St.

Catherine University
SOPHIA
2015 Sr. Seraphim Gibbons Undergraduate
Sr. Seraphim Gibbons Undergraduate Symposium
Symposium

A Three-Step Synthesis of Fluoxetine

Kristine Her
St. Catherine University

James Wollack
St. Catherine University

Meaghan Bruening
St. Catherine University

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Her, Kristine; Wollack, James; and Bruening, Meaghan, "A Three-Step Synthesis of Fluoxetine" (2015). Sr. Seraphim Gibbons
Undergraduate Symposium. 3.
https://sophia.stkate.edu/undergraduate_research_symposium/2015/Posters/3

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 Three Step Synthesis of Fluoxetine
Meaghan A. Bruening, Kristine N. Her
St. Catherine University
Abstract St. Paul, MN Discussion

Synthetic Schemes This three-step procedure encountered several synthetic difficulties,

Fluoxetine is the active ingredient in the antidepressant Prozac. It works
preventing completion of the reaction scheme. Instead of assembling
as a selective serotonin reuptake inhibitor to treat conditions including
fluoxetine, the final molecule synthesized was the product of an Aldol
depression and obsessive-compulsive disorder. To assemble this
reaction. Although the first reaction was supposed to proceed as a simple
molecule, a three-step synthesis was utilized. Intermediates included 1-
Proposed Path SN2 replacement, the chlorine atom leaving and being replaced with an
propanone, 3-(methylamino)-1-phenyl-(synthesized through an SN2
amine, the data collected conclusively proved this was not what
reaction between 3-chloropropiophenone and methylamine) and α-[2-
happened. Instead, the methylamine deprotonated the a carbon of 3-
(methylamino) ethyl] benzyl alcohol (synthesized through reduction of
chloropropiophenone, facilitating the attack of a second 3-
the first intermediate using NaBH4). The second intermediate was
chloropropiophenone molecule. This proceeded as an Aldol reaction,
subjected to 4-chlorobenzotrifluoride and sodium hydride to produce
Actual Product with the with final product being reprotonated. Although the reaction
the desired molecule, fluoxetine. Over the course of this multi-stage
was heated, suggesting the possibility of an Aldol condensation, the data
procedure, several synthetic difficulties led to the formation of
from both NMR and IR suggest the final condensation did not occur. No
unexpected products.
alkene functionality was present in the data.
The NMR data shows the appropriate peaks, splitting, and integration to
NMR and IR Data account for all of the protons expected in the Aldol product. The IR data
Fluoxetine Background requires more interpretation due to the expected OH stretch. Although
this stretch is supposed to occur around 3500 cm-1, this data shows a
whiterxn4-16-15_PROTON-1.jdf
stretch in the 2400-2500 cm-1 region. Although this is uncommon, it is
A new class of antidepressants, selective not unprecedented, and, due to the heavy conjugation of the molecule,
serotonin reuptake inhibitors (SSRIs), has 0.20 e a this down-shifted peak may represent the expected OH stretch.
f b
emerged within the last few decades. They Therefore, both data sets support the formation of an Aldol product.
treat a broad spectrum of conditions including g h
i
depression, obsessive-compulsive disorder, and c
Conclusion
0.15 d
bulimia nervosa. This class of medications has j
Normalized Intensity

been shown to be equally effective compared to This synthetic scheme resulted in an unsuccessful attempt to synthesize
older treatments, but contains far fewer adverse fluoxetine. Although the first reaction was supposed to proceed through
Fluoxetine side-effects. One of the leading antidepressants 0.10
i an SN2 mechanism, the weak base favored deprotonation at the a
of this type is fluoxetine. carbon. This, in combination with the poor leaving group ability of
Exposure to this medication alters the presynaptic serotonin chlorine, led to an Aldol reaction. In order to assemble the desired
c,b
transporter. Since this presynaptic transporter differs from those of d a molecule, alterations will need to be made to the procedure, or a new
0.05
other neurotransmitters such as dopamine and norepinephrine, SSRIs e f Extraction Set-Up Using
h synthetic scheme will need to be derived. Retrosynthetically, the first
are able to target and alter only the function and uptake of serotonin. j brine and CH2Cl2
g solvent could be replaced with water to “green up” the reaction.
SSRIs bind to the serotonin specific enzyme at the end of the However, since the desired synthesis did not occur in the optimized
transporter, modifying the shape and reducing the binding ability of 0
solvents, this green alternative may not be the best way to assemble the
1.83 1.00 2.08 2.03 11.73 1.04 0.93 0.96 2.39 2.06 2.93 0.84 0.98 5.98
serotonin. Because of the decreased binding, serotonin accumulates in molecule. The current procedure, without alterations, is not a good
the presynaptic transporter. Instead of being transported with the 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
synthetic path to follow in an undergraduate laboratory for fluoxetine
Chemical Shift (ppm)
enzyme, it is able to be captured, stored, and used later in the cell. synthesis.
This reallocation and redistribution of serotonin facilitates an array of 99
98
physiological alterations, aiding in the treatment and recovery from Future Directions
96
many physiological disorders.
94

92 • Repeat synthetic scheme using a protecting group on ketone

2404.72cm-1

90
1594.75cm-1
1474.73cm-1 Crude Reaction Product • Utilize a starting material with bromine instead of chlorine (improved
Green Chemistry
88 1675.54cm-1 1385.12cm-1 1152.51cm-1
1326.43cm-1
7 8 4 .7 8 c m -1

886.75cm-1
leaving group)
• Use X-ray crystallography to verify formation of Aldol product
%T

86 O-H 1300.77cm-1
1180.19cm-1
535.87cm-1

Green chemistry strives to improve 84

1445.77cm-1 1003.23cm-1
1042.11cm-1 • Design a new synthetic scheme using different reactions and starting
C=O 9 8 5 .8 9 c m - 1 553.75cm-1

the sustainability of chemical 82

1058.75cm-1

1215.38cm-1
940.15cm-1
731.08cm-1
655.89cm-1
669.31cm-1
materials
reactions, making them safer and 80
C=C 703.87cm-1

less hazardous. There are a variety 78 References

of ways to “green up” a reaction, 76 691.38cm-1
758.13cm-1

often focusing on the use of

74
4000 3500 3000 2500
cm-1
2000 1500 1000 500 450 Edward, J Guy. “Selective Serotonin Reuptake Inhibitors.” BMJ
catalysts, improving atom economy, 305(1992): 1644-1645. Web. 20 Apr. 2015.
and using less dangerous starting Stahl, Stephen M. “Mechanism of Action of Serotonin Selective
materials and reagents. Practical Green Chemistry Calculations Reuptake Inhibitors.” Journal of Affective Disorders 51.3 (1998): 215-
considerations must also be taken regarding the cost of the “green” 235. Web. 20 Apr. 2015.
alternative and the time required. Zelenin, Alexander. Synthesis of 3-​aminomethyl-​1-​propanol, a Fluoxetine
To improve this procedure, we retrosynthetically examined the first Comparison Parameters Methanol Water Precursor. Board of Regents, the University of Texas System, USA,
reaction and focused on safer solvents. Replacing the solvent of the Hazards Flammable, acute toxicity, organ None assignee. Patent US 20040102651. 27 May 2004. Web.
toxicity
first reaction, methanol, with water, would reduce the hazards, making
the reaction safer while decreasing cost. Cost $0.07/mL $0.02/mL Acknowledgements
Percent Yield Not Determined Not Determined
E Factor Not Determined Not Determined
This research project was funded by Minnesota Pollution Control Agency
Reaction Time, Temp 15 minuntes, Room Temperature Not Determined
green chemistry curriculum initiative.
Product Purity, byproducts Minimal Impurities Not Determined
Advice, assistance, and helpful suggestions from Dr. James W. Wollack
Waste produced ≈ 20 mL methanol Hydrochloric acid (0.17g)
Hydrochloric acid (0.17g) Methylamine (8.6g) (lab instructor)
Methylamine (8.6g)