The synthesis and pharmacological evaluation of (±)-2,3-seco- fentanyl analogues

Abstract

An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1-5.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting β-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93% yield), was successively reacted with NaH and BuLi, to form the highly reactive α,γ-dienolate anion 1.1a. Regio and chemoselective γ-alkylation of the dienolate with various primary and secondary alkyl halides furnished the β-keto-amides 1.2-1.5 (76-91%). Reductive animation of the keto-amides 1.1-1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1-2.5, afforded the β-anilino amides 3.1-3.5 (74-85 %). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1-4.5 were obtained (87-97%). The synthesis of (±)-2,3-seco-fentanyls 5.1-5.5 was completed by N-acylation of the diamines 4.1-4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86-95%). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5-6 times more active than morphine in rats, while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance, the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.