Background and overview[1]
3,3-Dichloro-1-(4-nitrophenyl)-2-piperidone is an important pharmaceutical intermediate, for example, it can be used to prepare apixaban derivatives. Apixaban is a small molecule selective FXa inhibitor of pyrazole derivatives. Similar to rivaroxaban, apixaban has two binding sites for factor Xa. The 4-methoxyphenyl moiety in the apixaban structure binds to the S1 pocket of factor Xa, and the aryllactam moiety binds to factor Xa. Factor S4 Pocket. Apixaban is a highly selective inhibitor of factor Thrombin is not affected, and apixaban selectively inhibits factor Xa 30,000 times more than other thrombins.
Preparation[1]
Synthesis of 1-(4-nitrophenyl)piperidin-2-one (II)
Add p-nitroaniline (40g, 0.28mol), dry tetrahydrofuran (600ml), and triethylamine (60mL, 0.44mol) into a 1000mL three-neck flask. Under mechanical stirring, add 5-chlorovaleryl chloride in batches. (56mL, 0.44mol), after addition, react at 60°C for 2h. Then the temperature was lowered to -10°C, and sodium tert-butoxide (69.8g, 0.92mol) was added in batches. During the addition process, the temperature was controlled below 0°C. After the addition, the temperature was raised to 50°C and the reaction was carried out for 6 hours. Tetrahydrofuran was evaporated under reduced pressure, and 500 mL of saturated sodium carbonate aqueous solution was added to the residue for slurry washing. A large amount of solid precipitated. The product was obtained by suction filtration, an earthy yellow solid, 52.6 g, m.p. 96-99°C, yield 85.4%.
Synthesis of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone (III)
Add compound II (40g, 0.18mol) and chlorobenzene (ml) into a 1000mL eggplant-shaped flask. Add phosphorus pentachloride (132.4g, 0.64mol) in batches while stirring. After the addition is completed, the temperature is raised to 55°C for reaction. 5h. Cool the reaction solution to room temperature, pour into 1000 mL of ice water, separate the lower layer, and extract with 3 × 200 mL of methylene chloride. Combine the organic phases, wash twice with 2 × 200 mL of water, once with saturated brine and once with anhydrous sodium sulfate. Dry and evaporate to dryness in methylene chloride to obtain the product, a light yellow solid, 49.4g, m.p. 115-117°C, yield 94.9%.
Apply[1]
3,3-Dichloro-1-(4-nitrophenyl)-2-piperidone can be used in 3-morpholinyl-1-(4-nitrophenyl)-5,6-di Synthesis of hydropyridin-2(1H)-one (IV): Add 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone (40g, 0.14mol) into a 500mL eggplant-shaped bottle ), morpholine (160ml, 1.84mol), heated to 130°C and reacted for 5h. Recover morpholine under reduced pressure, add mL of water to the residue, stir for 30 minutes and then filter and dry to obtain 57.8g of crude product. Recrystallize it 8 times with ethyl acetate to obtain the product, a light yellow solid, 27.2g, m.p. 158-160°C. Yield 64.5%.
Main reference materials
[1]CN201710733736.3 Apixaban derivatives and preparation methods and uses thereof
