Synthesis ofβ3 adrenergic receptor agonistLY377604 and its metabolite 4-hydroxycarbazole, labeled with carbon-14 and deuterium

Abstract

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.

1,2,3,9‐Tetrahydro‐4H‐carbazol‐4‐one and 8,9‐dihydropyrido‐[1,2‐a]indol‐6(7H)‐one from 1H‐indole‐2‐butanoic acid

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