hydromorphone from codeine via hydrocodone+HI

[hellman]

Ok,

So it is possible to convert codeine, relativly easily to hydrocodone, via Sodium Dichromate, And apparently it is possible then to turn Hydrocodone via Hbr(demethylate) into hydromorphone, But my question is, will HI do it as well,
I apologose if i have missed this,.

And if so, wouldn't that be beautiful?

Considering HI is sooooo easy to make these days,.

hellman

[Rhodium]

It's possible that HI works too, but in my opinion there is a greater risk of side-reactions taking place if you use HI, and it would be very sad if you found this out the hard way. As it has been proven that 48% HBr works great for this transformation, I see no reason to venture out into unknown territories when HBr is at least as easy to make as HI, see the posts below:

Post 466086

(Rhodium: "Anhydrous Gaseous Hydrogen Bromide", Methods Discourse)

Post 188229

(lugh: "Six Laboratory Preparations of Hydrobromic Acid", Methods Discourse)

[hellman]

thanx Rhod's

Just thinking about the little bees, that's all,.
And admitting i am still a little naive about opiate chemistry, at the moment,

So rhodium, do you think that HI would demethylate codeine into morphine?
As that is what happens when Bcl3 or Bbr3 is introduced, it is the Hbr that is doing the action, isn't it?

Cheers

Another also,
So sweet little HI, which can be made from phos acid and Iodine, could work, I gues it would be stretching it to think that conc. HCL might also work, with a long reflux,

Just out of curiuosity, does the hive know of any super opiates that can be made from OxyCodone, I heard a rumour once, that is all, Oxymorphone from methanesulfonic acid & DL-methionine seems so un OTC, but there would be replaceable similar precursors right?,

hellmun

[Rhodium]

So rhodium, do you think that HI would demethylate codeine into morphine?

Well, not in a useful way at least, as the formed morphine will directly rearrange into the powerful emetic apomorphine, which always forms when morphine is treated with strong acids, see

https://www.thevespiary.org/rhodium/Rhodium/chemistry/codeine2morphine.html

As that is what happens when Bcl3 or Bbr3 is introduced, it is the Hbr that is doing the action, isn't it?

No, the mechanism is like shown below. No acid is evolved until water is added to quench the reaction, and then it becomes diluted quickly anyway.

Ph-O-CH₃ + BBr₃ -> CH₃Br(g) + Ph-O-BBr₂

Ph-O-BBr₂ + H₂O -> Ph-OH + 2 HBr + B(OH)₃

[hellman]

I am going to have to go to uni,
This shit intrigues me too much, and not knowing all the mechanisms(rules) is so frustrating,.

I initially think, well why can;t we create an inhibitor, that won;t let the unwanted product form, or what if we weaken, dilute the acid, or what if we find out what percentage gets turned into the unwanted chem, and work a way of seperation,.

I know I am a dreamer, but as John Lennon, einstein and practically all other scientific discoveries that are made, by imagination,
then i don't feel so bad,.

Any good opiate chemistry books out there,?

hellman

[Rhodium]

Any good opiate chemistry books out there?

Definitely, see

Post 246207

(Rhodium: "Opioid Analgesics", Serious Chemistry)

[hellman]

It's on my christmas list,.

Thnx again,

hellmn

[SPISSHAK]

15% is the best you'll get according to trials
I have ref's i'll post later regarding HI opening theoxgen brigde to a phenol and other things.
The easiest way to a potent narcotic from codiene is PCL3 plus codiene to give the 6-chloro compuond reduction with Pd/C H2 to dihydrodesoxycodiene
(a potent narcotic in it's own right used in surgery)
demthylation of that with HBr to desomorphine 10X potency of morphine.
Imagine the potency of the 3- acetyl derivative.
tHAT BOOK WILL BE ON MY TO GET LIST! TOO i'LL SCAN IT AND UPLOAD IT TO RHODIUM'S PAGE!

[hellman]

Excellent,

I would love that book, I've been thinking about it all morning,

Pcl3 huh?, nice!

Why not just bang the codeine with Bcl3, then go to heroin, with Aco2,
Which as far as I know is say 5x more potent than morphine, in half the steps?

There is a super compound that brings Oxycodone, mixed with B-nitrostyrene, to something 10X that of morphine,.

Do ya know that one?

Desomorphine, is that about the same potency as OxyMorphone or HydroMorphone?

Sounds really good!!!!!!

Are we saying that rather than using BBr3 or Bcl3 we can use Pcl3?

I'll have to check the availability, but Bcl3 is very easy to get here in the land of Nod,.

hellman

Maybee i should change my name, to something softer, as my personailty is being updated, might as well get a new name as well,-smile

[SPISSHAK]

HI+ oxygen brigde (phenanthrene molecule) = catechol ring system
Rice, K.C., J. Med. chem 1977, 20,164

Scwart and Wallace "efficient synthesis of 14-hydroxymorphinones from codiene"
J. Med. Chem. 1981, 24:12 pg 1525-1528

"Demethyoxylation of N-allylnorcodiene derivatives"
J.Am. Chem. Soc. 75: 1953 pg 4963-4966

(note: this may provide an alternative demethylation procedure for codeine)

[SPISSHAK]

L. F. Small, K. C. Yuen and L. K. Eilers, Journ. Amer. Chem. Soc. 55, 3863 (1933)

DIHYDRODESOXYMORPHINE D, DESOMORPHINE OR PERMONID
This compound (IX) was discovered by Small[3] in the course of his research on those derivatives of morphine and codeine in which oxygen is no longer attached to carbon atom 6. It is prepared from &alpha-chlorocodide (X), which is itself obtained by the action of thionyl chloride on codeine (III). By catalytic reduction, &alpha-chlorocodide (X) gives dihydrodesoxycodeine D (XI), which yields dihydrodesoxymorphine D on demethylation.

This substance appears to be remarkably active, with an analgesic effect about ten times greater than that of morphine; its toxicity, although likewise exceeding that of morphine, is apparently only three times as great. Its action is described as being very rapid but of short duration, and not accompanied by vomiting. It has been given the commercial name of permonid in Switzerland, where it is used.

http://www.unodc.org/unodc/en/bulletin/bulletin_1951-01-01_2_page006.html#f003

[SPISSHAK]

describes heating morphine in 35% hcl to give a 5-6 dichloro morphide this precipitates out from the hydrochloric acid.
this is then dissolved in alkali KOH and titrated to nuetual in H2O and hydrogenated with palladium black to give desomorphine.
The aurthors made no mention of apomonrphine contamination but I suspect this is because apomorphine would remain dissolved in the acid solution while the dichlormorphide precips out.
how's that for Occam's razor???

http://l2.espacenet.com/espacenet/bnsviewer?CY=ep&LG=en&DB=EPD&PN=US2087134&ID=US+++2087134A1+I+

http://l2.espacenet.com/espacenet/bnsviewer?CY=ep&LG=en&DB=EPD&PN=US2087134&ID=US+++2087134A1+I+

[SPISSHAK]

from the previous desoxycodeine is the precursor to desoxy morphine here is a reference for the synthesis of a desoxycodeine.
Gates, M., Tschudi, G.: synthesis of racemic B-5-dihydrodesoxycodeine methyl ether
J.A.C.S., 1950, 72, 4839-40

[algebra]

This is a recent Knoll Pharmaceuticals Co. patent describing the single step rearrangement of codeine/morphine type alkaloids to the corresponding dihydromorphinones. Note the interesting purification procedure of the hydrogenated ketone- using the bisulfite addition product. The yields before purification seem to be realistic and accord with Rapoport’s unreported experimentation, of around 50% - unpublished findings, cited in J. Org. Chem.; 1950; 15(5); 1103-1107.

The patent is a useful elaboration on the German Patents 607931, 617238 and 623821, archived at Rhodium’s since it discusses in some detail the required reaction conditions and following workup/ purification steps – info not previously disclosed. An example is given for hydromorphone, but the patent also claims the general applicability of the synthesis for dihydrocodeinone (hydrocodone). The best way to to experiment with this would be a variation using codeine, with perhaps a simplifying of the purification steps (although i like the bisulfite idea), then quick reflux with HBr to demethylate --> dilaudid.


Cite:

http://l2.espacenet.com/espacenet/viewer?PN=WO0134608&CY=gb&LG=en&DB=EPD

HYDROMORPHINONE AND HYDROCODEINONE COMPOSITIONS AND METHODS FOR THEIR SYNTHESIS
WO0134608, 2001-05-17
inventor(s):   gault robert; sandison mark d; harclerode william h

Palladium Activation Procedure, (p17)

Palladium black (36.0g) and deionized (DI) water (36.0g) were sonicated to break down larger catalyst agglomerations. DI water (500mL) and concentrated Hcl (120 mL) were added. The nitrogen flow was adjusted to 1.4 ml/min and the suspension was heated. When the suspension reached 50degC the nitrogen flow was stoppend and a hydrogen flow of 1.0mL/min was initiated. The suspension was heated at 85degC for two hours, cooled and filtered through Whatman #542 paper. The preparation of “hydrogen-free” catalyst used the same procedure, except for the omission of hydrogen.

Example 1: synthesis of Hydromorphone Hydrochloride – “Current Process”

DI water (49.0g), concentrated HCl (12.0g), and activated palladium catalyst (3.6g) were charged to the reactor. The reactor was padded with nitrogen and heated to 50degC. The nitrogen was then turned off and the hydrogen flow was set to 0.2mL/Min. When the suspension reached 95degC, morphine hydrate (40.0g) was added to the reactor. The reaction mixture was maintained at 95degC for one hour. The reaction mixture was cooled to 40degC and sodium metabisulfite (26.4g) was added. The suspension was allowed to cool to room temperature and stirred overnight. The resulting sulfite adduct (30.3g, dry weight; 59% yield) was filtered and dried under vacuum.

The sulfite adduct (30.0g) and DI water (430g) were heated to reflux and 0.2g of activated charcoal was added. The activated charcoal was filtered after fifteen minutes. Sodium carbonate (12.6g) was added to the filtrate and the pH of the solution was adjusted to 9.0 with concentrated ammonium hydroxide (6mL). After stirring overnight, the suspension was filtered and the hydromorphone base (15.6g, dry weight; 41% yield) was dried under vacuum.

The hydromorphone base (15.0g) was dissolved in methanol/DI water (14ml, 50/50 by volume) and concentrated HCl/water (10mL, 50/50 by volume). The solution was filtered and n-propanol (42mL) was added. The suspension was stirred overnight, filtered, and vacuum dried. The dried hydromorphone hydrochloride (12.9g; 30% yield) contained 0.7% 8-hydroxyhydromorphone and 0.1% dihydromorphine.

[SPISSHAK]

in the purification step with sodium metabisulfite however, I think you could not add it to an acid solution like that without getting H2SO3 formation which is a breakdown product of sodium bisulfites.
another "hole" I see there is the ommision of the filtration of Pd black prior to addition of metabisulfite I wonder what else the author left out.

[algebra]

The morphine is freebase hydrate and 40g are added to 4.2g of Hcl (35% of 12g concentrated HCl by mass). this gives a mol ratio (i think) of 0.14/0.117 morh/Hcl.  i am not sure where the pH is supposed to be - but dont think its that acidic. the whole patent is just as likely to be a red herring for the detail though - given the notoriety of co's to protect their ip by obscuring or ommiting info - but there is a good review of the prior literature and it is interesting since almost nothing is known about the conditions required for the rearrangement. another odd thing is that there is no initial charging of the reactor solution with hydrogen but just a very low metered flow applied after the addition of the morph.

I think the easiest way to get to hydrocodone from codeine would be activated managanese dioxide oxidation to the the ketone (at Rhodiums) followed by CTH hydrogenation (avoiding the hydrogen generator setup). then demethylate for hydromorphone.

[Yoff]

Since at the Rhodium's "Codeine To Morphine Convertion Review" is said: "Cleavage of aromatic ethers are commonly effected by reflux with concentrated HBr or HI. This relatively simple method can unfortunately not be used on codeine, as the oxygen bridge at the 9,10 position on the morphinan carbon skeleton would also rupture, causing the rearrangement of the molecule to the very potent emetic apomorphine, completely devoid of opiate-like effects" and in some PDF, there refluxing 9 g of oxycodone with conc. HBr for 20 min yielding only 2,3 g oxymorphone, the result given in

https://www.thevespiary.org/rhodium/Rhodium/pdf/14-methoxymetopon.pdf

)), yielded 77% of 14-methoxymetopon looks surprising (of course only for me as I'm not a chemist). So, does such a different results only refer to slight differences (to my lame point of view) in structure? Can anyone real chemist here explain such increase in resistance against HHal from codeine -> DHC/oxycodeinone ->oxycodone -> 5,14-dimethoxyoxycodone along with increasing yields?
Another lame questions: 1. can boron triiodide as substitute for tribromide be made by treating boric acid with I2 and red phosphorous?
2. Is there any compounds helps demethylation  (I mean with HI) and therefore decrease conditions enough to prevent codeine from the rearrangement of the molecule?

[SPISSHAK]

but if you look at the mechanism by which apomorphine is formed (it'a very complicated multi step mechanism) you will see that the rearrangement starts at the 14 position.
when the 14 position gets attacked by protons the electron transfer pathway in the mechanism goes along the double bond in the cyclohexene ring.
this explains why you can demthylate those diyhdro compounds without this happening.

[Yoff]

Thanks SPISSHAK!
the rearrangement starts at the 14 position.but what about 4,5 oxygen bridge?
this explains why you can demthylate those diyhdro compounds without this happening.So does it mean the best way to demethylate codeine is to reduse its 7,8 double-bond before treating with HI / HBr?
And the yields is something I'm still interesting in... Can anybody explain this?? Ritter?....

[SPISSHAK]

think about this your suubjecting a strong acid to an alcohol (secondary) so this may be prone to undergo dehydration to the alkene and God only knows what side reactions would ensue.
in this context I would stick to the dihydro ketonic derivatives.
AKA hydrocodone.