Page 26 - Chiral Separation Techniques

Chiral Separation Techniques: A Practical Approach, Second, completely revised and updated edition
Edited by G. Subramanian
Copyright © 2001 Wiley-VCH Verlag GmbH
ISBNs: 3-527-29875-4 (Hardcover); 3-527-60036-1 (Electronic)
1 Techniques in Preparative

Chiral Separations

Pilar Franco and Cristina Minguillón

1.1 Introduction

The recognition of differences in the pharmacological activity of enantiomeric
molecules has created the need to administer them – and therefore to obtain them –
as isolated enantiomers. However, nowadays this problem affects not only the phar-
maceutical industry, but also the agrochemical industry and food additive producers,
both of which are increasingly concerned by this subject.
When chiral, drugs and other molecules obtained from natural sources or by
semisynthesis usually contain one of the possible enantiomeric forms. However,
those obtained by total synthesis often consist of mixtures of both enantiomers. In
order to develop commercially the isolated enantiomers, two alternative approaches
can be considered: (i) enantioselective synthesis of the desired enantiomer; or (ii)
separation of both isomers from a racemic mixture. The separation can be performed
on the target molecule or on one of its chemical precursors obtained from conven-
tional synthetic procedures. Both strategies have their advantages and drawbacks.
The separation of the enantiomers of a racemic mixture, when only one of them
is required, implies an important reduction in yield during the production step of the
target molecule. Techniques to racemize and recycle the unwanted enantiomer are
used to reduce the extent of this problem. However, the same fact becomes an advan-
tage in the development step of a drug, because it is the quickest way to have avail-
able both enantiomers in order to carry out the individual tests needed. In fact, even
if the separation/racemization approach is considered to be “not elegant“ by organic
synthetic chemists, it is nowadays the most often used for the production of single
enantiomers. The enantioselective synthetic approach has the main disadvantage of
the cost and time that could take the development of a synthetic path leading to the
desired enantiomer. Moreover, often the enantiomeric excesses obtained from an
enantioselective procedure are not sufficient to fulfil the requirements of the regula-
tory authorities. In that case, an enrichment step must be added to the enantioselec-
tive process.
All separation techniques which allow the isolation of a certain amount of prod-
uct can be qualified as being “preparative”. In contrast, analytical techniques are
devoted to detect the presence of substances in a sample and/or quantify them. How-