hxxp://www.scribd.com/doc/32141802/Synth-Evalution-of-2-3-Seco-Fentanyl

A structurally novel, 2,3 “seco” analogue of fentanyl has been synthesized by a
short and efficient procedure. Central-analgesic activity was found to be ca. 30 times lower
than fentanyl but still several times higher than morphine.

Interesting! Why not use the Mannich rxn to condense ephedrine with one equivalent of formaldehyde and a vast excess of acetone (to prevent the formation of complex mixtures), then reductive amination with aniline and acylation with propionic anhydride? Perhaps the product - 2,3 seco alphamethyl-betahydroxyfentanyl would be significantly more potent or more euphoric than what is described in this paper.

hxxp://books.google.com/books?id=wufUIdeynGsC&pg=PA248&lpg=PA248&dq=3-methylfentanyl+potency&source=bl&ots=9aMaOIpVl5&sig=7XDtaGLhGsZtA6Z6zbhSDnnx5R0&hl=en&ei=I6LQTpicHcmvgwely-CoDQ&sa=X&oi=book_result&ct=result&resnum=10&ved=0CFgQ6AEwCQ#v=onepage&q=3-methylfentanyl%20potency&f=false

Introduction of a beta-hydroxyl group into the carfentanil and sufentanil structures depresses potency by as much as 50%.

Ouch. Turns out that beta-hydroxy isn't useful unless there is a 3-methyl present, in which case the potency jumps. Replacing the hydroxyl with a keto depresses potency, amino nearly abolishes it, esterification reduces it by 10-fold.

How about instead of mucking about with alpha-methylfentanyls to extend duration (0.1x the therapeutic index of fentanyl, yikes), try 3-methylfentanyls? According to the WHO, 3-methylfentanyl has a duration of 4 hours. This is quite an improvement over fentanyl. See first attachment.

Assyl is brain damaged and unable to quite comprehend the table at the bottom of page 3 of the second pdf attached. It does appear to support the assertion that a 3-methyl drastically boosts duration of action.

3-methyl, as is better known, increases potency considerably (up to 10x over fentanyl) and increases the therapeutic index ~10x as well. With appropriate dilution, it is actually an unusually safe opioid.

That said - why not create an analog of 2,3-seco-fentanyl using MEK instead of acetone (using phenethylamine)? This will plop a methyl at what would be the 3-position if it were a ring (not opened/straight chain). It's rumored 2,3-seco-fentanyl lasts half as long as regular fentanyl, so it should help with this. Anything that lasts less than 3 hours is trash in Assyl's opinion. Also, it obviously should bump potency up from 5x morphine to a maximum of perhaps 50x. But this is a guess, of course, pharmacology isn't 1+1=2. Usually more like 1+1 = .05 or 1+1 = 1000. So be safe if experimenting with this until data is available.

Then again - it's possible the "virtual" 3-methyl could cancel out the toxicity of the alpha-methyl. Should this be the case, pseudoephedrine is the way to go. 3-methyl together with that beta hydroxy will mean greatly enhanced potency, possibly enhanced euphoria, hopefully enhanced safety... just need to not go crazy with the acylation step as acylating that beta hydroxy will knock potency down 10-fold - so no 12 hour reluxes or anything else goofy. What's nice about pseudoephedrine vs phenethylamine is you're already starting with a secondary amine, which means multiple condensation products from the Mannich rxn are avoided.

One thing that is lucky is the more active isomers would be formed by use of pseudoephedrine vs ephedrine. The isomers formed from pseudoephedrine should be very potent and selective mu-agonists. The ones formed from ephedrine should be largely delta and kappa agonists. It is rumored (no citations available for this, just blabber on msg boards) that some need a mixture of mu and delta agonism to get a euphoric effect, and that these individuals experience little euphoria from fentanyls due to selective mu agonism. If there's any truth to this, then a mixture of the pseudoephedrine and ephedrine derived products would probably treat these people well.

hxxp://www.scribd.com/doc/45346585/Enantiomers-of-Diastereomeric-cis-N-1-2-Hydroxy-2-phenylethyl-3-methyl-4-piperidyl-N-phenylpropanamides-Synthesis-X-ray-Analysis-and-Biological
(someone please check to make sure Assyl's stereochemistry is right - that pseudoephedrine would lead to the analogous stereoisomer of 1a)

Since the parent compound is only 5x morphine, any enhancements to potency are certainly welcome, though given the OTC nature of the reagents needed and their low cost, 5x morphine is not at all going to stand in the way. In fact, in some ways it could be nice - less risks from synthing or handling the material, or from powder hot spot ODs. The issue that really needs to be addressed is the excessively short duration.

Assyl I'm posting this just so you don't get discouraged, I wanted to let you know someone is reading with great interest but has not much to add at the moment. Keep up the good research and let us know of any experimental results you might find written down on a note you found on the side of the road or something of that nature. I will see what I can do about returning the favor if you do