. As a result, and in a drive to utilise state-of-the-art technology within our laboratory in order to redefine drug discovery practices, this work presents the use of flow chemistry within two distinct, and highly relevant applications. Imidazoheterocycles are motifs of foremost importance to the medicinal chemistry community, being present in clinical candidates and probes for a number of health indications. As a result, an effective and reliable synthetic preparation for their access and isolation would be invaluable. The first chapter involves the use of a combination of commercial flow apparatus to develop a chemical methodology for the efficient, sustainable, scalable and robust synthesis of aminated imidazoheterocycles via the Groebke-Blackburn-Bienaymé multicomponent reaction. Advantages of this process include the requirement for a reaction (residence) time of only 50 minutes, the tolerance of a wide range of functionality in all starting materials, and the facile scalability in flow, as demonstrated on multi-gram scale. A smaller, bespoke microfluidic system was then applied for the second chapter, where the use of flow equipment was validated in an ongoing programme within our laboratories, to rapidly generate a small library of diaminoquinazolines as potential antimalarials, following on from work at GSK’s infectious disease site in Tres Cantos, Madrid. Computational design elements were used to select small molecule targets based on frequently considered physicochemical parameters, and a tandem SNAr method was employed to produce decorated heterocyclic products in a short overall reaction time. This process represents a substantial acceleration in the synthesis of these compounds, facilitating far-reaching future work involving rapid drug design and access, and the potential for streamlining the preparative methods between small- and large-scale chemistry within early-stage discovery, especially within the pharmaceutical industry.
Advisor / supervisor
  • Kerr, William
Resource Type
  • Previously held under moratorium in Chemistry department (GSK) from 18/06/2019 until 18/06/2021.
Embargo Note
  • This thesis is restricted to Strathclyde users only until 18th June 2024.