A practical synthesis of tetrasubstituted imidazole p38 MAP kinase inhibitors: A new method for the synthesis of alpha-amidoketones

In this manuscript we disclose new synthetic methodology to prepare a member of a class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves a thiazolium catalyzed cross acyloin-type condensation of a pyridinealdehyde with an N-acylimine. The pyridinealdehyde was prepared in 3 steps and 68% yield from 2-chloro-4-cyano pyridine. The tosylamide precursor to the N-acyl imine was prepared in two steps and 93% yield from isonipecotic acid. We have demonstrated the scope and some preliminary mechanistic studies concerning this new reaction. The resulting alpha-ketoamide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in 6 steps and 38% overall yield.