Page 225 - 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)
8 Nonchromatographic Solid-Phase

Purification of Enantiomers

Neil E. Izatt, Ronald L. Bruening, Krzysztof E. Krakowiak,
Reed M. Izatt and Jerald S. Bradshaw

8.1 Introduction

In recent years, there has been increasing interest in the preparation of enantiomeric-
ally pure compounds [1, 2]. This interest was intensified by a statement issued in
1990 by the U.S. Food and Drug Administration (FDA) concerning development of
chiral drugs as single isomers or racemates [3]. Even though the FDA did not man-
date development of single isomers (racemates may be appropriate in certain cases),
pharmaceutical companies took this announcement as an indication of things to
come, and began careful study of both isomers in potential drugs. The logic behind
this development is clear. It has long been recognized that isomers, including enan-
tiomers, can have quite different properties. Apart from the fact that the dosage
needed is increased by having the “inert” isomer present, the “inert” isomer may
have properties that range from benign to beneficial to fatal. An example of an
“inert” isomer that produced devastating results was one of the enantiomers of
thalidomide [4], which caused severe malformations in children born to pregnant
women who took the drug by prescription. Only the unwanted isomer had this effect.
As a result of the factors described above, there has been a tremendous increase in
the production of chiral compounds. Sales of chiral drugs for antibiotic, cardiovas-
cular, hormone, central nervous system, cancer, antiviral, hematology, respiratory,
and gastrointestinal uses were nearly US $ 100 billion in 1998 [3]. In addition, sin-
gle enantiomer applications are found in the preparation of pesticides, biochemicals,
flavors, and aromas. The requirement for pure enantiomers in these applications
requires a critical assessment of the most cost-effective way to accomplish their
analysis and preparation.
Among the methods used to separate enantiomers are crystallization using a chir-
al auxiliary, chiral synthesis, and large-scale chromatography [3]. The choice of
these methods usually involves trade-offs, particularly in large-scale separations. In
the first and third cases, the similar chemical properties of enantiomers result in
small separation factors (α values), making it necessary for multiple separations
stages to be used in order to achieve satisfactory separations of 98 % or better. In
addition, each of these technologies requires the use of large amounts of solvent, and
the chiral throughput per sized separation material in the case of chromatography is