392-04-1

Methyl 4-Fluoro-2-hydroxybenzoate is a useful synthetic intermediate. It was used to prepare benzo[d]isoxazol-3-ol as D-amino acid oxidase inhibitors. It is also used in the discovery of hydroxy-indazole-carboxamides as inhibitors of Hsp90.

To a solution of 100 g (0.64 mol, 1.0 eq.) of 4-fluoro-2-hydroxybenzoic acid (XLIa) dissolved in 1 L of methanol at 0 °C was slowly added 100 mL of concentrated sulfuric acid. The reaction mixture was gradually warmed to room temperature and subsequently heated to reflux at 70 °C for 16 hours. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the methanol. The concentrated residue was redissolved in 1 L of ethyl acetate and washed sequentially with 500 mL of saturated aqueous sodium bicarbonate and 500 mL of saturated saline. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 95 g (0.56 mol, 87% yield) of methyl 4-fluoro-2-hydroxybenzoate (XLIIa).

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