Codeine methyl ether

Singer and Scammells have investigated the y-Mn02 oxidation of codeine methyl ether (CME) to thebaine in the ionic liquid [BMIM][BF4] [63]. The ionic liquid was used in different ways and with mixed results (Scheme 5.1-35). For example, the oxidation of CME in the ionic liquid gave 38 % yield after 120 hours. A similar reaction under biphasic conditions (with diethyl ether) gave a 36 % yield of thebaine. This reaction gave a 25 % yield of thebaine when carried out in tetrahydrofuran... 

Finally, it should be mentioned that ionic liquids have successfully been used in classical, stoichiometric oxidation reactions as well. Singer et al., for example, described the application of [BMIM][Bp4] in the oxidation of codeine methyl ether to thebaine [64]. The ionic liquid was used here as a very convenient solvent to extract excess Mn02 and associated impurities from the reaction mixture. 

W. R. Agyangar, S. R. Bhide, and U. R. Kalhote, Assay of semisynthetic codeine base with simultaneous determination of codei-methine and 06-codeine methyl ether as by-product impurities by HPLC, J. Chromatogr., 579 250 (1990). 

Codeine methyl ether affords a-codeimethine methyl ether on Hofmann [262-3] or Emde [294] degradation. 

Codeine [i] on heating in alcohol with [319-23] or without [324] acid, with [319-21] or without [322-4] hydrogen, in the presence of noble metal catalysts, undergoes rearrangement to dihydrocodeinone [xiv]. The yields claimed for the transformation are up to 95 per cent. [323], but Rapoport [304] was unable to obtain yields in excess of 50 per cent. Thebadnone-A [xxxvn] is a by-product in this reaction, and can be made the main product by modifying the conditions [325] (cf. the conversion of codeine methyl ether to thebainone-A enol methyl ether by sodium ethoxide). 

Codeine is unaffected by Grignard reagents [374], but codeine methyl ether forms simple addition complexes with ethyl- and phenyl-magnesium halides these are readily decomposed with liberation of the unchanged base [375]. 

When the chlorine of a-chlorocodide [lxix, R = Cl] is replaced by groups other than hydroxyl, the new substituent appears at C-8 (see Chap. VIII) and ethers of -codeine can be prepared by heating a-chlorocodide with alcohols or with the sodium salts of.phenols [353, 403, 418-20]. -codeine methyl ether methiodide can also be prepared by direct methylation of -codeine [411]. 

Catalytic reduction of i/i-codeine methyl ether [lxxxi] hydrochloride in acetic acid over platinum oxide gives 77 per cent, dihydro-i/j-codeine-A methyl ether and 16 per cent, tetrahydro- -codeine methyl ether Hodium and alcohol reduction affords almost 100 per cent, dihydro-i/r-o(idoine-C methyl ether, and only traces of dihydrodesoxycodeines [426]. IwtiHS of the group at C-8 is also observed during the sodium and alcohol reduction of 8-othylthiocodido [lxxxii] [427] (see Chap. XVII). 

Alkaline degradation of -codeine methiodide affords e-codeimethine [lxxxih], which resists isomerization [415, 428-9], and this on further degradation gives morphenol and acetylmethylmorphenol [428] (see Chap. VIII). Methine bases have also been prepared from i/r-codeine methyl ether [411, 419], dihydro-i/j-codeine-A [421] and its methyl ether [426], dihydro-i/j-codeine-B [421, 423], dihydro-i/f-codeine-C [295, 423] and its methyl ether [426], tetrahydro- -codeine [295] and its methyl ether [426]. 

Codeine methyl ether 140-141 MeOH prisms -194 22 EtOH 263... 

Totrahydro-0-codeine methyl ether 125-130 60% plates -5 30 EtOH ... 

The codeimethines can be esterified [5, 32-34, 14, 16-17, 20, 35-37] and methylated. Methylation can be accomplished by methyl sulphate or methyl iodide and cold 1 N. alkali, when quaternary salts of the methyl ethers are obtained [38-39]. The methyl ethers, however, are best prepared by degradation of the corresponding codeine methyl ethers. In this way a- [39-40], y- [41], and e- [41-42] codeimethine methyl ethers have been prepared, and the first two named can be converted to the /3- and 8-isomers respectively on heating with alcoholic alkali [39, 41]. Emde degradation of codeine methyl ether metho-chloride affords exclusively a-codeimethine methyl ether [43]. Hofmann degradation of the methiodides of /3- [38] and e- [42] codeimethine methyl ethers affords methylmorphenol [xvi, R = Me], ethylene, trimethylamine, and methanol. 

When thebaine [i] is reduced by sodium and boiling alcohol [1-3], or best by sodium in liquid ammonia [4-5], scission of the 4 5-oxygen bridge occurs with the addition of two atoms of hydrogen and production of a phenolic dihydrothebaine, for which the name dihydrothe-baine-< has now been adopted [5]. The sodium-ammonia reduction is rapid, simple, and results in excellent yields of product. Reduction of thebaine with lithium aluminium hydride also yields a phenolic base, /3-dihydrothebaine, which is isomeric with dihydrothebaine- [6], Dihydrothebaine- was first allotted the structure [n] on the basis of its reactions [3], and 3-dihydrothebaine the structure [m] with the abnormal configuration at C-14 on the basis of its hydrolysis to ]S-thebainone-A [iv] [6] thebainone-A enol methyl ether [m] with the normal configuration at C-14, which results from the isomerization of codeine methyl ether [v] under the influence of hot sodium ethoxide, is known to give thebainone-A [rv, C-14 epimer] on hydrolysis [3]. 

Thebainone-A can also be prepared by the catalytic rearrangement of codeine [vi] under the influence of palladized charcoal at 80° C. [2] by the hydrolysis of thebainone-A enol methyl ether [vn] (prepared by the rearrangement of codeine methyl ether on heating with sodium ethoxide) [3] by the hydrolysis of /j-ethylthiocodide [vm] (obtained by the action of sodium ethoxide on bromo- or /3-chlorocodide) [4-8] (see Chap. XVII) and, in small amount, by the hydrolysis of dihydrothe-baine- [iv] [3]. 

Methyldihydro-0-codeine methyl ether. 182-5-183 MeOH EtOAc + 121-0 23 EtOH 8... 

Methylmorphenol is also obtained as the final product of exhaustive methylation of codeine ethiodide [10], y-codeimethine (the C-6 epimer of [m]) [11] and e-codeimethine methyl ether [vn, R = CH3] (obtained by the degradation of (/(-codeine methyl ether [vi, R = CH3]) [12-13] the other substances produced during the degradation of [vn, R = CH3] are trimethylamine, ethylene, and methyl alcohol [12], 1-Bromomethyl-morphenol [vin] arises in like manner by the degradation of 1-bromo-codeine [10, 14-16] and ethylmorphenol from morphine-3-ethyl ether [17]. 

Codeine methyl ether (52) could be converted into thebaine by the known one-step procedure (Mn02 oxidation) reported by Rapoport (Scheme 12) [49]. On the... 

Scheme 11 Synthesis of codeine methyl ether by the Stork group...

Scheme 12 Conversion of codeine methyl ether to thebaine and codeine...

It has been proposed that the dihydrothebaine formed hy sodium reduction of thebaine (so-called phenolic dihydrothebaine) be renamed dihydrothebaine-

trivial name for an older one does not appear legitimate once a structure is established beyond doubt. We would prefer the term A < >-dehydrothebainol methyl ether for the sodium-ethanol or sodium-ammonia reduction product (CCCLIV), The lithium aluminum hydride reduction product would then be A h4).(jeijy(ji.o< hel3ajnol methyl ether (CCCLV), and the third isomer, obtained by base-catalyzed rearrangement of codeine methyl ether, would be A -dehydrothebainol methyl ether (CCCLVI). 

Simultaneous a-codeimethine, 0 -codeine methyl ether, meconic acid, morphine... 

Ayyangar, N.R. Bhide, S.R. Kalkote, U.R. Assay of semi-synthetic codeine beise with simultaneous determination of alpha-codeimethine and 06-codeine methyl ether as by-product impurities by high-performance liquid chromatography. J.Chromatogr., 1990, 519, 250-255... 

Both codeinone (74) and codeine methyl ether (77) are incorporated into morphine, suggesting the possibility of two paths for the conversion of thebaine into codeine. The recent experiments have confirmed the previous findings... 

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