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borohydride
08-28-2011, 07:23 AM
Title: '14-Hydroxylation of opiates: catalytic direct autoxidation of codeinone to 14-hydroxycodeinone'

Author(s): Zhang Q, Rich JO, Cotterill IC, Pantaleone DP, Michels PC

Publisher: Journal of the American Chemical Society [2005, 127(20):7286-7]

PMID:15898757

Abstract: 'Codeinone was efficiently and directly converted to 14-hydroxycodeinone by catalytic air oxidation in aqueous solution. A number of simple manganese and copper salts were identified to be effective catalysts, including MnSO4, KMnO4, and CuSO4. An appropriate reducing agent, such as sodium thiosulfate, is required in the reaction mixture presumably for the reduction of a detrimental peroxide intermediate. This discovery allows the more abundant codeine to be employed as the starting material for the synthesis of 14-hydroxylated opiate drugs without recourse to a thebaine-like intermediate. These discoveries were inspired from our study of microbial transformation of codeine to 14-hydroxycodeine by Mycobacterium neoaurum, where we found the actual 14-hydroxylation step is a chemical reaction rather than an enzymatic reaction, as previously believed.'

http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2005/jacsat.2005.127.issue-20/ja051682z/production/images/medium/ja051682zn00001.gif



Now, in conjunction with US Patent application 2001/0018519 (codeine->codeinone using γ-MnO2 with a 94% yield), this offers a 1-pot route for codeine->14-hydroxycodienone. While not so potent itself, it can be reduced to oxycodone by refluxing with sodium hydrosulfite (sodium dithionite) as per original German route from the 1930s. I've already posted a simple oxycodone->oxymorphone route.

As a (legal in many places) alternative, one can esterify the 14 -OH using, say, cinnamic anhydride. That last chemical will have to be ordered but in no way is it suspicious but it is $15-$16/gram in 10g batches. The product from the latter proved to be 125-175 x morphine in animal models.

http://upload.wikimedia.org/wikipedia/commons/thumb/7/7a/14-Cinnamoyloxycodeinone.png/220px-14-Cinnamoyloxycodeinone.png

14-Cinnamoyloxycodeinone


Not exactly OTC, but not far off & H2O as the solvent all the way (a BIG thing) plus a material around x 2 fentanyl in potency that isn't explicitly listed as a controlled drug anywhere in the world (but US/Oz/Nz chemists may wish to read their respective controlled drug analogues acts carefully).

Smaxie
08-28-2011, 09:11 AM
Whoa! Thanks for the post Boro, I hope I am smart enough to follow. I have been looking for a way to convert these useless hydros. Thanks.

borohydride
08-28-2011, 10:08 AM
Whoa! Thanks for the post Boro, I hope I am smart enough to follow. I have been looking for a way to convert these useless hydros. Thanks.

It won't hydroxylate hydrocodone, the ketone has to be conjugated; ( X-CH2=CH-CO-CH- ) X marks the spot. Codeinone & morphinone are the only materials it is designed to work on.

If you have hydrocodone, best move is to deprotect it to hydromorphone.

danny
08-28-2011, 10:41 AM
thats incredible, time for me to start hitting them chemistry books i bought, trouble is finding a lab to practise even the simple shit....

borohydride
08-28-2011, 11:14 AM
Trust me, you can get EVERYTHING you need via Ebay. If they don't mention a specific chemical, they can/will get it for you. Equipment goes without saying...

danny
08-28-2011, 11:53 AM
its not so much that boro as practising the simple fundamentals, just basic experiments before delving into opiate chemistry, finding the space and the equipment....my current living circumstances make it impossible for me to do it at 'home', altho' hopefully that wont be the case for ever...

JUNKYJAY
08-28-2011, 12:00 PM
Boro I wish i could do what you do so bad. I can get 100 tynol 1 with codiene for $10. Wish i could make something worth while from it. All I can do is a CWE so sad.
Your chemistry knowlege is awesome!

Slime Machine
08-28-2011, 09:47 PM
hey boro on a side note, could one strengthen morphine with cinnamic anhydride like is done with AA? if so, can they do it with just those 2 chems in a reflux or is a catalyst needed as well.

awesome post btw

borohydride
08-29-2011, 06:18 AM
hey boro on a side note, could one strengthen morphine with cinnamic anhydride like is done with AA? if so, can they do it with just those 2 chems in a reflux or is a catalyst needed as well.

That would just form the 3,6 dicinnamyl ester of morphine which will be less potent than M (but longer acting).

The 14 cinnamoyl ester of oxycodone, on the other hand, appears to be similarly (over x 100 M) potent to the material I mentioned above.

Woody Bear
09-06-2011, 08:54 PM
Title: '14-Hydroxylation of opiates: catalytic direct autoxidation of codeinone to 14-hydroxycodeinone'

Author(s): Zhang Q, Rich JO, Cotterill IC, Pantaleone DP, Michels PC

Publisher: Journal of the American Chemical Society [2005, 127(20):7286-7]

Great find borohydride, this definitely looks to be a reasonably OTC route, it gives good yields, and it should be doable to use this to convert codeine into oxycodone in 3 reactions, or 4 into oxymorphone. I had a friend of mine find me the article, but strangely the actual reaction wasn't in there, but it was published in the supporting info pdf, which is free for anyone to download. But I'm posting the 2 reactions they gave there:


14-Hydroxylation of Codeinone by Manganese(II) Sulfate and Sodium Thiosulfate
To a 50 mL plastic centrifuge tube were added 4.8 mL of phosphate buffer (75 mM, pH 8.0), 100 ÁL of codeinone (100 mM in DMF, 10 Ámole), 20 ÁL of sodium thiosulfate (640 mM in water, 25 Ámole), and 40 ÁL of MnSO 4 (0.88 mM in water, 0.035 Ámole). This reaction mixture was kept in a rotary shaker at 29 ░ C and 300 rpm for 3 h. A sample of this mixture (0.5 mL) was extracted with chloroform (0.5 mL), and the organic phase was separated and evaporated to dryness. The residue was dissolved in 100 ÁL of DMF for HPLC analysis. The result indicated ~85% of codeinone was converted to 14-hydroxycodeinone. The identity of the 14-hydroxycodeinone was supported by an HPLC retention time match to that from a standard sample, and confirmed by LCMS, which showed an m/z 314 [M+H] + in positive mode. The remaining reaction mixture was also extracted with chloroform, and the organic extract was evaporated to dryness. The residue showed a 1 H NMR spectrum match to that of a standard sample. This was also the general procedure.

14-Hydroxylation of Codeinone Using Potassium Permanganate and Sodium Thiosulfate.
To a 2 L glass reactor were added 500 mL of potassium phosphate buffer (50 mM, pH 6.6) and codeinone (0.5 g, 1.7 mmole) with stirring. After the codeinone had dissolved, the pH of the solution was adjusted to 8.0 with 45% KOH, and maintained automatically using 1 N NaOH and 1 N HCl. To this solution were added 5 mL of sodium thiosulfate (1 M in water, 5.0 mmole) and 0.3 mL of potassium permanganate (95 mM in water, 0.03 mmole). The reaction mixture was sparged with air and stirred at room temperature. After 2.5 h the pH of the solution was adjusted to 12.0 by the addition of 1 M NaOH and the product was extracted using methylene chloride (3 x 200 mL). The combined organic phase was dried (MgSO 4 ) and evaporated to give crude 14-hydroxycodeinone (357 mg) as an off-white solid. Crystallization from chloroform/petroleum ether (40/60) gave 14-hydroxycodeinone (300 mg, 57%) with purity greater than 99% by HPLC. 1 H NMR (500 MHz) spectrum in DMSO-d 6 was identical to that of a standard sample.

I actually like the second reaction using Potassium Permanganate better, because although it gives a lower yield, it's more OTC because it doesn't require Dimethyl Formamide. But most likely the DMF was just used as a solvent to dissolve the codeine and to extract the 14-hydroxycodeinone, so it's probably not critical in the first reaction. And most likely Manganese(II) Sulfate could get subsituted for Potassium Permanganate in the second reaction which probably would give higher yield.

borohydride
09-06-2011, 11:18 PM
Add:

US Patent application 9/835,525 - oxidation to codeinone with γ-MnO2 94% yield

Yo can likely go codeine->14-hydroxycodeinone in 1-pot.

The original reduction to oxycodone used refluxing sodium dithionite solution. OTC oxycodone?



US Patent 4,667,037 - dealkylation of opioid ethers

Then reflux with HCl + MgCl2 24 hours yields 93% oxymorphone. OTC Opana?