Exploiting the Physical Properties of Diethanolamine Boronic Esters for Process Improvements in AZD5718

Abstract

The process development toward synthesizing a diethanolamine (DEA) boronic ester and the subsequent Suzuki− Miyaura coupling (SMC) is disclosed herein. A one-pot lithiation−borylation−transesterification was successfully developed to isolate the DEA boronic ester as a stable crystalline solid and avoided the formation of boronic acid or pinacol boronic ester analogues, which have poor physical properties and purity profiles. The crystalline DEA boronic ester was also successfully employed in the SMC, and the improved input quality allowed for a simpler and more robust process to be developed with enhanced quality of the isolated intermediate. The borylation and SMC were operated on 60 and 350 kg scales, respectively, and generated 2300 kg of the active pharmaceutical ingredient AZD5718.