E Codeimethine

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]. 

Isocodeine can be degraded to y-codeimethine, the C-6 epimer of a-oodeimethine [15], and like the latter this undergoes isomerization in hot alcoholic alkali, S-codeimethine, epimeric with the /3-isomer, being formed [16]. -Codeine [xm] can be degraded to e-codeimethine [xiv]... 

Hydrogenation of -codeine in dilute acetic acid [65] or electrolytic reduction [55] affords dihydro- -codeine-B [xxv] obtained together with dihydro-i/r-codeine-C [xxvm] by reduction with sodium and alcohol [66]. These two compounds suffer Hofmann degradation in the usual way giving, respectively, dihydro-e-codeimethine-B [xxvi] [55, 60] and dihydro-e-codoimothine-C [xxix] [00], the latter also being... 

Hydrogenation of i/r-codeine in neutral solution affords tetrahydro-i/r-codeine [xxx] which yields tetrahydro-e-codeimethine-C [xxxi] on degradation, the latter being reducible to hexahydro-e-codeimethine [55, 65]. 

The methyl ethers of [xiv], [xxiv], [xxrx], and [xxxi] have been obtained by degradation of the corresponding (/(-codeine derivatives, [xiv], [xxix], and [xxxi] methyl ethers are reduced to hexahydro-e-codeimethine methyl ether, whilst the ether of [xxiv] is reduced to tetrahydro-e-codeimethine-A methyl ether [67]. 

In the same way that hydrolysis of a-chlorocodide gives isomers of codeine with no trace of codeine (see Chap. VIII) hydrolysis of a-chlorocodeimethine gives a mixture of y-, S-, and e-codeimethines, but no a-codeimethine. If the hydrolysis is carried out above 100° C., an additional product is a dihydrate of the e-isomer in which one molecule of water forms part of the molecular structure this is also formed from e-codeimethine by heating a solution of the acetate, and can be converted back to the normal form by heating above 80° C. in vacuo [72], a-chlorocodeimethine is regenerated by the action of phosphorus penta-chloride on y-codeimethine [63]. 

T(ilmhydro e codeimethine A methyl ol.lK r 98-5 50% EtOH plates + 54 27 EtOH ... 

In the same way that hydrolysis of a-chlorocodide gives a mixture of isomers of codeine but no codeine, so hydrolysis of a-chlorocodeimethine gives a mixture of y-, S-, and e-codeimethines but no a-codeimethine [67], y-Codeimethine also gives a-chlorocodeimethine on treatment with phosphorus pentachloride [68],... 

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]. 

Methyl-4-acetylmorphol [xxvn, R = Ac] is formed when codeine methiodide [29], a-codeimethine [m] [29, 38], a-codeimethine methiodide [7], e-codeimethine [vn, R = H] [19], a-chlorocodeimethine [xxvra] [39], and a-chlorocodeimethine methiodide [39] are heated with acetic anhydride, the basic products of these degradations being /3-dimethylaminoethanol [7, 39] and, in the last two cases, tetramethyl-ethylenediamine (see below) [39]. 

Bromination of e-codeimethine methyl ether [vn, R = Me] affords bromohydroxydihydro-e-codeimethine methyl ether, which on acetolysis gives 3 8-dimethoxy-4-acetoxyphenanthrene [85]. 

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. 

Bromination of a-codeimethine methyl ether in chloroform leads to bromohydroxydihydro-a-codeimethine methyl ether, which affords 3 6-dimethoxy-4-acetoxyphenanthrene on acetolysis [48], and in like manner the e-isomer can be degraded to 3 8-dimethoxy-4-acetoxy-phenanthrene [48]. 

Degradation of a-ethylthiocodide, or of bromocodide in the presence of ethylmercaptan, affords a-ethylthiocodeimethine [xlv], and this is isomerized by heating with sodium ethoxide to the phenolic /3-ethylthiocodide methine, also formed by the action of sodium ethoxide and ethylmercaptan on [xLin], These compounds, and S-ethylthio-codeimethine, which is really related to e- or -codeimethine, are discussed in Chapter XVII [73-74],... 

Desoxycodeine-E [xxx] pan be prepared by the lithium aluminium hydride reduction of codeine [n] p-toluenesulphonyl ester [17-18], Its structure is shown to be [xxx] by hydrogenation of the base to dihydrodesoxycodeine-D [xiii], degradation of the methiodide to desoxy-a-codeimethine [xxix], and isomerization of the latter to desoxy-/3-codeimethine [xxvin], production of cyanonordesoxy codeine-E [xxxi] by the action of cyanogen bromide on the base, and by the facts that desoxycodeine-E is neither a phenol nor an enol ether [17]. Desoxycodeine-E can be demethylated to desoxymorphine-E [62]. 

Though an early attempt to demethylate methylmorphenol failed [17], this can be accomplished quantitatively by hydrobromic acid [9], and presumably could also be effected by hot alcoholic alkali, as mor-phonol itself is obtained on heating the methiodides of a-codeimethine [ill] [18, 21], e-oodoimothine [vn, R = H] [19], and /3-codeimethine... 

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