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3-methylfentanyl

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Rhodium:
This is what I understand:
For N-phenethyl-piperidone-4, 4-piperidone, acetonitrile and phenethylbromide is used... right?

Yes, see the reaction diagram in https://www.thevespiary.org/rhodium/Rhodium/chemistry/fentanyl.html

4-Piperidone is alkylated with phenethylbromide in acetonitrile solution to give N-phenethyl-4-piperidone (abbreviated NPP in the diagram).

So would one be able to synthesize N-phenethyl-3-methyl-piperidone-4 by using methylethylketone instead of acetonitrile?

Your question does not make any sense - acetonitrile just acts as a solvent in this reaction. By what kind of reasoning did you arrive at this proposal?


Again, this is the question In asked, maybe my FSE skills aren't up to par.
"Could someone tell me or point me to any doc that explains how one would get N-phenethyl-3-methyl-piperidone-4 from 4-piperidone ?"
I checked again, and the FSE doesn't come up with any doc which contains this answer.

Of course not - there is no such thing! If you compare their structures you see that you would need to attach a methyl group next to the carbonyl to arrive at your target compound, and that chemical transformation only looks good on paper...

If you research general preparations of 4-piperidones (something which would be very reasonable to do if you are contemplating this kind of chemistry) you will soon discover that the available routes are rather few, the most important being the following:

Michael Reaction:
Post 60132 (missing) (Rhodium: "N-phenylethyl-4-piperidones via acrylates", Chemistry Discourse)
Mannich Reaction:
Post 496728 (Megatherium: "Discussing the Mannich reaction", Serious Chemistry)
Post 481189 (josef_k: "You can use this method to use the the mannich", Newbee Forum)
via Allylsilanes:
Post 411081 (thallium: "Total Synthesis of Fentanyl", Novel Discourse)
Post 411082 (thallium: "RESULTS AND DISCUSSION Our synthetic approach...", Novel Discourse)

HumbleStudent:
"Of course not - there is no such thing! If you compare their structures you see that you would need to attach a methyl group next to the carbonyl to arrive at your target compound, and that chemical transformation only looks good on paper..."

See, a simple answer with an excellent explanation which made me realize that I misunderstood a lot of the docs I've read and clearly shows my lack of real world knowledge.  Now I understand a lot more and know what stuff to reread.  Thank you.

P.S. - I have gone through all the links the 2 of you have provided before I posted my question, but being naive, I thought the piperidone-4 route was possible and was asking about that.  Now Rhodium has answered the question elegantly.

Bozakium:
Bee careful in your dreams. I seem to remember reading somewhere that the potency of these 3-substituted fentanys being more potent by weight than LSD. Just a dab will DO ya. Just remember, do spelled backward is od.

demorol:
The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues
M. D. Ivanovic, I. V. Micovic, S. Vuckovic, M. Prostran, Z. Todovic, V. D. Kiricojevic, J. B. Djordjevic and LJ. Dosen-Micovic
J. Serb. Chem. Soc. 69(7), 511–526 (2004)

Abstract

A general, five step method for the synthesis of 3-alkylfentanyl analogues (i.e., cis and trans 3-alkyl-4-anilidopiperidines 6.1–6.6) has been developed. The starting N-phenethyl-4-piperidone 1 was first converted into the cyclohexylimine derivative 2, alpha-deprotonated with butyllithium and the resulting imine anion efficiently monoalkylated with primary and secondary alkyl halides. After mild acid hydrolysis, the obtained 3-alkyl-4-piperidones 3.1–3.6 were isolated in good yields (79–85 %), then condensed with aniline to form imines 4.1–4.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1–5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1–5.6 (29–51 % yield) and trans 5.1–5.6 (19–27 % yield), with the cis/trans ratio in the range 7/3–6/4. The synthesis was concluded by N-acylation of the purified 5.1–5.6, with propionyl chloride, to afford cis and trans 3-alkyl-4-anilidopiperidines 6.1–6.6 (~95 % yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the 1H-NMR spectra. Of the twelve synthesized 3-alkylfentanyls, ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (±)-cis-3-Me fentanyl 6.1cis, (8 × fentanyl), and the novel (±)-cis-3-Et fentanyl 6.2cis, (1.5 × fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure-activity relationship (SAR) in this series of derivatives have been made.


Full text available for free at: http://www.shd.org.yu/htdocs/shd/Vol69/No7.html#1

Chemxer:
There is a very valuable paper on the synthesis and pharmacology of many fentanyl analogs, including 3-alkyl called, "Fentanyl-related compounds and derivatives: Current status and future prospects for pharmaceutical applications" by Ruben S. Vardanyan and Victor J. Hruby.
This may prove useful for understanding SAR relationships of fentanyl. It has given me some ideas for which I'm tempted to contact a chinese custom synth lab, as they are fairly far off the traditional fentanyl structure.

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