Synthesis of Fentanyl

[Yellow]

Fentanyl became known in the popular press, as it was used by the Russian Alpha-Team against terrorists in Moscow.
The popular press gave the impression of Fentanyl being a "narcotic agent".
It is so, when used in a HIGHLY diluted form - as it was in Moscow.
Pure Fentanyl is more likely to cause a very fast death if inhaled. The lethal dosis is 1 milligram. Definitely a potential weapon of mass destruction if made airborn in a crowded area.

Synthesis:1) Prepare 2 solutions as follows - (A) Dissolve 5 parts N-(4-piperidyl) propionanilide, 6,85 parts sodium carbonate, 0.05 parts potassium iodide in 120 parts hexane. (B) Dissolve 3.8 parts B-phenylethylchloride in 24 parts 4-methyl-2-pentanone.

2) Place solution A in a 3 necked flask equipped with a dropper, a mechanical stirrer, and a reflux head. Turn on the stirrer and add solution B slowly, dropwise until all is added. Plug the dropper neck, turn on the heating mantle, and reflux for 27 hours, with constant stirring.

3) Filter the mixture while hot and evaporate the liquid on a steam bath.

4) An oily residue remains which is dissolved in 160 parts diisopropyl ether and filtered several times until clear.

5) Concentrate this solution to a volume of about 70 parts.

6) Cool liquid for about two hours at a temperature of about 0 celsius to yield the fentanyl. ( White crystalline powder )


This is the official lab-synthesis for Fentanyl. And don't worry, I have chekked the spelling of the chemicals several times.
It is very compact, as it is written for a chemist with some experience in the synthesis of such compounds.
It can be carried out in most well equiped labs.

You should be aware, that Fentanyl is a controled substance. So even you just want a little for experimentation, the project should be keept secret.
Also, you should not order all the chemicals from the same company.

1 milligram of Fentanyl will kill any human in minutes if ingested or inhaled.
So you can come very far, with even a small amount.
The effect of Fentanyl on humans is similar to a massive overdose of heroine.

There does exist an antidote for Fentanyl. The Russian Alpha-Team was given this before the attack. That was why they stormed the building without gasmasks. This antidote would obviously be very handy, when making Fentanyl. But it is still keept secret by the Russians.

[mongo blongo]

Wow! Where did you get the synth for that?
It read it was actually Carfentanyl that was used in Moscow as it is MUCH more potent than Fentanyl and Sufentanil. The problem with these drugs is that they shut off the part of the brain which tells you to breath because they have a high affinity for mu opiate receptors which mediate analgesia and respiratory depression making it very dangerous to use. So why did they use the more potent Carfentanyl you ask? There is another drug (can't remember the name sorry) that will actually counteract the respiratory depression. This drug was dispersed with the Carfentanyl. The reason why so many people died was because they fell in positions which constricted their passages of breathing as far as I understand.

[nbk2000]

Naloxene (SP?) is a opiate-blocker, and has been used in conjunction with fentanyl-type chemicals in experiments as LLW's.

Also, your chemistry SUXZ, as you give a recipe without any mention of the 'alchemists art' that's required to make it.

Any idiot can (and just did) post a 'how' without understanding the 'why'. The Hive would be a good place to start learning from.

[Zeitgeist]

Interesting, i happen to have another file on the topic sitting around here so i'll share it:



The precursor used is N-Phenethyl-Piperidone (NPP) which can be easily synthesized from Piperidone and Phenethyl-Tosylate or Phenethyl-Bromide through a simple SN2 mechanism.

The NPP is reacting with Aniline giving the Imine derivative which is reduced to the 4-Anilino-N-Phenethyl- Piperidine (4-ANPP).

The 4-ANPP is then reacted with Propionyl Chloride giving Fentanyl HCl.

N-alkylation of 4-piperidone can be done in PTC conditions - and no need to isolate your piperidone as free base. Add to one liter of acetonitrile 3 mole finely powdered potassium carbonate, then add 10 g of PTC catalyst - TBAB or TEBA, or just polyethylene glycol-400.
Stir this suspension 15 min at 50-60°C, and then add in little portions your 4-piperidone hydrochloride, watching that the CO2 evolution wasn't too vigorous. Stir another hour at 50-60°C, and then add phenethylbromide dropwise , and stir 15-20 h at mild reflux. Then cool, and filter off inorganic salts - if filtration goes too slowly, add to suspension some (30-40 ml) saturated sodium sulphate solution, this makes the sticky precipitate granular and filterable.
You should yeild a slightly yellow solid with mp 60°C.


Synthesis of the Imine derivative of NPP:

10 mmole of NPP is dissolved in a minimal volume of Aniline (about 5-6 ml), then 1 gr of 4A Molecular Sieves is added.

The mix is really gently stirred (so that the Molecular Sieves aren't destroyed by the agitation) with a magnetic stirrer for about 24 H at room temperature.

Synthesis of the ANPP:

The reaction mixture from above is filtered from the Molecular Sieves which are rinsed with 2*2ml THF, the filtrate and washings are poured into a 50 ml flask, whereupon 20 ml dry Methanol is added, and the mix is stirred.

About 1-1.5gr of Sodium Borohydride is very slowly added to the mixture at room temperature, and the mix is stirred for about 2 h. The conversion into ANPP is checked with any method and if not completly reduced, add slowly another 0.5gr NaBH4 and stir for one more hour.

When the conversion into ANPP is complete (over 95%), evaporate the Methanol and THF under vacuum.

After the evaporation there is a mass formed from the Aniline, excess NaBH4 and ANPP complexed with borane.

Pour 50 ml of water into the flask, then destroy the complex by the slow addition of a small quantity of concentrated HCl (35%) until the pH is about 1, then the mix is well stirred for another hour. Now 50ml of a saturated NaCl solution is added to the mixture, and after about 10 min, a solid mass precipitates.

Separate the solid from the liquid with a filtration and keep the solid (this is ANPP hydrochloride) after washing it with a little saturated NaCl solution.

Add another 50ml of saturated NaCl solution and place the mix in the fridge (at about 2°C) and wait 2-3 h. If there is more precipitate, filter the solution and add the solid to the
first crop. The solid mass is ANPP which must be treated.

Dissolve the solid in about 60ml water and 2M NaOH until the pH reaches 12.5, then extract with 3*15ml Dichloromethane. Wash the CH2Cl2 phase with 5 ml water, and evaporate the solvent in vacuum. The residue is an oily yellow-orange liquid which spontaneously crystallizes, this is the ANPP which is pure enough for the next step.

The overall yield of ANPP is about 50-80%. The main loss of yield is during the purification process because the separation process between the excess of Aniline and ANPP is not optimized.

Conversion of ANPP to Fentanyl:

10mmols of ANPP are dissolved in about 8 ml of Pyridine with stirring, and then 12 mmoles of Propionyl Chloride is added dropwise to the reaction mixture at room temperature. The reaction is exothermic and the Propionyl Chloride must be carefully added, so that the
temperature doesn't rise over 60°C. You don't need a cooling bath, the temperature should be controlled with the addition rate of Propionyl Chloride and must stay between 30 and 60°C during the addition.

When all the Propionyl Chloride is added, the reaction mixture is stirred for about one hour at room temperature.

Check the conversion with any method and if not complete add another 1 mmol of Propionyl Chloride. Normally the conversion should be complete after the first operation but if there is too much Aniline you need more Propionyl Chloride.

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 2M 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 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 with a small quantity of Propionanilide as an impurity. 10-15ml Acetone is now added, and a white powder forms, which is Fentanyl HCl. Filter the solid and wash it with a small quantity (2*3ml) of acetone.

[akinrog]

This is an excerpt from pharmaceuital manufacturing encyclopedia regarding fentanyl synthesis. I hope this bit of information might be useful.
(Quote)
Raw Materials
1 -Benzyl4-1iperidone
Lithium aluminum hydride
Beta Phenylethyl chloride
Aniline
Propionic anhydride
Hydrogen

Manufacturing Process
To the stirred solution of 5 parts of N-(4-piperidyl)propionanilide, 6.85 parts sodium carbonate, 0.05 part potassium iodide in 120 parts hexone is added portionwise a solution of 3.8 parts 0-phenylethyl chloride in 24 parts 4-methyl-2-pentanone. The mixture is stirred and refluxed for 27 hours. The reaction mixture is filtered while hot, and the filtrate is evaporated. The oily residue is dissolved in 160 parts diisopropyl ether and the solution is filtered several times until clear, then concentrated to a volume of about 70 parts, The residue is then cooled for about 2 hours at temperatures near 0°C to yield N-[l-(P-phenylethyl)-4-piperidyll propionanilide, melting at about 83" to 84°C as described in US. Patent 3,141,823.
The starting material is prepared by reacting 1 -benzyl4piperidone with aniline, reducing the condensation product with lithium aluminum hydride, reacting the product thus obtained with propionic anhydride, then hydrogen.
(/unquote)

Note : Credit goes to Polyverone (sp?) who made this vonderful encyclopedia available

[akinrog]

Sorry posting again (since I am unable to edit my previous post) but while searching I found the following link on rhodium's web site about carfentanyl (which is said to be used in Moscow rescue raid and be 4000 times more potent than heroin).

Here is the Carfentanyl Link (http://www.rhodium.ws/chemistry/carfentanil.html)

I also found the following (https://www.the-hive.ws/forum/showflat.pl?Cat=&Number=411081&Search=true&URLForums=All_Forums%3Don&Name=&Subject=fentanyl%20synthesis&Body=&Text=&Searchpage=0&Limit=25&Old=all&To=now&OldDate=12-31-97&ToDate=04-12-04%2002%3A17&Type=&Order=date&Sort=DESC&nohelp=&Preview=on&PreviewChar=500&PostNo=&Rate=%3E%3D0&RateRemark=) at hive about fentanyl synthesis.

Anybody knows knockout time of this substance. I mean how long does it take to knock someone out with an overdose?

[Yellow]

If there are some confusion about "Fentanyl", it is most likely because Fentanyl has a lot of analogs. And it was an analog of Fentanyl that was used in Russia ( I am sorry that this was not specificly mentioned in the text ). But unfortunately, many chemists simply call them all "Fentanyl". But for use as a weapon, the only difference are that many of the analogs are more toxic than Fentanyl.
The formular that I have posted will result in "Fentanyl" - not an analog.

[Xave]

Somebody already linked to a page on rhodium. check out www.rhodium.ws/chemistry , scroll to the section on fentanyl. They have around 7-8 articles there. I've been researching a while back about this, and the potencies go like this (in terms of morhpine):

Morphine- 1x
Herion (DiAcetylMorphine)- 2x
Fentanyl - 166x
Sufentanyl-
Carfentanyl- 16600x
yes- 16,600 times stronger than morphine. no wonder thos people died. The opiate (mu, gamma and delta) receptor antagonist most commonly known if Naloxone, and when injected, almost immediately reverses all the effects of whichever opiate/opioid has been consumed.

The medicinal morhpine dosage is 5-20mg (I.m) for comparison.
Recreational smoked (i.e. inhaled) dosages of heroin are between 5-10mg.

"drugs are quick"

[redbull]

Considering Russia and the United States are working on Fentanyl based
non lethal chemical weapons, what is the best defense against them?

Do current NATO gas mask filters provide adequate protection?

Does anyone know if DMSO or another transdermal chemcial is being used?
(making it nessasary to wear protective clothing)

I presume terrorists should start packing nalaxone right next to the atropine
injector :D


As monday morning quarterback, what things should the terrorists have
done differently to be successful?

I'll say, use a dead-mans switch instead of a push button switch. The
terrorists should have been holding the trigger the whole time and then
when the agent knocked them out, they would have released it involuntarily
and the bombs would have gone off. Also useful if a sniper takes the
terrorist out...


I still can't imagine why people are into the whole suicide bomber thing?
I know its an effective technique but I guess I like living too much to do
it myself :D Now setting down a breifcase and casually walking out of
the theater is certainly do-able.