Codeinone, synthesis

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. 

The isolation of the cDNAs encoding the enzymes involved in diverse isoquinoline alkaloid formation in plants and microorganisms allowed the first metabolic engineering routes to be developed and paved the way for new ways of future production of isoquinoline alkaloids. For instance, transgenic opium poppy plants were created in which codeinone reductase was suppressed by RNAi, resulting in the substitution of morphine synthesis with the non-narcotic precursor reticuline [110]. In a similar approach, RNAi suppression or overexpression of salutaridinol 1-0-acetyltransferase in opium poppy led to accumulation of salutaridine or increase of morphine, codeine and thebaine content [111], suppression of the BBE led to accumulation of berberine in California poppy cells [112],... 

Codeine has also been prepared in 70% overall yield, again without purification of intermediate compounds, from dihydrothebainone (132) by the route (132) — (137) shown in Scheme 4. The initial product of the action of bromine and then alkali on dihydrothebainone is the 1,7-dibromo-derivative of dihydro-codeinone, which can be reduced to dihydrocodeinone (133). This may be converted into 7-bromodihydrocodeinone dimethyl ketal (136), which on treatment with potassium t-butoxide in DMSO at 120 °C is converted exclusively into thebaine, but at 60 °C the product is codeinone dimethyl ketal (137), which can be hydrolysed to codeinone (131).154 The process has obvious value in the possible synthesis of codeine via dihydrothebainone, for which a patent has been filed covering a process that proceeds from the reduced isoquinoline (138) 155 the conversion of A-formylnordihydrothebainone into dihydrothebainone by hydrolysis and reductive methylation and by ketalization, reduction, and hydrolysis has been reported.156... 

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]. 

It was at this time that we, at Reckitt and Colman became interested in the work of Professor Gordon Kirby on Diels-Alder reactions of thebaine with nitroso derivatives with the objective of providing a viable synthesis of 14-aminocodei-none. This would allow access to a wide range of 14-acylamino- and 14-alkyla-mino-codeinones and morphinones which could be improvements on the available derivatives of 14-hydroxycodeinone and oxycodone. 

The first indication that derivatives of 14-aminocodeinone and 14-aminomorphi-none could be accessible came from the reaction of thebaine with nitrosobenzene to yield a cyclic adduct (10a) which yielded 14p-phenylaminodihydrocodeinone (11a) on sequential hydrolysis and reduction (Scheme 1) [5]. Schwab then utilised this chemistry for the synthesis of a small series of 14-phenylaminodihydrocodei-nones and derivatives (11) [6]. Some codeinone derivatives produced by these reactions were evaluated in antinociceptive assays, showing that the (V-methyl derivatives (11a,b) had substantial activity in the writhing assay but only weak... 

Sebastian A, Bidlack JM, Jiang Q, Deecher D, Teitler M, Glick SD, Archer S (1993) 14(3-[(p-Nitrocinnamoyl)amino]morphinones, 14 3-[(p-nitrocmnamoyl)amino]-7,8-dihydromorphi-nones, and their codeinone analogues synthesis and receptor activity. J Med Chem 36 3154-3160... 

Phosphoryl chloride-Pyridine dehydration of alcohols [1, 878-879, at end]. Although thebaine (1) can be considered as the methyl enol ether of codeinone (2), no direct synthesis has been achieved. Rapoport123 has recently carried out a convenient indirect synthesis of (1) from Ae-dihydrothebaine (3). Addition of methyl hypobromite (generated from NBA in methanol) gave (4) in 62% yield, and this... 

Thebaine, which differs from codeine by the addition of methylene groups and the removal of two hydrogen atoms, is neither an analgesic nor an anti-tussive. Instead, it resembles strychnine and brucine in its spinal convulsant properties. It is not used in medicine it has utility, however, in the synthesis of codeinone derivatives, some of which are useful as analgesics. 

This synthesis of morphine is also a synthesis of thebaine (CCCLXXXVI), as the latter has recently been prepared from dihydro-codeinone by Rapoport et al. (424) ... 

Chemical studies on drug metabolism. Part 1. Stereospecific synthesis of codeine 7,8-oxide and codeinone 7,8-oxide... 

At the time of Fukuyama s publication a virtually identical approach was nearing completion in the Hudhcky group. Enone 127 (Scheme 19), analogous to 115, was synthesized in the c t-series in nine steps from diol 49, previously used in the synthesis of c t-codeine, Scheme 8. Cyclization of 127 to dienone 128 leaves only two steps to complete c t-codeinone (ent-116) [70, 71]. 

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... 

Moving forward from 59, six steps were required to convert this compound to 60. Vicinal dihydroxylation of the olefin was followed by oxidative cleavage of the intermediate diol using lead tetraacetate. Reductive amina-tion of the resulting aldehyde with methylamine, followed by acylation of the intermediate secondary amine gave the desired carbamate. Swern oxidation of the secondary alcohol, followed by enol ether formation gave 60. Elimination of -toluenesulfinic acid from 60 provided 61. Oxidation of this dienol ether to dienone 62 was followed by release of the secondary amine, followed by a conjugate addition reaction to establish the critical C-N bond. The remainder of the synthesis followed known chemistry. The mixture of enones 63 was converted to codeinone (35), codeine (3) and then morphine (1). 

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