Maui3
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Synthesis of An Old-School Antidepressant - From Rocket Fuel!
If you have depression or anxiety nowadays, the most likely drug you’re going to get is an SSRI (such as fluoxetine, citalopram, or sertraline). But
it wasn’t like this 60 years ago.
The Hilarious Story of the First Antidepressant!
(Allegedly) in 1952, the American military had too much rocket fuel (hydrazine) and didn’t know what to do with it. They sent this rocket fuel to
some chemists to develop new molecules. One chemist ended up developing a drug that he tested on rats with tuberculosis. After the drug seemed to work
for treating tuberculosis, the researchers were beyond excited. They decided to do a trial on a group of tuberculosis patients at a hospital. Being so
eager to see the effects on humans, they even sent a group of photographers to capture it.
After the drugs began to work, the terminally ill tuberculosis patients, who otherwise had little hope, suddenly became very hopeful and full of
energy. They even decided to dance together. The photographers were quick to capture this moment, which I find hilarious.
Soon after, the drug became not only a treatment for tuberculosis but also the first available treatment for depression and other psychiatric
conditions. Quickly, many other drugs with the same mechanism of action were created, including one called phenelzine, which is the one I synthesized.
Because these drugs have a very unselective mechanism of action, they can easily be toxic, so they are rarely used anymore. These drugs also increase
tyramine, which is already found in many aged foods, and this can result in an overdose if you eat a lot of aged cheese while on them.
But for patients with atypical or treatment-resistant depression, these rocket fuel drugs are still used to this day.
Structure and Failures
Most of these drugs are based on hydrazine. I synthesized phenelzine (2-phenylethylhydrazine), which should be easy from 2-phenylethylbromide and
hydrazine hydrate, but never is.
It took me about seven months because hydrazine kept magically vanishing from solution. Sometimes I got a solid instead of an oil or vice versa.
For synthesizing the hydrazine, I tried the urea + hypochlorite method and the ketazine route. The urea method caused foaming and
needed careful control (the foam does stain the hotplate, speaking from experience lol). Adding sulfuric acid didn’t precipitate hydrazine sulfate
because the solution was too dilute, for me. I couldn’t use hydrochloric acid either, since the hydrochloride salt is even more soluble.
The ketazine route gave low yields but was easier to scale. It uses methyl ethyl ketone, ammonia, and hypochlorite. Adding gelatin helps the yield,
but slows separation, so I skipped it. Acetone does not work well, since the acetone azine does not seperate. The product precipitates nicely with 30%
sulfuric acid.
2-Phenylethylhalide took only a few weeks. I first tried making the chloride by reacting 2-phenylethanol with 37% HCl, but like many
others say, it doesn’t work (thanks, Texium, DrBob, Keras, and kmno4). I switched to refluxing 2-phenylethanol with 48% hydrobromic acid to get the
bromide, which worked and was so easy.
2-Phenylethylhydrazine / Phenelzine (final product) was by far the most annoying step. Hydrazine kept decomposing, reacting with
something, or just simply vanishing magically. I tried this synthesis multiple times, tweaking variables, but never got it. I also attempted making it
from 2-phenylethylamine (made from phenylalanine) combined with methylethylketazine or chloramine. I could make all the starting materials, but never
the final product - no clue why. Finally, last week, I tried again with new variables - and it worked! Here’s how.
My Final and Successful Synthesis
2-Phenylethylbromide:
NOTE: This synthesis was adapted from C. C. Lee’s and J. W. Spinks procedure (https://cdnsciencepub.com/doi/pdf/10.1139/v54-132). Thank you to them!
Firstly 10 g of 2-phenylethanol were mixed with 56 g of 48% hydrobromic acid. The mixture turned milky. The mixture was heated under reflux for two
hours. First the mixture cleared up, then it turned a bit yellow. Ater the refluxing, the mixture was cooled to room temperature, and added to a bunch
of icewater. The 2-phenylethylbromide separates as a yellow thick oil at the bottom.
Crude Phenylethylbromide sinking in water.
The 2-phenylethylbromide was collected with a pipette, and washed with sodium bicarbonate solution (to remove excess HBr), whereafter it was dried
over sodium sulfate, until it turned clear.
Hydrazine Sulfate:
NOTE: This synthesis was adapted from NurdRage’s procedure (https://www.youtube.com/watch?v=UB7vwIFCnR0). Thank you to him!
NOTE: It is crucial to use only distilled or demineralised water, as tap water will cause the hydrazine to decompose.
In a large glass container (regular glass, not borosilicate, since no heating is needed), 500 mL of 25% ammonia solution was added. One gram of
gelatin may be added here, which slightly increases yield but prolongs the ketazine separation time. Then, 200 mL of methyl ethyl ketone was added.
The mixture was stirred vigorously while 124 g of 15% sodium hypochlorite was added slowly. Lower concentration hypochlorite can also be used. The
addition was slow enough to prevent the mixture from overheating. Stirring continued until bubbling stopped, then the mixture was stirred for an
additional 30 minutes.
Afterward, the mixture was allowed to separate, and the upper methylethylketazine layer was collected. Additional methylethylketazine was extracted
from the remaining solution using naphtha, which worked well. The naphtha extract and the pure methylethylketazine were combined.
About 200 mL of 30% sulfuric acid was heated to boiling (around 100 °C), then slowly added to the methylethylketazine layers while still hot. The
combined mixture was boiled at 80–100 °C with vigorous stirring for 30 minutes. After some time, all the methylethylketazine had reacted, leaving
only the aqueous layer. This was cooled in an ice bath to about 5–10 °C, causing hydrazine sulfate to precipitate as a white solid. The solid was
collected by vacuum filtration.
Hydrazine sulfate in Büchner Funnel.
Phenylethylhydrazine (Phenelzine):
NOTE: This synthesis was adapted from ChemicalBooks website (https://www.chemicalbook.com/ChemicalProductProperty_EN_CB04...), which did not list the source. Also, thanks to Niklas for giving me tips!
NOTE: It is crucial to use only distilled or demineralised water, as tap water will cause the hydrazine to decompose.
To a solution of 3.5 g sodium hydroxide in distilled water, placed in a 2-neck round bottom flask sitting in an ice bath, 5.8 g hydrazine sulfate was
added slowly in small portions. The temperature was kept below 15 °C during the addition. You can also use a premade solution of hydrazine hydrate
instead of making it by reacting hydrazine sulfate with the sodium hydroxide solution. Some ethanol was added, causing sodium sulfate to precipitate
from the reaction between hydrazine sulfate and sodium hydroxide. This is no problem.
The round bottom flask was equipped with a water-cooled condenser and an addition funnel containing 0.9 g phenylethylbromide in ethanol. The mixture
was heated to reflux, and while heating, the phenylethylbromide solution was added very slowly in drop portions. If, after the addition, the
phenylethylbromide is not dissolved, add more ethanol. I refluxed the mixture for 3 hours, though at least 4 hours is recommended. The smell changed a
bit but not enough to actually tell if anything had reacted.
Afterwards, the ethanol was evaporated, and the smell changed from similar to phenylethylbromide to something very different. Once all the ethanol had
evaporated, the product was extracted repeatedly with ethyl acetate. The ethyl acetate layer was slightly basic. At this point, I recommend adding a
solution of hydrochloric acid in a solvent that is soluble in ethyl acetate but in which the product is insoluble. I did not have this, so I slowly
added 30% hydrochloric acid to the ethyl acetate extract until the product precipitated as a white solid. Since there is also water in the
hydrochloric acid, some of the product will dissolve in it, which is why I added just enough for it to precipitate. You can boil some of the water
off, but adding a solution of hydrochloric acid in a solvent soluble in ethyl acetate, but in which the product is insoluble, is better. The mixture
turned violet, for some reason. The product was collected by filtration and dried with a hair dryer apparatus  .
Phenelzine HCl in a small crystallizing dish.
After drying the solid, a small sample was added to a test tube in a glycerol bath, and the melting point was analyzed by heating the glycerol bath.
The product on the sides of the test tube started to melt when the glycerol bath reached 170 °C, and it was fully melted at 175 °C, which confirms
it is the correct product, since the hydrochloride salt melts at 174 °C.
Phenelzine HCl in a test tube - not yet melted (around 120 C).
Phenelzine HCl in a test tube - beginning to melt (around 170 C).
[Edited on 14-7-2025 by Maui3]
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bnull
National Hazard
Posts: 847
Registered: 15-1-2024
Location: East Woods
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Mood: preparing copper salts and enjoying it
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Two things: (1) the reaction scheme picture is too large in comparison with the others, maybe you could re-scale it to, don't know, 50 or 60% of the
actual size; (2) you don't mention the yield of the final product.
As for the rest, it looks pretty neat.  Glad to see you finally managed to
tame the little bugger.
[Edited on 14-7-2025 by bnull]
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Maui3
Hazard to Others
Posts: 173
Registered: 9-9-2024
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Thank you bnull!
I will edit it now!
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