Continuous Flow Synthesis of the PARP-1/2 Inhibitor HYDAMTIQ: Synthetic Strategy, Optimization, and Green Metrics Evaluation

    • Paolo Filipponi
    • Bruno Cerra
    • Alessandro Piccinno
    • Emidio Camaioni
    • Antimo Gioiello
    • Laboratory of Medicinal and Advanced Synthetic Chemistry (Lab MASC), Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy

    2-((Dimethylamino)methyl)-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one (HYDAMTIQ), a potent PARP1/2 inhibitor, is currently being evaluated in preclinical trials for the treatment of ischemia and inflammatory diseases. The current batch synthesis, which includes a Suzuki-Miyaura reaction, a thermal cyclization, and a Mannich-type reaction, makes it a challenging target to prepare on a multigram scale and support compound development. Herein, a telescoped continuous flow synthesis of the key thieno[2,3-c]isoquinolin-5(4H)-one scaffold and much improved chromatography-free, downstream steps for HYDAMTIQ have been developed. Assessment of quantitative green metrics confirms the improved efficiency and sustainability of the newly developed flow route, providing a straightforward and versatile approach for scale-up and medicinal chemistry investigations.

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