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Picric-A
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[*] posted on 18-7-2009 at 15:10
Propofol Synthesis


Starting from one mole of Phenol, could i react it with two moles of Isopropyl chloride to produce Propofol (2,6-diisopropylphenol)?
thanks,
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DJF90
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[*] posted on 18-7-2009 at 15:16


Possibly, although it depends how you propose to run the reaction, catalysts, regioselectivity etc etc. More details needed. Give us the proposed synthesis and we can tell you if it will work or not. I am not going to spoonfeed you. Dont be lazy. And Nicodem must be getting really irritated with saying this so I'll say it for him - Threads opened without a reference are to be created in the Beginnings section.
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[*] posted on 18-7-2009 at 15:26


Well Propofol is an extremely potent sedative and prescription only medicine, which I expect, without checking, is likily a restricted drug for use by anaesthetists only.

DJF90: I expect Picric-A is alluding to the potential of using a FC alkylation of phenol! Would have been nice if he could have been bothered to have written out his theoretical route.

Don't end up like MJ...





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DJF90
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[*] posted on 18-7-2009 at 15:31


Well if thats his intentions he's playing with fire...

Yes I would expect the FC alkylation. There shouldnt be a problem with rearrangement of the carbocationic species. Problem is the unprotected 4-position. I'm not going to help this young lad make a potent anaesthetic so I'll leave it down to him to work out what needs to be done.
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Picric-A
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[*] posted on 18-7-2009 at 15:35


Sorry yes i should of put this is begginings, however i thought this is a very organic syntheis.
I havnt found a written synthesis for it which is why i intend on thinking up one.
@panziandi- this is for educational purposes only, i am not a meth cook, you should know that.
So far, react one mole of phenol with two moles of isopropyl chloride, using a anhydrous aluminium chloride catalyst. This is done under reflux for 2 hours till completion. the product is then seperated by pouring into water, which precipitates out the insoluble compopund.
I am not asking for spoon feeding, quite the contrary, i simple require you advise and expertise. Will the isopropyl groups go to the 2,6 positions? will the alcohol group not be affected?
thanks,
Just found this:
http://bio-che.mc.edu/valente/ch24.pdf
AlCl3 cat. can not be used, may try ZnCl2 made form zinc + dry Cl2

[Edited on 18-7-2009 by Picric-A]
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DJF90
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[*] posted on 18-7-2009 at 15:40


You are not considering the other problems with the synthesis, even though I hinted to one of them. This is organic synthesis, but without references it should still be posted in beginnings. I will remind you once more of the problem - what about the 4-postion? Although the phenol directs ortho and para, whats stopping an isopropyl group from going para? You need to block this position. Go and read perhaps and then come back when you have a suggestion. Remember a protecting group needs to be removable. The phenol should react with the AlCl3 lewis acid there. If the reaction was run under basic conditions then you may have the problem of williamson etherification, but AlCl3 is a good lewis acid so theres no worries about this.

Why use ZnCl2? Whats wrong with AlCl3? Yes O-alkylation is a side reaction but unless you fancy protecting the oxygen as well then you'll have to live with it and separate the byproduct from the product. You could protect the 4-position and the oxygen, and then deprotect in one step (possibly?)

[Edited on 18-7-2009 by DJF90]
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Picric-A
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[*] posted on 18-7-2009 at 15:46


The only thing i can think of off the top of my head is dinitrate the phenol, mono-reduce the ortho group with Na2S, yielding 2-amino-4-nitro-phenol, diazatozation of that followed by reacting with ethanol would yield 4-nitrophenol. FC alkylation of this yielding 2,6-diisopropyl-4-nitrophenol. Reduction,diazatozation--> react wit ethanol, would yield my product.
any thoughts?
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panziandi
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[*] posted on 18-7-2009 at 15:48


The 4 position is particularly "open" sterically I would expect FC to go 2,4 in preferance to 2,6 - so DJF90 is very correct in hinting the need to block the 4 position.

Technically you wouldn't be a "meth cook" if you are making Propofol since it is not related to methamphetamine "you should know that"





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DJF90
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[*] posted on 18-7-2009 at 15:51


Yea thats very long winded. Personally, I would sulfonate (protects 4-position), then acylate (AcCl - protects oxygen) then do the freidel crafts to form the protected product. Deprotection could then be affected by fairly dilute acid (2M?) to remove the sulfonic acid group and possibly the acyl group. If the acyl group is stubborn switching to basic hydrolysis after removal of the sulfonic acid will work (so long as the product is not base sensitive)

Finding an exemplar procedure for each reaction is down to you though.

[Edited on 18-7-2009 by DJF90]
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[*] posted on 18-7-2009 at 15:52


I believe if you generate a carbocation with iron or aluminum chloride, the OH on phenol will react making an alkyl aryl ether, and ring alkylation would be only a side product.

I think going with IPA and phosphoric acid will affect C-alkylation, although 2,4 vs 2,6 ratios I cannot predict off the top of my head, you will have to check some literature

EDIT: This article may be a place to start looking, I do not have access or I would have posted the entire article.

http://pubs.acs.org/doi/abs/10.1021/ie049141q



[Edited on 18-7-09 by The_Davster]




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[*] posted on 18-7-2009 at 15:55


I would almost definately assume 2,4- over 2,6-. However that is an interesting point you raise. Using the alcohol to generate the carbocation should work well. No need for AlCl3 either. Perhaps running the reaction in IPA (or at least with a large excess) to compensate losses due to formation of propene as a byproduct.
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18-7-2009 at 16:27
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[*] posted on 18-7-2009 at 16:40


The industrial synthesis seems to consist of alkylation of phenol with propylene at high temperatures and pressures.. not very suitable for the amateur.

According to this patent propofol can be effectively purified by low temperature recrystalization from petroleum ether. So even is the reaction you settle on isn't very selective, it should be possible to purify it fairly easily.

Another possibility is the claisen rearrangement of 2-isopropylphenyl isopropyl ether. It works according to this patent. They used an alumina catalyst in an autoclave, but you might be able to figure out an easier way to do it.

[Edited on 19-7-2009 by 497]
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[*] posted on 19-7-2009 at 13:36


Diazonium on 2,6-diisopropylaniline.
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[*] posted on 19-7-2009 at 14:08


Thats fine, but you still have to make the 2,6-diisoproylaniline...
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[*] posted on 19-7-2009 at 15:37


Quote: Originally posted by DJF90  
Thats fine, but you still have to make the 2,6-diisoproylaniline...


Anybody who can get AlCl3 for a Friedel-Crafts can get 2,6-diisopropylaniline.
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[*] posted on 19-7-2009 at 16:00


Quote: Originally posted by 497  
The industrial synthesis seems to consist of alkylation of phenol with propylene at high temperatures and pressures.. not very suitable for the amateur.

According to this patent propofol can be effectively purified by low temperature recrystalization from petroleum ether. So even is the reaction you settle on isn't very selective, it should be possible to purify it fairly easily.

Another possibility is the claisen rearrangement of 2-isopropylphenyl isopropyl ether. It works according to this patent. They used an alumina catalyst in an autoclave, but you might be able to figure out an easier way to do it.

[Edited on 19-7-2009 by 497]


Perhaps phenol and PP feedstock in bomb? Phenol from aspirin, and polypropylene OTC. But I have a feeling the PP would have to be 1st processed,amongst other things, because the harsh conditions required for favorable reaction might not work properly with the polymer (not certain, any comments?). It's a shame MJ made this drug now infamous...it's chemical structure otherwise makes it very unpopular for controls (tjeeze, it's just a substituted phenol). Intriguing like modafinil, but in reverse. The stimulant allows one to stay awake with a high quality of wakefullness/alertness. But you have to pay the piper later on with additional sleep. Short time periods of propofol induced anesthesia, apparently, could substitute for 8 hours of the real thing. Quite useful for touring, and those on tight schedules.
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[*] posted on 19-7-2009 at 16:35


"Short time periods of propofol induced anesthesia, apparently, could substitute for 8 hours of the real thing. Quite useful for touring, and those on tight schedules. "

Care to cite a reference for that tripe, Globey?

"Perhaps phenol and PP feedstock in bomb? Phenol from aspirin, and polypropylene OTC."

LOL. See signature below for further details.




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[*] posted on 20-7-2009 at 10:14


Quote: Originally posted by Globey  
Quote: Originally posted by 497  
The industrial synthesis seems to consist of alkylation of phenol with propylene at high temperatures and pressures.. not very suitable for the amateur.

According to this patent propofol can be effectively purified by low temperature recrystalization from petroleum ether. So even is the reaction you settle on isn't very selective, it should be possible to purify it fairly easily.

Another possibility is the claisen rearrangement of 2-isopropylphenyl isopropyl ether. It works according to this patent. They used an alumina catalyst in an autoclave, but you might be able to figure out an easier way to do it.

[Edited on 19-7-2009 by 497]


Perhaps phenol and PP feedstock in bomb? Phenol from aspirin, and polypropylene OTC. But I have a feeling the PP would have to be 1st processed,amongst other things, because the harsh conditions required for favorable reaction might not work properly with the polymer (not certain, any comments?). It's a shame MJ made this drug now infamous...it's chemical structure otherwise makes it very unpopular for controls (tjeeze, it's just a substituted phenol). Intriguing like modafinil, but in reverse. The stimulant allows one to stay awake with a high quality of wakefullness/alertness. But you have to pay the piper later on with additional sleep. Short time periods of propofol induced anesthesia, apparently, could substitute for 8 hours of the real thing. Quite useful for touring, and those on tight schedules.


Oh yes, and reason I never cited reference in 1st place is simply...I really have nothing to prove. I'm not trying to prove something. Just passing on something I read, My writings on these boards are mostly not intened to be read like a referenced study (with footnotes for everything). I really don;t understand so many people copping tude and asking for references for everything...i mean, screw you man. HEHE sorry but.
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[*] posted on 20-7-2009 at 10:32


People want references because they don't want to waste their time on things that won't work.
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[*] posted on 20-7-2009 at 11:41


First some confusion...
Globey: " It's a shame MJ made this drug now infamous" Who is MJ? I cannot think of any member who could be abbreviated like that.
and "so many people copping tude" what is copping tude?

That said I cannot see polypropylene rupturing C-C bonds and being used as a propene source. If I am wrong I will be pleasantly surprised.

entropy51: "Anybody who can get AlCl3 for a Friedel-Crafts can get 2,6-diisopropylaniline." Not necessarily. Synthesis of AlCl3 from common materials is much easier than that of diisopropylaniline.

Cursory googling indicates that propofol is synthesized in a method similar to what I suggested, but with unknown catalysts to favor 2,6.




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[*] posted on 20-7-2009 at 11:52


Let's run through the process of finding out this sort of information, while assuming that you don't have much access to expensive books or journals.

If you do have access to commercial publications I'd suggest starting with the Merck Index and/or chemical dictionaries. But let's assume that you need to read everything for free.

First stop, Wikipedia entry on propofol. You can see its chemical formula, structure, and some background about its introduction as a drug.

Next Google-search for propofol synthesis. The first hit is a J. Med. Chem. article about synthesis and SAR of propofol analogs. One might presume that the analog synthesis will give some hints as to the parent compound synthesis. You would need some help or a subscription to read the paper, though. Another trap is that they may start from commercially available compounds that are no more accessible to you than propofol itself is.

Since it is a drug of commercial significance, the patent literature is another good source of information. Go to Google Patents and search for propofol. Order by date, oldest first. Often the "most relevant" hits selected by Google, or newer patents, will contain information about drug delivery, packaging, or successors that aren't that interesting when you are looking for synthetic information. On the first page of propofol results ordered by date, oldest first, there is a promising hit -- "Process for the purification of 2,6-diisopropyl phenol." This patent, already mentioned by 497, tells how to purify propofol once it is made and also briefly mentions the typical industrial preparation -- Friedel-Crafts alkylation of phenol with propylene.

The patent title offers another hint: you will get more interesting search results if you search for diisopropylphenol. The name "propofol" is going to show up only in patents after the compound was well established as a drug. I would suggest not searching specifically for 2,6 diisopropylphenol because older patents will have OCR errors in them. It is best to search for the shortest string that has a reasonable likelihood of denoting your target. The longer you make your search string, the greater the chance that relevant results will be spuriously excluded due to imperfections in optical character recognition.

Once you've exhausted Google Patents other possibilities are to search non-US patents with e.g. esp@cenet, run similar searches on Google Scholar, and search again on Google Books. I would also suggest running searches on HathiTrust and archive.org relating to diisopropylphenol (note that the compound was known well before it came into use as an anesthetic, so there is hope of finding information in older public-domain works). If you need to learn more about F-C alkylation, propylene, phenol, recrystallization, or other topics that may have come up in your readings, HathiTrust and archive.org have abundant information. If you are looking for examples of laboratory-scale reactions similar to those needed to prepare this compound, do not neglect the Sciencemadness library, which has a fine collection of older experimental/laboratory tomes on both inorganic and organic chemistry.

In running through this research process myself I found that almost all synthesis is industrially oriented: low operating costs, high temperatures and/or pressures. If you need a specifically lab-friendly prep you probably need to search deeper and longer than I did or try to reason by analogy in constructing a synthesis. It is not always possible to find an already-published synthesis of a particular compound, or one that is convenient.




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[*] posted on 20-7-2009 at 16:29


Polverone ^^^ sage advice, all of it. Would just add that many times the earlier processes/synthetic schemes, are better suited towards the hobbyist. State of art processes consider mainly overall costs, with commodity (feedstock) cost being the primary driver here. And if your cranking out tons and tons of product, pennies DO MATTER (especially in regards to cost competitiveness). Although the raw materials may cost twice as much using a technically obsolete process, that old method may be much easier to perform on a small scale, in lieu of having sophisticated, dedicated equipment using the cheapest feedstocks.

Davstir = Michael Jackson! I think Google searches for "propofol" recently hit an all time high, since it was revealed (post mort) that he had been pining for the drug to one of his now former advice nurses. Also, I think the news article (cnn.com perhaps) might be where I read about propofol's unique sleep sparing properties.

RE what I said earlier: h**p://allnurses.com/nursing-news/propofol-abuse-growing-405120-page2.html


"I think the goal here was not to remain sedated for the entire sleep period, but rather to have a brief period to use the drug to feel refreshed afterward. Apparently, there are some studies that suggest that propofol has the ability to erase one’s overall feeling of cumalative sleep deprivation
. If that is truly what his goal in using it was, in fact, he may not have had more than a couple of hours of sleep daily in many years, due to the artificial feeling of refreshment."
"



[Edited on 21-7-2009 by Globey]
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[*] posted on 21-7-2009 at 04:57


Quote: Originally posted by Polverone  

Next Google-search for propofol synthesis. The first hit is a J. Med. Chem. article about synthesis and SAR of propofol analogs.

Synthesis, Biological Evaluation, and Preliminary Structure-Activity Considerations of a Series of Alkylphenols as Intravenous Anesthetic Agents
Roger James, John B. Glen
J. Med. Chem., 23 (1980) 1350–1357. DOI: 10.1021/jm00186a013
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[*] posted on 21-7-2009 at 07:38




Attachment: ALKYL_PHENOLS[1].pdf (144kB)
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Attachment: alkyl phenol ortho.pdf (136kB)
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