Efficient Resolution of Enantiomers by Coupling Preferential Crystallization and Dissolution. Part 1: Experimental Proof of Principle

Abstract

The resolution of enantiomers can be achieved by preferential crystallization as soon as they crystallize as a conglomerate. However, several successive and alternate crystallizations of each enantiomer as well as seeds of both enantiomers are required for this process to be efficient. The performance can be increased by using two tanks coupled via the liquid phase. In one subcooled tank, the crystallization of a single enantiomer is carried out by enantioselective seeding, while a suspension of racemic mixture in equilibrium at the saturation temperature with the liquid phase is present in a second tank. Over the course of the crystallization, the concentration of the seeded enantiomer decreases. Because of the liquid exchange, the crystallizing enantiomer becomes undersaturated in the second tank, leading to its selective dissolution. Crystallization and dissolution continue simultaneously in both tanks until the solid phase in the second tank becomes enantiopure. At this point, both suspensions can be filtrated, and each tank yields a pure enantiomer. The proof of principle has been successfully given for the resolution of DL-threonine. Besides reducing the number of steps needed to access both pure enantiomers, this process was found to be more productive than conventional alternatives of resolution by preferential crystallization. ■ INTRODUCTIONWhen a chiral molecule cannot be synthetized from a molecule of the chiral pool, a 50/50 mixture of both enantiomers is often obtained. In this case, the target enantiomer has to be separated from its antipode in a second step. Because of their mirror symmetry, most of their properties are identical, and dedicated resolution techniques are required. If the enantiomers form a conglomerate, their resolution by preferential crystallization is possible. 1 A supersaturated racemic solution eventually gives birth to nuclei of both enantiomers at the same time, leading to a racemic solid. However, if enantiopure seeds are introduced into the solution prior to nucleation, these seeds grow. The solid phase remains in the state of single chirality until the nucleation phenomenon occurs. Up to this point, the racemic mixture can be resolved yielding an enantiopure product. The mass of recovered enantiopure solid is however quite small as compared to the initial mixture (the yield of a single crystallization step is often about 10%). This can be improved by recycling the liquid phase, to selectively crystallize the antipode after the addition of racemic mixture and new seeding. Preferential crystallization therefore consists of successive and alternate crystallization steps of the enantiomers. The application of preferential crystallization requires a good knowledge of the thermodynamic and kinetic properties of the target molecules and involves a significant amount of manual handling. 2 The technology is time and cost consuming and can be difficult to apply for nonspecialists.During the past decade, a new variant of preferential crystallization has been developed. 3 Instead of c...

Effect of additives on the preferential crystallization of L-asparagine monohydrate

“…Many researchers have tried to circumvent this problem, for instance by using coupled batch crystallizers -crystallizing the preferred enantiomer in one crystallizer and the counter enantiomer in another crystallizer, with exchange of solution between the two crystallizers [13], coupled batch crystallizers with seeding of the preferred enantiomer in one crystallizer and allowing nucleation of the counter enantiomer in another crystallizer maintained at a different temperature [14,15], coupled batch crystallizers with a membrane between the crystallizers to prevent transport of crystals from one crystallizer to another [16], and racemization of the solute species to equalize the concentrations of the preferred and counter enantiomer [17,18], Another way to circumvent the crystallization of the counter enantiomer is to use tailor made additives to inhibit the nucleation and growth of the counter enantiomer. This will be convenient if the scale of the resolution is such that a fully batch system is most suitable and crystallization or recycling of the counter enantiomer is not required.…”

Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

“…An intelligent, worthwhile modification of the two‐tank circuit is the approach proposed in , . The method is based on the property of the conglomerate of any nonracemic composition, described in Sect.…”

Application of Continuous Preferential Crystallization to Efficiently Access Enantiopure Chemicals

“…The same group further extended their theoretical investigation to the resolution of asparagine 20 and subsequently developed a CPC2 protocol to allow facile recovery of both enantiomers of this amino acid on decagram scale. 51 An alternative method to the simultaneous preferential crystallization in a coupled batch operation mode was reported by Hein et al 52 and Levilain et al 53 In this variation, preferential crystallization occurs in only one vessel with selective dissolution in the second ( Figure 6). Seeding with a single enantiomer causes the mother liquor to be depleted only in this isomer.…”

“…53 In CPCD the theoretical maximum mass of both pure enantiomers depends only on the initial mass of racemic mixture applied to the dissolver while in CPC2 the maximum mass recovered is limited by the solubility difference between the initial and final temperatures applied in the crystallization process. As a caveat, the rate of the resolution may be higher in CPC2 as it relies on the crystal growth kinetics as well as the mass transfer between coupled crystallizers, which is governed by the flow rate.…”