Dimethyl Sulfoxide → 5-(2-Chloro-4-trifluoromethylphenoxy)-2-hydroxybenzoic acid

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A mixture of 46.27 grams (0.30 mole) of 2,5-dihydroxybenzoic acid, 79.51 grams (0.40 mole) of 3-chloro-4-fluoro benzotrifluoride, 124.45 grams (0.90 mole) of potassium carbonate and 500 milliliters of dimethylsulfoxide was heated, with stirring, at 100° C. for 26 hours. The reaction mixture was then cooled, poured into 1.25 liters of water and extracted three times with methylene chloride. After phase separation, the aqueous phase was acidified with concentrated hydrochloric acid and extracted with methylene chloride. Evaporation of solvent afforded 126.7 grams of 5-(2-chloro-4-trifluoromethylphenoxy)-2-hydroxybenzoic acid. A solution of 91.9 grams of this hydroxybenzoic acid in methanol was esterified in the presence of anhydrous hydrochloric acid affording 95.1 grams of methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-hydroxybenzoate. Using the procedure described by H. Boshagen, Chem. Ber. 100, 954 (1967), 69.51 grams (0.20 mole) of the ester, 20.85 grams (0.30 mole) of hydroxylamine hydrochloride and 28.29 grams (0.71 mole) of sodium hydroxide were reacted in aqueous dioxane. The crude reaction product was partially evaporated then acidified and extracted with methylene chloride. After evaporation of solvent, the residue was slurried with aqueous methanol and suction filtered affording 44.47 grams of 5-(2-chloro-4-trifluoromethylphenoxy)-2-hydroxybenzohydroxamic acid melting at 188°-191 ° C. Again using the procedure described by H. Boshagen, supra, 13.91 grams (0.04 mole) of the hydroxamic acid and 10.55 grams (0.089 mole) of thionyl chloride in 40 milliliters of tetrahydrofuran were reacted in the first step and 12.17 gram of triethylamine in 40 milliliters of dioxane were used in the second step. The crude product (8.86 grams) was slurried in methylene chloride and suction filtered affording 6.57 grams of 5-(2-chloro-4-trifluoromethylphenoxy)-3-hydroxybenzisoxazole melting at 167°-170° C. To a solution of 1.98 grams (0.006 mole) of the 3-hydroxybenzisoxazole and 2.43 grams (0.016 mole) of methyl bromoacetate in 20 milliliters of acetonitrile were added 1.80 grams (0.013 mole) of potassium carbonate. After stirring at room temperature for 22 hours, solvent was evaporated at reduced pressure, water and methylene chloride were added to the residue, the phases were separated and the organic layer was washed twice with water. Evaporation of solvent at reduced pressure afforded 2.61 grams of oil which was purified by column chromatography and identified by MS and NMR analysis as the desired product, 5-(2-chloro-4-trifluoromethylphenoxy)-3-hydroxybenzisoxazol-O-(acetic acid, methyl ester).

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