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Author: Subject: 14-hydroxy-7,8-dihydro-codeinone to 14-Hydroxydihydromorphinone via HBr or HCl
floraljoy
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smile.gif posted on 27-11-2007 at 17:54
14-hydroxy-7,8-dihydro-codeinone to 14-Hydroxydihydromorphinone via HBr or HCl


im interested in the conversion of 14-hydroxy-7,8-dihydro-codeinone to 14-Hydroxydihydromorphinone via HBR.
the first step would be to creat HBr from NaBr (or KBr) and H2SO4 and
then to distill it at 120 c (ish) from there it appears an extract
from, a rather common source, refluxed with the acid for 20 ish minutes then
ice water added and ph raized to 10 or 11. from there its just a basic
extraction. chloroform seems to be the solvent of choice, anyone have
any ideas for a nice alternative?

considering the difference between the starting compound and the final one im
suprized i havnt found any threads where someone has claimed to at
least tried a conversion.


heres some reading: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1955/77/i22/...

the first theoretical experiment would envolve 160mg of starting product (is it ok to just use the HCl salt?) any thoughts on letting the acid/product mixture sit at room temp for five days after teh reflux? i have seen patents that claim that this increased the yield for slightly different molecules. ill try and find it.

i understand that some may not like this thread so i was as descreat as i thought necessary...
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[*] posted on 27-11-2007 at 18:21


Your link is not valid it goes nowhere .....you might consider giving the journal information so someone can get it for you at the wanted reference and translation forum......solo


Maybe it's one of this..........probably the first one!


Derivatives of Morphine. I. 14-Hydroxydihydromorphinone
Ulrich Weiss
J. Am. Chem. Soc.; 1955; 77(22); 5891-5892.
First Page Full: PDF (282k)


Long-acting opiate agonists and antagonists: 14-hydroxydihydromorphinone hydrazones
Gavril W. Pasternak, Elliot F. Hahn
J. Med. Chem.; 1980; 23(6); 674-676.
First Page Full: PDF (421k)


Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone
Ikuo Iijima, Junichi Minamikawa, Arthur E. Jacobson, Arnold Brossi, Kenner C. Rice, Werner A. Klee
J. Med. Chem.; 1978; 21(4); 398-400.
First Page Full: PDF (381k)


Derivatives of Morphine. II.1 Demethylation of 14-hydroxycodeinone. 14-Hydroxymorphinone and 8,14-Dihydroxydihydromorphinone*
ULRICH WEISS
J. Org. Chem.; 1957; 22(11); 1505-1508.
First Page Full: PDF (529k)


Spiro[isobenzofuran-1(3H),4'-piperidines]. 3. Diuretic and antihypertensive properties of compounds containing a sulfur attached to nitrogen
Solomon S. Klioze, William J. Novick, , Jr.
J. Med. Chem.; 1978; 21(4); 400-403.
First Page Full: PDF (507k)


Effect of a 6-Cyano Substituent in 14-Oxygenated N-Methylmorphinans on Opioid Receptor Binding and Antinociceptive Potency
Spetea, M.; Greiner, E.; Aceto, M. D.; Harris, L. S.; Coop, A.; Schmidhammer, H.
J. Med. Chem.; (Brief Article); 2005; 48(15); 5052-5055. DOI: 10.1021/jm0580205
Abstract Full: HTML / PDF (78k) Supporting Information


Paradoxical effects of N-cyanoalkyl substituents upon the activities of several classes of opioids
Arthur E. Jacobson, Kenner C. Rice, Juergen Reden, Lillian Lupinacci, Arnold Brossi, Richard A. Streaty, Werner A. Klee
J. Med. Chem.; 1979; 22(3); 328-331.
First Page Full: PDF (516k)


14.alpha.,14'.beta.-[Dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinone) and 14.alpha.,14'.beta.-[Dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis-7,8-dihydro-N-(cyclopropyl- methyl)normorphinone: Chemistry and Opioid Binding Properties
Sydney Archer, Ahmad Seyed-Mozaffari, Qi Jiang, Jean M. Bidlack
J. Med. Chem.; 1994; 37(11); 1578-1585.
First Page Full: PDF (1151k)


14.beta.-(Bromoacetamido)morphine irreversibly labels .mu. opioid receptors in rat brain membranes
Jean M. Bidlack, David K. Frey, Ahmad Seyed-Mozaffari, Sydney Archer
Biochemistry; 1989; 28(10); 4333-4339.
First Page Full: PDF (932k)

Discovery of 1,5-Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Receptor Agonist Activity. 1. Optimization of the Agonist "Trigger"
Aquino, C. J.; Armour, D. R.; Berman, J. M.; Birkemo, L. S.; Carr, R. A. E.; Croom, D. K.; Dezube, M.; Dougherty, R. W., Jr.; Ervin, G. N.; Grizzle, M. K.; Head, J. E.; Hirst, G. C.; James, M. K.; Johnson, M. F.; Miller, L. J.; Queen, K. L.; Rimele, T. J.; Smith, D. N.; Sugg, E. E.
J. Med. Chem.; (Article); 1996; 39(2); 562-569. DOI: 10.1021/jm950626d




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[*] posted on 27-11-2007 at 19:10


so sorry about that...

Derivatives of Morphine. I. 14-Hydroxydihydromorphinone
Ulrich Weiss
J. Am. Chem. Soc.; 1955; 77(22) pp 5891 - 5892; DOI: 10.1021/ja01627a033

and heres most of it.

http://i232.photobucket.com/albums/ee36/floraljoy/untitled.j...

ok its a huge picture, couldnt find another quick way to give direct access to it. if you go to j a c s web site and click on first page instead of pdf, its all there.
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[*] posted on 27-11-2007 at 19:26


Derivatives of Morphine. I. 14-Hydroxydihydromorphinone
Ulrich Weiss
J. Am. Chem. Soc. 1955; 77(22) pp 5891 - 5892


Abstract
14-Hydroxydihydrocodeinone with concentrated hydrobromic acid yields 14-hydroxydihydromorphinone, an analgesic considerably more potent than morphine.

Attachment: Derivatives of Morphine. I. 14-Hydroxydihydromorphinone.pdf (282kB)
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[*] posted on 29-11-2007 at 10:26


Here is another ref. on the same substance, by the same authors:

Weiss & Daum, 'Derivatives of Morphine; IV 14-Hydroxymorphine & 14-Hydroxydihydromorphine' (1965) 8(1) J.Med Chem 123 {http://tinyurl.com/2g8uev}

They start from both 14-hydroxymorphinone and 14-hydroxycodeinone - the reduction of these to their dihydro equivalents is acheived with NaBH4, demethylation with HBr.

Also see: Weiss, 'Derivatives of Morphine. II Demethylation of 14-Hydroxycodeinone' (1957) 22(11) J.Org Chem 1505 {http://tinyurl.com/2kfw5r}

In this one 14-Hydroxycodeinone is demethylated, with attention being given to the actual demethylation step. Also note the author's spec's for workup - you extract with chloroform - too slow and you get a diff. product.

Has anyone got the third article in the series handy?




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[*] posted on 11-11-2012 at 13:55
new news but can you better it?


Significantly improved reaction conditions for the synthesis of oxycodone (1), /via/ the conventional two-step process involving oxidation of thebaine (3) into 14-hydroxycodeinone (5) and the subsequent reduction of 5/via/ catalytic hydrogenation, are reported. Employing the hydrochloride salt of thebaine (3) in the oxidation step, in place of the more traditionally used free base form of this opiate, now provides 5 in high yield and purity. For the reduction step, aqueous acetic acid has typically been employed as the solvent. However, this was found to generate varying amounts of 14-hydroxydihydrocodeine (16) as the dominant by-product. Instead, using 5% Pd/BaSO_4 as the catalyst and MeOH as the solvent completely eliminated the formation of 16, giving oxycodone (1) in high yield and purity, without the need to purify the intermediates. These improved conditions have also proved effective in the synthesis of other 14-hydroxyopiates, such as oxymorphone (2) and /N/-noroxymorphone...... I Was asking the elders here any new thoughts on this /? It's been goin on 60 yrs and in the last decade this and another synth have made great progress when they thought it could not be improved on.This is Aug 2012.Gaik b. Kok and Peter J. Scammells
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[*] posted on 11-11-2012 at 17:47


i know they prefer to use the poisoned version of Pd because it rearranges that 4,5 epoxide bride (regular pd that is)
less harsh conditions can be used in this patent by using promoters with the HBr

[Edited on 12-11-2012 by jon]

Attachment: US4667037A (1).pdf (331kB)
This file has been downloaded 575 times

[Edited on 12-11-2012 by jon]




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[*] posted on 11-11-2012 at 18:07


You don't even need bentley compounds. Even Naltrexone with phenylpropinoxy in the 14 position is full agonist, ~500 morphine. Unlike bup, full agonist.
Quote: Originally posted by popi  
Significantly improved reaction conditions for the synthesis of oxycodone (1), /via/ the conventional two-step process involving oxidation of thebaine (3) into 14-hydroxycodeinone (5) and the subsequent reduction of 5/via/ catalytic hydrogenation, are reported. Employing the hydrochloride salt of thebaine (3) in the oxidation step, in place of the more traditionally used free base form of this opiate, now provides 5 in high yield and purity. For the reduction step, aqueous acetic acid has typically been employed as the solvent. However, this was found to generate varying amounts of 14-hydroxydihydrocodeine (16) as the dominant by-product. Instead, using 5% Pd/BaSO_4 as the catalyst and MeOH as the solvent completely eliminated the formation of 16, giving oxycodone (1) in high yield and purity, without the need to purify the intermediates. These improved conditions have also proved effective in the synthesis of other 14-hydroxyopiates, such as oxymorphone (2) and /N/-noroxymorphone...... I Was asking the elders here any new thoughts on this /? It's been goin on 60 yrs and in the last decade this and another synth have made great progress when they thought it could not be improved on.This is Aug 2012.Gaik b. Kok and Peter J. Scammells
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[*] posted on 11-11-2012 at 19:22


we were modeling the 14 hydrocinnamoyl ester of naltrexone turns out it satisfied all of the SAR criteria and it could be made in two steps as opposed to 4-5 for the ether.

see attached paper:

there is some of the modeling we did.
look how the rings a and f are oriented perpendicularly, and slightly below the plane of ring a is ring f.
Exactl the criteria needed for uber opiod potency as explained in that paper i linked, it would be a worthy expiriment.

http://postimage.org/image/i5lyjz0ln



Attachment: 38722151-Synthesis-of-14-Alkoxymorphinan-Derivatives-and-Their-Pharmacological-Actions.pdf (785kB)
This file has been downloaded 914 times

Attachment: 63349878-The-Opiate-Receptor-A-Model-Explaining-Structure-Activity-Relationships-of-Opiate-Agonists-and-Antagonists-PNAS (860kB)
This file has been downloaded 641 times

[Edited on 12-11-2012 by jon]

[Edited on 12-11-2012 by jon]

[Edited on 12-11-2012 by jon]




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[*] posted on 12-11-2012 at 06:43


jon,

i hear if the tert cyclopropyl is replaced by classical methyl, the potency approaches etorphine & beyond. also have heard some of these while being pure potent mU+, have surprisingly little effect on respiratory tidal. curious what properties of the hybrid between these and a classic bentley. a LOT of things down there bumping into one another. nothing would surprise me.
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[*] posted on 12-11-2012 at 10:18


yeah but 300X fence is still pretty good considering the n-cpm is intact it has no significance at that point because the lipophilic side chain changes it's orientation in the opiate receptor this is all explained in the structure activity relationship paper.
i can get more research if you want it but start with that SAR paper.




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[*] posted on 16-11-2012 at 20:53


i just wanted to throw in a paper where the esterifyl naltrexone with cinnamic anhydride using 3 protected O
trialkyl silyl ethers this step can be skipped because you can selectively deacylate with 4% K2CO3 or 5% H2SO4

the same analogy as to why this is mixed agonist can be drawn with buprenorphine on of the methyl groups lies above the plane of ring a giving rise to mixed agonist activity.
the ring in this case is sterically constrained to about a 45 degree angle relationship to ring a because it's conjugated to the cinnamyl double bond.


[Edited on 17-11-2012 by jon]



[Edited on 17-11-2012 by jon]

Attachment: phpZ7JRrj (119kB)
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[Edited on 17-11-2012 by jon]




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[*] posted on 24-11-2012 at 14:08


Oxycodone to Numorphan? One prescription item, into another? Might be easier to start with Thebaine. There are several legally grown poppy varieties, that are just bursting with Thebaine. Additionally, the Aussies have developed a mutant strain of the traditional Opium poppy, that produces Thebaine rather than Morphine.

http://www.ncbi.nlm.nih.gov/pubmed/17401879

http://www.ncbi.nlm.nih.gov/pubmed/15066

[Edited on 24-11-2012 by zed]

[Edited on 24-11-2012 by zed]
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[*] posted on 25-11-2012 at 01:22


for aficionados the conversion is worthwhile except for the ridiculously small quantities involved and inherent demoralization with grinding up pills. These articles are very encouraging. Especially for those living in warmer climates. That said a zine on opium cultivation was published by a guy living in Washington state in the US PNW. I will try to follow up with botanical lit. on the species.



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[*] posted on 12-12-2012 at 18:07


Flora are you still there? Well your discrete thread is ok. |Zed yes oriental poppys roots are bomb for thebaine and yes in uk and aus they have the new high thebaine pop.You guys can grow this all ;over the world!The oil and narco gov are taking over ,that's why wwe are in turmoil.Grow it,and legally make analgesics.They are legal!!!They have up the anti ...Abs...Jon you know what they are selling now legit?The Gov.
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