Significant rate enhancement via potassium pivalate in a Miyaura borylation approach to verinurad

Abstract

We describe herein the significant rate-enhancing effect of employing potassium pivalate as a base in a Miyaura borylation. The manufacturing route to verinurad currently employs a Suzuki-Miyaura cross-coupling, requiring cryogenic conditions to generate the boronic acid coupling partner. This process has manufacturability challenges including those associated with low temperature operations and thus an alternative Miyaura borylation approach is described. High throughput screening was employed to investigate the effects of various carboxylate bases and their corresponding counterions on reactivity. Our results highlight potassium pivalate as producing exceptional rate acceleration. To the best of our knowledge this base has not previously been reported for use in Miyaura borylations. Diethanolamine transesterification is also reported as a facile and robust boronate isolation protocol. Successful application of this diethanolamine boronate ester in downstream cross-coupling chemistry has demonstrated the potential for this new route in commercial manufacture of verinurad.