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

• Published in: Organic process research & development Vol. 18; no. 11; pp. 1345 - 1353
• Main Authors: Filipponi, Paolo, Ostacolo, Carmine, Novellino, Ettore, Pellicciari, Roberto, Gioiello, Antimo
• Format: Journal Article
• Language: English
• Published: American Chemical Society 21.11.2014
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op500074h

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.