Development of a New Variant of the Migita Reaction for Carbon-Sulfur Bond Formation Used in the Manufacture of Tetrahydro-4-[3-[4-(2-methyl-1H-imidazol-1-yl)phenyl]thio]phenyl-2H-pyran-4-earboxamide

摘要

Palladium-catalyzed carbon-sulfur bond formation using modified Migita reaction conditions was explored and applied to the synthesis of a former antiasthma drug candidate,tetrahydro-4-[3-[4-(2-methyl-1H-hnidazol-1-yl)phenyl]thio]phenyl-2H-pyran-4-carboxamide(5).The reaction was developed into a general method for thioaryl halide cross-coupling,and a specific example of its use to synthesize a key intermediate,tetrahydro-4-[3-(4-fluorophenyl)thio]phenyl-2H-pyran-4-carboxamide(6)was demonstrated at large scale to provide phase II clinical supplies of 5.Comparison of the multistep phase I process and the two-step phase II process showed an overall yield advantage over the bond-forming steps from common starting material(1)to API 5 of 40%.The ligand effect in the modified Migita reaction is described in detail.The second step of the scale-up process illustrated formation of carbon-nitrogen bonds without use of palladium catalysis,providing a contrast to the first reaction;both reactions were developed into efficient single-vessel direct isolation processes.