Coumadin (warfarin) is an 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 use warfarin metabolite profiles from patients to improve understanding of the link between metabolism and treatment response. Phase 1 metabolism produces a variety of hydroxywarfarins which are converted to their glucuronide derivatives in Phase 2. Our goal is to synthesize standards for metabolic profiling. Common synthesis methods involve the generation of racemic products that require subsequent separation to obtain individual enantiomers. Alternatively, we have utilized green chemistry to synthesize hydroxywarfarins enantioselectively and thus avoid extra purification steps. We have prepared 6-, 7-, and 4'-hydroxywarfarins via an enantioselective, catalytic coupling using diphenylethylenediamine (dpen) enantiomers. For example, we demonstrated for the first time the enantioselective synthesis of R- and S-7-hydroxywarfarin (>99% ee after recrystallization as determined by chiral HPLC). We have also characterized the ratio of open-chain and cyclic hemiacetal forms of these hydroxywarfarins in various solvents via NMR. Taken together, these efforts provide a simple and effective route to generate critical enantiomeric standards for identifying biomarkers to help predict patient Coumadin dose-responses.

Enantioselective synthesis and characterization of phase 1 warfarin metabolites

247th National Meeting (2014)

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