Fentanyl Synthesis- Siegfried

Guest · Sat Feb 05, 2005 10:54 pm

1. Introduction
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 theoretic 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 100gr of very good street heroin.

2. Principle

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.

3. Procedure

a) 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.

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 (a) 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 completely reduced, add slowly another 0.5gr NaBH4 and stir for one more hour.

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

After the evaporation there is a mass formed from the Aniline, the excess NaBH4 and the 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 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 deg 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 the pH reaches 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, 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. There are perhaps some solutions to this, which will be discussed in the optimization and discussion section.

c) 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 deg 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 deg 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 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 leaved 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.

The Fentanyl HCl is now pure enough for use (>99.5%). The yield in this step is over 90%!

If not pure enough (it was never the case for me) you can purify it by recrystallisation from hot acetone.

d) Preparation of synthetic white Heroin for street use

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 which is the same as very good (30%) street heroin.

100mg of Fentanyl. HCl is dissolved in 2ml of Methanol. Weigh up 10g of Lactose and warm it at about 60-70 deg 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 the Lactose-Fentanyl 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!

Now you have a very high quality of street white Heroin.

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!

Remember that with 1gr of pure Fentanyl HCl you can make 100gr of very high quality Heroin!

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

e) Optimization and discussion

The overall yield of this synthesis is about 50-80% and the main loss of product is 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 Para-Fluoro- Aniline 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 the underground 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:

- Fentanyl is very addicting , much more than simple Heroin, the regular users of this synthetic white Heroin I described was really strongly addicted.
- The risk of overdose is really large, even with the dilution I described before, so test your stuff before selling it!

- The duration of the effects is a little shorter than with normal Heroin.

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Related texts:

N-Phenethyl-4-piperidone

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 dropwise phenethylbromide, 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.

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chemdude · Guest

swic has done this drug by scraping out gell from the patch.
Good drug.
Whats the OTC status on these chemicals needed to produce this?
Swic live in the states...

Guest · Tue Feb 08, 2005 7:50 am

Much to the suprise of many,

All ingredients are otc,

Have a look in Opioid Synthesis
Your topic is just beginning,.

Basically NPP can made essential in a few different ways, generally starting for PEA(phenethylamine)

There is A Dieckman Cyclization Method:
Uses Methyl acrylates,{nasty stuff}

And the Much shrowded in Disbelief
Double Mannich, using acetone, formaldehyde, & PEA

Will search for some more info immeadiatly

zaratystra · Wed Feb 16, 2005 6:28 pm

Sorry thes article is veri - veri old ...

I read in 1999.

zaratystra · Wed Feb 16, 2005 6:31 pm

woden · Wed Feb 16, 2005 7:36 pm

Alpha- and Beta-Prodine Type Compounds
A. H. Beckett, A. F. Casy, G. Kirk;
J. Med. Chem.; 1959; 1(1); 37-58.

rxn between acrylic acid ester and beta-phenethylamine..

N-Di-(2-carbethoxyethyl)-2’-phenylethylamine

Ethyl acrylate (300 g) was added with stirring to 2-phenylethylamine (121 g) in dry ethanol (200 ml) and the mixture refluxed for 48 h. The product was fractionally distilled under reduced pressure to give N-di-(2-carbethoxyethyl)-2’-phenylethylamine (303 g) as a colourless oil, b.p. 166-168’ (0.3 mm)

Dieckmann condensation..

N-2’-phenylethyl-4-piperidone ethylketal.

N-Di-(2-carbethoxyethyl)-2’-phenylethylamine (70 g) was added to a stirred suspension of bird shot sodium (10.8 g) in xylene (250 ml) and the mixture, protected from moisture, warmed to 50’ to initiate the reaction. A further quantity of base was then added drop-wise at a rate sufficient to maintain the reaction. Stirring was continued for 3 h after addition of the base, the mixture cooled, and water (250 ml) added drop-wise. The aqueous phase was separated, washed with ether (2 x 100 ml), and acidified with concentrated hydrochloric acid (congo red). The solution was saturated with anhydrous potassium carbonate and the yellow oil which separated extracted with ether (600 ml). After drying (K2CO3), the ether was evaporated to give crude N-2’-phenylethyl-3-carbethoxy-4-piperidone (103 g). The ketone was refluxed with aqueous 20 per cent hydrochloric acid (450 ml) for 3.5 h (negative reaction with ferric chloride). The product was evaporated to dryness under reduced pressure, the free base liberated with aqueous 25 per cent sodium hydroxide and extracted with ether. After drying (Na2SO4), the ether was evaporated and the residue treated with excess of alcoholic 10 per cent hydrochloric acid. The crystals (42 g) which separated were collected, the free base liberated with aqueous ammonia and extracted with ether. The ether was dried (Na2SO4) and the ether evaporated to give N-2‘-phenylethyl-4-piperidone ethylketal (35 g) as a pale yellow oil which could not be distilled. It gave a hydrochloride. needles from ethanol, m.p. 178-179' dec. The ketal gave a picrate, needles from ethanol, m.p. 136-137' dec.

N-2'-phenylethyl-4-piperidone.
A mixture of N-2'-phenylethyl-4-piperidone ethylketal (20 g) and dilute aqueous hydrochloric acid (150 ml) was refluxed for 2 h. cooled aid washed with ether. The free base was liberated with aqueous ammonia and extracted with ether. After drying (Na2SO4), the ether was evaporated and the residue (13.0 g) crystallized from light petroleum (b.p. 80-l00') to give N-2'-phenylethyl-4-piperidone (12.1 g), needles. m.p. 60.5-61.5'.

Guest · Fri Feb 18, 2005 2:44 pm

Great post Woden,

That is the article I was after,
there is one more that we must find,
where NPP is synth'd from
Acetone, formaldehyde and PEA,

It came from jacs I think

Zara:
Yes it is a very old post, somewhere to start as a reference,
Besides using the MMA and dieckman reaction, as in Woden's post,
there is the Magical Double mannich, of much simpler reagents,

It is very similar to the tempidone synth,
There is not alot of information about tempidoone that I am able to find

syn

64bandil · Busy Bee

I hate to sound like an old boring fart, but I really must warn against this particual compound.

IMO it has no recreational value. Sure, it feels nice, makes you drowsy etc. So if you must make it, do yourself the favour of trying it a few times and then flush the rest down the drain.

All of my friends are highly intelligent, well functional etc, and every single one got addicted to fentanyl when I cranked out a batch.

Physical addiction happens within two days of sporadic use. The physical withdrawal isn't the worst (just like a flu really). The absolutely worst part is, that you SEE how mellow you can get. Thus when you henceforth chill out (without the drug), you feel stressed, even though you'r mellow as ever. It's a very vile feeling, and it lasts for up to 6 months after discontinued fentanyl usage.

I have yet to see any positive effects from fentanyl.

So do yourself a favour and stay away from this one! Go make some psychedelics instead - much much better Cool

Regards
Old fart Bandil

IndoleAmine · Dreamreader Deluxe

Not to mention the dangers of sudden death through apnoea associated with accidental ingestions of even the smallest amounts of fentanyl....

(and it surely beats even diacetylmorphine when it comes to the addiction potential!! Bandil's right on that! I would always dismiss any opiate/opioid for a good old Bhang style hash milk chocolate, but thats just me...)

i_a

Cyrax · Sat Mar 26, 2005 12:44 am

Guest · Sat Mar 26, 2005 6:54 am

Good post 64Bandil,

It's an insideous drug, if not aware of the outcomes,

I would never recommend anyone taking any opiate, without quick access to a doctor that can prescribe an instant detoxification program using a long half-life optiate to ween of the drug,

On the other side of the coin, I know many people living very happy lives, on this road,
This drug in no way differentiates between social groups, it's underlying attribute is that it's mimics well being,

A 4 day binge will last for many weeks of uncorfatble feelings, and unrestlessness,

I do not arecommend this as a recreational drug, and it is here for informational purposes only

From my knowledge,
It is not a drug that you can have occasionally,
Once trodden, the path is a one way street,
it is akin tobacco, in it's abuse

Since the drug must be used every day to feel good, or get more to get high, it is riduculous to think one could make this a permanent thing,
one day, the shit is going to hit the fan,

Yo will find most "junkies' get their drug, subsidized by the government,
typically known as the methadone or bupermorphine treatment,

syn
About the chemistry

THE MOON RULES --1 · voted for the moon

I know first hand of the unrestlessness of this drug. I was hooked up to a pump for 4 days, every 3 minutes got injected. Got kicked out of the hospital, and sent home with 5mg vicodin (yeah I know). Never felt so bad in my life, well..., i dunno but really really bad. I always was against herion and its users, but it wasn't until coming home and feeling how I felt to where I was thinking of trying to get some. People who start out using herion first are just stupid, but I feel for people who go down the downward spiral of perscription pills/opiates (the ones who actually need it), because when you are sick and your access to your particualr pill dries up, you are only left with a., getting sick or b., getting somthing illicit and stronger/dirtier. It sucks. I have weened myself off the big gun opiates but still cannot seem to give up vicodin. Its weak and doesn't even get me high anymore but I get so sick that I just think i'm better off because methadone tends to be somthing people have a harder time getting off so. I heard of a drug that doesn't get you high and isn't addictive and it kills the withdrawls, anyone know which drug i'm talking about?

Soap · Tue Apr 12, 2005 5:54 am

ibogaine does "get you high" but ive heard great things about its use to help addiction. regardless of how terrible this drug is (fentanyl) , has anyone found any information in regards to the synth from acetone and the other otc chems? ive looked alll over...

Polverone · Tue Apr 12, 2005 6:32 am

stooge · Wed Apr 13, 2005 1:43 am

@THE MOON RULES:

apomorphine, 3 to 4 times a day for 3 days worked for me. didn't feel good afterwards, but the worst was done just by 3 sc. hits per day, puking first, then dozing till the next hit apomorphin. not bad at all for a withdrawal. could even sleep at night!
i almost gave up evangelising on this as no one seems to care for it anyway, but it's worth the try:)
just make sure to be as low dosed as possible when you start.