2-Methoxynaphthalene → 3-Phenoxyphenyl ethyl ketone

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For the preparation of the preferred aryl alkyl ketones, a Friedel-Crafts reaction can be used, e.g., to effect reaction according to the following general format ##STR7## wherein R" is the residue of the desired aryl (Ar) group and R1 is the residue of the carboxylic acyl halide. For example, the 6-methoxy-2-naphthyl propiophenone can be prepared by reacting 6-methoxynaphthalene with propionyl chloride in the presence of aluminum chloride in methylene chloride. The resulting 6-methoxy-2-naphthyl ethyl ketone is converted to the methyl enol ether starting material for this process by reacting it with trimethyl orthoformate in the presence of acid and heating in vacuo. The 3-phenoxyphenyl ethyl ketone methyl enol ether can be prepared by reacting 3-hydroxyphenyl ethyl ketone with phenyl bromide in the presence of potassium carbonate to form 3-phenoxyphenyl ethyl ketone and then reacting this ketone with trimethylorthoformate to form the ketal followed by heating with acid. The enol ether of 2-fluoro-4-biphenylyl ethyl ketone is formed by reacting 2-fluoro-4-biphenylyl ethyl ketone with trimethylorthoformate to form the ketal, then heating with p-toluenesulfonic acid in vacuo. The 2-fluoro-4-biphenylyl ethyl ketone can be prepared from 4-bromopropiophenone via 4'-bromo-3'-nitropropiophenone (See Chemical Abstracts, 61, p. 8232g), 4-propionyl-2-nitrobiphenyl (Ullman reaction), 4-propionyl-2-aminobiphenyl (reduction) and finally the Schiemann Reaction. See U.S. Patent No. 3,793,457, Example 1, for a similar synthesis of 2-fluoro-4-biphenylyl methyl ketone. The difluorobiphenyl ketone can be prepared by reacting 4-cyano-2,2'-difluorobiphenyl with ethyl magnesium bromide to form the difluoro biphenylyl ethyl ketone. See U.S. Pat. No. 3,755,427. This ketone can be converted to the enol ether by the procedure described above. A preferred method for preparing the enol ether for preparing ibuprofen esters according to this invention is set forth in the detailed examples below.

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