| John A Ragan1, Jeffery W. Raggon1, Paul D. Hill1, Brian P. Jones1, Ruth E. McDermott1, M. J. Munchhof2, M. M. Marx2, J. C. Casavant2, Beth A. Cooper2, Jonathan L. Doty2, and Yong Lu2. (1) Chemical Research and Development, Pfizer Global Research, Eastern Point Road, Groton, CT 06340, (2) Medicinal Chemistry, Pfizer Inc, Eastern Point Road, Groton, CT 06340 |
The multi-hundred 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.  |