Scott D. McCann*, Sean H. Dubina*, Birgit Kosjek, Embarek Alwedi, Taylor Behre, Samantha A. Burgess, Guilherme Dal Poggetto, Daniel A. DiRocco, Clara Hartmanshenn, Jonathan P. McMullen, Nilusha Padivitage and Alexandra C. Sun,
{"title":"贝珠替凡绿色可持续生产工艺的演变：第 5 部分──化学酵素非对映选择性氟化/DKR","authors":"Scott D. McCann*, Sean H. Dubina*, Birgit Kosjek, Embarek Alwedi, Taylor Behre, Samantha A. Burgess, Guilherme Dal Poggetto, Daniel A. DiRocco, Clara Hartmanshenn, Jonathan P. McMullen, Nilusha Padivitage and Alexandra C. Sun, ","doi":"10.1021/acs.oprd.3c00421","DOIUrl":null,"url":null,"abstract":"<p >A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced a precious metal catalyst with a ketoreductase (KRED) in the DKR. Achieving this one-pot reaction required several rounds of enzyme evolution that improved enzyme stability in the presence of acetonitrile and methanol. To maintain development progress and satisfy program timelines, process development around the reaction, workup, and isolation operations was performed in parallel with the enzyme evolution and required ongoing modification, as new variants were made available. Additionally, opportunities for improvements to product quality and process robustness were identified by resolving issues observed in piloting experiments.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 2","pages":"441–450"},"PeriodicalIF":3.5000,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 5─Chemoenzymatic Diastereoselective Fluorination/DKR\",\"authors\":\"Scott D. McCann*, Sean H. Dubina*, Birgit Kosjek, Embarek Alwedi, Taylor Behre, Samantha A. Burgess, Guilherme Dal Poggetto, Daniel A. DiRocco, Clara Hartmanshenn, Jonathan P. McMullen, Nilusha Padivitage and Alexandra C. Sun, \",\"doi\":\"10.1021/acs.oprd.3c00421\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced a precious metal catalyst with a ketoreductase (KRED) in the DKR. Achieving this one-pot reaction required several rounds of enzyme evolution that improved enzyme stability in the presence of acetonitrile and methanol. To maintain development progress and satisfy program timelines, process development around the reaction, workup, and isolation operations was performed in parallel with the enzyme evolution and required ongoing modification, as new variants were made available. Additionally, opportunities for improvements to product quality and process robustness were identified by resolving issues observed in piloting experiments.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":\"28 2\",\"pages\":\"441–450\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-02-07\",\"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.3c00421\",\"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.3c00421","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 5─Chemoenzymatic Diastereoselective Fluorination/DKR
A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced a precious metal catalyst with a ketoreductase (KRED) in the DKR. Achieving this one-pot reaction required several rounds of enzyme evolution that improved enzyme stability in the presence of acetonitrile and methanol. To maintain development progress and satisfy program timelines, process development around the reaction, workup, and isolation operations was performed in parallel with the enzyme evolution and required ongoing modification, as new variants were made available. Additionally, opportunities for improvements to product quality and process robustness were identified by resolving issues observed in piloting experiments.
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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