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 (https://www.thevespiary.org/talk/index.php?topic=9669.msg46608600#msg46608600)
(Rhodium: "Anhydrous Gaseous Hydrogen Bromide", Methods Discourse)
Post 188229 (https://www.thevespiary.org/talk/index.php?topic=9569.msg18822900#msg18822900)
(lugh: "Six Laboratory Preparations of Hydrobromic Acid", Methods Discourse)
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 (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
Any good opiate chemistry books out there?
Definitely, see Post 246207 (https://www.thevespiary.org/talk/index.php?topic=12438.msg24620700#msg24620700)
(Rhodium: "Opioid Analgesics", Serious Chemistry)
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 (http://www.unodc.org/unodc/en/bulletin/bulletin_1951-01-01_2_page006.html#f003)
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+)
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+)
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 (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.
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 (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?
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 (http://l2.espacenet.com/dips/viewer?PN=WO0056735&CY=gb&LG=en&DB=EPD)
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 (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) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=833817&dopt=Abstract)
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 (http://l2.espacenet.com/dips/viewer?PN=US2772270&CY=gb&LG=en&DB=EPD)
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 (http://l2.espacenet.com/dips/viewer?PN=US3394139&CY=gb&LG=en&DB=EPD)
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 (https://www.thevespiary.org/rhodium/Rhodium/chemistry/oxymorphone.bbr3.html)
http://www.blazetech.com/ADORA/ADORA_Advantage/ADORA_for_RMP/adora_for_rmp.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 (http://l2.espacenet.com/dips/viewer?PN=EP0164290&CY=gb&LG=en&DB=EPD)
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 (http://l2.espacenet.com/dips/viewer?PN=US4795813&CY=gb&LG=en&DB=EPD)
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 (http://l2.espacenet.com/dips/viewer?PN=GB854354&CY=gb&LG=en&DB=EPD)
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 (http://l2.espacenet.com/dips/viewer?PN=GB382124&CY=gb&LG=en&DB=EPD)
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 (https://www.thevespiary.org/talk/index.php?topic=12004.msg25963300#msg25963300)
(blue: "sweet mutha o hesu", Novel Discourse)
Demethylation with aniline hydrochloride (using HCL under pressure)
Chem. Ber. 49, 1371 (1916)
Post 430486 (https://www.thevespiary.org/talk/index.php?topic=12198.msg43048600#msg43048600)
(Lego: "Demethylation with aniline hydrochloride", Novel Discourse)
Aluminium iodide in ether cleavage
Post 422757 (https://www.thevespiary.org/talk/index.php?topic=9508.msg42275700#msg42275700)
(GC_MS: "Aluminium iodide in ether cleavage", Methods Discourse)
Tramadol demethylation:
http://sylvester.bth.rwth-aachen.de/dissertationen/2003/055/03_055.pdf (http://sylvester.bth.rwth-aachen.de/dissertationen/2003/055/03_055.pdf)
H2SO4 demethylation of vanillin:
Post 291912 (https://www.thevespiary.org/talk/index.php?topic=11807.msg29191200#msg29191200)
(Antoncho: "Demethylation of vanillin.", Novel Discourse)
Patent US3367972 (http://l2.espacenet.com/dips/viewer?PN=US3367972&CY=gb&LG=en&DB=EPD)
H2SO4 demethylation
Patent US2975214 (http://l2.espacenet.com/dips/viewer?PN=US2975214&CY=gb&LG=en&DB=EPD)
Aluminum bromide demethylation
Demethylation of 3,4,5-trimethoxybenzaldehyde to syringaldehyde using H2SO4 in near quantative yield.
Post 464344 (https://www.thevespiary.org/talk/index.php?topic=6355.msg46434400#msg46434400)
(imp: "Quantative 3,4,5-TMB to syringaldehyde", Chemistry Discourse)
JACS, vol. 74, pp.4262 (1952)
A mixture of 10 g. of recrystallized 3,4,5-trimethoxybenzaldehyde and 56 g. of concentrated sulfuric acid was maintained at 40 C in a water-bath for 8 hours and then allowed to stand overnight at room temperature. The mixture was stirred into 100 cc. of cold water and cooled. The clear solution was decanted from the little tar that separated and was extracted with ether. The ether was dried and distilled to yield 8.9 g. (96%) of almost pure (as indicated by chromatography) syringaldehyde which, upon crystallization from pet. ether melted at 109 C and did not depress the melting point of a mixture with authentic syringaldehyde.
The use of crude 3,4,5-trimethoxybenzaldehyde or of longer reaction times resulted in poorer yields and in much cruder products.
The article also describes selective methylation of 5-hydroxyvanillin, but the yields were bad and they got a mixture of 3,4,5-TMB, 3,4-dimethoxy-5-hydroxybenzaldehyde (good for metaescaline), syringaldehyde, and unreacted 5-hydroxyvanillin.
Eugenol -> Safrole
Post 289534 (https://www.thevespiary.org/talk/index.php?topic=11879.msg28953400#msg28953400)
(El_Zorro: "Eugenol-->Safrole directly?", Novel Discourse)
However the yeild is only 50% and it takes quite allot of LiCl. Hmm I wonder if you could recover the LiCl?
Patent EP1136481 (http://l2.espacenet.com/dips/viewer?PN=EP1136481&CY=gb&LG=en&DB=EPD)
A solution of 354 ml (2.30 mmol) of eugenol and 292 g (6.89 mol) of lithium chloride in 3.7 1 of N,N-dimethylformamide was refluxed for a total of 44 hours (h), and, after 4 h, 18 h and then 7 h, a further 292 g (6.89 mol) of lithium chloride were added each time. After cooling, 2 1 of toluene were added and the resultant precipitate was filtered off with suction and extracted with toluene. The organic extracts were combined and concentrated on a rotary evaporator. After flash chromatography (ether/pentane, 1:1, Rf = 0.37) on silica gel, 173 g (50%) of 4-allylcatechol were obtained.
L-Selectride as a General Reagent for the O-Demethylation and N-Decarbomethoxylation of Opium Alkaloids and Derivatives
Coop, A.; Janetka, J. W.; Lewis, J. W.; Rice, K. C.
J. Org. Chem. 63(13), 4392-4396 (1998)
https://www.thevespiary.org/rhodium/Rhodium/pdf/opium.alkaloid.o-demethylation.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/opium.alkaloid.o-demethylation.pdf)
DOI:10.1021/jo9801972
Osthenol(condensed version)
DMS (2,5ml) added to a suspension of anhydrous AlCl3 (0.33g, 2.5mmol) in CH2Cl2 (5ml) at 0degC with stirring until in solution. to this solution, osthol (0.24g, 1,0mmol) was added over 10 minutes at same temp. Allow temp to reach RT and stir 24hours, rxn was quenched in 1N HCl and extracted with CH2Cl2 and purifiied on column, yeild 62%
Molecules 2000, 5, 880-885, Gopalakrishan, Kasinath
www.mdpi.org
Boron Tribromide demethylation:
Rice, K. C. J. Med. Chem. 1977, 20, 164.
Yet this procedure suffers from the toxicity of the reagent and its incompatibility with acid sensitive substrates, a problem with all acidic O-demethylating reagents.
Bentley, K. W.; Hardy, D. G.; Meek, B. J. Am. Chem. Soc. 1967, 89, 3293.
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
Bentley, K. W.; Hardy, D. G. J. Am. Chem. Soc. 1967, 89, 3281.
In addition to problems encountered with the use of such harsh conditions, it has been observed that the reaction is somewhat unreliable on smaller (ca. 1 g) scales.
Coop, A., Ph.D. Thesis, University of Bristol, 1994.
This has led to the increased use of thiolate anions for laboratory scale demethylations which are toxic and require a weird solvent.
Lawson, J. A.; Degraw, J. I. J. Med. Chem. 1977, 20, 165.
Husbands, S. M.; Lewis, J. W. Bioorg. Med. Chem. Lett. 1995, 5, 2969
Patent GB937214 (http://l2.espacenet.com/dips/viewer?PN=GB937214&CY=gb&LG=en&DB=EPD)
Oripavine derivatives
K. W. Bentley
This is important because it is an example of a NaOH 3-O-demethylation of an opiate (thebaine derivative to oripavine derivative)
The invention comprises oripavine derivatives of the general formula wherein R1 is hydrogen, C1-3 alkyl or aryl and R2 is hydrogen, C1-8 alkyl or C2-8 alkenyl (which may be substituted on carbon atoms 1 to 5 by an alicyclic or aryl group) or a C5-7 alicyclic group (which may be unsubstituted or substituted by a C1-3 alkyl group)-with the proviso that R2 does not contain the system -CH-aryl or -CH-C=C attached to the carbon atom bearing the alcoholic hydroxyl group; salts of these compounds with pharmaceutically acceptable acids; 3-acyl esters of these compounds wherein the phenolic hydroxyl group is esterified with an acid CnH2n+1COOH, where n is 1-3, or with benzoic or nicotinic acid; a process for preparing the compounds of the above formula by demethylating the baine derivatives of the general formula by heating with an alkali metal hydroxide in the presence of a suitable solvent; and a process for preparing the 3-acyl esters by reacting a compound of the first general formula above with an acid anhydride or acid chloride. The products have depressant, analgesic, sedative and anti-tussive properties. Specification 925,723 is referred to.
Piglet says:
Lewis acid (titanium tertachloride) to O-demethylate
Hydrogen halides:
Dihydrocodeinone(hydrocodone) can be demethylated with 48%aq HBr to yield hydromorphone
J. Org. Chem. 3, 204 (1938)
9g Ethyldihydrocodeinone in 45ml 48% HBr, reflux 14 min, dilute with 100ml water and basify with NaOH. Wash with ether to remove non-phenolic material, add excess ammonium chloride and extract with 4000ml diethyl ether [in at least two dozen portions], evaporate the ether and recrystallize from alcohol to give 8.4g ethyldihydromorphone
48%aq HBr to demethylate the methoxy ether on about a half-dozen alkyl dihydrocodeinone derivatives via a 20-30 min. reflux.
"All yields are over 95%"
Ethers are cleaved by heating HBr or HI to give alkyl bromides or alkyl iodides
http://www.erowid.org/chemicals/dxm/dxm_chemistry1.shtml (http://www.erowid.org/chemicals/dxm/dxm_chemistry1.shtml)
Post 102586 (missing)
(Ranter: "Re: 'Grab your seats' (Safrole + HBr)", Chemistry Discourse)
Post 102609 (missing)
(CHEM GUY: "Re: 'Grab your seats' (Safrole + HBr)", Chemistry Discourse)
Post 477723 (https://www.thevespiary.org/talk/index.php?topic=6182.msg47772300#msg47772300)
(Dysprosium: "Dopamine or Tyramine Synthesis", Chemicals & Equipment)
They can be had by synthesizing 3,4-methylenedioxyphenethylamine or 4-methoxyphenethylamine and then dealkylate the aromatic substituents with refluxing with 48% HBr. What is your intended use for the substances?
Make aqueous HBr via H2SO4 + KBr or NaBr:
Post 477998 (https://www.thevespiary.org/talk/index.php?topic=7056.msg47799800#msg47799800)
(stratosphere: "bromine prep reaction", Chemistry Discourse)
Hydrobromic Acid (HBr)
prop: mp -88.5 C, bp -67.0 C, density of gas: 3.5 grams/liter,
The azeotrope is 47% and it boils at 126 C.
The gas dissolves as: 221 grams/ 100 mL in cold water, 130 gr/ 100 mL
hot water.(The CRC 64th Ed.)
Post 287791 (https://www.thevespiary.org/talk/index.php?topic=5273.msg28779100#msg28779100)
(Argox: "Whazzup with Big Orange and HCl?", Chemicals & Equipment)
Post 260254 (missing)
(kdog_x: "Br2 from MnO2", Chemicals & Equipment)
Post 258707 (missing)
(kdog_x: "BromoSafrole... Stable?", Chemicals & Equipment)
Six Laboratory Preparations of Hydrobromic Acid
Post 188229 (https://www.thevespiary.org/talk/index.php?topic=9569.msg18822900#msg18822900)
(lugh: "Six Laboratory Preparations of Hydrobromic Acid", Methods Discourse)
Make your own HBr (lame):
Post 170012 (missing)
(improv_chem: "Make your own HBr??", Chemicals & Equipment)
Best procedure for making 48% HBr:
http://groups.google.com/groups?hl=en&lr=&ie=UTF-8&oe=UTF-8&threadm=221302Z21081996%40anon.penet.fi&rnum=5&prev=/groups%3Fhl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8%26q%3Dhbr%2Bkbr%2Bh2so4%26sa%3DN%26tab%3Dwg (http://groups.google.com/groups?hl=en&lr=&ie=UTF-8&oe=UTF-8&threadm=221302Z21081996%40anon.penet.fi&rnum=5&prev=/groups%3Fhl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8%26q%3Dhbr%2Bkbr%2Bh2so4%26sa%3DN%26tab%3Dwg)
Re: Where to acquire 48% HBr?
Post 93965 (missing)
(sublime: "Where to acquire 48% HBr?", Chemicals & Equipment)
Hbr help ?!
Post 93249 (missing)
(andrew.z: "Hbr help ?!", Chemicals & Equipment)
Specialty gas suppliers and HBr
Post 88842 (missing)
(MukiBear: "Specialty gas suppliers and HBr", Chemicals & Equipment)
HBr gas price @ welding/speciality gas dist.
Post 86172 (missing)
(Niels Bohr: "HBr gas price @ welding/speciality gas dist.", Chemicals & Equipment)
Is "drain opener" type adequate for the generation of HBr from NaBr and aqHBr?
Post 87809 (missing)
(BeansMalice: "Concentrating HS2O4", Chemicals & Equipment)
HBr demethylation of 3-hydroxy-N-methylmorphinane (morphinan aka dromoran)
R. Grewe, A. Mondon and E. Nolte
Ann. 564, 161 (1949)
see also: Helv. Chim. Acta, 32, 821 (1949)
(Osmium) "Strong aq. acids will demethylate phenolethers. I've seen several other reactions where phenolethers were refluxed with H2SO4, and at least partial demethylation took place. para MeO will hydrolyse the fastest, ortho-MeO the slowest."
Post 289534 (https://www.thevespiary.org/talk/index.php?topic=11879.msg28953400#msg28953400)
(El_Zorro: "Eugenol-->Safrole directly?", Novel Discourse)
Antoncho:
There are basically three types of demethylating agents (all acidic, alkaline is also possible, but i'll leave that out):
- mineral acids (HBr, HCl, H2SO4)
- metal halides (AlBr3, FeCl3, etc)
- hydroclorides of organic bases (pyridinium*HCl, anilinium*HCl)
HydroChloric Acid Reduction:
https://www.thevespiary.org/rhodium/Rhodium/chemistry/eleusis/reduction.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/eleusis/reduction.html)
https://www.thevespiary.org/rhodium/Rhodium/chemistry/amphetamine.reduction.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/amphetamine.reduction.html)
HCOOH formic acid reduction
HI reduction
One approach to P2P utilizes a dissolving metal reduction of nitrostyrene with iron and hydrochloric acid [52-53] (Fig 4).
Use of the methyl ether function to protect hydroxyl groups has been limited by lack of effective and selective demethylation reagents. Recent reports have shown the cleavage of primary alkyl and phenolic methyl ethers by (Me)3SiI and of phenolic methyl ethers by CH3S03H and methionine. The combination of BF3.OEt2 and an aliphatic thiol has been shown to be effective in cleaving methyl ethers of primary and secondary This cleavage of secondary methyl ethers occurs with retention of configuration, and t'his reaction was therefore used in the total synthesis of gibberellins AI5 and A37.4 We have also shown that this reagent is effective for cleavage of benzyl ethers.
(a) M. E. Jung and M. A. Lyster,
J. Org. Chem., 42, 3761 (1977);
(b) T. L. Ho and G. A. Olah
Chem., Int. Ed. Engl., 15,774 (1976);
Synthesis, 417 (1977);
(c) H. Irie, N. Fujii, H. Ogawa, H. Yajima, M. Fujino, and S. Shinagawa,
J. Chem. Soc., Chem. Commun., 922 (1976)
Chem. Pharm. Bull., 25, 2929 (1977)
Regioselective O-demethylation of aporphines with methanesulfonic acid/methionine: an efficient one-pot transformation of thebaine to (R)(-)-2-methoxyapomorphine.
Berenyi, Sandor; Csutoras, Csaba; Gyulai, Susanna; Makleit, Sandor.
Synthetic Communications, 1995, 25(3), 283-8
Selective O-Demethylation of 7a-(Aminomethyl)-6,14-endo-ethenotetrahydro-thebaine
J. Org. Chem. 1986,51, 1620-1622
The conversion of 4 to 6 by selective O-demethylation at the 3-position had been accomplished in 7a-tertiary alcohol analogues by reaction with potassium hydroxide in diethylene glycol at 200-210C.
Prior art has shown that papaverine can be O-demethylated partially to the diphenol 6 by refluxing concentrated HCl and completely to the tetraphenol papaveroline by refluxing 48% HBr.
HCl: A. Boucherle and J. Alary, Bull. SOC. Chim. Fr., 1222 (1960)
HBr: J. V. Burba and M. F. Murnaghan, Biochem. Pharm., 14, 823 (1965)
The Illicit Preparation of Morphine and Heroin from Pharmaceutical Products Containing Codeine: 'Homebake' Laboratories in New Zealand
K.R. Bedford, S.L. Nolan, R. Onrust and J.D. Siegers
Forensic Science International 34(3), 197-204 (1987) (https://www.thevespiary.org/rhodium/Rhodium/chemistry/codeine.homebake.labs.html)
(https://www.thevespiary.org/rhodium/Rhodium/chemistry/codeine.homebake.labs.html)
Summary
Since 1983 a large number of small-scale illicit laboratories producing morphine and heroin from commercially available, codeine-based pharmaceutical products have been encountered in New Zealand. The codeine demethylation procedure is based on the use of pyridine hydrochloride Very simple laboratory equipment and reagents are required and these can be utilised by people with little or no chemical background, following a recipe-like procedure. The process yields a characteristic product known as 'homebake'. This process is fully described.