Application of Ring-Closing Metathesis Strategy to the Synthesis of Vaniprevir (MK-7009), a 20-Membered Macrocyclic HCV Protease Inhibitor

Abstract

Vaniprevir (MK-7009) bearing a 20-membered macrocycle and chiral components is a highly efficacious HCV protease inhibitor aiming for the treatment of chronic infection of hepatitis C virus. The efficient macrocyclization coupled with the assembling of key chiral components is of great challenge for the large-scale production of this structurally complex molecule. In this chapter, a convergent synthesis with a longest sequence of nine steps featuring highly efficient macrocyclization via ring-closing metathesis (RCM) along with the improvement in the syntheses of key components will be described. RCM for the construction of 20-membered macrocycle using low catalyst loading (0.2 mol%) and practically high concentration (0.13 M) was achieved by simultaneous and slow addition of ruthenium catalyst and the diene substrate. The strategy of using RCM in this cost-effective synthesis sets a new paradigm for the synthesis of several other macrocyclic HCV protease inhibitors at Merck Research Laboratories.