Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

Бредихин, А. А.; Бредихина, З. А.

doi:10.1002/ceat.201600649

Cited by 25 publications

(20 citation statements)

References 99 publications

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“…Due to the different, and sometimes opposite, biological effects between the eutomer and the distomer, access to pure enantiomers is mandatory. Different methods exist to obtain pure enantiomers, such as asymmetric synthesis or chiral chromatography but their costs are often prohibitive for industrial applications and resolution by crystallization is preferred . Among the different available resolution methods, Pasteurian resolution , preferential crystallization , and deracemization are popular.…”

Section: Introductionmentioning

confidence: 99%

Limitations of Preferential Enrichment: A Case Study on Tryptophan Ethyl Ester Hydrochloride

et al. 2019

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Since eutomer and distomer show different biological effects, access to pure enantiomers is essential. Preferential enrichment is a relatively new process of chiral resolution developed in the 90s. Extension of its scope was attempted with tryptophan ethyl ester hydrochloride. This salt meets one of the most important requirements for preferential enrichment, namely, a larger solubility for the pure enantiomers with reference to the racemic compound. But, due to the absence of a solid solution, this salt cannot perform preferential enrichment. This impossibility was endorsed by semi-empirical molecular modeling.

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Section: Introductionmentioning

confidence: 99%

Limitations of Preferential Enrichment: A Case Study on Tryptophan Ethyl Ester Hydrochloride

et al. 2019

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“…Solutions of this problem could be forming and crystallizing, e.g., the sodium salt, which was investigated by Faigl et al [35]. According to the phase diagram of the IBU-PhEA system, there is no eutectic composition in the investigated range [36], so it is promising to increase the optical purity of the salts by recrystallization [37]. Two approaches are described below to achieve pure diastereomeric salts: (i) the repeated resolution applying the half molar equivalent of the resolving agent and (ii) the recrystallization approach applying the molar equivalent of the resolving agent to the acid.…”

Section: Diastereomeric Enrichmentmentioning

confidence: 99%

Towards Diastereomeric Pure Salts with Antisolvent Methods

et al. 2018

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Chiral molecules, especially enantiomers and diastereomers of purity > 99 %, present a significant market share within the chemical, pharmaceutical, and flavor industries. Antisolvent precipitations, both batch and semicontinuous operations to serve the current trends in flow chemistry were demonstrated to be environmentally benign and efficient tools in achieving high optical purities. Although salts are known to be insoluble in supercritical CO 2 , instabilities of the nascent salts were detected and applied for increasing efficiency. Diastereomeric excess values of the crystalline products exceeded 99 % in maximum of three consecutive steps both by repeated resolution with half molar equivalent of the amine to the acid and by direct recrystallization of the salts.

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“…It has even been used in the production of chiral active pharmaceutical ingredients (Bredikhin & Bredikhina, 2017). However, the reasons why this occurs with a minority of molecules are not well understood (Pé rez-Garcia & Amabilino, 2007) and have not yet yielded to attempts to predict occurrence (D'Oria, Karanertzanis & Price, 2010;Pé rez-Garcia & Amabilino, 2007).…”

Section: Chemical Contextmentioning

confidence: 99%

Spontaneous resolution and crystal structure of (2S)-2-(3-nitrophenyl)-3-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one; crystal structure of rac-2-(4-nitrophenyl)-3-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one

et al. 2018

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The crystal structures of isomeric rac-2-(4-nitrophenyl)-3-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one (C16H14N2O3S) (1) and (2S)-2-(3-nitrophenyl)-3-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one (C16H14N2O3S) (2) are reported here. While 1 crystallizes in a centrosymmetric space group, the crystal of 2 chosen for data collection has molecules only with (2S) chirality. This is the result of spontaneous resolution during crystallization, as the synthesis produces a racemic mixture. A crystal with (2R) molecules was also found in the same crystallization vial (structure factors available). The six-membered thiazine ring in both 1 and 2 displays an envelope conformation with the S atom forming the flap. The aryl rings in both structures adopt an approximate V shape with angles between their planes of 46.97 (14)° in 1 and 58.37 (10)° in 2. In both structures, the molecules form layers in the ab plane. Within such a layer in 1, one of the O atoms of the nitrophenyl group accepts a C—H...O hydrogen bond from the CH group at position 5 of the thiazine ring of a molecule of opposite chirality, forming chains along the a-axis direction. Each of the thiazine rings also participate in C—H...O bonds with the same carbon atom as above, resulting in chains along the b-axis direction, albeit of monochiral type. Adjacent layers are consolidated along the c-axis direction by pairs of parallel hydrogen bonds (C—H...O type) between the nitrophenyl groups of enantiomers. In 2, the two C—H...O hydrogen bonds contribute to chain formation along the b-axis direction. Weak edge-to-face interactions between the aryl groups of neighbouring molecules in 1, and C—H...π interactions between a thiazine ring CH group and a phenyl group of a neighboring molecule in 2 are also observed.

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Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

Cited by 25 publications

References 99 publications

Limitations of Preferential Enrichment: A Case Study on Tryptophan Ethyl Ester Hydrochloride

Limitations of Preferential Enrichment: A Case Study on Tryptophan Ethyl Ester Hydrochloride

Towards Diastereomeric Pure Salts with Antisolvent Methods

Spontaneous resolution and crystal structure of (2S)-2-(3-nitrophenyl)-3-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one; crystal structure of rac-2-(4-nitrophenyl)-3-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one

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