CHAPTER III - Chemistry of 6,7-Benzomorphans

Abstract

This chapter discusses the chemistry of 6,7-benzomorphans—such as 5-alkyl-2(N)-methyl-6,7-benzomorphans; α- and β-5,9-dlalkyl-2(N)-methyl-6,7-benzomorphans; α- and β-9-hydroxy-2(N)-methyl-6,7-benzomorphans; N-substituted -6,7-benzomorphans; and optically active 5,9-dialkyl-6,7-benzomorphans. In a study described in the chapter, the simplest compound of the benzomorphan series—2,5-dimethyl-6,7-benzomorphan—was synthesized in three different ways. In the first and longest method, hydratroponitrile was the starting substance from which both the hydroaromatic and heterocyclic rings of 2,5-dimethyl-6,7-benzomorphan was constructed. The second route, with a starting compound 3,4-dihydro-l-methyl-2(1H) naphthalenone already containing the tetrahydronaphthalene skeleton of 2,5-dimethyl-6,7-benzomorphan, initially gave lower yields than the longer method. However, significant improvement of the shorter sequence was subsequently achieved. It was earlier believed that the substitution of any group for the N-methyl of morphine and similar entities would have a detrimental effect on analgesic activity. However, it was reported in 1956 that the replacement of methyl by phenethyl in the morphine molecule resulted in an eightfold increase in potency. This and similar modifications were reported for the morphinans and 4-phenylpiperidines. In many instances, the increase in potency was dramatic.