daxium (Stranger)
10-05-02 05:24
No 364406
      using palladium black and morphine sulphate......  Bookmark   

I am interested in trying the method on rhodium's site to change morphine to hydromorphone, I was looking at using the acid, morphine, and palladium black method. I need some information (help me Rhodium, please) and all valid input is greatly desired, do i have to change the morphine to a freebase before disolving in alcohol I was going to use isopropal alcohol the morphine sulphate and the palladium black reflux it and hopefully get hydromorphone from the result, without freebasing the morphine is this possible???
 
 
 
 
    blondie
(Hive Bee)
10-05-02 06:14
No 364412
      hydromorphone  Bookmark   

i havent heard of much success with this method - while it looks straightforward a complicated workup might be required - eg chromatography. Also there has been some discussion at the hive as to whether key details may have been left out of the procedure in the German patent.


Catalytic rearrangement of morphine has been described using palladium black. It is not possible, however, to carry out this process on a large scale that would be suitable for manufacturing since the procedure affords 30-35% of the undesired o-desmethylthebainone along with the desired product. Isolation of the pure product is very tedious and requires extensive purification.




maybe a another catalyst would be better


Preparation of Hydromorphone

A 100 ml three-necked round-bottomed flask equipped with a magnetic stirrer, gas inlet, gas outlet and a thermometer was flushed with nitrogen and charged with anhydrous methanol (10 ml) and methylene chloride (5 ml). The solvent was de-oxygenated by bubbling dry nitrogen through it for 10 minutes. Under a stream of nitrogen, bis(bicyclo›2.2.1.!hepta-2,5-diene)rhodium(I)tetrafluoroborate (112 mg, 0.0003M) and 1,4-bis(diphenyl-phosphino)butane (130 mg, 0.00031M) were added and the orange solution was stirred for 15 minutes at ambient temperature. Next, the solution was hydrogenated by bubbling hydrogen gas for 10 minutes. Excess hydrogen was removed by bubbling nitrogen through the solution for 5 minutes. The solution of the catalyst was warmed to 40.degree. C. and morphine (2.14 g, 0.0075M) was added under a moderate stream of nitrogen. The dark coloured solution was stirred for 4 hours at 40.degree. C. The .sup.1 H NMR of the crude indicated 88% of hydromorphone, 8% of unreacted morphine and 3 to 4% of an unidentified by-product. After removal of the solvents under vacuum, the crude hydromorphone was isolated by flash chromatography (ethyl acetate/methanol 3:1) as a brown solid (1.21 g, 56%) which was purified by recrystallisation from ethanol (25 ml) to give >98% pure hydromorphone (0.75 g, 35%).




both excerpts from US5847142

 
 
 
 
    Ritter
(Master Whacker)
10-07-02 05:32
No 365276
      stuff  Bookmark   

I knew that bottle of bis(bicyclo2.2.1.1hepta-2,5-diene)rhodium(I)tetrafluoroborate thats been sitting on my shelf collecting dust would have a great use one daytongue

If you want to make hydromorphone, in my educated opinion, I'd have to say that unless you have access to thebaine(very rare) the best route to follow is codeine==>dihydrocodeine==>hydrocodone==>hydromorphone.  Sounds tedious but in reality all three steps can be carried out in one day and each transformation proceeds in >85% yield.

See the hydrocodone document on Rhodiums page for details.
 
 
 
 
    daxium
(Stranger)
10-09-02 17:08
No 366507
      i was looking at that document................  Bookmark   

i was looking at that document, but there is one there that i was looking at called ../rhodium/chemistry /dihydromorphinones.html in rhodium's site and this is the method that i want to try i was hoping for an educated opinion on this
 
 
 
 
    SPISSHAK
(Hive Bee)
10-11-02 06:30
No 367154
      I agree  Bookmark   

I've heard mixed reports on that method, I've heard that Hydrochloric acid was the best medium to perform this reaction in.
Barring this oppenauer oxidation using benzophenone, and Potassium tert-butoxide, followed by work up and hydrogenation seems like your best route.
BTW I know benzophenone is available in fragrances and in nail poilish removers.
Let the rest of the community know how that catalytic rearrangement expiriment goes.
I could be that the oppenauer oxidation isn't suitable for something bearing a phenolic hydrogen like morphine, maybee another approach would need to be used.
I say this because of the catalyst used to facilitate proton abstraction from the cylohexenyl alcohol, Potassium tert butoxide, might interact with the phenol group as well back to the drawing board?

 
 
 
 
    Ritter
(Master Whacker)
10-12-02 21:23
No 367725
      K-tBuO and the phenol  Bookmark   

Spisshak,

You are definitely correct in assuming the K-tBuO would also deprotonate an exposed phenol possibly leading to a big mess.  If you take careful note of the scheme I laid out, you will notice that I compensate for this possible issue by not demethylating the methoxy group to the phenol until AFTER the Oppenauer oxidation is complete.  The demethylation of codeine has been elaborated on by Dope_Amine using BBr3(search his posts).  I see no reason why the same demethylation is not applicable to dihydrocodeinone(hydrocodone).
 
 
 
 
    SPISSHAK
(Hive Bee)
10-14-02 06:56
No 368337
      Demethylation of the hydrocodone  Bookmark   

Expiriments show that Pyridine.Hcl demthylation of this compound give
5% yeild.
Hydrogen iodide relflux (for 1 hour) which is way too long gave 15%
The typical demethylation using the hydrohalogenic acid (Hbr) gives ~ 30%.
The reason why 15% was gotten was that the reflux was carried on too long (1 hour) where typically it's 15 minutes at 130 degress C.
Also some technique was'nt employed (your supposed to add it while the acid is hot)
The lower yeild is the result of the oxygen bridge being turned into a catechol.
 
 
 
 
    blondie
(Hive Bee)
10-14-02 10:31
No 368394
      PhOCH3  Bookmark   

Ritter discovered a JOC article dealing with 7 alkyl substituted hydrocodone analogues being demethylated with much higher yield. also ive seen an oxymorhpone patent using a halo acid to demethylate oxycodone but with lower yields - although i get the feeling the 14hydroxy group makes the molecule a lot more susceptible to recyclisation/rearrangement - ie apomorphine transformation.

Spisshak are you summarising from refs, newsgroup discussion or experience? On rhodium's there is patent example dealing with CTH of 14hydroxycodeinone using sodium hypophosphite as a hydrogen donor and Pd/C - this may be a way of avoiding a parr type setup. can you say microwave?

Also there are other refs out there for the Oppenauer oxidation of  dihydrocodeine. ie various alkoxides ie Aluminium isopropanoate(sp) and cyclohexanone - although the quantitative conversion article already mentioned seems to support the highest yields. 

Someone should really try pyridine hcl demethylation of codeine with morphine as the target but using a microwave. 
 
 
 
 
    daxium
(Stranger)
10-15-02 07:24
No 368749
      good idea!!!  Bookmark   

give me a quick rundown of the situation and i'll give it a try microwave chemistry is sounding kinda fun right about nowwink