Greetings-

I've been looking around at all of the published methadone synthesis that are about, which of course methadone is extremely well documented. So I started poking around the opioids that were similar to methadone. Funny enough, I can't find a complete reaction scheme for dipipanone anywhere. I've checked in "Opioid Analgesics" by Paffit, as well as Paul Jansens seminal text on the subject. All of these basically just say to do the same methadone synthesis but sub-out 2-dimethylaminoethyl chloride instead of 2-dimethylaminoisopropyl chloride. Anyways, my actual question is what are the intermediate aminonitriles formed by this reaction? In the case of methadone, you have a high melting and low melting nitrile, and the low melting will recrystallize from cold hexane first. Any idea if 2 aminonitriles are formed with dipipanone synth? Also, is one the useful nitrile and the other not, or can they both, with the help of grignard, create the isomers of dipipanone? Also, if one is not useful, what is the standard method of separation? Is it similar to the cold hexane crystallization (and which one is the useful product, the initial crystallizing solid, or the one that crystallizes last)? Thanks for your help- just some scholarly intrest   -

A little update- I found an article from the Royal Chemistry Society ("Search for New Analgesics, Part IV, Variations in the Basic Side-chain of Amidone (w/ a Note on Some Pharmacological Results)", Ofner and Walton, RCS 2158, 1950) that has the original synthesis included (as well as many other similar opiods).  It's a fantastic article- if anyone is interested in a copy, please let me know.  The answer to my question is that yes, there are 2 different aminonitrile products.  And yes, the active aminonitrile is crystallized from hexane (@ 0 deg C) as the second product (in basic form) and as the first product (as a halide salt).  The conversion with grignard is not as easy as methadone, thought, because of an intermitent ketimine.  Apparently prolonged acid hydrolysis is
 needed.  I would still appreciate any practical advice or thoughts on this.  Thanks!
-bluealcoholflame

Thanks for the upload- I was afraid to put that article up here - draconian copyright laws and all.  I wasn't sure if it is still under copyright- I know I just couldn't find a free copy of it.  It ended up costing me 30 euros to download it from the RCS.

BTW- in the article dipipanone is listed as

6-Piperidino-4 : 4-diphenyl-5-methylhexan-3-one

Two more questions for anyone interested- in the notes it states that after reacting with grignard reagent, the resulting oil was refluxed with MEK(with what appears to be no other reagents), then refluxed with 20% Hydrobromic acid.
1) Why reflux in MEK?  I wouldn't think that the ketimine would react with MEK, unless this is some sort of purification step- they had already dissolved the oil in alcoholic HCl and evaporated it- why the MEK step?
2) The ketimine dihydrochloride was refluxed with 20% HBr acid- would HCl do the trick here? or, for that matter, any other halide acid?

Any help or ideas would be appreciated!

-bluealcoholflame

I'm going to tell you, without even looking at the article, that when an experiment's authors used HBr, or KCl, or Potassium Ethoxide.....Instead of something that you conveniently happen to have on hand, they often had a very good reason for using such a reagent.  Often,  it just worked better.

Substitute as you wish, but don't holler fraud, when you fail to achieve the authors results, using alternate reagents.  Sometimes, you can substitute pork for chicken, and sometimes you can't.