(-)-4-Hydroxymorphinanones: their synthesis and analgesic activity

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Abstract
A facile procedure is described for the conversion of morphine, via the diphosphate ester derivative followed by catalytic reduction and treatment with Li/NH3, to 3-deoxy-7,8-dihydromorphine (3). Oxidation with benzophenone tert-butoxide converted 3 to the ketone [4,5-epoxy-17-methylmorphinan-6-one (4)], which on treatment with Zn/NH4Cl formed (-)-4-hydroxymorphinan-6-one (5). Reaction of 5 with diazomethane formed the methyl ether [4-methoxy-17-methylmorphinan-6-one (6)]. The N-cyclopropylmethyl analogs of 4 and 5 were also prepared, i.e., [17-(cyclopropylmethyl)-4,5-epoxymorphinan-6-one (8c)] and [17-(cyclopropylmethyl)-4-hydroxymorphinan-6-one (9) from 4. The antinociceptive activity of these compounds was tested. Compounds 5, 6, 8c and 9 showed potent antiwrithing activity [in mice], and, based on these data, a structure-activity relationship in morphinans is discussed.

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