chiral switching

Question 1

what is chiral switching?

Answer 1

Chiral switching mostly relates to racemic drugs that have been on the market for several years and are approaching the end of their patent life.

By switching to the pure enantiomer, companies can argue that it is a new invention and take out a new patent. However, they have to prove that the pure enantiomer is an improvement on the original racemate and that they could not have reasonably expected to know that when the racemate was originally patented.

Ideally, the single enantiomer will be ready to reach the market just as the patent on the original racemate is expiring.

It is not possible to patent a new drug in its racemic form today, then expect to market it later as the pure enantiomer, as the issue of stereoisomerism is now an established fact.

Salbutamol is an example of a drug that has undergone chiral switching.

Question 2

shortening the lifetime of a drug

Answer 2

Antiasthmatic drugs are usually taken by inhalation, to reduce the changes of side effects elsewhere in the body. However, a significant amount is often swallowed and can be absorbed into the blood supply from the gastrointestinal tract.

Therefore it is desirable to have antiasthmatic drugs which are potent and stable in the lungs but which are metabolized in the blood supply.

Cromakalim has useful antiasthmatic properties but has cardiovascular side effects if it gets into the blood supply.

Further derivatives were prepared that would be quickly metabolized in the blood supply.

The ester group is labile due to esterases in the blood. These produce an inactive carboxylic acid derivative.

The phenol group is quickly conjugated by metabolic conjugating enzymes in the blood, and the metabolite is rapidly eliminated.

Question 3

synthesis of salbutamol

Answer 3

Step 1 – Friedel Craft acylation
Step 2 – Esterification
Step 3 – Bromination
Step 4 – Nucleophilic substitution
Step 5 – Reduction
Step 6 – Hydrogenation to effect deprotection