Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material

A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to kilogram-scale production was achieved using a short residence time (0.25 s) and noncryogenic temperature (0 °C), without the need to increase the number of reactors. A comparison of the flow process with a Miyaura borylation process suggested some potential benefit in the overall process operating efficiency from avoiding the use of Pd and genotoxic boron reagents.