Thebaine degradation

Codeine is therefore a methyl ether of morphine, whilst thebaine is a methyl ether of an enolic form of codeinone. There has been much discussion as to the function of the third or indifferent oxygen in the three alkaloids, and its nature has only been disclosed by a study of degradation products. 

Thebainone (Schopf), CigHjjOgN. This substance, which must be distinguished from Pschorr s thebainone (metothebainone of Schopf (see p. 248) ), is formed, along with the latter in the reduction of thebaine by stannous chloride in hydrochloric acid, and was isolated by Schopf and Hirsch. Its prior isolation by Pschorr, as confirmed by Morris and Small, has been referred to already. It crystallises with 0-5 HjO, has m.p. 151-2°, yields a hydriodide, m.p. 258-9°, methiodide, m.p. 223°, and an oxime, m.p. 185-6°. On catalytic hydrogenation it yields dihydrothebainone (LI), and can be degraded to 3 4 6-triacetoxyphenanthrene, m.p. 165-7°. On this basis formula (XLIX) is assigned to it. The mechanism of the formation of codeinone, thebainone and mefathebainone from thebaine is discussed by Schopf and Hirsch. ... 

Thebaine, codeine and morphine from poppy straw (Papaver somniferum) were extracted with carbon dioxide and various polar modifiers at 20 MPa and 40.5 °C. Kinetic extraction curves for morphine showed that 50% methanol in carbon dioxide was necessary in order to achieve quantitative yields in less than 20 min. A mixture of 25% methanol, 0.22% methylamine and 0.34% water had the same effect as 50% methanol in the catbon dioxide. However, it was also reported that, in spite of its strong extraction power, the methylamine-water mixture had a major drawback in that morphine in the presence of the amine degraded in the presence of light. Hence, carbon dioxide-methanol-water mixtures were investigated increasing the water content in the extraction fluid dramatically enhanced the extraction rate for thebaine [29]. 

Circumstantial evidence suggested that levorphanol ((-) 49, R = OH R = Me), because its pharmacodynamic profile is similar to that of morphine, has the same absolute configuration. Proof of absolute configuration came from Hellerbach s group,<35) who subjected it to Hofmann degradation, followed by oxidative steps to the dicarboxylic acid, 52, identical to that obtained from thebaine and abietic acid. 

Ozonolysis of thebaine<216) has been found to give three products. In two of these the unsaturated epoxymorphinan C-ring has been cleaved to give, as the major product (34%), the benzomorphan dicarboxylic acid (2c), and a furanobenzomorphan (14%) (2b). The minor component (3%) proved to be 14-hydroxycodeinone (2d) by comparison with an authentic sample. Compounds related to 2b have also been derived by a codeine degradation.(220)... 

Most phenanthrene alkaloids are easily synthesized by degradation of the corresponding aporphines. Many phenanthrenes were first prepared as aporphine derivatives for characterization or in the course of structural studies, and only later were they found in nature. Although the ready availability of most aporphines from natural sources makes this strategy very simple, it often does not constitute a formal total synthesis, and some approaches from simpler compounds have been published (29,105). Degradation of the morphine alkaloid thebaine (151) gives rise to a number of unnatural phenanthrenes (93,94,102, 104,113). 

On the basis of the degradation of thebaine to derivatives of thebaol and j8-dimotliylaminoothanol (Chap. XXVII) tho oxazine formulae... 

Elimination of one of the double bonds of thebaine results in a compound more amenable to exhaustive methylation, and alkaline degradation of dihydrothebaine methiodide affords, in good yield, dihydrothebaine methine [ix] [1, 15-16], which can be hydrogenated to the dihydromethine [x] [1], Further degradation of the methine [ix] methiodide results partly in regeneration of the base and partly in production of 6-methoxy-13-vinyltetrahydromorphenol methyl ether [xi] [15-16], which can be hydrolysed to 6-keto-13-vinylhexahydro-morphenol methyl ether [xn]. 

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],... 

The reduction of thebaine methiodide with sodium in liquid ammonia leads to dihydrothebaine- dihydromethine [xxx], also accessible by the reduction of dihydrothebaine- methiodide the methyl ether can be prepared in the same way from dihydrothebaine methyl ether methiodide. [xxx] can be hydrolysed by mineral acids to the-bainone-B dihydromethine [xxxi], and reduced with difficulty to dihydrothebainone dihydromethine AB-enol methyl ether. Its methiodide on reduction with sodium and ammonia yields 4-hydroxy-3 6-dimethoxy-13-ethyl-7 13 9 10-tetrahydrophenanthrene [Xxxii] and on alkaline degradation gives A6,8-6-methoxythebendiene [xxxm] [11],... 

Thebaine is easily degraded to phenanthrene derivatives, which in turn are derived from diphenyl, certain derivatives of which exhibit optical activity, and it is well known that the hypothesis of restricted rotation of the phenyl groups in presence of ortho-substituents of sufficient size harmonizes all the experimental data. 

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]. 

Oxidation of desmethoxydihydrosinomenine with silver nitrate results in linking of two molecules in the l T-position to give bis-1 T-desmethoxydihydrosinomenine, which can be degraded to bis-1 T-desmethoxydihydrosinomenine methine, bis-1 1 -desmethoxydihydrosinomenine dihydromethine, bis-1 T - 9 10-dehydro-( —)-thebenone, and bis-1 l -(—)-thebenone, all of which can be racemized with the corresponding compound prepared from the thebaine series [49]. 

When 1-bromosinomenilic acid [xcm] is warmed above 35° C. with 20 per cent, oleum degradation to the ketone 1-bromosinomenilone [xovi] occurs. The dibromo-acid [xcrv] loses water at 150° C. in vacuo over phosphorus pentoxide to give a lactide [69]. These derivatives have also been prepared in the thebaine series [74],... 

TRIHYDROXYPHENANTHRENE Whereas derivatives of codeine and morphine must undergo dehydration and loss of the hydroxyl group at C-6 for aromatization to occur, thebaine and codeinone can be degraded to aromatic compounds with retention of the oxygen substituent at C-6. 

These are all obtained by the degradation of derivatives of sinomen-ine [lxxxix] by methods similar to those used in the morphine-thebaine series. 

The facts that the degradation of the morphine alkaloids to fully aromatic phenanthrene derivatives is always accompanied by loss of the whole of the basic side-chain, and that loss of the latter is never observed independently of formation of such an aromatic derivative, led Gulland and Robinson [1, 118] to perceive that the nitrogen-containing side-chain must be so located that its extrusion is a necessary part of aromatization. The only positions for the attachment of the carbon end of the side-chain on this assumption are C-13 and C-14 of the phenanthrene skeleton, and the formulae [cxi] for codeine and [cxn] for thebaine were accordingly advanced [1], later being modified to [cxm] and [oxiv] respectively [118]. Such formulations allow the construction of plausible mechanisms for the degradation of the morphine alkaloids to phenanthrene derivatives. 

Fieser and Holmes [35], by the addition of butadiene and dimethyl-butadiene to ethyl 3 4-dihydro-a-naphthoate, were able to prepare [cxn, R = H] and [cxn, R = Me], and also the methoxy-compounds [cxm] and [cxiv] in a similar way [36], Reduction of [cxiv] afforded 3 4-dimethoxy-5 6 7 8 9 10 13 14-octahydrophenanthrene-13 -carb -oxylic acid [cxv], which is theoretically obtainable from [cxvi], a known product of degradation of thebaine [37].. Attempts to convert the carboxyl group of [cxv] to other substituents were made, and in this connexion [oxii, R = Me] was submitted to the Bouveault-Blano reduction followed by treatment of the product with phosphorus... 

Reticuline labeled with tritium was used in experiments to show 29) that thebaine (and consequently also codeine and morphine) arises from (— )-reticuline, which is in agreement with the known absolute configuration of these morphinane bases. Its intermediate is salutaridinol-I (not its epimer II) where the absolute configuration of the hydroxyl group was determined by isolation of L-glyceric acid (after degradation). 

By using 14C-morphine it could be shown that morphine is further degraded to such nonalkaloidal metabolites as thebaol (50), which is elaborated directly by the plant from thebaine (288,496). 

Scheme 13.24. The demonstration of the location of oxygen substituents in thebaine (and hence morphine and codeine) and the presence of a phenanthrene (barring rearrangement) system. The degradative work is from Vongerichten, E. Dittmer, O. Chem. Ber., 1906,39,1718. The synthesis, using the sodium salt of the 4-methoxyphenylacetic acid reacting with the nitrobenzaldehyde derivative (in acetic acid for 3 days at 100°C) followed by reduction [rron(II) sulfate], diazotization (sodium nitrite in methanolic sulfuric acid), cychzation, and pyrolysis (loss of carbon dioxide) was effected by Pschorr, H. Liebigs Ann. Chem., 1912, 391,40.

Morphine has a long history of use and abuse. It was the first so-called vegetable base drug isolated, an event recorded in 1805. Because morphine is basic, an early quantitation method was titration with an add. Morphine is subject to oxidation, so the morphine content of an extract can decrease after harvest. Similar degradation issues arise with the stimulant khat. Codeine, the 3-methyl ether of morphine, whose first extraction was recorded in 1832, is also found in the raw opium extracts. Opiates are used principally for pain relief thebaine is the oddball of the opiate alkaloid family, classified as a stimulant. The primary use of thebaine is as a starting point for the synthesis of oxycodone and other related semisynthetic compounds. Thebaine was also used as a poison. 

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