Synthesis and characterization of [N‐methyl‐3H]loperamide

Loperamide is a piperidine butyramide mu‐opiate receptor agonist and currently employed to treat diarrhea. Because a single past report of tritiating loperamide was limited to only a very low specific activity product without technical details or extensive analysis, the synthesis of [N‐methyl‐³H]loperamide at high specific activity is now described in detail. An imine precursor was alkylated with [³H]methyl iodide to obtain a quaternary intermediate, which was then reacted with 4‐(4‐chlorophenyl)‐4‐hydroxypiperidine to afford the desired product [N‐methyl‐³H]loperamide, characterized by thin layer chromatography (TLC), HPLC, MS, UV, and proton‐decoupled tritium NMR.