Chaomin Li*, Shujun Wang, Jianxin Yang, Cuicui Yuan, Dong Wang, Deju Shang and Erin M. O’Brien,
{"title":"从手性拆分到非对映选择性Ellman化学再到生物催化:BTK抑制剂BIIB091高效合成四氢苯并氮卓核心的途径进化","authors":"Chaomin Li*, Shujun Wang, Jianxin Yang, Cuicui Yuan, Dong Wang, Deju Shang and Erin M. O’Brien, ","doi":"10.1021/acs.oprd.3c00133","DOIUrl":null,"url":null,"abstract":"<p >Two improved routes to BIIB091 key tetrahydrobenzoazepine core (<b>1</b>) were developed to support tox and early clinical demands. The first improved route takes advantage of a diastereoselective Ellman’s sulfinimine reduction as the key step of chiral amine synthesis. This route was successfully scaled up to support API manufacturing for early clinical trials. The second improved route uses an amine transaminase (ATA) biocatalysis reaction of an N-Boc ketone (<b>15</b>) precursor, which was prepared by applying a trifluoroacetamide-protecting group for effective azepine ring construction and protecting group swap. The ATA route is demonstrated at a subkilogram scale and has the potential to become a late clinical and commercial route due to its significant improvements in synthetic efficiency, overall yield, and process greenness.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"27 8","pages":"1463–1473"},"PeriodicalIF":3.1000,"publicationDate":"2023-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"From Chiral Resolution to Diastereoselective Ellman Chemistry to Biocatalysis: Route Evolution for the Efficient Synthesis of the Tetrahydrobenzoazepine Core of BTK Inhibitor BIIB091\",\"authors\":\"Chaomin Li*, Shujun Wang, Jianxin Yang, Cuicui Yuan, Dong Wang, Deju Shang and Erin M. O’Brien, \",\"doi\":\"10.1021/acs.oprd.3c00133\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Two improved routes to BIIB091 key tetrahydrobenzoazepine core (<b>1</b>) were developed to support tox and early clinical demands. The first improved route takes advantage of a diastereoselective Ellman’s sulfinimine reduction as the key step of chiral amine synthesis. This route was successfully scaled up to support API manufacturing for early clinical trials. The second improved route uses an amine transaminase (ATA) biocatalysis reaction of an N-Boc ketone (<b>15</b>) precursor, which was prepared by applying a trifluoroacetamide-protecting group for effective azepine ring construction and protecting group swap. The ATA route is demonstrated at a subkilogram scale and has the potential to become a late clinical and commercial route due to its significant improvements in synthetic efficiency, overall yield, and process greenness.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":\"27 8\",\"pages\":\"1463–1473\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2023-07-18\",\"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.3c00133\",\"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.3c00133","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
From Chiral Resolution to Diastereoselective Ellman Chemistry to Biocatalysis: Route Evolution for the Efficient Synthesis of the Tetrahydrobenzoazepine Core of BTK Inhibitor BIIB091
Two improved routes to BIIB091 key tetrahydrobenzoazepine core (1) were developed to support tox and early clinical demands. The first improved route takes advantage of a diastereoselective Ellman’s sulfinimine reduction as the key step of chiral amine synthesis. This route was successfully scaled up to support API manufacturing for early clinical trials. The second improved route uses an amine transaminase (ATA) biocatalysis reaction of an N-Boc ketone (15) precursor, which was prepared by applying a trifluoroacetamide-protecting group for effective azepine ring construction and protecting group swap. The ATA route is demonstrated at a subkilogram scale and has the potential to become a late clinical and commercial route due to its significant improvements in synthetic efficiency, overall yield, and process greenness.
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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