Synthesis of β3 adrenergic receptor agonist LY377604 and its metabolite 4‐hydroxycarbazole, labeled with carbon‐14 and deuterium

Synthesis of 14C-radiolabeled 4-hydroxycarbazole was accomplished starting from aniline-[U-14C], based on zinc chloride initiated Fischer cyclization of the phenylhydrazone prepared from phenylhydrazine-[U-14C] and cyclohexane-1,3-dione. The resulting tetrahydrooxocarbazole was subjected to dehydrogenation–aromatization using palladium on carbon. The aromatized 4-hydroxycarbazole-[4b,5,6,7,8,8a-14C] was then used for the synthesis of 14C-labeled β3 adrenergic receptor agonist LY377604. The introduction of four deuteria in the carbazole fragment of LY377604 accomplished by its initial bromination and subsequent catalytic deuteration of the resulting tetrabromide. A similar approach was used for the conversion of 4-hydroxycarbazole into its tetradeutero-isotopomer. Copyright © 2005 John Wiley & Sons, Ltd.