Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography

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Abstract

Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34% overall yield and the second one in five steps and an overall yield of 69% starting from commercially available starting material 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (6). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the (S)-configuration. The (−)-enantiomer, ORG20864, was therefore assigned the (R)-stereochemistry. The biologically less active (+)-isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z′ for any known pharmaceutical substance.

Original languageEnglish (US)
Pages (from-to)2769-2774
Number of pages6
JournalTetrahedron
Volume74
Issue number22
DOIs
StatePublished - May 31 2018

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Stereochemistry
Enantiomers
X ray crystallography
X Ray Crystallography
Chromatography
Pharmaceutical Preparations
Column chromatography
Isomers
Crystal structure
thiophene-2-carboxylate

Keywords

  • Enantiomer separation
  • Female contraception
  • ORG9935
  • PDE3A inhibitor
  • Structure determination
  • Synthesis

PubMed: MeSH publication types

  • Journal Article

Cite this

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title = "Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography",
abstract = "Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34{\%} overall yield and the second one in five steps and an overall yield of 69{\%} starting from commercially available starting material 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (6). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the (S)-configuration. The (−)-enantiomer, ORG20864, was therefore assigned the (R)-stereochemistry. The biologically less active (+)-isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z′ for any known pharmaceutical substance.",
keywords = "Enantiomer separation, Female contraception, ORG9935, PDE3A inhibitor, Structure determination, Synthesis",
author = "Jakkaraj, {Sudhakar R} and Young, {Victor G} and Gunda Georg",
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T1 - Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography

AU - Jakkaraj, Sudhakar R

AU - Young, Victor G

AU - Georg, Gunda

PY - 2018/5/31

Y1 - 2018/5/31

N2 - Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34% overall yield and the second one in five steps and an overall yield of 69% starting from commercially available starting material 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (6). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the (S)-configuration. The (−)-enantiomer, ORG20864, was therefore assigned the (R)-stereochemistry. The biologically less active (+)-isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z′ for any known pharmaceutical substance.

AB - Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34% overall yield and the second one in five steps and an overall yield of 69% starting from commercially available starting material 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (6). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the (S)-configuration. The (−)-enantiomer, ORG20864, was therefore assigned the (R)-stereochemistry. The biologically less active (+)-isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z′ for any known pharmaceutical substance.

KW - Enantiomer separation

KW - Female contraception

KW - ORG9935

KW - PDE3A inhibitor

KW - Structure determination

KW - Synthesis

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