Synthesis of ¹⁴C‐ and ²H‐labeled 1,3‐dihydro‐3,3‐dimethyl‐5‐(1,4,5,6‐tetrahydro‐6‐oxo‐3‐pyridazinyl)‐2<i>H</i>‐indol‐2‐one (LY195115), an orally effective positive inotrope

Abstract

Abstract We have synthesized 14 C‐ and 2 H‐labeled 1,3‐dihydro‐3,3‐dimethyl‐5‐(1,4,5,6‐tetrahydro‐6‐oxo‐3‐pyridazinyl)‐2 H ‐indol‐2‐one (LY195115), an extremely potent, orally‐effective cardiotonic with inotropic and vasodilator activities. The 14 C‐label was introduced in the antepenultimate step by reaction of a β‐chloroketone precursor with Na 14 CN; acid‐catalyzed hydrolysis and cyclization with hydrazine provided the tetrahydropyridazinone bearing the 14 C‐label in the oxo‐carbon. 1,3‐Dihydro‐3,3‐di(methyl‐d 3 )‐2 H ‐indol‐2‐one was prepared by exhaustive methylation of 1‐acetyl‐1,3‐dihydro‐2 H ‐indol‐2‐one with sodium hydride and iodomethane‐d 3 , followed by removal of the nitrogen protecting group. This labeled material was converted in two steps to [ 2 H 6 ]‐LY195115.