Sciencemadness Discussion Board

Piracetam to Ethyl 2-Oxo-1-pyrrolidineacetate

underdosed - 8-5-2006 at 01:36

Hey, im looking to make some pramiracetam from piracetam, as per the synthetic routes in another thread, just wondering if anyone has any idea how to convert piracetam to Ethyl 2-Oxo-1-pyrrolidineacetate, effectively the acetamide to the acetate. Im thinking a base hydrolysis with ethanol?

Cheers,

Ud

Some ideas on Piracetam -> Pramiracetam?

plus - 12-11-2009 at 18:50

I'm going to just copypaste the post I made to sci.chem:
Quote:
Hi, I have a question regarding amide reactions. I have a molecule that has two amides, a primary and a tertiary, and I want to add a functional group to the primary amide to make it a secondary amide. I do not however want to affect the tertiary amide.

Specifically, I want to turn this:

http://upload.wikimedia.org/wikipedia/commons/e/e9/Piracetam...

Into this:

http://upload.wikimedia.org/wikipedia/commons/b/b2/Pramirace...

Quite honestly I'm not sure where to start. A reaction I have found online for the total synthesis of pramiracetam is as follows:

Bromoacetic acid reacts with thionyl sulfate to form the acid chloride, then is reacted with ethanol to form the ethyl ester. This ethyl ester is reacted with the sodium salt of 2-pyrrolidinone, which is synthesized by reacting 2-pyrrolidinone with sodium hydride in toluene and DMSO, in order to make ethyl 2-pyrrolidone-N-acetate. This is then reacted with N,N-Diisopropylamino ethylamine (CAS # 121-05-1) to make pramiracetam, which is then reacted with hydrochloric acid to make the hydrochloric acid salt.

If there were some way of turning piracetam into ethyl 2-pyrrolidone-N-acetate or a similar molecule, this setup could be greatly simplified. Anybody have any ideas?


I saw there was another thread here about the same idea, but it doesn't look like anyone had any ideas at that time.

So, what do you guys think?

(Edit by Nicodem: Merged with the old thread referenced above and removed the now bogus link.)

[Edited on 14/11/2009 by Nicodem]

Nicodem - 14-11-2009 at 10:09

Yes, it should be easy to selectively hydrolyse the -CONH2 of piracetam. This gives you 2-(pyrrolidin-2-on-1-yl)acetic acid which can be coupled with 2-(diisopropylamino)ethylamine to give pramiracetam.
Reflux in 1M NaOH should be enough for the first step. The work up would be a bit annoying due to the high aqueous solubility of the product, but with some ingenuity it would not be a problem. For the second step you can use CDI amide coupling or just make the acid chloride with oxalyl chloride or SOCl2 and then react it with the amine. Or you can use the boric acid catalysed coupling of carboxylic acids with amines as described at Organic Syntheses.

All this however does not make much sense because it would be simpler, more effective and much cheaper to just follow the usual synthesis of pramiracetam.

[Edited on 14/11/2009 by Nicodem]

plus - 14-11-2009 at 11:19

Checked out all the reagents in sigma aldrich... looks like by far THE most expensive reagent is the N,N-diisopropylamino ethylamine, at $91/100mL 97% purity. The total synthesis would cost about $784 per 940g, assuming 100% yield. This is cheaper than buying it outright, but still a large amount of money down.

I wonder if there is a cheaper way to synthesize the N,N-diisopropylamino ethylamine then...

Nicodem - 14-11-2009 at 11:55

If it is about economics, then you can always couple the 2-(pyrrolidin-2-on-1-yl)acetic acid with ethylenediamine (61.10EUR/1L) and then reductively isopropylate with acetone, H2 and Pd/C. Even though you would need an approximately fourfold excess of ethylenediamine to prevent diacylation, it would still be the cheaper, particularly since ethylenediamine can be obtained even cheaper in bulk and the excess can be recycled (with the boric acid method recycling would be very easy). This would however add another step in the synthesis.

DJF90 - 14-11-2009 at 13:50

I suppose you could say its a matter of what is more abundant, time or money. If you have the time to make the reagents/go a longer route, and if it saves you money, then why not? Sure it might be a bit of a "bother" but at the end of the day its all fun chemistry right?

mr.crow - 15-11-2009 at 12:39

You could synthesize the N,N-diisopropylamino ethylamine by blocking off one of the amino groups of ethylene diamine with phthalic anhydride, then alkylating the other one.

Can you form the amide with the acetic acid derivative, or do you need the acid chloride like the original procedure?

Z8320 - 13-12-2009 at 18:51

Quote: Originally posted by Nicodem  
If it is about economics, then you can always couple the 2-(pyrrolidin-2-on-1-yl)acetic acid with ethylenediamine (61.10EUR/1L) and then reductively isopropylate with acetone, H2 and Pd/C.


Is a high pressure palladium catalyzed reduction really necessary for this particular reductive amination? Would, for instance, hydrides or even aluminum amalgam not suffice? I don't really know enough about the reaction to answer it myself, but I don't think I'll ever get around to building that hydrogenator I've always wanted, so I thought I'd ask.