Derivatives of Dibenzopyran and Dibenzoxepin

Strategies for Organic Drug Synthesis and Design, Second Edition. By Daniel Lednicer Copyright 2009 John Wiley Sons, Inc. 

The dibenzopyranone ring system may be viewed as a chromone with an additional fused benzene ring and thus generally related to the antiasthmatic mediator release inhibitor cromolyn (see Chapter 11). Two dibenzopyranones have in fact been investigated for this indication in the clinic. Friedel-Crafts cyclization of the substituted cresyloxybenzoic acid (2-1) in sulfuric acid leads to the dibenzopyranone (2-2). The methyl group is then oxidized to a carboxylic acid by means of chromic acid. The acid is then converted to its sodium salt, xanoxate sodium (2-3) [2]. 

reaction of (4-3) with A, A -dimethylthioethanolamine leads to the incorporation of the basic side chain in (4-4) via a thioenol ether linkage. One of the methyl groups on nitrogen is then removed by reaction with phenyl chloroformate in the modern version of the von Braun reaction to afford fluradoline (4-5) [5]. 

The displacement of bromine from (5-1) with the phenoxide from meta-hydroxyphenylacetic acid (6-1) gives the phenyl ether (6-2). Saponification then leads to the dibasic acid (6-3). Ring closure of this compound with polyphosphoric acid gives the dibenzoxepinone. This product, isoxepac (6-4), not unexpectedly, displays NS AID activity [7]. 

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