Efficient and Scalable Synthesis of Ketoprofen: A Pyrolytic Aromatization Approach

The practical synthesis of the representative nonsteroidal anti-inflammatory drug ketoprofen has been accomplished in 44% overall yield on the decagram scale. The key features in this synthetic work involve a TiCl4-Et3N mediated aldol/enollactonization annulation to affect dihydrobenzofuranone core formation and the use of a highly efficient pyrolytic aromatization condition to facilitate the construction of the vital 2-arylpropionic acid (2-APA) moiety. Furthermore, the avoidance of hazardous chemicals and crystallization of several intermediates would be greatly beneficial to the scalable synthesis of ketoprofen.

Automated summary

The practical synthesis of ketoprofen, a representative nonsteroidal anti-inflammatory drug, has been achieved with an overall yield of 44% on a decagram scale. This synthetic approach involves the use of TiCl4-Et3N mediated aldol/enollactonization annulation for dihydrobenzofuranone core formation, and a highly efficient pyrolytic aromatization condition for the construction of the vital 2-arylpropionic acid (2-APA) moiety. The avoidance of hazardous chemicals and crystallization of several intermediates is beneficial for the scalable synthesis of ketoprofen.