Improved Methodology for the Preparation of Chiral Amines

hormone noradrenaline. The (R)-enantiomer of the betablocker does not give serious sideeffects,
but it does not add to the pharmacological effect either, so it can be considered as
‘isomeric ballast’. The most sold beta-blockers (propranolol, atenolol, metoprolol) were
developed in the 1970s and are still marketed as racemate. If these substances would have
been developed today, it can be expected that they would have been introduced as a single
enantiomer. [17]
Therefore from the points of view of safety and efficacy, the pure enantiomer is preferred
over the racemate in many marketed dosage forms. In past decades the pharmacopoeia was
dominated by racemates, but since the emergence of new technologies in the 1980s that
allowed the preparation of pure enantiomers in significant quantities, the awareness and
interest in the stereochemistry of drug action has increased. Although some ‘‘blockbuster’’
drugs, such as fluoxetine hydrochloride (Prozac) is still marketed as racemates. However, the
recent trend is toward marketing a single-enantiomer drugs. [18]
Previously the chiral drug is often synthesized in the racemic form, and it is frequently costly
to resolve the racemic mixture into the pure enantiomers. Another approach by
pharmaceutical companies is what is called racemic switch. This fashionable approach
involves the development of a pure enantiomer of the drug that is already marketed as a
racemate. This means if a patent on a drug that is marketed as a racemic mixture is expiring;
it is sometimes possible to obtain a new patent for the active enantiomer. In this way, the
pharmaceutical company retains the exclusive rights on the substance for another period, but
they will have to change their manufacturing method as well. [19]
Although only a minority of all racemic drugs has proved to be suitable for a racemic switch,
this development has boosted the development of new manufacturing and separation
methods. An example of a successful racemic switch is the local anaesthetic bupivacaine
(AstraZeneca's Marcain). The (S)-isomer is now marketed under the trade name Chirocaine.
This isomer was found to be substantially less cardiotoxic than the (R)-isomer, and therefore
a new patent was granted. Furthermore, the (S)-isomer of omeprazole (a proton pump
inhibitor by AstraZeneca, known as Losec/Prilosec) is now marketed as a single enantiomer
under the trade name Nexium. [20]
6