Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence,Organic Process Research & Development

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Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-03-22 , DOI: 10.1021/acs.oprd.2c00016
Hansjoerg Lehmann ₁ , Thomas Ruppen ₁ , Thomas Knoepfel ₁

Affiliation

Rapid synthesis and scale-up of active molecules to support the development process of new drug candidates is key in the pharmaceutical industry. Herein, we describe the development of a scalable continuous flow procedure for three key steps in the synthesis of 2H-indazoles, which were identified as highly potent and selective TLR7 and TLR8 antagonists. Transformation of hazardous diazonium salt and azide chemistries from the batch mode to continuous flow mode helped mitigate and limit the risks associated with the handling of large amounts of hazardous reagents and intermediates in the batch mode. In a two-step approach, we first screened and optimized the reaction parameter for a diazotization─azidation─cyclization three-step sequence using a commercial research-scale plug flow reactor. In the second step, we demonstrated the robustness and scalability of this reaction sequence, which finally enabled us to rapidly prepare and deliver the required amount of material in high quality.

中文翻译：

三步连续流动序列中重氮盐和叠氮化物的放大

活性分子的快速合成和放大以支持新候选药物的开发过程是制药行业的关键。在这里，我们描述了用于合成 2H-吲唑的三个关键步骤的可扩展连续流动程序的开发，这些步骤被确定为高效和选择性的 TLR7 和 TLR8 拮抗剂。将危险的重氮盐和叠氮化物从间歇模式转变为连续流动模式有助于减轻和限制与以间歇模式处理大量危险试剂和中间体相关的风险。在两步法中，我们首先使用商业研究规模的活塞流反应器筛选并优化了重氮化-叠氮化-环化三步序列的反应参数。在第二步中，

更新日期：2022-03-22

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