Of codeinone

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. ... 

Gates, M. (1953) The Conversion of Codeinone to Codeine. Journal of the American Chemical Society, 75, 4340 341. 

With a morphine biosynthetic gene in hand, we believed we could begin to address the question why only P. somniferum produces morphine, while other Papaver species such as P. rhoeas, P. orientale, and P. bracteatum do not. Unexpectedly, we found that the codeinone reductase transcript was present to some degree in all four species investigated. A review of the literature revealed no alkaloids reported in P. rhoeas for which codeinone reductase should participate in the synthesis. Similarly, P. orientale accumulates the alternate morphine biosynthetic precursor oripavine, but codeinone reductase is not involved in the biosynthesis of oripavine, acting instead after this alkaloid along the biosynthetic pathway to morphine.22 P. bracteatum produces the morphine precursor thebaine as a major alkaloid. As for oripavine in P. orientale, codeinone reductase would act in P. bracteatum after thebaine formation on the pathway to morphine. It appears, therefore, that the reason that P. rhoeas, P. orientale, and P. bracteatum do not produce morphine is not related to the absence of the transcript of the morphine biosynthesis-specific gene codeinone reductase. The expression of codeinone reductase may simply be an evolutionary remnant in these species. 

LENZ, R., ZENK, M.H., Purification and properties of codeinone reductase (NADPH) from Papaver somniferum cell cultures and differentiated plants, Eur. J. Biochem., 1995, 233, 132-139. 

UNTERLINNER, B LENZ, R KUTCHAN, T.M., Molecular cloning and functional heterologous expression of codeinone reductase The penultimate enzyme in morphine biosynthesis in the opium poppy Papaver somniferum, Plant J., 1999,18,465-475. 

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

Scheme 30. Biotransformation of codeinone and morphine by immobilized P. somniferum cells and peroxidases.

Hydrocodone Hydrocodone, 4,5-epoxy-3-methoxy-Af-methyl-6-oxomorphinane (3.1.27), is a compound that is chemically related to morphine and codeine. Hydrocodone is synthesized by the isomerization of codeine (3.1.20) using a palladium or platinum catalyst [18]. This drug has also been suggested to be synthesized by the hydration of codeinone [19] and by oxidation of dihydrocodeine [20]. 

Preparation of 14-hydroxycodeinone from denolsilyl ether of codeinone ... 

Peracetic acid solution (107.7 g of 9.0 wt % peracetic acid) at ambient temperature was added to a reaction flask equipped with mechanical stirrer and thermocouple, nitrogen inlet adapter and addition funnel. A 20 wt % stock solution of the dienolsilyl ether of codeinone (41.7 g) was added through the addition funnel over a period of about 5 min and the temperature of the contents maintained at 28°C. The batch was stirred at 22°C for at least 3 hours. In order to test reaction completeness, a small sample was withdrawn from the batch and quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The EtOAc layer was spotted onto a TLC plate and subsequently checked for the disappearance of starting dienolsilyl ether of codeinone. The TLC mobile phase was a mixture of 95 5 of dichloromethane and methanol plus 3-5 drops of concentrated ammonium hydroxide. If the reaction was adjudged incomplete, the mixture was stirred at the same temperature for an additional 2 hours then analyzed by TLC again. Alternatively completion of the reaction was pushed by the addition of 10 g of peracetic acid (9.0 wt %) and stirring for an additional 1 h (analysis was then once more performed using TLC). 

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... 

Table 3 Changes in polyamine levels during cell death induced by 3 hours of codeinone treatment...

C-ring contracted 4,5-epoxymorphinans (252) have been reported(379) during studies on the photolysis of codeinone analogs.<220,221) A 7-membered C-ring lactam (2a, Chap. 4) was isolated as a product of the Schmidt rearrangement of dihydrocodeinone.<380) In neither report were biological data presented. 

Oxidation of codeinone. Codeinone (1) and codeine are oxidized by peracids quantitatively to the N-oxide. However, codeinone can be oxidized in part to the 7,8-oxide (2) by H2O2 (3%) in the presence of NaOH at 0°. The product can be reduced to the 7,8-oxide of codeine (3), which may be a metabolite of codeine. 

Table 7.9 Sequence alignment (amino acids) of codeinone (CR) of selected taxa from plants, fungi and bacteria. Conserved sites are marked by x ...

Lenz R, Zenk MH. Stereoselective reduction of codeinone, the penultimate enzymic step during morphine biosynthesis in Papaver somniferum Tetrahedron Lett. 1995 36 2449-2452. UnterUnner B, Lenz R, Kutchan TM. Molecular cloning and functional expression of codeinone reductase. Plant J. 1999 18 465-475. 

In all the above-mentioned cases, the active component itself had to be determined. However, polarography often serves to determine toxic decomposition products or reaction intermediates in pharmaceutical synthesis. Besides the presence of codeinone in dihydrocodeinone [189], one can detect the presence and amount of toxic ketones in chloramphenicol [221] or of papaveraldine in papaverine [222]. 

Oxides of copper and silver are used to oxidize secondary alcohols in the vapor phase at 250-300 °C [349] or in the liquid phase at room temperature [380], respectively. A similar effect is achieved with lead tetraacetate in pyridine at room temperature. Benzhydrol is thus converted into benzophenone in 80% yield [442], The oxidation of codeine with silver carbonate requires 1 h of refluxing in benzene to give a 75% yield of codeinone [376],... 

Dihydrodesoxycodeine-D [xm], the only non-phenolic dihydro-desoxycodeine, can be prepared by the catalytic hydrogenation of a-chlorocodide [rv] [29], /3-chlorocodide [v, It = Cl] [7, 29], bromocodide [v, R = Br] [29], and desoxycodeine-C [ix] hydrochloride [6], It has also been reported to be formed by catalytic reduction of codeinone oxime [xlii] hydrochloride [30]. Dihydrodesoxycodeine-D methine [xlhi] results from Hofmann degradation of the methiodide [7], and a substance that is presumably the dihydromethine [xliv] is obtained by catalytic reduction of a-chlorocodeimethine [xlv] [26]. 

The production of a 3 4 6-trihydroxyphenanthrene derivative by the acotolysis of codeinone clearly indicates the position of the three oxygen atoms in this ketone [5]. A similar degradation takes place when codeinone methiodide is heated with alcohol at 160° C., 3-methoxy-4 6-dihydroxyphenanthrene and /3-dimethylaminoethyl ethyl ether boing the products [22]. 

Catalytic hydrogenation of codeinone using palladium [13] or Raney nickel [3] as catalyst affords dihydrocodeinone [vm], identical with the product prepared in other ways (see below). 

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