Author Topic: Mechanism of MPTP formation during MPPP synthesis? (Read 270 times)

timecube · « **on:** July 03, 2010, 09:18:07 PM »

I've been reading through a number of articles on MPTP, but practically all of them focus on the mechanism through which it causes Parkinson's symptoms with only casual mention of it's formation during MPPP synthesis.

I'm trying to understand the mechanism and conditions under which it forms in order to be sure synthesis of its analogues is avoided during modifications to loperamide and other compounds of similar structure. My understanding so far is that the intermediate alcohol is unstable except at low temperatures and correct pH levels, and dehydrates to the toxic MPTP when it destabilizes. If this is the case, then there should be no concern when working with loperamide or other compounds which are already stable at room temperature, but I would like to see some sort of lterature to back this up.

I will continue to look and post anything I find. Does anyone else have more detailed references?

jboogie · « **Reply #1 on:** July 04, 2010, 09:40:44 AM »

i can vaguely remember the discussion on this question, but iirc it was a temperature issue that caused the formation MPTP during the synthesis.

ill include a quote that may help.

from comments by David J. Heisterberg

Quote

MPTP is oxidized in vivo to MPP+, the toxic species. I think deprenyl showed some indication in preventing the oxidation. I don't think MPTP has any opiate activity itself, and I believe it was produced simply by accident. The reaction MPPP -> MPTP goes rapidly as temperature is increased.

in addition, i have a pdf that discusses the synthesis of some of the arylpiperidine derivatives that would answer all your questions i think. lemme see if i can upload the pdf fer ya...

timecube · « **Reply #2 on:** July 04, 2010, 11:22:30 AM »

Thank you for the paper!

Quote

The reaction of the arylmagnesium halide or lithiumaryl with l-alkyl-4-piperidones yields the piperidinols VI. The corresponding 2-piperidones[2] invariably gave 1,4,5,6-tetrahydropyridines, spontaneous dehydration occurring during the isolation of the reaction product.

This seems to lend some credence to my thinking, that the problem isn't so much with MPPP spontaneously dehydrating to form MPTP but with the unstable alcohol intermediary doing so.

From Weingarten, though:

Quote

The starting material was N-methyl-4-piperidone (MP), which was converted to 4-hydroxy-4-phenyl-N-methylpiperidine (HPMP) by phenyl lithium. The intermediate was then reacted with propionic anhydride to produce the ester and desired product, MPPP. Although the earlier batches had been successful, when the subject modified the procedure, the new reaction conditions resulted in dehydration of HPMP and MPPP to the undesirable side product, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

http://www.erowid.org/archive/rhodium/chemistry/mptp.serendipity.html

According to this, at least some portion on the finished product may be dehydrating as well, although it isn't clear how the author arrives at that conclusion. I'm trying to find some sort of compelling evidence one way or the other as to whether a stable intermediary alcohol has a reasonably concerning chance of dehydrating during esterification or not.

timecube · « **Reply #3 on:** July 04, 2010, 12:17:38 PM »

Quote

MPTP was formed during the reaction with the phenyl grignard, in the acylation step or if the intermediate alcohol was exposed to strongly acidic conditions. Due to the ease with which MPTP is formed it would be expected to be present in MPPP if inadequate sample purification occurs.

Soine, http://www.erowid.org/archive/rhodium/chemistry/clandestine.drug.synthesis.html#4-pp

I've come across casual mentions of adding the anhydride too fast, causing the temperature to rise to unsafe levels, but nothing to back up these claims. Most mentions I find are unfortunately just Kidston "made a mistake" without any real kind of detail or references.

Supposedly an analyst around the time tried to accurately reproduce the synthesis to discover where the error(s) occurred, but I have yet to find the report or any mention of it in real articles.

I just realized I read something wrong earlier too..

Quote

The corresponding 2-piperidones[2] invariably gave 1,4,5,6-tetrahydropyridines, spontaneous dehydration occurring during the isolation of the reaction product.

I was trying to skim through and didn't realize at first that it was referring to the 2-piperidones there which the paper doesn't work with any further rather than the 4-piperidones. Unfortunately there is no mention of accidental MPTP synthesis, only purposefully..

Quote

The alcohols VI can be readily dehydrated to the corresponding l-alkyl-4-aryl-l,2,5, 6-tetrahydropyridines, IX, by means of the usual reagents, such as potassium acid sulfate, hydrobromic acid, and thionyl chloride.

None of which explain accidental causes, other than perhaps unstable pH levels.

From another paper of theirs on the reactions with 2-piperidones:

Quote

Aryl- or aralky-magnesium halides were reacted with 1-methyl-2-piperidone. When the Grignard complex was decomposed in the normal manner, dehydration resulted, with formation of the 2-substituted-1,4,5,6-tetrahydro-1-methylpridines.

http://pubs.acs.org/doi/pdf/10.1021/jo01170a021

Something similar to this must be occurring at some point with the 4-piperidones under the right (wrong) conditions, but it still isn't clear to me what exactly.

heisenberg · « **Reply #4 on:** July 04, 2010, 02:16:10 PM »

The reason that it's temperature and heat sensitive is that the intermediate t-alcohol can easily be protonated, and leave as water (dehydration). This leaves a tertiary carbocation, which will easily eliminate off a proton from an adjacent carbon to form an alkene (MPTP).

The tertiary carbocation is reasonably stable, so very cold temperatures would be required to minimize its formation.

timecube · « **Reply #5 on:** July 04, 2010, 07:15:30 PM »

Quote from: heisenberg on July 04, 2010, 02:16:10 PM

The reason that it's temperature and heat sensitive is that the intermediate t-alcohol can easily be protonated, and leave as water (dehydration). This leaves a tertiary carbocation, which will easily eliminate off a proton from an adjacent carbon to form an alkene (MPTP).

The tertiary carbocation is reasonably stable, so very cold temperatures would be required to minimize its formation.

Then why is the exact same thing apparently not happening with loperamide under haphazard conditions? Is the resulting molecule just not a fit for the MAO enzymes?

jon · « **Reply #6 on:** July 04, 2010, 11:26:14 PM »

they were using the zeiring patents where a catylitic amount of sulfuric acid like 1 drop per 10 cc of propiononic anhydride is used to acylate the piperidinol.
the other suggestion in the patent is .5 grams of sodium acetate per 10 cc per gram of piperidinol.
i used the second route.
never got parkisons disease.
they must have used the first suggestion.
perhaps added too much sulfuric acid too.
i read the article about those two guys, that's what they were doing using h2so4 ala ziering and lee

timecube · « **Reply #7 on:** July 05, 2010, 03:28:23 AM »

MPPP was successfully produced and used for months before problems occurred, I'm just looking for potential problems before someone finds them the hard way.

I'm becoming reasonably convinced that in the absence of acidic conditions, dehydration shouldn't occur.

Vesp · « **Reply #8 on:** July 05, 2010, 06:00:15 AM »

Also, you might always want to consider separating them in case they form via chromatography, if that is at all possible, or perhaps find a reaction that destroys the bad one and/or also makes it easier to extract and does not effect the wanted one.

jon · « **Reply #9 on:** July 05, 2010, 07:38:01 AM »

the only thing i know is that they used more heat according to thier own accounts to speed up the reaction .
the tlc data i had for mptp was rf .42 on merck silica plates eluted with methanol/chloroform 3/1 and visuallized with iodoplatinate.
i'm positive the alcohol has to be protonated by a strong acid in order for the carbocation to form and h2o to leave.

timecube · « **Reply #10 on:** July 05, 2010, 10:18:11 AM »

Using the freebase in the reaction probably isn't a terrible idea as it may serve to absorb any stray protons to some extent. I'm not sure if there would be an effective way to separate out any undesired product other than via chromotography as Vesp suggests.

There is a boiling point listed for loperamide itself of 647.2 C at 760mmHg, so potentially under hard vacuum and high heat they could be fractioned but it seems really impractical.

I tried to get a copy of J Med Chem. 1990 Aug;33(8):2221-30 which evaluates the structural relationships of MPTP analogues to toxicity, but something is wrong with the PDF and half the pages are missing.

http://www.ncbi.nlm.nih.gov/pubmed/2374149

jon · « **Reply #11 on:** July 06, 2010, 01:57:10 AM »

the oh group has to be strongly protonated and heated for this to happen i would'nt sweat it much i used the hcl salt too just dissolve it in a highboiling chlorocarbon.
and acylate away no worries man.

nk40ouvm · « **Reply #12 on:** July 07, 2010, 06:05:46 AM »

Quote from: timecube on July 05, 2010, 10:18:11 AM

Using the freebase in the reaction probably isn't a terrible idea as it may serve to absorb any stray protons to some extent. I'm not sure if there would be an effective way to separate out any undesired product other than via chromotography as Vesp suggests.

There is a boiling point listed for loperamide itself of 647.2 C at 760mmHg, so potentially under hard vacuum and high heat they could be fractioned but it seems really impractical.

I tried to get a copy of J Med Chem. 1990 Aug;33(:2221-30 which evaluates the structural relationships of MPTP analogues to toxicity, but something is wrong with the PDF and half the pages are missing.

http://www.ncbi.nlm.nih.gov/pubmed/2374149

I had this article already, my copy seems fine.

timecube · « **Reply #13 on:** July 12, 2010, 07:57:14 AM »

Thank you. I'm not sure why it wasn't working right for me.

Assyl Fartrate · « **Reply #14 on:** March 23, 2011, 04:51:59 PM »

From what Assyl has read, a lot of damage can occur before symptoms are noted. It seems it takes a "critical mass" at which point Parkinsonian symptoms suddenly appear. Concerns have been described in the literature that the proliferation of MPPP back in the 80s may lead those users to develop Parkinson's later in life, due to enough damage being done to accelerate its onset, but not enough to be immediately symptomatic. Knowing this makes Assyl hesitant to indulge in any of these reverse esters.

jon · « **Reply #15 on:** April 02, 2011, 12:30:48 AM »

fartrate can you blow some of this wisdom on us? we would be glad to know the details meantime, if i catch the parkinsons i'll let you know.

Tsathoggua · « **Reply #16 on:** April 02, 2011, 12:38:05 AM »

IIRC you can lose somewhere near 70-80% of the dopaminergic neurones of the substantia nigra before parkinson's shows itself.

With MPTP toxicity, chances are you aren't going to be letting anybody know anything.

Look up the video articles on the web about the frozen addicts case, guys could barely move, speak or swallow, it totally fucked them a new one. From what I saw, it wasn't mere stiffness and shakyness, but near full-blown paralysis.

jon · « **Reply #17 on:** April 02, 2011, 01:07:24 AM »

fuck me.

atara · « **Reply #18 on:** April 02, 2011, 01:21:43 AM »

I would try to exclude the possibility entirely by replacing the piperidine with a pyrrolidine or an azepane.

For MPPP, I would use a test capable of determining the presence of an alkene... but... since, to the best of my knowledge, the starting material for MPPP is 4-piperidone, the same as fentanyl... I'd just make fentanyl. Or ohmefentanyl from styrene chlorohydrin.

EDIT: What jon said.

jon · « **Reply #19 on:** April 02, 2011, 01:25:46 AM »

i think styrene oxide works better the clorohydrin is just a synthon of the same.

Author Topic: Mechanism of MPTP formation during MPPP synthesis? (Read 270 times)

timecube

Mechanism of MPTP formation during MPPP synthesis?

jboogie

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timecube

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timecube

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heisenberg

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timecube

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jon

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timecube

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Vesp

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jon

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timecube

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jon

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nk40ouvm

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timecube

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Assyl Fartrate

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jon

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Tsathoggua

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jon

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atara

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jon

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