Qiang Yang*, Derek R. Starkey, Jingfan Yang, Radhe K. Vaid, Peng-Kai Kao, Charles B. Held, Mark D. Argentine, Derek Berglund, Alison Campbell Brewer, Jonas Y. Buser, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen and Fangyun Yang,
{"title":"甲氟格列酮中间体(S)-5-（2,2-二甲基四氢- 2h -吡喃-4-基）- 1h -吲哚的制备工艺研究第三部分。缩合相转移催化烷基化和环丙烷化工艺的发展","authors":"Qiang Yang*, Derek R. Starkey, Jingfan Yang, Radhe K. Vaid, Peng-Kai Kao, Charles B. Held, Mark D. Argentine, Derek Berglund, Alison Campbell Brewer, Jonas Y. Buser, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen and Fangyun Yang, ","doi":"10.1021/acs.oprd.5c00185","DOIUrl":null,"url":null,"abstract":"<p >A scalable 8-step route for a key (<i>S</i>)-5-(2,2-dimethyltetrahydro-2<i>H</i>-pyran-4-yl)-1<i>H</i>-indole intermediate for orforglipron was developed to support clinical trials. Highlights of process development results in this contribution include the following: (1) approximately 50% reduction of a key des-carbonyl impurity in the reductive removal of the Evans auxiliary by the introduction of MgCl<sub>2</sub> as a chelating agent for the reduction with LiBH<sub>4</sub>, (2) a telescoped process for PTC alkylation with chloroacetonitrile and subsequent cyclopropyl ring formation with an asymmetric cyclic sulfate avoiding the problematic isolation of the alkylation product, and (3) significantly improved isolated yield and stereoselectivity of the cyclopropyl ring formation by replacing KHMDS with LiO<i>t</i>-Bu as the base for the reaction. The developed process was successfully scaled up to >400 kg scale for each step to deliver a high-quality product in an overall yield of 22%, demonstrating the robustness of the optimized process.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 8","pages":"2018–2029"},"PeriodicalIF":3.5000,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part III. Development of a Telescoped Phase-Transfer-Catalyzed Alkylation and Cyclopropanation Process\",\"authors\":\"Qiang Yang*, Derek R. Starkey, Jingfan Yang, Radhe K. Vaid, Peng-Kai Kao, Charles B. Held, Mark D. Argentine, Derek Berglund, Alison Campbell Brewer, Jonas Y. Buser, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen and Fangyun Yang, \",\"doi\":\"10.1021/acs.oprd.5c00185\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >A scalable 8-step route for a key (<i>S</i>)-5-(2,2-dimethyltetrahydro-2<i>H</i>-pyran-4-yl)-1<i>H</i>-indole intermediate for orforglipron was developed to support clinical trials. Highlights of process development results in this contribution include the following: (1) approximately 50% reduction of a key des-carbonyl impurity in the reductive removal of the Evans auxiliary by the introduction of MgCl<sub>2</sub> as a chelating agent for the reduction with LiBH<sub>4</sub>, (2) a telescoped process for PTC alkylation with chloroacetonitrile and subsequent cyclopropyl ring formation with an asymmetric cyclic sulfate avoiding the problematic isolation of the alkylation product, and (3) significantly improved isolated yield and stereoselectivity of the cyclopropyl ring formation by replacing KHMDS with LiO<i>t</i>-Bu as the base for the reaction. The developed process was successfully scaled up to >400 kg scale for each step to deliver a high-quality product in an overall yield of 22%, demonstrating the robustness of the optimized process.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":\"29 8\",\"pages\":\"2018–2029\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-08-05\",\"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.5c00185\",\"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.5c00185","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part III. Development of a Telescoped Phase-Transfer-Catalyzed Alkylation and Cyclopropanation Process
A scalable 8-step route for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate for orforglipron was developed to support clinical trials. Highlights of process development results in this contribution include the following: (1) approximately 50% reduction of a key des-carbonyl impurity in the reductive removal of the Evans auxiliary by the introduction of MgCl2 as a chelating agent for the reduction with LiBH4, (2) a telescoped process for PTC alkylation with chloroacetonitrile and subsequent cyclopropyl ring formation with an asymmetric cyclic sulfate avoiding the problematic isolation of the alkylation product, and (3) significantly improved isolated yield and stereoselectivity of the cyclopropyl ring formation by replacing KHMDS with LiOt-Bu as the base for the reaction. The developed process was successfully scaled up to >400 kg scale for each step to deliver a high-quality product in an overall yield of 22%, demonstrating the robustness of the optimized process.
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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