Synthesis and stereochemistry of 3-methyl analogues of pethidine

Abstract

Diastereoisomeric 3-methyl analogues of pethidine and related 4-propionyl derivatives have been synthesized by the condensation of phenylacetonitrile with derivatives of N-2-hydroxyethyl-2-hydroxypropylamine. Isomeric forms of intermediate 4-cyanopiperidines have been isolated and their configurations have been established from ¹H n.m.r. data and by chemical correlations. Amides and amidines are by-products of these reactions. The β-diastereoisomer of 3-methylpethidine (cis 3-Me/4-Ph) is 11 times, and the α-isomer 1·3 times, more potent than pethidine in the mouse hot-plate test for analgesia.