Thebaines

Whereas the particular methylated derivative of laudanasoline (77, R = H) called (—)-reticii1ine (85) (59) gives rise to thebaine (84), codeiae (2,... 

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

Experiments in the selection of poppies for morphine production have also been made in Germany by Kiissner. The yields from capsules of two selections, over two years, were morphine 0-257 to 0-544 per cent, and codeine 0-011 to 0-029 per cent. From seven commercial varieties grown in plots of 50 square metres, the yields in grammes per square metre were seeds 141 to 200, capsules 65 to 116, morphine 0-123 to 0-471 and non-phenolic bases (codeine, thebaine, papaverine, narcotine, etc.) 0-043 to 0-131. 

The first scheme for the separation of the six chief alkaloids of opium, VIZ., morphine, codeine, thebaine, papaverine, narcotine and narceine, is probably that of Plugge. Much later Kljatschkina investigated for each of these six bases the properties by means of which isolation and estimation could probably be effected and, on the basis of the results, devised a plan for such analyses. More recently Anneler has published a detailed account of a scheme with the same objective. l Attention had already been given to complex, systematic analyses of this kind, in connection with examination of the mixtures of opium alkaloids, which have long been in use in medicine in these at first only morphine and other alkaloids were determined, but in the more recent schemes provision is made for the estimation of each alkaloid. ... 

The processes used in the manufacture of morphine are believed to be still based on that described by the Scottish chemist Gregory,in 1833, with improvements devised by Anderson. A description has been published by Schwyzer, who also deals with the manufactme of codeine, narcotine, cotarnine, and the commercially important morphine derivatives, diamorphine (diacetylmorphine), and ethylmorphine (morphine ethyl ether). More recently Barbier has given an account of processes, based on long experience in the preparation of alkaloids from opium. Kanewskaja has described a process for morphine, narcotine, codeine, thebaine and papaverine, and the same bases are dealt with by Chemnitius, with the addition of narceine, by Busse and Busse, and by Dott. It is of interest to note that a number of processes for the extraction and separation of opium alkaloids have been protected by patent in Soviet Russia. ... 

Laudanosine, C21H27O4N. This alkaloid occurs in the liquor from which thebaine is precipitated, and can be isolated by Hesse s method. The crude alkaloid is purified by extraction with small quantities of ether, in which laudanosine is soluble, and finally by precipitation with potassium iodide. The free base crystallises from hot benzene in needles, m.p. 89°, [ ] f 103-23° (EtOH), is soluble in alcohol, chloroform, hot benzene or... 

Thebaine, CjgHgiOgN. This base, which occurs in opium to the extent of 0-1 to 1 per cent., was first obtained by Pelletier and Thiboumery, who regarded it as isomeric with morphine, and named it paramorphine. It was examined by Kane, who first called it thebaine, and by Anderson, who described a method of isolation and provided the formula given above. It remains in the mother liquor after the removal of morphine and eodeine hydrochlorides in Gregory s process, and in Hesse s method of isolating it from this source is obtained as the acid tartrate. This is crystallised from hot water, and the alkaloid regenerated from it is reerystallised from dilute alcohol, from which it separates in leaflets, or from dry alcohol in prisms, m.p. 193°, — 218-6° (EtOH) or — 229-5°... 

GHC13). It is readily soluble in alcohol, chloroform or benzene, less so in ther, and almost insoluble in cold water, but sparingly so in ammonia or me-water. Thebaine behaves as a monoacidic base. The hydrochloride,... 

The three alkaloids concerned, morphine, codeine and thebaine, all behave as tertiary bases. Morphine contains two hydroxyl groups of which one is phenolic and the other a secondary alcohol group. On methylation of the phenolic hydroxyl codeine results. On oxidation, codeine is transformed into codeinone by conversion of the secondary alcohol group into a carbonyl group, and when thebaine is boiled with A-sulphuric acid for a few minutes, it is hydrolysed into codeinone and methyl sulphate, and in other ways thebaine has been shown to contain two methoxyl groups. That the relationship between the three alkaloids is close may be illustrated by the following slightly extended formula —... 

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. 

The three alkaloids all yield characteristic products on treatment with hydrochloric acid. In this way morphine yields ajjomorphine, apparently by loss of water codeine also yields ajjomorphine, accompanied by other products, but thebaine yields, with dilute hydrochloric acid, thebenine, and with strong hydrochloric acid, morphothebaine. These two are respectively secondary and tertiary bases, so that in the formation of thebenine a heterocyclic ring has been opened and a tertiary... 

It follows from the evidence thus obtained that morphine, an consequently codeine and thebaine, must be built up from the comple... 

Thebenine, CjgHjgOgN. This secondary amine, which differs by CHj in empirical composition from thebaine, is formed by the action of hot dilute hydrochloric acid on thebaine or codeinone, but not -codeinone, which does, however, yield triacetylthebenine and ethanolmethylamine... 

Morphothebaine, CigHigOgN. This tertiary base results from th( action of hydrochloric acid on thebaine at 80-90° in closed vessels, or ii a similar manner from codeinone. It forms colourless crystals, whicl become tinted green or blue when kept, m.p. 197° (dec.), [a]p ° — 130 (EtOH). The base furnishes a characteristic acid hydrochloride, Bg. 3HC1 colourless needles, m.p. 254-5°, which is converted by water or alcohol t< the normal hydrochdoride, B. HCl, minute needles, m.p. 256-60°. Th(... 

Mechanisms for the change of thebaine into thebenine have been suggested by Freund and Speyer, i i Gulland and Robinson and Schopf and Borkowsky and for the conversion of thebaine (or codeinone) into morphothebaine by the same authors and in addition by Gulland and Robinson and Wieland and Kotake. f ... 

Among other formulae which must be mentioned are those of Vis, which represents morphine as a benzyh soquinoline, Vongerichten, Bucherer, Gadamer and Klee, devised to account for the possible natural formation in P. orientate of isothebaine from thebaine, and the vinyl formula of Wieland and Kappelmeier. ... 

CjHj) picrate, m.p. 235° methiodide, m.p. 257°. To be distinguished from phenolic dihydrothebaine, m.p. 154° prepared by reduction of thebaine with sodium in alcohol. 

Thebainone methyl enolate. CuHjjOjN. This possible intermediate in the hydrogenation of thebaine to dihydrothebainone-J-5 6-methyl enolate (see above) has m.p. 154-6°, [a] ° -f 9-6° (EtOH). ... 

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