Open AccessChiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66
Author(s) -
Vivek Kumar,
Ashwini K. Banala,
Erick G. Garcia,
Jianjing Cao,
Thomas M. Keck,
Alessandro Bonifazi,
Jeffrey R. Deschamps,
Amy Hauck Newman
Publication year - 2014
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml500006v
Subject(s) - enantiomer , chemistry , dopamine receptor d3 , selectivity , linker , antagonist , stereochemistry , amide , medicinal chemistry , dopamine receptor d2 , receptor , organic chemistry , catalysis , biochemistry , computer science , operating system
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).