Joel T. Arcari, Catherine Buckley, Leanne M. Buzon, Yongbo Dan, Timothy Houck, Zuxi Jin, Chao Li, Peifang Li, Kai Liu, Yiyang Liu*, Javier Magano, Luis A. Martinez-Alsina, Bao Nguyen, Robert Pearson, Jared L. Piper*, John A. Ragan, Matthew R. Reese, Wanli Tian, Jared Van Haitsma, Michael G. Vetelino and Yuan Zhang,
{"title":"规模化品尼克氧化:BDK 抑制剂的工艺开发","authors":"Joel T. Arcari, Catherine Buckley, Leanne M. Buzon, Yongbo Dan, Timothy Houck, Zuxi Jin, Chao Li, Peifang Li, Kai Liu, Yiyang Liu*, Javier Magano, Luis A. Martinez-Alsina, Bao Nguyen, Robert Pearson, Jared L. Piper*, John A. Ragan, Matthew R. Reese, Wanli Tian, Jared Van Haitsma, Michael G. Vetelino and Yuan Zhang, ","doi":"10.1021/acs.oprd.4c00177","DOIUrl":null,"url":null,"abstract":"<p >The development of a safe and scalable Pinnick oxidation of an aldehyde to a carboxylic acid in the late-stage synthesis of a BDK inhibitor candidate, PF-07208254, is reported. Extensive process safety testing revealed a large exotherm with significant heat accumulation during oxidant addition, which was minimized through careful control of oxidant dosing, and higher dilutions ensured complete solubility of the reactants. The role of atmospheric oxygen in generating sulfuric acid in the product stream, leading to partial decomposition, was identified. The optimized process was safely executed on a kilogram scale to deliver high-quality API for toxicology and clinical studies.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pinnick Oxidation on Scale: Process Development of a BDK Inhibitor\",\"authors\":\"Joel T. Arcari, Catherine Buckley, Leanne M. Buzon, Yongbo Dan, Timothy Houck, Zuxi Jin, Chao Li, Peifang Li, Kai Liu, Yiyang Liu*, Javier Magano, Luis A. Martinez-Alsina, Bao Nguyen, Robert Pearson, Jared L. Piper*, John A. Ragan, Matthew R. Reese, Wanli Tian, Jared Van Haitsma, Michael G. Vetelino and Yuan Zhang, \",\"doi\":\"10.1021/acs.oprd.4c00177\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The development of a safe and scalable Pinnick oxidation of an aldehyde to a carboxylic acid in the late-stage synthesis of a BDK inhibitor candidate, PF-07208254, is reported. Extensive process safety testing revealed a large exotherm with significant heat accumulation during oxidant addition, which was minimized through careful control of oxidant dosing, and higher dilutions ensured complete solubility of the reactants. The role of atmospheric oxygen in generating sulfuric acid in the product stream, leading to partial decomposition, was identified. The optimized process was safely executed on a kilogram scale to deliver high-quality API for toxicology and clinical studies.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-07-03\",\"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.4c00177\",\"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.4c00177","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Pinnick Oxidation on Scale: Process Development of a BDK Inhibitor
The development of a safe and scalable Pinnick oxidation of an aldehyde to a carboxylic acid in the late-stage synthesis of a BDK inhibitor candidate, PF-07208254, is reported. Extensive process safety testing revealed a large exotherm with significant heat accumulation during oxidant addition, which was minimized through careful control of oxidant dosing, and higher dilutions ensured complete solubility of the reactants. The role of atmospheric oxygen in generating sulfuric acid in the product stream, leading to partial decomposition, was identified. The optimized process was safely executed on a kilogram scale to deliver high-quality API for toxicology and clinical studies.
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.