Synthesis 2017; 49(06): 1394-1400
DOI: 10.1055/s-0036-1588379
paper
© Georg Thieme Verlag Stuttgart · New York

Modified Synthesis of NOP Receptor Antagonist SB612111

David A. Perrey
a   Research Triangle Institute, Research Triangle Park, NC 27709, USA   eMail: yzhang@rti.org
,
Jun-Xu Li
b   Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14214, USA
,
Yanan Zhang*
a   Research Triangle Institute, Research Triangle Park, NC 27709, USA   eMail: yzhang@rti.org
› Institutsangaben
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Publikationsverlauf

Received: 09. September 2016

Accepted after revision: 27. November 2016

Publikationsdatum:
19. Dezember 2016 (online)


Abstract

SB612111 [(5S,7S)-7-{[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol] is a potent and selective antagonist of the nociception/orphanin FQ peptide (NOP) receptor. In the process of synthesizing cis-SB612111 to support ongoing animal studies, several key steps of the published syntheses in the patent literature proceeded in low yields in our hands, particularly in the route to the key intermediate 4-(2,6-dichlorophenyl)piperidine, the reduction of 7-[4-(2,6-dichlorophenyl)piperidine-1-carbonyl]-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one, the formation of (±)-6-methyl-12-oxatricyclo[8.2.1.02,7]trideca-2,4,6-trien-11-one, and the final reductive amination between (±)-6-methyl-12-oxatricyclo[8.2.1.02,7]trideca-2,4,6-trien-11-ol and 4-(2,6-dichlorophenyl)piperidine in the diastereoselective synthesis. We have thus explored various reaction conditions and successfully improved the yields for the necessary synthetic steps. We herein report our modified synthesis of SB612111 as the cis-diastereomers.

Supporting Information

 
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