- Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor.
Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor.
The Journal of organic chemistry (2019-01-11)
David M Barnes, Shashank Shekhar, Travis B Dunn, Jufang H Barkalow, Vincent S Chan, Thaddeus S Franczyk, Anthony R Haight, John E Hengeveld, Lawrence Kolaczkowski, Brian J Kotecki, Guangxin Liang, James C Marek, Maureen A McLaughlin, Donna K Montavon, James J Napier
PMID30629443
ABSTRACT
Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.
MATERIALS