title: Synthesis of isotope-labeled HSP90 inhibitor: [(13) CD3 ] and [(14) C]-TAK-459.
abstract: [(13) CD3 ]-TAK-459 (1A), an HSP90 inhibitor, was synthesized from [(13) CD3 ]-sodium methoxide in three steps in an overall yield of 29%. The key intermediate [(13) CD3 ]-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was synthesized in two steps from 2,6-dibromopyridine and stable isotope-labeled sodium methoxide. [(14) C]-TAK-459 (1B) was synthesized from [(14) C(U)]-guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [(14) C]-(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, was prepared by microwave-assisted condensation.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Isotope Chemistry Group, Millennium Pharmaceuticals Inc, 40 Landsdowne Street, Cambridge, MA, 02139, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Plesescu
authors.forename: Eric L
authors.initials: EL
authors.lastname: Elliott
authors.forename: Yuexian
authors.initials: Y
authors.lastname: Li
authors.forename: Shimoga R
authors.initials: SR
authors.lastname: Prakash
mesh_terms: D002250:Carbon Radioisotopes / Q000737:chemistry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*
chemical_list: C000597592:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one O-3,4-dihydroxybutyl oxide; D002250:Carbon Radioisotopes; D018841:HSP90 Heat-Shock Proteins; D011725:Pyridines; D011743:Pyrimidines; D019275:Radiopharmaceuticals
keywords: HSP90 inhibitor; [13CD3]-TAK-459; [14C]-TAK-459; microwave chemistry