Continuous Resolution and Deracemization of Chiral Compounds by Crystallization

Risultati finali

Scientific article of ESR13 on the tool for kinetic behaviour of crystallizing multicomponent chiral systems

This task will focus on enabling resolution through the crystallization behaviour. Chiral compounds can possess complex solid state, thermodynamic and crystallization behaviour. Pharmaceuticals have the tendency to form several competing solid forms, which may or may not enable chiral resolution. The crystallization of industrial chiral compounds takes place in complex multicomponent mixtures in which next to the enantiomers and solvent also other compounds (resolving agents, impurities, additives, anti-solvents) are influencing the process. Additionally, In hybrid reaction processes an additional complexity is the racemizing agent impacting on the phase diagram and crystallization behaviour. ESR13 will develop a screening tool quickly and reliably determine the crystallization-based resolution possibilities of a new chiral compound in multicomponent solutions.

Scientific article of ESR2 on Methods and Design Rules developed for Continuous Configurations of Crystallization-based Chiral Synthesis

Development of Continuous Crystallization-enabled Chiral Synthesis Processes. This part will be led by JtH at USTRATH with the involvement of ESR2 at USTRATH (experiments) and ESR4 at ETH (process modelling). There is a strong connection with ESR5 at RUN and ESR6 at SYNCOM working on batchwise crystallization-enabled chiral synthesis. Recently, it was shown that a combination of an aselective reversible reaction with Viedma Ripening leads to a chiral synthesis route [8]. ESR2 will transfer this new batchwise chiral synthesis route into continuous configurations. The partner SYNCOM is willing, during the industrial secondment, to facilitate the synthesis of substantial amount of raw material needed to perform long term continuous experiments.

Scientific article of ESR8 on optimization methods for Viedma Ripening

Viedma Ripening is a potential examples of Hybrid Resolution. ESR8 will optimize crystallization-based hybrid resolution techniques such as Viedma Ripening.

Scientific article of ESR1 on Design Rules for Batch and Continuous Resolution

This part will be led by ASM of OVGU with the involvement of ESR1 at OVGU and ESR4 at ETH. Substantial knowledge was acquired in the last decades in designing, optimizing and realizing large scale continuous processes, in particular in petro-chemistry for the production of (non-crystalline) bulk chemicals. Often a direct connection of a large number of reaction and separation steps could be successfully applied. To allow for such direct coupling and to avoid undesired buffer steps, the intrinsic time constants of the relevant sub-steps have to be identified and quantified. Building on this key information, a well-established theoretical framework is available striving to match the residence times of the components in all steps by identifying and establishing suitable operating conditions including a selection of the specific unit types and sizes. Hereby, the theoretical framework developed compares the characteristic times required by each relevant individual process step with the times provided in this step as characteristic residence times. Typically Damköhler-numbers are applied to facilitate and generalize the analysis. ESR1 will provide the framework for the design of batch and continuous crystallization processes based on dimensionless numbers.

Scientific article of ESR14 on the developed Process Analytical Tools based on chiroptical spectroscopy

Despite the importance of chirally pure crystalline products, there is no Process Analytical Tool (PAT) that can monitor the enantiomeric excess in the crystalline phase of a suspension during a resolution process. However, PAT are of key importance, particularly in the move towards continuous manufacturing as they will enable appropriate control of the processes, but also in batch processes relying on decracemization where detecting the endpoint can be achieved. ESR14 will develop a tool based on chiroptical spectroscopy and Second Harmonic Generation.

Scientific article of ESR7 on optimization methods for SOAT

ESR7 will optimize crystallization-based hybrid resolution techniques such as SOAT (Second Order Asymmetric Transformation). This task will develop crystallization-based hybrid resolution processes allowing high enantiomeric yields.

ESR presentation on tool during final conference

The ESRs will present their findings during the dedicated network events in short, focussed presentations

Scientific article of ESR15 on the Process Analysis Tools based on classical techniques with automated sampling.

Despite the importance of chirally pure crystalline products, there is no Process Analytical Tool (PAT) that can monitor the enantiomeric excess in the crystalline phase of a suspension during a resolution process. However, PAT are of key importance, particularly in the move towards continuous manufacturing as they will enable appropriate control of the processes, but also in batch processes relying on decracemization where detecting the endpoint can be achieved. ESR15 will enable such a tool using classical techniques with automated sampling.

Scientific article of ESR10 on methods to predict multicomponent conglomerate systems of chiral compounds

Only 5-10% of the chiral compounds form conglomerates while crystallization-based resolution techniques often rely on the discovery of a conglomerate forming system. This project will establish the formation principles of conglomerate co-crystals, salts, solvates and other solids using experimental screening as well as database mining and molecular simulation techniques. These formation principles will enable changing the solid state of a chiral compound from racemic compound to multicomponent conglomerate and thus open up the route towards resolution. This would lead to a 10-fold increase in the application of chiral resolution through preferential crystallization. ESR10 will develop crystal engineering approaches

Scientific article of ESR5 on new Routes for Viedma Ripening-based Chiral Synthesis

Chemists often find a way to produce some enantiomeric enrichment through synthesis, but usually do not reach the required purity directly. We have recently reported that the combination of a reaction, crystallisation and the process of Viedma ripening can lead to an enantiopure crystalline product. ESR5 will extend on this very promising combination identifying new opportunities for chiral synthesis based on reversible chemical reactions to racemize compounds.

Scientific article of ESR3 on Methods and Design Rules developed for Continuous Preferential Crystallization Techniques

This part will be led by MM at ETH with the involvement of ESR3 at OVGU and ESR4 at ETH. Both ESRs will have an approach that combines process modelling and experiments. Single enantiomeric crystals can be produced in different ways. If sufficient enrichment in the target enantiomer can be achieved by an upstream asymmetric synthesis step or by an ancillary technique, e.g. chiral chromatography, then a rather conventional cooling or antisolvent crystallization can be carried out. These processes exist both in the batch and in the continuous mode, which exhibit however different performance. Alternatively, there are at least two techniques, namely preferential crystallization and Viedma ripening, that allow forming single enantiomeric crystals starting from a racemic mixture (50/50 of the two enantiomers) using a very small amount of seeds of the target enantiomer. These processes have so far been operated in a batch mode, and making them continuous is a challenge. This task will deliver tools to design Crystallization-enabled Continuous Resolution Processes.

Scientific article of ESR4 on Methods and Design Rules developed for Continuous Viedma Ripening and on Process models for Crystallization-based Continuous Resolution

ESR4 will construct process models of continuous crystallization processes to be used for optimization and control, in relation to ESR1. Additionally, a process model will be developed that will aid the optimization and control of crystallization-enabled chiral synthesis in relation to ESR2. ESR4 will deliver process models for Crystallization-enabled Continuous Resolution Processes.

Scientific article of ESR11 on methods to change the solid state of a chiral compound to enable crystallization-based resolution

Only 5-10% of the chiral compounds form conglomerates while crystallization-based resolution techniques often rely on the discovery of a conglomerate forming system. This project will establish the formation principles of conglomerate co-crystals, salts, solvates and other solids using experimental screening as well as database mining and molecular simulation techniques. These formation principles will enable changing the solid state of a chiral compound from racemic compound to multicomponent conglomerate and thus open up the route towards resolution. This would lead to a 10-fold increase in the application of chiral resolution through preferential crystallization. ESR11 will develop high throughput pre-screening methods through in line detection of non centro-symmetric crystals –including efflorescent solvates.

Scientific article of ESR6 on new racemization routes and optimized deracemization processes using designed transition metal catalysts

Many chiral pharmaceuticals owe their chirality to the presence of secondary alcohol or amine functionalities for which the hydrogen attached to the chiral centre is not readily removed with bases. ESR6 will enable racemization by applying designed transition metal catalysts and optimize deracemization processes using these catalysts. This task will extend the range of compounds that can be produced by developing new opportunities for Viedma ripening-enabled and SOAT-enabled chiral synthesis routes. ESR6 will enable racemization by applying designed transition metal catalysts (D4.2). In addition to the racemization catalysts, the main factors influencing racemization rate (e.g. temperature, pH value, presence of additives, nature of solvent, presence of a solid product phase) will be identified.

Scientific article of ESR9 on new racemization methods using organocatalysts and enzymes.

Racemization is key in many deracemization strategies. As not all chiral compounds of interest can be racemized directly or fast enough, it is in many cases possible to overcome this limitation: we reported in 2009, that conglomerate deracemization of chiral organic compounds is possible, employing racemization that occurs via the reverse steps of reversible asymmetric organic reactions and with achiral or racemic catalysts. Racemization of chiral products in solution or at the crystal/solution interface will thus be achieved via (i) the reverse reaction step or (ii) direct racemization, e.g. in the α-position of CH-acidic compounds, both catalyzed by achiral (or racemic), environmentally friendly and cheap organocatalysts, highly active transition metal catalysts or by enzymes (e.g. racemase, epimerase). ESR9 will focus on the development of racemic and achiral catalysts for stereoselective reactions yielding chiral bioactive organic compounds or valuable building blocks of pharmaceuticals and which can be racemized either in solution or at the crystal/solution interface. This task will extend the range of available racemization reactions to enable Hybrid Resolution.

ESR presentation on tool during workshop 2 / conference

The ESRs will present their findings during the dedicated network events in short, focussed presentations

Scientific article of ESR12 on the tool to determine competing solid state behaviour in multicomponent chiral systems

This task will focus on enabling resolution through the crystallization behaviour. Chiral compounds can possess complex solid state, thermodynamic and crystallization behaviour. Pharmaceuticals have the tendency to form several competing solid forms, which may or may not enable chiral resolution. The crystallization of industrial chiral compounds takes place in complex multicomponent mixtures in which next to the enantiomers and solvent also other compounds (resolving agents, impurities, additives, anti-solvents) are influencing the process. Additionally, In hybrid reaction processes an additional complexity is the racemizing agent impacting on the phase diagram and crystallization behaviour. ESR12 will develop a screening tool for complex solid state and thermodynamic behaviour of chiral compounds in multicomponent solutions.

Pubblicazioni

Continuous enantioselective crystallization of chiral compounds in coupled fluidized beds

Autori: J. Gänsch, N. Huskova, K. Kerst, E. Temmel, H. Lorenz, M. Mangold, G. Janiga, A. Seidel-Morgenstern
Pubblicato in: Chemical Engineering Journal, Numero 422, 2021, Pagina/e 129627, ISSN 1385-8947
Editore: Elsevier BV
DOI: 10.1016/j.cej.2021.129627

Designing Isothermal Batch Deracemization Processes with Optimal Productivity: 1. Parametric Analysis Using a Population Balance Equation Model

Autori: Thomas Vetter
Pubblicato in: Crystal Growth & Design, Numero 20/7, 2020, Pagina/e 4293-4306, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.9b01581

Deracemization of NMPA via Temperature Cycles

Autori: Francesca Breveglieri, Giovanni Maria Maggioni, Marco Mazzotti
Pubblicato in: Crystal Growth & Design, Numero 18/3, 2018, Pagina/e 1873-1881, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.7b01746

Practical Role of Racemization Rates in Deracemization Kinetics and Process Productivities

Autori: Ryusei Oketani, Marine Hoquante, Clément Brandel, Pascal Cardinael, Gérard Coquerel
Pubblicato in: Crystal Growth & Design, Numero October 2018, 2018, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.8b01263

Population-Based Mathematical Model of Solid-State Deracemization via Temperature Cycles

Autori: Brigitta Bodák, Giovanni Maria Maggioni, Marco Mazzotti
Pubblicato in: Crystal Growth & Design, Numero 9 October 2018 (web), 2018, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.8b01292

Role of Additives during Deracemization Using Temperature Cycling

Autori: Giuseppe Belletti, Hugo Meekes, Floris P. J. T. Rutjes, Elias Vlieg
Pubblicato in: Crystal Growth & Design, Numero 2 October 2018 (web), 2018, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.8b00856

NH-form of a threonine-based Schiff base in the solid state

Autori: Ryusei Oketani, Hiroki Takahashi, Marine Hoquante, Clément Brandel, Pascal Cardinael, Gérard Coquerel
Pubblicato in: Journal of Molecular Structure, Numero 1184, 2019, Pagina/e 36-40, ISSN 0022-2860
Editore: Elsevier BV
DOI: 10.1016/j.molstruc.2019.01.093

Cocrystals in the Cambridge Structural Database: a network approach

Autori: Jan-Joris Devogelaer, Hugo Meekes, Elias Vlieg, René de Gelder
Pubblicato in: Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials, Numero 75/3, 2019, Pagina/e 371-383, ISSN 2052-5206
Editore: John Wiley and Sons Inc.
DOI: 10.1107/s2052520619004694

Resolution of Racemic Guaifenesin Applying a Coupled Preferential Crystallization-Selective Dissolution Process: Rational Process Development

Autori: Erik Temmel, Matthias J. Eicke, Francesca Cascella, Andreas Seidel-Morgenstern, Heike Lorenz
Pubblicato in: Crystal Growth & Design, 2019, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.8b01660

Resolution of an Atropisomeric Naphthamide by Second-Order Asymmetric Transformation: A Highly Productive Technique

Autori: Ryusei Oketani, Marine Hoquante, Clément Brandel, Pascal Cardinael, Gérard Coquerel
Pubblicato in: Organic Process Research & Development, 2019, ISSN 1083-6160
Editore: American Chemical Society
DOI: 10.1021/acs.oprd.9b00133

Role of Racemization Kinetics in the Deracemization Process via Temperature Cycles

Autori: Francesca Breveglieri, Marco Mazzotti
Pubblicato in: Crystal Growth & Design, 2019, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.9b00410

Deracemization in a complex quaternary system with a second‐order asymmetric transformation using phase diagram studies

Autori: Ryusei Oketani, Francesco Marin, Paul Tinnemans, Marine Hoquante, Anne Laurent, Clément Brandel, Pascal Cardinael, Hugo Meekes, Elias Vlieg, Yves Geerts, Gerard Coquerel
Pubblicato in: Chemistry – A European Journal, 2019, ISSN 0947-6539
Editore: John Wiley & Sons Ltd.
DOI: 10.1002/chem.201903338

Family of conglomerate forming systems composed of chlocyphos and alkyl-amine. Assessment of their resolution performances by using various modes of preferential crystallization

Autori: Aliou Mbodji, Gabin Gbabode, Morgane Sanselme, Nicolas Couvrat, Michel Leeman, Valérie Dupray, Richard M. Kellogg, Gérard Coquerel
Pubblicato in: Crystal Growth & Design, 2019, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.9b00568

Effect of Initial Conditions on Solid-State Deracemization via Temperature Cycles: A Model-Based Study

Autori: Brigitta Bodák, Giovanni Maria Maggioni, Marco Mazzotti
Pubblicato in: Crystal Growth & Design, Numero 19/11, 2019, Pagina/e 6552-6559, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.9b00988

Shortcut Model for Describing Isothermal Batch Preferential Crystallization of Conglomerates and Estimating the Productivity

Autori: Thiane Carneiro, Shashank Bhandari, Erik Temmel, Heike Lorenz, Andreas Seidel-Morgenstern
Pubblicato in: Crystal Growth & Design, Numero 19/9, 2019, Pagina/e 5189-5203, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.9b00592

Enabling Direct Preferential Crystallization in a Stable Racemic Compound System

Autori: Lina C. Harfouche, Clément Brandel, Yohann Cartigny, Joop H. ter Horst, Gérard Coquerel, Samuel Petit
Pubblicato in: Molecular Pharmaceutics, Numero 16/11, 2019, Pagina/e 4670-4676, ISSN 1543-8384
Editore: American Chemical Society
DOI: 10.1021/acs.molpharmaceut.9b00805

Photoracemization‐Based Viedma Ripening of a BINOL Derivative

Autori: Giuseppe Belletti, Carola Tortora, Indradevi D. Mellema, Paul Tinnemans, Hugo Meekes, Floris P. J. T. Rutjes, Svetlana B. Tsogoeva, Elias Vlieg
Pubblicato in: Chemistry – A European Journal, 2019, Pagina/e online, ISSN 0947-6539
Editore: John Wiley & Sons Ltd.
DOI: 10.1002/chem.201904382

Toward Continuous Deracemization via Racemic Crystal Transformation Monitored by in Situ Raman Spectroscopy

Autori: Christos Xiouras, Giuseppe Belletti, Raghunath Venkatramanan, Alison Nordon, Hugo Meekes, Elias Vlieg, Georgios D. Stefanidis, Joop H. Ter Horst
Pubblicato in: Crystal Growth & Design, Numero 19/10, 2019, Pagina/e 5858-5868, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.9b00867

Cocrystal design by network-based link prediction

Autori: Jan-Joris Devogelaer, Sander J. T. Brugman, Hugo Meekes, Paul Tinnemans, Elias Vlieg, René de Gelder
Pubblicato in: CrystEngComm, Numero 21/44, 2019, Pagina/e 6875-6885, ISSN 1466-8033
Editore: Royal Society of Chemistry
DOI: 10.1039/c9ce01110b

Efficient Resolution of Racemic Guaifenesin via Batch-Preferential Crystallization Processes

Autori: Francesca Cascella, Erik Temmel, Andreas Seidel-Morgenstern, Heike Lorenz
Pubblicato in: Organic Process Research & Development, Numero 24/1, 2020, Pagina/e 50-58, ISSN 1083-6160
Editore: American Chemical Society
DOI: 10.1021/acs.oprd.9b00413

Exploiting Ternary Solubility Phase Diagrams for Resolution of Enantiomers: An Instructive Example

Autori: Francesca Cascella, Andreas Seidel-Morgenstern, Heike Lorenz
Pubblicato in: Chemical Engineering & Technology, 2020, Pagina/e online, ISSN 0930-7516
Editore: Wiley - V C H Verlag GmbbH & Co.
DOI: 10.1002/ceat.201900421

Evidence of conglomerate with partial solid solutions in ethylammonium chlocyphos

Autori: Aliou Mbodji, Gabin Gbabode, Morgane Sanselme, Yohann Cartigny, Nicolas Couvrat, Michel Leeman, Valérie Dupray, Richard M. Kellogg, Gérard Coquerel
Pubblicato in: Crystal Growth & Design, 2020, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.9b01699

Discovery of New Proxyphylline Based Chiral Cocrystals: Solid State Landscape and Dehydration Mechanism

Autori: Lina C. Harfouche, Nicolas Couvrat, Morgane Sanselme, Clément Brandel, Yohann Cartigny, Samuel Petit, Gérard Coquerel
Pubblicato in: Crystal Growth & Design, 2020, ISSN 1528-7483
Editore: American Chemical Society
DOI: 10.1021/acs.cgd.0c00149

Speeding up Viedma Deracemization through Water catalyzed and Reactant Self‐catalyzed Racemization

Autori: Carola Tortora, Christina Mai, Francesca Cascella, Michael Mauksch, Andreas Seidel-Morgenstern, Heike Lorenz, Svetlana B. Tsogoeva
Pubblicato in: ChemPhysChem, 2020, ISSN 1439-4235
Editore: John Wiley & Sons Ltd.
DOI: 10.1002/cphc.202000493

Cocrystal prediction by artificial neural networks

Autori: Jan-Joris Devogelaer, Hugo Meekes, Paul Tinnemans, Elias Vlieg, Rene De Gelder
Pubblicato in: Angewandte Chemie International Edition, Numero Online: 14 August 2020, 2020, ISSN 1433-7851
Editore: John Wiley & Sons Ltd.
DOI: 10.1002/anie.202009467

Combining Incompatible Processes for Deracemization of a Praziquantel Derivative under Flow Conditions

Autori: Giulio Valenti, Dr. Paul Tinnemans, Dr. Iaroslav Baglai, Prof. Dr. Willem L. Noorduin, Dr. Bernard Kaptein, Dr. Michel Leeman, Prof. Joop H. ter Horst, Prof. Dr. Richard M. Kellogg
Pubblicato in: Angewandte Chemie International Edition, Numero 60(10), 2021, Pagina/e 5279-5282, ISSN 1433-7851
Editore: John Wiley & Sons Ltd.
DOI: 10.1002/anie.202013502

Performance Analysis and Model-Free Design of Deracemization via Temperature Cycles

Autori: Francesca Breveglieri, Iaroslav Baglai, Michel Leeman, Willem L. Noorduin, Richard M. Kellogg, Marco Mazzotti
Pubblicato in: Organic Process Research & Development, Numero 24/8, 2020, Pagina/e 1515-1522, ISSN 1083-6160
Editore: American Chemical Society
DOI: 10.1021/acs.oprd.0c00266

Chiral solid state screening and phase diagrams

Autori: Harfouche, Lina
Pubblicato in: https://www.theses.fr/2020NORMR007, Numero 1, 2020
Editore: University of Rouen

Practical aspects on how to deracemize atropizomers by means of crystallization

Autori: Oketani, Ryusei
Pubblicato in: https://tel.archives-ouvertes.fr/tel-02502796v1, Numero 1, 2019
Editore: University of Rouen

Recherche de Conglomérats pour la résolution chirale par voie de cristallisation

Autori: Mbodji, Aliou
Pubblicato in: https://tel.archives-ouvertes.fr/tel-02917352, Numero 1, 2020
Editore: University of Rouen

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