Total mechano-synthesis of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-acrylaldehyde—a pivotal intermediate of pitavastatin†

Jingbo Yu, Yanhua Zhang, Zehao Zheng and Weike Su
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Abstract

Pitavastatin (PTV), a potent cholesterol-lowering agent, holds considerable commercial appeal, driving chemists to fervently pursue its efficient and sustainable synthesis. Despite prolonged efforts over several decades, the quest for a simplified, more efficacious, and environmentally conscious manufacturing process for PTV remains a significant challenge. Our study introduces a three-step total mechano-synthesis, commencing with readily available 4-bromoquinoline, to produce the key intermediate (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-acrylaldehyde) of PTV. This methodology incorporates an extrusive Suzuki–Miyaura coupling, mechanochemical Minisci C–H alkylation, and extrusive oxidation Heck coupling, each thoroughly presented to display their scalability. Notably, we emphasize the extensive exploration of substrate versatility in Minisci reactions to access cyclopropane-bearing pharmaceutical compounds and natural products. This total mechano-synthesis route distinguishes itself through eco-friendly reaction conditions, exceptional stepwise efficiency, intuitive operability, and pronounced potential for large-scale implementation, paving the way for PTV's streamlined and sustainable manufacture.

Abstract Image

2-环丙基-4-(4-氟苯基)喹啉-3-丙烯醛的全机械合成--匹伐他汀†的关键中间体
匹伐他汀(PTV)是一种强效降低胆固醇的药物,具有相当大的商业吸引力,促使化学家们热衷于追求其高效和可持续的合成。尽管经过几十年的不懈努力,但寻求一种简化、高效、环保的 PTV 生产工艺仍然是一项重大挑战。我们的研究介绍了一种三步全机械合成法,从容易获得的 4-溴喹啉开始,生产 PTV 的关键中间体(2-环丙基-4-(4-氟苯基)喹啉-3-丙烯醛)。该方法包括外延式铃木-米亚乌拉偶联、机械化学米尼斯 C-H 烷基化和外延式氧化 Heck 偶联,每种方法都进行了详细介绍,以显示其可扩展性。值得注意的是,我们强调在 Minisci 反应中广泛探索底物的多功能性,以获得含环丙烷的药物化合物和天然产物。这种全机械合成路线通过生态友好的反应条件、卓越的分步效率、直观的可操作性以及大规模实施的明显潜力脱颖而出,为 PTV 的简化和可持续生产铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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