Soluble guanylate cyclase (sGC) stimulators are small molecules that increase nitric oxide (NO) signaling by binding to sGC, leading to an increase in cyclic guanosine monophosphate production. Such compounds have previously been studied clinically for noncentral nervous system (CNS) disorders. CY6463 is the first CNS-penetrant sGC stimulator to enter clinical trials and has the potential to positively impact a range of neurodegenerative diseases. In this paper, we present the development of an efficient, robust, and scalable synthesis of this compound that allowed for rapid generation of larger quantities of material, thereby accelerating advancement into early clinical studies, while minimizing the use of resources. The synthesis features a palladium-catalyzed one-pot Negishi coupling/cyanation sequence and a novel triazole formation from a Boc-protected amidrazone. Optimization of the reactions, safety considerations, and control of impurities, as well as a mechanistic study of the triazole formation reaction, are discussed.

中文翻译：

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加速开发 CY6463 的可扩展合成，CY6463 是一种用于治疗神经退行性疾病的 CNS 渗透性 sGC 刺激剂

可溶性鸟苷酸环化酶 (sGC) 刺激剂是一种小分子，可通过与 sGC 结合来增加一氧化氮 (NO) 信号，从而增加环磷酸鸟苷的产量。此类化合物先前已在临床上针对非中枢神经系统 (CNS) 疾病进行了研究。CY6463 是第一个进入临床试验的 CNS 渗透性 sGC 刺激剂，有可能对一系列神经退行性疾病产生积极影响。在本文中，我们介绍了该化合物的高效、稳健和可扩展合成的开发，该合成允许快速生成大量材料，从而加速早期临床研究的进展，同时最大限度地减少资源的使用。该合成具有钯催化的一锅 Negishi 偶联/氰化序列和由 Boc 保护的脒腙形成的新型三唑。讨论了反应的优化、安全考虑和杂质控制，以及三唑形成反应的机理研究。