Structural Analysis of d -Phenylglycinamide Salts Uncovers Potential Pitfalls in Chiral Resolution via Diastereomeric Salt Formation

Natalia Tumanova, Vanessa Seiler, Nikolay Tumanov, Koen Robeyns, Yaroslav Filinchuk, Johan Wouters, Tom Leyssens

Research output: Contribution to journalArticle

Abstract

d-Phenyglycinamide (d-PGA) was shown to form diastereomeric salts with a series of dicarboxylic acids (malic, methylsuccinic, camphoric) and the drug naproxen. Structural analysis of the 21 newly discovered forms was performed in order to investigate the potential of d-PGA as a base agent for chiral resolution via diastereomeric salt formation. Malic and methylsuccinic dicarboxylic acids formed salts with 1:1 and 2:1 stoichiometries, whereas camphoric acid and naproxen yielded only 1:1 salts. In the d-PGA/naproxen system, variable-temperature in situ synchrotron X-ray diffraction gave access to two additional nonambient 1:1 salts. d-PGA subjected to liquid-assisted grinding with the racemic forms of the tested compounds to study chiral resolution in the solid state yielded in most of the cases complicated mixtures of diastereomeric salts or salts with the racemates (when both enantiomers and d-PGA crystallize in one structure), thereby suggesting that the use of d-PGA for chiral resolution may be challenging.
Original languageEnglish
Pages (from-to)3652-3659
Number of pages8
JournalCrystal Growth & Design
Volume19
Issue number7
Early online date21 Jun 2019
DOIs
Publication statusPublished - 3 Jul 2019

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structural analysis
Structural analysis
Salts
salts
Naproxen
Dicarboxylic Acids
dicarboxylic acids
Acids
Enantiomers
enantiomers
grinding
phenylglycinamide
Synchrotrons
Stoichiometry
stoichiometry
synchrotrons
drugs
solid state
X ray diffraction
acids

Cite this

Tumanova, Natalia ; Seiler, Vanessa ; Tumanov, Nikolay ; Robeyns, Koen ; Filinchuk, Yaroslav ; Wouters, Johan ; Leyssens, Tom. / Structural Analysis of d -Phenylglycinamide Salts Uncovers Potential Pitfalls in Chiral Resolution via Diastereomeric Salt Formation. In: Crystal Growth & Design. 2019 ; Vol. 19, No. 7. pp. 3652-3659.
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Structural Analysis of d -Phenylglycinamide Salts Uncovers Potential Pitfalls in Chiral Resolution via Diastereomeric Salt Formation. / Tumanova, Natalia; Seiler, Vanessa; Tumanov, Nikolay; Robeyns, Koen; Filinchuk, Yaroslav; Wouters, Johan; Leyssens, Tom.

In: Crystal Growth & Design, Vol. 19, No. 7, 03.07.2019, p. 3652-3659.

Research output: Contribution to journalArticle

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AU - Tumanova, Natalia

AU - Seiler, Vanessa

AU - Tumanov, Nikolay

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AU - Filinchuk, Yaroslav

AU - Wouters, Johan

AU - Leyssens, Tom

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N2 - d-Phenyglycinamide (d-PGA) was shown to form diastereomeric salts with a series of dicarboxylic acids (malic, methylsuccinic, camphoric) and the drug naproxen. Structural analysis of the 21 newly discovered forms was performed in order to investigate the potential of d-PGA as a base agent for chiral resolution via diastereomeric salt formation. Malic and methylsuccinic dicarboxylic acids formed salts with 1:1 and 2:1 stoichiometries, whereas camphoric acid and naproxen yielded only 1:1 salts. In the d-PGA/naproxen system, variable-temperature in situ synchrotron X-ray diffraction gave access to two additional nonambient 1:1 salts. d-PGA subjected to liquid-assisted grinding with the racemic forms of the tested compounds to study chiral resolution in the solid state yielded in most of the cases complicated mixtures of diastereomeric salts or salts with the racemates (when both enantiomers and d-PGA crystallize in one structure), thereby suggesting that the use of d-PGA for chiral resolution may be challenging.

AB - d-Phenyglycinamide (d-PGA) was shown to form diastereomeric salts with a series of dicarboxylic acids (malic, methylsuccinic, camphoric) and the drug naproxen. Structural analysis of the 21 newly discovered forms was performed in order to investigate the potential of d-PGA as a base agent for chiral resolution via diastereomeric salt formation. Malic and methylsuccinic dicarboxylic acids formed salts with 1:1 and 2:1 stoichiometries, whereas camphoric acid and naproxen yielded only 1:1 salts. In the d-PGA/naproxen system, variable-temperature in situ synchrotron X-ray diffraction gave access to two additional nonambient 1:1 salts. d-PGA subjected to liquid-assisted grinding with the racemic forms of the tested compounds to study chiral resolution in the solid state yielded in most of the cases complicated mixtures of diastereomeric salts or salts with the racemates (when both enantiomers and d-PGA crystallize in one structure), thereby suggesting that the use of d-PGA for chiral resolution may be challenging.

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