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Author: Subject: Michael Addition and the Synthesis of Aminoglutethimide
Sauron
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[*] posted on 21-8-2007 at 00:07
Michael Addition and the Synthesis of Aminoglutethimide


I am studying the preparation of the interesting anticancer drug aminoglutethimide for essenatially personal reasons.
Its close chemical relative glutethimide almost killed me when I was 15.

At that time I was a high school student and I had a urinary tract infection. It was being treated with gantrasin, a sulfa. The regime was two pills 500 mg each four times a day, at 8 am, 12 noon, 4 pm and 8 pm.

I went through the first prescription and my dad went to the neighborhood pharmacy K&B now out of business, for a refill. He returned about 7 pm, and so I was ready to take my 8 pm pills after dinner.

I noticed that the refill pills were marked CIBA unlike the first batch but they were same size shape and color and neither I nor anyone else thought anything was amiss. So I took them.

Next morning awoke normally and took two more. Went to school, and at lunch took two more. About an hour later I slid right out of my chair in class.

I was unconscious for three days. The pharmacist had inadvertently swapped my sulfa for Doriden 500 mg, a powerful sedative, normal adult dose 1 per 24 hrs. I had ingested six in about 16 hours.

The generic name for this drug is glutethimide and I am given to understand that it is no longer on the market. (Actually it is on the market but rarely prescribed.)

The compound is 3-phenyl-3-ethylglutarimide and it is made by the Michael addition of 3-bromopropionic acid (or its ester) to a-cyanopropyl benzene. That is just phenylacetonitrile with an ethyl group added at the benzylic position, possibly by another Michael addition.

I am certainly not interested in making Doriden, which anyway would be illegal (it is a controlled substance) but I have become fascinated with the Michael addition, also known as the Michael reaction or condensation. It was first described in J.Prakt.Chem. in 1887 and is extremely versatile. It is definined as the base catalyzed conjugate addition of a nuclephile with a conjugated unsaturated system.

The main review of this classic reaction seems a wee bit hard to come by. It is in Org.Reactions 10, p.179-555 (1959).

The forum library has only vols 1-3 and the ftp site, vols 25 and on. How annoying.

Thanks to sparkgap for suggesting the shift in focus in this thread.

[Edited on 22-8-2007 by Sauron]
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vulture
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[*] posted on 21-8-2007 at 03:03


You might want to check a standard reference work like Organikum (again sorry ;) ) or March's advanced organic chemistry for more recent references.

The possibilities with michael additions are virtually endless, but there are a number of fine points which require some care.




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Sauron
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[*] posted on 21-8-2007 at 03:26


Thanks. I do have Organikum 21st ed. on hand now, and I also have March's text.

Vogel has an example of two, and Org.Syn. quite a few, judging by a preliminary search for preps using methyl acrylate. (Maybe not all this reaction.)

I have decided not to elaborate on the prep of glutethimide since I see to my horror that its abuse has not died out, it is apparently used in concert with codeine. Ugh, The medical use of Doriden on the other hand is almost totally passe.

So I will have to find some other exemplar to illustrate the use of this reaction.

-----------------

I ordered a second hand copy of Org.Reactions v.10 (hardcover) for $25, thanks to not_important for pointing it out to me.

March's Advanced Organic Chemistry was really not very useful. And Organikum will be slow plodding due to language issues. I really wish Wiley would bring this out in English.



[Edited on 22-8-2007 by Sauron]
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[*] posted on 22-8-2007 at 02:09


Here's an experiment involving Michael addition for those who like me have an interest in this type of procedure. Surely some of the starting materials can be changed to what ever is available. If anyone has other examples and procedures us amatures can attempt please post them as this is interesting work.

http://www.cerlabs.com/experiments/0534681417.pdf
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[*] posted on 22-8-2007 at 02:49


As I might have imagined, you have already searched Rhodium and found little to help you. I was curious myself, so I did. The only thing I found, besides the structure, was Shulgin's piece on "Future Drugs of Abuse." He thinks that glutethimide is one, as well as analogues.
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sparkgap
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[*] posted on 22-8-2007 at 02:55


Slightly off-topic:

"...It was being treated with gantracin, a sulfa."

I believe you meant Gantrisin (sulfisoxazole), which was a product of Hoffmann La Roche, unlike Doriden.

In any case, its congener aminoglutethimide (brand name Cytadren, from the same company that brought you Doriden) is not only a sedative but an aromatase inhibitor that fiddles with the body's synthesis of estrogens and corticosteroids. This is used in treating Cushing's syndrome. The only difference is an amino group in the para position of the benzene ring. :) Maybe you could do that instead.

sparky (~_~)




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Sauron
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[*] posted on 22-8-2007 at 03:38


Thanks for the correction and suggestion. If the Cytadren is not an abuse drug, or a DEA scheduled controlled substance I will be happy to describe its preparation. The only difference would be in the use of 4-aminobenzyl cyanide, or alternatively 4-propylaniline, as the starting material.

A preliminary googling indicates no sign og abuse of this compound.

The final structural target is 3-ethyl-3-(4-aminophenyl)-piperidine-2,6-dione. Piperidine-2,6-dione is of course glutarimide, the cyclic imide of glutaric acid.

So the preparation of aminogluthethimide consists of the following steps:

Preparation of a-cyano-4-aminopropylbenzene or a-ethyl-4-aminophenylacetonitrile.

Michael addition of a suitable reagent (several are about equally useful) to the first product. The useful reagents include methyl acrylate, methyl 3-bromopropionate, etc.

Cyclization of the resulting product

The first step can be done from 4-aminopropylbenzene by brominating the benzylic carbon and then replacing the Br with cyanide.

Or, it can be performed by the Michael addition of acetaldehyde (for example) or ethyl bromide (just as suitable) to 4-aminophenylacetonitrile. The amino group may need to be protected by, say, acetylation.

The resulting compound still has an available benzylic hydrogen that can be abstracted by strong base and attacked in a further Michael addition.

The literature Michael bases are NaNH2 and KOH.

So in the second step we do just that and now we have the makings of a glutarimide.

The literature condensing agents are sulfuric acid or SnCl4 in AcOH or AcOH/Ac2O.

The final chore is removal of the acetyl group from the aniline which is trivial.

Now that I have stuck my neck out I will go look up the actual lit. and patent and see if I got this right or not. I will report back with references.


[Edited on 22-8-2007 by Sauron]
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[*] posted on 22-8-2007 at 03:53


It is not a controlled/scheduled drug, presumably because its effect on the endocrines would be quite the deterrent to its use as a sedative, despite it exhibiting depressant effects. ;)

I mean, I don't want to take something to help me sleep for the night and wake up the next day find that I now am the proud owner of a pair of man-boobs. :D

sparky (~_~)




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Sauron
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[*] posted on 22-8-2007 at 04:56


In some circles the boobs would be the primary desired effect.

Anyway here is the US patent to CIBA for this stuff. The aacetylation is covered therein, but their preferred strategy is to employ the 4-nitrophenyl and then reduce it catalytically. Makes sense.

There are no other surprises.

Note the use of a PTC in one of the early examples in which methyl acrylate is used. Alleviates the solubility issues.

There may be some references to the primary literature in this patent.

he ACS journals are certainly worth a look too.


[Edited on 22-8-2007 by Sauron]

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[*] posted on 22-8-2007 at 21:22


Here is the overall reaction scheme. Other variations are possible, as the Michael addition is an extremely broad reaction with much scope.

Also the penultimate cyclization can be accomplished from the nitrile ester, the diamide, the dinitrile, or mononitrile (as shown) or other combinations of glutaric acid derivatives.

The patent states that proceeding via the p-nitrophenyl precursor is the preferred embodiment of the invention but it is also possible to employ the p-aminophenyl intermediate if it is protected, then liberated later.

Aminoglutethimide is used in hormone therapy and cancer therapy especially against breast cancer. It is also an abortifacient.

[Edited on 23-8-2007 by Sauron]

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