An Alternate and Efficient Synthetic Process for a Metabolic Dysfunction-Associated Steatohepatitis Drug: Resmetirom

A novel, efficient, and streamlined process was developed for resmetirom, a first-in-class THR-β agonist for the treatment of MASH. The key innovation of this novel process was the ingenious utilization of a “one-pot” reaction, which simultaneously accomplished aromatic cyclization and the hydrolysis of 3-chloro-4-isopropylpyridazine. This breakthrough circumvented steps of amino protection and deprotection, effectively streamlining the synthetic route from eight linear steps to four steps while maintaining mild reaction conditions. Using commercially available raw materials, the optimized process provided a rapid pathway to synthesize multigram quantities of resmetirom with an assay purity of 98.8% and a corrected overall yield of 44.3%.