Benzoic acid, 4-fluoro-2-hydroxy-, methyl ester

A solution of 4-fluoro-2-hydroxybenzoic acid (5.0 g, 32 mmol) and HTo a solution of 100 g (0.64 mol, 1.0 eq.) of 1, 4-fluoro-2-hydroxybenzoic acid (XLIa) in 1 L of MeOH at 0 °C was slowly added 100 mL of concentrated sulfuric acid at 0 °C. The mixture was allowed to warm to room temperature and then heated at 70 °C for 16 h. The mixture was then allowed to cool to room temperature and concentrated under reducedpressure. The residue was redissolved in 1 L of ethyl acetate and washed with 500 mL of sat. NaHCO3 followed by 500 mL of brine. The organic phase was dried (Na2SO4), filtered and the solvent was removed in vacuo to provide 95 g (0.56 mol, 87percent) of methyl 4-fluoro-2- hydroxybenzoate (XLIIa).Methanol (4L) was added to a dry 10L four-necked flask, 4-Fluorosalicylic acid (500 g, 3.20 mol) was added with stirring, Then SOCl2 (761 g, 6.40 mol) was added slowly, During the reaction temperature, so that it does not exceed 60 , Canada completed, Insulation reaction for about 5h, TLC test until the reaction is completed, the reaction mixture was concentrated under reduced pressure to a volume of 1.5L, Cool to -5-0 , Stirring crystallization 2h after filtration, the filter cake with an appropriate amount of ice methanol until neutral, A white solid was obtained and dried under reduced pressure at 30 ° C for 12h, 432 g of methyl 4-fluorosalicylic acid was obtained in a yield of 74.9percent.mp 39.4 ~ 40.2 ° C.B. Methyl-2-hydroxy-4-fluorobenzoate (3) Crude (2) was suspended in absolute methanol (500 mL), and concentrated sulfuric acid (100 mL) was added slowly. The suspension was heated at reflux overnight. To the suspension was added water (300 mL) and the methanol was mostly removed under vacuum, but without heating, to avoid sublimation of the product. The precipitate was collected, and dissolved in organic solvent (such as dichloromethane), dried with Na2SC>4, and the solvent was evaporated, again without heat, to yield (3) (22.8 g, 134 mmol).To a solution of 4-fluoro-2-hydroxybenzoic acid (20 g) in MeOH (300 mL) at 0 °C was added sulfuric acid (20.49 mL) dropwise. The reaction mixture was heated to 60 °C and was stirred for 2 days. The reaction mixture was concentrated under reduced pressure and the residue poured into water and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (17 g). GSMS m/z 170.1 (MGeneral procedure: The Ru(MesCOExample 33: Intermediate 87--Methyl 4-fluoro-2-hydroxybenzoate [0418] To 4-fluoro-2-hydroxybenzoic acid (5.33g, 0. 034MOL) in anhydrous methanol (26mL), under nitrogen at room temperature, was added sulfuric acid (1. 5ML). The reaction mixture was brought to reflux and kept under reflux overnight. More sulfuric acid (2. 5mL) was added and the reaction mixture kept under reflux overnight. Half the solvent was removed in vacuo and the remaining solution poured over ice-H2O. The product was then extracted with ET20 (2X). The combined ether extracts were washed with a cold solution of saturated sodium bicarbonate, treated with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. 5.49g (95percent) of methyl 4-fluoro-2-hydroxybenzoate were isolated as a white solid. Its identity was confirmed BY#x0;HNMR.Reference Example 48 A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of (trimethylsilyl) diazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the (trimethylsilyl) diazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give the title compound (10.4 g, 98percent) as a solid. 1NMR FD-MS, m/e 170 (m+) Analysis forCgH7FO3 :Calcd: C, 56.48 ; H, 4.15 ;Found: C, 56.17 ; H, 4.28.

Molecular Weight:170.14
XLogP3:2.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:170.03792224
Monoisotopic Mass:170.03792224
Topological Polar Surface Area:46.5
Heavy Atom Count:12
Complexity:172
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes