The development and execution of a nickel-catalyzed borylation/palladium-catalyzed Suzuki telescoped process utilizing the inexpensive NiCl2·6H2O precatalyst for the borylation step are reported. The ...

A safe and scalable synthesis of A, a key aryl boronate ester intermediate toward an immunology asset udifitimod, via a Ni-catalyzed Miyaura borylation is reported. High-throughput experimentation, design of experiment, and reagent stability/compatibility studies were used to optimize the reaction conditions and furnish the borylation of aryl sulfamate B in 80–85% yield and >98% purity/potency. Significant hydrogen off-gassing was observed during the reaction, metal remediation, and crystallization steps of the first-generation process, and efforts were made to quantify, understand, and mitigate this off-gassing to ensure a safe and reliable scale-up. Two multikilogram batches of the process were successfully run to afford A in an average 85% yield, >99% potency, and ≤28 ppm residual Ni. Using the mechanistic learnings from this work, a second-generation process was developed which significantly reduced hydrogen off-gassing at all steps of the process, as well as increasing final yield and reducing process mass intensity. This second-generation process was demonstrated on a 1 kg scale to afford the product in 90% yield, >99% purity/potency, and 50 ppm residual Ni.