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

[13CD3]‐TAK‐459 (1A), an HSP90 inhibitor, was synthesized from [13CD3]‐sodium methoxide in three steps in an overall yield of 29%. The key intermediate [13CD3]‐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. [14C]‐TAK‐459 (1B) was synthesized from [14C(U)]‐guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [14C]‐(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. The internal standard [13CD3]‐TAK‐459 (3) was rapidly synthesized in three steps from the labeled methanol. The radiolabeled version [14C]‐TAK‐459 (7) was prepared in five steps from commercially available [14C(U)]‐guanidine hydrochloride (5). The key step in this synthesis was the condensation of guanidine with 4 under microwave conditions versus the traditional reflux methodology.