Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 Inhibitors

    • Paolo Filipponi
    • Carmine Ostacolo
    • Ettore Novellino
    • Roberto Pellicciari†§
    • Antimo Gioiello*†
    • Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, I-06123 Perugia, Italy
    • Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Napoli, Italy §TES Pharma S.r.l., Corciano (Perugia), Italy

    An efficient multistep method for the continuous flow synthesis of thieno[2,3-c]isoquinolin-5(4H)-one-A (TIQ-A), an important pharmacological tool and building block for PARP-1 inhibitors, has been developed. The synthesis involves a Suzuki coupling reaction to generate 3-phenylthiophene-2-carboxylic acid which is transformed into the corresponding acyl azide and readily cyclized by a thermal Curtius rearrangement. A statistical design of experiments (DoE) was employed as a valuable support for decision-making of further experiments enabling the development of a robust and reliable protocol for large-scale preparation. As a result, the reactions are facile, safe, and easy to scale-up. The large-scale applicability of this improved flow method was tested by conducting the reactions on multigram scale to produce the desired product in high yield and quality for biopharmacological appraisals.

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