(91b) Hybrid Processes to Separate Enantiomers

Hybrid processes to separate enantiomers

Andreas Seidel-Morgenstern and Heike
Lorenz

Max Planck Institute for Dynamics of
Complex Technical Systems

Sandtorstr. 1, 39106 Magdeburg
(Germany)

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 enantiomer. 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 [2] and preparative
chromatography [3, 4] with subsequent enantioselective
crystallization. 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.

The attractive incorporation of racemizing
the counter-enantiomer into process schemes will be finally 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-Morgensten, Separation of Racemic Bicalutamide
by an Optimized Combination

     of Continuous
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. ProcessRes. Dev. 16 (2012) 343-352.