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 solids 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 (400ml) into a 1000mL eggplant-shaped flask. Add phosphorus pentachloride (132.4g, 0.64mol) in batches while stirring. After adding, raise the temperature 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 400 mL of saturated brine, and wash 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 400 mL of water to the residue, stir for 30 minutes, filter with suction, and dry to obtain 57.8 g of crude product. Recrystallize it 8 times with ethyl acetate to obtain the product, a light yellow solid, 27.2 g, m.p. 158-160°C. Yield 64.5%.
Main reference materials
[1]CN201710733736.3 Apixaban derivatives and preparation methods and uses
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