5-AMino-2-chloro-4-fluoro-benzoic acid Methyl ester

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 5-amino-2-chloro-4-fluorobenzoate (152 mg, 0.75 mmol) and pyridine (0.07 mL, 0.82 mmol) in 3 mL CH2Cl2 was added methanesulfonyl chloride (0.06 mL, 0.82 mmol). After 3 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and filtered through a silica plug to provide methyl 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoate (96 mg, 44%) as a solid (ESI-MS 280 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M−H)), which was used without further purification. the reaction mixture was washed with saturated aqueous NaHCO3 filtered through a silica plug

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-fluoro-4-chloro-5-methoxycarbonylaniline (1.0 g, 5 mmol) in THF (10 mL) was added dropwist to a solution of diphosgene (2.0 g, 10 mmol) in toluene (20 mL) with stirring at room temperature. The reaction mixture was stirred at room temperature for one hour and then heated to reflux for 4 hours. The mixture was then cooled to room temperature and the solvents were evaporated under reduced pressure to give 1.1 g of 2-fluoro-4-chloro-5-methoxycarbonylphenyl isocyanate as a solid. This was used for the next step without further purification. The reaction mixture was stirred at room temperature for one hour heated to reflux for 4 hours The mixture was then cooled to room temperature the solvents were evaporated under reduced pressure