DRUG SYNTHESIS FOR COLLEGE OF PHARMACY

Ihsan Ikhtiarudin, M.Si (e-mail: ihsan@lecturer.unri.ac.id)

This handout was made to understanding some important reactions in drug synthesis. The reactions
including functionalization (adding a functional group), functional group interconversion (FGI, converting a
functional group into other functional group), and C-C bonds formation (developing a carbon skeleton).
In this handout, we tried to explain some synthesis steps of popular drugs that have farmacological
effects such asantipyretic, analgesic, anesthetic, anti-inflammatory, anti-asthma, antibacterial and others.
In addition, we also discussed synthesis of some important starting materials in synthesis drug.

1. Synthesis of salicylic acid (2-hydroxybenzoic acid)

The salicylic acid was prepared via carboxylation of phenolate ion and followed by adding of an acid.
Beside it was used an antibacterial, the salicylic acid is an important starting material for drug
synthesis.

The methyl salicylate is one of the compound that produced by esterification of salicylic acid and
methanol and was used as balsam component, such as muscular balsam, Geliga. This balsam is
containing 30% of methyl salicylate. In addition, the salicylic acid was also used as starting material for
aspirin synthesis.

2. Synthesis of salbutamol
 Salbutamol was used as an anti asthma drug. It was developed from the modification of
Norepinephrine, a natural neuro transmitter. Norepinephrine stimulates a and b-adrenoceptors in the
body, a more specific drug was need that targeted only the b-adrenoceptors.
The replacement of one hydrogens on the amine with a isopropyl group produced isoproterenol
(isoprenaline) which has increased stimulation of b-adrenoceptors whilst a reduced stimulation of a-
adrenoceptors. However Isoproterenol was not metabolically stable and was inactivated by the
enzyme catechol O-methyltransferase. Another disadvantage was that there are two types of b-
adrenoceptors, b1 and b2, isoproterenol activated both receptors receptors. The activation of b1
adrenoceptors in the cardiovascular system gave rise to side effects such as palpitations and cardiac
arrhythmia.
The replacement of an isopropyl group with a t-butyl group and one alcohol group on the
aromatic ring was replaced by a methanol group. Salbutamol only stimulates b1 adrenoceptors and it
also metabolically stable with an active time of about six hours in the body.
There are several ways that can be used to synthesize salbutamol. In this handout, we explained
the synthesis of salbutamol via resolution of benzyl protected arylethanolamine.

Note: Please write the retrosynthesis analysis was explained!

To understand about retrosynthesis of salbutamol, you need to recall:
1. Disconnection of C-O Ester
2. Disconnection of C-C Acylation F.C.
3. Disconnection of C-O Ether
 4. Halogenation of Ketone
5. Disconnection of 1,2-difungtionalised of carbonyl compounds
6. FGI

Materi:

1,2-difungtionalised of carbonyl compounds

Halogenation of Ketone
A Review

1,3-difungtionalised of carbonyl compounds

A Review

Synthesis:
A Review

Synthesis:
3. Synthesis of propoxycaine (a local anesthetic drug)
Remember the synthesis of cyclomethycaine, benzocaine and paracetamol to help you understanding
the propoxycaine synthesis.
4. Synthesis of Ibuprofen (an anti-inflammatory drug)
a. Synthesis in organic laboratory

b. Synthesis in industrial scale

5.