Codeine from codeinone

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... 

Jacobson and others(390) analyzed the H-nmr spectra at 100 MHz of codeine and isocodeine derivatives, previously reported at 60 MHz,(391) in order to establish the conformation of the spiro-oxirane derived from codeinone.<200) Double irradiation and NOE experiments confirmed the structure illustrated (91). 

The position attributed to the oxygen was based on the conviction that a carbonyl oxygen (in codeinone and pseudocodeinone) would not migrate. Hence Pschorr s syntheses of 3 4 6-trimethoxyphenan-throno, obtainable from codeinone, and 3 4 8-trimethoxyphenanthrene, obtainable from pseudocodeinone, fixed the positions of the carbonyl group of the ketones, and therefore those of the sec-alcoholic groups of codeine and pseudocodeine also. 

A further patent for the production of codeine, via codeinone, from thebaine has been published. " Codeine has been shown to be oxidized by manganese dioxide to 14-hydroxycodeinone the reaction is presumed to proceed via codeinone since 6-acetylcodeine is not affected by the same reagent. 6-O-Methanesulphonyl-dihydrocodeine has been shown to react with tetra-butylammonium fluoride, lithium chloride, and lithium bromide, with inversion at C-6, to give the related 6-halogeno-dihydrocodides, but when the ester is heated with sodium iodide in dimethylformamide the product is A -deoxycodeine (deoxycodeine-C) (143). Reductive amination of naltrexone with 2,2 -dihy-droxydiethylamine and sodium cyanoborohydride yields the 6-amino-compound (144 R = OH), which can be converted by carbon tetrachloride and tri-... 

Codeinone, CjaHijOgN. This ketone (XLVII) corresponds to the secondary alcohol codeine and its stereoisomeride wocodeine. It may be prepared by oxidising codeine with potassium permanganate in acetone or with potassium dichromate in dilute sulphuric acid and in various other ways. Codeinone can be reduced to codeine electrolytically or by chemical methods. It crystallises from alcohol in prisms, m.p. 185-6, [a]J, ° — 205° (EtOH). The hydrochloride, B. HCl. HjO, has m.p. 179-80°, picrate, m.p. 205°, methiodide, B. CHjI. 2H2O, m.p. 180°. 

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... 

The acetylation of morphine and of codeine by aspirin202 and the enzymatic hydrolysis of heroin203 and the reduction of codeinone204 have been studied. Dihydronorcodeine and dihydromorphine have been isolated from urine as metabolites of dihydrocodeine.205 Patents have been published covering the preparation of -(cyclopropylmethyOnormorphine,206 the conversion of thebaine into codeinone,207 and the preparation of nalorphine 6-sulphate.208 Salts of codeine and ethylmorphine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one have been prepared.209 The circular dichroism210,211 and fluorescence characteristics212 of morphine and related bases have been studied. 

Morphine and related alkaloids are specific to the genus Papaver (Berberidaceae), although the antipodal series of alkaloids is distributed in the Menisperma-ceae. Early in the biosynthesis of morphine, an inversion at C-1 of (5)-reticuline occurs, followed by ortho-para benzylic coupling to afford salutaridine. Stereospecific reduction and cyclization-elimination affords the 4,5-Ether bridge and thebaine. The dominant pathway from this point involves neopinone, codeinone, codeine, and morphine. Again, most of the enzymes in this sequence were isolated and characterized by Zenk s group (Fig. 30). 

There are two possible biosynthetic pathways for the conversion of thebaine to morphine, Fig. (67) [148]. One is orthodoxically known in the litreatures [4, 130, 131], that is morphine biosynthesis from thebaine via codeinone and codeine. Another one i.e. the first ever demonstrated by Brochmann-Hanssen in 1984 [149], is the biosynthesis via oripavine and morphinone. The transformed clone could synthesize codeine but lacked morphine though the non-transformed clone obtained from the same plant material accumulated morphine at the latter developmental stage (Table 21). This suppressed morphine content was also observed in the opium derived from the transformed P. somniferum plants that had been... 

This base, which has also been called neoisomorphine, can be prepared like a- and /3-isomorphines by the hydrolysis of a-chlorocodide [453-4, 463, 611] and of bromomorphide [454], It differs from /S-isomorphine only in the arrangement of the alcoholic group, as is shown by its methylation to (/(-codeine [453-4, 463, 611], which on oxidation gives the same -codeinone as does allo- -codeine [464, 611, 615]. 

Catalytic hydrogenation of codeine proceeds rapidly with saturation of the 7 8 double bond and formation of dihydrocodeine [m, R = OH] [267-9], also obtainable by the electrolytic reduction of codeine [270], the catalytic reduction of neopine [xm] [271], the methylation of dihydromorphine [272], and the catalytic reduction of dihydro-codeinone [xiv] [273]. By the latter method the optical antipode of dihydrocodeine may be prepared from the sinomenine series [274-5] (see Chap. XXVII). Both enantiomorphs can be demethylated to the corresponding dihydromorphines [269, 274-5]. Dihydrocodeine methyl ether is identical with tetrahydrothebaine [276-8] (see Chap. XIII). 

That isocodeine differs from codeine only in the spatial arrangement of the —CH OH— group was shown by the oxidation of both bases to the same ketone, codeinone [xxvn] [305],... 

Allo- r-codeine is the third product of hydrolysis of a-chlorocodide [244-5, 250], /3-chlorocodide [238, 243, 250], bromocodide [243-4, 251, 253, 407], and iodocodide [247], It differs from -codeine only in the spatial arrangement of the —CH-OH— group, as is shown by the production of i/i-codeinone when it is oxidized [305, 407, 416]. It is related to /3-isomorphine, from which it can be prepared by methylation [ 245, 253]. Though it is formed by the hydrolysis of a-chlorocodide it yields /3-chlorocodide exclusively when treated with phosphorus penta-chloride [238, 305]. 

Dihydro-i/< -codeinone is obtained in 40 per cent, yield by the Oppenauer oxidation of dihydroallo-with phosphorus pentachloride gives 8-chloro- and 1 8-dichlorodihydrocodide, which are also produced in the same way from dihydro-i/ -codeine-A thionyl chloride effects chlorination in the aromatic nucleus only. With phosphorus tribromide it apparently suffers replacement of the hydroxyl group by bromine, loss of hydrogen bromide, and demethylation, as the product is desoxymorphine-D [240] (see Chap. VIII). 

Hydrogenation in neutral or weakly acid solution with a palladium catalyst affords tetrahydro-i/r-codeinone [xxix] [7, 28] which is further reduced by sodium and alcohol to tetrahydro-i/r-codeine [xxx], the latter being obtained directly from i/r-codeinone by sodium and alcohol reduction. In no case do derivatives of allo-[Pg.171]

Codeinone [A] has now been shown to result in 30-40 per cent, yield from the Oppenauer oxidation of codeine -codeinone cannot be prepared in the same way from r-codeine. 

Thebaine [v] is an enol ether and though fairly stable in cold dilute acid is hydrolysed to codeinone [vi] on standing with N. sulphuric acid for several weeks in the cold or six to seven minutes at 100° C. [75], and codeinone can also be isolated from the orange-red solution of thebaine in concentrated hydrochloric acid [76], In this way the relationship of the alkaloid to codeine and morphine was established. The yield of codeinone is very poor (< 7 per cent.), doubtless as a result of the ease with which thebaine undergoes rearrangement in acid solution. 

Methoxy-4 8-diacetoxyphenanthrene [Lxxxm]. /3-Dimethyl-aminoethanol and [Lxxxm] are formed when i/r-codeinone [lxxxiv] is heated with acetic anhydride, but the main product of this reaction is triacetylthebenine [lxxxv, R = Ac] [89]. i/r-Codeinone methiodide and ethanol at 160° C. give 3-methoxy-4 8-dihydroxyphenanthrene [89-90], which on methylation affords 3 4 8-trimethoxyphenanthrene [90], identical with an authentic specimen prepared in the usual way from 2-nitroveratric aldehyde and 2-methoxyphenylacetic acid [67]. In this way the location of the hydroxyl group in i/r-codeine and allo- -codeine, at C-8, was proved. 

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