Chiral resolution and serendipitous fluorination reaction for the selective dopamine d3 receptor antagonist BAK2-66

Vivek Kumar, Ashwini K. Banala, Erick G. Garcia, Jianjing Cao, Thomas M. Keck, Alessandro Bonifazi, Jeffery R. Deschamps, Amy Hauck Newman

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)647-651
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume5
Issue number6
DOIs
StatePublished - Jun 12 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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