Codeine dihydro

HMe,codeine,dihydro- Various analgesics, Determination in Corasil C18 1220x2.3... 

One of the more benign ancillary activities of morphine lies in its activity in suppressing the cough reflex. Catalytic reduction of codeine (1-2) leads to the dihydro derivative (4-1). Oppenauer oxidation of the hydroxyl group leads to hydrocodone (4-2) [3], a compound used extensively in cough remedies it is of note, however, that this drug retains considerable opioid activity. 

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... 

Dihydro codeine 26 8 13 blue ite — One at Rf 16 dug and metabolite have elongated pots... 

Catalytic reduction of the base in dilute acetic acid with palladised barium sulphate as catalyst yields tetrahydro-y-isomorphine [C-8 opimer of xxxix] (also available by the demethylation of tetrahydro- -codeine), but no tetrahydrodesoxymorphine [xl], whilst hydrogenation of the hydrochloride in glacial acetic acid with a platinum oxide catalyst affords 50 per cent, tetrahydro-y-isomorphine and 50 per cent, dihydro-y-isomorphine [C-8 epimer of xli], which is best prepared by the demethylation of dihydro-i/i-codeine-A [616]. The catalytic reduction of i/ccodeine follows a similar pattern [617] (see Chap. IV). 

Dihydro-y-lsomorphine-3-methyl ether see dihydro-0-codeine-A (Chap. IV). ... 

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). 

Dihydro-electrolytic reduction of desoxycodeine-C [xv] to dihydro-desoxycodeine-B [lxxiv], and dihydro-i/r-codeine-C the structure [lxxhi] by analogy with the sodium and alcohol reduction of desoxycodeine-C to dihydrodesoxycodeine-C [lxxv] sodium and alcohol reductions have a known tendency to effect 1 4 addition of hydrogen to an allylic ether [248, 281, 423]. (Cf. the reduction of thebaine [lxxvii] to dihydrothebaine-< [lxxvih] [265, 405, 424].)... 

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). 

Unlike dihydrocodeine and dihydroallo-i/r-codeine-A (q.v.) but like dihydroisocodeine, dihydro->p - codeine-A is resistant to Oppenauer oxidation from which only unchanged alcohol can be recovered [304]. 

Replacement of Hydroxyl When (/(-Codeine is treated with phosphorus pentachloride or thionyl chloride allylic rearrangement occurs and a-chlorocodide is formed [238, 428], /3-Chlorocodide results when -codeine is heated under pressure with concentrated hydrochloric acid, but this doubtless arises by rearrangement of the a-isomer first formed [243], Bromocodide is produced by the interaction of (/(-codeine and phosphorus tribromide [428]. With phosphorus pentachloride dihydro- -codeine-A gives 8-chlorodihydrocodide, with thionyl chloride chlorination only occurs in the aromatic nucleus, and with phosphorus tribromide a poor yield of 8-bromodihydrocodide is obtained [240]. Tetrahydro- r-codeine gives tetrahydro-i/j-cblorocodide with phosphorus pentachloride [295]. 

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]. 

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). 

Dihydro-0-codeine-A methyl ether. 127 EtOH + EjO plates + 35 25 EtOH 426... 

Degradation of dihydro- -codeine-A [xxm] yields dihydro-e-codei-methine-A [xxrv], which can be reduced only to tetrahydro-e-codei-methine-A [xxn]. 

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... 

In general the double bond seems to be less reactive in neopine than in codeine, e.g. reduction proceeds less readily [3] and oxidation to a dihydroxy dihydro-compound cannot be effected with permanganate [fi]. Noopino is recovered unchanged from attempts to oxidize it to a kototio with chromic aoid [5]. 

R = OMe] and on reduction with sodium and alcohol yields dihydro- r-codeine-C methyl ether [xxxix, R = OMe] [53]. Such ethers are readily formed by heating a-chlorocodide with alcohols [52, 54] or with the sodium salts of phenols in alcohol [49, 51]. a-Chloromorphide gives y-isomorphine-8-ethers under similar conditions [55]. 

This base is formed together with a small quantity of 1 8-dichloro-dihydrocodide by the action of phosphorus pentachloride on dihydro-i/r-codeine-A [xlih] and its epimer dihydroallo- -codeine-A. It is an exceptionally stable substance, being unaffected by electrolytic or socjium and alcohol reduction heating with sodium methoxide under pressure simply causes demethylation to 8-chlorodihydromorphide [19], but prolonged boiling with sodium in cycZohexanol causes loss of hydro-genchloride and production of desoxycodeine-D [lh, R = Me] and a small amount of the demethylated substance, desoxymorphino-D [lii, R = H] [19, 80]. 

A base m.p. 130-132° C. obtained by the hydrogenation of dihydro-desoxycodeine-C, when pure has m.p. 144-145° C. and is in fact (/3-) tetrahydrodesoxycodeine [28]. Speyer and Krauss [35] also claimed to have prepared a-tetrahydrodesoxycodeine by the reduction of allo-i/r-chlorocodide, later shown to be /3-chlorocodide [36], but reinvestigation of the reduction revealed the production of only dihydrodesoxycodeine-D and (/3-) tetrahydrodesoxycodeine [21]. The desoxytetrahydro-iji-codeine obtained by the catalytic reduction of tetrahydro-i/<-chlorocodide and stated to be identical with a-tetrahydrodesoxycodeine [35] is too inadequately described to admit identification. 

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