Synthesis of pethidine

Pethidine (meperidine), a synthetic opioid analgesic, was first prepared in 1939. Its classic synthesis exploits the acidity of the CH₂ of phenylacetonitrile, activated both by the aromatic ring and by the cyano group.

With two equivalents of sodium amide, the nitrile is alkylated twice by bis(2-chloroethyl)methylamine; the second alkylation is intramolecular and closes the piperidine ring. Finally, the nitrile is converted into the ethyl ester with ethanol under acidic conditions.