According to Casy & Parfitt's book "Opioid Analgesics", this article will contain all the data you want, in detail.
N-4-Substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin.
Van Bever WF, Niemegeers CJ, Schellekens KH, Janssen PA., Arzneimittelforschung. 1976;26(8):1548-51.
Medline (PMID=12771) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12771&dopt=Abstract)
The intravenous analgesic activity and toxicity of a novel series of N-[4-substituted 1-(2-arylethyl)-4-piperidinyl]-N-phenylpropanamides was studied in rats. Onset, potency and duration of analgesic action were assessed in the tail withdrawal test and compared with the activity of fentanyl, (+)-cis-3-methylfentanyl (R 26 800), morphine, and pethidine. All compounds studied were found to be extremely potent analgesics characterized by an unusually high safety margin. Methyl 4-[N-(1-oxopropyl)-N-phenyl-amino]-1-(2-phenylethyl)-4-piperidinecarboxylate (R 31 833; lowest ED50 = 0.00032 mg/kg) is the most potent compound (10 031 times morphine). cis-Methyl 3-methyl-4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidine carboxylate (R 32 792) is the longest acting compound (more than 8 h at 4 times the lowest ED50) and N-[4-(1-oxopropyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 33 352) is the shortest acting compound (0.74 h at 4 times the lowest ED50) of the 4-substituted fentanyl derivatives. N-[4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 30 730) was selected for further investigation. R 30 730 has a rapid onset of action and is 4521 times more potent than morphine at the time of peak effect; it has a relatively short duration of action comparable to that of fentanyl and its safety margin (LD50/lowest ED50 = 25 211) is unusually high.
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Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs.
Niemegeers CJ, Schellekens KH, Van Bever WF, Janssen PA., Arzneimittelforschung. 1976;26(8):1551-6.
Medline (PMID=12772) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12772&dopt=Abstract)
Sufentanil (R 30 730), N-[4-methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide, is a chemically novel, highly potent and extremely safe intravenous morphine-like agent in laboratory animals. In mice R 30 730 i.v. is 2304 times more potent than morphine (hot plate ED50's: 0.0028 and 6.45 mg/kg, respectively). The i.v. safety margin of R 30 730 in mice is 1 : 6 679 (LD50 = 18.7 mg/kg). Under the same experimental conditions the safety margin of pethidine is 1 : 7.97, of morphine 1 : 34.9 and of fentanyl 1 : 454. In rats R 30 730 i.v. is 4521 times more potent than morphine (tail withdrawal test ED50's: 0.00071 and 3.21 mg/kg, respectively). The i.v. safety margin of R 30 730 in rats is 1 : 25 211 (LD50 : 17.9 mg/kg). Under the latter experimental conditions the safety margin of pethidine is 1 : 4.80, of morphine 1 : 69.5 and of fentanyl 1 : 277. In dogs R 30 730 i.v. is 2429 times more potent than morphine (apomorphine antagonism test ED50's: 0.00028 and 0.68 mg/kg, respectively). The i.v. safety margin in dogs is approximately 1 : 50 000, the LD50 being +/- 14.0 mg/kg. All morphine-like effects of R 30 730 are immediately antagonized by nalorphine. These pharmacological findings are relevant in connection to the increasing interest for use of morphinomimetics in anesthesia.
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Studies on synthesis and relationship between analgesic activity and receptor affinity for 3-methyl fentanyl derivatives.
Jin WQ, Xu H, Zhu YC, Fang SN, Xia XL, Huang ZM, Ge BL, Chi ZQ., Sci Sin. 1981 May;24(5):710-20.
Medline (PMID=6264594) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6264594&dopt=Abstract)
In the present paper, the synthesis and analgesic activity (mice, i.p. hot plate test) of the derivatives of 3-methyl fentanyl are briefly described. Compound 7302, cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropionamide (cis: 3-methyl/4-N-phenylpropionamide) is found to be the most potent analgesic agent in this series synthesized by our laboratory (ED50 = 0.0022 mg/kg). The analgesic activity of 7302 is 28 times more potent than that of fentanyl and 6300 times more than that of morphine. The partition coefficients of 10 compounds in the series are determined by high performance liquid chromatography (HPLC) and their log p values are about 3. There are no regular relationships between the analgesic activity and partition coefficients. Study on the specific binding of 8 out of the above 10 compounds to crude synaptic plasma membrane (P2-fraction) of mouse brain demonstrates that there is an excellent statistical linear correlation (r = 0.998) between the analgesic potency and the specific binding affinity. The result shows that the analgesic potency of the derivatives of this series is mainly dependent on binding affinity for opiate receptor.
What I found:
Post 438010 (https://www.thevespiary.org/talk/index.php?topic=11507.msg43801000#msg43801000)
(pHarmacist: "Substituted N-Phenylpropanamides", Novel Discourse)
Post 60132 (missing)
(Rhodium: "N-phenylethyl-4-piperidones via acrylates", Chemistry Discourse)
Dunno NOTHING about opioid/fentanyl chemistry, but TFSE turned up LOADS of even whole threads about the topic when searching for "3-methylfentannyl"...
I SERIOUSLY doubt that all those texts are only about its pharmacology!!!!
Greetz A
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 (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 (https://www.thevespiary.org/talk/index.php?topic=12448.msg49672800#msg49672800)
(Megatherium: "Discussing the Mannich reaction", Serious Chemistry)
Post 481189 (https://www.thevespiary.org/talk/index.php?topic=10423.msg48118900#msg48118900)
(josef_k: "You can use this method to use the the mannich", Newbee Forum)
via Allylsilanes:
Post 411081 (https://www.thevespiary.org/talk/index.php?topic=12134.msg41108100#msg41108100)
(thallium: "Total Synthesis of Fentanyl", Novel Discourse)
Post 411082 (https://www.thevespiary.org/talk/index.php?topic=12134.msg41108200#msg41108200)
(thallium: "RESULTS AND DISCUSSION Our synthetic approach...", Novel Discourse)
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 (http://www.shd.org.yu/htdocs/shd/Vol69/No7.html#1)