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 ?-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 ?,?-dienolate anion 1.1a. Regio and chemoselective ?-alkylation of the dienolate with various primary and secondary alkyl halides furnished the ?-keto-amides 1.2?1.5 (76?91 %). Reductive amination 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 ?-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.