@article{
author = "Ivanović, Milovan D. and Mićović, I.V. and Vučković, Sonja M. and Prostran, Milica Š. and Todorović, Zoran M. and Kricojević, V.D. and Popović-Djordjević, Jelena and Došen-Mićović, Ljiljana I.",
year = "2004",
abstract = "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, α-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., Razvijen je opšti metod za sintezu 3-alkil analoga fentanila (tj. cis i trans 3-alkil-4-anilidopiperidina 6.1–6.6) u pet faza. Polazni N-fenetil-4-piperidon 1 prvo je preveden u cikloheksiliminski derivat 2, α-deprotonovan butillitijumom, a postali iminski anjon efikasno monoalkilovan primarnim i sekundarnim alkilhalogenidima. Posle blage kisele hidrolize, nastali 3-alkil-4-piperidoni 3.1–3.6 izolovani su u dobrim prinosima (79–85 %), zatim kondenzovani sa anilinom do imina 4.1–4.6. Redukcijom ovih imina (LiAlH4/THF) dobijene su cis/trans smese 3-alkil-4-anilinopiperidina 5.1–5.6. Kvantitativnim hromatografskim razdvajanjem dijastereoizomera na stubu Al2O3 izolovani su čisti cis 5.1–5.6 (prinos 29–51 %) i trans 5.1–5.6 (prinos 19–27 %), gde je cis/trans odnos bio u opsegu 7/3–6/4. Sinteza je završena N-acilovanjem prečišćenih intermedijera 5.1–5.6 pomoću propionil-hlorida, pri čemu su postali cis i trans 3-alkil-4-anilidopiperidini 6.1–6.6 (prinos _ 95 %, kao monooksalatne soli). Ni u jednoj fazi nije pokušano razdvajanje enantiomera. Relativna, cis/trans, stereohemija preliminarno je određena iz 1H-NMRspektra. Od dvanaest sintetisanih 3-alkil-fentanila, deset jedinjenja (dva poznata i osam novih, sva u obliku monookasalatnih soli) preliminarno su testirana kao analgetici na pacovima, poredeći aktivnost sa fentanilom.Osim poznatog (±)-cis-3-Me fentanila 6.1 cis, (8 x fentanil), i novog (±)-cis-3-Et fentanila 6.2 cis, (1,5 x fentanil), svi ostali bili su manje aktivni ili neaktivni. Izvedeni su određeni, preliminarni zaključci u vezi odnosa strukture i aktivnosti u ovoj seriji derivata.",
publisher = "Srpsko hemijsko društvo, Beograd",
journal = "JOURNAL OF THE SERBIAN CHEMICAL SOCIETY",
title = "The synthesis and preliminary pharmacological evaluation of racemic cis and trans 3-alkylfentanyl analogues, Sinteza i preliminarni farmakološki testovi recemskih cis i trans 3-alkilanaloga fentanila",
pages = "526-511",
number = "7",
volume = "69",
doi = "10.2298/JSC0407511I"
}
