The title indolomorphinan derivative was synthesized by Fisher indole synthesis from the known 14-O-ethyl-5-methylnaltrexone (I) and phenylhydrazine hydrochloride (II) in refluxing acetic acid, followed by conversion to the corresponding hydrochloride salt.
A further procedure for the preparation of (I) from naltrexone (III) has been reported. Naltrexone (III) was O-alkylated with diethyl sulfate in the presence of NaH to give (IV). Deprotonation of (IV) using the combination potassium tert-butoxide/butyllithium, followed by methylation with dimethyl sulfate, yielded the 5-methyl derivative (V). The aryl- and enol ether groups of (V) were then cleaved by means of concentrated HBr.