Development of a multigram synthetic process to clinical candidate TMP195, a class IIa histone deacetylase selective inhibitor

IF 2.2 4区化学 Q2 Engineering

Chemical Papers Pub Date : 2024-11-06 DOI:10.1007/s11696-024-03769-9

Siyuan Wang, Wenchao Zhang, Han Qin, Meidi Luo, Rui Lin, Jiachen Wen, Dan Liu

{"title":"Development of a multigram synthetic process to clinical candidate TMP195, a class IIa histone deacetylase selective inhibitor","authors":"Siyuan Wang, Wenchao Zhang, Han Qin, Meidi Luo, Rui Lin, Jiachen Wen, Dan Liu","doi":"10.1007/s11696-024-03769-9","DOIUrl":null,"url":null,"abstract":"<div><p><b>TMP195</b> is a highly profiled clinical candidate demonstrating class IIa histone deacetylase (HDAC) selective inhibition. Current preparation of <b>TMP195</b> is limited to subgram-scale due to the requirement of tedious (post-)experimental procedures and the uses of hazardous reagents. To fulfill the unmet need for the bulky synthesis of <b>TMP195</b> for the future clinical study, we have carried out its synthetic research. The present study provides a novel synthetic process suitable for the multigram-scale synthesis of <b>TMP195</b>. Its overall yield has increased significantly from the literature to the present, with respective values of 9% and 45%. Notably, the proposed process is more efficient and facile, characterized by accelerated reaction rates from 40 h to within 19 h and a streamlined post-reaction column chromatography purification from five reactions to just one. Additionally, the proposed process is more environmentally friendly, featured by the solvent-free synthesis of key intermediate 4-(chloromethyl)-2-phenyloxazole and replacement of non-toxic cyanide source. This newly proposed synthetic process is highly stable and repeatable under 10 gramme scale counted by benzamide as starting material.</p><h3>Graphical abstract</h3>\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":513,"journal":{"name":"Chemical Papers","volume":"78 18","pages":"9559 - 9568"},"PeriodicalIF":2.2000,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Papers","FirstCategoryId":"92","ListUrlMain":"https://link.springer.com/article/10.1007/s11696-024-03769-9","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Engineering","Score":null,"Total":0}

引用次数: 0

Abstract

TMP195 is a highly profiled clinical candidate demonstrating class IIa histone deacetylase (HDAC) selective inhibition. Current preparation of TMP195 is limited to subgram-scale due to the requirement of tedious (post-)experimental procedures and the uses of hazardous reagents. To fulfill the unmet need for the bulky synthesis of TMP195 for the future clinical study, we have carried out its synthetic research. The present study provides a novel synthetic process suitable for the multigram-scale synthesis of TMP195. Its overall yield has increased significantly from the literature to the present, with respective values of 9% and 45%. Notably, the proposed process is more efficient and facile, characterized by accelerated reaction rates from 40 h to within 19 h and a streamlined post-reaction column chromatography purification from five reactions to just one. Additionally, the proposed process is more environmentally friendly, featured by the solvent-free synthesis of key intermediate 4-(chloromethyl)-2-phenyloxazole and replacement of non-toxic cyanide source. This newly proposed synthetic process is highly stable and repeatable under 10 gramme scale counted by benzamide as starting material.

Graphical abstract

Abstract Image

查看原文本刊更多论文

为临床候选药物 TMP195（一种 IIa 类组蛋白去乙酰化酶选择性抑制剂）开发多克合成工艺

TMP195 是一种具有高度特征性的临床候选药物，具有 IIa 类组蛋白去乙酰化酶 (HDAC) 选择性抑制作用。由于需要繁琐的（后）实验程序和使用危险试剂，目前 TMP195 的制备仅限于亚克规模。为了满足未来临床研究对 TMP195 大体积合成的需求，我们开展了其合成研究。本研究提供了一种适用于多克级合成 TMP195 的新型合成工艺。从文献到现在，其总产率大幅提高，分别达到 9% 和 45%。值得注意的是，所提出的工艺更高效、更简便，其特点是反应速率从 40 小时加快到 19 小时内，反应后柱层析纯化从五个反应简化到仅一个反应。此外，建议的工艺还更加环保，其特点是无溶剂合成关键中间体 4-（氯甲基）-2-苯基噁唑和替代无毒氰源。以苯甲酰胺为起始原料，新提出的合成工艺在 10 克规模下具有高度稳定性和可重复性。

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分钟内获得全文求助全文

来源期刊

Chemical Papers Chemical Engineering-General Chemical Engineering

CiteScore

3.30

自引率

4.50%

发文量

590

期刊介绍： Chemical Papers is a peer-reviewed, international journal devoted to basic and applied chemical research. It has a broad scope covering the chemical sciences, but favors interdisciplinary research and studies that bring chemistry together with other disciplines.