STEREOISOMERS OF 3-METHYLFENTANYL:SYNTHESIS,ABSOLUTE CONFIGURATION AND ANALGESIC ACTIVITY

Fractional crystallization of fumarate salt and oxalate salt of the mixture of cisand trans-N-(3-methyl-4-piperidyl)-aniline (6) gave pure cis-6 fumarate salt and trans-6·oxalate salt respectively, four optically pure 6 were obtained via resolution of cis-6 and trans-6 with D-and Ltartaric acid. Respective reaction of the optically pure 6 with phenylethyl bromide following propionylation gave optically active 3-methylfentanyl (2). The absolute configuration was confirmed: cis-(+)-2 as (3R, 4S), cis-(—)-2 as (3S, 4R), trans-(+)-2 as (3S, 4R), trans-(—)-2 as (3R, 4R). Pharmacological results showed that the configuration of two chiral centers in 2 was very important for analgesic potency. The median effective dose (ED₅₀) of cis-(+)-2, which is the most potent among the four isomers, was found to be 0.00767 mg/kg (in mice, ip., hot plate) with 2600 times as potent as morphine while 119 and 1.5 times as potent as cis-(—)-2 and cis-(±)-2 respectively. The potency ratio between trans-(+)-2 and morphine was calculated as 450: 1, while that between trans-(+)-2 and trans-(—)-2 as 4: 1.