Cocrystallization‐Induced Spontaneous Deracemization: A General Thermodynamic Approach to Deracemization

Abstract

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.

Fungicide Precursor Racemization Kinetics for Deracemization in Complex Systems

“…For 3 experiments, the acid is in excess compared to DBU and for the remaining 3, DBU is in excess. All experiments were carried out in toluene, the solvent used in the deracemization process [9] . The evolution of the enantiomeric excess over time is given in Figure 10.…”

“…All the solvents used were commercially available and of analytical grade. Finally, the acid added to the system, (S)‐3‐phenylbutyric acid, was commercially purchased as racemic from Sigma Aldrich (98 %) and then resolved [9] by using either (S)‐ or (R)‐phenylethylamine, [27] purchased from VWR (≥98 %).…”

“…We applied it on the compound (R,S)‐4,4‐dimethyl‐1‐(4‐fluorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pentan‐3‐one [(R,S)‐BnFTP] a racemic, non‐salt and non‐conglomerate forming compound, that makes a suitable conglomerate co‐crystal with the chiral compound 3‐phenylbutyric acid (PBA). Initial trials showed how a continuous set‐up can lead to a deracemization of the racemate in 4 days [9] . The set‐up of the process is similar to the one developed for temperature cycling Viedma ripening by Coquerel et al [7] .…”

“…In this context, we recently developed a novel deracemization method based on a co-crystallization approach: Cocrystallization induced deracemization. [9] We applied it on the compound (R,S)-4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-pentan-3-one [(R,S)-BnFTP] a racemic, non-salt and non-conglomerate forming compound, that makes a suitable conglomerate co-crystal with the chiral compound 3-phenylbutyric acid (PBA). Initial trials showed how a continuous set-up can lead to a deracemization of the racemate in 4 days.…”

“…Initial trials showed how a continuous set-up can lead to a deracemization of the racemate in 4 days. [9] The set-up of the process is similar to the one developed for temperature cycling Viedma ripening by Coquerel et al [7] As this process combines crystallization aspects with a racemization reaction, optimization of the system requires a full understanding of the underlying thermodynamics and kinetics of all physical and chemical processes involved.…”