Yeah that was what I meant, a silly mistake seeing as though 4-methylfentanyl exists. Regarding its lethality, well you can see from the Moscow theater hostage crisis just how dangerous fentanyl and analogs in general can be. The people passed out where piled on top of each other out the front, it is well known the actual potentially lethal side effect caused by this series of drug in general comes from respiratory depression. Fentanyl compounds are used in anesthesia , and the anesthesiologists allowed to use these drugs have to be acutely aware of the fact. They have been co administering other drugs to combat that specific side effect (maybe if wanted to take it, cut it with some diazapam ? ). But as you stated alpha-methylfentanyl was also notorious, but when they introduced it to the black market as China White a lot dropped.... But it did so well that some herion users still call heroin of exceptionally high quality China White to this day!

The Synthesis and Preliminary Pharmacological Evaluation of 4-Methyl Fentanyl
Ivan V. Micovic, Milica S Prostran, Milovan D. Ivanovic , Ljiljana Dos Sonja M. Vuckovic and Vesna D. Kiricojevic
Bioorganic & Medicinal Chemistry Letters 10 (2000) 2011–2014

Abstract;
The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N -ethoxycarbonyl-4-piperidone (  20% overall yield). In the key step, N- phenylation of secondary aliphatic amide intermediare was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl.


http://designer-drugs.com/pte/12.162.180.114/dcd/pdf/4-methyl-fentanyl.pdf

Quote from: Naf1 on April 13, 2010, 03:21:00 AM

If benzaldehyde and ammonia were swapped for formaldehyde and phenethylamine respectively and reacted with methyl ethyl ketone via Mannich reaction as per the paper the yield would drop but the required precursor for 4-methylfentanyl would be produced.

Do you mean 3-methylfentanyl?  It seems straightforward, but one of the problems with it is that effective and lethal doses haven't been established to the same extent as for fentanyl, and uniform dosing is more difficult to ensure making it notorious for ODs just like a-methylfentanyl.

I think a 3-methylfentanyl would be difficult to make from the proposed method because it would involve converting one of the COOH's on the piperidone dicarboxylic acid into a CH3.

*As I understand it, the mechanism is two mannich reactions in a row. The product would need to be decarboxylated to get to the ketone.

The reaction itself might be tricky in practice, because of the possibility of an imine also forming on the b-oxoglutaric ester. Perhaps those issues could be avoided by careful addition of the reagents. *

yeah heisenburg that's what my dumbass done figured since formaldehyde is gonna be much beeter electrophile than the keto function of glutaric diester. but you know it gets tricky cause that keto group is sandwhichiched between two electron withdrawing moieties.
but also steric factors come into play also lechatlier's pricinple cause ya know two moles of aldehyde and one mole ketone lots of variables.
 but that keto ester is going to split right up(saponify) in dilute h2so4.
  shit that's even better than the dickman condensation who wants to fuck with mettallic sodium anyhow?
'scuse my french just having a shit day oops!
 

You got it yet
From Wiki, obviously tropinone is not the target so taking the mechanism up from step 3;

This reaction is described as an intramolecular "double Mannich reaction" for obvious reasons. It is not unique in this regard, as others have also attempted it in piperidine synthesis.
In place of acetone, acetonedicarboxylic acid is known as the "synthetic equivalent" the 1,3-dicarboxylic acid groups are so-called "activating groups" to facilitate the ring forming reactions. The calcium salt is there as a "buffer" as it is claimed that higher yields are possible if the reaction is conducted at "physiological pH".

The main features apparent from the reaction sequence below are:

• 1 Nucleophilic addition of methylamine to succinaldehyde, followed by loss of water to create an imine
• 2 Intramolecular addition of the imine to the second aldehyde unit and first ring closure
• 3 Intermolecular Mannich reaction of the enolate of acetone dicarboxylate
• 4 New enolate formation and new imine formation with loss of water for
• 5 Second intramolecular mannich reaction and second ring closure
• 6 Loss of 2 carboxylic groups to tropinone

http://en.wikipedia.org/wiki/Tropinone

He got that from wiki..

Also, I have a hard time believing that the rxn works unless you use the ester instead of the free acid.

As for decarboxylating the product of the Petrenko-Kritschenko synthesis, will 25% HCl work as in http://jghx.fjirsm.ac.cn/jghx/2009No6/617-3621.pdf ?

LOL, I was merely pointing out the tropinone syntheses because those papers document the discovery of that technique, it was that which than paved the way for people to recreate with piperidines. Then that technique was ultimately applied to the Petrenko-Kritschenko Piperidone Synthesis to produce fentanyls. So although I am partial to a little nose candy that was in no way a coke advertisement, those papers are important history! Just imagine the pyrrolidine is not there!;

Coke-a-Cola now sponsoring Clandestine Chemists

Coming this Summer; A double mouthed bottle, so you and your friends can enjoy that Coke goodness together.
Thermometer adapter lids, and Coke a Cola tm reflux kits  sold separately.
So fill your flasks with snow and run out and get a Coke-a-Cola Round bottom flask for your clandestine lab, today!

(Now that was an advertisement for Coke!)

Regarding my comment above;

Theoretical study on the mechanism of Robinson’s synthesis of tropinone
Nityagopal Mondal, Sannyasi Charan Mandal, Gourab Kanti Das* and Sarbananda Mukherjee
J. Chem. Research (S),
2003, 580-583

Abstract; Ab initio quantum mechanical calculation reveals that the first Mannich reaction in Robinson’s tropinone synthesis
involves both carbon–carbon bond formation and water elimination, which is followed by tautomerisation and a
second Mannich reaction to form the protonated tropinone.

http://127.0.0.1/Naf1/tropinone.robinson.mechanism.pdf

Now where talking!;

"It was found that during the formation
of the C–C bond the hydroxyl group of the enol part in reactant
2 is deprotonated and the leaving proton combines with the
hydroxyl group of the pyrrolidine part in reactant 1 to form a
detached water molecule (Fig.3). Hence TS-1 not only directs
the C–C bond formation but is also responsible for the
elimination of water to generate the product (P1)
This observation allows us to draw the first step as a cyclic
process as shown in Scheme 2.

The second step involves the tautomerisation. We have
investigated this process as a water-assisted step in which an
external water molecule transfers one hydrogen atom from the
carbon to the oxygen atom of the reactant by a relay
mechanism. The TS (TS-2) is shown in Fig 4. IRC calculation
confirms the formation of the enol from the keto structure
through TS-2. Although we have used a single water molecule
as catalyst, more than one molecule may be involved in
tautomerisation and that may also reduce the activation energy
of the process."

So you can see that the loss of a water molecule in this case is not reversible, and in fact after losing the molecule of water tautomerism is then catalysed (assisted) by reacting with a molecule of water. So water actually pushes that step forward.

That was not organic reaction vol 1..... But the paper I posted on the first page, and my comments! The Mannich reaction is covered in Organic reactions and even piperidone synthesis from the mannich reaction covered but not that method!

The Preparation of Some Piperidine Derivatives by the Mannich Reaction
BY C. R. NOLLERAN D V. BALIAH

A number of piperidones have been prepared by
the Mannich reaction .It should be possible to
extend the use of this reaction for the synthesis of
a large variety of 4-piperidones with different substituents
in the 1,2,3,5 and 6 positions.

Accordingly
glacial acetic acid was tried as a solvent
and reaction took place rapidly, the isolation of
pure products was easy, and the yields were very
satisfactory.

http://127.0.0.1/Naf1/4-piperidones-one-pot-1.pdf

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

Organic Reactions vol 1

"Aldehydes other than formaldehyde may be used in certain condensations
of the Mannich type. Those which have been studied are
acetaldehyde, phenylacetaldehyde, benzaldehyde, and anisaldehyde.
These have been employed successfully with acetone, cyclohexanone,
and esters of acetonedicarboxylic acid. The reactions appear to be
limited to ammonia and primary amines and their salts. With acetone,
aniline, and benzaldehyde a piperidone is obtained.4"*

An open chain product is obtained from cyclohexanone, phenylacetaldehyde
and benzylamine

Substituted piperidones are always produced when esters of acetonedicarboxylic
acid are employed, as in the reaction of the methyl ester
with allylamine and benzaldehyde.

Similar piperidones have been obtained by substituting for allylamine
the following: ammonia,4" methylamine,34 ethylamine,4d and /3-hydroxyethylamine;
84 by employing acetaldehyde, instead of benzaldehyde,
with ammonium bromide,39 methylamine,39 benzylamine,39 and /3-phenylethylamine;
39 and by using allylamine, anisaldehyde, and methyl
acetonedicarboxylate .34

http://asterix.msp.univie.ac.at/.Chemistry%20eBooks%20Collection/Organic/Organic%20reactions%20-%20Vol%201%20-%20Adams.pdf

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

"sure the yeilds would be shit but when your dealing with oh-me-fentanyl low yeilds don't really matter"

Exactly!

Just before I get started on the actual question, I had posted this before but....

Since fentanyl and co. are used extensively in anesthetics and medicine, the topic of its lethality due to the high respiratory depression levels has been addressed numerous times in the scientific literature. They have found that co administering  fentanyl with certain drugs such as diazapam they where able to reduce respiratory depression without affecting the analgesic qualities at all. I have not extensively searched through the literature regarding this so there could be better ways to go about it, but being able to reduce its lethality considerably by just cutting with diazapam maybe should be the first step when synthing this compound.

The value of fentanyl/diazepam anesthesia for experimental operations
   European Archives of Oto-Rhino-Laryngology

http://www.springerlink.com/content/l5820xu55p732628/

A more sensible approach than the rhodium paper would be to mix your powder that you are going to cut with (example 1:20 diazapam:lactose), weigh out how much you are going to need corresponding with how much fentanyl you have. Say you created diazapam lactose powder for 10,000 doses, your best bet would be to buy 10,000 already pressed placebo tablets. Create a solution of fentanyl citrate: 0.63 g in water: 300 g, with that solution shake it and shake it again, load your pippette, set the volume of the pipette to 0.003 ml, and press the trigger over a pill, go to the next press the trigger so on...... Once that solution is spread out evenly over 10,000 pills, the pills will contain 63ug per pill if you wanted less or more you would add less or more fentanyl citrate to the solution.

Read more: http://www.faqs.org/patents/app/20080226717#ixzz0mYdIRDCC




Hitting hot spots ect is not a concern as each pill contains 1 dose no more, same as LSD blotters people say they dip the sheet (bull, the pipette like above is set to 250 micrograms in the case of lsd and a sheet pumped out fairly quickly) as would the pills if you had them lined up on a table (add some dye to the solution so you never double up ect). I know one fentanyl type of pill is made and they mix the ingredients for 50 hours before proceeding.

edit: I am in a rush, those quantities stated above are probably off but you get the idea!