{"title":"大规模可缩减制备埃多沙班关键手性环己烷顺式二胺中间体的新方法","authors":"Dingding Yuan, Qiujun Peng, Wenwen Xia, Wansheng Yu, Libo Ruan, Yaping Wang, Yu Chen* and Xianhua Pan*, ","doi":"10.1021/acs.oprd.4c00039","DOIUrl":null,"url":null,"abstract":"<p >A new synthesis of <i>tert</i>-butyl (1<i>R</i>,2<i>S</i>,5<i>S</i>)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, a key intermediate of edoxaban, is disclosed. This compound is a cyclohexane <i>cis</i>-diamine whose structure is a synthetic challenge. The known synthetic methods suffer from drawbacks, such as low yield, long reaction times, as well as excessive use of NaN<sub>3</sub>. The new method includes a total of nine steps starting from the known compound, (1<i>S</i>,4<i>S</i>,5<i>S</i>)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one, whose γ-butyrolactone frame is ring-opened to form <i>trans</i>-3-azido-4-hydroxy cyclohexane after the first two steps. Subsequent oxidation leads to the formation of a cyclohexanone, which is then transformed to <i>cis</i>-diamine through enzyme-catalyzed asymmetric reductive amination, acylation with CbzCl, and reduction of the azido group successively. The target, <i>tert</i>-butyl (1<i>R</i>,2<i>S</i>,5<i>S</i>)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, is finally formed through acylation with (Boc)<sub>2</sub>O, followed by deprotection of the Cbz group using hydrogenation.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 7","pages":"2623–2634"},"PeriodicalIF":3.5000,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"New Method to Large-Scalable Preparation of the Key Chiral Cyclohexane cis-Diamine Intermediate for Edoxaban\",\"authors\":\"Dingding Yuan, Qiujun Peng, Wenwen Xia, Wansheng Yu, Libo Ruan, Yaping Wang, Yu Chen* and Xianhua Pan*, \",\"doi\":\"10.1021/acs.oprd.4c00039\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >A new synthesis of <i>tert</i>-butyl (1<i>R</i>,2<i>S</i>,5<i>S</i>)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, a key intermediate of edoxaban, is disclosed. This compound is a cyclohexane <i>cis</i>-diamine whose structure is a synthetic challenge. The known synthetic methods suffer from drawbacks, such as low yield, long reaction times, as well as excessive use of NaN<sub>3</sub>. The new method includes a total of nine steps starting from the known compound, (1<i>S</i>,4<i>S</i>,5<i>S</i>)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one, whose γ-butyrolactone frame is ring-opened to form <i>trans</i>-3-azido-4-hydroxy cyclohexane after the first two steps. Subsequent oxidation leads to the formation of a cyclohexanone, which is then transformed to <i>cis</i>-diamine through enzyme-catalyzed asymmetric reductive amination, acylation with CbzCl, and reduction of the azido group successively. The target, <i>tert</i>-butyl (1<i>R</i>,2<i>S</i>,5<i>S</i>)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, is finally formed through acylation with (Boc)<sub>2</sub>O, followed by deprotection of the Cbz group using hydrogenation.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":\"28 7\",\"pages\":\"2623–2634\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-06-14\",\"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.4c00039\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00039","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
New Method to Large-Scalable Preparation of the Key Chiral Cyclohexane cis-Diamine Intermediate for Edoxaban
A new synthesis of tert-butyl (1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, a key intermediate of edoxaban, is disclosed. This compound is a cyclohexane cis-diamine whose structure is a synthetic challenge. The known synthetic methods suffer from drawbacks, such as low yield, long reaction times, as well as excessive use of NaN3. The new method includes a total of nine steps starting from the known compound, (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one, whose γ-butyrolactone frame is ring-opened to form trans-3-azido-4-hydroxy cyclohexane after the first two steps. Subsequent oxidation leads to the formation of a cyclohexanone, which is then transformed to cis-diamine through enzyme-catalyzed asymmetric reductive amination, acylation with CbzCl, and reduction of the azido group successively. The target, tert-butyl (1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, is finally formed through acylation with (Boc)2O, followed by deprotection of the Cbz group using hydrogenation.
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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
