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Synthesis 2007(10): 1547-1553  
DOI: 10.1055/s-2007-966037
PAPER
© Georg Thieme Verlag Stuttgart · New York

A New Approach to the Synthesis of the Nonpeptide NOP Receptor Antagonist J-113397

Agnieszka Sulima, John Folk, Arthur E. Jacobson, Kenner C. Rice*
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-0815, USA
Fax: +1(301)020589; e-Mail: kr21f@nih.gov;
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Publication History

Received 18 January 2007
Publication Date:
02 May 2007 (online)

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Abstract

A new synthesis that eliminates the need for chromatographic separation in order to obtain multigram quantities of J-113397, a competitive antagonist of the N/OFQ-NOP receptor system, is reported. N-Benzyl protected 4-oxopiperidinecarboxylate was used as the starting material to obtain an N-benzyl intermediate that could be resolved at a relatively early stage in the synthesis. The crucial step in the synthesis was reduction of the double bond of the β-enaminoester functionality of 1-benzyl-4-(3-ethyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester, since Pd/C reduction gave inseparable mixtures. It could be reduced and epimerized to the desired trans diastere­oisomer in a one-pot reaction by treatment with magnesium metal in methanol.

Key words

NOP antagonist - receptor - synthesis - enantiomeric resolution­ - β-enaminoester reduction