Streamlined Processes for the Synthesis of a Farnesyl Transferase Inhibitor Drug Candidate

As part of a fast-paced oncology program, quinolinone 1 was discovered and developed as a potent inhibitor of farnesyl transferase for the treatment of cancer. The initial synthesis, which suffered from a lengthy linear sequence and a late-stage chromatographic resolution, was deemed not amenable to large-scale production. While investigating alternate routes to address these issues, the original synthesis was successively improved and streamlined. This enabled route supplied the timely production of drug substance required to support early toxicological and clinical studies. Several iterations of the process were made, and as a result of these improvements, an efficient four-step sequence was developed for the synthesis of quinolinone d-tartrate 2 starting from readily available outsourced intermediate 5 in 26% overall yield, including a classical resolution. The key features of the synthesis include a Castro−Stevens coupling, an imidazole Grignard addition, and a concomitant classical resolution/final s...