Kotick M P, Leland D L, Polazzi J O, Howes J F, Bousquet A R
J Med Chem. 1981 Dec;24(12):1445-50. doi: 10.1021/jm00144a015.
The preparation of a series of 7 alpha-alkylated dihydrocodeinones is described. N-(Cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 7 alpha-methyl (a series) or 7 alpha, 8 beta-dimethyl (b series) substituted dihydronorcodeinones (7) were prepared from the appropriately substituted N-(cycloalkylmethyl)-4-hydroxymorphinan-6-ones (5) by dibromination, 4,5-epoxy ring closure, and catalytic debromination. Treatment of 7 with BBr3 gave low yields of the corresponding 3-phenols 8. Alternatively, reaction of dihydrocodeinone (10) with dimethylformamide dimethyl acetal gave the 7-[(dimethylamino)methylene] adduct 11, which was hydrogenated to 7 alpha-methyl- (12) or 7 alpha-(hydroxymethyl)dihydrocodeinone (13). Treatment of 11 with lithium reagents, followed by hydrogenation, gave a mixture of 7 alpha-alkyl (15c-f) compounds and the corresponding 4,5-epoxy-cleaved products 16. Reaction of 11 with alpha-ethoxyvinyllithium gave intermediate 17, which on hydrolysis and hydrogenation yielded the 6,7-furyl (18) or pyrroyl (19) derivative. N-(Cycloalkylmethyl)-14-hydroxydihydronorcodeinones 23P,B reacted with dimethylformamide dimethyl acetal to give 25P,B, which were hydrogenated to the 7 alpha-methyl compounds 26P,B and O-demethylated to give 27P,B. The 7 alpha-methyl-N-methyl compounds were about equipotent with dihydrocodeinone. Derivatives with larger alkyl groups were less potent. Corresponding N-(cycloalkylmethyl) compounds did not show strong mixed agonist-narcotic antagonist activity.
