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Author: Subject: Carbamazepine Synthesis
PrussianBlue
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[*] posted on 7-2-2018 at 16:50
Carbamazepine Synthesis


I'm not sure if this is the correct place to post this, so please let me know if I should move it. With that aside, I am looking for any and all knowledge on the synthesis of carbamazepine for an undergraduate project. A few quick database searches pointed me in the direction of reacting iminostilbene with one of a variety of reagents to attach the amide. I plan on performing much/all of my research with legitimate databases and search techniques (as I am expected to do), but I am curious as to what the forum may offer.
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ninhydric1
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[*] posted on 7-2-2018 at 17:28


This is supposed to be in Beginnings.

https://commons.wikimedia.org/wiki/File:Carbamazepine_syn.pn...
Starting from 5H-dibenzo[b,f]azepine. Good luck finding this though.




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[*] posted on 7-2-2018 at 17:46


Its a anti convalescent and i think fairly old. So maybe expired patents?
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[*] posted on 7-2-2018 at 20:39


There has been a deccent ammount of research done on this compound already, however most routes are still rather tricky.
These references may be of some use.
http://pubs.rsc.org/en/content/articlehtml/2013/ob/c3ob41252...
https://journals.prous.com/journals/servlet/xmlxsl/pk_journa...

This one from that journal ref looks nice.


Most of the reagents are simple enough, nothing overly exotic except perhaps dimethyl carbonate, which is usually made from phosgene, i suspect however that there may be some more convenient ways to acetylate that amine.
PPA i suspect is polyphosphoric acid given that the reaction appears to be a dehydration and the same reaction can be used for the prep of a compound im interested in.

Note: if you need help getting access to references, feel free to post the references here as im sure somebody will have access.
This thread does also kinda belong in beginnings i think but we will see where the mods want to put it.
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ninhydric1
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[*] posted on 7-2-2018 at 22:09


There is a phosgene-less synthesis I found that uses MeOH and CO2 with KOMe as a catalyst in the presence of MeI. Link below:
https://link.springer.com/article/10.1007/s10562-005-7158-2
EDIT: Not great yield though, but better than phosgene IMO.

[Edited on 2-8-2018 by ninhydric1]




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[*] posted on 8-2-2018 at 00:26


Would make a great chem player video!! Like the aspirin to paracetamol one.
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[*] posted on 16-2-2018 at 05:27
Potential Reactions


Does anyone have any comments/concerns regarding these two potential reactions? If we are able to obtain the precursor for the first reaction, we will likely take that route. Otherwise, we will have to go with the second pathway.

Attachment: Carbamazepine Synthesis PDF.pdf (31kB)
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[*] posted on 16-2-2018 at 15:53


Well they are both the same reaction as far as i can tell.
the first reaction would still require the formation of the N-acyl chloride, which is the pain is the ass part.
The amination is simple enough although i suspect you may want to do it in anhydrous conditions, acyl chlorides usually hydrolyze in water to form carboxylic acids, N-acyl chlorides however may not behave the same at those temperatures however.

Personally i would avoid water wherever possible and instead opt to bubble dry ammonia gas through the toluene, acyl chloride, tiethylamine mixture to avoid H2O.
an excess of ammonia will make no difference and simply precipitate as ammonium chloride, you will also get triethylamine hydrochloride precipitation as well.

Assuming you were able to acquire triphosgene and safely handle it, i would see no reason why you couldn't acomplish this in one pot.
Of coarse acquiring triphosgene may be rather mad.
As pointed out in another recent thread dimethyl carbonate is rare but accessible to us amateurs, it may be smarter to first prepare the carboxylic acid using dimethyl carbonate and then simply chlorinate that using thionyl chlorine or phosphorous pentachloride or phosphoryl chloride.
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PrussianBlue
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[*] posted on 17-2-2018 at 05:44


Sorry, I should have specified why I chose two identical reactions. This is for an undergraduate class project, so we have access to nearly everything we need. My primary concern is if we are able to obtain the N-acyl chloride, will the amination still be as simple as adding a source of ammonia? Or do the conditions from the acylation in some way harbor the amination? The second pathway is directly from a paper, but we are trying to save on cost, hence the interest in skipping the first step.
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[*] posted on 17-2-2018 at 23:01


Quote: Originally posted by PrussianBlue  
The second pathway is directly from a paper, but we are trying to save on cost, hence the interest in skipping the first step.

this is how you do it in one step :D -https://patents.google.com/patent/US7015322
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[*] posted on 8-3-2018 at 15:42
Carbamazepine Synthesis Troubles


Maybe someone here will understand my synthesis woes...

For the first attempt, the following procedure was carried out:

-0.1973g Dibenz[b,f]azepine-5-carbonyl chloride was added to a 10mL beaker along with a stir bar
-2.0mL of toluene were added and the solution/suspension was stirred for about 10 minutes
-The solution was still very cloudy, so toluene was added until most of the solid had dissolved (roughly 5mL total volume)
-Conc. NH4OH was added dropwise (about 2mL -- precipitate was expected to form immediately upon addition)
-Solid was filtered off and was found to be starting material based upon melting point

Attempt #2:

-Same as 1, but only 2mL of toluene were used in total and the NH4OH was added to the suspension after only 1 minute of stirring
-The filtered solid was once again found to be the starting material


Does anyone know why this carbamoyl chloride is so unreactive with the ammonia? I am basing this off of a paper (attached) that produced the Dibenz[b,f]azepine-5-carbonyl chloride in situ, so I am guessing this may be the root of the problem.

Attachment: ChemInform_Abstract_Convenient_Syntheses_of_Halo-D.pdf (460kB)
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[*] posted on 10-3-2018 at 12:16


I understand your problem. Unexpectedly unreactive acid chloride.
I would expect at least partial hydrolysis or better: amidation but not that you can recover the starting material unchanged.

Problem is, your acid chloride is stericaly very similar to a 2,6-disubstituted benzoil chloride. They are the least reactive as I heard. Maybe you should check their reactions and maybe you could get tips or learn tricks on how to deal with this particular type of sterics. Those tricks may be applicable to your azepine as well.

Anyway, as a quick and dirty last resort, I would try gassing the chloride with anhydrous ammonia gas. You work with small ammounts of chlorides and it would not require much ammonia to saturate the compound, even if it was dissolved in toluene. You could even generate the ammonia gas yourself!
Would it work? I don't know. At least it would be easy to recover the acid chloride if it wouldn't. :-)
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[*] posted on 10-3-2018 at 17:51


I was toying with the idea of just bubbling ammonia through the solution and I may end up trying it next week. Would there be any immediate issues with running the original reaction with a reflux? If it ends up being successful, it would save me the time of setting up an ammonia generator.
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[*] posted on 10-3-2018 at 19:38


Ammonia is not very soluble in toluene and probably not very reactive either. If you want to use toluene as the solvent you will probably need to use a pressure reactor. If I were to run this reaction with the carbamoyl chloride I would use dry pyridine as the solvent. The pyridine will activate the carbamoyl chloride as well as provide a polar aprotic reaction environment.

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[*] posted on 13-3-2018 at 09:28


You are probably over this but yes, try the original reaction at reflux temperature too! And don't forget to report back. :-)
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[*] posted on 13-3-2018 at 11:03


I'll be back in the lab tomorrow afternoon. I think I'm going to run it under reflux for an hour and run another at room temp for roughly the same amount of time. If neither of these work, I may try adding a small amount of Et3N and see if that activates the substrate enough to react with the ammonia.
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[*] posted on 20-3-2018 at 13:43


Tried a 1 hour reflux and nothing appeared to change other than that the solid was able to completely dissolve at the elevated temperature. This week, I will be adding a catalytic amount of Et3N as a last ditch effort. Does anyone have any last minute suggestions?
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