Sciencemadness Discussion Board - Pyrimethamine Synthesis?

Pyrimethamine Synthesis?

Assured Fish - 31-1-2016 at 20:06

Ok so Im sure everyone has heard or read about the scandle involving Daraprim and how the CEO of a pharmaceutical company (not sure which one) mr Martin Shkreli raised the price of the drug from $13.50 a pill to $750 a pill making it even more expensive than cocaine. Now this happened back in September so Im sure the price has gone back down to something reasonable but I decided to do some quick research into the drug and found that its actually a medicine used to treat or prevent certain protozoan infections. It is used i believe as an anti malaria pill as well but how it treats people with immune deficiency disorders like HIV is that it helps to treat a parasite called Toxoplasma gondii which infects humans with a condition called Toxoplasmosis. Toxoplasma gondii is that weird little parasite that has a life cycle between cat and mice that works by making the mice more attracted to cats so then the mouse is more likely to be eaten by a cat and so allowing the life cycle to continue. Toxoplasmosis is also well known to affect humans in a normally non lethal way and maybe even affect there habits somewhat making people more attracted to cats and resulting in something i like to call crazy cat lady syndrome, of coarse this might not actually be true and is subject to more research but if you have an immune deficiency disorder it may cause the parasite to become lethal and cause potential problems.

Basically i want to synthesize this compound, not because i live in a tropical country with malaria but because i really fucken want to and it might be fun although it might be a wile before i am able to do the experiments.

Ive done a bit of research into how i would go about synthesizing this compound and have thought about starting from aspartic acid and this other compound that i am having alot of trouble naming but i thought it was a phosphic acid methyl glycine or something similar to acetamide which you can see in this first image number 2.

From what i understand the ATCase is an enzyme that uses phosphoric acid as a leaving group but i want to do a similar reaction only using a different leaving group in an amination to yield Carbamoyl aspartic acid which could then be dehydrated into 4,5-dihydroorotic acid, im not sure what leaving group would work in this fashion and i will need a bit of help on the reaction.

Next my idea was to carry out a Arndt-Eistert reaction using ethanediazonium which is kinda scary because its an azide. I was wondering if the Arndt-Eistert reaction had to used specifically a chloride or could it be substituted with another halide and if so can phosphorous tribromide be prepared using white P instead of red P?
I would then follow that up with a decarboxylation to yield 4-ethyl-2,6-dioxo-1,3-diazinane or 4,5-dihydroorotic acid with an ethyl group instead of a carboxylic acid.
(sorry cant find a picture)

From 4-ethyl-2,6-dioxo-1,3-diazinane i would carry out a reductive amination although i dont want to use AlHg for this because theres 2 ketones to reduce and this i think will reduce my yields to something stupid, so i have some platinum and i was wondering if there is a way to carry out a hydrogenation using Adams catalyst (since thats easy to prepare) at standard pressure without using a pipe bomb apparatus?

Then im not sure if it would be a better idea to carry out an oxidation of the pyrimidine ring using a platinum catalyst to reform the double bonds before halogenating the 5 position or to do the oxidation after.

The next step would be the halogenation of the 5 position on the pyrimidine structure but im not sure what halogenating agent would do that without attacking the ethyl group on the 6 position.

My simple and perhaps stupid idea was to then perform a grignar reaction with bromobenzene and then chlorinate the para position on the benzene ring to yield
5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine.

Now it might be smarter to change the order of some of these reactions to prevent some side reactions but i think ive done pretty good so far, also is there a better way to attach the benzene ring to the 6 position that doesn't involve using a halide so that i could instead chlorinate the benzene ring before hand and increase the yield a little bit?

I might have been a little inconsistent with my naming but i think its all correct, i apologize for the lack of pictures but i don't have a cord to connect my phone to my computer to upload photos of my drawings.
Here is where i got some of my information i cant be bothered doing proper references.

https://en.wikipedia.org/wiki/4,5-Dihydroorotic_acid

https://en.wikipedia.org/wiki/Toxoplasma_gondii

http://www.drugs.com/cdi/pyrimethamine.html

https://en.wikipedia.org/wiki/Arndt%E2%80%93Eistert_reaction

http://www.cdc.gov/parasites/toxoplasmosis/health_profession...

Cheers Assured Fish

795px-Synthesis_of_carbamoyl_aspartic_acid.svg.png - 13kB

[Edited on 1-2-2016 by Assured Fish]

Metacelsus - 1-2-2016 at 08:30

There are much easier ways (and I also see numerous problems with your scheme).

Consider starting from (4-chlorophenyl)acetonitrile, as in this paper: http://pubs.acs.org/doi/abs/10.1021/ja01152a060

halogen - 1-2-2016 at 10:49

To me, the funny thing about the pyrimethamine is, according to the synthetic scheme on wikipedia, aside from the starting material (4-chlorophenyl)acetonitrile, the precursors are relatively simple and mandane. No, that's not the funny thing, that's the setup to the punchline. I phrased it wrong. The funny thing is that unsubstituted phenylacetonitrile is a recognized precursor to amfetamine: there are probably a number of 'meth labs' with stock of this compound right now.

If the 4 chlorination works well, or if the 4-dechloro pyrimethamine is effective (which is not necessarily likely! some times, that one little change makes a terribly big difference) then there is potential for a hilarious situation where charitable 'meth cooks' can contribute to the public good. Not saying it's likely, it would just be amusing.

Tsjerk - 1-2-2016 at 14:07

Halogenation of an unsubstituted phenyl ring is quite hard, at least without destroying the rest of the molecule .. Also I'm pretty sure the not chlorinated version of this drug is not going to be effective in any way.

clearly_not_atara - 1-2-2016 at 18:18

Quote:

then there is potential for a hilarious situation where charitable 'meth cooks' can contribute to the public good. Not saying it's likely, it would just be amusing.

You would probably not be able to accomplish this before someone else fixes the price issue, you know? Even if you could, you can't distribute this, and I would recommend against using it.

In any case, the requisite 4-chlorophenylacetonitrile might be obtained by an Ullmann-Goldberg-type reaction between p-dichlorobenzene (mothball) and acetonitrile with CuI and a strong base.

Dr.Bob - 1-2-2016 at 19:11

The drug is available from many compounding pharmacies with a prescription, the FDA has said that it will allow that due to the issues surrounding the current drug source. The active ingredient is available cheap from two companies to pharmacies. So eventually people will find cheaper sources. TCI sells it for $113/5g.

I do hope that Shkreli ends up in jail, as he is a greedy bastard. But the price will come down eventually, once some other generic suppliers get through the FDA process. Shkreli tried to make that difficult, but they can't stop other companies for but so long. If Turing goes bankrupt, then other companies will be much less likely to try such crap. And if enough people write their congressperson, then they can fix the mess they made in the laws to allow such crap. Shkreli is no more a scientist trying to cure disease than Bernie Madoff.

zed - 2-2-2016 at 14:50

This scandal is no more odious than than the story of Harvoni. The ingredients were developed to a certain extent with the aid of U.S. taxpayer money. After several buyouts, the material is now controlled by the Giliad corporation.

Harvoni has become the method of choice for treating Hep C.. If you can afford it. Other wise, you can eventually die, unlamented.

It runs about $1000 dollars per tablet in the U.S.. Over 100,000 dollars for the 12 week course.

The tablets can be manufactured for about a dollar each. And, the initial investments have already been recovered. No relief in sight. At least in the U.S., where the company has spent freely on lobbying efforts.

Trust me, in most of the rest of the world, the price is much, much, lower. Especially so in India. The Indian government saw the need for the drug, and the scale of the price raping the original manufacturers were engaging in, and they flat out refused to issue an Indian patent. No patent, equals, no proprietary rights....equals the product entering the public domain. A free for all.

In India, the course of treatment, costs about a thousand dollars. Period.

The inventor has a right to make money. Lots of it. But, at a certain point, a reasonable government will exercise the right of eminent domain.

Sorry! Too important to the public health. We are buying you out.

[Edited on 2-2-2016 by zed]

[Edited on 2-2-2016 by zed]

AvBaeyer - 2-2-2016 at 19:08

Zed,

The pricing strategy in pharma , as you probably know, has little to do with cost of product development and production. These costs, despite what we are told, are quite low overall. The price is set by "value to the patient/customer" as determined by marketing studies. That often means how much will you, the patient, pay to not die. Of course much of the ultimate cost is born by insurance, ie. the rest of us. Consequently, at least in the US, the patient never is really faced with the real bill for treatment. That is why in large part drug costs in the US are so high.

AvB

Dr.Bob - 3-2-2016 at 07:05

Harmoni is somewhat different. There are many other treatments available, most of which are not as good or effective, but people don't die overnight of Hep C, it is mostly harmless until it creates chronic problems. But delaying treatment for a while has little effect. And the drug will come off patent eventually and be much cheaper. But Gilead did spend a lot to to the clinical trials, which now cost millions to billions of dollars, so they do deserve some ability to recoup their investments, but I will agree that they are charging too much, but as new treatments come out (and they are coming quickly), the price will fall quickly, which is why they are in such a hurry to make something before the drug becomes obsolete. And little if any government money was used for the R & D on it. So that is the way that things should work, only the prices have become too high now.

Daraprim was discovered by Burroughs Wellcome (by Nobel prize winners, Elions and Hitching), a drug discovery group owned by a charitable trust, many years ago, and was sold at nearly cost for many years. When BW started becoming financially untenable, their board sold the company to Glaxo, who paid a lot for it, and the new Glaxo-Wellcome was able to continue discovering new drugs, but did raise prices to allow the company to grow better. The Wellcome trust went from being worth about a billion dollars into a fund worth over 10 billion in a short time, which shows that perhaps charitable trusts are not good at running pharma companies, as they now fund far more medical R & D than they ever did before. But that is a whole other story.

The drug went off patent many years ago, but since the market was so small in the US, no generic company was willing to go through the FDA process to sell it in the US. Eventually GW, (then GSK) sold the marketing rights to Daraprim to another company, which sold it again, each time the new buyer raised prices. Then Turing bought it, and using a loophole in FDA process, found a way to hold off generics, while also raising the price to levels way above what it is worth, and he did not do any R & D with that money, only used it to pay off his previous Ponzi scheme victims... So that case is a combination of no real CURRENT R & D prices, loopholes to prevent generics, and greed. If Daraprim was a newly discovered drug, it would be allowed some market exclusivity as an orphan drug, but it is not new, so that should not be the case. But the US drug laws have many complex bits and pieces than Turing is trying to use to create a loophole. That could be fixed easily or the FDA can just allow compounding pharmacies to sell it, which they have done.

CuReUS - 5-2-2016 at 06:43

let us stick to the chemistry rather than debating on what and what not the drug companies should do

atara is the only one till now to propose a route for the synthesis of the starting compound , p-choroacetonitrile(although there is no reference to back it up)
It would be good if someone found out a route to make the nitrile starting from styrene.But sadly,even though I searched a lot,I couldn't find a route to make p-chlorostyrene directly from styrene

Tsjerk - 5-2-2016 at 14:49

I would suggest making 4-chloro-toluene, partially oxidizing that to the aldehyde, making the cyanide out of that and go from there. Long way but doable without a industrial setup

If you can do the first step on a multi-molar scale the rest is reasonably doable.

Metacelsus - 5-2-2016 at 20:29

If you have 4-chlorotoluene, you could also try brominating it to 4-chlorobenzyl bromide, and then reacting that with a cyanide salt. This might be a better way than trying to selectively oxidize to the aldehyde.

However, 4-chlorotoluene isn't available to the amateur chemist (although it is for registered businesses; VWR sells it at $123/kg).

Edit:
One amateur-feasible route to 4-chlorotoluene would be from 4-toluidine by a Sandmeyer reaction.

You could also try directly chlorinating toluene with a Lewis acid catalyst, but you'd have to separate the various products.

[Edited on 2-6-2016 by Cheddite Cheese]

Assured Fish - 5-2-2016 at 22:54

Apologies for not replying sooner

Quote:

Cheddite Cheese

posted on 2-2-2016 at 04:30
There are much easier ways (and I also see numerous problems with your scheme).

Consider starting from (4-chlorophenyl)acetonitrile, as in this paper: http://pubs.acs.org/doi/abs/10.1021/ja01152a060

This is probably an easier way to go about although i still wanna make some 4,5-dihydroorotic acid which could then be used to make different pyrimidinediamine analogs.

Quote:

Tsjerk

posted on 2-2-2016 at 10:07
Halogenation of an unsubstituted phenyl ring is quite hard, at least without destroying the rest of the molecule .. Also I'm pretty sure the not chlorinated version of this drug is not going to be effective in any way.

Thanks if i follow my route i will oxidize the ring before attempting to attack the 5 position.

I have no intention of synthesizing this drug to sell it or make profit i was just interested in its antimicrobial properties and its synthesis.

I am guess you are all referring to this route.

I dont really know much about the synthesis of guanidine and triethyl orthoformate, but i guess you just throw sodium in methanol to precipitate sodium methoxide (sounds like fun) but for the synthesis of (4-chlorophenyl)acetonitrile could you not chlorinate aniline then separate the o-chloroaniline, then react p-chloroaniline with sodium or potassium nitrate and HCL followed by copper cyanide.

Nitro benzene to benzylamine_1401441909432.png - 76kB

And for the synthesis of 4,5-dihydroorotic acid i was thinking of synthesizing bromocarbamoyl like so
COBr2 + NH3 -----> CH2ONBr
COBr2 being carbonyl bromide
CBr4 + H2SO4 -----> COBr2
Acording to Wiki carbon tetrabromide is used in the plastic and rubber industry but i still wouldnt know where to purchase it ( i live in new zealand) it could again be synthesized but im not sure how i would go about doing this. Alternatively if i can make phosphorous tribromide from white P then i could react sodium carbonate with ammonia and then with HCL to precipitate NaCl then react with PBr3.

Could i use Polyphosphoric acid/Pyrophosphoric acid to dehydrate the N-carbamoyl aspartic acid to dihydroorotic acide?

Cheers Assured Fish

[Edited on 6-2-2016 by Assured Fish]

CuReUS - 6-2-2016 at 05:44

Quote: Originally posted by Tsjerk

I would suggest making 4-chloro-toluene, partially oxidizing that to the aldehyde, making the cyanide out of that

how would you make the cyanide from the aldehyde ?

Quote: Originally posted by Cheddite Cheese

If you have 4-chlorotoluene, you could also try brominating it to 4-chlorobenzyl bromide, and then reacting that with a cyanide salt. This might be a better way than trying to selectively oxidize to the aldehyde.

but keep in mind that the benzylbromide would be a tear gas and working with cyanide could be dangerous( and also quite hard to get in some places)
if tsjerk can convert the aldehyde to cyanide,then one could easily get the aldehyde from toluene using MASON

Quote: Originally posted by Assured Fish

but for the synthesis of (4-chlorophenyl)acetonitrile could you not chlorinate aniline then separate the o-chloroaniline, then react p-chloroaniline with sodium or potassium nitrate and HCL followed by copper cyanide.

you would get benzonitrile not phenylacetonitrile

Quote:

And for the synthesis of 4,5-dihydroorotic acid i was thinking of synthesizing bromocarbamoyl like so
COBr2 + NH3 -----> CH2ONBr
COBr2 being carbonyl bromide
CBr4 + H2SO4 -----> COBr2

won't carbonyl bromide have toxicity similar to phosgene ?

[Edited on 6-2-2016 by CuReUS]

halogen - 6-2-2016 at 12:17

Chlorine is a bit unreactive for these types of things, atara, or not atara... While hydrogen is no substitute for chlorine, perhaps bromine is? In that case, though it would not be a simple procedure to hit benzene with iron bromide and extra bromine, these are all things that threads on sciencemadness have dealt with successfully. The reaction with copper acetonitrile is then considerably more likely to work.

Assured Fish - 6-2-2016 at 15:28

Quote:

Quote: Originally posted by CuReUS

you would get benzonitrile not phenylacetonitrile

Damn i wasn't paying enough attention. Ok this is tedious and putting in two extra steps and twice the reagents but you could reduce the benzonitrile to the benzylamine and then again react with copper cyanide and HCL.

zed - 6-2-2016 at 15:46

Well, if you could easily obtain p-chloro-phenylalanine, you might be able to deconstruct that molecule to produce your desired starting material.

Or, P-chlorobenzaldehyde is pretty cheap. Reduce it with isopropylalcohol to
P-chloro-benzylalcohol. Convert it to the benzylchloride, and thence to the nitrile.

[Edited on 7-2-2016 by zed]

clearly_not_atara - 6-2-2016 at 17:34

Quote:

Chlorine is a bit unreactive for these types of things, atara, or not atara... While hydrogen is no substitute for chlorine, perhaps bromine is? In that case, though it would not be a simple procedure to hit benzene with iron bromide and extra bromine, these are all things that threads on sciencemadness have dealt with successfully. The reaction with copper acetonitrile is then considerably more likely to work.

I think the best alternative, if you assume you can just buy shit, would be to chlorinate phenol with something mild like NCS, then react with Tf2O, and use that for the Ullmann reaction. However, I think dichlorobenzene deserves a try -- chlorine is a good EWG, which makes this more reactive than a monochlorobenzene. Here's a patent for example using p-dichlorobenzene in the Ullmann reaction at 165 C:

http://www.google.com/patents/US4766253

Quote:

In U.S. Pat. No. 3,472,782 and U.S. Pat. No. 3,371,120, 1,4-dichlorobenzene is reacted with 3-chlorophenolate at 165° C. under CuCl/KI catalysis to give 3,4'-dichlorodiphenyl ether.

It reacts once, but not twice, since the product is less electron-deficient and thus less reactive. And acetonitrilate is probably way more reactive than m-chlorophenolate (less steric hindrance, much more basic).

EDIT: Attached is a review of the Ullmann condensation with a number of such reactions on aryl chlorides; it appears that carbanions are highly active in the reaction, so much so that we might be concerned with over-alkylation.

Attachment: rossi2004.pdf (2.7MB)
This file has been downloaded 943 times

EDIT 2: I found a paper discussing mono-alkylation of p-dichlorobenzene specifically, via electrochemistry:

http://pubs.acs.org/doi/abs/10.1021/jo00106a009

[Edited on 7-2-2016 by clearly_not_atara]

CuReUS - 7-2-2016 at 06:27

Quote: Originally posted by Assured Fish

I am not sure that would work

Quote: Originally posted by zed

Well, if you could easily obtain p-chloro-phenylalanine, you might be able to deconstruct that molecule to produce your desired starting material.

I found a reference for making the nitrile with 2-aryl amino acid ,but not phenylalanine

,( they even use p-chloro derivative as one of their substrates to get a good yield of 86% )
https://www.thieme-connect.com/products/ejournals/abstract/1...

Quote:

Or, P-chlorobenzaldehyde is pretty cheap. Reduce it with isopropylalcohol to
P-chloro-benzylalcohol. Convert it to the benzylchloride, and thence to the nitrile

an MPV reduction,not bad ,but don't you think it would be easier to do a cross cannizaro with formaldehyde to get the alcohol

.Then IMHO, it would be better to tosylate it rather than convert it into halide for the CN substitution

Quote: Originally posted by clearly_not_atara

I think the best alternative, if you assume you can just buy shit, would be to chlorinate phenol with something mild like NCS, then react with Tf2O, and use that for the Ullmann reaction.

calm down atara,how will using phenol help us get phenylacetonitrile ? how will you convert the notorious -OH group to CH₂CN ?

Quote:

EDIT: Attached is a review of the Ullmann condensation with a number of such reactions on aryl chlorides; it appears that carbanions are highly active in the reaction, so much so that we might be concerned with over-alkylation.

In this review,there are references for the reactions of aryl halides with cyanomethyl anions and the results are quite bad

(although they are not ulmann reactions )

http://pubs.acs.org/doi/abs/10.1021/jo00963a012 (31% yield of acetonitrile with chlorobenzene)

http://pubs.acs.org/doi/abs/10.1021/jo01329a015 (17% yield)
and these reactions are radicle based(like ulmann),so an EWG in the ring would decrease the yield furthur

EDIT: I followed zed's idea and I think I have found an OTC source of p-chloro phenylalanine .Apparantly its a drug called fenclonine
https://raypeatforum.com/community/threads/affordable-source...

you can get p-chloro phenylacetonitrile from that using this reaction
http://www.sciencemadness.org/talk/viewthread.php?tid=32534

[Edited on 8-2-2016 by CuReUS]

[Edited on 8-2-2016 by CuReUS]

zed - 13-2-2016 at 14:12

Might be better routes, but I have read of Benzaldehydes being reduced to BenzylAlcohols, in Quantative yield by excess Isopropyl Alcohol, under pressure.

The conversion of Alcohol to Halide is well documented, as is that of Halide to Nitrile.

Involves Na/K CN, which demands care, but it is do-able.

Most of us are familiar with the idea of degradation/decarboxylation of amino-acid to nitrile, but I find no references.......where folks claim to have reproduced the original experimenters results, with good yields.

P-Chloroaniline has some potential as a starting material. It is cheap.

But perhaps the path is too convoluted. DiazoniumBromide+ Ethylacrylate (anhydrous conditions)=Cl-C6H4-CH2CH(Br)COOEt. Treat with ammonia, hydrolyse, decarboxylate/dehydrate....To produce the PhenylAcetonitrile.

Oh, nevermind. Now that I have actually written it out, it seems cumbersome. Too many steps, equals too low an overall yield.

[Edited on 13-2-2016 by zed]

halogen - 16-2-2016 at 20:20

I like the PDCB route very much, at least, I like the aspect of it that it involves PDCB. Acetonitrile is obtained, if impure, by pyrolysis of acetamide, which means every component besides time would be readily available to the inhabitants, thus illustrating (though perhaps not demonstrating, for reasons of health and safety) the value of chemical education. This is probably why Nurdrage has set the compound as his goal, andhe could be reading the very thread.

If PDCB does not prove to be a good substrate (the latter two papers deal with a radical mechanism, which I didn't think was how the ullmann coupling works ordinarily, but maybe I'm wrong) for whatever reason, for example, if heat/time is used to force the chlorine, the acetonitrile might be reprotonated by the product first forming a diphenylacetonitrile; C6H4ICl would probably most simply be made via the grignard reagent of dichlorobenzene and I2... but PhCl, PhICl2 by decomposition, and maybe terephthalic acid mercury salt (if the "double" hunsdieker reaction works as well as with benzoate), etc.

A book has suggestions on the topic of aryl iodide installation:
https://books.google.com/books?id=BPcxrmIgLKMC&pg=PA631

Zed's para-chlorophenylalanine would be the most elegant solution.
aka. (thanks, google!) https://en.wikipedia.org/wiki/Fenclonine
"a selective and irreversible inhibitor of tryptophan hydroxylase... It has been used experimentally to treat carcinoid syndrome, but the side effects, mostly hypersensitivity reactions and psychiatric disturbances, have prevented development for this use. It is used in scientific research in humans[4] and animals[2] to investigate the effects of serotonin depletion."

I love the internet. You know are ancestors couldn't do anything like this? My love and amazement might seem strange unless you consider that. None of em. For millions of years. Back the time of the dinosaurs. Even the Flintstones only had television.

[Edited on 17-2-2016 by halogen]

clearly_not_atara - 17-2-2016 at 16:12

I've looked at references and there seem to be some issues with using acetonitrile directly, in fact it's very common to see Ullmann reactions featuring the tetrakis(acetonitrile)copper(I) complex. In Ullmann reactions featuring this complex you never see the alkylation of acetonitrile, and because the acetonitrile anion is prone to polymerization it might not be very efficient to use bases strong enough to deprotonate it. Most studies featuring the anion of acetonitrile use it at -78 C or colder and require a superbase like nBuLi. In fact there are essentially no references to the Ullmann reaction using a carbanion nucleophile to displace an aryl chloride, which suggests that it only occurs with nitro-substituted arenes, if at all.

However, it does appear that both p-bromochlorobenzene and p-iodochlorobenzene undergo the desired reaction, which is tantalizing. There are other reactions that feature the alpha-arylation of nitriles with aryl chlorides, such as this:

http://onlinelibrary.wiley.com/doi/10.1002/anie.200351954/fu...

but they all require complex catalysts.

[Edited on 18-2-2016 by clearly_not_atara]

Delta - 23-2-2016 at 15:51

Quote: Originally posted by CuReUS

if tsjerk can convert the aldehyde to cyanide,then one could easily get the aldehyde from toluene using MASON
[Edited on 6-2-2016 by CuReUS]

Forgive me, but what is MASON. I have heard of partial oxidation of toluene to benzaldehyde using chromyl chloride or chromic anhydride/acetic anhydride, but not MASON.

clearly_not_atara - 23-2-2016 at 21:04

Quote:

calm down atara,how will using phenol help us get phenylacetonitrile ? how will you convert the notorious -OH group to CH2CN ?

In the post I had said "Tf2O" which was a joke, but upon consideration the Appel reaction can be used with triphenylphosphine and sulfuryl chloride which aren't entirely out of reach, certainly if you plan on doing anything at the scale that would be required to affect the pyrimethamine market you should probably be able to source TPP. In particular this means that you could convert tyrosine to the nitrile and use the Appel.

https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/fi...

CuReUS - 24-2-2016 at 03:09

Quote: Originally posted by clearly_not_atara

I've looked at references and there seem to be some issues with using acetonitrile directly... In fact there are essentially no references to the Ullmann reaction using a carbanion nucleophile to displace an aryl chloride, which suggests that it only occurs with nitro-substituted arenes, if at all.

However, it does appear that both p-bromochlorobenzene and p-iodochlorobenzene undergo the desired reaction, which is tantalizing.

I am sorry to say atara,but you seem to be talking in riddles.One moment you say alkylation with carbanion is not possible,and the next moment you say that its possible in dihalogenated arenes.
if there were no references on the alkylation with acetonitrile,how did you know it would work ? was it your own idea ? then you should have mentioned that .
pls post the references here .

Quote:

Most studies featuring the anion of acetonitrile use it at -78 C or colder and require a superbase like nBuLi.

I don't see why this should be a problem . -78'C is difficult to achieve , but its possible and nBuLi is cheap

Quote: Originally posted by Delta

Quote: Originally posted by CuReUS

if tsjerk can convert the aldehyde to cyanide,then one could easily get the aldehyde from toluene using MASON
[Edited on 6-2-2016 by CuReUS]

Forgive me, but what is MASON. I have heard of partial oxidation of toluene to benzaldehyde using chromyl chloride or chromic anhydride/acetic anhydride, but not MASON.

MASON is an acronym i made for the electrolytic oxidation of toluene to benzaldehyde because I kept on forgetting the name of the salt used.It stands for Manganese Ammonium perSulphate electrolytic OxidatioN
http://www.sciencemadness.org/talk/viewthread.php?tid=2223&a...

Quote: Originally posted by clearly_not_atara

Quote:

calm down atara,how will using phenol help us get phenylacetonitrile ? how will you convert the notorious -OH group to CH2CN ?

In the post I had said "Tf2O" which was a joke, but upon consideration the Appel reaction can be used with triphenylphosphine and sulfuryl chloride. In particular this means that you could convert tyrosine to the nitrile and use the Appel.

Hmmm, appel reaction didn't come to my mind but now that you mention it,it sounds like a superb idea . a member recently mentioned the appel reaction in his post. And the funniest thing is that acetonitrile is used as a solvent in the appel reaction,so we might be able to use the nitrile we get from tyrosine as the solvent itself

(just kidding)
http://www.sciencemadness.org/talk/viewthread.php?tid=63182#...

the tyrosine route might be the next best thing after fenclonine

[Edited on 24-2-2016 by CuReUS]

clearly_not_atara - 25-2-2016 at 17:34

Quote:

if there were no references on the alkylation with acetonitrile,how did you know it would work ? was it your own idea ? then you should have mentioned that .

I saw it in a paper while I was doing research on the question a few days ago, but I didn't save the reference because I didn't think that p-bromochlorobenzene was a reasonable intermediate anyway. p-dichlorobenzene was unreactive but p-bromochlorobenzene had an (iirc) 40% yield. I don't remember the conditions either, for what it's worth. I've just spent quite a while looking for it and I can't find it again, sorry. (aaaaaargh!!)

[Edited on 26-2-2016 by clearly_not_atara]

CuReUS - 23-5-2016 at 23:01

I was thinking about this synthesis and it dawned upon me that the reason we got stuck was because all of us kept p-choro phenylacetonitrile as our target compound from the get-go instead of thinking about other routes.
I think there might be an easier approach which bypasses the phenylacetonitrile

we could monoarylate malononitrile using p-chlorobromobenzene and then react the p-chloro-2-phenylpropane dinitrile with 1 mole of ethylMgBr,which would be slowly dripped into the flask containing dinitrile under vigorous stirring.

ref for the monoarylation- SYNGENTA PARTICIPATIONS AG Patent: WO2004/50607 A1, 2004
(they use bromobenzene,but I think p-chlorobromobenzene would also work)

Assured Fish - 29-5-2016 at 00:32

Quote:

I was thinking about this synthesis and it dawned upon me that the reason we got stuck was because all of us kept p-choro phenylacetonitrile as our target compound from the get-go instead of thinking about other routes. I think there might be an easier approach which bypasses the phenylacetonitrile we could monoarylate malononitrile using p-chlorobromobenzene and then react the p-chloro-2-phenylpropane dinitrile with 1 mole of ethylMgBr,which would be slowly dripped into the flask containing dinitrile under vigorous stirring. ref for the monoarylation- SYNGENTA PARTICIPATIONS AG Patent: WO2004/50607 A1, 2004 (they use bromobenzene,but I think p-chlorobromobenzene would also work)

But the malonitrile would also attack the chloride leaving us with side reactions such as 2-(4-phenyldipropane) dinitrile and 4-bromo-2-phenylpropane dinitrile.

CuReUS - 29-5-2016 at 01:37

first of all,thank you so much for reviving the thread,I thought it died

Quote: Originally posted by Assured Fish

But the malonitrile would also attack the chloride leaving us with side reactions such as 2-(4-phenyldipropane) dinitrile and 4-bromo-2-phenylpropane dinitrile.

that is a possibility,but keep in mind that the bromine is a better leaving group and if the concentration of dinitrile was kept at a minimum,this side reaction could be avoided.After all,there are many reactions where Br in the ring reacts more preferentially compared to Cl.Infact,atara's first idea(condensation between acetonitrile and p-chlorobromobenzene) used this very logic

anyways,after some thinking,I realised that this too is not a good route because the dinitrile is not easy to obtain.Until now,atara's tyrosine idea is the only one that is good enough IMHO
If only triphenylphosphine could be made from OTC chemicals

[Edited on 29-5-2016 by CuReUS]

A high school synthesis of Daraprim

sparkgap - 15-6-2017 at 16:45

It apparently hasn't been posted on this thread, but recently some Australian students tried a relatively safer (than the patented synthesis) method for synthesizing pyrimethamine. Their notes can be found here.

sparky (~_~)

Assured Fish - 15-6-2017 at 19:22

@sparkgap somebody should probably give this to NurdRage, It appears the kids added a third methylation step as well as using potassium tert-butoxide instead of sodium methoxide in the second step to form 2-(4-chlorophenyl)-3-oxopentanenitrile.
I remember hearing about this and brushing it off as if the kids just went out and bought the benzylnitrile and followed the patent.
The old always underestimate the young.

Dr.Bob - 16-6-2017 at 17:47

The kids were directed by a trained chemist, they did not just randomly do this. But it is a great learning experience, and shows both that the compound is not only practical to make, and the process can be improved, most likely, to be better, but it also teaches some of the non-science aspects of the problem.

zed - 24-4-2021 at 18:40

Well, it has been a while, but I did stumble across a paper related to this topic today.

A decent yield of P-chloro-aniline, from Acetanilide. It utilizes TCCA.

Recent reports of Aniline being readily produced by the decarboxylation of PABA, with this report of easy Para Chlorination of Acetanilide add up to an easier synthesis of this material.

Now coupling the Diazonium salt of that Chloro Aniline, to produce the Amino-Acid isn't a certainty, but it is helpful if you can easily and cheaply make the precursors..

https://www.scielo.br/pdf/qn/v31n1/a30v31n1.pdf

Translation:

To a suspension of acetanilide (0.68 g, 5 mmol) in H2SO4 conc. (6.0 mL) in a 25 mL Beaker, kept under magnetic stirring in an ice bath, between 0 and 4 ° C, trichloroisocyanuric acid (0.52 g, 25 mmol). After 15 min, the reaction solution was poured into a Beaker containing approximately 50 mL of ice (Scheme 1). The formed precipitate was vacuum filtered in a Büchner funnel and recrystallized in a water / ethanol mixture (70:30). Para-chloroacetanilide was obtained, after recrystallization, in 56% yield and characterized by melting point: 178 ° C (literature 178-179 ° C) and spectroscopic data from IR, 1H NMR and 13C NMR.

Hydrolysis of para-chloroacetanilide
In a round-bottom flask connected to a reflux condenser, 1.76 g of para-chloroacetanilide and 10 mL of 70% (w / w) solution of H2SO4 were added. The mixture was refluxed for 40 min and poured, still hot, into 50 ml of cold distilled water, followed by the addition of 40 ml of 20% NaOH aqueous solution (or enough to precipitate precipitate). White). The white precipitate formed was vacuum filtered in a Büchner funnel and washed with ice water (Scheme 1). Para-chloroaniline was obtained in 56% yield and characterized by the melting point 72 ° C (literature 72.5 ° C) and the data of IR, 1H NMR and 13C NMR.

RESULTS AND DISCUSSION
Electrophilic halogenation of aromatic compounds is a widely studied reaction in organic chemistry. It occurs through an electrophilic substitution, with the attack on the electrophile by the electrons of the pi connection of the aromatic ring. The slow reaction step is the formation of the Wheland cationic intermediate, which then loses a proton, to restore aromaticity. The entry of the electrophile is governed by the nature of the substituent that is attached to the aromatic ring.
In the case of chlorination of acetanilide, the substitution can occur in the ortho and para positions, due to the increase in the electronic density of the ring conferred by the NHAc activator group. It was observed by gas chromatography that only the monochlorinated product in the position for the aromatic ring was obtained from the precipitate formed, after the reaction was poured over ice. However, after neutralizing the acid solution with aqueous NaOH solution and proceeding with the extraction of the aqueous phase with ethyl acetate, the presence of the monochlorinated product in the ortho- (dashes) position was verified by GC-MS and dichlorinated product, in addition to para-chloroacetanilide.
When the acidic aqueous phase obtained after washing with water is concentrated by heating, fine crystals in the form of reddish needles form on the bottom of the beaker. The infrared spectrum showed that these are crystals of isocyanuric acid 6.
It is possible to increase the yield of para-chloroacetanilide if the acid solution of the chlorination reaction is neutralized with sodium hydroxide and then extracted with ethyl acetate. It is necessary to
However, it is necessary to recrystallize the solid formed twice with a water / ethanol mixture (70:30), to remove ortho-chloroacetanilide and 2,4-dichloroacetanilide. This procedure results in a total yield of 62% of pure para-chloroacetanilide.

CONCLUSION
This work shows a new possibility of using trichloroisocyanuric acid, a cheap and easy-to-handle reagent. This can be used, successfully, for the chlorination of aromatic systems activated in experimental classes of Chemistry and Pharmacy courses.
Because it is a very fast reaction, it allows the student to synthesize, recrystallize and hydrolyze para-chloroacetanilide to para-chloroaniline in the same class.
Chlorination of acetanilide with ATCI or the commercial product Genclor has numerous advantages over N-chlorosuccinimide and N-chlorosaccharin. In addition to being a very low price reagent (R $ 6.00 - 200 g), it is more selective for obtaining the chlorinated product in the para position and, after neutralization, the saline solution can be discarded without major concerns.

[Edited on 25-4-2021 by zed]

[Edited on 25-4-2021 by zed]