Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia. Different strategies were used to develop the route, including Design of Experiments (DoE), high-throughput experimentation (HTE), and application of desorption electrospray ionization mass spectrometry (DESI-MS) to optimize and telescope the amidation and Sonogashira couplings to prepare the target compound, HSN608, a potent FLT3 inhibitor. Findings from these statistical design and automation studies helped streamline our workflow to achieve 10-fold and 5-fold reductions in the catalyst and cocatalyst loadings, respectively, in the synthesis. The application of high-throughput tools combined with a telescoped continuous synthesis method enabled an efficient and safe synthesis of this lead compound using the hazardous coupling reagent HATU while minimizing byproduct formation.

中文翻译：

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高通量工具在连续连续流合成炔基萘啶抗癌剂HSN608中的应用

开发连续合成的先导化合物以支持体内研究和临床前评估仍然是一个欠发达的领域。我们报告了一种用于治疗急性髓性白血病FLT3突变的炔基萘吡啶铅化合物的望远镜连续流合成。采用了不同的策略来开发路线，包括实验设计（DoE），高通量实验（HTE）以及应用解吸电喷雾电离质谱（DESI-MS）来优化和望远镜化酰胺化和Sonogashira偶联以制备目标化合物HSN608，一种有效的FLT3抑制剂。这些统计设计和自动化研究的结果有助于简化我们的工作流程，从而在合成过程中分别减少了10倍和5倍的催化剂和助催化剂负载量。