S S symmetry Article Possibilities of Exploiting Kinetic Control in the Continuous Fractional Crystallization of Diastereomeric Mixtures Dorottya Fruzsina Bánhegyi , Elemér Fogassy and Emese Pálovics * Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] (D.F.B.); [email protected] (E.F.) * Correspondence: [email protected] Abstract: For rapid and kinetic control-influenced resolutions, it is advisable to choose a resolving agent with the highest possible eutectic composition (eeEuResAg). It may also be advantageous to add the crystalline resolving agent directly to the solution of the racemic compound. In addition, the use of a quasi-racemic resolving agent or amphoteric resolving agent can provide kinetic resolution. In some cases, the continuous fractional crystallization of diastereomeric salts requires the salt of the resolving agent (Ca2+, Na+, etc.) or other achiral additives (thiourea) that cause rapid crystallization and provide high diastereomeric purity. A further advantage may be the sequential use of the same resolving agent that is capable of forming crystalline diastereomers with both enantiomers when using kinetic control (tandem resolution). Keywords: kinetic control; continuous fractional crystallization; diastereomeric salt formation; eutectic composition Citation: Bánhegyi, D.F.; Fogassy, E.; Pálovics, E. Possibilities of Exploiting 1. Introduction Kinetic Control in the Continuous In the case of the pharmaceutical industry, the development of continuous technologies Fractional Crystallization of can be beneficial to ensure constant product quality. The development of such procedures Diastereomeric Mixtures. Symmetry requires a special approach, and the demand for enantiomeric separation is increasing. 2021, 13, 1516. https://doi.org/ 10.3390/sym13081516 In such cases, if the separation is to be accomplished by crystallization, the separation of conglomerate-forming enantiomeric mixtures can be conducted directly, but the separation Academic Editor: György Keglevich of the more common (in the majority of cases) racemate-forming enantiomers [1] cannot be resolved directly (with good efficiency) only by fractional crystallization of diastereomeric Received: 22 June 2021 mixtures formed with so-called chiral resolving agents (foreign chiral compounds) [2]. Accepted: 16 August 2021 Our group has regularly reported on the investigation of the separation of enantiomers Published: 18 August 2021 of various structures, during which we studied the dependence of the separation efficiency (F = Y*eeDia)[3] on the choice of the resolving agent, the solvent, the reaction conditions, Publisher’s Note: MDPI stays neutral and the crystallization time [4–12]. with regard to jurisdictional claims in We found that the F parameter, which is suitable for comparison of the separations, published maps and institutional affil- is the function of the eutectic composition of the enantiomeric mixtures, of the racemic iations. compound, or of the enantiomeric mixtures of the resolving agent, namely, because the eeDia separable from the crystalline diastereomer is approximately the same as the eeRac (the eutectic composition of the racemic compound) or the eeResAg (the eutectic composition of the resolving agent). Elucidating which one is the determinant in a given case depends Copyright: © 2021 by the authors. on the solvent (i.e., the possible presence of achiral compounds) and, in the case of a given Licensee MDPI, Basel, Switzerland. solvent (at the same temperature), on the time of crystallization (the time between mixing This article is an open access article and filtration). Thus, it is advantageous if the determining eeEu is as close as possible to distributed under the terms and 100% of the eutectic composition of the racemic compound or the resolving agent. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Symmetry 2021, 13, 1516. https://doi.org/10.3390/sym13081516 https://www.mdpi.com/journal/symmetry Symmetry 2021, 13, x FOR PEER REVIEW 2 of 9 Symmetry 2021, 13, 1516 as possible to 100% of the eutectic composition of the racemic compound2 or of the 9 resolving agent. 2. Applied Methods for Exploiting the Kinetic Control—Distribution between Two 2. Applied MethodsPhases for Exploiting the Kinetic Control—Distribution between Two Phases 2.1. Continuous Industrial2.1. Continuous Processes: Industrial Liquid Processes:1 + Solid 1Liquidto Liguid1 + Solid2 +1 Solidto Liguid2 2 + Solid2 Previously, an industrialPreviously, process an industrial was developed process was in developed 1975 under in the1975 leadership under the ofleadership of Elemér Fogassy,Elemér currently Fogassy, working currently in our working group, to in produceour group, the to crystalline produce the diastereomeric crystalline diastereomeric salt of one of thesalt racemic of one intermediates of the racemic ofinte chloramphenicolrmediates of chloramphenicol ((R,R)-AD)) via((R,R a)- continuousAD)) via a continuous process (Figure1process)[13]. (Figure 1) [13]. Figure 1.Figure Scheme 1. ofScheme the procedure of the procedure developed developedfor the rapid for and the cont rapidinuous and crystallization continuous crystallization of the diastereomeric of the salt of racemic diastereomericAD with the predominancy salt of racemic of kineticAD with control. the predominancy of kinetic control. In the process, aIn 0.5 the equivalent process, a of0.5 solid equivalent (R)-acid of.Ca solid1/2 (isR)- continuouslyacid.Ca1/2 is continuously added to the added to the aqueous solutionaqueous of the racemic solutionAD of the.HCl racemic in a stirred AD.HCl apparatus in a stirred from apparatus which the from suspension which the suspension of the salt of the immediately crystallizing (R,R)-AD.(R)-acid is fed continuously to a filter. Under laboratory conditions, complete crystallization is immediate, while, in an industrial apparatus, mixing and filtration takes approximately 45 min (which can also be considered immediate crystallization under these conditions). If the same reaction is carried out from an aqueous solution of the ammonium salt of the (R)-acid instead of the calcium salt (by a single-phase salt–salt reaction), the crystalliza- tion takes 6–8 h. Symmetry 2021,, 13,, xx FORFOR PEERPEER REVIEWREVIEW 3 of 9 of the salt of the immediately crystallizing (R,R)-AD.(R)-acid is fed continuously to a filter. Under laboratory conditions, complete crystallization is immediate, while, in an industrial apparatus, mixing and filtration takes approximately 45 min (which can also be considered immediate crystallization under these conditions). Symmetry 2021, 13, 1516 If the same reaction is carried out from an aqueous solution of the ammonium salt3 of of 9 the (R)-acid instead of the calcium salt (by a single-phase salt–salt reaction), the crystallization takes 6–8 h. Thus, a rapid salt–salt reaction between the liquid–solid phases occurs here, during whichThus, another a rapid solid–liquid salt–salt reaction equilibrium between is the formed liquid–solid in the phases reaction occurs mixture. here, during This equilibriumwhich another has solid–liquid shifted almost equilibrium quantitatively is formed toward in the the reaction new solid mixture. phase, This although equilibrium the has shifted almost quantitatively toward the new solid phase, although the (R)-acid.Ca1/2 (R)-acid.Ca1/2 salt alone precipitates almost quantitatively from water. The eeEu salt alone precipitates almost quantitatively from water. The eeEu compositions of both the compositions of both the racemic AD and (R)-acid provides high eeDia values. Clearly, racemic AD and (R)-acid provides high ee values. Clearly, kinetic control has prevailed. kinetic control has prevailed. It appears Diathat if a sufficiently poorly soluble salt of the It appears that if a sufficiently poorly soluble salt of the resolving agent is chosen, kinetic resolving agent is chosen, kinetic control can be expected. control can be expected. 2.2. The Application of a Quasi-Racemic Resolving Agent with a Related Structure 2.2. The The Application Application of of a a Quasi-Racemic Resolving Agent with a Related Structure The resolution of racemic AD.HCl was also investigated by adding to the aqueous The resolution of racemic AD.HCl was also investigated by adding to the aqueousaqueous solution an aqueous mixture of the acidic (R,R)-DBTA.Na salt (that has a close molecular solutionsolution an an aqueous aqueous mixture mixture of the acidic acidic ( (R,,R)-)-DBTA.Na salt (that has a close molecular structure to the (R)-acid.Ca1/2 salt) in a 0.5 molar equivalent; however, the purity of the structure to the (R)-acid.Ca1/2 salt) in a 0.5 molar equivalent; however, the purity of the salt salt enantiomers precipitated from the resulting solution in 1 h was barely measurable enantiomers precipitated from the resulting solution in 1 h was barely measurable (eeDia of ~0.02)(eeDia of and ~0.02) was lowandeven was afterlow 12even h of after crystallization, 12 h of crystallization, although theeutectic although composition the eutectic of compositionboth the racemic of bothAD theand racemic the resolving AD and agent the resolving was above agent 80% was (Figure above2). 80% (Figure 2). Figure 2. A resolving agent with a related structure. IfIf wewe applyapply 0.5 0.5 mol mol of (ofS,S ()-S,STA)-.NaTA.Na with with the same the same resolving resolving agent,