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

• Published in: Organic process research & development Vol. 7; no. 5; pp. 676 - 683
• Main Authors: Ragan, J. A, Raggon, J. W, Hill, P. D, Jones, B. P, McDermott, R. E, Munchhof, M. J, Marx, M. A, Casavant, J. M, Cooper, B. A, Doty, J. L, Lu, Y
• Format: Journal Article
• Language: English
• Published: American Chemical Society 01-09-2003
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op0340457

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.