Antidepressants Based on Dihydroanthracenes

The contraction of the central ring in the classical tricyclic agents to a dihydroanthra-cene is compatible with antidepressant activity though the resulting compounds at first sight more closely resemble the antipsychotic phenothiazines. Most of this small group of drugs owe their antidepressant activities to the inhibition of the reuptake of norepinephrine. 

A rather more complex scheme is required for the preparation of a derivative that bears a trifluoromethyl substituent on one of the benzene rings. The scheme starts with the condensation of the nitrile group in (32-1) with phenyhnagnesium bromide to give the corresponding imine treatment with aqueous acid leads to the substituted benzophenone (32-2). The future methyl on one of the bridges is introduced in a sequence involving the addition of a trimethylsulfonium yhde. 

The hrst step in the preparation of the antidepressant maprotiline (33-5) takes advantage of the acidity of anthrone protons for incorporation of the side chain. Thus treatment of (30-1) with ethyl acrylate and a relatively mild base leads to the Michael adduct saponihcation of the ester group gives the corresponding acid (33-1). The ketone group is then reduced by means of zinc and ammonium hydroxide. Dehydration of the hrst-formed alcohol under acidic conditions leads to the formation of fully aromatic anthracene (33-2). Diels-Alder addition of ethylene under high pressure leads to the addition across the 9,10 positions and the formation of the central 2,2,2-bicyclooctyl moiety (33-3). The hnal steps involve the construction of the typical antidepressant side chain. The acid in (33-3) is thus converted to an acid chloride and that function reacted with methylamine to form the amide (33-4). Reduction to a secondary amine completes the synthesis of (33-5) [33]. 

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