Author Topic: Elaboration of 2,3-seco-fentanyl synthesis  (Read 3149 times)

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Cyrax

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Elaboration of 2,3-seco-fentanyl synthesis
« on: August 24, 2002, 04:05:00 PM »
Check out the synthesis of 2,3-seco-fentanyl on Rhodium's site:
 

https://www.thevespiary.org/rhodium/Rhodium/pdf/secofentanyl.pdf



The synthesis is sketchy.  There isn't a descent labo procedure  :( .

I thought that we, the bees of The Hive, can solve this problem  :) .  So, detailed synthetic procedures of the steps for the preparation of the 2,3-seco-fentanyl or modifications hereoff are the objective of this thread.

If you don't mind, I 'll start backwards.  I am kind of a retrosynthetic dude.

Cyrax

  • Guest
The synthesis could be completed by the acylation ...
« Reply #1 on: August 24, 2002, 04:42:00 PM »
The synthesis could be completed by the acylation of the secundary amine (3) function with propionylchloride, followed by precipitation of the monooxalate salt (4)

The stated reaction conditions are: EtCOCl, Et3N, DCM, rt 3-4h.

DCM is indeed a very good solvent for this reaction, but CHCl3 is even a better one.  If you want proof, I'll search the damned patent - but you could just as well trust me.  Therefore I would recommend a procedure a la J. Med. Chem. (1989) vol 32 p 663 - 671.  They do the reaction on 1-(phenethyl)-4-(heteroanilino)-piperidines, but we could just as well take our amine (3)

Procedure:
 "To a stirring mixture of 1 g of the 4-(heteroanilino)piperidine [read amine (3)], 1 mL of triethylamine and 8 mL of CHCl3 was added, via a disposable pipet, a solution of propionyl chloride (1.2 molar equivalent) in 2 mL of CHCl3.  The mixing was usually mildly exothermic."

In the article, the reaction was completed in 30 minutes, but I guess it could do no harm to let the reaction run 4 hours.  Oh, and another thing: use DRY solvent.

I think a workup a la

https://www.thevespiary.org/rhodium/Rhodium/chemistry/fentanyl.html

would be just fine:

"The reaction mix is then poured into 80 ml water with stirring, and conc HCl (about 35%) is added dropwise until the pH falls below 1.5. This operation can be done with another procedure as follows: Prepare 80 ml of 2N HCl and simply pour the reaction mix into this solution. This results in the pyridine and the fentanyl turns into their respective hydrochlorides. The solution is then left with stirring for about 30min. The Pyridine HCl [read Et3N.HCl]is not soluble in CH2Cl2, while the nonpolar Fentanyl HCl is. Extract the solution with 3*20ml of CH2Cl2, then wash the organic phase with 2*10ml saturated NaCl solution.

The solvent is evaporated under vacuum, and a yellow mass is formed which consists of Fentanyl hydrochloride"

The J. Med. Chem. article says: "Hydrogen oxalate salts were prepared from 1 molar equivalent of oxalic acid in i-PrOH followed by recrystallization from the i-PrOH medium"

Cyrax

  • Guest
Li/Na Borohydride and Trimethylchlorosilane
« Reply #2 on: August 24, 2002, 06:36:00 PM »
Reductive deoxygenation of the amide (2) function with diborane generated in situ (NaBH4, BF3Et2O) clearly furnished the diamine (3)

Reaction conditions: NaBH4, BF3Et2O, diglyme, 0-80°C, 4h, then HCl/H2O

The problem with this step is that diborane and BF3 are extremely toxic gasses.  Okay, the diborane is generated in situ and you can buy a BF3 etherate solution, but I still find it a bad idea.  Therefore, I propose the trimethylsilyl chloride - NaBH4 reduction.  The examples show that amides can be reduced to the corresponding amines, and this is exactly what we want here.

Lithium/Sodium Borohydride and Trimethylchlorosilane - An Unusually Strong and Versatile Reducing Agent

Angew. Chem. Int. Ed. Engl. Vol 28, No. 2, 218-220 (1989)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/nabh4-tmscl.html)

You can also do the reduction with LiAlH4, but I think the previous procedure would be more convenient.

Cyrax

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The intermediate was reductively aminated with ...
« Reply #3 on: August 25, 2002, 04:26:00 AM »
The intermediate (1) was reductively aminated with aniline using Zn dust in acetic acid, to afford anilino-amide (2).

The reaction conditions are: PhNH2, Zn, AcOH, rt 12h, reflux 3h

Usually, they condense the ketone with PhNH2 by refluxing it in toluene and azeotropically removing the H2O while the imine forms.  Then the imine is reduced with NaBH4 in MeOH.

In Synthesis (1991) p 1043 - 1045, they do those 2 steps in one. In this article, they condense PhNH2 with cyclohexanone and reduce it to afford N-cyclohexylaniline.

Procedure:
 "Into a 500 mL  three necked flask equipped with mechanical stirrer, reflux condenser and thermometer are combined AcOH (250 ml), H2O (25 ml), activated Zn dust (78.45 g, 1.20 mol), aniline (27.94 g, 27.3 ml, 0.30 mol) and cyclohexanone (29.44 g, 31.3 ml, 0.30 mol).  Stirring is initiated and after a modestly exothermic reaction (ca. 30 min), the mixture is heated on a water bath (2h, 60 – 70 °C).  After cooling, the mixture is diluted with MeOH (100 ml), and filtered with a sinter funnel.  The solids are washed with MeOH (2 x 100 mL), and the combined filtrates are concentrated at 50 °C with a rotary evaporator.  Crushed ice (100 g), and DCM (200 mL), are added to the residue with shaking, followed with excess 25 % NH4OH until pH is ca. 10.  The organic layer is separated, the aqueous layer is extracted with DCM (2 x 100 mL), and the combined extracts dried (MgSO4).  The residue is distilled to afford pure N-cyclohexylaniline; yield: 47.4 g (90 %)"

Just let the reaction sit 12 hours at room temperature,
and then heat it to 60 - 70 °C for 3 hours.

Cyrax

  • Guest
Methyl phenethylamine was condensed with methyl ...
« Reply #4 on: August 25, 2002, 05:38:00 AM »
Methyl phenethylamine was condensed with methyl acetoacetate to yield the ketoamide (1).

Reaction conditions: 170 °C, neat 30 min.

I do not have procedures for this (for the moment).  Do they use a solvent or do they just mix equimolar amounts and heat it to 170 °C for 30 min.?

I 'll have to check out the references, but I have no time right now. 
So many things to do, so little time  :( .

I would appreciate it if I could get some feedback.  So, what do you think about it?

Cyrax

  • Guest
Dose
« Reply #5 on: August 25, 2002, 06:20:00 AM »
In

https://www.thevespiary.org/rhodium/Rhodium/pdf/secofentanyl.pdf

they say that in rats the central analgesic activity is 30 times lower than that of fentanyl, but 5 - 10 times higher than morphine.  The ED50 of 2,3-seco-fentanyl is 0.35 mg/kg, compared to 0.011 mg/kg for fentanyl citrate and 3.15 mg/kg for morphine sulphate.

So, one might think: A human of say 70 kg, requires a dose of 70 x 0.35 = 24,5 mg.  Well, I can assure you, if you would attempt this, you will most certainly drop dead instantly.  Those ED50s are for rodents, not for humans!!!

The IV recreational dose of fentanyl is 0.025 mg (inject SLOWLY during 1 - 2 minutes, if you inject too fast there will be skeletal muscular rigidity and will die from respiratory depression).  That's like 2.5 times the ED50 of rats, so a human equals a 2.5 kg rat  :) .

The IV dose of morphine is 5 - 10 mg.

So, I think a good IV dose of the 2,3-seco-fentanyl would be something like 0.5 - 1 mg.

In

http://www.ch.ic.ac.uk/ectoc/echet98/pub/028/index.htm

they say that the relative potency is 1/100 - 1/20 of that of fentanyl.  So it will be 1 - 5 times as potent as morphine.  I am a little bit confused here, since the previous article says it is 5 - 10 times as potent as morphine ...

However, I still believe 0.5 mg will be just fine for starters.  If it isn't enough, one could inject more the next time (if you OD the first time, there will be no next time).

So, we can conclude that the 2,3-seco-fentanyl is between 30 - 100 times less powerfull than fentanyl.  I am not happy about these inaccurate figures  >:( , but that is what the articles above mention.


Check out this song: "Rigor Mortis" from "Flesh & Bones".

Cyrax

  • Guest
The silence is bone chilling :-( .
« Reply #6 on: August 27, 2002, 05:25:00 AM »
The silence is bone-chilling  :( .

I have a distinct feeling that The Couch is more popular than all the Drug Related Forums together.

Nemo_Tenetur

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No no !
« Reply #7 on: August 27, 2002, 06:44:00 AM »
Look at Dr_Heckyll's Hive law #1. I really appreciate your excellent work in the fentanyl area. Few reply does not automatically mean few interest, many bees are not as far as you!
Keep on, Cyrax!

Barium

  • Guest
I know all to well what the silence is like.
« Reply #8 on: August 27, 2002, 06:53:00 AM »
I know all to well what the silence is like.
Pearls to the swines, that´s what it is.

I seriously doubt if I´ll continue to share my hard earned procedures at all... :(
Particulary if my procedures ends up in the hands of guys like Cyril....*shiver*

Cyrax

  • Guest
OK, I am :-) to see that at least some bees ...
« Reply #9 on: August 27, 2002, 07:22:00 AM »
OK, I am  :)  to see that at least some bees appreciate my work.  Thanks Nemo_Tenetur and ChemisTris.

Barium, I understand you very well.  I think that Dr_Heckylls # 1 Hive law is very true.  There are also times I think that my posts are pearls to the swine, but when I see that a few bees like my posts, it makes it all the effort worth.

moo

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Barium
« Reply #10 on: August 27, 2002, 08:00:00 AM »
This is getting offtopic. You see, not all of us have anything to add or comment, when someone as well-equipped and skilled as you seem to be, posts a new and tested procedure. Many a bee is strictly OTC/ghetto and has no access to such chemicals/facilities as you and therefore gains nothing practical. It doesn't mean those people do not respect your work. Hell, who true bee could not respect it?

By the way, why not try the nitroalkene reduction a'la Varma & Kabalka, but generating the BH3-THF complex in situ from NaBH4 with I2 or even 95% H2SO4, a'la amino acid reductions? Why 95%? To find out whether it is OK to have the extra water there or not, making it even more practical. If there ever will be an electrolytic NaBH4 production write-up the two methods could make a great pair. One-pot, high yield, inert atmosphere is a minor detail.

Now, there's some input for you, please keep up the pioneering work! I seriously hope the part about Cyril was a joke. Even though The Hive is aimed against such a principle, when reading certain individuals' posts one should remember the Sun Tzu quote: those who speak, do not know; those who know, do not speak.

Barium

  • Guest
Post deleted by Rhodium
« Reply #11 on: August 27, 2002, 08:26:00 AM »

blondie

  • Guest
secofentanyl
« Reply #12 on: August 27, 2002, 03:37:00 PM »
Cyrax, dont want to go off topic but am watching/reading with interest - just dont have anything to contribute.

slappy

  • Guest
:(
« Reply #13 on: August 29, 2002, 10:51:00 PM »
Barium,

Please don't stop sharing your work. Yes, while I would agree that it is like casting pearls before swine, there are many here, including I, who follow your work with great interest, and really do appreciate your efforts.

ChambeRed

  • Guest
I read all the chemistry forums religiously as ...
« Reply #14 on: August 31, 2002, 05:45:00 PM »
I read all the chemistry forums religiously as I'm sure many many other bee's do that like me just don't post in those formus because it would just increase the clutter/good stuff ratio.Personally I love reading about new work being done than anything else,it's just inspiring.Keep it up guys we love you for it :) and dream of a day swim can give back.Peace

Bee's don't die,we just multiply.

pHarmacist

  • Guest
Analog
« Reply #15 on: September 30, 2002, 02:43:00 PM »
In the first step one could actually use methamthetamine instead of N-Me-phenetylamine as precursor, this compound is easier to obtain and the product - (alpha-methyl) analog would - if SAR isn't unpredictible in this case - be by far stronger than 2,3-seco-fentanyl...

pHarmacist

Cyrax

  • Guest
Yeah pHarmacist, that sounds like a good idea.
« Reply #16 on: October 01, 2002, 03:58:00 PM »
Yeah pHarmacist, that sounds like a good idea.  Although ... meth is a rather valuable precursor.  If you 'd like a more powerfull analog, I suggest replacing the phenyl ring with a 2-thienyl group.  Then one obtains the thio-2,3-seco-fentanyl analog.  As a general rule the thio fentanyls are more powerfull, because of the increased liposolubility.

dioulasso

  • Guest
Mannich reaction
« Reply #17 on: December 13, 2002, 03:59:00 AM »
I was wondering wether one could use the mannich reaction between an excess of acetone and methyl-phenethyl-amine (with paraformaldehyde) to yeald a precursor for 2,3-seco-fentanyl (something similar: OrgSyn. CV4, 281)
Or is there some conformational reason why the above method is used (with the decarbonylation)?
If this would work, than in a similar reaction using methyl-ethyl-ketone one could possibly make the 2,3-seco analoge of 3-methyl-fentanyl. Of course this is just speculation.

dioulasso

  • Guest
Is anybody out there!?
« Reply #18 on: December 20, 2002, 05:43:00 AM »
Is anybody out there!?
I would be very glad if someone would post an opinion on this.
Thanks!