{"title":"巴洛沙韦 Marboxil 工艺杂质的鉴定、合成、表征和控制策略的制定","authors":"Huixiong Lu, Guobin Xu, Jingping Kou, Shuming Wu, Jiebin Zeng, Yuting Liu, Jidi Lin, Yongbo Xu, Wei Shang, Yaoyao Li and Zhongqing Wang*, ","doi":"10.1021/acs.oprd.4c00011","DOIUrl":null,"url":null,"abstract":"<p >This manuscript provides a comprehensive summary of 12 process impurities in baloxavir marboxil, including four previously unreported impurities. Through identification, synthesis, and characterization using MS and NMR techniques, the formation pathways of each impurity were proposed to enhance the understanding of the process. Corresponding control strategies were established. Three batches of kilogram-scale demonstrations were conducted, resulting in baloxavir marboxil with a yield of 51%, purity exceeding 99.8%, and a single impurity detected at <0.10%, all achieved from chiral starting material <b>A-1</b>. Notably, the two genotoxic impurities were effectively purged to levels below detection limits, meeting the criteria specified by the Threshold of Toxicological Concern (TTC).</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification, Synthesis, Characterization, and Control Strategy Establishment for Process Impurities of Baloxavir Marboxil\",\"authors\":\"Huixiong Lu, Guobin Xu, Jingping Kou, Shuming Wu, Jiebin Zeng, Yuting Liu, Jidi Lin, Yongbo Xu, Wei Shang, Yaoyao Li and Zhongqing Wang*, \",\"doi\":\"10.1021/acs.oprd.4c00011\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >This manuscript provides a comprehensive summary of 12 process impurities in baloxavir marboxil, including four previously unreported impurities. Through identification, synthesis, and characterization using MS and NMR techniques, the formation pathways of each impurity were proposed to enhance the understanding of the process. Corresponding control strategies were established. Three batches of kilogram-scale demonstrations were conducted, resulting in baloxavir marboxil with a yield of 51%, purity exceeding 99.8%, and a single impurity detected at <0.10%, all achieved from chiral starting material <b>A-1</b>. Notably, the two genotoxic impurities were effectively purged to levels below detection limits, meeting the criteria specified by the Threshold of Toxicological Concern (TTC).</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-03-22\",\"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.4c00011\",\"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.4c00011","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Identification, Synthesis, Characterization, and Control Strategy Establishment for Process Impurities of Baloxavir Marboxil
This manuscript provides a comprehensive summary of 12 process impurities in baloxavir marboxil, including four previously unreported impurities. Through identification, synthesis, and characterization using MS and NMR techniques, the formation pathways of each impurity were proposed to enhance the understanding of the process. Corresponding control strategies were established. Three batches of kilogram-scale demonstrations were conducted, resulting in baloxavir marboxil with a yield of 51%, purity exceeding 99.8%, and a single impurity detected at <0.10%, all achieved from chiral starting material A-1. Notably, the two genotoxic impurities were effectively purged to levels below detection limits, meeting the criteria specified by the Threshold of Toxicological Concern (TTC).
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.