Codeine Hofmann degradation

Sargent and Joshi(385) have transformed dihydrocodeinone, via a Hofmann degradation product, to the dihydromorphinone position isomer 225. It had an MHP (sc) ED50 of 24.6 mg/kg, about one third codeine. 

Alkaline degradation of codeine methiodide affords a-codeimethine [xxi] [185, 285], which can be isomerized by alcoholic alkali to /3-codeimethine [xxn] [187, 286-7], also obtainable by the degradation of neopine [xm] methiodide [271]. The degradation of codeine ethiodide follows a similar course [288]. These bases suffer dehydration and loss of the basic side-chain when heated with acetic anhydride and sodium acetate (when acetylmethylmorphol [xxm] is formed [187, 289-90]), and when subjected to further Hofmann degradation (which leads to methylmorphenol [xxiv] [290-2]). The resulting aromatic phenan-threne derivatives are of considerable importance in the elucidation of the basic structure of the morphine alkaloids and are discussed in detail in Chapter XXVII. 

Hofmann degradation of codeine sulphonic acid methiodide [xliv] affords tetramethylethylenediamin and a substance C16H11S06K, possibly [xlv] [339, 350], whilst degradation of /3-dihydrocodeine sulphonic acid methohydroxide affords tetramethylethylenediamine, but the nitrogen-free product was not isolated [341]. 

Hofmann degradation of isocodeine follows the same course as the degradation of codeine, giving in the first step y-codeimethine the C-6 epimer of [xxi], which can be isomerized to S-codeimethine, the C-6 epimer of [xxn], and in the second step methylmorphenol [xxrv] [252, 410] (see Chap. VI). Dihydroisocodeine can be degraded to a methine base and a nitrogen-free substance [295]. 

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. 

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... 

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

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