Application of Continuous Preferential Crystallization to Efficiently Access Enantiopure Chemicals

Rougeot, Céline; Hein, Jason E.

doi:10.1021/acs.oprd.5b00141

Cited by 77 publications

(69 citation statements)

References 52 publications

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“…Vital prerequisites for both Viedma ripening of chiral compounds and SOAT are solution phase racemization and conglomerate crystallization 29 . However, most chiral compounds, when crystallized from a racemic solution, form racemic compounds 22 (i.e.…”

Section: Introductionmentioning

confidence: 99%

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Xiouras

Horst

Gerven

et al. 2017

Crystal Growth & Design

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It has been recently observed that coupling Viedma ripening with a seeded in-situ metastable racemic crystal to conglomerate transformation leads to accelerated and complete deracemization: crystal transformation-enhanced deracemization. By means of a simple kinetic model, we show that the mechanistic pathway of this new process depends profoundly on the interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is suppressed (e.g. by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals. Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared to conventional Viedma ripening, while it autocorrects for the main disadvantage of SOAT, i.e. the accidental nucleation of the counter enantiomer. In addition, crystal transformation-enhanced deracemization extends the range of applicability of solid-state deracemization processes to compounds that form metastable racemic crystals. interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is 3 suppressed (e.g. by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals.Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared ...

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Section: Introductionmentioning

confidence: 99%

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Xiouras

Horst

Gerven

et al. 2017

Crystal Growth & Design

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“…As expected from the racemization behavior of 1 , a short crystallization duration of 10 h resulted in a low ee of the isolated crystals, whereas a crystallization duration of 20 h furnished a high ee with a maximum of 97 % ee . To confirm the reproducibility of the experiment, we performed SOAT with the same duration and used seed crystals of the opposite enantiomer, which afforded an average ee of 90 % after 20 h. The average volumetric productivity, which indicates the quantity of the desired product that can be obtained per time unit and volume, was 6.5 g h −1 L −1 % for the process. Compared with our previous study, in which we determined the productivity by both SOAT and TCID, the productivity in the present work is low owing to the long crystallization duration caused by the low racemization rate.…”

Section: Resultsmentioning

confidence: 98%

Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

Oketani

Marin

Tinnemans³

et al. 2019

Chemistry A European J

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A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second‐order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate‐forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

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“…Preferential crystallization is a purification technique first used in 1853 by Pasteur for the resolution of sodium ammonium tartrate tetrahydrate enantiomers, and since then, it has been used for similar purposes . The basic underlying idea of this technique is that crystallization can achieve purification not only because of a difference between the thermodynamic driving forces (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…different solubility curves) but also due to differences in the compounds' crystallization kinetics. By seeding a crystallizer containing a liquid solution with the desired compound, conditions are applied which promote the growth of crystals of the desired molecule and its consumption from the liquid phase, while the impurity only starts crystallizing when its supersaturation level is sufficiently high to start nucleation . Despite its logical application to conglomerate forming enantiomers, the applicability of preferential crystallization can be extended to other organic molecules .…”

Section: Introductionmentioning

confidence: 99%

Preferential crystallization for the purification of similar hydrophobic polyphenols

Silva

Vieira

Ottens

2018

J of Chemical Tech & Biotech

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BACKGROUNDPreferential crystallization is a common technique used in the purification of enantiomers, proving that crystallization may also be applied to the purification of very similar molecules by seeding the solution with the desired compound. Nonetheless, its application to other organic molecules is less widely documented in the literature. Knowing that chemically related polyphenols are generally co‐produced by fermentation and their purification can be too expensive for their market value, this technique may contribute to developing a downstream process with less expensive steps. The goal of this work is to show the applicability of the preferential crystallization concept to the purification of similar polyphenols – naringenin and trans‐resveratrol – with either single or coupled crystallizers.RESULTSAfter developing the required crystallization kinetic models, an experiment using two coupled vessels was devised, where a 63% yield of naringenin and 44% yield of trans‐resveratrol was obtained, with ≥98% purity in both cases. When the vessels were working independently, 81% of pure trans‐resveratrol (started 60% pure) and 70% of pure naringenin (started 68% pure) were recovered.CONCLUSIONThe experiments performed show the possibility of separately purifying two similar molecules (from 60% to roughly 100%) with promising yields, despite their similar solubility. This method, which can be significantly improved, might provide an economically attractive way for the production of low added value products. © 2017 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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Application of Continuous Preferential Crystallization to Efficiently Access Enantiopure Chemicals

Cited by 77 publications

References 52 publications

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

Preferential crystallization for the purification of similar hydrophobic polyphenols

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