Process development of ABT-450 – A first generation NS3/4A protease inhibitor for HCV

ABT-450 (8), a potent hepatitis C (HCV) NS3/4A protease inhibitor, was approved as part of AbbVie's first generation HCV treatment for the United States in December 2014. A series of process optimizations were developed over six years to support the program starting with recycling of a previous protease inhibitor candidate through route development and final process. This discussion will focus on optimization of the final six steps starting from dipeptide 12 and amino acid 13 and highlights the use of a large scale ring closing metathesis (RCM), reactive crystallizations for isolation of intermediates, and detailed process understanding of the final sulfonamide coupling. The process provides ABT-450 (8) in 72% overall yield for the final 6 steps.