To a solution of N,N-di-Boc-4-bromo-2,6-difluoro-phenylamine (5.59 g, 13.7 mmol) obtained in Step A in Example 1-D-18, palladium acetate (308 mg, 1.37 mmol), S-Phos (1.12 g, 27.4 mmol) and cesium carbonate (8.93 g, 27.4 mmol) in toluene (100 ml), 1-methyl-piperazine (6.08 ml, 54.8 mmol) was added, followed by stirring at 100° C. for 16 hours. After cooling to room temperature, 100 ml of ethyl acetate was added, which was washed with water (100 ml) and saturated aqueous ammonium chloride solution (100 ml). The organic layer was dried over sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1), whereby a mixture of N-Boc-4-(4-methyl-piperazin-1-yl)-2,6-difluoro-phenylamine and 1-Boc-4-methylpiperazine was obtained. This was dissolved in ethyl acetate (60 ml), and 6M−HCl aqueous solution (30 ml) was added, followed by stirring at room temperature for 3 hours. To this, 5M-NaOH aqueous solution was added to adjust the pH to 8, followed by extraction with ethyl acetate (100 ml×2), and the organic layer was washed with brine. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 20/1), to obtain the desired compound as a brown solid (2.16 g, 69%).
