This thesis describes the synthesis of 5-deuteropyrimidine-4-carboxylic acid. Deuterium was introduced at the site 5 in the ring, which could allow the study of a secondary kinetic isotope effect in the action of the enzyme orotidine 5′-monophosphate decarboxylase (OMPDC), which catalyses the decarboxylation reaction in the conversion of orotidine 5′-monophosphate (OMP) to uridine 5′-monophosphate (UMP). This reaction represents the final step in nucleotide biosynthesis in the Plasmodium falciparum parasite, which is responsible for most of the fatal cases of malaria in humans. The synthesis was carried out in three steps, first converting the carboxyl group to an ortho-directing amide group. In the next step, the molecule was deprotonated at the site 5 using an organolithium reagent and deuterium was introduced into the molecule by subsequent electrophilic substitution with heavy water. In the final step, the amide group was converted back to the carboxyl functional group by basic hydrolysis and the final 5-deuteropyrimidine-4-carboxylic acid was isolated. The ester functional group was also tried as a directing group in the synthesis process, but no deuteration took place. A new compound, N,N-diisopropyl-5-(pyrimidin-4-carbonyl)pyrimidin-4-carboxamide, not yet described in the literature, was obtained. Both synthesised compounds were characterised by NMR techniques, IR spectroscopy, melting point measurement and high resolution mass spectrometry. The synthesised 5-deuteropyrimidine-4-carboxylic acid was sent to the project partners at Queen's University in Kingston (Ontario, Canada) to carry out studies on reaction kinetics and the secondary kinetic isotope effect.
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