(543f) Development and Scale-up of a Robust Two Step Telescope Reaction and Crystallization Via High-Throughput Experimentation and in-Line Process Monitoring

High-throughput experimentation, in-line process monitoring, and modeling were utilized to rapidly develop a complex reaction sequence and isolation, demonstrating a standard approach to efficient process development at BMS. A two-step telescope reaction and isolation were developed to produce a key intermediate in a process to generate active pharmaceutical ingredient. The first step in the telescope involves a S_N1 reaction between an amine group and a Br-ester electrophile. After a series of aqueous extractions and a drying distillation the product is carried into a cyclization reaction in the presence of an isothiocyanate fragment and isolated directly as an oxalic acid salt. Leveraging high-throughput experimentation and design of experiments, optimized reaction conditions for both steps in the telescope were achieved to significantly increase reaction rate while reducing impurity formation. Additional development on the extractive work-up following the S_N1 reaction eliminated variability in product losses to the aqueous phase. Finally, implementing solubility modeling via DynoChem and process analytical technology, a new crystallization was developed to minimize yield losses and ensure high filtration flux. The final process conditions have been scaled up in multiple pilot plant batches and demonstrated to produce high quality product with >90% yield.