0-Codeimethine 6-methyl

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

Isocodeine methyl ether, prepared from the methyl ether methiodide [411] or by methylating isocodeine-N-oxide and reducing the product [265], cannot be isomerized to thebainone methyl enolate by heating with sodium ethoxide [265]. On degradation it yields y-codeimethine methyl ether [411]. 

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]. 

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]. 

Acetyl-i3-codcimethine. — methiodide rormyl-0-codcimethine. 0-codeimethine methyl ether 82... 

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]. 

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]. 

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]. 

The quaternary salts of codeine and its isomers can be degraded to unsaturated bases to which the general term methylmorphimethine has hitherto been applied, but here the less cumbersome and more systematic term codeimethine [1] will be used, the term methylmorphimethine being reserved for the derivatives obtained from nuclear methylated morphines. The term dihydromethine will be applied to bases in which the double bond introduced by degradation has been saturated. In this way a convenient and unambiguous system of nomenclature is available. 

When codeinone [xxxv] is treated with lithium methyl a nearly quantitative yield of one isomer of 6-methylcodeine [xxxvi] is obtained, and this can be degraded to 6-methyl-a-codeimethine [xxxvn], which can be isomerized to 6-methyl-/3-codeimothine [xxxvm]. Dry distillation of the methohydroxide of [xxxvn] affords 6-methylmorphenol methyl ether [xxxix] [69]. 

Vongerichten reported the isolation, as a by-product in the preparation of 3 4-diacetoxyphenanthrene by heating diacetyl-morphine with silver acetate and acetic anhydride at 180° C., of a /3-morphi-methine that could be methylated to /3-codeimethine methiodide [88], Repetition of this work revealed the product to be a monoacetylated /3-morphimethine that can be methylated and hydrolysed to /3-codeimethine, and reduced to [lxxi, R = Ac] [51]. 

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

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]. 

The hydrolysis of 3-methyl-4-acetylmorphol yields 3-methylmorphol [xxix, R = H] [29], which also results from heating codeine methiodide [41] and a-codeimethine [41] with sodium ethoxide at 160° C., and a-chlorocodeimethine with ether and ethyl alcohol at 100° C. [42], the basic products being /3-dimethylaminoethyl ethyl ether [41] and tetra-methylethylenediamine [42],... 

Codeine dihydromethine [xn] has now been prepared by the sodium-ammonia reduction of codeine methiodide, together with dihydrodesoxy-codeine-C dihydromethine [xiii]. Both [xii] and [xni] result from the sodium and liquid ammonia reduction of a-codeimethine [xiv] [2] (cf. p. 106). The sodium and liquid ammonia reduction of dihydrocodeine methiodide affords a-tetrahydrocodeimethine, and the reduction of /3-codeimethine [xv] yields neopine dihydromethine [xvi]. When the methiodide of the latter is heated with sodium cyciohexyloxide in cyciohexanol a mixture of methyl-morphenol [xvn] and (-f-)-6-hydroxy-3-methoxy-5 6 7 8 9 10-hexahydro-phenanthrylene-4 5-oxide [xviii] is obtained. The latter structure is assigned to the product on account of the close resemblance of its ultra-violet absorption spectrum to that of a-codeimethine. This represents a new type of degradation with hydrolytic scission of the side-chain [2]. Metathebainone methine has also been degraded in this way [2]. 

Assay of semisynthetic codeine base with simultaneous determination of. alpha.-codeimethine and 06-codeine methyl ether as by-product impurities by high-performance liquid chromatography Ayyangar, N. R. Bhide, S. R. Kalkote, U. R. 

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

---