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

Sudhakar R. Jakkaraj; Victor G. Young; Gunda I. Georg

doi:10.1016/j.tet.2018.04.045

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

Sudhakar R. Jakkaraj, Victor G. Young, Gunda I. Georg

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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 language	English (US)
Pages (from-to)	2769-2774
Number of pages	6
Journal	Tetrahedron
Volume	74
Issue number	22
DOIs	https://doi.org/10.1016/j.tet.2018.04.045
State	Published - May 31 2018

Bibliographical note

Funding Information:
Financial support for this project is gratefully acknowledged from the NICHD : 1U01HD076542 (GIG), HHSN275201300017C (GIG), and U54 HD055744 (Jeffrey Jensen, OHSU). The determination of the ORG9935 purity and the separation of the ORG9935 enantiomers were carried out by Shanghai ChemPartner Co., Ltd. China. Partial support for the purchase of the Bruker-AXS Venture PHOTON-II diffractometer was obtained through the National Science Foundation Major Research Instrumentation grant award # 1229400 .

Funding Information:
Financial support for this project is gratefully acknowledged from the NICHD: 1U01HD076542 (GIG), HHSN275201300017C (GIG), and U54 HD055744 (Jeffrey Jensen, OHSU). The determination of the ORG9935 purity and the separation of the ORG9935 enantiomers were carried out by Shanghai ChemPartner Co., Ltd. China. Partial support for the purchase of the Bruker-AXS Venture PHOTON-II diffractometer was obtained through the National Science Foundation Major Research Instrumentation grant award #1229400.

Publisher Copyright:
© 2018 The Authors

Keywords

Enantiomer separation
Female contraception
ORG9935
PDE3A inhibitor
Structure determination
Synthesis

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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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.",

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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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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