3-FLUORO-5-METHYLBENZOIC ACID

660416-38-6

518070-19-4

1. 30 mL of concentrated hydrochloric acid was slowly added to 75 mL of an aqueous suspension containing 20 g (95.6 mmol) of dimethyl 5-aminoisophthalate at -5 °C. Subsequently 7.5 g (109 mmol) of sodium nitrite was added in batches and the reaction mixture was stirred for 15 minutes. 2. 18 mL (100 mmol, 48% aqueous solution) of tetrafluoroboric acid was added and the mixture continued to be stirred for 30 minutes at 0 °C. The reaction mixture was purified by filtration. The precipitate was collected by filtration and washed with 60 mL of cold methanol and 60 mL of ether. 3. The residue was heated to decomposition in an oil bath at about 110°C. After cooling, it was diluted with ether, concentrated and purified by rapid chromatography on silica gel using 5% ethyl acetate/hexane as eluent to give 9.0 g (44%) of white fluffy solid product. 4. A 41 mL methanol suspension of 1.7 g (8.0 mmol) dimethyl 5-fluoroisophthalate was mixed with 7.2 mL (7.2 mmol) of 1.0 N sodium hydroxide and stirred overnight at room temperature. After concentration, the residue was dissolved in water, transferred to a partition funnel, and the aqueous layer was washed three times with dichloromethane, followed by acidification to pH 2 with 1.0 N hydrochloric acid. 5. The precipitate was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuum to give 1.3 g (83%) of 5-fluoroisophthalic acid monomethyl ester as a white solid. 6. In an ice bath, 2.2 mL (16.0 mmol) of triethylamine and 1.0 mL (8.0 mmol) of isobutyl chloroformate were added to a 20 mL solution of dichloromethane with 1.3 g (6.7 mmol) of mono-methyl 5-fluoroisophthalate, which was subsequently warmed to room temperature and stirred for 2 hours. After filtration and concentration, the residue was dissolved in 10 mL of tetrahydrofuran and 3 mL of a 3 mL aqueous solution of 1.1 g (29.02 mmol) of sodium borohydride was slowly added. 7. After 1 hour of reaction, it was quenched with methanol, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by rapid column chromatography on silica gel using 30% ethyl acetate/hexane as eluent gave 667 mg (54%) of methyl 3-fluoro-5-hydroxymethylbenzoate as a colorless oil. 8. 2 mL of ethanol was added to a round-bottomed flask containing 667 mg (3.6 mmol) methyl 3-fluoro-5-hydroxymethylbenzoate and 300 mg 10% palladium/activated carbon under argon protection. The flask was evacuated and filled with hydrogen and stirred for 2 h. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated to give 520 mg (87%) of methyl 3-fluoro-5-methylbenzoate. 9. 7.4 mL (3.7 mmol) of 0.5 N lithium hydroxide was added to a 7.4 mL solution of methyl 3-fluoro-5-methylbenzoate in tetrahydrofuran at 75 °C and stirred for 2 hours. After the solvent was removed in vacuum, the residue was dissolved in a small amount of water and acidified to pH 2 with 10% aqueous hydrochloric acid. 10. After extraction with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 469 mg (98%) 3-fluoro-5-methylbenzoic acid as a white solid.