Synthesis 2017; 49(14): 3126-3136
DOI: 10.1055/s-0036-1588985
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3-N-Carbomethoxyfentanyl

Ivana I. Jevtića, Ljiljana I. Došen-Mićovića, Evica R. Ivanovićb, Nina M. Todorovićc, Milovan D. Ivanović*a
  • aFaculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia   Email: misai@chem.bg.ac.rs
  • bFaculty of Agriculture, University of Belgrade, Nemanjina 6, 11080 Belgrade-Zemun, Serbia
  • cInstitute of Chemistry, Technology and Metallurgy, Center of Chemistry, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia
Further Information

Publication History

Received: 03 February 2017

Accepted after revision: 08 March 2017

Publication Date:
03 April 2017 (eFirst)

Abstract

The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (±)-cis and (±)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.

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