Author Topic: The Making of Modafinil  (Read 8667 times)

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Antoncho

  • Guest
The Making of Modafinil
« on: April 27, 2003, 09:26:00 PM »
Here's our hosting fee for the month ;)  :P  ;) .

This outstanding job has been done by Fomalhaut and Dionket, The Lazy and The Lazier of HyperLab :) .






I noticed this beast in Rh's archive quite a long time ago - the structure's pretty simple and seems easy to assemble. However, the synth itself was a lil bit (here follows an untranslatable obscene neologism, literary meaning 'cunning asshole-ish' :) ). But recently I plugged this word into Rambler (RuNet search engine) and what I saw really knocked off my pants! Over 200 docs, each one pathetically elated: turns out that our friend is an ideal cure from sleepiness, a pronounced nootropic, makes super-soldiers from ordinary people :)  and so on and so forth...

So the decision was fast: make it and taste it!

As I said above, the method of synthesis on Rh's was a bit too much of a pain, so the Consilium of The Lazy and The Lazier, after some thinking, delivered The Quick And Easy Synth Of Modafinil! That's how it went...
 
 



2-benzhydryl-sulfanylacetamide.

Diphenylbromomethane (4,95g = 0.02 moles) and thiourea (1,52g=0.02moles) were refluxed in 20mls water for 30mins. As the synth from Rh's says, a clear solution must have been formed in 5 mins, but in the end we still had a lot of oil at the bottom (the reasion to blame was old, semidecomposed diphenylbromomethane - when we opened the can, it emitted HBr). We were too lazy to separate the oil , so 2.5g (0.04moles) KOH in 15mls water was added straight and the reflux continued for 30 more mins. A disgusting stench filled the lab.

Thus obtained solution of potassium salt of diphenylmercaptane was cooled to 50-60 C and 1.9g (0.02moles) of chloroacetamide was added thereto. The mixtr was left to its own devices for 2hours - the precipitated oil crystallized. The xtals were filtered, washed thrice w/water, thrice w/ether (removing all benzhydrol). After drying there was obtained 1.9g (37%) of  finely divided crystals with mp of 111 C.

With fresh diphenylbromomethane this will give not less than 80% - otherwise I'll bee a reddish (this is an idiom which I am again unable to translate :) ).


Modafinil

Into the solution of 3.6g benzhydrylsulfanylacetamide (0.014moles) in 15mls of GAA there was added 3mls (~0.03moles) 30% hydrogene peroxide. The mixture was left at RT (15 Ñ in our case, better not to heat above) for 20 hrs. Then into the solution there was added 30mls aqua, scratching the walls with a glass rod. After 1 hr the precipitate was filtered, washed w/water twice, then w/ether and dried. Yield - 2,3g (61%), mp - 158-159 C. After some time the mother liquor yielded some more product but we were too lazy to work it up.






The bioassay was positive and quite interesting. Anyone wants to check this out?




Antoncho


P.S. Chloroacetamide synthesis:

http://orgsyn.org/orgsyn/prep.asp?prep=cv1p0153


foxy2

  • Guest
The bioassay was positive and quite ...
« Reply #1 on: April 27, 2003, 09:47:00 PM »
The bioassay was positive and quite interesting.

Care to elaborate?

LiquidGaia

  • Guest
from the good drug guide....
« Reply #2 on: April 28, 2003, 12:32:00 AM »
"...modafinil ('Provigil') is a memory-improving and mood-brightening psychostimulant. It enhances wakefulness and vigilance, but its pharmacological profile is notably different from the amphetamines, methylphenidate (Ritalin) or cocaine. Modafinil is less likely to cause jitteriness, anxiety, or excess locomotor activity - or lead to a hypersomnolent 'rebound effect' - than traditional stimulants. Subjectively, it feels smoother and cleaner than the amphetamines too.

        Current research suggests modafinil, like its older and better-tested analogue adrafinil, is a safe, effective and well-tolerated agent. It is long-acting and doesn't tend to cause peripheral sympathetic stimulation. Yet its CNS action isn't fully understood. Modafinil induces wakefulness in part by its action in the anterior hypothalamus. Its dopamine-releasing action in the nucleus accumbens is weak and dose-dependent; the likelihood of dose-escalation and tolerance is apparently small. Modafinil has central alpha 1-adrenergic agonist effects i.e. it directly stimulates the receptors. More significant, perhaps, is its ability to increase excitatory glutamatergic transmission. This reduces local GABAergic transmission, thereby diminishing GABA(A) receptor signalling on the mesolimbic dopamine terminals.

        Modafinil is proving clinically useful in the treatment of narcolepsy, a neurological disorder marked by uncontrollable attacks of daytime sleepiness. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins. Orexin neurons are activated by modafinil. Orexinergic neurons are found exclusively in the lateral hypothalamic area, but their fibers project to the entire central nervous system. Genetically modified orexin-knockout animals offer a model of human narcolepsy.

         Experimentally, modafinil is also used in the treatment of Alzheimer's disease, depression, attention-deficit disorder, myotonic dystrophy, age-related memory decline, idiopathic hypersomnia and everyday cat-napping.

        Prudence, however, should be exercised in drastically curtailing one's sleep. Prolonged sleeplessness weakens immune function. Animals tortured in sleep-deprivation experiments eventually die from massive bacterial infections of the blood..."
----
hopefully is of some help. very interesting chem though


Chimimanie

  • Guest
Starting materials
« Reply #3 on: April 28, 2003, 12:40:00 AM »
Please note that chlorodiphenylmethane or benzhydrol+KBr+H2SO4 can bee used as starting material too.

And yes, chlorodiphenylmethane must bee distilled before use, especially if the chemical is trouble and has a depressed melting point.

Has someone got a cloroacetamide synthesis starting from cloroacetic acid?

Antoncho, how were the effects?

Modafinil should bee stimulating in the 300-400 mg range, but nootropic in the 90-100 mg.

Antoncho

  • Guest
The complete synthesis of Modafinil
« Reply #4 on: May 03, 2003, 08:58:00 AM »
Dear Bees!

Beelow you can see the synth of Modafinil from scratch – using essentially benzyl chloride and chloroacetic acid as starting ingredients. It was actually performed quite recently by our comrades Fomalhaut and Dionket, so you can ask any additional questions you want. Compliments are also much welcome :) .

The original can bee found at

Post 430070 (missing)

(Fomalhaut: "Ñèíòåç Ìîäàôèíèëà îò À äî ß", Russian HyperLab)
.






1. Diphenylmethane.
SOP (Syntheses of Organic Preparates) v.2, p. 233

Into a 5-liter flask equipped w/a RC and a S-shaped tube connected to a addition funnel there’s placed 10g amalgamated Al grit (Note 1) and 2000g (2.3 L, 25.6moles) of benzene, which has been dehydrated by distillation (discarding the initial turbid portion). Benzene is heated to boiling, then heating removed and 500g of benzyl chloride are added at such rate that the soln continuously boils (Note 2). HCl is evolved. After the addition’s over (usually ~1hr) the mixtr is heated for 10-15mins or until HCl evolution stops. Upon cooling the solution is decanted from some tar (Note 3), washed w/5% NaOH and water. After drying w/CaCl2 benzene’s removed and the residue vac distilled , collecting: 125 C/10mmHg, main fraction 125-130 C/10mmHg, up till 150 C. Redistillation of 1st and 3rd fractions gives some additional qtties of the product which are pooled w/2nd fraction. The latter is frozen, the small qtty of unfrozen oil is decanted from the xtals.
The yield is 330-350 g (49.5-52.5%), mp 24-25 C

Notes:

1.   Aluminium grit washed w/ether for defatting is stirred for several mins in 5% aq HgCl2, quickly washed w/water, then MeOH. Used immediately.
2.   Occasionally the rxn takes some time to start. Initially one adds not more than 50-60g and the mixtr is heated until appearance of  HCl indicates the beginning of the rxn. If one adds too much BzCl at once the contents of the rxn may bee thrown out onto the ceiling.
3.   In this same flask containing aluminium and traces of tarry byproduct one may conduct several more syntheses, in which case no initial delay of the rxn is observed.


2. Diphenyl bromide.
Of our own device

Into the solution of DPM (84g, 0.5moles) in 300mls CCl4 bromine (25.8mls, 0.5moles) was added in small portions under UV lamp irradiation and temperature of ~60-70 C. The end of the addition funnel should bee immersed into the liquid, the deeper is the better. Each subsequent portion was added after discoloration of the previous one. To prevent loss of
bromine with HBr stream a RC with a double (?) was used. After the last portion’s color was gone, the mixtr was cooled, washed w/ice water, sat. cold aq NaHCO3, and once again icewater. Dried over CaCl2 and rotovapped off the solvt.
The remaining oil upon cooling solidified into a light-yellow xtalline mass. Yield of crude product – 105%, it was used w/out further purification. Should bee used as soon as possible (begins to smoke after 24hrs in a fridge).


3. Ethyl chloroacetate
Titze & Eicher, p. 576

A soln of 40g (887mmole, 50mls) EtOH, 47.3g (500mmole) chloroacetic acid and 2g tosic acid in 100mls CHCl3 is refluxed for 5hrs with a water-removing trap. The rxn mixtr is allowed to cool, washed w/water, sat. NaHCO3, brine and dried over Na2SO4. The solvt is stripped off, the residue vac distilled – yield 47.3g (72%), èç 73-74 Ñ/50mmHg


4. Chloroacetamide
SOP v.1, p.476

Into a 2L RBF equipped w/a mech stirrer immersed in a icebath there’s placed 215g (1.75moles) ethyl chloroacetate. At 0-5 Ñ and energetic stirring there’s added 200g of well chilled aq. NH3 (d=0.9). The mixtr is stirred in the cold for 15mins, then another 200mls aq. NH3 is added and stirring cont’d for 15 more minutes. The mixtr is allowed to stand for 30mins, the precipitated product is filtered and washed twice with 2x100-120mls water. The yield of air-dried product is 128-138g (78-84%), mp 118-199 C, traces of moisture depress mp very significantly.


5. 2-Benzhydrylsulfanylacetamide.

130g (~0,5moles) of crude diphenylmethylbromide was boiled in 500mls water with 0,5moles thiourea and further treated with alkali (1.25moles NaOH) and chloroacetamide (0,5moles) as described in

Post 429898

(Antoncho: "The Making of Modafinil", Novel Discourse)
. The yield of product was 80g (62% counting on starting diphenylmethane).

There was one difference though. Addition of DPM-bromide into the thiourea soln was carried not in one portion, but rather by dissolving the stuff in 60-70mls IPA and dripping it into the boiling mixtr thru an addition funnel. Upon which the rxn mixture assumed bright blue color  :)  ::)  :)  and Dionket had an hysterical seizure :)  fearing that all was lost. Happily, that wasn’t the case. After 10min reflux almost all DPM-Br dissolved, after addition of alkali color disappeared and an oil precipitated.


6. Modafinil

80g of 2-benzhydrylsulfanylacetamide in 400mls GAA was oxidized with 60mls (approx. 2x xcess) 30% hydrogene peroxide at 10-15 C. Addition of H2O2 causes significant warming, good cooling was required. Better not heat it above 15 C – it will overoxidize to the sulfone. Reaction time is ~20hrs. After dilution w/water to 1,5L and filtering there was obtained 76g (89%) of crude Modafinil. Rextallization from MeOH (~1 liter) gave 36g (43%) of product – since we are greedy, obviously we’re going to evaporate the mother liquor to get out the rest ;) , but this haven’t been done as of now (the lab’s closed – it’s May Holidays in Russia).






As far as the subjective effects are concerned, I was going to translate Dionket’s comments  but found two excellent threads on the Hive :

Post 253501 (missing)

(PapaSmerck: "Modafinil Experiences?", General Discourse)
&

Post 385999 (missing)

(methadist: "Provigil", General Discourse)
in which this subject is covered completely. Sounds similar to our comrades’ experience in every respect (xcept they used dosages of 200mgs).


It appears to bee an ideal upper without noticeable side-effects and addictive properties. Personally I'd give very much for an opportunity to have some or make some :)  In Russia, they don't even sell it on prescription :(







Antoncho

Chimimanie

  • Guest
Thank you russian bees!
« Reply #5 on: May 03, 2003, 10:49:00 AM »
Thank you russian bees!

Fomalhaut and Dionket have done a very good work, that is much appreciated ;D .

I have just another synthesis of ethyl chloroacetate to share, i have it at hand so here it is:

Ethyl chloroacetate:
A mixture of 65g of A. R. monochloroacetic acid, 95g of absolute ethyl alchohol, and 11g of concentrated sulphuric acid was refluxed for 36 hours. This yielded, when worked up as above (one wash sodium hydrogenocarbonate, one wash water, dried on MgSO4 and fractionated by distillation), 65g of pure ethyl chloroacetate, bp 142°C/751mmHg.
ref: J Chem Soc 1948, 647

And to be completely OTC, chloroacetic acid can bee made from hydrolysis of trichloroethylene by H2SO4 followed by distillation, but I have not a ref here, sorry.

...and benzhydrol can be made from sodium dithionite reduction of benzophenone as well.

All by all you guys have made a great work, thanx again hyperlab ;) .

Polverone

  • Guest
chloroacetic acid from trichloroethylene
« Reply #6 on: May 10, 2003, 02:22:00 PM »
From Ullmann's Encyclopedia:

Equal amounts of trichloroethylene and 75 % sulfuric acid are reacted at 130 – 140 °C in a continuous process so that with complete trichloroethylene conversion, the resultant reaction mixture contains about 50 % chloroacetic acid and 1 – 2 % water. This blend is vacuum distilled to give pure chloroacetic acid. During this process the vapors are washed with water, which is returned to the sulfuric acid as a diluent. The resultant hydrogen chloride gas is washed with the fresh trichloroethylene and then purified by freezing and absorbing in water.



Is that enough info to go on? I personally find this quite interesting, as I have a number of chloroacetic acid uses in mind and this seems a lot nicer than bubbling chlorine through a mixture of hot, irradiated acetic acid and phosphorus...

Edit: Whoops, there is one thing that gives me pause: I don't have a convenient way to conduct reactions under pressure, and the BP of TCE at 1 atm is about 87 C, well below the temperature employed above. But perhaps with extended reflux it can still be done without a pressure vessel. I can hope, anyway.




ClearLight

  • Guest
UV Irradiation?
« Reply #7 on: May 10, 2003, 07:05:00 PM »
Was this carried out in quartz glass or overhead illumination?


Chemikaze

  • Guest
Sulphur
« Reply #8 on: May 10, 2003, 11:24:00 PM »
Is that enough info to go on? I personally find this quite interesting, as I have a number of chloroacetic acid uses in mind and this seems a lot nicer than bubbling chlorine through a mixture of hot, irradiated acetic acid and phosphorus...


You could use sulphur instead of phosphorous to yield chloroacetic acid.


Polverone

  • Guest
I don't like chlorine
« Reply #9 on: May 11, 2003, 08:15:00 PM »
It's mostly the idea of generating and using liters of Cl2 that I find unpleasant. That and the fact that I'd end up with a mixture of chloroacetic acids instead of pure monochloroacetic. I'm attempting the hydrolysis of TCE with H2SO4 now at moderate (below TCE BP) temperatures. The mixture has acquired a definite odor of chloroacetic acid (yuck) but it's going slow and the acid has turned black. It almost makes me wish I wasn't starting with hardware store materials.  :P


Chimimanie

  • Guest
Hi everyone! :-) I just found a great patent...
« Reply #10 on: May 15, 2003, 02:38:00 PM »
Hi everyone! :)

I just found a great patent on the same pathway, but even better since it start from benzhydrol.

Those guyz got a 90%+ yield from benzhydrol to the diphenylmethanethioacetamide with 95% purity in 2 steps! 8)

They synthetise the bromide in situ and react it with thiourea in a one pot reaction (even better: it is very scalable!). Then they react the salt with chloroacetamide (by generating the thiolate in situ). They filter, wash and get an excellent yield with a good purity of the thioacetamide.

They synth 200g batch in a 2L vessel, solvent is water with ethyl acetate for the recrystallisation, truly, this is the way to go! ;D  (if the patent is not bunk :o ).

Final yield of modafinil, after recrystallisation is 125g, 67% from 130g benzhydrol. 8)  :P
 

Patent US2002183552



This is a part of the experimental section:

Preparation of isothiouronium Salt (IV).

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux {106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.

Preparation of diphenylmethylthioacetamide.

A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water {700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added. The reaction mixture was heated to 85°C and stirred until all the solid was dissolved. Then, it was cooled to 60°C and chloroacetamide (80 g, O.84 mole, 1.2 eq.) was added in five portions hour at 60-70°C during one hour. The suspension is stirred at 70°C for 4-5 hours. The mixture was filtered while warm and the cake was washed with hot water (250 ml). Diphenylmethylthioacetamide crude wet is obtained [220 gr., HPLC assay: 78%, HPLC purity: 95%, yield: 95% (from diphenylmethanol.)]

20 gr. of the product was recrystallized twice from ethyl acetate, dried in vacuo to give 15 gr. of pure title compound.

Preparation of Modafinil.

A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained above and glacial acetic acid (610 mL). The mixture was heated to 40°C and stirred until full dissolution is achieved. 5.8% H2O2 solution (500g, 1.2 eq) was added dropwise during 0.5 hours at 40-45°C. The reaction mixture was stirred at 40-45°C for 4 hours. Then sodium metabisulfite (18.3g) in 610 mL water was added in order to quench the unreacted H2O2 and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15°C and filtered. The cake was washed with water (610 mL) and dried on air to obtain crude wet Modafinil (205 g). Reslurry in refluxing ethyl acetate, followed by recrystallization from methanol:water (4:1) solution afforded pure Modafinil [125 g, HPLC assay: 99.9%, HPLC purity: 99.9%, yield: 67% (from diphenylmethanol)]. :P  


 

;D

xeno_tropic

  • Guest
Modafinil
« Reply #11 on: September 22, 2003, 09:21:00 AM »
I found it a whole bunch of no fun.
Awake, but no recreational aspect.
Awake for quite a while.
There are similar compounds called Unifiram and Sunifiram, one of the derivatives looks even simpler to make than Modafinil (#9 in the synth ref). These are active s.c. in the sub-milligram range.

Antoncho

  • Guest
Clarification?
« Reply #12 on: September 22, 2003, 09:49:00 AM »
>There are similar compounds called Unifiram and Sunifiram, one of the derivatives looks even simpler to make than Modafinil (#9 in the synth ref). These are active s.c. in the sub-milligram range.

May i very humbly inquire what it means? What synth ref?

Very interesting, to say the least.



Antoncho

P.S. Of course, Modafinil isn't recreationally active, this is the whole point of it: to stay awake when there's such a need and not to get addicted/not to fuck up one's brain etc.

Which is quite something, given the fact that many of Hive bees have unlimited supplies of 'traditional' stimulants :)

thallium

  • Guest
There are similar compounds called Unifiram...
« Reply #13 on: September 22, 2003, 12:15:00 PM »
There are similar compounds called Unifiram and Sunifiram

I fail to see the similarities between two "racetam"-nootropics and modafinil/adrafinil.

Structure of unifiram and sunifiram:

http://www.bentham.org/sample-issues/cpd8-2/gualtieri/fig4.gif



Also, read

http://www.bentham.org/sample-issues/cpd8-2/gualtieri/gualtiei-ms.htm

and

Medline (PMID=12070754)

.


myodyne

  • Guest
What is the common thing?
« Reply #14 on: September 24, 2003, 02:12:00 PM »
I wonder why these new piracetam analogues are similar with Modafinil in action

They are considered CNS stimulants apart from cognition enhancers? I cannot believe that..

There is an exception to the rule of piracetam analogues : oxiracetam (hydroxy-piracetam) seems to have psychostimulant activity... 

Synthesis of Oxiracetam:

Patent US4118396


Lilienthal

  • Guest
Modafinil and Ro 01-6128
« Reply #15 on: October 07, 2003, 08:45:00 AM »
Hey, what do you think about this one:

Modafinil:











Molecule:

modafinil ("NC(CS(C(C2=CC=CC=C2)C1=CC=CC=C1)=O)=O")


Ro 01-6128:











Molecule:

Ro 01-6128 ("O=C(C(C2=CC=CC=C2)C1=CC=CC=C1)NC(OCC)=O")



The latter one is a positive allosteric modulator of metabotropic glutamate receptors (mGluR1)!

Proc. Natl. Acad. Sci. USA. 98(23): 13402–13407 (2001):
Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site.

Medline (PMID=11606768)


DOI:

10.1073/pnas.231358298


http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11606768

(free full-text)

psilocin

  • Guest
Nitrogen atmosphere
« Reply #16 on: November 07, 2003, 10:42:00 PM »
Much respect for bringing these novel routes up.
Nootropics seem to have much potential for the efficiency seekers. 

I was wondering about the nitrogen.
What's the oxidation potential for the reaction or does the nitrogen serve some other purpose.


In regards to the sertraline - are we talking about some analog? Alpha 1 adrogenic agonist vs. SSRI? mmm.. [?]
I'm not sure which potential was had in mind regarding this compoud. My experience showed mimimal antidepressant activity and lot's of  anxiety.




A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water {700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added.


:)  :)  :)


Chimimanie

  • Guest
No need of nitrogen
« Reply #17 on: November 08, 2003, 05:54:00 AM »
It works just as great without the nitrogen (most patents do not use it at all), its only an hydrolises of the thiouronium salt to the thiolate. You just have to put the salt, NaOH and heat till you got a trouble solution, with no more solid material floating around.

The following SN2 is a breeze too.  8)

Sometime a blue solution can bee obtained, it is nothing to worry about. In the final step, you just have to filter off the solid which did not dissolve when the crude thioacetamide is put in the GAA/H2O2, bee4 crashing the soluble one with water.

Do not forget to slurry the modafinil in EtOAc and then recrystallize it from aqueous MeOH, as the crystalline shape of modafinil is important for the kinetic and quality of effects, at least according to

Patent EP0966962

and

Patent US2002043207

.

psilocin

  • Guest
testing the purity
« Reply #18 on: November 24, 2003, 11:56:00 PM »
Any success with the methods mentioned?
Any potential difficulties one might face?
I'm concerned with potential inpurities.

Which method would one use to test the purity of the compound?
I understand IR is the most productive.[?] Is there spectrum
 for this compound available for reference or how would one
verify the spectrum ?



;)

Antoncho

  • Guest
Success stories
« Reply #19 on: November 25, 2003, 02:14:00 AM »
Fallen Angel has successfully made Modafinil by Fomalhaut's method. He experienced some difficulties with bromination - says all of the apparatus must bee strictly glass and some peroxide is needed to effectively shift the rxn towards the radical mechanism. Apart from that, all worked fine, just as described.

Assholium successfully made Modafinil by the method from the patent found by Chimimanie. It turned out there was a mistake in the original text:

Preparation of isothiouronium Salt (IV).

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux {106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.


The quantity of HBr stated here is excessive and leads to complete hydrolysis of the initially formed isothiouronium salt. The acid should bee added until the rxn mixtr turns completely clear (about half as much as the patent says). Sort of titration :)  Further addition will result in precipitation of heavy stinky oil, diPh-methyltiol.


It was generally agreed that the second route, starting from benzhydrol, is much simpler and is thus the preferred pathway of synthesis.

Benhydrol itself can bee conveniently made:

a) from benzaldehyde and PhMgBr
b) from benzophenone (FC benzoylation of benzene) followed by reduction with, say, Al isopropylate.


Hope someone finds it useful.


Antoncho

psilocin

  • Guest
Antoncho - you guys are great!
« Reply #20 on: November 25, 2003, 02:27:00 AM »
Antoncho - you guys are great!
I apreciate all the information, especially the mistake you identified in the patent.
 It it might have caused major confusion and alot of headaches for me and others, I suppose. 


Regarding the benzhydrol -   it is available if one cares to look.

Recent research revealed a quote of 25$ / KG .
You just have to find the big quantity supplier. This one seemed to care to offer small amount as well.

Of course, it's easier to make some yourself in some cases.
  8)


psilocin

  • Guest
Titration..
« Reply #21 on: January 17, 2004, 04:38:00 PM »
well well..
i thought i would look into this further!
I quick question for antoncho:
With the given initial quantity for HBr at 260mL,
i suppose 130 mL would be sufficient?
When exactly does one stop adding HBr?
Does "complete clear" mean that emulsion dissapears as well? Or are we simply clearing up the watery part?


Antoncho

  • Guest
Can't say more than that.
« Reply #22 on: January 17, 2004, 11:27:00 PM »
Unfortunately, i have no firther details about this. I just translated Assholium's translation to the word. He didn't specify the actual qtty of acid.



Does "complete clear" mean that emulsion dissapears as well?

Well, to me it looks like that.


Antoncho

Vitus_Verdegast

  • Guest
enantiomers of modafinil
« Reply #23 on: May 11, 2004, 03:57:00 PM »
Synthesis and determination of the absolute configuration of the enantiomers of modafinil
Thomas Prisinzanoa, John Podobinskia, Kevin Tidgewella, Min Luoa and Dale Swensonb

Tetrahedron: Asymmetry 15(6), 1053-1058 (2004)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/modafinil.enantiomers.pdf)
DOI:

10.1016/j.tetasy.2004.01.039



a Division of Medicinal & Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242-1112, USA
b Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242, USA


Abstract
The asymmetric synthesis of both enantiomers of modafinil, a unique CNS stimulant with a reduced abuse liability, is described. This approach effectively prepares modafinil on a multigram scale in several steps from benzhydrol. The described synthetic route has also been used to produce the more water soluble analogue, adrafinil. X-ray crystallographic analysis on (-)-(diphenylmethanesulfinyl)acetic acid has determined the absolute configuration to be R.


Graphical Abstract




Stereochemistry Abstract



(S)-(+)-(Diphenylmethanesulfinyl)acetic acid
C15H14O3S


[alpha]D22 + 40.2 (c=1.11, MeOH)
Source of chirality: resolution via diastereomeric salt formation with (R)-(+)-alpha-methylbenzylamine
Absolute configuration: S


methyl_ethyl

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Moda?nil: A Novel Facile Synthesis
« Reply #24 on: July 28, 2004, 09:02:00 PM »
Anti-Narcoleptic Agent Moda?nil and Its Sulfone: A Novel
Facile Synthesis and Potential Anti-Epileptic Activity

Nithiananda Chatterjie, James P. Stables, Hsin Wang, and George J. Alexander
Neurochemical Research, Vol. 29, No. 8, August 2004 (© 2004), pp. 1481–1486



Abstract:

We report a facile procedure to synthesize racemic moda?nil (diphenylmethylsul?nylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Moda?nil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of moda?nil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of moda?nil is also nontoxic and almost as effective as an anticonvulsant as the parent.

Experimental

Diphenylmethylthioacetic Acid (3)
Benzhydryl bromide (14.78 gm, 0.059 mole) was dissolved in 75 ml of acetone in a 250-ml round-bottomed ?ask. To this solution was added dropwise sodium mercaptoacetate (6.59 g, 0.058 mole) in about 60 ml of H2O; the mixture was stirred under N2 for 2 h at room temperature and was thereafter warmed at about 60–70°C for 1 h. The reaction mixture was evaporated to dryness and taken up in CH2Cl2 and saturated aqueous NaHCO3. The organic extract was rejected, and the aqueous phase was treated with acid to pH 2 and chilled. Suction ?ltration gave the 6.9 g of the acid (3, 46%), mp 125°C. Rf  0.2. Recrystallization from MeOH/H2O gave mp 126–128°C.

Diphenylmethylthioacetamide (4)
Diphenylmethylthioacetic acid (19.5 g, 0.076 mole)
in 114 ml of dry benzene was taken in a 250-ml roundbottomed
?ask attached to a re?ux condenser, under N2 gas. To this was added thionyl chloride (19.5 ml, 0.097 mole) with a dropping funnel. The mixture was stirred at room temperature with a magnetic stirrer and re?uxed for 1 h. Thereafter, the mixture was evaporated under low pressure to give a yellow oil that was taken up in about 100 ml of CH2Cl2 and ?ltered to yield a clear orange solution. This was chilled in ice water and added slowly to an ice-cold solution of concentrated NH4OH in H2O (40:40 ml). The ensuing mixture was stirred for 1 h and shaken well in a separatory funnel. The organic layer was dried (Na2SO4) and evaporated to dryness to give 14.39 g (54%) of the amide (4), mp 108–109°C (lit2 110°C). Rf  0.8. Recrystallization from CH3OH/H2O gave mp 109–110°C.

Diphenylmethylsul?nylacetamide (moda?nil, 1)
Diphenylthioacetamide (3.46 g, 0.013 mole) was  taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30% H2O2 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was ?ltered under suction and washed with ice-cold water to give 1.5 g of white crystals (43%), mp 159–160°C. Rf  0.6. Recrystallization from hot MeOH gave mp 161–162°C

Diphenylmethylsufonylacetamide (2)
Diphenylmethylthioacetamide (2.5 g, 0.009 mole) (reg. No. 118779-53-6) was dissolved in about 12 ml of glacial acetic acid and 3 ml of 30% H2O2 and set aside overnight (16 h or more). The next day, the mixture was diluted with 100 ml of H2O and set aside to cool in the refrigerator. Upon ?ltration and drying, 2.1 g (80%) of 2 was obtained as a white powder. Rf  0.89. The melting  point of sample after recrystallization from absolute EtOH was 195–197°C.

One aspect of our preparation of moda?nil needs further mention. When diphenylmethylthioacetamide (4) is being oxidized by H2O2, care must be taken to keep the reaction mixture cool, and workup should be done in a timely manner. Allowing the reaction to go to 24 h or longer at room temperature results in the formation of the sulfone (2). The paper by Mu et al. (3) does not discuss this possibility. In our hands, the procedure stated therein led to the higher melting sulfone and not the moda?nil. Our NMR data for the newly prepared moda?nil preparation are in consonance with the data of the patented commercial product. It should be noted that the methylene protons in moda?nil are geminally
coupled and appear as a pair of doublets. This is due to the fact that the adjacent sulfoxide moiety is chiral, and therefore the methylene protons adjacent to it wind up being diastereotopic with different chemical shifts and coupling. In the sulfone 2, the methylene protons appear as a singlet due to the fact that the adjacent sulfone moiety is achiral, thus making the two protons equivalent. Moda?nil 1 is, however, an equal mixture of enantiomers, as in the reported patent and publication (2,3).
 

RESULTS
The chemical pathway leading to moda?nil may be
represented in Scheme 1.


see pdf for further information and references,

:)

m_e