Modified synthesis of NOP receptor antagonist SB612111

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[8.2.1.0(2,7)] trideca-2,4,6-trien-11-one, and the final reductive amination between (+/-)-6-methyl-12-oxatricyclo[ 8.2.1.0(2,7)] 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.