Processes leading to enantiomerically pure compounds are of utmost importance, in particular for the pharmaceutical industry. Starting from a racemic mixture, crystallization‐induced diastereomeric transformation allows in theory for 100 % transformation of the desired enantiomer. However, this method has the inherent limiting requirement for the organic compound to form a salt. Herein, this limitation is lifted by introducing cocrystallization in the context of thermodynamic deracemization, with the process applied to a model chiral fungicide. We report a new general single thermodynamic deracemization process based on cocrystallization for the deracemization of (R,S)‐4,4‐dimethyl‐1‐(4‐fluorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)pentan‐3‐one. This study demonstrates the feasibility of this novel approach and paves the way to further development of such processes.
We recently introduced a thermodynamically based deracemization process, co-crystallization-induced spontaneous deracemization (CoISD). Following the successful development of the CoISD process, we aimed at improving both yield and deracemization and, consequently, the productivity of the process. As the process is based on co-crystallization of the target enantiomer combined with a racemization reaction of the undesired enantiomer, both reaction and crystallization kinetics and thermodynamics need to be considered for optimization. Taking previously published kinetic parameters into account, here we investigate the nature of the solvent, concentration of the racemizing agent, equivalent of the acid co-former, and temperature of the crystallization cell. The evaluation of each parameter allowed for improvement of the yield and/or deracemization, ultimately providing an optimized process with a yield of 73% of pure co-crystals for an overall deracemization of 80%, in parallel, highlighting the viability of recycling the remaining mother liquors.
Processes leading to enantiomerically pure compounds are of utmost importance, in particular for the pharmaceutical industry. Starting from a racemic mixture, crystallization‐induced diastereomeric transformation allows in theory for 100 % transformation of the desired enantiomer. However, this method has the inherent limiting requirement for the organic compound to form a salt. Herein, this limitation is lifted by introducing cocrystallization in the context of thermodynamic deracemization, with the process applied to a model chiral fungicide. We report a new general single thermodynamic deracemization process based on cocrystallization for the deracemization of (R,S)‐4,4‐dimethyl‐1‐(4‐fluorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)pentan‐3‐one. This study demonstrates the feasibility of this novel approach and paves the way to further development of such processes.
In the racemization area, the keto-enol equilibrium is a major player when it comes to racemizing α-chiral carbonyl compounds. The racemization kinetics in the co-crystal induced deracemization of a fungicide precursor is complex as next to the racemization catalyst, which is a base, an acidic co-former is used to ensure the crystallization of the co-crystal. Here we show that understanding of the racemization kinetics of the target compound is of key importance for optimization of the co-crystallization based deracemization process. The racemization rates in solution as a function of solvent and base concentration were determined by measuring the decreasing enrichment of the chiral ketone due to racemization over time, using a polarimeter setup with a continuous recycling loop through the polarimeter cell. The established racemization kinetics model aligns with the experimental data giving access to the intrinsic racemization rate constant. The proposed mechanism is first order with respect to the enantiomeric excess of the target compound and the base-catalyst concentration. The solvent is shown to strongly affect the racemization constant, with protic solvents increasing this rate substantially due to hydrogen-bond stabilization of the enolate. Finally, we observed the presence of the chiral acid co-former to alter the reaction mechanism albeit remaining first order with respect to the enantiomeric excess. Though more complex, the mechanism still followed Arrhenius law, providing key information on the impact of temperature.
Title of the poster: Resolution of a triazol-containing compound through co-crystallisation Triazoles are a special class of heterocyclic compounds with a broad spectrum of biological activities such as antimicrobial, cytotoxic, antihistaminic, anti-inflammatory or anticancer [1] , consequently very interesting for pharmaceutical companies. Moreover, in those industries, 50% of the marketed drug compounds contain a chiral center [2] , essential to their functioning. Where one enantiomer has the desired pharmacological effect, the other might be inactive or have adverse effects (e.g. Thalidomide). In spite of important advances in asymmetric synthesis, the most prominent way to chiral drugs still involves formation of a racemic compound followed by its resolution by a physical process.
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