Fentanyl Synthesis- Siegfried

lusitania · Sun Jun 05, 2005 12:26 pm

so even if the drug is evil....because all the chems are otc one could produce this chem on a large scale right? like 100g of fentyl in a single run? I'm not planning on doing this, but from reading it sounds possible..right?

Guest · Tue Jun 07, 2005 10:35 am

All synthetic pathways definately are possible,
Often it can all boil down to the purity of the reagents prior to synthesis.
The sociocultural attitudes towards all drugs is not under debate in this forum, as the chemistry is our primary focus.

It would be incredibly unwise to manufacture any drug that contravenes the law,. Period.
And whether the drug is of theraputic and/or social value, may each individual decide for himself.
Whether drugs are actually harmfull or gateways to the evolution of mankind, is definately a good discussion in and as we grow, we will address these things,

Piperidone, can be simply manufactured through the Mannich Reaction,
Where an aldehyde(formaldehyde), Amine(PEA), and a ketone?(acetone) are condensed to form the nitrogen containing hetrocyclic Piperidone.

Patents are needed to complete this synthesis,

syn

sony · Tue Jun 07, 2005 5:45 pm

Yes in theory this mannich reaction should be possible and im sure someone has tried this out, however it seems pretty hard if possible at all to obtain 4-piperidone in even moderate yields and good purity as the main product even when strict reaction conditions/controlled addition are performed.
The conditions have to be pretty much optimal to get the cyclic 4-piperidone and even then 2,2-dimethyl- and 2,2,6,6-tetramethyl-4-piperidone are pretty much impossible to avoid.

Another problem that comes in mind with this mechanism is the polymerisation of 4-piperidone because the ketone and the amine group of 4-piperidone will be reactive during this mannich reaction.

Stinging_Nettle · Sat Jun 11, 2005 6:13 pm

I agree more with the make a small amount and flush the remainder down the sink mentality than start from scratch and get loads attititude. Having said that if one has 100g 4-piperidone.HCl.H2O this is a safety catch since you still have quite a lot of work to do. If you have 25g N-(2-phenylethyl)-4-piperidone you have saved yourself alot of work and kept your discretion but the smell of fentanyl is only around the corner.

Stinging_Nettle · Sat Jun 11, 2005 6:50 pm

[Chem. Pharm. Bull. 33(5)1826-1835(1985)]

A solution of an aniline (30 x 1.2mmol) and 1-alkyl-4-oxo-piperidine (30mmol) in benzene (12ml) was refluxed (20h) or stirred at room temperature (50-70h) in the presence of molecular sieve 4A (6g). Et2O was added, then the molecular sieve was filtered off and washed with Et2O. The filtrate and washing were combined and concentrated, and the residue was dissolved in 95% EtOH (50ml). To the stirred solution was added NaBH4 (15mmol) and the solution was stirred at room temperature for 5h. After removal of EtOH, H2O was added and the mixture was extracted with CH2Cl2. The extract was evaporated and the residue was crystallized from Et2O-petroleum-ether. Yield 81% mp 96-98C

lusitania · Wed Jun 15, 2005 9:21 am

yeah i don't plan on doing this...or even venturing into a lab with this synth in mine for several, several years, just wonderin.

Fentasies · Wed Jul 13, 2005 2:32 am

You talk about addiction like its a bad thing. Not in SWIM and my eyes... but to each his/her/its own

piglet · Sat Sep 24, 2005 8:23 pm

The Siegfried synthesis is shot through with omissions and mistakes. Has anyone dreamed this route? I think not. I'm surprised Rhodium posted it without really commenting on it. So, what ARE these faults...

Synthesis of N-phenylethyl 4 piperidone: K2CO3 isn't soluable in CH3CN but KBr is (a little). Also, your PTC will filter through so you don't end up with a pure product, you end up with a mixture. Plus, no weights are given for the Phenyl ethyl bromide or piperidone hydrochloride. I ASSUME 1 mole of each, but who can say?

Synthesis of ANPP: 'Aniline, the excess NaBH4 and the ANPP complexed with borane'. Err, I would have thought that sodium tetramethoxy borate would be formed?

ANPP->Fentanyl: 'the non-polar fentanyl hydrochloride' errr... well since it's a salt, it IS polar. I suggest triethylamine in place of pyridine. Then you can freebase your product, distill off the TEA & extract into DCM to get pureish product.

Am I being too picky here?

java · Consumer

Here is a recent review and synthesis of some of the analogues.............java

--------------------------------------------------------------------------------------

The synthesis and pharmacological evaluation of ( )-2,3-seco-fentanyl analogues*
M. D. IVANOVI],a,**# I. V. MI]OVI],a,+ S. VU^KOVI],b M. PROSTRAN,b Z.
TODOROVI],b E. R. IVANOVI],c V. D. KIRICOJEVI],d# J. B. DJORDJEVI],c and LJ.
DO[EN-MI]OVI]c#
J. Serb. Chem. Soc. 69 (11) 955–968 (2004)

http://www.shd.org.yu/htdocs/shd/Vol69/No11/V69-No11-15.pdf

Abstract:
An efficient, five-step synthetic approach to various acyclic 1,3-diamines
has been developed and applied to the preparation of a novel class of open-chained
fentanyl analogues. The acyclic derivatives 5.1–5.5 (all new compounds) were synthesized
with the aim of estimating the significance of the piperidine ring for the
opioid analgesic activity of anilido-piperidines. The starting -keto-amide 1.1, prepared
by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 %
yield), was successively reacted with NaH and BuLi, to form the highly reactive
, -dienolate anion 1.1a. Regio and chemoselective -alkylation of the dienolate
with various primary and secondary alkyl halides furnished the -keto-amides
1.2–1.5 (76–91 %). Reductive amination of the keto-amides 1.1–1.5 with aniline
and Zn powder in acetic acid, via the enamine intermediates 2.1–2.5, afforded the
-anilino amides 3.1–3.5 (74–85 %). After reductive deoxygenation of the tertiary
amide group, using in situ generated diborane, the corresponding 1,3-diamines
4.1–4.5 were obtained (87–97 %). The synthesis of ( )-2,3-seco-fentanyls 5.1–5.5
was completed by N-acylation of the diamines 4.1–4.5 with propionyl chloride, followed
by precipitation of the monooxalate salts (86–95 %). The parent compound,
2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than
fentanyl but still 5–6 times more active than morphine in rats, while i-Pr derivative
5.3 was inactive. Apart from the pharmacological significance, the general procedure
described herein may afford various functionalized, 1,3-diamines as potential
complexing agents and building blocks for the synthesis of aza-crown ethers.

Stinging_Nettle · Sat Sep 24, 2005 9:21 pm

Obviously we know that the Siegfried method can be followed because people with no chemical background (maybe some college) were able to pull it off using syntheses they found published 'over the internet'. But without getting too deeply involved in synthetic discussions it should be possible to make other alkaloids from 4-piperidone. Again without wanting to say anything too specific (mainly due to the range of options and different persons preferences) drugs such as PEPAP for example.

nobodyimportant · Sun Sep 25, 2005 8:55 am

But following Siegfried's method step by step religiously does NOT work. TRUST SWIM on this one. Too many flaws and errors. There are ofcourse easier ways and also some "quiet similar" ro Siegfried's, but one has to know chemistry well enough to be able to pull it off. Also, getting N-phenylethyl 4 piperidone from 4-piperidone HCl isn't all that hard.

Again don't ask what are the steps etc. I DO NOT OR NEVER HAVE made anything. okay? I'm just saying that Siegfried's method is terribly flawed if followed to the letter and that there are easier methods.

But this is all theoretical, right?

piglet · Tue Sep 27, 2005 4:31 pm

http://www.anakata.hack.se/index/structures/route/fentanyl.jpg

This shows a very similar route, so i THINK the overall stratergy is sound, just the details are wrong. If i remember the original Jaansen patent, they make N-phenyl ethyl piperidone in toluene with a methyl sulfonic acid catalyst at an elevated temperature.
Oh, and the side products from the NPP the ANPP step are trimethoxt borane and sodium methoxide...