Naloxone & friends

It might look like a sin converting the useful oxycodone to "antidrug", but i think if these antidrugs would be more available to opioid abusers, many deaths because of accidental overdoses could be omitted. But on the other hand that would make powerful drugs such as fentanyls safer and could result in even more abusers...

Search revealed some similiar drugs (by structure and action): Naltrexone, Nalmefene, Nalorphine, Levallorphanol

And another one, Amiphenazole, which seems more interesting to me, because of its simpler structure (5-phenyl-2,4-thiazolediamine), which means synthesis form more easily available chemicals. The ref from first post it is synthed from thiourea and a-halo-phenylacetonitrile (which can probably be made by reacting benzalchloride with alkali cyanide).

Refs. (don't even have abstracts )
Davis, W. et al.: J. Chem. Soc. (JSCOA9) 1955, 3491.
Chase, B.H. et al.: J. Chem. Soc. (JSCOA9) 1955,4443.

[Edited on 15-9-2006 by tr41414]

I meen you really don't have to work with cyanogen bromide, I'd prefer to do the key step analogous to the following using allyl bromide or iodide, ultimately making naloxone the leaving group:



First Intermediate


To a stirred flask were added 12.8 g of 8,9-dihydroelymoclavine (Kawaken), 10.6 g of 1-iodopropane, 0.42 g of anhydrous sodium carbonate, and 25 ml of molecular sieve-dried N-methylpyrrolidinone. A nitrogen atmosphere was maintained over the mixture while it was stirred and heated to 75 DEG .

The reaction was allowed to continue at constant temperature for about 18 hours, and was then analyzed by liquid chromatography on a Zorbax CN column, eluting with 4:1 methanol:0.1 M ammonium acetate, using a 290 nm detector. (Zorbax CN is obtained from DuPont). No 8,9-dihydroelymoclavine was detected in the reaction mixture, illustrating complete conversion to the first intermediate.

The reaction mixture, about 39 ml in volume, was divided into five equal aliquots for further experiments.


Second Intermediate


One of the aliquots of the first intermediate mixture obtained above was combined under dry nitrogen with 39 ml of molecular sieve-dried pyridine in a 100 ml flask equipped with a nitrogen inlet, ice bath, thermometer and stirrer. The solution was chilled to 0 DEG , and 2.86 g of methanesulfonyl chloride was added dropwise, taking care that the temperature of the reaction mixture did not exceed 5 DEG . The addition time was about 8 minutes.

The reaction mixture was monitored by liquid chromatography as explained in the step above, and it was found after one hour of stirring at about 0 DEG that the mixture contained 5.9% of the first intermediate. After two and a half hours, the content of the first intermediate was down to about 4%, and the reaction mixture was advanced to the next step of the process.


Sodium Thiomethoxide


Thirty ml of molecular sieve-dried N-methylpyrrolidinone was added under a nitrogen blanket to a flask, and was chilled to -5 DEG . Then 6.2 ml of methanethiol and 4.0 g of powdered sodium hydroxide were added. The temperature of the mixture immediately rose to 5 DEG , and the mixture was cooled and stirred for one hour, maintaining the temperature at about -2 DEG .


Pergolide


To the above mixture was added the second intermediate mixture, allowing the temperature to rise exothermically to 21 DEG . The mixture was stirred at ambient temperature for 15 minutes and was then heated to 80 DEG and stirred at that temperature for 2 hours. The reaction was then quenched by the addition of 60 ml of water, and the aqueous mixture was cooled to 5 DEG and filtered. The solid was washed with 60 ml of water, and dried in a vacuum oven at 50 DEG overnight. Analysis of the dried solid showed that it was 94.1% pure pergolide. The yield was 2.86 g, equivalent to 90.8% yield, based on the starting 8,9-dihydroelymoclavine.

[Edited on 15-9-2006 by Sandmeyer]

Porcelain vessel? I think using quartz tube might be better, but it would probably shatter upon cooling down (because of salt xtalyzing). Sadly BX3 are incompatible with metals...

I agree that boric trihalides are nasty stuff... And as for me experimenting with this kinda stuff, i mostly do only theoretical chemistry