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Synthesis of Fentanyl

By Siegfried

HTML/Gfx by Rhodium


I'm french speaking organic chemist so excuse my rusty english [most things corrected by me - Rhodium].

Fentanyl and its analogs are among of the most powerful opiate agonists, but their synthesis are often hard. Here is a synthesis of Fentanyl which can be easily adapted for the other analogs (para-Fluoro-Fentanyl, alpha-Methyl-Fentanyl).

This procedure is not theoretical and have been tested and improved many times over. This synthesis is conducted at room temperature so you don't need any special apparatus.

Fentanyl is a very interesting component for underground chemistry because one gram of pure fentanyl is equivalent of 100 g of very good street heroin.


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 which is then purified.


N-Phenethyl-4-piperidone (NPP)

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.

Yield almost quantitative (trust me), and no distillation needed - as result you have slightly yellow solid with mp 60°C.

a. Synthesis of NPP N-Phenyl-Imine

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.

The conversion have repeatedly been calculated with MS and is more than 99%, so the next phase can be conducted without any purification.

b. Synthesis of the ANPP

The reaction mixture from the previous step 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 1-1.5 g 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 0.5 g NaBH4 and stir for one more hour. When the conversion into ANPP is complete (over 95%), evaporate the Methanol and THF under vacuum.

The residual mass consists of 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 pH ~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 precipitate.

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 2N NaOH until pH > 12.5, then extract with 3×15ml CH2Cl2. 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, consisting of ANPP 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. There are perhaps some solutions to this, which will be discussed in the optimization and discussion chapter.

c. Conversion of ANPP to Fentanyl

10 mmol ANPP is dissolved in about 8 ml of dry, pure pyridine with stirring, and then 12 mmol of propionyl chloride is added dropwise to the reaction mixture at room temperature. The reaction is exothermic and the temperature should be controlled by carefully adjusting the addition rate, and it must be kept between 30-60°C at all times. When all the propionyl chloride is added, the reaction mixture is stirred for about one hour at room temperature.

Check the conversion with any suitable method (TLC/GC) 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 left from step A, you need more Propionyl Chloride.

The reaction mix is then poured into 80 ml water with stirring, and concentrated HCl (~35%) is added dropwise until pH < 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 turning into their respective hydrochloride salts. The solution is then stirred for about 30 min. Pyridine·HCl is not soluble in CH2Cl2, while the nonpolar Fentanyl·HCl is. Extract the solution with 3×20ml of CH2Cl2, then wash the pooled organic extracts with 2×10ml saturated NaCl solution.

The solvent is evaporated under vacuum, and a yellow mass is formed which consists of Fentanyl hydrochloride contaminated with a small quantity of propionanilide, which was formed by the action of propionyl chloride on residual aniline from step A. 10-15 mL acetone is now added, and a white powder forms, which is Fentanyl·HCl. Filter the solid and wash it with a small quantity (2×3 mL) of acetone.

The Fentanyl Hydrochloride is now pure enough for use (>99.5%), the yield of this step exceeding 90%! If it would still be impure (it was never the case for me) you can purify it by recrystallisation from hot acetone.

Dilution of fentanyl powder

The pure Fentanyl can not be used as is, because it's much, much too strong and MUST be diluted, else there will be a lot of overdoses!

The following procedure gives a white heroin wich is the same strength as very good (30%) street heroin.

100mg of Fentanyl·HCl is dissolved in 2ml of methanol. Weigh up 10g of lactose and warm it to about 60-70°C into a large dish with a hotplate. Add the methanolic solution of Fentanyl dropwise at regular intervals into the warm lactose for a good pre-mix. Wait until all the methanol is evaporated and mix thoroughly. This is crucial because if this is not thoroughly mixed, there will be a part of the Lactose without Fentanyl and part of the Lactose with too much Fentanyl, possibly causing dramatic overdoses!

This type of Heroin was used and sold during a year, and the feedback of the consumers was very good. The consumers were very happy and didn't want the usual brown Heroin anymore. So be careful, some people (the Mafia and other dealers) will perhaps turn very jealous!

DON'T USE and DON'T SELL pure Fentanyl HCl, this is a very toxic material which will cause many overdoses if not diluted!

Optimization and discussion

The overall yield of this synthesis is about 50-80% and the main loss of material occurs during the purification of ANPP in step B. There are perhaps other alternatives for the separation of Aniline and ANPP (recrystallisation, distillation). I think a good solution is extracting the Aniline and ANPP together and separate them with the evaporation of Aniline under vacuum, then recrystallize the ANPP in a suitable solvent.

Para-Fluoro-Fentanyl can be synthetised with this procedure using p-fluoroaniline instead of plain aniline, but the purification process must be adapted.

The very powerful alpha-Methyl-Fentanyl can also be synthetised with this method using N-(2-Phenylpropyl)-Piperidinone which can be synthetised from 1-Phenyl-2-Bromopropane and Piperidinone or other methods. The 1-Phenyl-2-Bromopropane is used in clandestine manufacture of amphetamine, and the procedure of the synthesis of this compound can be easily adapted for the creation of N-(2-Phenylpropyl)-Piperidinone or the NPP (N-Phenethyl- Piperidinone).

Fentanyl is a very good and powerful opiate but there are some remarks: