To summarize: Lots of different things have been used to 3-O-demethylate opioids, these include H2SO4, NaOH, KOH, HCl, HBr, HI, HF, Pyridine HCl, Anilidine HCl, Aluminum Iodide, and L-Selectride. Some things cause massive re-arrangement of the opioid molecule. Some things cause low yields, other high yields. This is just a collection of references, not advice.
I am not a chemist, so I can't really comment on the applicabilities of these references to this situation, but I hope that somebody more skilled than I will find something useful in here. Anything which says "Available on my hard drive", I will try to put in this thread in the next 24 hours, if you are reading this a week later and I haven't gotten around to it for a specific reference, PM me and call me a lazy-ass and tell me which article you need, and I'll PM you the article.
Patent WO0056735
Page 8:
The 3-methyl ether may be deprotected (demethylated) using standard demethylation conditions.
metal cyanide, metal halide, meratapide, in an inert solvent at elevated temperatures (100-250C)
Deprotection may also be accomplished by reacted the protected compound in HBr, HF, HCl, or HI in water or acetic acid!
The preferred method is reacting the protected compound with Boron Tribromide (preferred) or other Boron Trihalide.
6-acetyl groups may be removed with a metal hydroxide (NaOH) or a metal carbonate in a polar solvent such as methanol.
Demethylation thread, talks about heterocodeine at the bottom:
Post 3992 (missing)
(psyloxy: "Codeine --> Morphine", Chemistry Discourse)Novel analgesics and molecular rearrangements in the morphine-thebaine group. I. Ketones derived from 6,14-endo-ethenotetrahydrothebaine
(This may or may not have to do with demethylation)
J. Am. Chem. Soc. 1967; 89, 3267 - Available on hard drive
Novel analgesics and molecular rearrangements in the morphine-thebaine group. II. Alcohols derived from 6,14-endo-etheno- and 6,14-endo-ethanotetrahydrothebaine
J. Am. Chem. Soc. 1967; 89; 3273-3280 - Available on hard drive
Novel analgesics and molecular rearrangements in the morphine-thebaine group. III. Alcohols of the 6,14-endo-ethenotetrahydrooripavine series and derived analogs of N-allylnormorphine and -norcodeine
J. Am. Chem. Soc. 1967; 89; 3281-3292 - Available on hard drive
Referenced by J. Org. Chem. 1998, 63, 4392-4396 as "A number of basic reagents have thus been developed for the demethylation of such compounds, the most widely used being potassium hydroxide at 200 °C."
Referenced by "Opioid Analgesics: Chemistry and Receptors" (Casy and Parfitt) Chapter 2 - Ref (331) as (referring to etorphine analogs): "Cleavage of 3-OMe must be performed under base conditions in view of the facile rearrangement in acids of opiods of this type. Potassium hydroxide in diethylene glycol at 200-220C proved to be the most effective conditions affording theoripavines.
Novel analgesics and molecular rearrangements in the morphine-thebaine group. IV. Acid-catalyzed rearrangements of alcohols of the 6,14-endo-ethenotetrahydrothebaine series
J. Am. Chem. Soc. 1967; 89; 3293-3303 - Available on hard drive
Novel analgesics and molecular rearrangements in the morphine-thebaine group. V. Derivatives of 7,8-dihydrocyclohexeno[1',2':8,14]codeinone
J. Am. Chem. Soc. 1967; 89; 3303-3311 - Available on hard drive
Novel analgesics and molecular rearrangements in the morphine-thebaine group. VI. Base-catalyzed rearrangements in the 6-14-endo-ethenotetrahydrothebaine series
J. Am. Chem. Soc. 1967; 89, 3312
Referenced by "Opioid Analgesics: Chemistry and Receptors" (Casy and Parfitt) Chapter 2 - Ref (351) as "Base (KOH) catalyzed rearrangements of 7a and 7b ketones of the 6,14 endo etheno and ... have also been shown to afford bridged systems the chemistry of which was investigated."
(Uploaded file not existing)3-O-demethylation in these series is often difficult because 7-substituted 6,14-endeo-ethenotetrahydrothebaines are subject to acid catalyzed rearrangements, and 7 ketones and esters undergo base-catalyzed transformations.
It was shown however that ethyl 6,14-endo-ethenotetrahydrothebaine-7alpha-carboxylate was sequentially 3-O-demethylated, 6-O-demethylated and the 7-ester hydrolized by HBr/HOAc at room temperature.
J. Knoll J. Pharm. Pharmacol 27, 99 (1975)
Referenced by "Opioid Analgesics: Chemistry and Receptors" (Casy and Parfitt) Chapter 2 - Ref (256)
The Illicit Preparation of Morphine and Heroin from Pharmaceutical Products Containing Codeine: 'Homebake' Laboratories in New Zealand
Forensic Science International, v34, 1987, pp 197-204
Acid-Catalyzed Rearrangements in the Nepenthone Series
J. Org. Chem.; 1958; 23(11); 1720-1725
Available on my hard drive
Base-Catalyzed Rearrangements in the Nepenthone Series
J. Org. Chem.; 1958; 23(11); 1725-1730
Available on my hard drive as - jo01105a040 Base-Catalyzed Rearrangements in the Nepenthone Series.pdf
A similar NaOH or KOH catalyzed rearrangement of the dihydrothebaine-quinone occurred.
Referenced by "Opioid Analgesics: Chemistry and Receptors" (Casy and Parfitt) Chapter 2 - Ref (353)
J. Chem. Soc (C) 2233 (1969)
The observation that the tertiary hydroxyl of Oxycodone survived even the rather drastic conditions of the demethylation reaction suggested a study of the analogous demethylation of 14-hydroxycodeinone.
R. E. Lutz and L. F. Small, J . Org. Chem., 4, 220 (1939), concerning the unusual stability of this OH group.
M. Freund and E. Speyer, J . Pralcl. Chem., (2) 94, 135 (1916).
It has been found that 14-hydroxydihydrocodeinone can be demethylated normally with aqueous HBr to give 14-hydroxydihydromorphinone, a compound of considerable analgesic activity.
J. Am. Chem. Soc., 77, 5891 (1955)
Unsuccessful demethylations of Thebaine to Oripavine:
Andre, J. D.; Dormoy, J. R.; Heymes, A. Synth. Commun. 1992, 22, 2313.
Referenced by "Opioid Analgesics: Chemistry and Receptors" (Casy and Parfitt) Chapter 2 - Ref (5)
Lawson, J. A.; Degraw, J. I. J. Med. Chem. 1977, 20, 165.
Referenced by "Opioid Analgesics: Chemistry and Receptors" (Casy and Parfitt) Chapter 2 - Ref (6)
Chem. Pharm. Bull. 1984, 32, 1268.
Referenced by "Opioid Analgesics: Chemistry and Receptors" (Casy and Parfitt) Chapter 2 - Ref (7)
codeine to morphine:
J am chem soc 78 1680 (1956)
J am chem soc 73 5900 (1951)
Proc Jap Acad 30, 76, (1954)
Chem, Abs 50, 1052h (1956)
https://www.thevespiary.org/rhodium/Rhodium/chemistry/codeine2morphine.html
Hydride-Promoted Demethylation of Methyl Ethers, Tet. Lett. 35(47), 8727-8730 (1994)
H. Rapoport, The Preparation of Morphine-N-Methyl-C14, J. Am. Chem. Soc., 73, 5900 (1951)
H. Rapoport, Delta-7-Desoxymorphine, J. Am. Chem. Soc., 73, 5485 (1951)
K. Bedford, Illicit Preparation of Morphine from Codeine in NZ, Forensic Sci. Int. 34(3), 197-204 (1987)
K.C. Rice, A Rapid, High-Yield Conversion of Codeine to Morphine, J. Med. Chem., 20(1), 164 (1977)
An Improved Method for O-Demethylation of Codeine
J. Med. Chem., 20(1), 165 (1977)
Medline (PMID=833817)
Regioselective O-demethylation using a Boron Tribromide substitute - methanesulfonic acid/methionine reagent
Synth Commun 1992 - Ref unknown
7alpha aminomethyl derivatives were also made... analgesic and antitussive potencies increased in the usual manner from 3-O-demethylation
(355) K. W. Bentley J. Chem. Soc. (C) 2237 (1969)
Demethylation of codeine->;;;morphine and 14-hydroxycodeineone->;;;14-hydroxymorphinone using L-Selectride:
163 A. Coop, J. W. Janetka, J. W. Lewis and K. C. Rice, Heterocycles, 1998, 63, 4392.
Patent US2772270
14-hydroxymorphinone and 8, 14-dihydroxydihydromorphinone (Production via 3-O-demethylation of 14-hydroxycodeinone)
Production of the above compounds from 14-hydroxycodeinone using HBr. This surprised the author because it seems improbable that 14-hydroxycodeinone could withstand the harsh conditions of demethylation.
The author recrystallized from ethanol and benzene. Other Non-polars are possible.
Influences favoring the appearance of (Oxymorphone) are more prolonged boiling with HBr, or prolonged exposure during isolation to acidic or alkaline reaction.
10 grams of 14-hydroxycodeinone are introduced into 100ml of concentrated aqueous hydrobromic acid. The stirred mixture is brought to boiling and kept refluxing vigorously for 25 minutes. It is then allowed to cool and kept at room temperature for 5 days.
A solution of 40 grams of Sodium Hydroxide in 70ml water are added in several small portions, preventing excess heat evolution with cooling.
The liquid is then extracted in 4 portions of 40ml chloroform each.
The aqueous phase is acidified with dilute HCl, treated with charcoal, allowed to stand for several days.
The liquid is then adjusted to a pH of 7-8. On standing for several days oxymorphone base crystallizes in good yield. The crystals are filtered off. These can be recrystallized in boiling water.
Salts with any acid may be created by dissolving in an equivalant amount of aqueous acid and evaporating.
Patent US3394139
Describes 4 methods of converting 3-methoxy morphinans to 3-hydroxy morphinans (oxycodone->;;;oxymorphone) (codeine->;;;morphine) (Levomethorphan->;;;levorphan) (10X potency increase for each) (see also: CH445514, US3300500, GB1006337)
According to the present invention, the starting 3-methoxy-6-oxo-N-phenethyl-7-dehydromorphinan (cis) and 3-methoxy-6-oxo-N-phenethylmorphinan (cis) are subjected to hydrolytic fission by a per se conventional procedure which is employed for fission of alkyl phenyl ethers. Some examples of such procedures are as follows: (1) treatment with a mineral acid (e.g. hydrobromic acid, hydroiodic acid) while heating; (2) treatment with a halogenated aluminum compound (e.g. aluminum chloride, aluminum bromide, aluminum iodide) or a halogenated boron compound (e.g. boron fluodide, boron chloride) in the presence or absence of an inert solvent (e.g benzene, tolune) while heating, followed by treatment with water or an acid; (3) treatment with an acid addition salt of pyridine base (e.g. pyridine hydrochloride, pyridine hydrobromide) while heating; (4) treatment with an alkali (e.g. potassium hydroxide, sodium hydroxide) in an inert solvent (e.g. triethylene glycol, diethylene glycol), preferably in the presence of an antioxidizing agent (e.g. hydrazine), while heating.
The resulting 3-hydroxy-6-oxo-N-phenethyl-7=dehydro-morphinan (cis) and 3-hydroxy-6-oxo-N-phenethylmorphinan (cis) form acid addition salts with organic and inorganic acids. Illustrative acid addition salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, tartrate, salicylate, benzoate, malate, citrate, acetate, etc.
Boron tribromide is moisture sensitive and decomposes upon contact with water with the evolution of hydrogen bromide.
https://www.thevespiary.org/rhodium/Rhodium/chemistry/oxymorphone.bbr3.html
http://www.blazetech.com/ADORA/ADORA_Advantage/ADORA_for_RMP/adora_for_rmp.html
Boron trichloride: Chemical reactions with moisture result in the formation of hydrogen chloride (HCl) and heat.
Patent EP0164290
Process for the dealkylation of alcaloids and intermediates.
See also: NZ212193 ES8603893 Demethylation of 14-hydroxy morphinan(s), esp. thebaine
A process for the dealkylation of 14-hydroxymorphinan alkaloids, characterized in that it consists in : 1) reacting the 14-hydroxy derivative of the formula : see diagramm : EP0164290,P5,F6 in which R' is CH3 or COCH3 , with excess ethyl chloroformate, in the presence of potassium carbonate and in a solvent, 2) subjecting the resulting carbamate of the formula : see diagramm : EP0164290,P5,F2 in which R' is CH3 or COCH3 , to hydrolysis in a strong acid medium to give the corresponding dealkylated derivative of the formula : see diagramm : EP0164290,P5,F3 in which R is CH3 or hydrogen.
Patent US4795813
Synthesis of derivatives of codeine and other 3-O-alkylmorphines
See Page 4 for a simple oxycodone synth and the demethylation stuff (demethylation uses BBr3)
Patent GB854354
A new and improved morphine derivative
The invention comprises 14-hydroxydihydromorphine and therapeutically acceptable salts thereof, particularly the bitartrate and hydrochloride, together with processes for the preparation of the base (a) by reduction of 14-hydroxydihydromorphinone with an ethanolic suspension of sodium borohydride, (b) by demethylation of 14-hydroxydihydrocodeine B with hydrobromic acid. The products are useful as narcotic, analgesic and sedative agents
Patent GB382124
Improvements relating to the demethylation of alkaloids containing methoxy groups
Harmol and harmalol are manufactured by the demethylation of harmine and harmaline respectively by the action of sulphuric acid of 45-70 per cent and 40-55 per cent concentration respectively, at an elevated temperature but not exceeding 155 DEG C. Examples describe the manufacture of harmol from harmine by the action of 50 per cent sulphuric acid at 155 DEG C. and of 60 per cent sulphuric acid at 150-155 DEG C., and of harmalol from harmaline by the action of 50 per cent sulphuric acid at 155 DEG C.
20 parts of (60% H2SO4 in H20) boiled at 150-155C for 2 Hours with 1 part of an O-Methyl alkaloid = 98% yield of the O-demethylated product
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.
Post 259633
(blue: "sweet mutha o hesu", Novel Discourse)Demethylation with aniline hydrochloride (using HCL under pressure)
Chem. Ber. 49, 1371 (1916)
Post 430486
(Lego: "Demethylation with aniline hydrochloride", Novel Discourse)Aluminium iodide in ether cleavage
Post 422757
(GC_MS: "Aluminium iodide in ether cleavage", Methods Discourse)