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Author: Subject: Better synthesis route to Favipiravir anyone?
Dr.Bob
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[*] posted on 19-3-2020 at 08:54
Better synthesis route to Favipiravir anyone?


The drug Favipiravir is reported to be useful in treating coronacirus, according to public reports, and scientific papers.

https://www.yahoo.com/news/japanese-flu-drug-appears-effecti...

https://www.theguardian.com/world/2020/mar/18/japanese-flu-d...

It may be available in some quantitites, but the routes I find in Scifinder are horrible, and hard to make in simple conditions, or from easy starting materials. This would be a great target for some brainstorming, however, be aware that if you come up with a great route and publish it here, it would be come public domain, so you might not get rich, but you would be very poipular with other people and the world. So just a thought.

The structure is linked below, from wikipedia,

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

Here are some reactions below to make it I could find:

I am happy to test out anything that looks promising, if I can get the starting materials. Pyrazines are not common, so a route starting from commodity chemicals would be great. But I will try to find any SM I can.



Attachment: Favipiravir Syntheses.pdf (1.5MB)
This file has been downloaded 117 times

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clearly_not_atara
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[*] posted on 19-3-2020 at 10:25


I suspect that this reaction will be extremely difficult regardless of the chosen method of preparation. Adding that fluorine is not easy. For example, the synthesis of the desfluoro compound is available in one step from aminomalondiamide and glyoxal:

http://wprim.whocc.org.cn/admin/article/articleDetail?WPRIMI...

but it took the researchers a lot more steps -- protections and deprotections -- to achieve the necessary fluorination. The synthesis of this compound has been a high-value target for a while!

EDIT:

Ullmann reaction of glyoxylamide with 1-fluoro-2-iodoethylene should result in N-fluorovinylation. See:
https://pubs.acs.org/doi/10.1021/ol035355c

Reaction of this with ammonia and sodium cyanide gives the Strecker aminonitrile -- this is the Strecker amino acid synthesis. See attached picture.

Reaction of the complicated thing with Br2/NEt3 will result in addition to the alkene, Sn2 amine addition and then dehydrobromination to give 3-cyano-5-fluoro-2-pyrazinone.

Selective hydrolysis of this nitrile with H2O2 gives favipiravir.

1-fluoro-3-aza-4-oxo-5-amino-5-cyanopentene.png - 6kB

EDIT2: It may appear that 1,2-bromofluoroethylene would be cheaper. However, bromine monofluoride cannot be isolated. Iodine monofluoride should react with acetylene at appropriately low temperatures (-78 C) to generate the relevant crosslinker.

[Edited on 19-3-2020 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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Dr.Bob
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[*] posted on 19-3-2020 at 15:13


That's a great example of some ideas. I am curious to look at the des-fluoro, as there are some newer ways to install fluorine coming out now, as well as the idea of the bottom reaction. I don't expect us to cure a disease, but this will certainly increase demand for favipiravir, at a time when it may be hard to get from China or India.

So as chemists, this is one of the things we can do to help society. I would ask about making the Gilead drug, remdesivir, but it is one of the more complex pharma compounds I have ever seen, even in the antivirals, which are commonly tough. So I don;t think it will be easy to scale up without major facilities. But favipiravir looks much more approachable and also appears to work against many viruses, so maybe more useful. So thanks.
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CuReUS
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[*] posted on 20-3-2020 at 13:13


1.Synthesis of 2-hydroxypyrazine - https://pubs.acs.org/doi/10.1021/ja01126a070

https://patents.google.com/patent/US2805223A/en

2.Duff reaction on 2-hydroxypyrazine-https://en.wikipedia.org/wiki/Duff_reaction

3.P-flourination - https://www.sciencedirect.com/science/article/abs/pii/S00221...

4.Direct conversion of aldehyde to favipiravir - https://www.thieme-connect.com/products/ejournals/pdf/10.105...



favipiravir.png - 3kB

EDIT - Instead of doing a duff reaction in step 2,we can do a Reimer–Tiemann reaction with CCl4 to get the acid directly.Then the last step would be done with just NH3 and TCT (TCT might not be required if the COOH gets converted to COOF during the flourination :D)

[Edited on 21-3-2020 by CuReUS]
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clearly_not_atara
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[*] posted on 20-3-2020 at 16:58


CuReUS: elemental fluorine seems a bit bold for a substrate bearing an aldehyde. Likewise for a substrate bearing an amide. Maybe form a cyclic acetal? Of course, elemental fluorine always seems bold...



[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 21-3-2020 at 06:00


Quote: Originally posted by clearly_not_atara  
CuReUS: elemental fluorine seems a bit bold for a substrate bearing an aldehyde. Likewise for a substrate bearing an amide. Maybe form a cyclic acetal?
Are you suggesting the aldehyde would be turned into a diflouro compound ? In that case,we will be able to hydrolyse it back during the workup and no protection would be required.
But what happens to amides when they react with flourine ?
I found some papers on the electrochemical fluorination of organic compounds
https://link.springer.com/article/10.1023/B:RUJO.0000036072....

https://pubs.rsc.org/en/content/articlelanding/2011/cc/c1cc1...
Quote:
Of course, elemental fluorine always seems bold...
Desperate times call for desperate measures :(
But this paper suggests some ways to tame F2 - https://www.sciencedirect.com/science/article/abs/pii/S00221...

1.Using Flourodec for generating F2
2.Diluting it with N2
3.Using strong protic solvents like H2SO4 or HCOOH
Quote: Originally posted by clearly_not_atara  
the synthesis of the desfluoro compound is available in one step from aminomalondiamide and glyoxal
I wonder if we could p-flourinate that using the paper I linked to get favipiravir ?

[Edited on 22-3-2020 by CuReUS]
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[*] posted on 21-3-2020 at 12:13


Does anyone have a full synthesis of remdesivir? Not because I want to produce it but because i can't find it.. I'm a bit sick. Me and my girlfriend are quarantined because we scored a 100% symptoms. We are fine though.
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[*] posted on 21-3-2020 at 12:40


Quote: Originally posted by Tsjerk  
Does anyone have a full synthesis of remdesivir? Not because I want to produce it but because i can't find it.. I'm a bit sick. Me and my girlfriend are quarantined because we scored a 100% symptoms. We are fine though.

https://newdrugapprovals.org/2020/03/12/remdesivir-%e3%83%ac... scroll down a little and you'll find synthesis and patents
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[*] posted on 21-3-2020 at 14:24


Tsjerk if you and your gf are not elderly and do not have other serious diseases you have very good chances that your immunity destroys every infection faster than you synthesize the antiviral compound
your last sentence is very good sign - "we are fine though"
these special medicals usually require advanced factory/lab equipment




If there is a heaven, it seems not to be materially based. Does chemistry exist there and if yes, how does it look like? Are there good souls well supplied with laboratory equipment, glass, chemicals and information?
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clearly_not_atara
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[*] posted on 24-3-2020 at 17:32


So I thought a bit more about the route I posted.

Unfortunately, glyoxylamide is not commercially available. It also might not be very stable considering the tendency of aldehydes to react with primary amides -- an equilibrium, but glyoxylates are very reactive aldehydes. And I'm not sure that the N-vinylation conditions will tolerate aldehydes. However, I had forgotten that they do tolerate amines.

So instead we start with ethyl glyoxylate and sodium cyanide with an excess of ammonia in ethanol. The aminonitrile forms first, and then the ester undergoes aminolysis. This should give mostly the stable 2-cyanoglycinamide, which can then be N-fluorovinylated with 1,2-iodofluoroethylene.

In the third step I think it would be most advantageous to start with the ammonium salt in some polar solvent (that isn't easily oxidized) and add one equivalent of bromine, which will add to the alkene, followed by base, which will close the ring. There is the question of whether we will get a 5-membered ring or a 6-membered ring; the former is typically favorable, but the angles around the amide bond are fixed at 120 degrees, which promote the formation of the correct product. Then adding one more equivalent of bromine should take us to the pyrazine; I'm not sure if the 1-, 3- or 4- position will react first, but either should react with one equivalent of bromine to give a product that easily eliminates to pyrazine.

Scheme attached. Of course we hope the fluorine atom doesn't eliminate as HF under the reaction conditions. I expect it to be "kinetically protected", that is, lost relatively slowly, so the reaction can still complete.

faripiravir.png - 42kB




[Edited on 04-20-1969 by clearly_not_atara]
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