Fluoxetine (Prozac)

General aspects
Fluoxetine is a drug which is used against O NH
physical disorder. The antidepressant is a CH3
F
selective serotonin reuptake inhibitor
(SSRI). 1975 received the American
F
pharmaceutical company Eli Lilly a patent F
for this active ingredient and began to
market in 1985. It was celebrated at this
time as an auspicious miracle drug, not
Fig.1 Fluoxetine.
least because it was considered stimulus
enhancing. Meanwhile, however, serious
doubts about the drug have arisen.
Therefore, the manufacturer warns in the package insert of suicidal thoughts and
behavior. Fluoxetine is commercially known inter alia under the name Prozac.

View of the molecule:

Fluoxetine may occur as R- and S- enantiomer (see Figure 2). In the marketed drug
both enantiomers are included. Although only the R- enantiomer is considered to be
effective, though no hazards of the S- enantiomer are known, therefore separation of
the in the synthesis resulting of racemic is not required.

R-enatiomer S-enatiomer

Fig.2 Structures of the two enantiomers of fluoxetine

 Synthesis:
Fluoxetine can be synthesized in various ways. In the following, a retrosynthetic view
is performed referring to the synthesis by Eli Lilly.

O NH
CH3
F
F
F
A

OH X NH
CH3
Ether-
synthesis F

F
F B C

Improve the
leaving group

HO NH
O Reduction CH3
CH3
NH

E D

O
Mannich-
reaction NH2 O CH3
H3C
F CH2
G H

From the schematic representation it appears that starting from methylamine (F),
formaldehyde (G) and acetophenone (H) a Mannich reaction is carried out, which
leads to E. By reducing the carbonyl function the alcohol (D) is formed. For the
following ether synthesis, it is to be considered that the alcohol group on D must be
converted into a better leaving group, so we get C. C is to be reacted with 4- trifluor –
methylphenol (B) to fluoxetine (A).
Mechanism of Action:
Fluoxetine belongs to the selective serotonin reuptake inhibitors (SSRI). The mode of
action is consistent with the monoamine – deficiency hypothesis that depressions are
traced back to a lack of monoamine, such as serotonin or norepinephrine in the
synaptic cleft. The mode of action of fluoxetine is based on the inhibition of protein for
reuptake of serotonin (serotonin transporter). This has the consequence that the
nerve cell, which secretes serotonin on nerve conduction, does not reuptake. Thus,
serotonin lingers much longer in the synaptic cleft and thus aroused a lot longer to do
the following nerve cell. However, there are reasons to doubt the monoamine -
deficiency hypothesis, as for example, other antidepressants do not increase the
concentration of monoamine in the synaptic cleft.
.

Fig.3 Impulse conduction in the Fig.4 Impulse conduction in the

synaptic cleft without taking synaptic cleft with Fluoxetine as
SSRI. SSRI.

Side Effects:
As with many other medicines against depression, side effects may also occur with
fluoxetine. The most common side effects: insomnia, headache, diarrhea, nausea,
fatigue.

Sources:
 K. Peter, C. Vollhart, N. E. Schore, Organische Chemie, Wiley-VCH, 5, 2011
 Dissertation von Carl Gregor Wolf von Wolff „Die Wirkung selektiver Serotonin-
Wiederaufnahme-Hemmer auf die assoziative synaptische Langzeit-plastizität
im Hippocampus der Ratte“ Albert-Ludwigs-Universität Freiburg, 2007
 http://de.wikipedia.org/wiki/Fluoxetin
 http://de.wikipedia.org/wiki/Serotonin
 https://www.youtube.com/watch?v=s48PbbE7E5Q
 http://www.taz.de/1/archiv/?dig=2007/01/12/a0259
 http://pi.lilly.com/us/prozac.pdf