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A general, five step method for the synthesis of 3-alkylfentanyl analogues (i.e., cis and trans 3-alkyl-4-anilidopiperidines 6.1?6.6) has been developed. The starting N-phenethyl- 4-piperidone 1 was first converted into the cyclohexylimine derivative 2, ?-deprotonated with butyllithium and the resulting imine anion efficiently monoalkylated with primary and secondary alkyl halides. After mild acid hydrolysis, the obtained 3-alkyl-4-piperidones 3.1?3.6 were isolated in good yields (79?85 %), then condensed with aniline to form imines 4.1?4.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1?5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1?5.6 (29?51 % yield) and trans 5.1?5.6 (19?27%yield) with the cis/trans ratio in the range 7/3?6/4. The synthesiswas concluded by N-acylation of the purified 5.1?5.6, with propionyl chloride, to afford cis and trans 3-alkyl- 4-anilidopiperidines 6.1?6.6 (? 95 % yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the 1H-NMR spectra. Of the twelve synthesized 3-alkylfentanyls, ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (?)-cis-3-Me fentanyl 6.1cis, (8 x fentanyl), and the novel (?)-cis-3-Et fentanyl 6.2 cis, (1.5 x fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure- activity relationship (SAR) in this series of derivatives have been made.

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