There is a very well written and VERY readable book The

							                                Synthesis of Prozac
Objective
The goal of this experiment is:
•       To synthesis Prozac in four simple steps from commercially available
starting products.
•       To introduce you to the type of language prevalent in chemical journals.



Grading
You will be assessed on:
Observations during the course of the synthesis.
Balanced chemical equations.
TLC values of starting mixture and reaction mixture.
NMR characterization.
TA evaluation of lab procedure.



Introduction
Welcome to the world of Eli Lilly. In 1988, Dista Products (a division of Eli
Lilly) got FDA approval for the distribution of a brand new drug for tre atment
of depression. The ripples were felt rapidly. Where as Ritalin was once the drug
for mental disorders that was on everyone's tongue, a new drug quickly replaced
it and surpassed it. It's name was Prozac. Part of the beauty of Prozac is its
simplicity. It can be produced in four simple steps from commercially available
products starting products. And in fact that is what you will do for this lab
(however, due to time limitations you will only perform the first 3 steps of the
synthesis). The only other difference between the work you will be doing and
the Prozac sold in stores is the fact that the molecule you will be synthesizing
will be racemic. As you can see above there is a stereocenter on the carbon
adjacent to unsubstituted benzene ring. Though it is possible to synthesize the
molecule in a stereoselective manner, again, it will not be done due to time
constraints. With this we give you the synthesis of Prozac.
The lab itself is designed to do two things. The first is obvious, to impart the
knowledge of synthesis, and synthetic techniques to you, the aspiring student.
The second less obvious reason is to get you used to the type of language often
seen in chemical journals. As you will soon see, the language of an experimental
section is cryptic, terse, direct, and close to a language in itself. Hopefully, after
4 weeks of reading it you will begin to understand the meanings implied in the
words, the beauty of the language of chemistry. Or at the very least it will make
more sense to you then when you began.
As far as techniques go, you will see a plethora of new ones in this lab. Many of
the ones that have theory associated with them will be explained in separate
sections of the experimental section. Several of them will be demonstrated by
your TA. Some you will have to ask about in class. Last but not least you also
have one last resource available. There is a very well written and VERY
readable book (The Organic Chemistry Survival Manual) by James Zubrick that
explains many techniques and pieces of equipment.

Experimental
Techniques: THIN LAYER CHROMOTOGRAPHY (TLC)
NOTE: All TLC plates that have glass backing go into the sharps container.
They may not be sharp when you use them but odds are the glass will end
up that way.
TLC is one of the most commonly used techniques in chemistry. It allows a
chemist to accurately and rapidly analyze very small quantities of material. In
this experiment you will use TLC to monitor reactions as well as assess the
purity of your product.
TLC is run on a plastic plate (or aluminum) that has been coated with a very thin
layer of silica. The silica on the plate, being polar itself, is strongly attracted to
polar materials, and any polar material on the plate will tend to stick to it. When
you place a small spot of material at the bottom of the plate, it will be carried up
the plate by the solvent as capillary action proceeds.




The most polar components of the sample will be very attracted to the stationary
silica gel and not move very far up the plate. The least polar materials will have
no attraction at all for the silica and will dissolve in the solvent well, thus
moving up the plate at the same speed as the solvent itself. As time goes on, the
compounds within the sample will become separated on the plate according to
polarity. The most polar molecules will be stuck at the bottom while the least
polar will flow quickly to the top.

TLC spots are identified by their Rf value, which is the ratio of the distances the
spots ran to the distance the solvent itself ran. Thus the Rf is calculated by
dividing the distance the spot ran by the distance the solvent ran. You can see
that the spots on the plate shown above have Rf values of 0.25, 0.72, and 0.87.
It can be useful to run several samples on the same TLC plate to easily compare
the components of one sample with the components of another. If the same
molecule is contained in two different samples, when you run the samples
together on the same plate this molecule will run the same distance for both
samples and you will see two spots right next to each other. The size and
intensity of the spots are indicative of the amount of material, so you can see
which sample contains more of the material.
Procedure
The procedure will be listed on the subsequent pages. Your work will progress
as follows:
Day 1: Complete the first reaction. While the reaction progresses, monitor it
by TLC. This is a long day, be prepared to come in and work. Start reaction 2.
Day 2: Work up the second reaction.
Day 3: Complete the third reaction. This will be another long day.
Day 4: Complete the fourth reaction.

Reaction 1
A solution of 3-chloro-1-propiophenone (1.5 g, 8.8 mmol) in 44 mL methanol
(0.20 M) in a 250 mL round-bottomed flask was treated with 175 mg sodium
borohydride (4.4 mmol, 0.5 eq). A stir bar was added, and the mixture was
stirred for 15 min at ambient temperature, whereupon the reaction was shown to
be complete by TLC (silica gel, 9:1 hexane/ethyl acetate). Sodium dihydrogen
phosphate (4.0 g, 25 mmol, 6 eq) was added to quench the reaction, and most of
the methanol was removed by rotary evaporation. The residue was partitioned
between 100 mL hexane and 100 mL water in a separatory funnel. The aqueous
layer was discarded, and the organic layer was washed twice more with 50-mL
portions of water. The organic layer was dried with 0.5 g anhydrous magnesium
sulfate and concentrated to dryness on the rotary evaporator to provide 3-
chloro-1-phenyl-1-propanol (1.5 g, >99%) as a white crystalline solid, which
was used without further purification. Rf sm: 0.31 (orange), prod: 0.14 (blue)
(9:1 hexane/ethyl acetate, p-anisaldehyde);

FTIR: 3250, 1453, 1043, 1020, 773 cm -1 ; 1 H NMR (500 MHz, CDCl3): d
7.26-7.38 (m, 5H, Ph-H), 4.96 (ddd, J=4.0, 4.0, 8.5 Hz, 1H, PhCHOH), 3.75
(ddd, J=5.6, 8.2, 10.9 Hz, 1H, CH(H)Cl), 3.57 (ddd, J=5.9, 5.9, 11.4 Hz, 1H,
CH(H)Cl), 2.25 (m, 1H, CH(H)CH2Cl), 2.10 (m, 1H, CH(H)CH2Cl), 1.93 (d,
J=3.5 Hz, 1H, PhC(H)OH).


Reaction 2
To a foil-wrapped 500-mL round-bottomed flask containing 200 mL of acetone
saturated with sodium iodide was added 3-chloro-1-phenyl-1-propanol (904 mg,
5.30 mmol). The vessel was equipped with a condenser and a stirbar, and the
mixture was heated to reflux. After stirring for 23 h, the mixture was cooled to
23 °C, 40 mL water was added and the mixture was concentrated, taking care to
exclude light. [It is important t hat the reaction is performed in the dark in order
to isolate the iodoalcohol as a white crystalline solid.] The resulting aqueous
phase (40 mL) was extracted with peroxide-free ether (3 ´ 50 mL), and the
combined organic layers were washed with brine (10 mL), dried with anhydrous
magnesium sulfate, and concentrated on the rotary evaporator to provide 1.41 g
(5.3 mmol, >99%) of 3-iodo-1-phenyl-1-propanol as a white crystalline solid,
which was used without further purification. FTIR: 3240, 1455, 1226, 1170,
1111, 1025 762 cm -1 ; 1 H NMR (500 MHz, CDCl3): d 7.26 -7.35 (m, 5H,
Ph-H), 4.83 (dt, J=4.1, 8.1 Hz, 1H, PhCHOH), 3.32 (dt, J=7.4, 9.6 Hz, 1H,
CH(H)I), 3.20 (dt, J=6.4, 9.7 Hz, 1H, CH(H)I), 2.27 (m, 1H, CH(H)CH2I), 2.18
(m, 1H, CH(H)CH2I), 1.88 (d, J=3.4 Hz, 1H, PhC(H)OH).

Reaction 3
A solution of methylamine (40% in wa ter, 23 mL, 290 mmol, 50 eq) in 30 mL
tetrahydrofuran was cooled to 0 °C. 3-Iodo-1-phenyl-1-propanol (1.5 g, 5.8
mmol) in 10 mL THF was added. The resulting colorless solution was allowed
to warm to ambient temperature, and was then stirred for 2 h. Water (5 mL) was
added and air was bubbled through the solution for 30 min. The mixture was
concentrated on the rotary evaporator, and the resulting aqueous layer was
extracted with methylene chloride (3 x 50 mL), dried with anhydrous sodium
sulfate, and concent rated on the rotary evaporator to provide 972 mg of
3-(methylamino)-1-phenyl-1-propanol as a light yellow oil. The product was
used without further purification. FTIR: 2930, 1452, 1064, 750 cm -1 ; 1 H
NMR (500 MHz, CDCl3): d 7.23-7.39 (m, 5H, Ph-H), 4.95 (dd, J=3.0, 8.7 Hz,
1H, PhCHOH), 2.89 (m, 2H, CH2NHCH3), 2.46 (s, 3H, NHCH3), 1.88 (m, 1H,
CH(H)CH2N), 1.78 (m, 1H, CH(H)CH2N).

Reaction 4
Sodium hydride dispersion in mineral oil (50%, 306 mg, 6.4 mmol, 1.1 eq) was
put into a baked 100-mL round-bottomed flask. The flask was equipped with a
stir bar and sealed with a septum under nitrogen.
3-(Methylamino)-1-phenyl-1-propanol (957 mg, 5.8 mmol, dried azeotropically
with toluene) was dissolved in 10 mL dimethylacetamide and added via a




syringe. The mixture was stirred for 5 min at ambient temperature, whereupon it
was warmed to 70 °C and stirred for 30 min. p Chlorobenzotrifluoride (1.94 mL,
14.5 mmol, 2.5 eq) was added and the mixture was heated to 100 °C for 2 h.
After cooling to 23 °C the mixture was quenched with water (15 mL) and
extracted with toluene (3 ´ 50 mL). The organic layers were combined, washed
with basic brine (2 x (2 mL 1 M NaOH in 15 mL brine)), dried with anhydrous
sodium sulfate, and concentrated on the rotary evaporator. The resulting oil was
dissolved in ether and treated with 10 mL ethereal HCl (10 mL). The precipitate
was collected on a Büchner funnel and dried to give 1.92 g (5.56 mmol, 96%)
fluoxetine HCl as an off white powder. Recrystallization in ethyl acetate/hexane
afforded white needles: FTIR: 2748, 2706, 1327, 1246, 1110, 1068 cm -1 ; 1 H
NMR (500 MHz, CDCl3): d 9.73 (brs, 2H, NH2CH3), 7.42 (d, J=8.7 Hz, 2H,
Ar-H), 7.26-7.35 (m, 5H, Ph-H), 6.90 (d, J=8.7 Hz, 2H, Ar-H), 5.48 (d, J=4.3,
8.2 Hz, 1H, PhCHOAr), 3.13 (br s, 2H, CH2NHCH3), 2.63 (s, 3H, NHCH3),
2.50 (m, 1H, CH(H)CH2N).