Optimized Process and Quality Evaluation for Ketamine Hydrochloride

In this study, we developed an enhanced and efficient kilogram-scale synthesis method for ketamine hydrochloride. We discovered that using N-bromosuccinimide (NBS) instead of HBr/H2O2 improved the conversion rate of the bromination reaction from 88% to 99% and led to a milder and steadier reaction. Besides, CH3NH2/K2CO3 was used in the methylamination reaction to shorten the reaction time from 80 to 15 h, with an 80% yield of 1-((2-chlorophenyl) (methylimino) methyl) cyclopentanol hydrochloride (6) and 99.5% purity. Furthermore, the residue on ignition of ketamine hydrochloride decreased from 3.00% to below 0.10% with extra aqueous base washing. Several related impurities of ketamine hydrochloride were also assessed, and the clarity and color of the ketamine hydrochloride solution were investigated. In summary, the optimized process was industrially scalable and able to control the final quality of ketamine hydrochloride.