FRIEDEL-CRAFTS SYNTHESIS OF 4-(3,4-DICHLOROPHENYL)-3,4-DIHYDRO-1(2H)-NAPHTHALENONE, A KEY INTERMEDIATE IN THE PREPARATION OF THE ANTIDEPRESSANT SERTRALINE

Sertraline, a potent competitive inhibitor of synaptosomal serotonin uptake,1has demonstrated excellent efficacy as an antidepressant.2A key intermediate in the synthesis of sertraline is tetralone 5, which was originally prepared in five steps and 8% overall yield from 3,4-di-chlorobenzoyl chloride.3In this route, a Stobbe reaction on 3,4-dichlorophenyl ketone was utilized to assemble all of the necessary carbon atoms. Decarboxylation and subsequent reduction of the Stobbe product gave diaryl acid 4, which was converted into 5 with a Friedel-Crafts cyclization. A more efficient preparation of 5 was conceived, which employed Friedel-Crafts reactions to construct all of the carbon—carbon bonds. Initially, this new synthesis of 5 was achieved in four steps but was further consolidated into three steps by performing a double Friedel-Crafts reaction. © 1990, American Chemical Society. All rights reserved.