Going-with-the-flow: nickel-catalysed Suzuki–Miyaura cross-couplings in continuous flow and translation into APIs savolitinib and baxdrostat

Abstract

Nickel-catalysed cross-coupling reactions offer a versatile and more sustainable approach to forming carbon–carbon bonds, expanding the scope of accessible structures and enabling new synthetic strategies. The use of flow chemistry in catalysis can offer several advantages over traditional batch conditions, including faster rates, better heat and mass transfer and ease of scaling up. In this work we report the translation of a benchmark nickel-catalysed Suzuki–Miyaura cross-coupling reaction into continuous flow. Using a Design of Experiment approach, high yield of cross-coupled product has been achieved at 1 mol% catalyst loadings which was not attainable in batch under analogous conditions. Optimised conditions were transferred directly to two APIs, savolitinib and a baxdrostat intermediate, with good conversion established without any further screening of conditions.