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.

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…Under these circumstances, single or repetitive equilibration-crystallization processes can be performed separately, either successively [50] or simultaneously. [51] These diastereomer transformations are AT1-driven, the crystallization functions solely as a means of product separation and thus are not considered as CIDT. But even so the recently published example [51] describing a continuous reaction set-up has a lot of features in common with CIDT and is presented in Scheme 26, Section 3.1.…”

“…The reaction conditions favoring equilibration between diastereomers are often incompatible with the settings permitting crystallization. Under these circumstances, single or repetitive equilibration‐crystallization processes can be performed separately, either successively [50] or simultaneously [51] . These diastereomer transformations are AT1‐driven, the crystallization functions solely as a means of product separation and thus are not considered as CIDT.…”

“…These diastereomer transformations are AT1‐driven, the crystallization functions solely as a means of product separation and thus are not considered as CIDT. But even so the recently published example [51] describing a continuous reaction set‐up has a lot of features in common with CIDT and is presented in Scheme 26, Section 3.1.…”

Co-crystals of Praziquantel: Discovery by Network-Based Link Prediction

“…The latter approach has previously been shown to be a viable strategy for achieving enantiomerically pure substances. [25][26][27] Figure 1: Praziquantel. Praziquantel 28 (PZQ; Figure 1) is an anthelmintic drug used in the preventive treatment against schistosomiasis, a disease caused by parasitic flatworms, and suffers from a number of the abovementioned issues.…”

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

“…1,8-Diazabicyclo-[5.4.0]undec-7-ene (DBU) was chosen as the racemizing agent, since the use of one equivalent of DBU at room Disorder is left out for clarity. [40] Scheme 2. Principle of the cocrystallization-induced spontaneous deracemization process.…”