Direct Construction of Chiral Ether via Highly Efficient Heck Reaction and N-Directed Asymmetric Hydrogenation for Large-Scale Synthesis of MALT1 Inhibitor RGT-068A

Chemical process development efforts leading to the large-scale production of RGT-068A are discussed. Process optimization resulted in (1) successful replacement of the Stille coupling reaction involving toxic stannane reagent via highly efficient Heck reaction of methyl vinyl ether, (2) construction of the chiral ether unit through N-directed Ru-catalyzed asymmetric hydrogenation avoiding super-critical fluid chromatography (SFC) chiral separation, and (3) a streamlined process with a significantly improved overall yield of about 25%, 5-fold higher than the original discovery synthetic route, which enabled the delivery of high-quality material for IND-enabling studies.