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), ItalyRead the publication that featured this abstract
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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