Thebaine demethylation

Thebaine has been converted into the 14-substituted compound (136 R = SCN) by treatment with (SCN)2, and this gives the ketal (136 R = OMe) when treated with methanol. The initial product (136 R = SCN) is hydrolysed to the codeinone by sodium bicarbonate, and reduction of this with lithium aluminium hydride gives 14-mercaptocodeine (137), which can be demethylated to 14-mercaptomorphine by boron trifluoride.166... 

A new method for the demethylation of codeine to morphine, previously a capricious reaction, has been reported, the product being obtained in good yield. Demethylation by boron tribromide in chloroform gives 90—91%150 and by potassium t-butoxide in propanethiol gives 80% morphine.151 A patent describes an improved method for the preparation of codeinone from thebaine, by adding the alkaloid to anhydrous hydrogen bromide in solution in methylene chloride and dibutyl ether at -20 °C, in the presence of small quantities of iodine, followed by hydrolysis with aqueous sodium bicarbonate. The claimed yields of codeinone are 95% crude and 90% after purification.152 Codeinohe is an intermediate in the conversion of thebaine into codeine. An overall yield of 85% of codeine from thebaine, without purification of any of the intermediates, has been claimed for an... 

Papaver Alkaloids.—Biosynthesis of morphine (36) occurs, in Papaver somniferum, through reticuline (33) by way of thebaine (35). The sequence from (35) to (36) involves, inter alia, two O-demethylations, with that at the methoxy-group at C-6 occurring first.1,2 Confirmation that the other methoxy-group is not demethylated first in this Papaver species obtains from the failure to detect oripavine (37), which is found in other Papaver species, as a natural constituent of P. somniferum. The experiment involved attempted isolation of radioactive (37), using inactive alkaloid as carrier, following a feeding experiment with radioactive reticuline (33).37... 

FAO (131) was synthesized from the 7a-amino-6,14-encfo-ethenomorphi-nan (140) which is available from thebaine in three steps as described by Bentley and his coworkers [201], Selective O-demethylation of the phenolic ether function of (140) with boron tribromide afforded the phenol (141) which was treated with methylfumaroyl chloride to yield FAO (131) [96],... 

Diethylazodicarboxylate may be employed as a reagent for the N-demethylation of thebaine to northebaine via an N-Me addition product. However, when thebaine was dissolved in diethylazodicarboxylate and allowed to stand, the hexacyclic product 251 was isolated,<9a) presumably from the Diels-Alder intermediate 249, and after hydrolysis gave 250. The putative intermediates 249 and 250 defied isolation. 

The morphinan-6-one (99), available from thebaine,<36,94,95) has been reacted with lithium dialkylcuprates to give 8/3-alkylmorphinan-6-ones(96) (100) (Scheme 3.14). Variation of the N-substituent was effected by standard procedures, and reductive removal of the carbonyl under Huang-Minlon conditions to 101 also caused some 3-O-demethylation. Similar pathways were used for isomorphinan-6-ones and isomorphinans (102). 

Tetrahydrothebaine [m] was first prepared by Schopf and Winter-halder [5] and shown to be identical with dihydromorphine dimethyl ether. It is best prepared from thebaine by hydrogenation of the hydrochloride in glacial acetic acid over platinum oxide [22-23], or of the base in ethanol over W. 6 Raney nickel [24]. It can be demethylated to dihydromorphine by hydriodic acid or aluminium chloride [22-23]. The Hofmann degradation has not been studied, but hydrogenation of a-oodeimothine methyl ether [xxxix] affords a-tetrahydrocodeimethine methyl other [xl], which is tetrahydrothebaine dihydromethino [25],... 

Acetylphenyldihydrothebaine is formed by acetylation of the phenol [1, 14], Methyl and ethyl ethers of phenyldihydrothebaine were prepared by Freund, who degraded both to nitrogen-free substances [1]. Demethylation of phenyldihydrothebaine affords norphenyldihydro-thebaine [xxxi] which can be methylated to phenyldihydrothebaine methyl ether [1, 4, 8]. The latter is stable to ozonolysis [15]. 

Catalytic hydrogenation of thebaine-quinone over platinum oxide in glacial acetic acid proceeds with the rapid absorption of one mole of hydrogen and the somewhat slower absorption of a second mole to give tetrahydro-thebaine-quinone [xvm]. If the reduction is stopped after the first mole of hydrogen has been absorbed, a product that is probably mainly [xix] is obtained it is believed to be mainly [xrx] as mainly non-phenolic matter is obtained after one minute s boiling with concentrated acid, under which conditions [xvi] is isomerized to [xvh] [3]. Attempted demethylation of [xvni] with hydriodic acid affords only tars [3]. 

Applying mechanism (a) to the rearrangement of thebaine-hydro-quinono we have attack of the cyclic ether oxygen by a proton and demethylation of the methoxyl group, followed by the electron-shifts a, b, c, d (formula xxxiv]), loss of a proton from the hydroxyl group... 

Demethylation of flavothebaone with hydrobromic acid gives 0-desmethylflavothebaone [li], also obtained by heating thebaine-hydroquinone with concentrated hydrobromic acid [2]. 

Morphothebaine was first believed to be simply a demethylated thebaine and to have the composition C17H15OH(OH)2 [3], but later was correctly shown to have the formula C18H1903N, and to contain one methoxyl group [7]. It contains two phenolic hydroxyl groups and cannot be converted back to thebaine [7]. 

This mechanism involves several forced assumptions and is very-improbable. The initial reaction when thebaine [i] is treated with concentrated hydrochloric acid is undoubtedly addition of a proton at the cyclic ether link the subsequent processes may be regarded in either of two ways. Demethylation is assumed in both cases. 

Thebenol can be methylated to methebenol and acetylated on evaporation with 30 per cent, potassium hydroxide [7] or fusion with aniline hydrochloride [12] it is demethylated to northebenol, which, like thebenol itself, gives an iodhydrin on heating with concentrated hydriodic acid [7]. Thebenol contains an asymmetric carbon atom, but attempts to resolve it by condensing it with glucose residues yielded only decomposition products [12], The hydrocarbon pyrene [vi] is formed when thebenol is distilled with zinc-dust or reduced with hydriodic acid [7] pyrene is also obtained from thebaine under the same conditions [13]. 

Attempts to convert oripavine (the 3-demethylated analogue of thebaine) to an analogue of thebenine failed to give clearly-defined products [26]. 

An analogous scheme for thebaine can be written from a partially demethylated laudanine (CXX)XCV). 

P. somniferum andP. setigerum (Section Mecones). It follows that not all Papaver species are capable of demethylating and hydrogenating thebaine to codeine and morphine. 

Rapoport el al. described a simple preparation of 6-O-demethyl-salutaridine (43e) from thebaine with sodium bisulfite in an oxygen atmosphere (494). In another synthesis, 14-bromocodeinone (47b) in Claisen s alkali yields 6-O-demethylsalutaridine (495). Methylation of this compound with diazomethane gives rise to O-methylsalutaridine (43d). The following reaction sequence appears to account for the production of... 

An improved N-demethylation of morphine, codeine, and 6,7-benzo-morphane was carried out in 90% overall yield (523). The demethylation of thebaine to 6-O-demethylsalutaridine (43e) has been reported (494). Attention was also paid to the preparation of tosyloxy and mesyloxy derivatives of some morphinanes, e.g., morphine, codeine, dihydromorphine (49c), dihydrocodeine (49a), 14-hydroxycodeine (46), and 14-hydroxydihydrocodeine (49b) (524). The rearrangements of all these derivatives as well as the Beckmann and Schmidt rearrangements of 6-oxomorphine bases have also been studied (525). 

Thebaine (192) is found in numerous plants of the sections Orthorhoeades, Pilosa, Miltantha, and Macrantha. The phenolic ortho-para oxidation leading to the formation of thebaine is shown to be a common phenomenon, whereas the specific ability to demethylate the methoxy groups to produce morphine (204) or codeine (198) appears to be a rare characteristic (Fig. 4). 

The conversion of reticuline (44) into morphinan alkaloids, which occurs with loss of tritium from C-1 in P. somniferum (see above)," has been observed also for the formation of thebaine (46) in P. bracteatum, a plant which produces this alkaloid but not codeine or morphine. Radioactive 1,2-dehydroreticuline (47) labelled both reticuline (44) and thebaine (46), whilst radioactive reticuline again labelled thebaine (46). ° Codeinone (48) and codeine (50) are biosynthetic intermediates between thebaine (46) and morphine (51) in P. somniferum, and it was shown that (48) was efficiently reduced to (50) in P. bracteatumf It is apparent that alkaloid biosynthesis in the two plants is similar, with the important difference that in P. bracteatum the enzymes which effect demethylation of (46) are missing, and so biosynthesis goes no further than thebaine (46). 

An improved rapid procedure for the preparation of normorphine and norcodeine by A/-demethylation with phenyl chloroformate followed by hydrazine has been reported.An efficient synthesis of N-cyclobutylmethylnoroxymorphone (naltrexone) from thebaine, via 14-hydroxy-codeinone, has been described,as have preparations of A/-tetrahydrofurfuryl-noroxymorphone and of N-s-alkyl- and N-t-alkyl-normorphines. ° N-Demethylation and O-de-ethylation of 3-O-ethylmorphine by rat hepatic microsomes has been observed.A patent has been published covering the... 

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