876-08-4

152460-10-1

404844-11-7

1. 6-Methyl-N1-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine (10.0 g, 36.0 mmol) and triethylamine (10.0 ml, 72.2 mmol) were dissolved in tetrahydrofuran (100 mL). The solution was cooled to 0 °C with stirring and kept for 10 min. 2. A solution of 4-(chloromethyl)benzoyl chloride (7.8 g, 41.4 mmol) in tetrahydrofuran (50 mL) was added dropwise. After stirring at 0 °C for 4 h, water (500 mL) was added dropwise to the reaction mixture and a pale yellow precipitate appeared. 3. The precipitate was collected by filtration, washed with water (2 x 500 ml) and dried under reduced pressure to afford 4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (15.1 g, yield: 97.4%) as a light yellow solid. 4. The substance (4 g, 93 mmol) and tert-butyl piperazine carboxylate (8.8 g, 465 mmol) were dissolved in N-methyl-2-pyrrolidone (20 mL). The solution was reacted under microwave conditions at 120°C for 1 hr. 5. After cooling to room temperature, dichloromethane (50 mL) was added to the reaction mixture. The resulting mixture was extracted with 1M hydrochloric acid (20mL). The acidic aqueous phase was neutralized with sodium carbonate and then extracted with dichloromethane (2 x 50 mL). 6. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (pentane/ethyl acetate) to give 4 g of 4-(4-((4-methyl-3-((4-(4-(pyridin-3-yl)pyrimidin-2- yl)tert-butyl)amino)phenyl)carbamoyl)benzyl)piperazine-1-carboxylate (72% yield) as a yellow solid. 7. The substance (580 mg, 1 mmol) was dissolved in an ethyl acetate solution of hydrochloric acid (5 mL, 4 M). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-ylmethyl)benzamide hydrochloride. 8. (5Z,8Z,11Z,14Z,17Z)-Eicos-5,8,11,14,17-pentaenoic acid (EPA, 0.27 g, 0.92 mmol) was substituted with HATU (0.47 g, 1.24 mmol), triethylamine (0.25 g, 2.49 mmol), and N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2 -yl)amino)phenyl)-4-(piperazin-1-ylmethyl)benzamide hydrochloride (0.4 g, 0.83 mmol) were reacted in 15 mL of dichloromethane. The reaction mixture was stirred at room temperature for 16 hours. 9. The reaction mixture was diluted with dichloromethane (100 mL). The organic layer was washed with aqueous ammonium chloride (3 x 100 mL), brine (3 x 100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (gradient elution, 2:1 pentane/ethyl acetate to 100% ethyl acetate) to give 0.4 g of 4-((4-((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-pentenoyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)) pyrimidin-2-yl)amino)phenyl)benzamide (62% yield).