%0 Journal Article %A Gao, Shenghua %A Gao, Xuezhi %A Yang, Zhezhou %A Zhang, Fuli %D 2020 %T Process Research and Impurity Control Strategy of Esketamine %U https://acs.figshare.com/articles/journal_contribution/Process_Research_and_Impurity_Control_Strategy_of_Esketamine/12049143 %R 10.1021/acs.oprd.9b00553.s001 %2 https://ndownloader.figshare.com/files/22142592 %K ICH-grade quality %K mother liquors %K undesired isomer %K chiral resolution %K Critical process parameters %K ketamine %K impurity %K control strategies %K times recycling %K Impurity Control Strategy %K process Research %K racemization %K process-related impurities %K aluminum chloride %K formation mechanisms %K esketamine %X An improved synthesis of (S)-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the (S)-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity. The ICH-grade quality (S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable. %I ACS Publications