Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow

This article describes two routes toward the synthesis of cis or trans C2,3,5,7-tetrasubstituted dihydrobenzofurans as potent and selective bromodomain and extra-terminal BD2 inhibitors, followed by the optimization of the synthesis of the lead molecule GSK973 to support pre-clinical efficacy and safety studies. The use of flow chemistry for a Claisen rearrangement, extensive optimization of the fluorination step, and high-yielding aminocarbonylation were key to generate the required 50 g of material. The identified new route also represents a robust starting point for further optimization.