Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

Citations Over TimeTop 22% of 2014 papers

Abstract

The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)1H-indole-2-carboxamide (( R )-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). ( R )-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than ( R )-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutyl-product (8).

Related Papers

• → Differential visualization of dopamine D2 and D3 receptors in rat brain(1993)23 cited
• → A New Robust and Versatile Tetradentate Linker for Amides To be Cleaved under Mild Conditions by Unusual Complexation of the Amide Nitrogen to Cu++(2009)12 cited
• → Dopamine D2/D3 receptor agonists produce antidepressant‐like effects in the rat forced swim test through co‐activation of both receptor subtypes(2008)1 cited
• → Development and Application of a Carbonyl-13C-Enriched Backbone Amide Linker for Solid-Phase Reaction Monitoring(2001)12 cited
• → DOPAMINE D1, D2, D3, D4 RECEPTOR GENE POLYMORPHISMS AND SCHIZOPHRENIA(1992)