Page 222 - Chiral Separation Techniques

200 7 Chiral Derivatization Chromatography

Fig. 7-17. Type IV: Derivative with best selectivity.
scale separation, only optimized conditions must be used, as small increases in
selectivity, resolution and loading capacity will yield major increases in productiv-
ity. Several intermediates in the synthetic route of an enantiopure compound must be
thoroughly examined. If an intermediate can be derivatized to a compound which has
a known selectivity on a CSP, this may lead to a tremendous increase in productivity.
An example of this approach was described by Francotte, in which racemates
bearing the benzoyl group could be separated on the CSP cellulose-tribenzoate
(CTB). Using this CSP, differently substituted benzoyl-derivatives showed different
selectivities. By testing the ortho-, meta- and para-methoxy-benzoyl-derivatives of
different racemic alcohols it was possible to identify for every drug substance the
optimum derivative [32]. Unfortunately, the same benzoyl-isomer was not the best
for all substances to be separated, indicating that chiral recognition and therefore
separation is dependent not only on the derivatizing group but also on the structure
of the derivatized compound.

7.2.5 Type V: Reactive Separation

The final type of reaction covers not only chromatographic resolution but also con-
version of a derivatized racemate to an unichiral product. Derivatives of chiral com-
pounds can be converted by enzymes with a high enantiospecificity. Again, this
approach offers the highest value when applied to the preparative separation of race-
mates. A production strategy for an unichiral compound can be set up when the tar-
get compound is derivatized to a molecule which is stereochemically specifically
converted by an enzyme. The resulting two compounds (the target compound and the
derivate of the other enantiomer of the target compound) can be separated on a nor-
mal silica or reversed-phase sorbent (Fig. 7-18).
This strategy, for the production of (S)-ibuprofen, is illustrated in Fig. 7-19.
Ibuprofen is derivatized to the corresponding sulphonmethyl ester, but only one
enantiomer of this compound is converted by a protease to (S)-ibuprofen [33]. The
resulting (S)-ibuprofen and the unreacted ibuprofen sulphonmethyl ester can be sep-