Separation of enantiomers

In the recent years chirality of pharmaceuticals and agrochemical compounds has reached a great importance. Although many of drugs used are optically active, the majority of synthetic drugs are produced as racemates. According to FDA's (Food and Drug Administration, USA) policy statement and also to guidelines of the Japan authorities new optically active drugs should be prepared for marketing in their enantiomerically pure form.

Separation of enantiomers called resolution is not a simple procedure. Physical and physico-chemical properties of enantiomers are the same, different properties can be reached by derivatisation with some optically active compounds. These products are the diastereomers which can be separated by a range of methods. Fractionated crystallisation is the most common industrial process, while chromatographic methods are superior in analytical scale [3]. Although, theoretically almost all racemates may be separated via partial or total diastereomeric salt (complex) formation and crystallisation from a proper solvent, this method has a lot of disadvantages: complete enantiomer separation can not be achieved in one step; a small amount of the wanted form is retained in the mother liquor; a great amount of active resolution agent is needed; the widely used organic solvents cause impurities in the product [4]. These problems can be eliminated if the separation is achieved by supercritical fluid extraction using carbon dioxide (CO2).

The applicability of SFE for resolution of some acids and bases has been proved by the researchers of our laboratory. The project is run with co-operation with the Department of Organic Chemical Technology. The basic idea of the resolution is that after the partial diastereomer formation of the racemate only the free enantiomeric mixture is soluble in supercritical carbon dioxide.
On the left side is shown the flow sheet of the resolution process. This can be divided into three parts: preparation of the sample, extractionand processing the raffinate. In case of different compounds all the part-processes need to be optimised. The following parameters are to describe the result of the resolution: enantiomeric excess (ee), yield (Y), and selectivity (F).

It was not suprising, because the effect of the used solvent on the selectivity is already known [I]. On the other hand, sometimes the chiral differentiation is higher in SCFs than in organic solvents. The resolution of cis-chrysanthemic acid by S-(+)-benzylamino-1-butanol resolution agent led to 99 % ee in one step[II], while in water-chloroform liquid-liquid extraction system only 28% is achieved [III].

It was experienced, that the physical properites of the carbon dioxide as pressure and temperature(also density, viscosity etc.) influence the chiral differantiation. It suggests, that the extraction step is more than a simple separationII. For example the higher pressure is better for the resolution of cis- and trans- permetric acids[IV], but has no effect in other cases [V].

The scale up of some supercritical extraction processes are already proved to be possible (ex. see the decoffeination of coffee or tee) and the industrial use has serious adventages: the carbon dioxide is quite cheap and enviromentally benign; it does not contaminate the product, because under atmosferic pressure and room temperature it is a gas; and the soluting strange is easily contorlable by pressure and temperature. The main disadventage is the cost of the equipment, but longer run it may be economical.