Cross-Coupling Methods for the Large-Scale Preparation of an Imidazole−Thienopyridine: Synthesis of [2-(3-Methyl-3H-imidazol-4-yl)- thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine

The multihundred-gram synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2- b ]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine ( 1 ) is described utilizing a Stille cross-coupling of an iodothienopyridine ( 3 ) with 5-(tributylstannyl)-1-methylimidazole ( 11 ). Several cross-coupling methods were evaluated for the conversion of thienopyridine 3 to imidazole−thienopyridine 2, but only two were effective: the Stille coupling and a Negishi cross-coupling of the organozinc reagent derived from 2-( tert -butyldimethylsilyl)-1-methylimidazole and iodothienopyridine ( 3 ). The latter procedure worked well on laboratory scale (<50 g), but was capricious upon scale-up. The issues with scale-up of an organostannane reagent are discussed, including control and analysis of organotin levels.