Systematic Optimization of a Robust Telescoped Process for a BTK Inhibitor with Atropisomer Control by High-Throughput Experimentation, Design of Experiments, and Linear Regression

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The development of a telescoped process for the API step in the route to a reversible inhibitor of BTK is reported. Although a robust and effective reaction and crystallization was previously implemented, concerns around the storage and stability of the penultimate material led to investigating a telescoped process. Utilizing design of experiments (DoE) to understand impacts to the API reaction and high-throughput extractions (HTEx) to optimize the workup, a process was rapidly developed to achieve the same quality API with an overall 13% improvement to yield and 41% improvement in the process mass intensity (PMI).