Bibo Jiang, Haibo Pan, Jiajia Liu, Xiaojie Zhang, Qian Wang, Tao Zhang* and Fuli Zhang*,
{"title":"Optimized Process and Quality Evaluation for Ketamine Hydrochloride","authors":"Bibo Jiang, Haibo Pan, Jiajia Liu, Xiaojie Zhang, Qian Wang, Tao Zhang* and Fuli Zhang*, ","doi":"10.1021/acs.oprd.3c00082","DOIUrl":null,"url":null,"abstract":"<p >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/H<sub>2</sub>O<sub>2</sub> improved the conversion rate of the bromination reaction from 88% to 99% and led to a milder and steadier reaction. Besides, CH<sub>3</sub>NH<sub>2</sub>/K<sub>2</sub>CO<sub>3</sub> 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 (<b>6</b>) 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.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"27 7","pages":"1330–1338"},"PeriodicalIF":3.1000,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.3c00082","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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