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.