Development of an Inherently Safe and Scalable Nickel-Catalyzed\nBorylation Process of an Aryl Sulfamate

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