多克级合成临床评估中的 polo 样激酶抑制剂 volasertib

IF 2.2 4区化学 Q2 Engineering

Chemical Papers Pub Date : 2024-10-10 DOI:10.1007/s11696-024-03708-8

Kang Wang, Dong Zhao, Mingli Jin, Yuan Li, Lei Sun, Yanli Zhu, Chen Wang, Shuang Li, Yu Wang, Qianying Miao, Xiao Chen, Yanfang Zhao, Yunlei Hou

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引用次数: 0

摘要

本文介绍了一种实用、改进和高效的方法，用于多克级合成可注射的生物可用性强的 PLK1 选择性抑制剂 volasertib。这一优化的关键在于设计和开发了一种新的合成策略，其中包括通过硝基还原序列制备关键中间体 4-氨基-N-{4-[4-(环丙基甲基)哌嗪-1-基]环己基}-3-甲氧基苯甲酰胺（W-5），以及通过还原环化和 N-甲基化反应制备 (7R)-2-chloro-7-ethyl-7,8-dihydro-8-(1-methylethyl)-6(5H)-pteridinone (W-11)。所开发的工艺总收率为 46%，使我们能够快速合成多克纯度为 99.42% 的伏拉塞替布。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Multigram-scale synthesis of volasertib, an inhibitor of polo-like kinases in clinical evaluation

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Multigram-scale synthesis of volasertib, an inhibitor of polo-like kinases in clinical evaluation

This paper described the development of a practical, improved and efficient method for the multigram-scale synthesis of volasertib, an injectable bioavailable potent and selective inhibitor of PLK1. The key to this optimization was the design and development of a novel synthetic strategy, which involved the preparation of key intermediate 4-amino-N-{4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-3-methoxybenzamide (W-5) through nitro reduction sequence and (7R)-2-chloro-7-ethyl-7,8-dihydro-8-(1-methylethyl)-6(5H)-pteridinone (W-11) through reductive cyclization and N-methylation reaction. The developed process provided 46% overall yield, which enabled us to rapidly synthesize multi-gram quantities of volasertib in 99.42% purity.

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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.