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<p>As a potent and selective gonadotropin-releasing hormone (GnRH) antagonist, linzagolix, has recently been approved for the treatment of uterine fibroids. 6-Methoxy-2,3-difluorobenzaldehyde is the key intermediate during the synthetic process of linzagolix. Conventional batch-scale lithiation of aromatic compounds is inherently associated with considerable thermal hazards, which originates from the exothermic decomposition of reaction intermediates or products. Specifically, the loss of cooling efficiency or rapid reagent addition can readily trigger uncontrolled runaway reactions, a critical safety issue that underscores the need for the development of robust, scalable alternative synthetic protocols. Herein, we developed a novel continuous flow synthesis of 6-methoxy-2,3-difluorobenzaldehyde. Beyond mitigating the inherent safety risks posed by intermediate instability, this approach also establishes a practical, highly efficient protocol amenable to large-scale manufacturing.</p> Graphical Abstract <p></p>

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Novel continuous flow synthesis of 6-methoxy-2,3-difluorobenzaldehyde, the key intermediate of linzagolix

  • 期刊论文

  • 发表日期：

    2026年3月9日

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  • Wei Jiang,
  • Jian Huang,
  • Dun Wang

摘要

As a potent and selective gonadotropin-releasing hormone (GnRH) antagonist, linzagolix, has recently been approved for the treatment of uterine fibroids. 6-Methoxy-2,3-difluorobenzaldehyde is the key intermediate during the synthetic process of linzagolix. Conventional batch-scale lithiation of aromatic compounds is inherently associated with considerable thermal hazards, which originates from the exothermic decomposition of reaction intermediates or products. Specifically, the loss of cooling efficiency or rapid reagent addition can readily trigger uncontrolled runaway reactions, a critical safety issue that underscores the need for the development of robust, scalable alternative synthetic protocols. Herein, we developed a novel continuous flow synthesis of 6-methoxy-2,3-difluorobenzaldehyde. Beyond mitigating the inherent safety risks posed by intermediate instability, this approach also establishes a practical, highly efficient protocol amenable to large-scale manufacturing.

Graphical Abstract