Biomedical Engineering Reference
In-Depth Information
H
CH 3
H
CH 3
CO 2 H
CO 2 H
MeO
( S )-Ibuprofen (eutomer)
( S )-Naproxen (eutomer)
FIGURE 5.11
Examples of drugs where one enantiomer is converted into the other in the body.
5.5 METHODS FOR OBTAINING PURE STEREOISOMERS
Unfortunately, the preparation of pure stereoisomers is not trivial: a reaction between two achiral
starting materials, in an achiral environment, cannot generate a chiral product. A description of the
main methods to achieve pure chiral compounds, illustrated by examples of commercially available
therapeutic agents is given in the following sections.
5.5.1 R ESOLUTION OF R ACEMATES BY C RYSTALLIZATION OF D IASTEREOMERS
Perhaps the oldest and most often used method of separation of racemic mixtures, resolution, is still
widely used in the pharmaceutical industry. Direct crystallization in a chiral medium can sometimes
be performed, although the most common method utilizes formation of diastereomers by salt forma-
tion of the racemate with a chiral acid or base. Hence, differential crystallization of the diastereo-
meric salts allows the resolution of the individual enantiomers. Amino acids, alkaloid bases, and some
other synthetically derived compounds are usually the i rst options selected as resolving agents.
The main disadvantages of this method are the need to obtain crystals in the i rst instance and
the maximum 50% in the theoretical yield. Therefore, the racemization and the recycling of the
unwanted isomer as well as several crystallizations are often performed in order to increase the eco-
nomic viability of the procedure. Once the desired purity of the diastereomer has been achieved, the
chiral auxiliary can then be removed to furnish the enantiomerically pure compound (Figure 5.12).
Although an inexpensive and well-established procedure, i nding the best resolving agent can often
be challenging. Some criteria for choice of reagent are detailed as follows:
1. The asymmetric center should be near to the group used for salt formation.
2. The resultant salt should have a rigid structure.
3. Strong acids and bases are preferred.
4. The resolving agent must be stable under the reaction conditions but easily recovered after
crystallization.
(Diastereomers)
( R )-A
( RS )-B
( R , R )-AB
+
( S , R )-AB
Separate
( R , R )-AB
( S , R )-AB
( R )-B
( S )-B
FIGURE 5.12
Schematic procedure for resolution of a racemate by crystallization of its diastereomeric salt.
 
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