Methanol → 3-(1-cyanocyclopropyl)-N-{4-methoxy-3-[(2-{[(4-methylpiperazin-1-yl)acetyl]amino}[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]phenyl}benzamide

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Reaction Steps

To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (457 mg, 998 μmol) produced in Example C1(vii) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (474 mg, 2.05 mmol), N,N-dimethylpyridine-4-amine (51.3 mg, 420 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg, 2.10 mmol), and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction solution, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and tetrahydrofuran (10 mL), and the solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL). The earlier 0.1N hydrochloric acid washing solution was neutralized (pH 7.0) with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (419 mg, 70%) as colorless crystals.

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