{"title":"巴洛沙韦 Marboxil 的实用生产工艺：有效选择和替换保护基团，促进结晶诱导的非对映异构体转化","authors":"Nobuaki Fukui*, Setsuya Shibahara, Toshikatsu Maki, Tatsuhiko Ueno, Shuichi Yanagisawa, Kazuya Okamoto, Emi Tanimoto, Takafumi Ohara, Tatsuro Yasukata and Takayuki Tsuritani, ","doi":"10.1021/acs.oprd.3c00503","DOIUrl":null,"url":null,"abstract":"<p >Baloxavir marboxil (BXM) is an influenza antiviral drug that exploits a cap-dependent endonuclease (CEN) inhibitor. The synthesis route used in the initial CMC development study had several problems hampering scale-up, such as poor stereochemical outcome which decreased the yield, usage of a corrosive reagent, and a cumbersome protocol for the key step. We addressed these problems to enable practical and operation-friendly manufacture of BXM at a larger production scale for early and successive CMC development. The new route includes the following steps: (1) a magnesium-mediated alkoxy displacement reaction to prepare an intermediate without loss of optical purity and (2) diastereoselective preparation of an intermediate via a dehydration condensation reaction with a crystallization-induced diastereomer transformation (CIDT) process. This facile route enabled scalable manufacturing to supply BXM.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Practical Manufacturing Process for Baloxavir Marboxil: Effective Selection and Replacement of Protective Group toward Enhancement of Crystallization-Induced Diastereomer Transformation\",\"authors\":\"Nobuaki Fukui*, Setsuya Shibahara, Toshikatsu Maki, Tatsuhiko Ueno, Shuichi Yanagisawa, Kazuya Okamoto, Emi Tanimoto, Takafumi Ohara, Tatsuro Yasukata and Takayuki Tsuritani, \",\"doi\":\"10.1021/acs.oprd.3c00503\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Baloxavir marboxil (BXM) is an influenza antiviral drug that exploits a cap-dependent endonuclease (CEN) inhibitor. The synthesis route used in the initial CMC development study had several problems hampering scale-up, such as poor stereochemical outcome which decreased the yield, usage of a corrosive reagent, and a cumbersome protocol for the key step. We addressed these problems to enable practical and operation-friendly manufacture of BXM at a larger production scale for early and successive CMC development. The new route includes the following steps: (1) a magnesium-mediated alkoxy displacement reaction to prepare an intermediate without loss of optical purity and (2) diastereoselective preparation of an intermediate via a dehydration condensation reaction with a crystallization-induced diastereomer transformation (CIDT) process. This facile route enabled scalable manufacturing to supply BXM.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-04-04\",\"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.3c00503\",\"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.3c00503","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Practical Manufacturing Process for Baloxavir Marboxil: Effective Selection and Replacement of Protective Group toward Enhancement of Crystallization-Induced Diastereomer Transformation
Baloxavir marboxil (BXM) is an influenza antiviral drug that exploits a cap-dependent endonuclease (CEN) inhibitor. The synthesis route used in the initial CMC development study had several problems hampering scale-up, such as poor stereochemical outcome which decreased the yield, usage of a corrosive reagent, and a cumbersome protocol for the key step. We addressed these problems to enable practical and operation-friendly manufacture of BXM at a larger production scale for early and successive CMC development. The new route includes the following steps: (1) a magnesium-mediated alkoxy displacement reaction to prepare an intermediate without loss of optical purity and (2) diastereoselective preparation of an intermediate via a dehydration condensation reaction with a crystallization-induced diastereomer transformation (CIDT) process. This facile route enabled scalable manufacturing to supply BXM.
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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