Towards the Development of a Commercial Process To Produce Muvalaplin. Part I: Preparation of a Key Intermediate by an Evans Auxiliary-Assisted Asymmetric Alkylation

Herein, we describe the development of a large-scale process for an intermediate in the synthesis of muvalaplin, a small-molecule lipoprotein(a) inhibitor for the potential treatment of cardiovascular disease. After initially identifying and exploring different methods for installing the required stereochemistry, we focused on an auxiliary-controlled asymmetric alkylation and developed an early-phase route into a scalable process. Each step was optimized, leading to improvements in safety, robustness, and cost of goods, which ultimately resulted in a 35% yield increase over four steps and a 2× reduction in PMI. The process was safely scaled to >100 kg, thus ensuring clinical supply and laying the foundation for a commercial route.