Structural Analysis of d-Phenylglycinamide Salts Uncovers Potential Pitfalls in Chiral Resolution via Diastereomeric Salt Formation
(2019) Crystal Growth & Design — Vol. 19, n° 7, p. 3652-3659 (2019)
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- Authors
Tumanova, Natalia 
Tumanov, Nikolay
- Abstract
- We studied the ability of D-phenyglycinamide to form diastereomeric salts with a series of dicarboxylic acids, i.e., malic, methylsuccinic, camphoric, and a drug naproxen in order to investigate its potential as an agent for chiral resolution. D-phenylglycinamide readily formed salts with the aforementioned compounds – we discovered 21 salts in total. In the case of malic and methylsuccinic acids, besides the salts with the 1:1 stoichiometry, we also found 2:1 salts and a two-step reaction mechanism was suggested, with the 2:1 salts being an intermediate preceding the formation of 1:1 salts. In the case of camphoric acid, only hydrated 1:1 salts were identified. In the Dphenylglicinamide/naproxen system, multiple 1:1 salts were identified, including hydrated D-PGA salts with S- and RS-naproxen. Variable-temperature in situ synchrotron X-ray diffraction was used to study selected samples. In the naproxen system, it gave access to two additional unhydrated polymorphs. The possibility of chiral resolution in solid state was tested via liquid-assisted grinding of D-PGA with the racemic forms of all the compounds: 1:1 combinations of all the salts with dicarboxylic acids yielded 1:1 diastereomeric salts, whereas 2:1 combinations for malic and methylsuccinic acids resulted in the 2:1 salts with the racemate. Unlike, dicarboxylic acids, when DPGA was ground with RS-naproxen it directly led to the salts with racemic naproxen, thereby showing no chiral resolution in solid state. We also report the structure of D-phenylglycinamide itself for the first time. The results of this work showed that D-phenylglycinamide is a viable base for diastereomeric salt formation with carboxylic acids and uncovered some pitfalls that can be encountered when it is used for chiral resolution
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Citations
Tumanova, N., Seiler, V. K., Tumanov, N., Robeyns, K., Filinchuk, Y., Wouters, J., & Leyssens, T. (2019). Structural Analysis of d-Phenylglycinamide Salts Uncovers Potential Pitfalls in Chiral Resolution via Diastereomeric Salt Formation. Crystal Growth & Design, 19(7), 3652-3659. https://doi.org/10.1021/acs.cgd.8b01769 (Original work published 2019)