Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two SNAr Reactions, Oxidation and Suzuki Coupling

A sustainable second-generation process for GDC-0134 was developed with a particular focus on safety and greenness, while complying with strong specifications to supply pivotal clinical studies. Through these efforts, we discovered solvents to replace the solvents classified as substances of very high concern by the REACH regulation in two SNAr steps. We further established a safer and faster way to oxidize the sulfanyl to the sulfonyl intermediate by dosing H2O2 at higher temperatures, reducing accumulation while minimizing uncontrolled H2O2 decomposition. The reaction conditions for the Suzuki coupling and the second SNAr were modified to increase the selectivity in these two steps. A change in the solvent for the final crystallization allowed operation at higher concentrations and delivery of a highly pure active pharmaceutical ingredient (API). The new improved process reduced the process mass intensity by approximately 40% and was successfully used to produce 150 kg of GDC-0134.

Automated summary

A sustainable second-generation process for GDC-0134 was developed to meet the safety and greenness requirements of supplying pivotal clinical studies. The process involved the discovery of alternative solvents and improved reaction conditions, resulting in a significant reduction in process mass intensity and the successful production of a large amount of GDC-0134.