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

doi:10.1021/ml500006v

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 journal › Article › peer-review

16 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 language	English (US)
Pages (from-to)	647-651
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	6
DOIs	https://doi.org/10.1021/ml500006v
State	Published - Jun 12 2014
Externally published	Yes

Keywords

asymmetric catalysis
DAST
dopamine
enantioselectivity

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml500006v

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

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).",

keywords = "asymmetric catalysis, DAST, dopamine, enantioselectivity",

author = "Vivek Kumar and Banala, {Ashwini K.} and Garcia, {Erick G.} and Jianjing Cao and Keck, {Thomas M.} and Alessandro Bonifazi and Deschamps, {Jeffery R.} and Newman, {Amy Hauck}",

year = "2014",

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doi = "10.1021/ml500006v",

language = "English (US)",

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journal = "ACS Medicinal Chemistry Letters",

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T1 - Chiral resolution and serendipitous fluorination reaction for the selective dopamine d3 receptor antagonist BAK2-66

AU - Kumar, Vivek

AU - Banala, Ashwini K.

AU - Garcia, Erick G.

AU - Cao, Jianjing

AU - Keck, Thomas M.

AU - Bonifazi, Alessandro

AU - Deschamps, Jeffery R.

AU - Newman, Amy Hauck

PY - 2014/6/12

Y1 - 2014/6/12

N2 - 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).

AB - 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).

KW - asymmetric catalysis

KW - DAST

KW - dopamine

KW - enantioselectivity

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

Abstract

Keywords

ASJC Scopus subject areas

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