title: A potent IκB kinase-β 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-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.
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Bachir
authors.initials: B
authors.lastname: Latli
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Magnus
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Hrapchak
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Busacca
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D002250:Carbon Radioisotopes / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D003903:Deuterium / Q000737:chemistry*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007553:Isotope Labeling; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011854:Radiochemistry; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000624965:3-amino-4-(1,1-difluoropropyl)-6-(4-methanesulfonylpiperidin-1-yl)thieno(2,3-b)pyridine-2-carboxylic acid amide; D000893:Anti-Inflammatory Agents; D002250:Carbon Radioisotopes; D002264:Carboxylic Acids; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013876:Thiophenes; D003903:Deuterium; D051550:I-kappa B Kinase
keywords: IKK-β; carbon-14; deuterium; radiosynthesis; thienopyridines