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Ketamine is a versatile anesthetic and a novel antidepressant. Today, intravenous infusions of ketamine are utilized to treat various psychiatric disorders, such as depression. While oral delivery of ketamine offers superior patient convenience, the intravenous route remains preferable due to the poor bioavailability of orally administered ketamine.

Ketamine is extensively degraded in liver by first-pass metabolism. Deuterium, a stable isotope of hydrogen, presents a validated approach to address this problem. By exchanging the metabolically unstable hydrogen atoms in the ketamine molecule with deuterium, it is possible to increase the metabolic stability, and perhaps even the bioavailability of ketamine. This is due to the considerably greater bond strength observed in carbon-deuterium bonds when compared to carbon-hydrogen bonds.

The main objective of this study was to synthesize the compound d3-ketamine via the replacement of labile methyl-hydrogens in ketamine with deuterium. However, due to time limitations, the synthesis of d3-ketamine was not complete. Nonetheless, the synthesis of ketamine and norketamine was successfully accomplished, and their synthesis pathways were significantly optimized.

Additionally, as an unexpected outcome, this project led to the isolation of ketamine carbonate, a potential ketamine prodrug that may exhibit superior antidepressant efficacy compared to ketamine. However, further studies are required to characterize the compound’s PKPD profiles. This research not only improves our understanding of ketamine synthesis but also opens the door to potentially more effective oral treatments for psychiatric disorders.