Pitfalls and rewards of preferential crystallization

Levilain, Guillaume; Coquerel, Gérard

doi:10.1039/c001895c

Cited by 118 publications

(109 citation statements)

References 41 publications

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“…[1] It relies on the selective crystallization of one enantiomer from a supersaturated solution of a racemic or nearly racemic mixture. Such a resolution strategy, called entrainment, [2] is used in industry. [2,3] On a laboratory scale, it is the method of choice when several grams or tens of grams of two enantiomers of an optically active substance are required.…”

Section: Introductionmentioning

confidence: 99%

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Preferential Crystallization of a Helicene–Viologen Hybrid – An Efficient Method to Resolve [5]Helquat Enantiomers on a 20 g Scale

et al. 2011

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The bistriflate salt of racemic [5]helquat 1 was found to form a conglomerate. Based on this finding, the preferential crystallization of this chiral helicene–viologen hybrid was developed to deliver pure enantiomers on a 20 g scale (10.5 g of each enantiomer). To the best of our knowledge, this is the largest amount of nonracemic helicene‐like compound obtained by preferential crystallization to date. The absolute configuration of the P enantiomer was confirmed by X‐ray crystal structure analysis. The chromatography‐free synthesis of racemic 1 on a multigram scale (30 g) is also presented as an entry point to this resolution study.

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Section: Introductionmentioning

confidence: 99%

“…Such a resolution strategy, called entrainment, [2] is used in industry. [2,3] On a laboratory scale, it is the method of choice when several grams or tens of grams of two enantiomers of an optically active substance are required. A major restriction is that this method can only be used for conglomerates, i.e.…”

Section: Introductionmentioning

confidence: 99%

Preferential Crystallization of a Helicene–Viologen Hybrid – An Efficient Method to Resolve [5]Helquat Enantiomers on a 20 g Scale

et al. 2011

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“…In this process, seeding of the preferred enantiomer in a supersaturated racemic solution allows for selective nucleation/growth of only that enantiomer 24 . The main disadvantage of this process is that primary nucleation of the counter enantiomer can occur 25 . The application of in-situ grinding in SOAT processes has been shown to suppress the nucleation of the counter enantiomer up to a certain extend 26,27 , while it can also function as a "safety catch" for SOAT leading to complete deracemization through Viedma ripening 28 .…”

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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“…Leistungsfä-higkeit und Grenzen der Methode sind außerdem in einem Beitrag von Levilain und Coquerel erläutert. [100] Das Verständnis des Phänomens der Konglomeratbildung, auch als spontane Racematspaltung bei Kristallisation bezeichnet, ist als "eine der grçßten Herausforderungen in der Stereochemie" [101] beschrieben, und mehrere Über-sichtsartikel widmen sich diesem Thema (z. B. Lit.…”

Section: Klassische Racematspaltungunclassified

Verfahren zur Enantiomerentrennung

Lorenz

Seidel‐Morgenstern

2014

Angewandte Chemie

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Die Verfügbarkeit reiner Enantiomere ist von steigender Bedeutung für die pharmazeutische Industrie sowie auch für die Agrochemie und Biotechnologie. Generell gibt es zwei konkurrierende Ansätze zur Gewinnung von reinen Enantiomeren. Der “chirale” Ansatz basiert auf der Entwicklung einer asymmetrischen Synthese, die selektiv eines der Enantiomere liefert. Der “racemische” Ansatz basiert auf der Trennung eines Gemischs der beiden Enantiomere, wobei hier in den letzten Jahren bemerkenswerte Fortschritte erzielt werden konnten. Dieser Aufsatz fokussiert insbesondere auf enantioselektive Kristallisationsprozesse und präparative Chromatographie, einschließlich hybrider Trennprozesse und der zusätzlichen Integration von Racemisierungsschritten. Zur Illustration dienen mehrere in unserem Arbeitskreis untersuchte Trennungen.

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Pitfalls and rewards of preferential crystallization

Cited by 118 publications

References 41 publications

Preferential Crystallization of a Helicene–Viologen Hybrid – An Efficient Method to Resolve [5]Helquat Enantiomers on a 20 g Scale

Preferential Crystallization of a Helicene–Viologen Hybrid – An Efficient Method to Resolve [5]Helquat Enantiomers on a 20 g Scale

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Verfahren zur Enantiomerentrennung

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