Codeine catalytic rearrangement

Hydromorphone [466-99-9] (31) and hydrocodone [125-29-1] (32) are isomers of morphine and codeine, respectively. Hydromorphone can be prepared by catalytic rearrangement of morphine (49) or by oxidation of the aliphatic hydroxyl group of dihydromorphine (50). Hydrocodone can be similarly prepared. As an antitussive, hydromorphone is several times more active than morphine and hydrocodone is slightly more active than codeine. Hydromorphone has a much higher addiction potential than hydrocodone. 

Dihydrocodeinone and dihydromorphinone can be prepared by the catalytic rearrangement of codeine [i] and morphine respectively on heating solutions of the base in alcohol, with [48-52] or without [53] acid, with [48-50] or without [51-53] hydrogen, in the presence of noble metal catalysts. The yields reported by Knoll and Co. for this method are up to 95 per cent. [52], but Rapoport claims that the maximum is about 50 per cent. [47]. As a by-product in this rearrangement phenolic bases were noted and these may be made the principal products by modifying the conditions. In this way thebainone-A [xix] can be prepared from codeine, and its analogue, O-desmethylthebainone-A, from morphine in 60 per cent, yield [54] (see Chap. XV). 

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]. 

Hydrocodone, 4,5-Epoxy-3-methoxy- 17-methvt-morphinan-6-one dihydrocodeinone Bekadid Dicodid. C,H31NOj mol wt 299.36. C 72.21%, H 7-07%, N 4.68%, O [6,03%. Prepn by hydrogenation of codeinone Mannich, Lowenheim, Arch. Pharm. 258, 295 (1920) by oxidation of dihydrocodeine, Ger. pat. 415,097 (1925 to E. Merck), Frdl. 15, 1518 (1925-1927) by catalytic rearrangement of codeine Ger. pet. 623,821. Industrial prepn from dihydrocodeine Pfister. Tishler, U.S. pal, 2,715,626 (1955 to Merck Co-)-Toxicity data Eddy, Reid, J. Pharmacol. Exp. Ther. 52,468 (1934). Review Small. Lutz. "Chemistry of the Opium Alkaloids, Suppl. No. 103, Public Health Reports, Washington (1932). 

Catalytic reduction of codeine (2) affords the analgesic dihydrocodeine (7) Oxidation of the alcohol at 6 by means of the Oppenauer reaction gives hydrocodone (9)an agent once used extensively as an antitussive. It is of note that treatment of codeine under strongly acidic conditions similarly affords hydrocodone by a very unusual rearrangement of an allyl alcohol to the corresponding enol, followed by ketonization. 

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