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]

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.