Download Prozac Paper (Second Draft)

A. Heersche, J. Powell M., and Wespetal
Organic Chemistry II
Dr. Lois Ablin
4 April, 2011
Fluoxetine Hydrochloride (Prozac)
Fluoxetine (trade name Prozac) is one of the most widely prescribed pharmaceuticals in the
United States. In the year 2007, over 22.2 million prescriptions were dispensed for Prozac or
one of its many generic equivalents. Introduced in 1987 by the Eli Lilly Company, Prozac is
used to treat a number of psychotropic disorders including major depression and obsessivecompulsive disorder (FDA 7-9).
Fluoxetine’s molecular structure can be seen in Figure 1.
Figure 1 – The Structure of Prozac (Fluoxetine)
Fluoxetine’s IUPAC name is N-methyl-3-phenyl-3-[(trifluoromethyl)phenoxy]propan-1-amine.
This name reflects the molecule’s functional groups – an ether, a secondary amine, two phenyls,
and three alkylfluorides. These functional groups are showcased in figure 2.
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Figure 2 – Functional Groups of Fluoxetine
In addition to possessing several varied functional groups, fluoxetine also contains seven
different types of covalent bonds. These include highly stable bonds such as the conjugated
carbon-to-carbon double bonds of the phenyl groups and relatively unstable bonds such as the
carbon-to-nitrogen single bonds of the amine. All seven bond types are described in figure 3.
Figure 3 – Bond Types in Fluoxetine
C=C
C−C
C−F
C−H
C−N
C−O
H−N
Count
6
10
3
17
2
2
1
Length (Å)
1.4
1.4
1.4
1.1
1.4
1.4
1.0
Energy (KJ/mol)
602
346
485
411
305
358
386
Fluoxetine’s has received a Chemical Abstracts Service registry number of 54910-89-3.
Its molecular formula is C17H18F3NO, and its molar mass is 309.33 g/mol (O’Neil 4185). Under
standard laboratory conditions, Fluoxetine is a white to off-white crystalline solid. Pure samples
exhibit a melting point of 158.4-158.9 degrees Celsius. Fluoxetine is practically insoluble in
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water and has a maximum aqueous solubility of 14 mg/mL. The LD50 for mice is 248 mg/kg, and
for rats it is 452 mg/kg (O’Neil 4185).
Fluoxetine’s third carbon is the compound’s only stereogenic center. For this reason, the
two structures seen in figure 4 are the compound’s only two enantiomers.
Figure 4 – The Enantiomers of Fluoxetine
Therapeutic preparations of fluoxetine are racemic mixtures of (R)-fluoxetine and (S)-fluoxetine.
Both enantiomers are highly specific and potent serotonin reuptake inhibitors; however, (S)fluoxetine is eliminated from the body more slowly than its (R) counterpart. For this reason, the
predominant enantiomer found in blood plasma is (S)-fluoxetine (FDA 2).
Fluoxetine’s 1HNMR spectrum is given in figure 5 on the following page.
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Figure 5 – 1HNMR Spectrum of Fluoxetine
(a)
(a)
(d)
(b)
(c)
(e)
(d)
(c)
(a)
(b)
(e)
Several multiplets (a) are present in the 7.0-7.8 ppm region. These signals correspond to the
protons of the two aromatic rings. A triplet (b) can be seen at 5.20 ppm. This downfield signal
corresponds to the highly deshielded proton of the third carbon on fluoxetine’s aliphatic carbon
chain. A second triplet (c) is located at 2.68 ppm. This signal corresponds to the two protons of
the first carbon of the compound’s aliphatic carbon chain. The singlet (d) appearing at 2.43 ppm
corresponds to the three protons of the amine’s methyl group. Finally, the doublet of triplets (e)
at 2.07 ppm corresponds to the protons of the second carbon of fluoxetine’s aliphatic carbon
chain.
(Infrared spectrum with discussion of major peaks)
While several viable syntheses exist for fluoxetine, one particular synthesis is
especially practical for undergraduate laboratories. While some syntheses use toxic
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compounds such as the reducing agent B2H6 and the chlorinating agent SOCl2 to yield
fluoxetine, there is at least one synthesis that circumvents these hazardous reagents. The
synthesis given by Perrine, Sabanayagam, and Reynolds instead uses the less hazardous
reagents NaBH4 and KOCMe3. Furthermore, while other syntheses require use of the costly
compound 4-(trifluoromethyl)phenol, the synthesis avoids this compound and instead requires
the inexpensive 1-chloro-4-(trifluoromethyl)benzene. For these reasons, the synthesis given in
Figure 1 is best suited for introductory laboratories.
Figure 1 – A Synthesis of Fluoxetine
1
2
3
4
5
The commercially available compound 3-(dimethylamino)-1-phenylpropan-1-one (1) is reduced
with sodium borohydride (NaBH4) to form 3-(dimethylamino)-1-phenylpropan-1-ol (2). This
alcohol is deprotonated with potassium t-butoxide (KOCMe3) and undergoes aromatic
substitution onto 1-chloro-4-(trifluoromethyl)benzene (3). Aromatic substitution in the polar
aprotic solvent DMAA yields the drug precursor “N-methyl-Prozac” (4). NMP is converted to
Prozac (fluoxetine, 5) via N-demethylation with cyanogen bromide (CNBr).
Fluoxetine’s main activity and mechanism of action in vivo is as a selective serotonin
reuptake inhibitor (SSRI). Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter
associated with the mental sensation of well-being. In healthy neurons, 5-hydroxytryptamine is
synthesized from the amino acid tryptophan via catalysis by tryptophanhydroxylase (TH) and
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aromatic aminoacid decarboxylase (AADC). Newly generated serotonin is stored in vesicles in
the axon terminal and then released into the synaptic space. The freed serotonin molecules
activate 5-HT receptors on the adjacent dendrites. Over time, the serotonin in the synaptic space
is either degraded by monoamine oxidase or collected by the 5-HT transporters on the axon. In
the latter case, the serotonin is placed in vesicles and reused. A significant contributing factor to
major depression is the overactive reuptake of serotonin. If the 5-HT transporters remove
serotonin too quickly, neurological imbalances including depression can occur. Fluoxetine and
other selective serotonin reuptake inhibitors block a portion of the 5-HT transporters and
increase the serotonin available to the dendritic 5-HT receptors. This mechanism of selectively
inhibiting serotonin reuptake can restore neurological balance and reduce the symptoms of
depression (Wong, Perry, and Bymaster 767).
A new non-SSRI mechanism of action for fluoxetine has been recently discovered by
medicinal chemists. In 2006, Pinna and co-workers reported that fluoxetine and its N-desmethyl
congener norfluoxetine selectively increase brain neurosteroid content at doses inadequate to
inhibit serotonin reuptake. Pinna believes that fluoxetine’s pharmacologic actions would be
described more accurately as a “selective brain steroidogenic stimulant.” This pharmacology is
consistent with neurosteroids known involvement in human brain pathophysiology, such as
major depression, postpartum depression, post-traumatic stress disorder, and various anxiety
disorder (Daniels 1039). Consequently, Prozac’s health effects seem to be derived from not only
its ability to selectively inhibit serotonin reuptake, but also its ability to increase brain
neurosteroids.
Fluoxetine is indicated for a number of psychotropic disorders. The drug’s most common
indication is for the treatment of major depressive disorder in adults. This disorder is
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characterized by a prominent and persistent depressed or dysphoric mood that significantly
affects the ability of the individual to function. Depression in children and adolescents has also
been effectively treated with Prozac (FDA 7-8).
Another indication for this prominent antidepressant is in the treatment of obsessivecompulsive disorder. Individuals with this disorder suffer from obsessions or compulsions that
cause marked distress, are time-consuming, or interfere significantly with day-to-day life.
Prozac’s effectiveness in the treatment of OCD was firmly established in 13-week trials with
adults as well as with pediatric patients. Fluoxetine is also indicated to treat bulimia nervosa.
Bulimia, a behavioral disorder characterized by binge eating and subsequent purging, has been
treated successfully with Prozac. Other uses for this SSRI include the treatment of panic
disorders and premenstrual dysphoric disorder (FDA 8-9).
Because of the relatively low incidence of adverse effects, fluoxetine has gained
widespread use in the past twenty years. However, a few adverse effects should be noted. These
effects include nausea (24% incidence), nervousness, insomnia (15% incidence), sedation,
headache, dizziness, dry mouth, diarrhea, constipation, sweating, tremor, anorexia, and sexual
dysfunction. Occurring in 3% if patients, rashes signal a potentially serious side effect and
warrant immediate discontinuation of the medicine. Overall, roughly 15% of all patients
prescribed fluoxetine will discontinue its use due to adverse side effects (Stokes 1191).
Fluoxetine is contraindicated in a few important situations. This pharmaceutical is not to
be prescribed to any patient with a known allergy to SSRI’s. Since SSRIs can cause lifethreatening allergic reactions, treatment should be immediately discontinued if the patient
develops a rash. Potentially fatal reactions have also occurred with concomitant use of
monoamine oxidase inhibitors, thioridazine, or pimozide with fluoxetine. Therefore, patients
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should discontinue usage of these medications at least two weeks before the first dose of
fluoxetine. Additionally, fluoxetine should be discontinued at least five weeks before starting
treatment with one of these three medications (NIH 3). Herbal medications such as St. John’s
wort or tryptophan should be avoided while taking fluoxetine. Since both of these over-thecounter medications raise serotonin levels, a serious condition known as serotonin syndrome
may occur (Mayo 3).
When fluoxetine was introduced in 1987, it represented a monumental step forward in the
treatment of depression. Fluoxetine proved to treat depression more effectively than its
predecessors with substantially fewer and more benign side effects. With the ease of once a day
dosing and the relatively low side effect profile, patient compliance is high (Stokes 1224).
Clearly, fluoxetine has revolutionized the treatment approach for depression. As a medical
professional, I would certainly recommend this compound to an individual suffering from
depression or other related disorders.
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Works Cited
Food and Drug Administration. Prozac. Feb. 2004. 22 Mar. 2011<http://www.fda.gov/ohrms/
dockets/ac/04/briefing/4006B1_05_Prozac-label.pdf>.
Daniels, R. Nathan and Craig Lindsley. “A New, Non-SSRI Mechanism of Action for Prozac.”
Current Topics in Medicinal Chemistry 7 (2007): 1039.
Lide, David R. CRC Handbook of Chemistry and Physics: a Ready-reference Book of Chemical
and Physical Data: 2008-2009. 90th ed. Boca Raton: CRC, 2009.
Mayo Clinic Staff. “Selective Serotonin Reuptake Inhibitors.” Mayo Clinic News. Dec. 2010.
25 March 2011 <http://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v%3Aproject=
medlineplus&query=prozac&x=12&y=16.html>.
National Institute of Health. Fluoxetine. March 2011. 22 Mar. 2011<http://www.nlm.nih.gov/
medlineplus/druginfo/meds/a689006.html>.
O’Neil, Maryadele, Patricia Heckelman, Cherie Koch, and Kristin Roman, eds. The Merck
Index. 14th ed. Whitehouse Station: Merck Research Laboratories, 2006.
Perrine, Daniel M., Nathan R. Sabanayagam, and Kristy J. Reynolds. “The Synthesis of NMP, a
Fluoxetine (Prozac) Precursor, in the Introductory Organic Laboratory.” In the
Laboratory: Notes for the Instructor.
Stokes, Peter E. and Aliza Holtz. “Fluoxetine Tenth Anniversary Update: The Progress
Continues.” Clinical Therapeutics 19 (1997): 1137-1250.
Wong, David T., Kenneth W. Perry, and Frank Porter Bymaster. "Access: The Discovery of
Fluoxetine Hydrochloride (Prozac): Nature Reviews Drug Discovery." Nature Publishing
Group: Science Journals, Jobs, and Information. Web. 10 Mar. 2011.
<http://www.nature.com/nrd/journal/v4/n9/authors/nrd1821.html>.