chemrox
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dumbshit question of the week - reversed ester
Hi all,
what is a:
"reversed ester?" I have heard this term used often in a medicinal chemistry context.
Thanks!
CRX
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sparkgap
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The last time I heard "reversed ester" was on a discussion of pethidine/meperidine and structural analogues like the prodines.
Essentially, if you treat pethidine as an ester of the form R<sub>1</sub>-C(=O)O-R<sub>2</sub>, then the prodines would be
something like R<sub>1</sub>-O-C(=O)-R<sub>2</sub>.
The reason this term was coined is that these "reversed esters" tended to be converted in the body to Parkinson's-inducing metabolites like MPTP; thus
these series of compounds eventually fell into disuse as analgesics.
sparky (~_~)
"What's UTFSE? I keep hearing about it, but I can't be arsed to search for the answer..."
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Sauron
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BERGER, ZIERING & LEE, J. org. Chem ., 1947, 12, 904
Yep, pethidine analogs, I will have the paper in a minute, but indeed it looks like the same lil trick that the guy pulled on demerol to make that
disastrous super-demerol that fried a lot of people's brains with irreversible Parkinsonian type symptoms. Including notably his own.
The above paper is a Roche team, though.
Print this out and tack it up on your wall with a bright red MarksALot notation:
THINGS NOT TO DO!!
[Edited on 27-9-2007 by Sauron]
Attachment: jo01170a023.pdf (413kB)
This file has been downloaded 622 times
Sic gorgeamus a los subjectatus nunc.
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Nicodem
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The term "reversed {some chemical group}" in medicinal chemistry means that you talk about reversing the bonding orientation of a certain two bonding
group to make a potentially bioisosteric modification on a lead compound. For example: the reversed amide analogue of the common drug acetaminophen
(p-hydroxyacetanilide) would be N-methyl-p-hydroxybenzamide. This would most probably be a failure as a bioisostere for
acetaminophen-like activity, but in other cases such new drug designing operation gives good results.
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chemrox
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Thanks Nicodem. The above answers all make sense as I started this reading awhile back to learn about the meperidine-MPTP connection. I was
surprised to hear that the prodines were taken off the market because they also produced MPTP in vitro. I'd sure like to see a reference for that. I
thought they were dumped for pretty much the same reason heroin and oxymorphone were; folks liked them too much. That or the market for meperidine
was good enough and covered the turf. Hence the Knaus cmpds never got manufactured despite being cheap and easy to produce and highly effective.
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Slimz
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ok stupid question from me time.. im reading this wich is clearly over my head, but im trying to figure out the difference between reversed and an
isomer or a steroisomeris.? Is it (and im guessing here) because of the bond's being reversed and not the location of the bond ?
Johnny was a chemist’s son, but now he is no more. What Johnny thought was H2O was H2SO4
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Nicodem
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The concept of reversed whatever comes from the medicinal chemistry terminology and has nothing to do with the concept of isomerism (as used
in chemical terminology). The only connection is in that incidentally the new compounds designed using this concept are constitutional isomers to the
original lead compound.
PS: WTF do I have to read about synthetic opiods in this thread! Isn't the internet cluttered with that kind of crap already?
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stygian
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I knew MPTP was a possible byproduct of manufacture, but do these esters indeed metabolise to the neurotoxic compounds? even with a 3-methyl or
similar in place?
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Slimz
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Nicodem.. that makes sense.. thanks for the clarification.
Johnny was a chemist’s son, but now he is no more. What Johnny thought was H2O was H2SO4
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sparkgap
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My apologies for raking at your sensibilities, good Nicodem; *they* were the most popular example I knew. Your general definition is of course
correct.
Now about those reversed esters... I no longer have the internal memos from the company I was once with, but indeed the concern that the prodines can
easily undergo elimination to MPTP-like compounds in vivo was the reason for them being pulled out, apart from the low prescription volume
associated with them.
sparky (~_~)
"What's UTFSE? I keep hearing about it, but I can't be arsed to search for the answer..."
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Sauron
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Reversed is not the same as stereochemically inverted. For one thing a reversed ester may be achiral.
Reversed means, as brother Nicodem pointed out elegantly, that the bond order is reversed.
For an ester, R-C(O)-OR1, that is product of an alcohol or phenol R1OH and a carboxylic acid RCOOH, the REVERSED ester would be
R-O-C(O)-R1
which is product of alcohol ROH and acid R1COOH.
All to do with connectivity.
I hope this is now clear for everyone.
For example benzyl Propionate is the "reversed ester" of ethyl phenylacetate.
PhCH2OC(O)Et C10H12O2
EtOC(O)CH2Ph C10H12O2
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chemrox
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So to bring it back to the literature examples, I am curious to know if anyone tried making the esters of pethidine and found them analgetically
wanting. Maybe Casey covers this, I shall look tonight. Meanwhile, @Sauron- the prodines are attractive practice compounds as simple heterocycles
except for the legal situation here in the US. One would not go near them for that reason alone but I'm wondering where to get more data on the
statement that all the prodines lead metabolically to neurotoxins. If that is so why not pethidine itself or is it that reversed ester moiety? I'm
not asking for answers. I will see what I can find in the literature but if you know a paper that's on point please pass it along. I found the
Mansfield-Schmidt approach kind of elegant in its simplicity. It looks a bit like a Michael doesn't it? Or am I thinking of a different mech?
@Sauron & Nicodem - thanks for elucidating the reversed ester questions.
[Edited on 28-9-2007 by chemrox]
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Sauron
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Try that paper I cited, third post from the top.
Anytime where the carboxyl moiety is in the 4-position (of piperidine) which is obviously the case when starting from 4-piperidone, the MtPt can arise
by decarboxylation. That can occur from too high a pot temperature, as in the case of the idiot who was cooking super-demerol; or in vivo, or by any
number of pathways and processes. It is simply an unacceptable risk pharmacologically to have essentially a prodrug for MpTp on the market.
We have had threads on this topic before, I'm sure if you UTFSE on MPTP you will find them complete with structural drawings, I remember posting in
those threads myself.
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chemrox
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@ Sauron and in addition (I did some reading):
Mansfield & Schmidle synthesized a number of 1-R-4-phenyl-1,2,3,6-tetrahydropyridines from a-Me-styrene, NH4Cl, formalin and/or Me-am. Reviewing
their papers and patents, it seems you can pop out MPTP just by changing reactant ratios and/or temps. That's scary shit. But I was thinking that
maybe subbing in another olefin for a-Me-styrene, one could use their approach to get partially saturated pyridines with relative ease. Also one could
try another a-alkyl-styrene for the aromatic renditions... just a few random and unrefined thoughts.
@Sparkgap- thanks for correcting my terminology "in vivo"
@Sauron II: then decarboxylation of demerol leads to Mptp? Why aren't there all kinds of jerking people who had pain shots at the hospital? Or why
doesn't it?
[Edited on 2-10-2007 by chemrox]
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stygian
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I was quite convinced that it was the 4-OH intermediates that would easily dehydrate to MPTP, never have actually read of this issue with normal
meperidine (though thats still not saying much, better safe (informed?) than sorry). I believe the route with alphamethylstyrene also proceeds
through the 4-OH intermediate.
Ive heard some say that leaving the 4-OLi or 4-OMgBr instead of hydrolysing and using all anhydrous reagents, the easily-dehydratable intermediate
could be bypassed altogether.
I'm glad I read this thread though, in vivo metabolic byproducts was something I had not considered. Thanks 
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chemrox
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in vivo metabloic products might be a laboratory legend in this case I have yet to see a paper on it and I've been looking around .. mostly the ACS
journals I admit ...
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jon
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mptp gets produced when the 4-hydroxy intermediate gets dehydrated under acidic conditions. a strong acid will do this but to avoid this from
happening all together best to avoid the intermediate altogether and use the triazine route since it's run dry (w/o water) there's no possibility of
this intermediate coming into the fray.
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chemrox
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| Quote: | Now about those reversed esters... I no longer have the internal memos from the company I was once with, but indeed the concern that the prodines can
easily undergo elimination to MPTP-like compounds in vivo was the reason for them being pulled out, apart from the low prescription volume
associated with them.
sparky (~_~) |
I can't find any literature on this anywhere. Sparky can you put a time period on this memo .. decade anyway? I didn't want to belabor the prodine
topic but since it came up I'd like to deal with the industrial legends about MPTP somehow.
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