{"title":"竞争性钾酸阻滞剂非舒拉赞的新型高效合成","authors":"Wei Qian, Fangyuan Hu, Qianxi Feng, Jiahui Ren, Qiaohong Huang, Shiling Liu, Fei Ling, Chunlin Wen, Yu Feng* and Weihui Zhong*, ","doi":"10.1021/acs.oprd.5c00255","DOIUrl":null,"url":null,"abstract":"<p >Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). The conventional synthesis route involves preparing methyl 5-(2,4-difluorophenyl)-4-methoxy-1<i>H</i>-pyrrole-3-carboxylate (<b>7</b>), a key intermediate associated with toxicity concerns, environmental pollution, and low yields. This article aims to develop an innovative synthetic strategy to overcome these limitations. Our approach utilizes 3-aminopropionitrile and methyl 2-(2,4-difluorophenyl)-2-oxoacetate (<b>20</b>) as key precursors for a streamlined one-pot synthesis of the cyano-containing pyrrole <b>23</b>, achieving a 90.0% yield. A significant advancement is the subsequent implementation of hydrogen gas as an ecofriendly reductant for direct cyano-to-aldehyde conversion. Starting from cost-effective 1,3-difluorobenzene (<b>18</b>), the optimized six-step route delivers fexuprazan hydrochloride (<b>1</b>) with an overall yield of 42.6% at kilogram scale. This improved protocol demonstrates significant advantages in process economics, operational simplicity, and environmental sustainability, establishing a robust platform for industrial-scale manufacture.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2400–2409"},"PeriodicalIF":3.5000,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Novel and Efficient Synthesis of Potassium-Competitive Acid Blocker Fexuprazan\",\"authors\":\"Wei Qian, Fangyuan Hu, Qianxi Feng, Jiahui Ren, Qiaohong Huang, Shiling Liu, Fei Ling, Chunlin Wen, Yu Feng* and Weihui Zhong*, \",\"doi\":\"10.1021/acs.oprd.5c00255\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). The conventional synthesis route involves preparing methyl 5-(2,4-difluorophenyl)-4-methoxy-1<i>H</i>-pyrrole-3-carboxylate (<b>7</b>), a key intermediate associated with toxicity concerns, environmental pollution, and low yields. This article aims to develop an innovative synthetic strategy to overcome these limitations. Our approach utilizes 3-aminopropionitrile and methyl 2-(2,4-difluorophenyl)-2-oxoacetate (<b>20</b>) as key precursors for a streamlined one-pot synthesis of the cyano-containing pyrrole <b>23</b>, achieving a 90.0% yield. A significant advancement is the subsequent implementation of hydrogen gas as an ecofriendly reductant for direct cyano-to-aldehyde conversion. Starting from cost-effective 1,3-difluorobenzene (<b>18</b>), the optimized six-step route delivers fexuprazan hydrochloride (<b>1</b>) with an overall yield of 42.6% at kilogram scale. This improved protocol demonstrates significant advantages in process economics, operational simplicity, and environmental sustainability, establishing a robust platform for industrial-scale manufacture.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":\"29 9\",\"pages\":\"2400–2409\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-09-05\",\"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.5c00255\",\"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.5c00255","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Novel and Efficient Synthesis of Potassium-Competitive Acid Blocker Fexuprazan
Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). The conventional synthesis route involves preparing methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate (7), a key intermediate associated with toxicity concerns, environmental pollution, and low yields. This article aims to develop an innovative synthetic strategy to overcome these limitations. Our approach utilizes 3-aminopropionitrile and methyl 2-(2,4-difluorophenyl)-2-oxoacetate (20) as key precursors for a streamlined one-pot synthesis of the cyano-containing pyrrole 23, achieving a 90.0% yield. A significant advancement is the subsequent implementation of hydrogen gas as an ecofriendly reductant for direct cyano-to-aldehyde conversion. Starting from cost-effective 1,3-difluorobenzene (18), the optimized six-step route delivers fexuprazan hydrochloride (1) with an overall yield of 42.6% at kilogram scale. This improved protocol demonstrates significant advantages in process economics, operational simplicity, and environmental sustainability, establishing a robust platform for industrial-scale manufacture.
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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