Analgesic narcotic antagonists. 6. 7 beta, 8 beta-Methano- and 7 beta, 8 beta-epoxydihydrocodeinone.
Reaction of codeinone (2) with CH2N2 in the presence of Pd(OAc)2 yielded mixtures of starting material and (2) and 7 beta, 8 beta-methanodihydrocodeinone (3). Initial resolution of this mixture was achieved via carbonyl reduction followed by chromatography to give pure 7 beta, 8 beta-methanodihydrocodeine (4), which was oxidized to 3. Reaction of the mixture containing 2 and 3 with mercaptoethanol and NaOH [2 leads to 8 beta-[(hydroxyethyl)thio]dihydrocodeinone (5)] allowed selective crystallization of 3. The beta configuration of the cyclopropane ring in 3 was established by cleavage with aqueous HCl to give the 8 beta-(chloromethyl) compound 6, followed by carbonyl reduction and dehalogenation to 8 beta-methyldihydrocodeine (8). Reaction of the N-(cycloalkylmethyl) derivatives (13 and 18) of 2 with CH2N2/Pd(OA)2 gave potential mixed agonist-antagonists and 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 7 beta, 8 beta-epoxydihydrocodeinone (22) as the hemimethanol ketal (21). Compound 3 was about ninefold more potent an agonist than dihydrocodeine, and the N-(cyclopropylmethyl)-7 beta, 8 beta-methano compound 19 had moderately potent mixed agonist-narcotic antagonist properties.
D000701:Analgesics, Opioid; D000818:Animals; D003061:Codeine / Q000031:analogs & derivatives*; D006853:Hydrocodone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009292:Narcotic Antagonists; D051381:Rats; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D006853:Hydrocodone; C031095:7,8-epoxydihydrocodeinone; C031094:7,8-methanodihydrocodeinone; D003061:Codeine