Lewis Acid-Catalyzed Racemization and Recycling of the Undesired (R)‑Ketamine

• Published in: Organic process research & development Vol. 24; no. 2; pp. 301 - 305
• Main Authors: Gao, Shenghua, Gao, Xuezhi, Li, Houyong, Yang, Anjiang, Yang, Zhezhou, Zhang, Fuli
• Format: Journal Article
• Language: English
• Published: American Chemical Society 21.02.2020
• Subjects: Lewis acid; racemization; ketamine; NMDA receptor antagonist
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.9b00436

The first detailed description of the Lewis acid-catalyzed racemization of (R)-ketamine is reported. A process for racemization of the undesired (R)-ketamine enantiomer produced from the resolution for preparing the NMDA receptor antagonist (S)-ketamine was developed in quantitative yield with 99% chemical purity in the presence of a Lewis acid at 150 °C. Varying degrees of racemization were observed in the presence of various frequently used Lewis acids separately, and the catalytic efficiencies were arranged as follows: MgCl2 ≈ AlCl3 > FeCl3 > ZnCl2 > BF3 > CaCl2. The racemized ketamine was subsequently resolved using l-(+)-tartaric acid to obtain (S)-ketamine in 41% yield with 99.5% ee. Such a concise and cost-efficient approach for the racemization can be industrially useful to recycle the waste (R)-ketamine enantiomer into the resolution process to obtain (S)-ketamine.