Synthesis of methoxetamine, its metabolites and deuterium labelled analog as analytical standards and their HPLC and chiral capillary electrophoresis separation

Abstract

Methoxetamine, a designer drug marketed as a replacement for the dissociative anaesthetic ketamine, has been associated with significant numbers of hospital related intoxications and deaths in Europe. The fast and user-friendly identification and quantification of methoxetamine and its metabolites is a key factor for successful treatment of intoxication. Therefore, we suggested a convenient preparation method which was used for the synthesis of methoxetamine, seven methoxetamine metabolites and a deuterium labelled derivative as analytical standards. Methoxetamine and normethoxetamine were used as starting materials for the preparation of O-demethylated and N-dealkylated metabolites. The multistep synthesis starts from commercially available compounds and offers good yields. Our prepared analytical standards were used for the confirmation of the suggested structure of methoxetamine metabolites in rat urine by LCMS. Capillary electrophoresis was used for the chiral separation of MXE and its metabolites using β-cyclodextrin, carboxymethylated β-cyclodextrin, and sulphated β-cyclodextrin as chiral selectors at various concentrations. Chiral separation was successful for four analytes. A mixture of MXE and its metabolites was subsequently analyzed under optimal conditions, i.e. when using 15 mmol L⁻¹ β-cyclodextrin in 50 mmol L⁻¹ phosphate buffer, pH 2.5. In this case, chiral separation was achieved for three analytes and all analytes were separated from each other.