Hydrocodone and hydromorphone are widely used semisynthetic narcotic analgesics possessing also useful antitussive properties. Hydrocodone is also an important intermediate for the synthesis of other opioid analgesics, e.g. dihydrocodeine.
Hydrocodone has been prepared by reduction of codeinone (Arch. Pharm (1920), 258, 295; J. Am Chem. Soc (1950), 72, 3247, U.S. Pat. No. 5,571,685) or thebaine (DE Pat. No. 441,613). However, since codeinone is obtained by oxidation of codeine in low to moderate yields, and thebaine is a relatively scarce alkaloid, these methods have little practical value.
A number of methods describe convenient one-pot isomerization of codeine to hydrocodone and morphine to hydromorphone in the presence of noble metal catalysts (examples may be found in “The Chemistry of the Morphine Alkaloids” by Bentley, K. W.; U.S. Pat. No. 2,544,291; U.S. Pat. No. 5,847,142, WO Pat. No. 0134608). Unfortunately these processes require large amounts of expensive metals of the platinum group, or call for exotic organometallic catalysts. Also isomerization is complicated by uncontrollable side reactions, requiring introduction of laborious purification procedures, and resulting in substantial yield loss.
Hydrocodone and hydromorphone have been prepared by Oppenauer oxidation of dihydrocodeine or dihydromorphine correspondingly (U.S. Pat. No. 2,649,454; U.S. Pat. No. 2,654,756; Synth. Commun. (2000), 30, 3195). The starting materials for the oxidation, dihydrocodeine or dihydromorphine, may be synthesized by hydrogenation of morphine or codeine. Hydrogenation is typically performed in solvents, such as aqueous acetic acid (J. Org. Chem. (1950), 15, 1105), ethyl acetate (Synth. Commun. (2000), 30, 3195), or ethanol (Ann. (1923), 433, 269), that are not compatible with the reaction media for Oppenauer oxidation. This makes necessary solvent removal and isolation of the products of hydrogenation, and, compared to the convenient one-pot syntheses discussed above, adds additional steps to the process of hydrocodone or hydromorphone preparation.
A need thus remains for an efficient, economical, and practical process for the production of hydrocodone, hydromorphone and related compounds.