A potent IκB kinase-ß inhibitor labeled with carbon-14 and deuterium.

ABSTRACT

3-Amino-4-(1,1-difluoro-propyl)-6-(4-methanesulfonyl-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylic acid amide (1) is a potent IκB Kinase-ß (IKK-ß) inhibitor. The efficient preparations of this compound labeled with carbon-14 and deuterium are described. The carbon-14 synthesis was accomplished in six radiochemical steps in 25% overall yield. The key transformations were the modified Guareschi-Thorpe condensation of 2-cyano-(14) C-acetamide and a keto-ester followed by chlorination to 2,6-dichloropyridine derivative in one pot. The isolated dichloropyridine was then converted in three steps in one pot to [(14) C]-(1). The carbon-14 labeled (1) was isolated with a specific activity of 54.3 mCi/mmol and radiochemical purity of 99.8%. The deuterium labeled (1) was obtained in eight steps and in 57% overall chemical yield using 4-hydroxypiperidine-2,2,3,3,4,5,5,6,6-(2) H9 . The final three steps of this synthesis were run in one pot.