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Kinetics and mechanism of H/D exchange reactions and racemisation in aqueous solutions: configurational stability of ester and amide arylglycine derivatives

Ballard, Andrew 2011. Kinetics and mechanism of H/D exchange reactions and racemisation in aqueous solutions: configurational stability of ester and amide arylglycine derivatives. PhD Thesis, Cardiff University.

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Abstract

The configurational stability of a range of stereogenic centres in aqueous media has been studied, with the goal of understanding the structural and environmental factors contributing to configurational instability. This information will be of use to the pharmaceutical industry, for which the chiral integrity of drug compounds is imperative. Chapter 1 outlines the background to this project, providing an overview of pharmacological racemisation including potential mechanisms, examples from literature, and the methodology used. Chapter 2 focuses on database mining studies undertaken on AstraZeneca compound libraries, the results of which guided the structures investigated in the rest of the thesis. Most compounds in the libraries do not appear at risk of racemisation. Of those that do, stereogenic centres with proton, carbonyl, aromatic and nitrogen substituents appear most frequently. Chapter 3 discusses experimental work determining rate constants of proton-deuterium exchange (as a model for racemisation) under physiological conditions, for a set of TV-acetyl arylglycine methyl esters. These rate constants suggest that such compounds are susceptible to in vivo racemisation through an SeI mechanism. Chapter 4 outlines experimental work determining rate constants of proton-deuterium exchange, for a set of N-substituted phenylglycine amides. These compounds undergo H/D exchange through an SeI mechanism, although the rate at which H/D exchange occurs suggests they would not be at risk of in vivo racemisation. These results show that an amide substituent is far weaker than a methyl ester in facilitating racemisation. Chapter 5 reports the results of computational studies performed on the compounds investigated in Chapters 3 and 4. The energy gap between a molecule and its anion when deprotonated at the stereogenic centre was correlated with the experimentally determined data, suggesting that prediction of configurational instability for novel compounds may be possible. This correlation only holds when the PCM solvent model is used in calculations.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
ISBN: 9781303222931
Date of First Compliant Deposit: 30 March 2016
Last Modified: 09 Jan 2018 20:24
URI: http://orca-mwe.cf.ac.uk/id/eprint/55130

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