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Author: Subject: Pyrimethamine Synthesis?
CuReUS
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[*] posted on 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 :D :D (just kidding)
http://www.sciencemadness.org/talk/viewthread.php?tid=63182#...

the tyrosine route might be the next best thing after fenclonine :o

[Edited on 24-2-2016 by CuReUS]
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clearly_not_atara
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[*] posted on 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]
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CuReUS
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[*] posted on 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)
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Assured Fish
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[*] posted on 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. :(
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CuReUS
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[*] posted on 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]
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thumbup.gif posted on 15-6-2017 at 16:45
A high school synthesis of Daraprim


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 (~_~)




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[*] posted on 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.
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[*] posted on 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.
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