Prodine Analog Via 2-Methyl-1-Butene..

[Bwiti]

What's up?! In

Patent US2765315

(Preparation Of Esters):

"Our process comprises reacting a-methylstyrene, a-ethylstyrene, isobutylene, or 2-methyl-1-butene with a N,N',N"-trimethylhexahydro-1,3,5-triazine and a monocarboxylic acid of the formula R'COOH, where R' is an alkyl group, particularly an alkyl group of not over two carbon atoms. These three reactants are mixed and the mixture is heated between 80* and 125*C.."

  I've heard a lot about the production of 1-methyl-4-phenyl-4-acetoxypiperidine from a-methylstyrene, but what about synthing an active analgesic from 2-methyl-1-butene instead? The patent lists it as a suitable precursor, but doesn't use it in any of their examples.. Guess I have two questions; Would product made from 2-methyl-1-butene be active, or are the folks in the patent full of shit? Any references that use the above precursor? Peace!

[Rhodium]

I find it hard to believe that the product N-methyl-4-acetoxy-piperidine would be an active opioid, but by hydrolyzing the ester and oxidizing the alcohol to a ketone you'll get N-methyl-4-piperidone, a nice precursor to many other opioids.

The quaternary methiodide of N-methyl-4-piperidines are easily turned into other N-alkyl analogs by transamination (with for example 2-phenethylamine) - search for Drone's old Tropane Fentanyl analog thread for references.

[Megatherium]

Hey Bwiti!  

I searched an hour in my closet of articles for you   , I think you might find this interesting   .  Here are analgesic activity data for prodine analogs.  You have a low melting beta (trans) and a high melting alpha (cis) analog of prodine.  In prodine, the 3-piperidine substituent is methyl.  Now, I have this article where they made some analogs of prodine, with other substituents on the 3 position than methyl.
           R (in 3 position)        Analgesic activity
alpha      -CH3                           1
beta       -CH3                           7
alpha      -CH2-CH3                    1.1
beta       -CH2-CH3                    1.25
alpha      -CH2-CH=CH2               11
beta       -CH2-CH=CH2               3
alpha      -CH2-CH=CH-CH3          0.03
beta       -CH2-CH=CH-CH3          0.04

For the analgesic activity, they take morphine as a standard (with an analgesic activity value of 1)

I made no typing error: with the allyl, the alpha isomer is the most potent.

Now, concerning the ref. ...         ... The article is called  "Piperidine derivatives. IV. 1,3-disubstituted-4-aryl-4-acyloyl piperidines", the authors are: A. Zieging, Alex Motchane and John Lee.  It is published in november 1957, the volume is 22 and the pages are 1521 - 1528.  However, I must have been in a hurry when I copied the article, since I completly forgot to write down from which journal it is.  I think it is JOC, but it can equally good be J. Chem. Soc. ... or even JACS.  Well, sorry about that.

Oh, and do I need to say that these analogs can equally good can be made like in the above patent?

I've heard a lot about the production of 1-methyl-4-phenyl-4-acetoxypiperidine from a-methylstyrene, but what about synthing an active analgesic from 2-methyl-1-butene instead?

With 2-methyl-1-butene, you 'd get a prodine compound where the phenyl on the 4-position of the piperidine ring is replaced by a methyl.  Now, since the phenyl on the 4-position is quite essential for analgesic activity, I don't think using 2-methyl-1-butene would be a good idea.  And certainly not with the acetoxy, as a general rule, it is always less potent thant the propionoxy ester.

Cheers  

[SPISSHAK]

acetoxy, or propionoxy esters. The ones you mention the 3,methyl substituents there?

[Megatherium]

https://www.thevespiary.org/rhodium/Rhodium/pdf/pethidine.reverse.esters.pdf

[Megatherium]

Hmm ... It is always nice to see people starting their own threads ...

Post 438017

(pHarmacist: "Prodine Derivatives (iR spectrum included)", Novel Discourse), so that the information isn't scattered around all over the place (grinch)   .  Or is Bwiti 's thread not good enough for you?  Well, it was JOC after all.

Mabey you could post JOC (1947) p 911  Piperidine derivatives. V. 1,3-dialkyl-4-aryl-4-acyloxypiperidines.  Albert Ziering, John Lee in another thread too (preferably in yet another forum)?  


Why dont you take a subscribtion on this magazine

http://www.asshole.org/

  ?  

Apothecarius, transite ad inferos (i.e. pharmacist go to hell, in case you are a dumb motherfucker who hasn't got a classical education).

If this is the way thing are going here, I post my future messages WITHOUT REFERENCES.  In case I haven't made myself clear, you got me upset -big time   .  It isn't the first time this shit happened:

Post 436680

(Megatherium: "Somebody typed his ass of some time ago on...", Serious Chemistry)


Canis latrans semper mordet in cauda apothecarii  

[Bwiti]

Thanks for that .pdf Megatherium! Damn, you'd think that with all this analgesic knowledge floating around, I could buy something decent that'll nicely fuck me up, but instead all I can find is over-cut heroin that my nostrils strongly object to, and it hardly gets me high!
  So, as far as US2765315 goes, the only realistic options(to get active product) are a-ethylstyrene and a-methylstyrene? That kind of makes me want to tear my own face off because a-methylstyrene is hard to get, and a-ethylstyrene is damn-near impossible to get.. That's a total bummer, because it's an easy synth..

[Megatherium]

Well, I 'm sure you saw the alpha-ethylstyrene synthesis Rhodium posted:

Post 432214

(Rhodium: "Wittig Synthesis of alpha-Ethylstyrene", Methods Discourse).  Propiophenone is a rather common chemical. n-BuLi might bee harder to get (and it is more difficult to handle, since it requires abslolute dry conditions - no shit - and a nitrogen atmosphere).  And BTW, the patent is the only way to go to get an injectable compound (i.e. don't screw around with the piperidone route like in that .PDF article ... or bad things are likely to happen to the substantia nigra of your brain).

[Aurelius]

perhaps we need to find an easier route to these chemicals.  I'm quite interested in Bwiti's project here and am willing to help.  Mmm.. prodine...

[Aurelius]

Post 397865 (missing)

(Aurelius: "US patent 2765315  Prodine and analogues", General Discourse)

[SPISSHAK]

tertiary alcohols are the easiest to dehyrate any process producing these compound involving acylation of a piperidinol is asking for trouble but ther may be one out.
 This is cool you can instead of hyrolysing the oxolithium compound formed from phenyl lithium and the piperidone.
you can directly esterify this oxo lithium compound avoiding dealing withtertiary alcohols altogether.
if you want to go this route this is the safest way from piperidone.
Because h2o can't eliminate from a oxy lithium compound meaning no chance of MPTP formation.
Peace.