Innovative Approaches to the Imidazo[4,5-b]pyridine Ring System. Development of an Efficient Process for Industrial-Scale Production of a Key Intermediate for Potent Angiotensin II Receptor Antagonists

Two syntheses of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, an important intermediate for the synthesis of several potent angiotensin II antagonists, have been investigated. The first route involves conversion of 1,1-bis(methylthio)-2-nitroethene (17) to 2-amino-4,6-dimethyl-3-nitropyridine (6); catalytic hydrogenation of 2-amino-4,6-dimethyl-3-nitropyridine in propionic acid gave 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in high yield. In the second synthesis, propionitrile is converted to imidate hydrochloride 15, which is neutralised and reacted with aminoacetonitrile in the presence of acetylacetone to give 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in 55% overall yield. The propionitrile route was scaled up to produce 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in the pilot plant