Synthesis of isotope-labeled HSP90 inhibitor: [13CD3] and [14C]-TAK-459

[(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.