31462-59-6

3438-46-8

31462-59-6

1. Oxidation reaction: Selenium dioxide (8.82 g, 0.079 mol) was slowly added to a stirred solution of 4-methylpyrimidine (5.0 g, 0.053 mol) in pyridine (55 mL) at room temperature. The reaction mixture was stirred at 55°C for 2 hours, then warmed to 80°C and continued stirring for 3.5 hours. After completion of the reaction, it was cooled to room temperature and stirred overnight, the reaction mixture was filtered and the residue was washed with pyridine. The pyridine solution was combined and concentrated, and the resulting pyrimidine-4-carboxylic acid was washed with water to remove traces of selenium dioxide. Yield: 5.3 g, 80.5% yield. 2. Esterification reaction: Concentrated pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) was dissolved in methanol (170 mL) and hydrochloric acid (2 mL, room temperature) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, neutralized with 10% sodium bicarbonate solution and concentrated. The esterified product was extracted with ether, dried over anhydrous sodium sulfate and concentrated to give methyl pyrimidine-4-carboxylate as a yellow solid. Yield: 3.3 g, yield 57.55%. 3. Amidation reaction: Trimethylacetyl chloride (11.30g, 0.093mol) was added dropwise to a solution of triethylamine (15.75g, 0.155mol) and 4-chloroaniline (10.0g, 0.078mol) in benzene (500mL) at 0℃. The reaction mixture was gradually warmed to room temperature and stirred for 3 hours. Upon completion of the reaction, it was quenched with water, extracted with ethyl acetate, washed sequentially with water and brine, and dried over anhydrous sodium sulfate. The resulting solid product was recrystallized from petroleum ether. Yield: 14.0 g, 84.43% yield. 4. Lithiation reaction: To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (3.5 g, 0.0165 mol) in tetrahydrofuran (50 mL) was added a hexane solution of n-butyllithium (2.64 g, 1.2 M, 0.041 mol) at 0 °C. The reaction was followed by stirring for 2 hours. After stirring at 0 °C for 2 h, the reaction was cooled to -70 °C and a tetrahydrofuran (25 mL) solution of methyl pyrimidine-4-carboxylate (3.18 g, 0.023 mol) was slowly added. The reaction mixture was then warmed to room temperature and stirred overnight. Ether (50 mL) and water (50 mL) were added and the organic layer was separated. The aqueous layer was further extracted with ether and the organic layers were combined, washed sequentially with water and brine and dried over anhydrous sodium sulfate. After concentration, the product was purified by column chromatography. Yield: 1.7 g, yield 32.69%. 5. Deprotection reaction: 70% sulfuric acid solution (10 mL) of protected aminoketone (1.7 g, 0.0054 mol) was heated at 95 °C overnight. After cooling to room temperature, it was alkalized with 10% sodium hydroxide solution, extracted with dichloromethane, washed sequentially with water and brine, and dried over anhydrous sodium sulfate. After concentration, the product was purified by basic alumina column chromatography to obtain the target compound. Yield: 0.20 g, 16% yield.