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

Breveglieri, Francesca; Baglai, Iaroslav; Leeman, Michel; Noorduin, Wim L.; Kellogg, Richard M.; Mazzotti, Marco

doi:10.1021/acs.oprd.0c00266

Cited by 14 publications

(38 citation statements)

References 18 publications

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“…In the present study the feasibility of complete chiral resolution via the use of a tubular temperature cycler with recycle stream was demonstrated for a racemic mixture of crystals. While comprehensively exploring the design space of such a process is out of reach due to the large amount of different parameters [21], here our aim was to capture those which show the biggest influence on the deracemization rate. Without doing extensive optimization, in the present study we were able to show, that the benefit of very fast heating and cooling rates achieved in such tubular reactors is effective also when it comes to deracemization.…”

Section: Discussionmentioning

confidence: 99%

“…Previous investigations have shown, that the amount of catalyst present is only critical if the racemization step is rate limiting for at least one part of the multiple-step deracemization process via temperature cycles, and hence is system-specific [21]. In Fig.…”

Section: Effect Of Different Amounts Of Catalystmentioning

confidence: 98%

“…Existing literature addressing deracemization reveals no general agreement on the impact of various factors governing the shape of ee profiles during temperature cycling. While some results show an inflection point in the progress of ee with the number of temperature cycles [6,10,25,26], others show an exponential character throughout the evolution of the enantiomeric excess [8,9,21].…”

Section: Effect Of Initial Enantiomeric Excess Ee(0)and Particle Sizementioning

confidence: 98%

“…NMPA was chosen as a model substance as it has been used in recent publications in the field [9,[20][21][22][23]. For each experiment, NMPA was added to ethanol (99.8 %, denat.)…”

Section: Setup and Equipmentmentioning

confidence: 99%

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Complete chiral resolution in a continuous flow crystallizer with recycle stream

2021

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Repeated temperature cycling of crystals from a conglomerate forming chiral substance suspended in their saturated solution has shown to be effective in converting a mixture of both enantiomers into an enantiomerically pure state. While by now a large number of different setups has been demonstrated, here we show for the first time how a continuous flow temperature cycler with recycle stream is capable of establishing enantiopurity while converting a racemic starting suspension. By capturing the most significant parameters influencing the process kinetics a competitive productivity could be achieved. We show, that fast crystal dissolution at high undersaturations and fast crystal growth at high supersaturations are speeding up the process as long as nucleation can be kept to a minimum or avoided at all. Temperature cycling has shown to result in a shift towards larger sizes for the particle size distribution of the crystals suspended, which is detrimental to the present process governed by size-dependent solubility. By implementing an ultrasound unit recycled material was comminuted, resulting in nearly stable deracemization rates. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Different Amounts Of Catalystmentioning

confidence: 98%

Section: Effect Of Initial Enantiomeric Excess Ee(0)and Particle Sizementioning

confidence: 98%

“…NMPA was chosen as a model substance as it has been used in recent publications in the field [9,[20][21][22][23]. For each experiment, NMPA was added to ethanol (99.8 %, denat.)…”

Section: Setup and Equipmentmentioning

confidence: 99%

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Complete chiral resolution in a continuous flow crystallizer with recycle stream

2021

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“… 36 The experimental and analytical protocols followed were those described in our previous works with NMPA, 12 CPG, and tLEU. 13 …”

Section: Methodsmentioning

confidence: 99%

Deracemization via Periodic and Non-periodic Temperature Cycles: Rationalization and Experimental Validation of a Simplified Process Design Approach

Breveglieri

Bodák

Mazzotti

2021

Org. Process Res. Dev.

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Solid-state deracemization via temperature cycles is a promising technique that combines crystallization and racemization in the same batch process to attain enantiomer purification. This method is particularly attractive because the target enantiomer can be isolated with a 100% yield, and a large number of operating parameters can be adjusted to do this effectively. However, this implies that several choices need to be made to design the process for a new compound. In this work, we provide a solution to this dilemma by suggesting a simplified model-free design approach based on a single dimensionless parameter, that is, the dissolution factor, that represents the cycle capacity. This quantity is obtained from a novel rescaling of the model equations proposed in previous work and acts as a handy design parameter because it only depends on the operating conditions, such as the suspension density, the enantiomeric excess, and the difference in solubility between high and low temperatures in the cycle. With extensive modeling studies, supported by experimental results, we demonstrate the primary and general effect of the dissolution factor on the deracemization process and thus its relevance for the process design. Through both experiments and simulations, we rationalize and evaluate the process performance when periodic and non-periodic temperature cycles are applied to the deracemization of virtual and real compounds with different properties, that is, growth rate and solubility. Based on the approach proposed here, we clarify how the combined effect of more operating conditions can be exploited to obtain quasi-optimal process performance, which results superior when deracemization via periodic temperature cycles is performed.

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

Valenti

Tinnemans²,

Baglai

et al. 2021

Angewandte Chemie

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An efficient deracemization method for conversion of the racemate to the desirable (R)-enantiomer of Praziquantel has been developed by coupling incompatible racemization and crystallization processes. By a library approach, a derivative that crystallizes as a conglomerate has been identified. Racemization occurs via reversible hydrogenation over a palladium on carbon (Pd/C) packed column at 130 8C, whereas deracemization is achieved by alternating crystal growth/ dissolution steps with temperature cycling between 5-15 8C. These incompatible processes are combined by means of a flow system resulting in complete deracemization of the solid phase to the desired (R)-enantiomer (98 % ee). Such an unprecedented deracemization by a decoupled crystallization/racemization approach can readily be turned into a practical process and opens new opportunities for the development of essential enantiomerically pure building blocks that require harsh methods for racemization.

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

Cited by 14 publications

References 18 publications

Complete chiral resolution in a continuous flow crystallizer with recycle stream

Complete chiral resolution in a continuous flow crystallizer with recycle stream

Deracemization via Periodic and Non-periodic Temperature Cycles: Rationalization and Experimental Validation of a Simplified Process Design Approach

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

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