4-CHLORO-3-HYDROXY-BENZOIC ACID METHYL ESTER

Thionyl chloride (6 g) was added to a solution of 4-chloro-3-hydroxybenzoic acid (4.4 g, 25.50 mmol) in methanol (100 mL) and the reaction was stirred for 2 h at 70°C. Then the reaction was concentrated in vacuo. The resulting solution was diluted with n-hexane (50 mL). The solids were collected by filtration, dried in an oven under reduced pressure to afford methyl 4-chloro-3-hydroxybenzoate as a light yellow solid (4 g, 84percent). LC/MS (ES, m/z): [M+H]General procedure: To a solution of 2-fluoro-5-hydroxybenzoic acid(1.56 g, 10 mmol) in anhydrous methanol (10 mL), thionly chloride (1.42 mL, 20mmol) was added dropwise at 0 °C. The reaction was allowed to warm to rt andreflux for 3 h. The solvent was removed under reduced pressure, water wasadded, and the mixture was extracted with DCM (80 mL). The organic layer was washedwith water, saturated brine, dried over anhydrous sodium sulfate, evaporated togive title compound as a white solid (1.5 g, 88percent yield), which was used in thefollowing step without any further purificationExample 82; 2-{4-Chloro-3-(4-pyridylmethoxy)phenyl]-3-(hydrohydroxyphosphoryl)propylamine (82)Step 1: Methyl 4-chloro-3-hydroxy benzoate (82a)Commercially available 2-chloro-5-(methoxycarbonyl)phenylboronic acid (14.01 mmol, 3 g) was dissolved in 30 mL of 1:1 dichloromethane and water. Thirty-percent (30percent) v/v hydrogen peroxide (28.02 mmol, 1.59 mL) was added and the reaction mixture was stirred at room temperature overnight. The two layers were separated and the dichloromethane layers were evaporated in vacuo to give the title compound (82a) in 92percent yield.Example 14: Intermediate 25d-Methyl 4-chloro-3-hydroxybenzoate [0399] Commercial 2-chloro-5-trifluoromethyl-phenol (5 g, 25 mmol) was added to concentrated sulfuric acid (37 g, 375 mmol) under exclusion of moisture and heated under stirring to 100°C. The reaction mixture was stirred at this temperature for 1 hour, then cooled to ambient temperature and poured slowly into anhydrous methanol (300 ml). The obtained solution was refluxed for 3 hours, followed by stirring at ambient temperature overnight. The solvent was removed in vacuo to a final volume of-159 ml and then poured carefully into 10percent aqueous sodium bicarbonate solution (300 ml). The product was extracted with ether (3 x 100 ml), the combined organic layers washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated to dryness to yield 4.2 g (90.5percent) of methyl 4-chloro-3-hydroxybenzoate as an off-white solid: mp 100-1°C ; MS (APCI) FRALZ 187 ([M+H] +).Methyl-4-chloro-3-hydroxybenzoate (2) was prepared according to the literature method

Molecular Weight:186.59
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:186.0083718
Monoisotopic Mass:186.0083718
Topological Polar Surface Area:46.5
Heavy Atom Count:12
Complexity:172
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes