Niklas
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Synthesis of Modafinil
Modafinil is a narcolepsy medication exhibiting (mild) stimulant and eugeroic properties. Besides other medical uses including the prescription for
multiple sclerosis, ADHD or depression, it also finds illicit use as a cognitive enhancer (“smart drug“) as it can increase focus and productivity
in individuals. It is a somewhat rare example of a non-amphetamine stimulant, and the exact mechanism of function hasn’t been determined yet [1].
Fig.1: Chemical structure of modafinil
Synthetically I think it’s quite a fun target, and it’s a rather nice introductory multistep synthesis. The most often employed procedure starts
from benzhydrol, which is converted to diphenylthioacetamide via its isothiouronium salt followed simple oxidation to the sulfoxide [2]. As I had
neither benzhydrol nor chloroacetamide around I extended this path to include the reduction of benzophenone using zinc (sodium borohydride may of
course also be used) and the ammonolysis of ethyl chloroacetate (not included on the figure) [3][4].
Fig.2: Synthesis of modafinil from benzophenone
Chloroacetamide:
21,5 g of ethyl chloroacetate (175 mmol) (Note 1) were weighed out in a 250 ml round bottom flask and cooled below 5°C with the help of an ice-salt
bath. With strong (!) magnetic stirring 20 ml of cooled 25% ammonia (267 mmol) were slowly added dropwise, and the stirring continued for 15 more min
afterwards, during which the mixture first turned cloudy with a crystalline solid suddenly starting to precipitate. The cycle of adding 20 ml ammonia
solution (267 mmol, 534 mmol in total) and stirring for 15 min was repeated, and the flask then left to stand in the ice bath for 30 minutes. The
white precipitate of chloroacetamide was removed by vacuum filtration, washed with a small amount of dest. water, and dried in the vacuum desiccator
till constant weight. From this 12,78 g (77,9%, 78-84% lit.) of a white crystalline powder were collected melting at 118-120°C (119-120°C lit.)
Note 1: The ethyl chloroacetate was prepared by p-TSA catalyzed Fischer-esterification of chloroacetic acid and ethanol in 73% yield.
 
Fig.3-4: Synthesis of chloroacetamide
Fig.5: The collected chloroacetamide
Benzhydrol:
A 500 ml two-neck round bottom flask, equipped with a thermometer and a short air-cooled Dimroth-condenser, was charged with 30 g benzophenone (165
mmol) and 30 g of commercial zinc powder (459 mmol). 300 ml of 96% ethanol were added as the solvent, the mixture magnetically stirred, and 30 g of
sodium hydroxide (750 mmol) gradually added by removing the condenser and replacing it with a powder addition funnel. This caused the temperature to
rise to around 40°C over the course of the next couple minutes, and the mixture to take on a slight bluish tint. As soon as the temperature started
dropping again the flask was lowered into a warm water bath and the suspension then stirred at 60°C (internal temperature) for 2,5 h. Excess zinc was
removed by filtration through glass wool while hot (Note 1), the filter cake washed twice with a little boiling 96% ethanol, and the resulting cloudy
solution decanted from a little remaining zinc directly into 1,5 l of dest. water, instantly causing a white solid to separate. Things were acidified
using 90 ml of 37% hydrochloric acid, the mixture left to stand outside over night, and the crude product collected by vacuum filtration. The partly
crystalline, partly amorphous solid was washed with dest. water, pulled dry until the droprate had decreased significantly, and then recrystallized
from 96% ethanol / water, starting at 30 ml of the ethanol. Due to the tendency of benzhydrol to oil out the mixture was strongly stirred magnetically
during the cooling process until the colorless oil had solidified, and things then cooled down to -20°C in a freezer over night. The crystalline
product was again removed by vacuum filtration, washed with a little dest, water, and dried on the air in front of a fireplace (Note 2). From this
27,63 g (90,9%) of a white crystalline powder were collected appearing pure on analysis with TLC (6:1 hexane / ethylacetate). benzhydrol rf=0,33,
benzophenone rf=0,55
Note 1: It is essential to assist this process with a vacuum, as otherwise the filtration will take exceedingly long with product loss due to
crystallization inside the funnel on cooling.
Note 2: The same approach could be successfully applied for the reduction of fluorenone to fluorenol in a somewhat lower yield of 81,5% due to
mechanical losses, resulting in a white fibrous solid appearing pure on analysis with TLC. This substance interestingly exhibits eugeroic properties
as well, determined to be around 40% stronger than those of modafinil in animal tests [5].
 
Fig.6-7: Synthesis of benzhydrol
 
Fig.8-9: The collected benzhydrol and the corresponding TLC
Diphenylmethylthioacetamide:
A 250 ml round bottom flask was charged with 27,43 g of benzhydrol (149 mmol) and 13,72 g of thiourea (180 mmol) and these solids were taken up in 70
ml of dest. water by magnetically stirring the mixture. The flask was equipped with a pressure equalizing addition funnel containing 60 ml of 48%
hydrobromic acid, and set into heating block warmed to 100°C. As soon as all the benzhydrol had melted, with strong stirring, the acid was slowly
added at a rate of 1 drop per second (Note 1), during which time the cloudy mixture turned a slight yellow color. The addition funnel was then
switched out for a water-cooled Dimroth condenser, and the emulsion refluxed for 30 minutes, after which it basically looked the same. On stopping the
stirring a heavy yellow oil layer consisting of thiobenzhydrol separated, which solidified to a completely solid block on cooling over night
impossible to get out of the flask, so things were remelted by heating to a reflux and then left to cool down while stirring. The precipitated beads
of intermediate thiol were removed by vacuum filtration, washed with dest. water, and stored under argon until use. Around 50 g of crude wet
thiobenzhydrol were thus obtained as yellowish opaque beads.
These beads were crushed into a powder using a mortar and pestle , and the resulting powder transferred into a 500 ml three-neck round bottom flask
equipped with mechanical stirring and a gas adapter leading to an argon line. Under a mild stream of argon 140 ml of dest. water were added through
the empty sideneck to suspend the solid, the flask stoppered, and then lowered into a glycerol bath warmed to 65°C. On reaching this temperature the
solid started to clump a little, and a saturated solution of 7 g sodium hydroxide (175 mmol) was quickly added through the sideneck. The bath
temperature was increased to 90°C causing the solid to melt again, and eventually 7 more g of sodium hydroxide (175 mmol, 350 mmol in total) were
added as a solution to allow the thiol to fully convert to the water soluble sodium salt. After 30 min only a small quantity of a cloudy oil remained
undissolved, so the heating bath was lowered barely below the flask, the stopper again removed, and 16,88 g of chloroacetamide (181 mmol) (Note 2)
added under a stream of argon with the help of a powder addition funnel over the course of 10 min. After a short delay an off-white solid started
separating, and strong stirring was continued for 20 h (Note 3) while heating in the glycerol bath now cooled to 75°C. During this period the
precipitate turned into granular light orange solid, which was then vacuum filtered off while hot, crushed with the back of a stopper, and washed
first with cold and then with 50 ml of boiling dest. water. From this around 44 g of crude wet product was collected, which was recrystallized from
ethyl acetate, the resulting cream colored solid collected by vacuum filtration, and most of the remaining colored impurities removed by washing twice
with 50 ml of 96% ethanol each (Note 4). After drying under vacuum 27,21 g (71,6%, 78% lit.) of a slightly off-white amorphous solid were collected
melting at 110-111°C (110°C lit.).
Note 1: The procedure says to only add hydrobromic acid until the solution is completely clear, so the intermediate isothiouronium bromide doesn’t
get hydrolized to the thiol. I must have missed that endpoint somehow, but as the thiobenzhydrol would have been made in-situ in the following
reaction anyway that turned out to not be a big deal. The increased oxygen sensitivity and unpleasant, H2S-like smell (although this was barely
noticeable in the solid state) are something to consider though.
Note 2: The chloroacetamide used consists of both the sample the synthesis of which was described above and a commercial sample from TCI.
Note 3: Only a reaction time of 5 h is actually required, I just had the reaction run over night and could only work it up the following afternoon.
This extensive reaction time may be what caused the formation of the colored impurities, but that’s just a guess.
Note 4: By pulling off the ethyl acetate from the combined mother liquors and washes under vacuum a sticky orange oil remained which solidified into a
gummy solid on standing for a couple days. While this likely contained at least a couple more grams of product, it was deemed not worth the effort
purifying.
 
Fig.10-11: Synthesis of thiobenzhydrol
Fig.12: The collected thiobenzhydrol
 
Fig.13-14: Synthesis of diphenylmethylthioacetamide and the collected product
Diphenylmethylsulfinylacetamide (Modafinil):
In a 500 ml round bottom flask, standing in an glycerol bath warmed to 45°C, 26,87 g of diphenylmethylthioacetamide (104 mmol) were dissolved in 110
ml of glacial acetic acid with the help of magnetic stirring. To the resulting light yellow solution 11,5 ml of 30% hydrogen peroxide (113 mmol) were
added dropwise with the help of a graduated pipette, the flask capped with a septum, and the mixture kept in the glycerol bath with stirring for
around 17 h. The visually unchanged mixture was dumped into 400 ml dest. water, the precipitated solid removed by vacuum filtration after standing in
the fridge for a couple of hours, and the cream colored filter cake washed first with water and then twice with 25 ml ethyl acetate each, removing a
lot of of the colored impurities. The off-white solid was pulled dry on the Büchner funnel, recrystallized from methanol / dest. water, and again
removed by vacuum filtration. The same washings as before were repeated, and the crystalline product dried under vacuum till constant weight, from
which 25,68 g (90,3%, 73% lit.) of a slightly off-white powder were collected, appearing to have a less polar impurity on analysis with TLC (2:1
dichloromethane / ethylacetate) (Note 1). To hopefully remove the remaining contaminants the solid was slurried in just enough ethyl acetate to fully
cover things, the solid removed by vacuum filtration again, washed with 25 ml of additional ethyl acetate (Note 2), and again dried under vacuum. From
this 23,04 g (81%, 73% lit.; 52,7% total yield from benzophenone) of white shiny crystals melting at 161°C (161-164°C lit.) still appearing to
contain a ever so slight amount of the mentioned less polar impurity on analysis with TLC (2:1 dichloromethane / ethylacetate) (Note 1) (Note 3).
modafinil rf=0,44, impurity rf=0,58
Note 1: I personally assume this to be unreacted thioether, as no excess of hydrogen peroxide is used, and I didn’t bother determining the exact
concentration and just believed the label of the bottle. Annoyingly I didn’t keep a reference to check that, but assuming it is there shouldn’t be
much of a change in pharmacological effects as it would be metabolically oxidized to modafinil anyway.
Note 2: By boiling off the volatiles (methanol, ethyl acetate) from the modafinil containing mother liquors and washes another crop of product could
be collected that hasn’t yet been isolated and characterized.
Note 3: To afford a completely pure somewhat higher melting product the step of slurrying the modafinil in ethyl acetate may be repeated, though it
should presumably already have sufficient purity for most purposes as is.
 
Fig.15-16: Synthesis of diphenylmethylsulfinylacetamide
 
Fig.17-18: The collected modafinil and the corresponding TLC
Sources:
[1] https://www.drugs.com/monograph/modafinil.html
[2] https://erowid.org/archive/rhodium/chemistry/adrafinil.modaf...
[3] http://www.orgsyn.org/demo.aspx?prep=CV1P0090
[4] http://orgsyn.org/demo.aspx?prep=cv1p0153
[5] https://doi.org/10.1016/j.bmcl.2012.04.031
[Edited on 17-3-2025 by Niklas]
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DraconicAcid
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I think I was prescribed some of that once- it didn't work for me. But I wonder if it would make cool acac-like complexes.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Dr.Bob
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Nice job, that is a pretty nice synthesis. An extra purification would be a good idea just in case.
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Fery
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Niklas - great synthesis and thanks for sharing! Good yields, clean and very skilled work. I love these synthesis of medical substances.
I remember synthesizing benzhydrol decades ago, it was my first reaction where i used NaBH4 (but it lacked the nice blue color you experienced).
Today the only one indication for modafinil in my country is narcolepsy. In all other cases the risks are higher than benefits, so it was revoked even
in indications like idiopatic hypersomnia (being sleepy during days). It was never used for treatment of either depression nor ADHD in my country
(there are plenty of other proven and efficient substances). State Institute for Drug Control is extremely careful here.
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Mateo_swe
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Love to read these really well documented sythesis posts, very nice indeed.
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Niklas
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Thanks ya‘ll!
Today I decided that I may give the ethyl acetate slurrying another shot in hopes of removing the remaining impurity, resulting in 21,38 g of product
after drying under vacuum, with the mother liquors being added to the above mentioned crop and the ethyl acetate boiled down again (while this sample
will likely contain substantially more of the impurity it should be sufficient for testing DraconicAcid‘s idea of using it as a ligand, personally
see it working as such as well).
And while this process did end up increasing the melting point to 162-163°C, and therefore definitely helped in some way, I can unfortunately still
detect a substance with a rf of 0,58 besides the 0,44 product spot (I fucked up those values in the writeup btw, corrected them now), be it as an even
fainter spot.
I guess one could just do this washing step over and over, but at this point I couldn’t be bothered to loose even more of my product. I‘d be keen
to hear your suggestions on fully purifying the modafinil, but either way I will soon likely send it in to be tested with GCMS what should hopefully
give some clearance whether things are really just unreacted thioether and can therefore considerably be ignored.
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Dr.Bob
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You could take all of the mixed and impure material and run a quick column on it to get the bulk of the desired material pure, then combine the good
batches and try to crystallize it. That is how we do most my work. I try to get the bulk of the material from a crystallization, then col. purify
the rest, and sometimes that is pure enough to act as a great seed crystal for the bulk of the material and helps get it really pure. I have made
some materials up to 99.9% or better purity that way. But again, it depends on the use.
I have mostly made research grade materials, for in-vitro work, sometimes for animal models, but making things for humans is typically GMP work, which
is even more onerous and requires insane amounts of validation, C, analytical work and more. Only done a few things for that, and mostly let others
do the analytical work then, as I did not have validated machines in research typically. That's why I am amazed at the photos I have seen from China
and India plants where many generics were made, as few of those labs would even be considered research quality labs in the US. I think things are
mostly improving with world pressure to do better, but it often makes me feel that my quality is overkill compared to some things I have seen. And
you really would be scared to see some of the forensic data I have seen from street drugs (I have friends who work in analytical labs that look at
them.) One compound from a local bust had 17 different compounds in one drugs that was labelled as "Oxy".
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DraconicAcid
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I'm a bit surprised that basic zinc will reduce the ketone to an alcohol. Every organic class I've taken or taught uses acidic zinc to reduce a
benzylic carbonyl to an alkane.
Good to learn.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Niklas
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It’s fairly interesting indeed, I assume it only works for a rather limited scope of such heavily conjugated diarylketones though. Based on the
bluish color I would guess it to proceed via ketyl intermediate, what in itself is also quite interesting, as enough building up to produce a visible
color change without really any exclusion of water of oxygen isn’t something I would generally expect for such.
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Niklas
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Quote: Originally posted by Dr.Bob  | | You could take all of the mixed and impure material and run a quick column on it to get the bulk of the desired material pure, then combine the good
batches and try to crystallize it. That is how we do most my work. I try to get the bulk of the material from a crystallization, then col. purify
the rest, and sometimes that is pure enough to act as a great seed crystal for the bulk of the material and helps get it really pure. I have made
some materials up to 99.9% or better purity that way. But again, it depends on the use. |
Thanks for the suggestions, while I would generally prefer not to have to use a column, I guess with DCVC it may be a little less wasteful (just gotta
get the right size of silica, but I‘ve been wanting to do so soon anyway). I don’t think it matters that much honestly, as even if I do
decide to consume the modafinil it definitely wouldn’t be a daily thing but rather something I‘d only do to evaluate the effects (directly
comparing it to fluorenol may be pretty interesting honestly), but either way I‘ll wait for the analysis results first and then see how I move on
with things.
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Metacelsus
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Cool, I remember this is also possible to prepare via Bunte salt via a similar method that uses benzhydrol and chloroacetamide. https://www.sciencemadness.org/whisper/viewthread.php?tid=61...
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Niklas
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Interesting observation I made while cleaning the glassware from the thiol synthesis, in high dilution it surprisingly smells quite nice, kinda
fruity, probably best compared with grapefruit. Very much resembles the smell of thioterpineol to me
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Fery
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Great that you observed grapefruit scent!
It could be something similar to:
p-Menth-1-ene-8-thiol
http://foodb.ca/compounds/FDB014423
2-Bornanethiol
https://pubchem.ncbi.nlm.nih.gov/compound/2-Bornanethiol
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