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Author: Subject: MPPP/MPTP Parkinsonism
contrived
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[*] posted on 10-3-2007 at 18:55
MPPP/MPTP Parkinsonism


where could I read up on the MPPP syn and the issues that lead to the sideproduct that causes Parkinsonism?

Google didn't lead to very much nor did Rhodium archives if I used it correctly..
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[*] posted on 10-3-2007 at 19:07


I believe this was in one of the forensic-science journals. Very famous incident.

Two bent chemists set out to make fentanyls and found that too hard so they changed course, but messed it up. As a consequence they messed themselves up permanently and rather acutely. So they made a contribution to medical science - the hard way. Moral: if you can't do the QC don't do the pharm.

I think I saw ref. to the journal article in Aldrich catalog under listing for the bad product, now a research tool. You might look for it there or on Google.
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[*] posted on 10-3-2007 at 20:47


you mean they started out to make a-methyl fentanyl and went to MPPP instead? What is MPPP?
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[*] posted on 10-3-2007 at 21:03


I forget which fentanyl they wanted to make but they apparently discovered it was too difficult for them so they changed target compounds to something totally different. An analog of Demerol (meperidine) Demerol was and is a very useful analgestic clinically but is not too popular among addicts. MPPP is longer acting and has less unpleasant side effects so these guys set out to make MPPP. Being too cheap to buy a GC-MS they did not know they were producing MPTP as a byproduct and so took no steps to remove it. In vivo, MAO converts MPTP to MPP+ which is very bad news. Addicts as young as late teens with symptoms of elderly advanced parkinsonism. There were some fatalities as well, maybe they were the luck ones.

How many addicts suffered as a result of their avarice, greed and incompetence?

Who knows? A lot.


Pardon me, but if you do not know what MPPP is, why do you wish to know how to prepare it? Seems a bit odd.

I hope you don't want to emulate these fellows, very bad karma there.

I had to edit and replace the sketch below, MPPP structure was incorrect. Some websites give incorrect names for these. Below are the correct structures and IUPAC nomenclature.

[Edited on 11-3-2007 by Sauron]

MPTP.jpg - 10kB
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[*] posted on 10-3-2007 at 21:32


That compound is MPTP!

It does not matter what they were trying to do...The Chemistry was poor, and many paid the price.

I made a small comment here:

http://www.sciencemadness.org/talk/viewthread.php?tid=7996&a...

If you do not have adequate analytical instruments or technique do not *ever* make a *compound* for other human beings to consume! Do not fall to the dark side and try to profit with illicit pharmies!

Just my $0.02,

O3




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[*] posted on 10-3-2007 at 22:08


Quote:
Pardon me, but if you do not know what MPPP is, why do you wish to know how to prepare it? Seems a bit odd.



Most certainly not. Curiosity (mainly) combined with the desire to never approach that material in work with saturated heterocycles. What's odd about wanting to learn?

[Edited on 10-3-2007 by contrived]
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[*] posted on 10-3-2007 at 22:13


They were not the only ones hurt btw I remember reading about a number of people in California showing up with Parkinsonism.

The worst karma imaginable
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[*] posted on 10-3-2007 at 22:48


Nothing bad about wanting to learn.

As you can see above, MPPP is a two carbon homolog of Demerol, which itself is a derivative of our old friend isonipecotic acid, an analog of nicotinic acid (important vitamin.)

But they botched the C-C bond formation and ended up with the tetrahydropyridine instead, and monoamine oxidase turns that into the 1-methyl-4-phenylpyridinium ion MPP+ and that is what does the damage. Selective destruction of dopaminergic neurons. Advanced parkinsonism or death in hours to weeks.

See J.W.Langston et al, Science, 219 979 (1983)

Other refs Merck Index 12th Monograph 6376

Attachment from a thesis gives whole sordid MPPP/MPTP story including fate of the 23 year old chemist ( dead) and relationship to PD.

@O3, very well said. But not only the technology to analyze, but to purify as well, a GC-MS would have told them there was an impurity but they still would have needed HPLC to get rid of it.

I suppose there might be such a creature as an ethical drug cook, but I have yet to meet one. You know what they cut speed with in Thailand? Strychnine, gramoxone (aka paraquat) and caffeine. The strychnine makes it harder to withdraw. Cute, huh?




[Edited on 11-3-2007 by Sauron]

Attachment: Chapter1-3[1].pdf (381kB)
This file has been downloaded 717 times

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[*] posted on 11-3-2007 at 00:44


piperidone, bisulfite adduct, NaCN and aniline to make 4-piperidinophenylcarbonitrile
condense with propionyl chloride
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[*] posted on 11-3-2007 at 01:12


Well, N-methylpiperidone

The relationship to phencyclidine is worth noting as well as some commonality with the fentanyls.

See what he did with demerol? Flipped the side chain around.
Demerol -C(=O)OEt carboxyethyl and MPPP -O(C=O)Et propionoxy

Attachment from thesis suggests he cut corners, reduced rxn time and upped temperature. I suspect that the structural switch to a teriary hydroxyl made side rxn elimination to the tetrahydropyridine essentially inevitable. Nothing like that in prep of demerol.

He paid the price, dead age 23. OD'd and suffering PD effects of his own MPTP.

REALLY bad news is that no one figured out the neorotoxicity of MTPT and its presence in what had by then been on the street for 4 years till 1983, while the zero case died in 79.

No wonder DEA watches propionic anhydride and propionyl chloride lika a hawk, not to mention piperidine.
-----------------------------------

Actually the thesis chapter says the route used was phenyllithium and N-methylpiperidone, then condensation with propionic anhydride in presence of H2SO4.

And MPTP could form by dehydration of the intermediate tertiary alcohol, or elimination of propionic acid from the MPPP.

[Edited on 11-3-2007 by Sauron]
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[*] posted on 11-3-2007 at 12:17


but it could be done ala Strecker ... I thought they were after MPPP not demerol (?) ruined a lot of lives ..

some literature suggesting MPTP effects reversible in like 4-16 years .. have you heard/read?
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[*] posted on 11-3-2007 at 13:31


No, I hadn't seen that, and yes MPPP was the target not demerol. The addicts didn't like demerol, too short acting and too harsh side effects, MPPP had a heroin like feel to it (so I am told). It was a big hit on the street as "super demerol" till the tremors started.

I can see the cyanohydrin formation via NaCN on the bisulfite adduct of the piperidone, and the acid chloride or anhydride on the resultant OH is clear. The C-C bond formation between aniline and the nitrilo group is your Strecker? I will have to have a look at it. Nice to have an alternative to lithiation. Not that this product is one I aspire to...just as a matter of principle.

[Edited on 12-3-2007 by Sauron]
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[*] posted on 11-3-2007 at 14:36


The synthesis of demerol is briefly shown in Organikum, where another route is used: Benzyl cyanide is condensed with N-methyl-bis(2-chlorethyl)amine in the presence of a very strong base to form 4-phenyl-4-cyano-N-methylpiperidine.
Heating this with H2SO4 and absolute ethanol then directly yields demerol by hydrolysis and esterification of the cyano group.
This is the original synthesis of demerol, which is really remarkably simple. The catch is that N-methyl-bis(2-chlorethyl)amine is a chemical weapon, a nitrogen mustard, and has powerful vesiccant and carcinogenic effects.
This is the reason why the new, more complicated synthesis starting with isonicotinic acid was developed.




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[*] posted on 11-3-2007 at 14:58


The nitrogen mustards form an impotant part of the cancer chemotherapeutic arsenal, an entire realm of medicine which developed from those nasty chemical weapons. There's an old saying: It's an ill wind that blows no good.

Anyway the synthesist was just using this nitrogen mustard to form the N-methylpiperidine ring and there are non-vessicant alternatives to do that, I'm sure.

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

@contrived, I refreshed my memory about Strecker synthesis. That gets you an alpha-aminonitrile which you can then take to an a-amino acid. That will not get you anywhere near MPPP, nor will it get you to meperidine (Demerol). It would instead get you the product at right

And how do you condense a (tertiary) nitrile with an acyl chloride?

The scheme you proposed was (quote) "piperidone, bisulfite adduct, NaCN and aniline to make piperidinophenylcarbonitrile..."

Compare to the structure on the left, which is two trivial steps away from the insanely potent Carfentanyl. Those steps being hydrolysis/esterification of the carbonitrile and, acylation of the aniline N w/propionyl chloride or Pr2O.

I suppose I hardly need to point out that as soon as you have a 4-aminophenylpiperidine structural fragment you are venturing into fentanyl country and that is a risky place to be for several different reasons. One, legality. This is about as illegal as you can get, and very aggressively enforced. Two, autointoxication. Some (most) of the fentanyls are so potent, on a weight basis, that they need to be handled as if they were chemical weapons. In fact, some of them have been used as incapacitants. Remember the movie theatre hostage incident in Russia? The agent used to knock out the terrorists was carfentanyl. And it killed about 1/3 of the hostages, anyway. So, be warned.



[Edited on 13-3-2007 by Sauron]

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[*] posted on 13-3-2007 at 00:47


Furthermore carfewntanyl has been used for political assassination. The plane crash that killed Pakistan's PM Zia along with most of his top military brass, the US Ambassador and the US defense attache was probably caused by a device which rendered the flight crew unconscious by means of carfentanyl. Such a device was within the capabilities of the Pakistan Inter Service Intelligence, and the KGB, both bitter enemies of Zia al_Haq.

Source: chemical warfare consultants reviewing physical evidentiary findings collected by US FBI team in Pakistan. Private communication 1990.
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[*] posted on 13-3-2007 at 08:32


I did about this for one of my presentations at uni :P

It was a terrible situation for all involved and as has been mentioned, the worst possible karma! There is a video out there called 'the frozen addicts' which is all about it.

They now use MPPP in the mouse model for parkinsons (well among other animals) and it has done a lot to forward the understanding/treatment of parkinsons. Giving these addicts/victims embryonic foetal dopaminergic cells has helped to alleviate their conditions somewhat (don't know how permanent though).

Its funny how the most horrible tragedys can result in pushing forward science, swings and roundabouts!
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[*] posted on 13-3-2007 at 09:29


It's the primate model for parkinsonism. That certainly includes man. Note that the precursor of MPTP and thus MPP+ does not arise in the preparation of the fentanyls or of meperidine, only of MPPP and its analogs with an -OH or O-acyl in the 4 position of the piperidine ring that can dehydrate or eliminate to the tetrahydropyridine.

Even then, proper synthetic precautions and rigorous purification, such as are the norm in the pharmaceutical industry, would preclude the presence of such neurotoxic byproduct in the final product. This happy situation simply does not exist in the drug world. The chemist who first made "super demerol" was a polydrug abuser who died of an overdose. He didn't know that he was making MPTP along with his MPPP and in fact he was taking synthetic shortcuts that increased the occuence of MPTP. He was his own first parkinson's victim. He was treated while still alive and autopsied at NIMH Bethesda in 1979 but the findings awaited correlation four years later with four new cases before the connection was spotted. Unfortunately his "super demerol" had not died with him, it was picked up by an ethnic Mexican drug gang and widely distrubuted for several years.
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