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Synthesis of 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 orally effective positive inotrope
Author(s) -
Robertson David W.,
Krushinski Joseph H.,
Kau Don
Publication year - 1986
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580230402
Subject(s) - chemistry , hydrazine (antidepressant) , medicinal chemistry , sodium hydride , hydrolysis , reagent , nitrogen , stereochemistry , organic chemistry , chromatography
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.