Piperidine Analogues

[Sedrick]

Hi folks,
this is my first post in a few years now. I keep losing my passwords sohave to change username. OK, I dont currently have access to Beilstain aka crossfire nor can I access JACS etc. SWIM is sure you can feel his pain
Anyhow, I was very interested in the claims made by Shulgin in the future drugs of abuse paper on Rhodiums site. Rspecially the claims concerning the 4,4-diphenyl piperidine analogues of methadone that were exceptionally high potency and duration of action. SWIM just wanted to know for reference purposes what the structure of these compounds are. They sound extremely powerful and have probably been shadowed away toward this end. Still, any help would be appreciated. This is a good place to start a thread, so thanks everybody

[scarmani]

Sorry Sedrick, this is not really addressing your point about 4,4-diphenylpiperidine analogues, but it's slightly related -- it has to do with synthesizing intermediates for very potent fentanyl analogs such as carfentanil.  (I hope this is an acceptable thread to post the reference):


An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate
V. D. Kiricojevi, M. D. Ivanovi, I. V. Micovic, J. B. Djordjevic, G.M. Roglic
J.Serb.Chem.Soc. 67(12), 793–802 (2002)

http://www.shd.org.yu/htdocs/shd/Vol67/No12/V67-No12-01.pdf

Abstract:
An efficient synthesis of methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate(7) has been developed,starting from 1-benzylpiperidin-4-one (1).  The  compound is a key intermediate in the synthesis of new generation, highly active narcotic analgesics, such as remifintanil, as well as the novel classes of fentanyl analogues.  An optimized Strecker-type condensation of piperidone 1 with aniline and HCN yielded the anilino-nitrile 2 (~90 %) which, upon selective hydrolysis with conc.H2SO4, gave the anilino-amide 3.  After vigorous basic hydrolysis of 3, followed by acidification and successive treatment with SOCl2 and MeOH, the anilino-ester 5 was obtained (40–45 %, in 3 steps).  N-Acylation of 5 with propionyl chloride yielded the anilido-ester 6 (70–80 %).  [[ is this carfentanil? ]] In the final step, the catalytic N-debenzylation of 6 was examined under various conditions and optimized to yield 7 in near quantitative yields.


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Getting back to your question, I guess the structure of the compounds Shulgin mentions would look something similar to this, but I could be completely wrong:

Molecule:

4,4-diphenyl-6-(piperidin-1-yl)heptan-3-one ("CCC(C(C2=CC=CC=C2)(C3=CC=CC=C3)CC(N1CCCCC1)C)=O")



The reference given in the Shulgin article for these analogs is:
P. A. J. Janssen and C. A. M. van der Eycken, "The Chemical Anatomy of Potent Morphine-like Analgesics." Drugs Affecting the Central Nervous System, (A. Burger, ed.), Dekker, New York 1968, pp. 25-60.

[Sedrick]

Well I dont really want to be fooling around with HCN. If I worked for a huge company with all the facilities etc, different story.. I read on this site that N,N-Diethyl methadone is inferior whereas N,N-diethyletonitazine was superior. Perhaps this has something to do with entropy changes on formation of a six membered ring? But then again in PCP the six membered ring compound did not work particularly well.