Early Process Development of a Heterobifunctional Protein Degrader

We present the process development of 1, a heterobifunctional Bruton’s Tyrosine Kinase (BTK) degrader. Optimization and reorganization of the discovery synthesis resulted in a scalable process suitable for preparation of API for the GLP-Tox (600 g) and planned FIH studies (5.7 kg). The FIH process achieved an average yield of 86% over the final four stages. Selective optimization of reaction conditions, modeling and high-throughput experimentation were applied strategically to address scale up challenges posed by this novel class of API.