Early Process Development of CH7057288, a Benzofuran-Containing Selective NTRK Inhibitor

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-01-03 DOI:10.1021/acs.oprd.3c00434

Tomohiro Oki*, Junichi Shiina, Hiroshi Fukuda, Minoru Yamawaki, Yasushi Kito, Masaki Tomizawa, Hiroshi Iwamura, Masao Tsukazaki, Azusa Toya, Shun Tsuzaki, Naoto Hama, Akira Kawase, Kenichi Nomura, Hisashi Ito and Kenji Maeda,

{"title":"Early Process Development of CH7057288, a Benzofuran-Containing Selective NTRK Inhibitor","authors":"Tomohiro Oki*, Junichi Shiina, Hiroshi Fukuda, Minoru Yamawaki, Yasushi Kito, Masaki Tomizawa, Hiroshi Iwamura, Masao Tsukazaki, Azusa Toya, Shun Tsuzaki, Naoto Hama, Akira Kawase, Kenichi Nomura, Hisashi Ito and Kenji Maeda, ","doi":"10.1021/acs.oprd.3c00434","DOIUrl":null,"url":null,"abstract":"<p >This work describes the development of a scalable manufacturing process for CH7057288, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor that selectively targets NTRK positive cancers. NTRK fusions are extremely attractive and promising therapeutic targets, and in order to deliver CH7057288 as a new treatment option for patients, it is crucial to be able to rapidly supply a large amount of this innovative drug for GLP toxicology studies and first-in-human (FIH) studies. By employing an 11-step process, we have been able to synthesize CH7057288 from methyl 2-(3-aminophenyl)-2-methylpropanoate with high purity and in excellent yield. The distinguishing features of this process include sequential double cyclization, leading to four-membered benzofuran-fused heterocycles. By employing this process, we successfully produced a total of 5.5 kg of CH7057288.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 6","pages":"2213–2225"},"PeriodicalIF":3.1000,"publicationDate":"2024-01-03","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.3c00434","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}

引用次数: 0

Abstract

This work describes the development of a scalable manufacturing process for CH7057288, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor that selectively targets NTRK positive cancers. NTRK fusions are extremely attractive and promising therapeutic targets, and in order to deliver CH7057288 as a new treatment option for patients, it is crucial to be able to rapidly supply a large amount of this innovative drug for GLP toxicology studies and first-in-human (FIH) studies. By employing an 11-step process, we have been able to synthesize CH7057288 from methyl 2-(3-aminophenyl)-2-methylpropanoate with high purity and in excellent yield. The distinguishing features of this process include sequential double cyclization, leading to four-membered benzofuran-fused heterocycles. By employing this process, we successfully produced a total of 5.5 kg of CH7057288.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

含苯并呋喃的选择性 NTRK 抑制剂 CH7057288 的早期工艺开发

这项工作描述了 CH7057288 可扩展生产工艺的开发过程，CH7057288 是一种神经营养酪氨酸受体激酶 (NTRK) 抑制剂，可选择性地靶向 NTRK 阳性癌症。NTRK融合是极具吸引力和前景的治疗靶点，为了将CH7057288作为一种新的治疗方案提供给患者，关键是要能够为GLP毒理学研究和首次人体试验（FIH）快速提供大量这种创新药物。通过采用 11 步工艺，我们从 2-(3-氨基苯基)-2-甲基丙酸甲酯合成出了 CH7057288，纯度高、收率高。该工艺的显著特点是连续双环化，生成四元苯并呋喃融合杂环。通过采用这一工艺，我们成功制得了 5.5 千克 CH7057288。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

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.