Analgesic Narcotic Antagonists. 6. 7β,8β-Methano- and 7β,8β-Epoxydihydrocodeinone

Article abstract of DOI:10.1021/jm00138a016

Reaction of codeinone (2) with CH2N2 in the presence of Pd(OAc)2 yielded mixtures of starting material (2) and 7β,8β-methanodihydrocodeinone (3).Initial resolution of this mixture was achieved via carbonyl reduction followed by chromatography to give pure 7β,8β-methanodihydrocodeine (4), which was oxidized to 3.Reaction of the mixture containing 2 and 3 with mercaptoethanol and NaOH <2 -> 8β-<(hydroxyethyl)thio>dihydrocodeinone (5)> allowed selective crystallization of 3.The β configuration of the cyclopropane ring in 3 was established by cleavage with aqueous HCl to give the 8β-(chloromethyl) compound 6, followed by carbonyl reduction and dehalogenation to 8β-methyldihydrocodeine (8).Reaction of the N-(cycloalkylmethyl) derivatives (13 and 18) of 2 with CH2N2/Pd(OAc)2 gave potential mixed agonist-antagonists 14 and 19, which were purified by reduction-oxidation (14) or mercaptoethanol-base treatment (19).Compound 2, on oxidation with alkaline peroxide, gave the previously reported 7β,8β-epoxydihydrocodeinone (22) as the hemimethanol ketal (21).Compound 3 was about ninefold more potent an agonist than dihydrocodeine, and N-(cyclopropylmethyl)-7β,8β-methano compound 19 had moderately potent, mixed agonist-narcotic antagonist properties.