Syntheses of (±)-2-[(Inden-7-yloxy) methyl] morpholine Hydrochloride (YM-08054, Indeloxazine Hydrochloride) and Its Derivatives with Potential Cerebral-Activating and Antidepressive Properties

The synthesis of (±)-2-[(inden-7-yloxy) methyl] morpholine hydrochloride (7·HCl, YM-08054, indeloxazine hydrochloride) and its optical resolution into levo- and dextro-isomers were investigated. A practical synthetic method for 7·HCl was established by employing preferential crystallization from an equilibrium mixture of 7·HCl and its tautomer, (±)-2-[(inden-4-yloxy)-methyl] morpholine hydrochloride (6·HCl), in the presence of a catalytic amount of base in MeOH. It was found that 7·HCl and its levo-rotatory isomer ((-)-7·HCl) showed not only strong antidepressive activities, but also potent cerebral-activating properties. The syntheses and pharmacological activities of related compounds are also discussed briefly.