Bromine → N-(5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide

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Potassium thiocyanate (1.50 g, 3.53 mmol) was suspended in acetic acid (15 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (1.42 g, 3.22 mmol) in acetic acid (15 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (591 mg, 3.70 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 20 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (150 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→20/80), and the obtained solution was concentrated under reduced pressure to give the title compound (1.41 g, 83%) as a yellow amorphous substance.

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