To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (79.4 mg), triethylamine (0.125 ml) and water (0.10 ml), followed by stirring at room temperature for 6 hr. To the reaction mixture were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (19.9 mg) and triethylamine (0.032 ml), followed by stirring at room temperature for 2 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1 then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (19.7 mg, 43.4%).
