{"title":"Development of a Scalable Route with Efficient Stereoisomer Control to YZJ-1139, an Orexin Receptor Antagonist","authors":"Zhenya Zeng*, Jiangbo Zhang, Miao Jia, Bo Wu, Xunzhi Cai, Xingsong Zhang, Yixiao Feng, Youhong Ma, Qingfu Gao, Zonglei Fei","doi":"10.1021/acs.oprd.1c00457","DOIUrl":null,"url":null,"abstract":"<p >An effort toward the synthesis and process development of the orexin receptor antagonist YZJ-1139(<b>1</b>) was described in this article. YZJ-1139(<b>1</b>) contains the azabicyclic nortropane structure with three chiral centers. By the original process, highly pure intermediates or API could be obtained by chromatography with a relatively low yield. To remove the undesirable stereoisomers as early as possible, intermediate <b>13</b> with (<i>R</i>)-α-phenethyl was synthesized by the Robinson–Sch?pf reaction and easily purified as hydrochloride. The single crystal X-ray study was used to confirm the stereo configuration of <b>13·HCl</b> and <b>18·HCl</b>. The protecting group could be easily removed by transfer hydrogenation, resulting in enantiomerically pure intermediate <b>3</b> as a <span>d</span>-tartarate. The overall yield for preparing YZJ-1139(<b>1</b>) was significantly increased, and this cost-efficient process might be promising in future commercial productions.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"26 2","pages":"447–457"},"PeriodicalIF":3.5000,"publicationDate":"2022-01-27","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.1c00457","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
An effort toward the synthesis and process development of the orexin receptor antagonist YZJ-1139(1) was described in this article. YZJ-1139(1) contains the azabicyclic nortropane structure with three chiral centers. By the original process, highly pure intermediates or API could be obtained by chromatography with a relatively low yield. To remove the undesirable stereoisomers as early as possible, intermediate 13 with (R)-α-phenethyl was synthesized by the Robinson–Sch?pf reaction and easily purified as hydrochloride. The single crystal X-ray study was used to confirm the stereo configuration of 13·HCl and 18·HCl. The protecting group could be easily removed by transfer hydrogenation, resulting in enantiomerically pure intermediate 3 as a d-tartarate. The overall yield for preparing YZJ-1139(1) was significantly increased, and this cost-efficient process might be promising in future commercial productions.
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.