bomb40
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Synthesis of oxiracetam
Hi,everyone!
I'm studying the synthesis of oxiracetam(chemical name:2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide).
After several steps I get 4-(trimethylsilyloxy)pyrrolidin-2-one.Then I want it react with ethyl bromoacetate.
I have a problem,the reaction seems not well,there are only
a little TM and byproduct in the solution,and still have much 4-(trimethylsilyloxy)pyrrolidin-2-one not react.
I need your help,any suggestion will be appreciated.
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Klute
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What solvent, temperature and reaction times did you use? We can't help without any details....
What base did you use? Maybe your bromoacetate is getting hydrolyzed...
[Edited on 11-9-2008 by Klute]
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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bomb40
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The solvent I used is 1,4-dioxane,the temperature is about 120,the base is NaH,and 1.2 eq ethyl bromoacetate is used. But after 20h,there are still
much 4-(trimethylsilyloxy)pyrrolidin-2-one not react!
So,I did't know why,many thanks!
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Klute
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Did you preform the enolate, or directly add all 3 reagents?
Maybe you could try using DMF as a solvent, at 120°C, and possibly heat more (if you don't detect too much side reactions at thoses temps) if there
is still alot of unreacted product..
Mayeb you could try using a little more alkyl halide, there isn't any other alkylations possible, especially if you keep the amount of NaH just above
stoechiometric.
Some alkylations can be evry long, especially with somewhat hindered substrates, so you could leave the reaction to run for 48H or more, but might
need to keep the temp lower for long periods.
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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bomb40
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At first I add NaH in the solution of 4-(trimethylsilyloxy)pyrrolidin-2-one in 1,4-dioxane,the mixture was heated at
50-60°C for about 1h.then ethyl bromoacetate was added to the mixture,which was reflux for 20h at 120°C.
But there was still much byproduct,and only a little TM in the solution,so I think the hydroxy had been deprodected, and reacted with the reagent
ethyl bromoacetate,as you say "there isn't any other alkylations possible". Maybe that was the problem.
I will have a rest for 3 days.It is Mid-Autumn Festival in China. I will try to leave the reaction to run for more time
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Nicodem
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Vague questions are not particularly welcome since unanswerable. If you open a thread asking for a solution of your problem then you are also expected
to provide all the necessary information. It is for your own benefit to do so (as simple logic can tell you). Instead, you ask for a solution of your
problem without providing neither the references or the experimental. So what are we supposed to do? Guesswork?
Are you following a published procedure and what is the reference? Include the full experimental! What were the byproducts (are you concluding from
TLC results?; a speculative identification of byproducts according to NMR results would be welcome; do these products still contain the TMS
protection?; How many TMS singlets and how many CH2CO singlets do you observe in the 1H NMR of the product mixture and give their integration ratio?)?
The TMS protection of alcohols is sometimes base labile and not always appropriate. Have you tried a more full proof protection before (like
t-butyldimethylsilyl) and had success under the same reaction conditions? And finally the most important info you failed to provide: How was the
dioxane dried?
PS: Please take notice that this forum is oriented toward amateur chemistry and is not supposed to be supporting chemists who are paid and equipped to
do their job, particularly not for solving their job related problems.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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chemrox
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How are you stirring the mixtures? Sometimes inadequate mixing causes problems and I second klutes comments about the length of time sometimes
required. Not sure why DMF would be better (Klute?).
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Klute
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DMF is a very good solvent for alkylations as it solvates the counter ion of the anion to somepoint, and thus exacerbates the nucleophilic caracter
(of the amide enolate in this case). Sa, it's high bp ables higher reaction temps, when this is usefull...
I hadn't thought of deprotection. I'm not very familiar with silane protections. But as you said there was alot of TM in solution, I considered you
had analyzed the products and identified them.
As Nicodem suggested, you should check your solvent, and perhaps try another few onbes (DMF, THF, etc). It is strange becasue theses are the standard
amide alkylation conditions, and your substrate doesn't seem excessively hindered..
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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bomb40
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Many thanks to Nicodem,it's my first time to come to this forum.I'm sorry for what I had done which seems not suitable.
All the method that published procedure mentioned(e.g.US patent) I had tried,and seems not well.There is always much unreacted
4-(trimethylsilyloxy)pyrrolidin-2-one.
I think the bromoacetate is getting hydrolyzed in a basic conditons.
I concluded the byproducts from HPLC results.
The 1,4-dioxane was dried by a rotary evaporation at 75°C.
To chemrox:
I am stirring the mixture by a mechanical stirrer,so the mixing is not a problem.
The 4-(trimethylsilyloxy)pyrrolidin-2-one can dissolved in solvent dioxane,so I think
the solvent is also not a problem.
DMF would be better ,why? I do not like DMF, because of it's high boiling point.
i
To chemrox:
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Klute
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DMF is good because it turns your anion more nucleophilic.
You mighy want to distill your dioxane over sodium or similar, it might not be dry enough, so you have NaOH from hydrolysis of NaH and/or your anion
in the reaction mixture, which hydrolyzes your ester to somepoint.. The alcohol formed with then neutralize more anion, etc etc. THF, distilled from
benzophenone ketyl, or just sodium, might be as suitable, and less toxic than dioxane.
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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Nicodem
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| Quote: | Originally posted by bomb40
The 1,4-dioxane was dried by a rotary evaporation at 75°C. |
Since when is rotavaping dioxane a method for its drying? Dry it properly and thoroughly (check a manual on what is used for its drying). Dixane is
hygroscopic and if you use it straight out of bottle you can't expect anything good when used in an N-alkylation of an amide with NaH as base. Just
check the pKa differences of pyrrolidinone and H2O and maybe then it will more clear to you why you get low conversions and a bunch of side products.
...and you still didn't provide the reference!
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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bomb40
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I'll try distilling my dioxane.
Yes,dioxane is hygroscopic.
Maybe the dioxane is not dry enough,and my ester had been hydrolyzed.
...By the way,the refrence I am following is US patent 3459738.
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Klute
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Distill it over some dessicant, like Na or Na/benzophenone ketyl. Simple distillation will not dry it, just like rotovaping it. This trick only works
with toluene and similar, even them there is a few 100's ppms water left
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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Sandmeyer
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I hope this is not another case of a simple seller exploiting the forum...
Ican't resist to ask - what's the logic behind using ethyl bromoacetate and not chloroacetamid?
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Klute
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Chances are chloroacetmaide is more acid than the pyyrolidinone, and would simply neutralize the anion.
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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kolpak
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I'll bet it was wet dioxane 
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bomb40
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I checked some manual,and found distilling dioxane is not safe.
Because the dioxane may contain some peroxide, distilling it may cause explosion.
So I want to know wether I can dry it by adding some NaH to react with the water left,but not distill it.
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Klute
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If you check for peroxides (starch/iodide paper) and treat them if present (bisulfite, FeSO4, etc), distilling dioxane isn't any more da,ngerous than
distilling THF or ether.
In this case, adding exces NaH might not do the trick as the formed NaOh will hydrolyse your ester. You will need to distill the dried solvent.
haven't you got a sodium/benzophenone still? Most labs do. Use THF if that's what you got refluxing in a still..
Rotavaping wet dioxane is far more dangerous, although you see you are still alive and in one piece
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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kolpak
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Look body, just find Purification of Laboratory Chemicals (5th Edition) - it is easy available on internets. This is the best handbook oh purification
with particular methods for each of the widely used laboratory chemicals.
Distilling over benzophenone-sodium ketyl will distroy peroxides if any and water.
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Barium
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Bomb40, you really should devote more attention to the basic skills for organic synthesis. You are not equipped with enough knowledge yet to handle
reagents like sodium hydride. This is just meant as a friendly advice.
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bomb40
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Thank you for your friendly advice,Barium!
I'll work hard and consolidate the basic skills for organic synthesis.
...I have distilled my dioxane,it seems well. I put some sodium in it and and refulxed for 7-8h.Then distilled it
at normal pressure.
Yes,as klute say,"distilling dioxane isn't any more dangerous than distilling THF or ether".
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