Co-Crystallization-Induced Spontaneous Deracemization: An Optimization Study

Abstract

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.

Recent advances in the field of chiral crystallization

“…Table 2 lists several successful applications of this technique for a variety of compounds. [63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] Compounds that have similar chemical structures tend to form cocrystals. The first reported cases of chiral cocrystallization were in Water 1981 and used amino acids as additives for the cocrystallization of other amino acids.…”

“…As is shown in Figure 10, Guillot et al accomplished this. 78 The requirements for this type of deracemization are analogous to that of normal attritionenhanced deracemization. However, whereas the chiral compound of interest needs to be able to racemize in solution, the cocrystallization agent must not be able to racemize under the experimental conditions.…”

“…Using the process shown in Figure 10 produced an enantiomeric excess of 73% from a racemic solution. 78…”

“…This requires the use of enantiomerically pure cocrystallization additives. Table 2 lists several successful applications of this technique for a variety of compounds 63–80 . Compounds that have similar chemical structures tend to form cocrystals.…”

Stereochemical switch driven by crystallization: Interplay between stoichiometry and configuration of the products

“…In the realms of stereoselective synthesis, the option of driving a reaction equilibrium towards a selectively crystallizing stereoisomer appears to be particularly appealing. Supposing that these reactions provide diastereomeric species, the phenomenon is termed crystallization‐induced diastereomer transformation (CIDT) (for reviews, see Kolarovič and Jakubec 9 and Brands and Davies 10 and for the most up‐to‐date examples, see previous studies 11–18 ). A thermodynamic nature of the process typically allows for a straightforward reaction setup, and even syntheses featuring complex reaction equilibria can furnish crystalline products in very good yields and high purities.…”