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-1<i>H</i>-imidazol-1-yl)phenyl]thio]phenyl-2<i>H</i>-pyran-4-carboxamide

Abstract

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-imidazol-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.