Studies on morphinan derivatives. II. The synthesis of d-3-methyl-N-methylmorphinan, a new antitussive.

N-Methyl-5, 6, 7, 8-tetrahydroisoquinolinium bromide (IV) was reacted with p-methylbenzyl chloride by means of Grignard reaction to obtain 1-(4-methylbenzyl)-2-methyl-1, 2, 5, 6, 7, 8-hexahydroisoquinoline (V). V was immediately reduced to 1-(4-methylbenzyl)-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline (VI) with sodium borohydride. VI was resolved by means of L(+)-tartaric acid. d, l and dl-VI were cyclized to d, l and dl-3-methyl-N-methylmorphinan (II), respectively, by treating them with 85% phosphoric acid at 135-150°. Several 3-methyl-N-alkyl and alkenyl-morphinan derivatives were synthesized from 3-methylmorphinan (VIII), which was prepared by demethylation of II, by treating it with alkyl and alkenyl halides. Antitussive activities of d-II were 1.5 times as strong as that of dextrometorphan (Ib), and a toxicity of d-II was lower than that of Ib. Furthermore, d-II did not form any physical dependence.