Hydrogen Bromide → 2-(4-Hydroxyphenyl)-3-methylbutyric acid

Participants

Reaction Steps

53.1 g of p-methoxyphenylacetonitrile was alkylated with 51.4 g of isopropyl bromide in NaOH/H2O/toluene/Aliquot 336 at reflux for 24 hours. (See, for example, U.S. Pat. Nos. 4,056,509 and 4,144,264.) The crude product was hydrolyzed and demethylated in refluxing concentrated HBr to give α-isopropyl 4-hydroxyphenylacetic acid at 69% overall yeild. The hydroxy acid was alkylated with chlorodifluoromethane in the presence of sodium hydroxide and water according to the procedure set forth at page 2 of British Patent Application No. 2017668A to give crude α-isopropyl-4-difluoromethoxyphenylacetic acid at 62 wt%. 15.9 g of this acid was then reacted with 18.7 g of α-cyano-3-phenoxybenzyl bromide in a mixed solvent of sodium carbonate, water and toluene for 4 hours at 70° C. to give crude difluoromethoxy ester. This ester was purified by chromatography on a silica gel column to yield the final product having an isomer pair ratio of about 50/50.

Provenance & Evidence