Development of a robust ring-closing metathesis reaction in the synthesis of SB-462795, a cathepsin K inhibitor

The development of a robust and high-yielding ring-closing metathesis (RCM) reaction and its demonstration on multikilogram scale are described. A detailed understanding of the impact of impurities on the RCM reaction was achieved using a variety of chemical and statistical methods. Specifically, individual impurities were evaluated in spiking studies to identify those that negatively affected the RCM reaction. Projection methods (PCA and PLS) were applied to historical data to identify the main sources of variation in starting material quality and determine the main detrimental impurities that impeded the RCM reaction. The synthesis of the starting material was then modified to adequately control these key impurities, which in turn ensured a robust RCM process. Finally, the robustness of the RCM reaction was assessed using a probability-based approach.