%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