Synthetic methodology utilized to prepare substituted imidazole p38 MAP kinase inhibitors.

In this manuscript, we review the synthetic methods utilized to prepare a variety of imidazole p38 MAP kinase inhibitors. Several methods have been used to prepare the key templates that are discussed; manipulation of the heterocycles around the imidazole core are also considered in the context of their biological activity. Finally, we discuss new synthetic methodologies discovered in our laboratories, which are useful for the preparation of a member of this class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves the thiazolium-catalyzed cross-benzoin condensation of a pyridine aldehyde with an N-acylimine. The pyridine aldehyde was prepared in three steps and 68% yield from 2-chloro-4-cyanopyridine. The tosylamide precursor to the N-acylimine was prepared in two steps and 93% yield from isonipecotic acid. We demonstrate 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 six steps and 38% overall yield.