Synthesis of carbon‐14 labeled ketamine and norketamine

Ketamine is a well‐known general anesthetic that inhibits cerebral NMDA receptors. Norketamine is a major circulating metabolite of this drug. A nasal spray formulation of esketamine, the S enantiomer of ketamine, is under development for the management of treatment‐resistant depression. To assess the pharmacokinetic properties, C‐14 labeled ketamine and norketamine were prepared separately from commercially available [ 14 C]CuCN through a five‐step sequence with the C‐14 label at the quaternary carbon of the cyclohexyl ring. Chiral resolution of [ 14 C]ketamine and chiral column separation of [ 14 C]norketamine resolved/separated the ( S )‐enantiomers from ( R )‐enantiomers.