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New methods for rapid h/d exchange and related processing using microwave irradiation

Banci, Gabriele 2013. New methods for rapid h/d exchange and related processing using microwave irradiation. PhD Thesis, Cardiff University.
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Abstract

Microwave mediated H/D exchanges have been studiedin this thesis. The purpose of these studies is to validate an efficient method for replacing hydrogen by deuterium in molecules with biological and pharmaceutical activity. As a result of this, such deuterated compounds would be helpful during the investigation of pharmacological and metabolic studies. At the beginning of this research, aniline derivatives weremainly employed as substrates. Their importance in drug synthesis makes the corresponding labelled compounds useful as building blocks. During these studies a Pt catalyst wasemployed. As a consequence of its strong efficiency, fully deuterated compounds were obtained in many cases. In the first part of this research, yields were based on ratios between non-deuterated and deuterated original compounds. However, due to solubility problems and metal-complex formation, this parameter was found to vary considerably. Therefore, an analytical method, involving introduction of a non-deuterated acetyl group to the labelled substratewas employed, so that the acetyl group could be regarded as an internal reference for 1HNMR integration, allowing quantification of deuterium incorporation at all positions in the molecular structure. Kinetic experiments have also enabled the best conditions to be defined for the exchange reactions. Lastly, as a consequence of a reductive process, Pt0 has been recognized as a serious problem for calculating final yield. An appropriate method for eliminating it from the solutions has therefore been applied. A valid Pt mediated H/D mechanism has been proposed, based on suggestions from the literature that Pt can move around both aromatic rings and alkyl side chains. To try to get evidence for such a mechanism, different alkylanilines have been used, giving useful information regarding metal activity, particularly with respect to steric aspects. In the last part of the work, as a consequence of its importance in pharmaceutical chemistry, heterocyclic derivatives have been investigated. Satisfactory results have permitted the method to be explioted for some relevant drugs.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:23
URI: http://orca-mwe.cf.ac.uk/id/eprint/49931

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