Coumadin (warfarin) is a commonly used anticoagulation drug for the treatment and/or prevention of thromboembolic events. Maintaining an optimal drug dose is challenging due to high inter-individual variability in patient response and a narrow therapeutic range. We are collaborating to use warfarin metabolite profiles from patients to improve understanding of the link between warfarin metabolism and response to treatment. These studies require authentic standards for warfarin enantiomers and their many metabolites, including hydroxywarfarins and glucuronides. We are employing green chemistry for enantioselective synthesis of these metabolites as standards for metabolite profiling. The synthesis involves an aldol condensation and an enantioselective, catalytic coupling with 4-hydroxycoumarins using diphenylethylenediamine (dpen) enantiomers. As determined by chiral HPLC, we obtained >99%ee for recrystallized R- and S -warfarin, and demonstrated for the first time the enantioselective synthesis of R- and S-6-hydroxywarfarin (97%ee and 93%ee, respectively). A variety of glucuronidation procedures are also under investigation.

Approaches to the synthesis of glucuronide derivatives of enantiomerically-enriched warfarin (Coumadin) metabolites

243rd National Meeting (2012)

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