Thesis

New treatments for inflammatory diseases : optimisation and understanding of key processes

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Awarding institution
  • University of Strathclyde
Date of award
  • 2012
Thesis identifier
  • T15164
Person Identifier (Local)
  • 201060632
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Department, School or Faculty
Abstract
  • This thesis is split into two main parts, both concerned with new treatments for inflammatory diseases. Section 3 details the investigation and optimisation of anazide reduction to prepare a key amine intermediate, which was required in the synthetic route to a desired spleen tyrosine kinase (Syk) inhibitor. This targeted compound was required for toxicological studies prior to commencing phase I clinical trials for the treatment of inflammatory diseases such as rheumatoid arthritis and urticaria. The chemistry was optimised to allow preparation of 552 g of the requisite amine in quantitative yield with excellent control over a number of process impurities. Section 4 discusses darapladib, an inhibitor of lipoprotein-associated phospholipase A₂, which is in phase III clinical trials for the treatment of atherosclerosis. The preparation of a key carboxylic acid intermediate was investigated, incorporating experimental design methods to determine the effect of varying work-up parameters on impurities and yield. The main impurity of interest was 4-fluorobenzyl chloride. In order to demonstrate control over this impurity, its fate and effects in the downstream chemistry were determined. The development and verification of a predictive kinetic model for the reaction of 4-fluorobenzyl chloride during the final amidation transformation are discussed. The thesis also provides an overview of the variable work programmes typically experienced by process chemists. In particular, the contrast between the level of detail and understanding required for late phase projects, and the need for rapid material delivery in early phase projects, is exemplified.
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  • Previously held under moratorium in Chemistry department (GSK) from March 2013 until March 2018.
DOI
Date Created
  • 2012
Former identifier
  • 9912708393402996
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