Hybrid Processes to Separate Enantiomers

Enantiomers are pairwise occurring molecules, which are non-superimposable mirror images one of the other. Due to homochirality of life, there is a large interest and need to produce pure enantiomers in the pharmaceutical, fine chemical, food and agrochemical industries. Their provision is a challenging task since standard non-selective chemical synthesis always leads to racemic (50:50) mixtures and there is tremendous interest in the mentioned industries to develop innovative methods allowing for a faster access to pure enantiomers. The first essential information for a rational selection of appropriate separation processes is the identification of the type of phase diagram for the specific chiral compound of interest. In the simplest but rare case that the chiral compound crystallizes as a conglomerate, it is most attractive to apply directly preferential crystallization [1]. However, more frequently racemic compounds are formed during crystallization from racemic feed mixtures. In these cases an initial enrichment is required prior to crystallizing a pure anantiomer. This enrichment might be provided by a partially selective synthesis or can be generated by an initial alternative separation process. The presentation will summarize results of several case studies devoted to combine membrane separation and preparative chromatography [3, 4] with subsequent enantioselective crystallization [2-4]. The specific degree of enrichment required for successful crystallization was specified always based on preliminary measurements of ternary phase diagrams. Some of the examples were studied in the frame of the European project INTENANT (INTegrated synthesis and purification of single ENANTiomers), which attempted to combine the potential of the two rivaling general approaches, namely the development of a) enantioselective synthesis methods and b) physical methods aiming to separate efficiently mixtures of the two enantiomers. Finally, the attractive possibility of racemizing and recycling less valuable counter-enantiomers will be also discussed. References [1] G. Coquerel, Preferential Crystallization in Novel Optical Resolution Technologies, N. Sakai, R. Hirayama, R. Tamura, Eds., Springer (Berlin, Heidelberg), 1-51, 2007. [2] L. Gou, S. Robl, K. Leonhard, H. Lorenz, M. Sordo, A. Butka, S. Kesselheim, M. Wolff, A. Seidel-Morgenstern, K. Schaber, A Hybrid Process for Chiral Separation of Compound Forming Systems, Chirality 23 (2011) 118-127. [3] H. Kaemmerer, Z. Horvath, J. W. Lee, M. Kaspereit, R. Arnell, M. Hedberg, B. Herschend, M. J. Jones, K. Larson, H. Lorenz, A. Seidel-Morgenstern, Separation of Racemic Bicalutamide by an Optimized Combination of Continous Chromatography and Selective Crystallization, Org. Process Res. Dev. 16 (2012) 331-342. [4] J. von Langermann, M. Kaspereit, M. Shakeri, H. Lorenz, M. Hedberg, M. J. Jones, K. Larson, B. Herschend, R. Arnell, E. Temmel, J.-E. Bäckvall, A. Kienle, A. Seidel-Morgenstern, Design of an Integrated Process of Chromatography, Crystallization and Racemization for the Resolution of 2',6'-Pipecoloxylidide, Org. Process Res. Dev. 16 (2012) 343-352