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

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‐β (IKK‐β) 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‐14C‐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 [14C]‐(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‐2,2,3,3,4,5,5,6,6‐2H9. The final three steps of this synthesis were run in one pot. Carbon‐14 labeled (1) was prepared in six radiochemical steps in 25% radiochemical yield using a modified Guareschi–Thorpe reaction followed by a three‐step‐one‐pot reaction that included an SNAr, a condensation with thioacetamide, and a cyclization. The deuterium labeled (1) was obtained in eight steps in 58% overall chemical yield using 4‐hydroxypiperidine‐2,2,3,3,4,5,5,6,6‐2H9. Similarly to the carbon‐14 synthesis, the deuterium synthesis features a three‐step‐one‐pot reaction using dichloronicotinonitrile derivative to afford [2H9]‐(1).