Studies on Morphinan Derivatives. I. The Synthesis of Several New 3-Substituted Derivatives of N-Methylmorphinan having Antitussive Activities

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1, 3-Dihydroxy-5, 6, 7, 8-tetrahydroisoquinoline (VI) was synthesized from ethyl 2-ethoxycarbonyl-cyclohexylidene-cyanoacetate (IV) by treating it with concentrated sulfuric acid at 80-90° for five hours. 5, 6, 7, 8-Tetrahydroisoquinoline (VIII) was synthesized from VI by first chlorinating it to form 1, 3-dichloro-5, 6, 7, 8-tetrahydroisoquinoline (VII) and then reducing VII with zinc dust in acetic acid. The synthesis of 3-hydroxy-N-methylmorphinan (II) starting from VIII was carried out according to the methods reported by Grewe and Schnider, et al. with some modifications. Several new 3-substituted derivatives of N-methylmorphinan were synthesized from II. In these derivatives, d-N, N'-dimethyl-3, 3'-(carbonyldioxy)-dimorphinan (d-XVIII) synthesized from d-II and phosgene showed nearly the same antitussive activities as dextrometorphan (I) and a toxicity lower than the latter. Furthermore, d-XVIII did not form any physical dependence.