Scaling up a C-H Borylation: Addressing the Safety Concerns of an Iridium-Catalyzed Process for Multikilo Scale Manufacture

ABSTRACT: Iridium-catalyzed C-H borylation reactions are a rapid and versatile entry into Suzuki coupling partners, but their inherent safety issues can limit their use in large-scale manufacture. The stoichiometric byproduct from this reaction, HBpin, can liberate hydrogen gas on contact with moisture in air, as well as acting as an effective borylating agent in the reaction, resulting in an additional pathway for the generation of hydrogen. Using a targeted, multidisciplinary approach, a C-H borylation process to generate a key intermediate in the synthesis of an API was redesigned in preparation for large-scale manufacture. Through careful evaluation of the existing process and the use of high-throughput experimentation, PAT techniques, NMR, process safety experimentation, and process engineering, the process was constructed so that inherent risks associated with this reaction were minimized and contained to a final controlled quench of the reactive byproducts of the reaction. The final process was transferred to a manufacturing facility, delivering >70 kg of the borylated product over two batches.

Automated summary

In this study, a targeted approach was used to redesign the C-H borylation process, minimizing the inherent risks associated with the reaction, and successfully transferring the final process to large-scale manufacturing.