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trionic
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[*] posted on 14-6-2013 at 01:16
Diazepine synth options


Hi everyone! I'm a new user here but have been lurking around for a year or so. I'm a budding chemistry student.

Anyway, I'm working on synthesizing a fairly benign pharmaceutical product. I have done alot of research online and found out that there are multiple ways to do the synth.

If you start out with 2-amino-5-chlorobenzophenone you can either methylate this first by tosylating with tosylCl, Alkylating w. DMSO and finally hydrolyzing in H2O+H2So4.

Or proceed immediately to cyclocondensation with glycine ethyl ester or as I found out on rhodium; chloroacetyl chloride,hexamine and toluenesulfonic acid to afford the cyclocondensated product with an amino group that now may be methylated and NH2->N to afford the Diazepam. The one description I can find on this matter just mentions using DMS, does this mean that tosylation is not required?



I also found an interesting route starting out from 1-Chloro-4-nitrobenzene and benzyl cyanide(phenylacetonitrile) But no description, just an image.

I'm a bit confused here, maybe someone has some pointers on how to go about this the easiest way?

I hope that I'm not being offensive by asking these questions. May I also add that I'm working on a micro-scale for personal use since restrictive pharmaceutical policies where I'm at forbids me a prescription even though I have a long standing diagnosis of severe anxiety disorder.


diazepam from nitrochlorobenzene.jpg - 56kB

[Edited on 14-6-2013 by trionic]
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KrysHalide
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[*] posted on 14-6-2013 at 02:43


First of all, that isn't DMSO (dimethylsulfoxide, an aprotic polar solvent) but dimethylsulfate, a very toxic and hazardous alkylating agent.. Do not get both mixed up, there are completly different!!

The second process just makes your chloro-amino-benzophenone in two first steps, alkylating your chloronitrobenzen, then intramolecular condensation with benzyl alcohol.. The heterocyle is then reductively opened, offering an aniline (which is alkylated by the DMS) and your benzophenone moity.

From then on, acylation with chloroacetyl chloride (nasty stuff), amination with hexamine (sommelet reaction) and intramolecular condensation..

Don't want to discourage you, but this seems like a complicated synthesis for someone with only basic knowledge and experience.. I would first try out easier synths, because handliung DMS and ClAcCl is not begginer-friendly..




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trionic
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[*] posted on 14-6-2013 at 02:53


Hi!
Thank you for the pointers! I'll make sure to not mix up the dmso. I have already done some fairly complicated synth's like 2-methyl-3-(2-methylphenyl)-4-(3H)-quinazolinone from Anthranilic acid with excellent yield, so I think I might pull this off.. I know about the ClAcCl, I already have some and I will do this in the fume hood. Don't worry! :) The Sulfate do worry me though, I won't do it... I'll either have to methylate with a more safe agent or try to find some pre-methylated 2-a-5cbp

I can get 2-amino-5-chlorobenzophenone or phenylacetonitrile etc. from my local supplier. But not the methylated 2-methylamino so that's why I'm asking about the best way to start this synth...

[Edited on 14-6-2013 by trionic]

[Edited on 14-6-2013 by trionic]
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simba
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[*] posted on 14-6-2013 at 07:10


You can do the methylation with methyl iodide instead, which is pretty nasty also, but much less dimethyl sulfate.
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KrysHalide
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[*] posted on 14-6-2013 at 10:09


You will not be able to directly methylate the primary amine without giving tertiary and quaternary amines.. Check out a thread about "monomethylation of primary amines" by klute, protection via benzaldehyde-imine will offert pur mono-methyl amines.

Sulfonates would be a safer option here, methyl tosylate (cf Klute), or methyl methane sulfonate (cf Ullmann, in the sulfuric duff thread) are easily obtainable and pretty efficient.

Si if I were you, I would react your amino-chlorobenzophenone with the glycinate est, using cat. TsOH in toluene,, and a dean stark for best results, then add TsOMe in toluene, gently reflux, and workup., that seems like it.

But if you really plan on using your chloracetyl chloride, add it diluted in DCM to your mono-methylated substrate in DCM, don't bother purifying after the mono-methylation, a simple A/B gives a very clean product) at 0°C with an equivalent of triethylamine, wash off the EtN.HCl when done, and proceed to cyclization (again, a dean stark could be usefull)

[Edited on 14-6-2013 by KrysHalide]




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Nicodem
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14-6-2013 at 11:51
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[*] posted on 14-6-2013 at 12:24


Quote: Originally posted by trionic  
The one description I can find on this matter just mentions using DMS, does this mean that tosylation is not required?

Think about it. If you N-tosylate it, then there will be no position left to N-methylate it.

Quote: Originally posted by simba  
You can do the methylation with methyl iodide instead, which is pretty nasty also, but much less dimethyl sulfate.

Do you have a reference in support of this? What is the N-methylation vs. C-methylation selectivity?
Quote: Originally posted by KrysHalide  
You will not be able to directly methylate the primary amine without giving tertiary and quaternary amines.. Check out a thread about "monomethylation of primary amines" by klute, protection via benzaldehyde-imine will offert pur mono-methyl amines.

Are there any examples of this strategy being applied to anilines? Imines are poorly nucleophilic and the imines derived from the aromatic amines are even so very much less nucleophilic.
Quote:
Si if I were you, I would react your amino-chlorobenzophenone with the glycinate est, using cat. TsOH in toluene,, and a dean stark for best results, then add TsOMe in toluene, gently reflux, and workup., that seems like it.

Anilides don't get N-methylated so easily. They generally need to be deprotonated first. Some aliphatic amides do get slowly methylated with in their neutral form with methyl sulfonates or dimethyl sulfate, but in such a case the O-methylated product is the kinetic product obtained (e.g., like in the reaction of DMF with dimethyl sulfate).




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[*] posted on 14-6-2013 at 12:51


Good point, I had somehow abstracted the fact that it was an aromatic amine.. My comments do not apply here then...



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[*] posted on 14-6-2013 at 14:14


Quote: Originally posted by Nicodem  

Do you have a reference in support of this? What is the N-methylation vs. C-methylation selectivity?


http://www.scielo.br/scielo.php?pid=s0103-50531998000400010&...
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trionic
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[*] posted on 20-6-2013 at 17:33


All this seems a bit tricky.. I'm now consedering making a certain nitrated compund instead. This way I don't have to consider methylation since the diazepines with the n2o group has an amino group instead of methyl group. The missing necesseray precursor is available for me and everyting else like Chloroacetyl chlorode,hexamine, solvents etc. i got already.. I'm gonna order some nitrated precursors instead now. Wish me luck!
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[*] posted on 26-6-2013 at 11:30


The first question is: HOW to make 2-amino-5-chlorobenzophenone?

Side reaction is posted in attachment, so how do you think to prevent amide formation by performing a FC acylation?

You can claim everything here on the internet but without peer - reviewed articles it isn't true in science.
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The second question is what is the reason that p-chloroaniline reacts in a alkaline environment to form the product in scheme 2?

If you have a source and don't like to post it down here, just send a PM.

Off - topic
Diazepam is OTC here in Indonesia. My opinion is if Valium is not legal, why is alcohol then legal?





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[*] posted on 26-6-2013 at 21:49


Are we talking about diazepine or diazepam? Either way the benzodiazepines are among the nastiest sedatives ever invented. Be kind to yourself and make some quaalude. An undergraduate ought to be able to handle that synth. Or how about a glass of warm rice wine?



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[*] posted on 27-6-2013 at 04:07


As biochemist I don't recommend methaqualone or barbituates either. It can cause not only dependence but also the dose is pretty high, OD is a big risk.

Withdrawals are dangerous when the subject is diazepam with the diazepan ring. In rare cases (like some Vietnam veteran's) the DOSE is simply too high and in that particular case you get strong withdrawal symptoms that are dangerous (first 10 days): spasm, shaky, headache (3 days), sweating, dilated pupils and the chance of getting a seizure. These symptoms go over and most patients are fully recovered after 1 or 2 years. Please read the Ashton manual.

Sternbach, L. (inventor of Librium) did perform the reaction in the scheme above by a reaction between p-chloro aniline and benzoyl chloride in the presence of ZnCl2 as Lewis acid. He use diluted sulphuric acid in acetic acid but I don't know why?

Difficult synthesis however, you need a vacuumpump to prepare p-chloro aniline and you must prepare benzoyl chloride outside! Fuming HCl escapes very rapidly by slightly heating. You can buy a car battery to fix the job outside.

Also, use a excess of benzoyl chloride for that FC acylation. Reaction time: 8-9 hours.

Take care!
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[*] posted on 27-6-2014 at 19:49


Sorry guys, I forgot about this thread!

TO answer some questions... I have been addicted to diazepam/benzoes and had two seizures during withdrawal. But I don't touch that stuff any more since my Doctor gave me a nice prescription for LYRICA (pregabalin) which is also addictive, but hey,, I have REALLY bad anxiety and diagnosis from several psychologiststs!

Anyway, I Have synthesized Methaqualone and enjoyed it but the dosage is too high I mean 300mg for one dose? I would prefer to synth something in the 1-2mg dosage range :) And you who suggest Alcohol!? NO way i'm drinking solvents, mmkay!

Anyway you can see my new thread that I'm going to make clonazepam just because I still have all the chems and it would be a shame to let them just sit on the shelf plus, my mad supplier got me some sickly nice precursors.


NEW THREAD
https://www.sciencemadness.org/whisper/viewthread.php?tid=30...
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