Synthetic and Chromatographic Challenges and Strategies for Multigram Manufacture of KRASG12C Inhibitors

In one of our drug development projects, we identified potent KRASG12C inhibitors for treatment of cancer. For our early preclinical studies, we needed a strategy to enable supply of two candidates in a cost-effective and productive manner. The active pharmaceutical ingredients (APIs) were structurally complex and were initially obtained via long linear sequences resulting in time-consuming manufactures. In addition, both two candidates comprised a biaryl fragment with hindered rotation along the chiral axis. As a result, a pair of stable atropisomers was generated for each candidate. With special attention to the chromatographic challenges for the atropisomer separation and for the API purification, this article describes our initial efforts to develop synthetic routes that were amenable for multigram synthesis of our two drug candidates. In particular, the consequences of implementing a key Suzuki reaction late or early in the sequence are discussed.