some time ago I read about Piracetam, a nootropic substance, which is able to increase the brain function for learning or remembering things. It is
also used to treat Alzheimer and dementia. Piracetam - wikipedia
I can get 2-Pyrrolidone for the synthesis of Piracetam and I also have a synthesis for the last step from the ethyl-2-oxo-pyrrolidine acetate to the
2-oxo-pyrrolidine acetamide. (see link below)
Has someone a complete synthesis from 2-pyrrolidone or can someone please help me with the missing step(s) from the 2-pyrrolidone to the
ethyl-2-oxo-pyrrolidine acetate?
"how do I make.."
chemrox - 13-10-2007 at 20:47
The forum kind of frowns on "how do I make.." questions. Yours was a little more discreet and you had looked a few things up but you should really be
asking how to research chemistry rather than how to do a particular synthesis. Sit down with a pencil and place 2-pyrollidone on the page and then
place the structure (you looked it up) for piracetam on the page. Now see if you can write steps from the one to the other that make sense. Called
"retrosynthesis" it s the way a lot of new agents are discovered. You have the last step or two don't you? From the ethyl-2-oxo-pyrrolidine acetate
to the 2-oxo-pyrrolidine acetamide? Piracetam's chemical name is 2-oxo-1-pyrrolidine acetamide. You have only now to work out going from
2-pyrollidone to ethyl-2-oxo-pyrollidine? There's help available here for getting the articles if your library access is limited. There are some
excellent handbooks on how to do chemical research. Read one of them.
[Edited on 13-10-2007 by chemrox]Sauron - 13-10-2007 at 21:14
That's the way to do it if you can't find the complete prep in the literature.
Searching the literature is another art, but a necessary one.
If I were in your shoes I would first look in Merck Index, if Piracetam is in there they will provide references you can look up. In this instance
Merck 12th Ed refers to US patent 3459738 which you can get in pdf from www.freepatentsonline.com, which is as the name indicates, free. Ah, I see you already HAVE this patent. So I will have a look at it and see what
your problem might be...
Given the simplicity of the molecule I would say that this is not a really great exemplar of the virtues of retrosynthesis. It's a no-brainer.
Okay, it seems to me that you are having trouble either deciding what is the structure of ethyl 2-oxo-pyrollidine acetate which is admittedly ratshit
for nomenclature, the patent lawyer ought to be flogged out of town; or else you are asking how to get from 2-pyrillolidone to "ethyl
2-oxo-pyrollidine acetate"
Your problems are resolved by the structure, which reveals that the mysterious ester is the ethyl ester of 2-pyrollidone-N-acetic acid, and the patent
example 4 is simply the ammonolysis of said ester to the corresponding acetamine.
With that clearly in mind, if I were wanting to prepare this, I would make or obtain ethyl bromoacetate. This is nasty stuff and is highly corrosive
and very lachrymatory and the governments don't much like it because it is one of the starting materials for a military agent called BZ. But it is
rather easy to make.
If you react that with 2-pyrollidone under appropriate conditions you will have your 2-ox0-pyrollidineacetic acid ethyl ester.
Org.Syn. has the prep of ethyl bromoacetate which if I recall, requires acetic acid, acetic anhydride, bromine, ethanol, and a lil H2SO4 (two steps,
making the bromoacetic acid then esterifying it in situ.)
You WILL need a fume hood. As I said it is VERY NASTY STUFF. It was a WWI war gas candidate.
Org.Syn. also holds the secrets of the addition to the N-position, but that is harder to find. Look under 3-Quinuclidinone, the first step or maybe
the second is reaction of a piperidine with ethylbromoacetate.
As I said a no brainer.
Now how do you plan to rigorously purify your product to pharmacologically acceptable norms of purity? Are you set up for HPLC?
[Edited on 14-10-2007 by Sauron]chemrox - 13-10-2007 at 22:46
Quote:
Look under 3-Quinuclidinone, the first step or maybe the second is reaction of a piperidine with ethylbromoacetate.
[Edited on 13-10-2007 by chemrox]Sauron - 13-10-2007 at 22:50
The example I am sending him to in OS is as stated, he can sort out how to use ethyl bromoacetate in his reaction by analogy.
As far as I know piracetam is not in Org.Syn. and neither is 2-pyrollidone-1-acetic acid, or its esters, or its amides. I could be wrong about that.Sergei_Eisenstein - 14-10-2007 at 03:07
Quote:
Has someone a complete synthesis from 2-pyrrolidone or can someone please help me with the missing step(s) from the 2-pyrrolidone to the
ethyl-2-oxo-pyrrolidine acetate?
This is traditionally done by making an alkali salt of 2-pyrrolidone, most practically achieved by using the strong base NaH.
Quote:
Given the simplicity of the molecule I would say that this is not a really great exemplar of the virtues of retrosynthesis. It's a no-brainer.
I disagree. You'd be surprised how many "catches" you can find in a simple molecule as this and give your students a hard time finding out. I find
"no-brainer" a particularly unhappy choice of words for a process such as retrosynthesis.
Also, it is not strictly necessary to use ethyl bromoacetate; ethyl chloroacetate will do equally well (still lachrimatory, but not as notorious). You
may find it easier to obtain or handle. It is also reported that piracetam can be obtained by reacting an alkali salt of 2-pyrrolidone with
2-chloroacetamide (lachrimator as well), though from the theoretical POV, addition of the alkylating agent should be slow. Further, you many find
DE2759297 an interesting (alternative) read.Sauron - 14-10-2007 at 04:12
Indeed, in Example 1 and some of the subserquent examples in the US patent cited by the thread author (and Merck), attached, q.v., the NaH is used.
Why the patent omits this and the use of N-chloroacetamide (also in Example 1 by analogy) is not clear, most likely patent lawyer playing games.
I am reasonably certain that the thread author will not be able to purchase either ethylhaloacetate nor the N-chloroacetamide in Germany where, I
believe, all are classified as T. Therefore he will be obliged to prepare his own reagents.
The thread author being German may be handier than I with that DE patent you cited. Does it differ substantially from the above?
I am not particularly certain that NaH could not be replaced by NaOH or KOH particularly in alcohol. Or, for that matter Na metal. If the lactam is
inert to NaH it ought to be just as happy with these.
[Edited on 14-10-2007 by Sauron]
Attachment: 3459738.pdf (135kB) This file has been downloaded 1023 times
thefips - 14-10-2007 at 07:55
Thanks a lot for the answers
I once read about Piracetam in the internet and thought it would be a very interesting synthesis for practice.
For taking it, the doses would be very high and that would be too dangerous because of the by-products.
I have no access to a HPLC at the moment, DC would be easy, but probably not ok for traces of dangerous by-products.
And Sauron, you are right, I am not able to purchase ethylhaloacetate, but the synthesis of it is not really difficult and I have the chemicals for it
here, but i wonder if it is intelligent to handle lachrimatories like ethylbromoacetate.Sauron - 14-10-2007 at 08:18
With a hood, not a big problem.
Use goggles and gloves and keep the sash down as much as possible.Sergei_Eisenstein - 14-10-2007 at 12:08
This is sciencemadness. Nobody here really handles lachrimators in a hood. That's for sissies.
Unless you really want to synthesize piracetam for the chemical experience, wouldn't it be more "convenient" to buy the product in a pharmacy?Sauron - 14-10-2007 at 15:21
Well, I'm a sissy then. There are worse things than lacrimators. I'm an old chemist, not a bold one, and there are no old, bold chemists.
Everyday examples: H2S, Cl2, SO2, thiols, hydrogen halides. As far as I'm concerned they belong in a hood. Megacorrosives like SOCl2, SO3, oleum,
likewise. I'm already blind in one eye and can't see worth a shit out of the other, I'd like to hang on to what's left for as long as I can, thank
you. So I coddle it by using a hood, glove box, scrubber, etc. Call me a wimp.
[Edited on 15-10-2007 by Sauron]chemrox - 14-10-2007 at 21:27
And all this time I had assumed Sergei to be a chemist. Handling lacrimators in a hood "is for sissys" indeed!Antwain - 14-10-2007 at 23:38
Damn straight! Real men snort them and then rub them in their eyes. thefips - 15-10-2007 at 08:28
A hood is a good idea, or in the garden with a fan.
I once had a bad experience with cleaning up equipment from making benzyl bromide
the tears ran out of my eyes like a waterfall, only from the bucket with water for the first washing.
with other substances especially H2S I would not feel save enough without a hood. if someone doesn´t think about the savety, the reaction or the
apparatus bad things could happen and even lead to death...Sauron - 15-10-2007 at 08:34
