(367a) Leveraging of Modeling and Automation in Development of a Control Strategy for a cGMP Buchwald-Hartwig Cross-Coupling

The Buchwald-Hartwig cross-coupling has become one of the most important aryl-heteroatom bond connection strategies available to the pharmaceutical industry. Owing to high selectivity, mild processing conditions, and broad availability of palladium sources and ligands, Buchwald-Hartwig reactions are conceptually well-suited for late introduction into the GMP synthesis. Despite these advantages, poor predictability upon scale-up as well as complex and/or expensive options for palladium removal can combine to limit the overall use of such transformations in the synthetic route.

This contribution focuses on control strategy development for a Buchwald-Hartwig cross-coupling introduced late in a drug substance synthetic route. Key to the control strategy was the control of the residual aryl halide process intermediate, process induced impurities, and palladium to single digit ppm levels in the drug substance. The talk outlines how automation and data-rich sampling were leveraged to enable reaction characterization. Informed by the data, a kinetic model was developed that incorporated both the catalytic cycle and mass transfer of the coordinated catalyst to the surface of the heterogeneous base. Once verified, the model was applied to determine critical process parameters and tested to predict potential failure modes of the process Critical Quality Attributes (CQAs). In addition, development of a homogeneous coordination and liquid-liquid extraction strategy for palladium removal will be discussed. Optimization of a liquid-phase approach afforded a palladium removal process with considerable cost and operational advantages relative to adsorption on functionalized silica. The overall control strategy for both the reaction and subsequent Pd removal was successfully transferred from the lab to full cGMP production scale to deliver more than 600 kg of drug substance.