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RESEARCH ARTICLE
Contents Vol 72(3)

In Pursuit of Fluorinated Sigma Receptor Ligand Candidates Related to [18F]-FPS*

Rasha S. Jwad A B , Alan H. C. Pang A , Luke Hunter A and Roger W. Read A C
+ Author Affiliations
- Author Affiliations

A School of Chemistry, The University of New South Wales (UNSW), Sydney, NSW 2052, Australia.

B Department of Chemistry, College of Science, Al-Nahrain University, Al-Jadriya, Baghdad 10070, Iraq.

C Corresponding author. Email: r.read@unsw.edu.au

Australian Journal of Chemistry 72(3) 213-225 https://doi.org/10.1071/CH18510
Submitted: 19 October 2018  Accepted: 19 November 2018   Published: 10 December 2018

Abstract

This paper describes the synthesis of N-arylmethyl(1-benzyl) and N-aroyl(1-benzoyl) 4-(4-fluoromethylphenoxymethyl)piperidines as potential sigma receptor ligands analogous to the potent and highly selective sigma-1 ligand [18F]-FPS, but with enhanced or alternative binding and transport profiles. The synthesis involves N-aroylation of 4-hydroxmethylpiperidine or ethyl nipecotate, functional group manipulation of the ester group or simple activation of the hydroxyl group to introduce the phenoxy component, and subsequent functional group manipulation to reduce the amide group and introduce the fluorine into the fluoromethyl substituent. In its development, the synthesis was found to require early N-aroylation of the piperidine precursor to avoid complications due to anchimeric assistance by its nitrogen in subsequent displacement reactions. New evidence is presented on the pathway followed in a literature report of direct displacement of a benzylic hydroxyl group by fluoride ion under Appel-like conditions. Relevant to the literature report, the halide ion in the fluoromethylphenoxy 1-benzylpiperidine derivatives was surprisingly labile to hydrolytic displacement on chromatography and this aspect is worthy of further study. Moreover, the NMR spectra of the amides were complicated by geometric isomerism about the amide C(O)–N bond, but detailed analysis of spectra from 2-anisoyl derivatives allowed the assignment of diastereomeric contributors to consistent, secondary atropisomerism about the aryl–C(O) bond.


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