Rogelio P. Frutos*, Thomas G. Tampone, Frank Gerstmann, Dirk Weber, Tobias Brodmann, Robert Hagenkötter, Jocelyn Abella, Bing-Shiou Yang, Jason Mulder, Sonia Rodriguez, Heewon Lee, Joe Gao and Jinhua J. Song,
{"title":"开发用于合成选择性 PDE4B 抑制剂 Nerandomilast（BI 1015550）的可扩展不对称工艺","authors":"Rogelio P. Frutos*, Thomas G. Tampone, Frank Gerstmann, Dirk Weber, Tobias Brodmann, Robert Hagenkötter, Jocelyn Abella, Bing-Shiou Yang, Jason Mulder, Sonia Rodriguez, Heewon Lee, Joe Gao and Jinhua J. Song, ","doi":"10.1021/acs.oprd.4c0030910.1021/acs.oprd.4c00309","DOIUrl":null,"url":null,"abstract":"<p >A robust and scalable synthesis process for Nerandomilast (<b>1</b>, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidin-4-yl)amino)cyclobutyl)methanol (<b>4</b>) by means of a regioselective S<sub>N</sub>Ar reaction between (1-aminocyclobutyl)methanol (<b>6</b>) and 2,4-dichloro-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidine (<b>5</b>), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (<b>3</b>) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (<i>R</i>)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidine 5-oxide (<b>2</b>).</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of a Scalable Asymmetric Process for the Synthesis of Selective PDE4B Inhibitor Nerandomilast (BI 1015550)\",\"authors\":\"Rogelio P. Frutos*, Thomas G. Tampone, Frank Gerstmann, Dirk Weber, Tobias Brodmann, Robert Hagenkötter, Jocelyn Abella, Bing-Shiou Yang, Jason Mulder, Sonia Rodriguez, Heewon Lee, Joe Gao and Jinhua J. Song, \",\"doi\":\"10.1021/acs.oprd.4c0030910.1021/acs.oprd.4c00309\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >A robust and scalable synthesis process for Nerandomilast (<b>1</b>, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidin-4-yl)amino)cyclobutyl)methanol (<b>4</b>) by means of a regioselective S<sub>N</sub>Ar reaction between (1-aminocyclobutyl)methanol (<b>6</b>) and 2,4-dichloro-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidine (<b>5</b>), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (<b>3</b>) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (<i>R</i>)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidine 5-oxide (<b>2</b>).</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-09-05\",\"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.4c00309\",\"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.4c00309","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 Scalable Asymmetric Process for the Synthesis of Selective PDE4B Inhibitor Nerandomilast (BI 1015550)
A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective SNAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).
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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
