Sciencemadness Discussion Board

ibuprofen and it's derivatives

Jor - 19-4-2011 at 09:26

I am soon planning (I think about 1-2 months) to isolate ibuprofen in it's pure form and isolate some of it's derivatives.

First the ibuprofen will be extracted from the pulverised drug with hot hexane (3mL per gram), filtered and the hexane evaporated.

Next something I wanna do is nitrate it followed by esterification (either the methyl or ethyl ester).
http://rasayanjournal.com/View-document/266-SYNTHESIS-OF-SOM...

Next I wanted to perform some more steps on the product.
I have no specific goal, just doing some organic synthesis.
I was thinking of performing a Grignard on the ester with either i-PrBr or EtBr, giving the t-alcohol. But what effect does the grignard have on the nitro-group? I could instead first reduce the nitro (before esterificaation, does the dithionite affect the carboxylic acid?) to amine with dithionite, acetylate with Ac2O, followed by esterification and Grignard. Then I could reflux with 40% HBr (this does hydrolyse an amide right?) and react the alkyl bromide with KCN to form the nitrile (what condition are required for this reaction), followed by hydrolysis with moderately conc. H2SO4.

I'm just making up some ideas, the point is that I want to perform a series of organic reaction, a total synthesis, of some compound in wich a variety of reactions are used. I prefer to work with higher boiling/melting compounds (like Ibuprofen instead of for example toluene or benzene as starting material) as solids can be crystallised while most liquids have to be distilled and this is a lot more work. Besides this is more exotic chemistry.

So do you guys have any idea of an interesting pathway starting from Ibuprofen involving like 5-6 steps? I have quite some chemicals, but I do not have things like borohydride to reduce ketones, I not have the catalyst and apparatus to do hydrogenations, etc.

Nicodem - 19-4-2011 at 12:39

Excellent approach to amateur chemistry! That is exactly the philosophy that I applied when still doing experiments at home and I highly encourage it.

Though most of the products will be solids and thus recrystallizable and in principle characterizable, you will nevertheless encounter a few problems with identifications. Since you don't have the spectroscopic instruments needed for structure determination, you are pretty much limited to mp measurements, derivatization and basic chemical properties as identification tools. This might be a problem, because many of the products derived from ibuprofen will be new compounds, thus having no literature data to compare with. Sometimes you will be able to confirm some functional groups by derivatization, but you need the proper reagents for this. Purity can be checked by TLC and mp interval.

Anyway, you should start with simple transformation first. I suggest you to first form some amides of ibuprofen. Plain amide should be doable by heating in urea melt at 150 °C. Other amides can be done by boric acid catalysed amidation in refluxing toluene. Amides are nice to work with as they are usually nicely crystalline and are good for further transformations. You can try to dehydrate the plain amide to the nitrile by reflux in acetic anhydride. The nitrile is a good substrate for the addition of Grignards or for reduction to the amine (for example with Zn/NiCl2).

If you have ortho-phenylenediamine or some related diamine, you should make the benzimidazole derivative of ibuprofen. This is classical old heterocyclic chemistry and often it takes no more than reflux in 4M HCl.

You can check what you get by oxidation of ibuprofen with KMnO4, K2Cr2O7/H2SO4, reflux in dilute HNO3, etc. If you get the corresponding aryl alkyl ketone(s), you can use them as starting material for some further transformations.

Nitration sounds fine. The reduction can be done with Na2S2O4/Na2CO3/H2O (dithionite does not affect the carboxy), but you might have troubles isolating the product (carefully neutralizing to the isoelectric point of the anilino acid...). You might want to try the reduction on the ester, amide or nitrile counterpart instead. Nitro groups react with grignard reagents, but so do anilides, so it is not like you would achieve much protection by N-acetylation.

The addition of methyl- and ethylmagnesiums on ibuprofen was already discussed and some info posted (UTFSE; also in regard to naproxen). What you get is a tertiary alcohol. These can be brominated via SN1 (using HBr as you propose), however this gives you a tert-alkyl bromide which can not be used in SN2 substitutions (like the alkylations of cyanide) as they give the elimination product instead. However, tert-alcohols are perfect for other SN1 reactions, one of the interesting ones being the Ritter reaction. By performing it on acetonitrile you can get the corresponding N-(tert-alkyl)acetamide.

Let me know which part you are interested in and I'll find you the references you need.

Jor - 19-4-2011 at 13:35

It is indeed a problem that I don't have access to IR/H-NMR/Mass spectrometry. We have it at uni but I do not like the idea of going to uni with some home-made exotic chemical. Melting point is also a problem as you say as don't think there is literature on some of the compounds. I do have TLC soon (I am soon to recieve some TLC plates) so these are probably my best bet.

I have made amides before by heating with urea (phthalimide from phthalic anhydride and urea) and it works great, so this indeed sounds interesting.
The conversion to nitrile should also be possible but I rather use phophorus pentoxide as dehydrating agent (although I have lots of acetic anhydride). how much Ac2O do you need? I recall trying to dehydrate phthalamide with Ac2O but I made a mistake and it failed. Anyway I used many equivalents of Ac2O for 1 eq. of the amide. Can you also use say 1,5-2 eq. of Ac2O in AcOH?

I think doing a Grignard on the nitrile is not the best idea, because Grignard reaction with the ester of ibuprofen will give the same product?
What is the procedure for reducing the nitrile to amine? Is this done in water? If so NiSO4 should work too I guess.

I don't have phenylene diamine. I could prepare it (I made about 5 grams of acetanilide this weekend from aniline in AcOH/Ac2O, So i can use this). I have plenty of ethylene diamine but thats ofcourse not useful here.
I you want I can send a list of reagents I have, by PM. This avoids calling reactions wich i can't do.

The oxidation with K2Cr2O7 in H2SO4, do you need conc. H2SO4 or can you use dilute acid? I am not too fond of the idea of using CrO3 (forms in conc. H2SO4) with organics...
i don't see why it wouldn't form the ketone, it' the only possible product right. Only the benzylic carbon is easily oxidised.

if I reduce the nitro-compound of the ester with dithionite in aqueous Na2CO3, isn't the ester simply hydrolysed by the mild alkaline environment?

I like the idea of the Ritter reaction. I have about 250-300mL acetonitril with hardly any uses so far....

Of your ideas I like the most:

Ibu --> amide --> nitril --> amine

For the t-alcohol:

Ibu --> Et or Me ester --> Grignard --> Ritter reaction.

i'll leave the nitration for later.

Ofcourse it will take some time before I can start (I need to recieve some solvents (like hexane for TLC), the TLC plates, some distillation glassware, vacuumpump, etc. All wich I am ordering this month.




[Edited on 19-4-2011 by Jor]

[Edited on 19-4-2011 by Jor]

ItalianChemist - 21-4-2011 at 01:48

Very interesting :)
I've just extracted about 18g of ibuprofen, this evening I will do 2-(3-nitro-4-isobutyl phenyl) Propanoic acid, is it used to make explosives?
Does anyone have the MSDS?

Jor - 21-4-2011 at 03:50

How did you extract it? With hexane/pentane/heptane/pet ether or some more polar solvent?

I wanna use hexanes for this:

http://www.freepatentsonline.com/5300301.html

blogfast25 - 21-4-2011 at 03:59

Quote: Originally posted by Jor  

I have no specific goal, just doing some organic synthesis.
I was thinking of performing a Grignard on the ester with either i-PrBr or EtBr, giving the t-alcohol.


We're always looking for ideas for t-alcohols from OTC materials in the thread below. What would be the structure you have in mind, please?

ItalianChemist - 21-4-2011 at 04:09

Quote: Originally posted by Jor  
How did you extract it? With hexane/pentane/heptane/pet ether or some more polar solvent?

I used 100ml of boiling n-hexane to extract about 18g of ibuprofen

[Edited on 21-4-2011 by ItalianChemist]

[Edited on 21-4-2011 by ItalianChemist]

ScienceSquirrel - 21-4-2011 at 04:21

Quote: Originally posted by blogfast25  
Quote: Originally posted by Jor  

I have no specific goal, just doing some organic synthesis.
I was thinking of performing a Grignard on the ester with either i-PrBr or EtBr, giving the t-alcohol.


We're always looking for ideas for t-alcohols from OTC materials in the thread below. What would be the structure you have in mind, please?


You can easily work that out from looking at the structure of ibuprofen;

http://en.wikipedia.org/wiki/Ibuprofen

I think it would be 2 - ( 4- isobutylphenyl )-1,1-dialkyl*- propanol but I am a little rusty. :)
* where alkyl = i-Pr or Et

I doubt the reaction would work with the isopropyl as it would be just too sterically hindered, I would try methyl to start with.
It might work out a bit too expensive for making potassium! :(

Nicodem - 21-4-2011 at 10:57

Quote: Originally posted by Jor  
Of your ideas I like the most:

Ibu --> amide --> nitril --> amine

Unfortunatelly, I could get no references for a ibuprophenamide->ibuprophenitrile transformation. Related alpha-methylphenylacetamides are most commonly dehydrated to the nitriles using SOCl2/PhMe(catalytic DMF) or other less common reagents. Use of P2O5 for a related amide is described in Synthesis (1986) 239-240.
In regard to using lower excess of acetic anhydride, I'm not sure. Perhaps you can use just 3 to 5 equivalents. For example, in JACS 71, 2650-2652, they reflux 32 mmol of 2,2-di(p-chlorophenyl)acetamide in 45 mL (CH3CO)2O to get the nitrile (that is 15 equivalents!). So, if you do have P2O5, you can consider using that instead.

Nitriles can be reduced using Zn or Al metal dissolving reductions in the presence of NiCl2 or NiSO4. There should already be some articles posted on these methods. I will look for them next time, if you don't find them inbetween.

Ibuprophenamide: mp 106-107 °C (see supporting info of DOI: 10.1021/jo801580g ; also has info about p-isobutylacetophenone). Ibuprophenitrile is a "colorless liquid" and I could not get the bp. I could not get the mp of "ibuprophenamine" hydrochloride or any other salt.

blogfast25 - 21-4-2011 at 11:57

Right now I'd pay well for having a catalyst for 'redox Na', SS. A starting point.

I'll see how far Jor gets with this first. Thedimethyl tertiary alcohol would certainly be of interest to me...

Jor - 24-4-2011 at 17:41

Italian Chemist, how is your progress on the nitration of ibuprofen?

I just bought my Vacuubrand MZ2C pump (pulls around 75mbar wich is enough for my purposes, completely resistant to all gasses) for a goof price (150 EUR) from another dutch amateur chemist and I am soon to recieve a lot more glassware, some required solvents and the TLC plates, wich make me ready to go for this experiment! However, I will not be home in like 2 weeks, but I can't wait!

Therefore I have been already thinking on what I will do when i get home. I will just give the procedures I would follow if I would have to make them up right now:

-Extract ibuprofen:

Extract with boiling hexanes, 3mL for every gram.

-Ibuprophenamide

Intimately mix 1 eq. of ibuprofen with 2 eq. of urea (I know only one is needed, but the stuff is cheap!). Heat at 150C until gas evolution ceases (when I did phthalimide, the mixture at once became solid and frothed). Then wash out the solids wich water, filter, wash with more water. This product should be pure enough for the next step?

Does boric catalysed amidation only work with aliphatic amines or would aniline work as well? I also wondered, when I would use ethylenediamine as the amine, I could possibly obtain a polymer right? That might be interesting to try.

I really don't like the idea of using 15 equivalents of Ac2O to convert the amide in nitrile! I don't see why 3-5 wouldn't work. Maybe you won't be able to dissolve all the amide, but that wouldn't matter too much right?
Amide (s) <--> Amide (Ac2O)
When the amide is dehydrated, more amide should dissolve and react. the only reason I see why it wouldn't work is the higher concentration of AcOH interfering wich I don't think is true. Isn't the reason why the chemist use such a large excess that Ac2O is actually very cheap (they don't have availability issues) and it's much more convenient to use many, many equivalents (so it can effectively dissolve all amide)?
If I woulld dehydrate the amide with P2O5, would mixing it very quickly with excess P2O5 (how much would be needed, it's a solid solid reaction, and the P2O5 tends to get sticky when it absorbs water, preventing underlying material to react) and heating it for 1 hour at say 80C be sufficient? Then quench the reaction mixture with a large excess off ice cold water (does phosphoric acid hydrolyse the nitrile quickly if preventive measures are taken to keep the solution cool?), and extract with ether or DCM, dry with MgSO4 and remove the solvent by distillation or under vacuum?

I think I would simply use a 1:1 hexanes/acetone for TLC, and visualise with a few I2 crystals in a closed chamber.

I have no idea what would be the procedure for the reduction of the nitrile to the amine, I haven't used the search engine on all possible keywords, but I haven't found much. Urushibara catalysts? Is that what you are referring to Nicodem?

Or I could just hydrolyse the nitrile again to obtain ibuprofen :D

Maybe it would be more efficient to do a Hoffman Rearrangment on the amide, on the other hand the two steps (amide->nitrile->amine) sound much more fun and a challenge.

The other steps:
Ibu --> Et or Me ester --> Grignard --> Ritter reaction.

Esterify according to procedure in my first post.

For the Grignard I will use EtBr. I wonder, how can you dry EtBr. Can I dry it over P2O5?
Considering the ether I would be using, I don't like to make just the required dry ether for the reaction and then have to do it again for another Grignard, so I think I will make 100-150mL. MgSO4--> reflux over Na, and distillation.
Can the excess ether be stored over KOH or MgSO4 to keep it dry enough? I will toss in a tip of anhydrous Na2SO3 too. I have some ether over Na2SO3, and it does a good job to keep it peroxide free (before I added it, it contained some peroxides).
I have done a Grignard before, under nitrogen, but a dry apparatus with a CaCl2 guard tube should be enough as well right?
Then after Grignard usual workup with dilute acid, extraction with solvent (ether?), wash with aqueous NaHCO3, water, dry the organic layer over MgSO4 or K2CO3 and remove solvent.

Then I could do a Ritter reaction with acetonitrile or form the ethyl ether by reaction with EtBr. When forming the alkoxide, the reaction is probably very slow. What solvent must be used for this? I guess the high boiling point of toluene makes it a nice candidate but I don't think the sodium salt is soluble.
What should be the procedure for the Ritter reaction. I read that it can be done in AcOH/H2SO4? I read that you can activate the reaction with triflic anhydride (I have 10mL of this) ? However, in catalytic amounts?

Would a-bromination of ibuprofen in DCM work well, in the presence of a little red P? This would also open new pathways.

Then finally, does anyone have advice on recrystallising some of the solid products named above? I know how I can find a good solvent(mixture) but if there are general solvents wich work well on compounds like these it avoids all the hassle.
I have available when I start:
Acetone, ethanol, methanol, iPrOH, hexanes, toluene, dichloromethane, ether, GAA, MeCN,. I have CCl4, CHCl3 (not much) and benzene, but I'd rather avoid these.

Magic Muzzlet - 24-4-2011 at 17:55

Just so you know, so many precautions and steps are not necessary for Grignard reactions. I have performed many with a few different alkyl halides (EtBr is easiest to start) and you do not need nitrogen or drying the ether over P2O5.
Each time i have run one, even with making my own ether to be used in one, drying with NaOH and storing over KOH, distillation from the KOH, itis plenty dry enough.
It is dry enough that merely activation of the Mg with acid is enough to ensure the reaction will start, of course use CaCl2 tube, but inert gas isn't necessary.
Maybe just because i live in a dry area, some may disagree with my advice. I am just saying, I've never had a Grignard fail on me, each time I do it like i have said.

Store the ether on KOH for a few days though,

Edit: EtBr dried and stored on CaCl2 has worked fine for me in the past, I would say no need for the P2O5 there.

[Edited on 25-4-2011 by Magic Muzzlet]

ItalianChemist - 26-4-2011 at 09:43

I've tried to nitrate ibuprofen and I obtained a yellow oil, not yellow crystals...:(

Nicodem - 8-5-2011 at 13:55

Quote: Originally posted by Jor  

Intimately mix 1 eq. of ibuprofen with 2 eq. of urea (I know only one is needed, but the stuff is cheap!). Heat at 150C until gas evolution ceases (when I did phthalimide, the mixture at once became solid and frothed). Then wash out the solids wich water, filter, wash with more water. This product should be pure enough for the next step?

Water is unlikely to leach out all the side products and impurities. I suggest you to follow a standard extraction based work up and finish with a recrystallization. OK, maybe you can skip the extraction by doing the trituration in water, but then do a recrystallization to get a similarly pure product. But all this depends on the reaction conversion and amounts of urea condensation products.
Whatever reaction you do, I suggest you to always recrystallize every solid product you get untill it is TLC pure. Recrystallization is not always needed for purification, but since you have no access to spectroscopic tools for the product identification, you need to recrystallize anyway for the m.p. test.
For examples of urea based amidations, I suggest you to check, beside the literature, also smuv's experiments on benzamide synthesis.
Quote:
Does boric catalysed amidation only work with aliphatic amines or would aniline work as well? I also wondered, when I would use ethylenediamine as the amine, I could possibly obtain a polymer right? That might be interesting to try.

No, it works well also for anilines and the anilide of ibuprophen certainly is a nice target.
With ethylenediamine you would not get a polymer. You would obtain either the N,N'-diacyl derivative or the imidazoline derivative of ibuprophen. I don't know which would form, but I have a feeling the imidazoline formation is likely. This would probably be an oil at RT, while the diamide would be crystaline solid.
Quote:
I really don't like the idea of using 15 equivalents of Ac2O to convert the amide in nitrile! I don't see why 3-5 wouldn't work. Maybe you won't be able to dissolve all the amide, but that wouldn't matter too much right?

The reaction in suspension would probably do just fine, but it is about kinetics in my opinion. The less excess of Ac2O, the slower the reaction and might not reach the full conversion in any useful time.
Quote:
If I woulld dehydrate the amide with P2O5, would mixing it very quickly with excess P2O5 (how much would be needed, it's a solid solid reaction, and the P2O5 tends to get sticky when it absorbs water, preventing underlying material to react) and heating it for 1 hour at say 80C be sufficient?

I don't know, but why don't you just follow the experimental in the article I gave you the reference for?
Quote:
I think I would simply use a 1:1 hexanes/acetone for TLC, and visualise with a few I2 crystals in a closed chamber.

That would be too polar for most analytes in these series of reactions. If you have to use acetone instead of ethyl acetate, then try with ranges from 15 : 1 to 3 : 1. Its hard to tell for acetone, as most people grew a feeling only for standard mobile phases (like hexanes/ethyl acetate or CHCl3/MeOH for polar stuff). Remember that carboxylic acids tend to trail on TLC unless you add a few drops of acetic or trifluoroacetic acid in the mobile phase. Primary and secondary aliphatic amines tend to stay immobile. Tertiary amines usually trail as well unless you add a few drops of Et3N, or NH3 where applicable. Aromatic amines (e.g., anilines) behave normaly. Iodine for visualisation might not show everything. You might consider buying a 254 nm UV lamp. You can get some simple ones (battery run) for about 150 EUR or less. Or you can use the KMnO4/Na2CO3(aq) solution for visualization. This one is practically totally general and once you get used to it, it simple to use.
Quote:
I have no idea what would be the procedure for the reduction of the nitrile to the amine, I haven't used the search engine on all possible keywords, but I haven't found much. Urushibara catalysts? Is that what you are referring to Nicodem?

You have an example of nitrile reduction with the Zn/Ni couple in patent FR971429 (I guess you undestand enough French to understand the pertaining example). The Hive post No. 270027 contains the translation of Académie des Sciences (1941) 304-305 where this same method is used for reduction of nitriles. There are other references, but at the moment I can't really go trough my files.
There is plenty of documentation of Urushibara-type reductions of nitriles as well, but I think you can find that on the forum already. Otherwise, I'll see to bring up some papers when you will have some nitriles made.
Quote:
Maybe it would be more efficient to do a Hoffman Rearrangment on the amide, on the other hand the two steps (amide->nitrile->amine) sound much more fun and a challenge.

Once you have made enough of the amide, you can play with different transformations.
Quote:
Considering the ether I would be using, I don't like to make just the required dry ether for the reaction and then have to do it again for another Grignard, so I think I will make 100-150mL. MgSO4--> reflux over Na, and distillation.

That is overkill. Just dry it over NaOH or KOH and use without distillation. Should be enough for starting the reaction of EtBr.
Quote:
Then I could do a Ritter reaction with acetonitrile or form the ethyl ether by reaction with EtBr.

You can't make ethyl ethers by alkylation of t-alcohols. Remember that tBuOK is a base usefull for many aplications exactly because it is nearly non-nucleophilic. In fact, the product of EtMgBr addition on ibuprophen esters would be so crowded, that I have doubts you will get much of it even after prolonged reflux. It is likely that the intermediate ketone enolizes faster than it reacts with EtMgBr. In such case you get the ketone after quenching the magnesium enolate (more likely a mixture with the t-alcohol).
Quote:
What should be the procedure for the Ritter reaction. I read that it can be done in AcOH/H2SO4? I read that you can activate the reaction with triflic anhydride (I have 10mL of this) ? However, in catalytic amounts?

Don't waste something as expensive as Tf2O for such a simple reaction. Check the literature for the conditions of some similar t-alcohols and use those condition. A mixture of MeCOOH/H2SO4, for example 10 : 1 for a couple of hours at 50 °C, usually works just fine for t-alcohols.
Urea can be used as the nucleophile instead of nitriles in a Ritter-like reaction. You get the corresponding N-(t-alkyl)urea as the product (should be a solid).
Quote:
Would a-bromination of ibuprofen in DCM work well, in the presence of a little red P? This would also open new pathways.

The Hell-Volhard-Zelinsky halogenations should work on this substrate, I think, but I'm not sure about the conditions you give. Check the literature for related substrates.
Quote:
Then finally, does anyone have advice on recrystallising some of the solid products named above? I know how I can find a good solvent(mixture) but if there are general solvents wich work well on compounds like these it avoids all the hassle.

I think you can get by with either EtOH/H2O or iPrOH/H2O mixtures, or toluene, or toluene/hexane, for most such products. I would not use any other you list.

Nicodem - 5-11-2012 at 13:25

Quote: Originally posted by Nicodem  
Quote:
Does boric catalysed amidation only work with aliphatic amines or would aniline work as well? I also wondered, when I would use ethylenediamine as the amine, I could possibly obtain a polymer right? That might be interesting to try.

No, it works well also for anilines and the anilide of ibuprophen certainly is a nice target.
With ethylenediamine you would not get a polymer. You would obtain either the N,N'-diacyl derivative or the imidazoline derivative of ibuprophen. I don't know which would form, but I have a feeling the imidazoline formation is likely. This would probably be an oil at RT, while the diamide would be crystaline solid.

Just stumbled upon an ASAP article and remembered this old post. Finally some authors tried the boric acid catalysed condensation of carboxylic acids with aliphatic 1,2-diamines and the products are indeed imidazolines rather than the N,N'-diacyl diamines (DOI: 10.1021/op300254q). An earlier report from the last year describes a study on the boric acid catalysed condensation of carboxylic acids with ortho-benzenediamines to give benzimidazoles (DOI: 10.1002/hlca.201100064).