Hoechst Roussel Pharmaceuticals

Gregory M Jobin

Thomas B Lee

Gregory M Shutske

George E Lee

An improved process for the preparation of 2-chloro-1,3-dimethoxybenzene involving the reaction of [2,6-dimethoxyphenyl]lithium with chlorinating agents is disclosed. 2-Chloro-1,3-dimethoxybenzene is useful as a starting material for the synthesis of pharmacologically valuable 1,2-benzisoxazoloxyacetic acids.

Process for the preparation of 2-chloro-1,3-dimethoxybenzene

A method for the preparation of 6,11-dihydro-11-oxodibenz[b,e]oxepin-acetic acids having pharmaceutical activity is disclosed. Compounds represented by the formula: ##STR1## wherein R is OH or Cl are provided as intermediates. An aldehyde of the formula: ##STR2## wherein R.sub.1 is a lower alkyl, e.g., 1 to 4 carbon atoms, is reacted with chloroform and aqueous base to form an .alpha.-hydroxy dicarboxylic acid. Alternatively, the aldehyde can be converted to the corresponding cyanohydrin, which is then converted to the corresponding .alpha.-hydroxy dicarboxylic acid. The .alpha.-hydroxy dicarboxylic acid can also be prepared from reaction of a halogenated toluate of the formula: ##STR3## wherein X is Cl or Br with mandelic acid or a derivative thereof of the formula: ##STR4## wherein R.sub.3 and R.sub.4 are independently selected from hydrogen and alkyl of 1 to 4 carbon atoms. The .alpha.-hydroxy dicarboxylic acid is cyclized and then converted to the oxepin acetic acid by reduction. Alternatively, the .alpha.-hydroxy dicarboxylic acid is cyclized and converted to an .alpha.-chloro-substituted oxepin acetic acid, which is then converted to the unsubstituted oxepin acetic acid by reductive removal of chlorine.

Process for preparation of 6,11-dihydro-11-oxodibenz[b,e]oxepinacetic

A method of preparing substituted acylbenzenes is disclosed. The method comprises reacting selected acylhalides or equivalents with a selected poly-substituted benzene in the presence of an acylating catalyst comprising a clay.

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Bridgewater, NJ, United States of America

Gregory M Jobin