New Fentanyl, help needed from Russian bees

[Cyrax]

I came across a very strange looking fentanyl analog, one with a 2,5-dimethylpiperidone skeleton.  Well, never seen that before ...  I am wondering about the pharmacological effect, what is the ED50 of that analog?  And what is the procedure for the synthesis of that 1-(2-phenethyl)-2,5-dimethyl-4-piperidone, i.e. the precursor of the fentanyl?
The only information I have is the reference of a Russian patent.  If one of our Russian friends could fetch the patent and see if it is any good, I would be gratefull.
I am especially curious about the synthesis of that piperidone.

1-(2-PHENETHYL)-2,5-DIMETHYL-4-N-PROPIONYL-ANILINOPIPERIDINE OR ITS SALTS POSSESSING ANALGETIC EFFECT AND METHOD OF PRODUCING SAME 
Patent Number: SU736583 
Publication date: 1985-11-30 
Inventor(s): VARTANYAN S A (SU); VARTANYAN R S (SU); ZHAMAGORTSYAN V N (SU); MARTIROSYAN V O (SU); VLASENKO E V (SU); AZLIVYAN A S (SU); DURGARYAN L K (SU) 
Applicant(s): INST TONKOJ ORCH KHIM IM A L M (SU) 
Requested Patent: SU736583 
Application Number: SU19782669375 19781004 

[Ritter]

Hi Cyrax,

Please see: Journal of Pharmaceautical Sciences, Vol. 62, No. 6, p.983-6, June 1973  

2,5 dimethyl fentanyl derivatives are synthesized and tested for analgesic activity in this paper.  Not only did this research group find that 2,5 dimethylfentanyl is a mildly active agonist, but surprisingly they also found that the benzyl derivative has significant analgesic activity!  3-methyl benzyl fentanyl had an ED50 of 36.67mg/kg whereas 2,5dimethyl benzylfentanyl had an ED50 of 65.14mg/kg.  So here is one more piece of info to help blow the idea that all benzyl fentanyls are inactive out the door!

[Cyrax]

Thanks for this information Ritter.  I will see I can fetch that article.  It will take some time and effort, but I am kind of a persistent dude   .  Could you complete the ref. by giving also the pages where the article can be found.  I will never get the journal physically in my hands, just a copy of the requested pages (thus it is quite essential).

I think 3-methyl fentanyl is so extraordinary potent that even the benzyl analog is active.  The 3 methyl has some irreversible binding effect (if my memory serves me right), hence it has a long activity (4 hours).

If someone has acces to a .PDF file of that article, this would save me quite some work.

One only needs three things in life: a good education, a good health and a good accountant.

[blondie]

Cyrax, my library which is closed at the moment has the journal - give me till the morning and i can post at least an ocr version.

[Ritter]

Cyrax, check my orginal post, I corrected my mistake with page numbers.  Anyway I can answer another one of your questions from your original post---how do they make 1-phenethyl-(2,5 dimethylpiperidone-4)?  Simple-they dont.  There is a much simpler method out there for making anilinopiperidine derivatives and that is to start out with the appropriately corresponding pyridine with a hologen at the 4 position.  This is either linked (nucleophilic displacement) with aniline via lots of heat for a low yield or using SWIR's extra special Pd(Ph3)4 coupling procedure in 75% yields. 

Next the heterocycle is made into a quartenary amine by reflux with phenethylbromide and reduced with NaBH4 to produce a high yield of the desired phenethyl(substituted)piperidinoaniline.  A touch of propionyl chloride and you're at home base!

[Cyrax]

Whow, I am impressed!

I saw that the tetrakis(triphenylphosphine)palladium catalyzed coupling between the halopyridine and aniline is discussed in

Post 285766

(Ritter: "COndensing aniline and halopyridine", Chemistry Discourse).  Could you give some more of your experience with this reaction?  A detailed lab procedure would be appreciated.

[Rhodium]

You can use an aniline and 4-halopyridine like this too:

http://forkat.anorg.chemie.tu-muenchen.de/2/pdf/f2be00b5.pdf

[Cyrax]

The benzyne mechanisme, hmm, I see.

Rhodium, my German is not too great, so I read only the part you translated.  But will the aniline will react with the 4-chloropyridine at the 3 position or at the 4 position?  If the aniline reacts at the 4 position, a carbanion will be formed at the 3 position and vice versa.   In order to see wich product will be formed, we should know which carbanion is the most stable.  So, which is?

Ritter, in your post you asked for other ideas.  Well, I am not a organo-transition metal complex wiz, but what do you think about this: the 4-chloropyridine is a èta-6 ligand and CO is a èta-2 ligand.  When Cr(CO)6 reacts with 4-chloropyridine, there will be a ligand exchange and a 4-chloropyridine-Cr(CO)3 complex forms.  The Cr(CO)3 sucks the crap (i.e. the electrons) out of the aryl ring, so it becomes very electrondeficient.  Now, the aniline can do a nucleophilic attack on the 4 position, effectively replacing the halogen.  The downside is that:
 1) you need to use a stoichiometric amount of Cr(CO)6
 2) Cr(CO)6 is like very toxic.  You see that during complex formation, the aryl displaces 3 CO molecules.  Watch out!!!

I thought that the PdL4 (with L = PPh3) used to be a catalytic reaction, I don't really understand why you need so much of that stuff.  A ref. for this reaction is certainly wellcome, I am intrigued.

I have another question. I think the answer will be 'yes', but if someone could confirm it, I will be   .  Can one reduce the 4-anilinopyridine to the 4-anilino-1-piperidine with Na / EtOH.  Can this be done under the conditions of the pyridine reduction?  The anilino ring will remain intact, right?

[blondie]

Cyrax, there were a few structures and tables so i did not do an ocr left the 4 pages as images - around 200k each. they are too large to display correctly in a browser window but will print to an A4 size with an image viewer - so hard copy should be good. the terminal/scanner i am on doesnt have a pdf converter so i couldnt get them into a more friendly format unfortunately. hope it helps.

http://www.geocities.com/robran445/

[Cyrax]

Blondie, you did really some excellent (rate that post as such, hint hint) work.  That article is very interesting.  It provides an entire new approach for the synthesis of fentanyls + further insight to the SAR of those compounds.
This approach would make the synthesis of alpha-methyl fentanyl compounds easy:
 * couple 4-halopyridine to aniline with Pd(PPh3)4
 * reduce the pyridine ring to the piperidine with 10 % Pd / C
 * the piperidine base does a SN2 on P2Pol mesylate (cfr

Post 336572

(Cyrax: "Rhodium, I see your reason for concern: esters of ...", Chemistry Discourse))
 * acylate with propionyl chloride

Thanks again Blondie, you are a star   .

Here are a few German sentences, so that you can assess my German: Acetyl-alpha-methyl-fentanyl ist eine Derivate des Narcoanalgetickums Fentanyl.  Es ist stark verbreitet in USA und hat ein Morphinäquivalenz 10.  Nach Matthias Bastigkeit, ein Fachdozent für Pharmakologie.

Had everyone ever heard about this 'acetyl China White' (10 x morphine), which should be widely repanded in the states?
I looked everywhere for info about acetyl analogs of fentanyl, but I hardly found anything   .  It is a Schedule I opioid, but further no information whatsoever.  If someone has info about acetyl fentanyls, I am interested.

Link: [

http://www.gifte.de/fentanyl.htm

]

[Cyrax]

I want to point out that the reduction of the N-phenethyl-4-anilino pyridinium bromide is a synthetic beauty, at least from mechanistic point of view.  Treating a N-alkyl pyridinium halide with NaBH4 gives hydride reduction of the 2 position, yielding a N-alkyl 1,2-dihydropyridine.  However, the reduction usually doesn't stop at this stage.  Overreduction gives rise to the N-alkyl 1,2,3,6-tetrahydropyridine.  If there is a N atom at the 4 position (like in N-phenethyl 1,2,3,6-tetrahydro-4-anilino-pyridine) one sees that the NH group on C4 and the double bound between C4 and C5 is just an enamine functional group.  This means C5 is nucleophilic, and when it grabs a proton from the solvent (or from the water in the solvent), this results in the formation of an iminium ion at the C4, which is reduced with NaBH4 to give the N-phenethyl-4-anilino piperidine.

If Ritter only posted the procedure ..., that would just make my day.

[Ritter]

OK, I'm finally ready to give it all up to you guys:

Synth of pyridinylanilines using EXPENSIVE Pd(Ph3P)4 in stoichiometric portions:  Tet. Lett. 25, 3175(1984)
That ref does not specifically synth the exact desired compound however is demonstrates how the Pd catalyst can be used to couple an arylamine and arylhalide in high yield.

The procedure for converting the pyridine nucleus into the N-alkyl substituted piperidine via NaBH4 reduction can be found in

Patent US3821231

I'll provide details for synthing 4 halo-pyridine in the next few days.

[Cyrax]

Thanks Ritter, you are my hero   .

Concerning that synthesis of the 4-halo pyridine, I guess you did the reaction on the pyridine N-oxide.  In elecrophilic aromatic substitution, the 3 position of the pyridine ring is the most reactive.

An example is given in Traité de chimie organique, Vollardt, 2th ed. p 1004:
                     
               Br2, H2SO4, SO3
 pyridine   -------------------> 3-bromo pyridine (86 %)

              NaNO3, fuming H2SO4, 300 °C
 pyridine   -------------------------------> 3-nitro pyridine (4,5 %)

It is safe to say pyridine is not very reactive towards electrophilic substitution, isn't it?


I guess everybody is on a holiday here, it's all so quit and still in the hive.

[blondie]

Cyrax, you guys have the imagination are doing the real spadework researching the references - however its still exciting to contribute to the collective endeavour of the hive where swim can. i am sure you have already seen this but for completeness Rhodium has a list of refs for pyridine reduction.

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pcp/precurs_synth.html

[Cyrax]

Blondie, your contribution is most certainly appreciated.  At least someone is interested in these posts.  Since there is so little reply - I start wondering.  Mabey it's time to start looking for a new field of research...

I think that in this case, it would not be very wise to do a Pt catalytic hydrogenation: there is the risk that not only the pyridinium ring, but also the benzene rings will get reduced.  However, mabey I am too worried, if one carefully monitors the reaction + if one does the Parr not under draconic conditions, the over reduction will be prevented (I hope).

Pyridine is intrinsically less reactive than benzene (toward electrophilic substitution) because nitrogen is more electronegative than carbon.  The N in the ring is a net acceptor of pi electron density.  A more important reason for the decreased reactivity is the fact that the N has a electron pair that is not part of the aromatic ring.  The basic N will get protonated or complexed with a Lewis acid under many of the conditions typical of electrophilic substitution reactions.  The positive formal charge of the resulting salt further reduces the reactivity toward electrophiles.  The N acts as a strongly destabilizing internal electron-withdrowing substituent in the 2- and 4- electophile-pyridine addition intermediates.  The N also deactivates the 3 position, but less thand the 2- and 4- positions.  Hence the addition - elimination (i.e. substitution) will take place at the C3.

[Antoncho]

Please note that although the title of the thread asked for help of Russian bees (many of whom, let me assure you, are very eager to help The Hive in any way they can) - nevertheless there ain't no replies from any of them here.

Personally i was delighted - but not very much surprised - to see that.

'Cause opiates are the BIGGEST EVIL of Russia - and i literally don't know any Russian who wouldn't have at least one friend whose life was ruined by H (and the like).

Not to imply that Russians are in any way more susceptible to opiates than any other nation..........

Opiates are OBJECTIVELY a MAJOR evil. An evil - independently on the set, setting and the person who uses them. A threat for survival.


Please, please, my winged broters-and-sisters - i'm not blaming anyone, i understand very well people like Cyrax, Ritter - with all my huge respect for Ritter  - and all the rest interested in this topic (but not PrimoPyro, though!!! Gosh, i still can't believe it!).

BUT, in my not-so-humble opinion, anyone who synthesizes opiates for sale deserves, if bot to bee put in jail for life, but at least to be permanently forbidden to do chemistry.

Beecause it's exactly like making explosives and selling them to terrorists - only much worse     . Kills more - SO MUCH MORE - people per gram, i mean .







Yours very sincerely,



Antoncho

[Cyrax]

Antoncho, I understand your reason for concern.

And if you read my posts you will notice that I refrain myself giving complete and detailed 'from scratch' synthesises, because I don't want to write cookbook recepts (although I could easily do this) for that one rotten apple who doesn't give a shit about the consumer's health and wants to make a quick buck over the death of addicted people.  I think that most of us bees are sensible people.  If you may remember, I said in one of my posts that this class of drugs is far to potent for recreational use.

I am a scientist, not a murderer.  Every information can be used for inappropriate objectives, but does this mean that one cannot discuss it?  I am approaching this topic from an academical point of view.  Am I a bad person?

But please, if bees find these posts offensive, inappropriate or prone for misuse, I will stop posting about this topic.

Antoncho, tell me, what happend with PrimoPyro?  What can't you still believe?  What did he do?

Take care,
Cyrax


Death smiles at us, the only thing we can do is to smile back   .

[Ritter]

Hi Antoncho,

I just wanted to take the opportunity to address your statement:
BUT, in my not-so-humble opinion, anyone who synthesizes opiates for sale deserves, if not to bee put in jail for life, but at least to be permanently forbidden to do chemistry.

I couldn't say it better myself.  This is the exact reasoning behind why I never released the much-touted web page I put so much effort into.  My vast knowledge of opiate chemistry will never be revealed in such a way that could allow any shitheads to profit from a disease as horrific as opiate addiction.  I know what it has done to my own life; opiate abuse is the ultimate harbinger of death.

[SPISSHAK]

Nah that's just subjective opinion.
Nothing wrong with opiates, IMHO.

[blondie]

i am not sure where this thread is headed, - i agree with Antoncho that it is not a good thing to sell opiates/opioids since the potential for harm is so high. but then i am probably a heretic at the hive given that i feel the same about mdma.

anyway here are some synths for 4-chloro pyridine. unfortunately the only journal i have access to is Chemische Berichte and none of the early volumes.
Ber 1899, 32, 1308
Ber 1924, 57, 1182
Recl Trav Chim Pays Bas 1939, 58, 885
Actra Chem Scand 1970, 24, 3435

will unsubstituted pyridine (without alkyl groups) n-oxide substitute at the 4 position with phosphorus oxychloride? note this chem is watched since it may be used in developing sarin.

if so then this synth for pyridine n-oxide might be promising.

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0828