A potent IκB kinase‐β inhibitor labeled with carbon‐14 and deuterium. (13th April 2016) - Latli, Bachir
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‐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‐ 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. Abstract : 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‐ 2 H9 . Similarly to the carbon‐14 synthesis, the deuterium synthesis features a three‐step‐one‐pot reaction using dichloronicotinonitrile derivative to afford [ 2 H9 ]‐(1 ).