3-FLUORO-4-HYDROXY-BENZOICACIDMETHYLESTER

Methyl 3-fluoro-4-hydroxybenzoate (T10.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (commercially available from Sigma- Aldrich, St. Louis, MO, USA) (5.03 g, 32.22 mmol) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the resulting mixture was diluted with diethyl ether. The organic phase was washed carefully two times with saturated aqueous NaHCOMethyl 3-fluoro-4-hydroxybenzoate (T25.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (5.03 g, 32.22 mmol)(comrnercially available from Aldrich) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the mixture was diluted with diethyl ether. The organic phase was washed carefully twice with saturated aqueous NaHCOHydroxy -aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester- General procedure4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCOHydroxy-aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester - General procedure; [0157] 4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was re fluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCOA solution of 3-fluoro-4-hydroxybenzoic acid (5.00 g, 32.0 mmol) in 15percent methanolic sulfuric acid solution (50 mL) was heated at reflux over 48 h, then poured upon ice and extracted with ethyl acetate. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSOIntermediate 26: methyl 3-fluoro-4-hydroxybenzoate Step i) Production of methyl 3-fluoro-4-hydroxybenzoate Methyl 3-bromo-5-fluoro-4-hydroxybenzoate (T10.2). Bromine (1.60 mL, 31.1 mmol) was added dropwise with stirring over 30 minutes to an ice-cooled solution of T10.1 (4.79 g, 28.1 mmol) in a 1 :1 mixture of DCM (20 mL) and AcOH (20 mL). Upon complete addition, the reaction mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After stirring at room temperature for 40 hours, the mixture was diluted with EtOAc. The resulting solution was washed twice with aqueous saturated Na2SO3, once with water, and once with brine. After drying over anhydrous MgSO4, filtration, and concentration, the white solid was identified as T10.2 (6.69 g, 95percent yield). 1H NMR (400 MHz, CDCl3) 8.05 (1 H, m), 7.75 (1 H, dd, J=10.6, 2.0 Hz), 6.12 (1 H, s), 3.94 (3 H, s).Methyl 3-bromo-5-fluoro-4-hydroxybenzoate (T25.2). Bromine (1.60 mL, 31.1 mmol) was added dropwise with stirring over 30 minutes to an ice-cooled solution of T25.1 (4.79 g, 28.1 mmol) in a 1 : 1 mixture of DCM (20 mL) and acetic acid (20 mL). Upon complete addition, the reaction mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After stirring at room temperature for 40 hours, the mixture was diluted with EtOAc, and then the resulting solution was washed twice with aqueous saturated Na2SO3, once with water, and once with brine. After drying over anhydrous magnesium sulfate, filtration, and concentration, the white solid T25.2 was obtained 6.69 g, 95percent yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.05 (1 H, m), 7.75 (1 H, dd, J=10.6, 2.0 Hz), 6.12 (1 H, s), 3.94 (3 H, s).b) 3-Bromo-5-fluoro-4-hydroxybenzoic acid methyl ester To a solution of Intermediate 27: Methyl 3-bromo-5-fluoro-4-hydroxybenzoate _: To a stirred solution of Into a 100mL round-bottomed was added 4-hydroxyl-2-fluorobenzoic acid (1 g), methanol (10 mL), and concentrated sulfuric acid (98%, 0.1 mL). The mixture was heated to reflux for 10 hr. After the reaction finished, the mixture was poured into 100 mL ice water and filtration gave pure product A, R1 is fluoro, R2 is hydrogen, (lg) as white solid.

Molecular Weight:170.14
XLogP3:1.5
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