Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence

    • Hansjoerg Lehmanna
    • Thomas Ruppena
    • Thomas Knoepfela
    • aGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland

    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.

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