Preparation method of medicine intermediate 3-[(3-amino-4-methylaminobenzoyl) (pyridine-2-yl)amino] ethyl propionate

[0031] Example 1:

[0032] Under the protection of nitrogen, dissolve 1.5g ethyl 3-[(3-nitro-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate in 20ml ethanol and add 0.3g pentahydrate dropwise 3ml aqueous solution of copper sulfate. After cooling to 3 degrees Celsius in an ice bath, add 0.46 g of sodium borohydride in two batches, control the temperature to be lower than 10 degrees Celsius, and increase the temperature to 20 degrees Celsius within one hour and keep the reaction. The reaction was monitored by TLC, and the reaction was complete after half an hour. The reaction was quenched by adding 20 mL of saturated ammonium chloride, and extracted with 30 mL of ethyl acetate. The dichloromethane layer was filtered by adding 10 g of anhydrous sodium sulfate and spin-dried to obtain a brown oil. Add 5 ml of isopropanol to recrystallize and dry to obtain 1.1 g of gray powder solid, namely 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionic acid ethyl ester. 80% yield,

[0033] Example 2:

[0034] Under the protection of nitrogen, dissolve 20g ethyl 3-[(3-nitro-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate in 200ml tetrahydrofuran, and add 1.5g copper sulfate pentahydrate 20ml aqueous solution. After cooling to 3 degrees Celsius in an ice bath, add 5 g of sodium borohydride in three batches, control the temperature to be lower than 15 degrees Celsius, and increase the temperature to 25 degrees Celsius within one hour and keep the reaction. The reaction was monitored by TLC, and the reaction was complete after half an hour. The reaction was quenched by adding 200 mL saturated ammonium chloride and extracted with 600 mL dichloromethane. The dichloromethane layer was filtered by adding 100 g anhydrous sodium sulfate and spin-dried to obtain a brown oil. Add ethanol / water for recrystallization and vacuum drying to obtain 2 g of gray powder solid, namely ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate. Yield 82%, purity 9

[0035] Example 3:

[0036] Under nitrogen protection, 20g of ethyl 3-[(3-nitro-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate was dissolved in 200ml of tetrahydrofuran, and 5g of sodium borohydride was added. After cooling to 3 degrees Celsius in an ice bath, slowly drip 1.5g of 20ml aqueous solution of copper sulfate pentahydrate, and control the temperature not to exceed 20 degrees Celsius. After the addition, the temperature was raised to 25 degrees Celsius and the reaction was maintained. The reaction was monitored by TLC, and the reaction was complete after half an hour. The reaction was quenched by adding 200 mL saturated ammonium chloride, and extracted with 600 mL dichloromethane. The dichloromethane layer was filtered by adding 100 g anhydrous sodium sulfate and spin-dried to obtain a brown oil. Add ethanol / water for recrystallization and vacuum drying to obtain 2 g of gray powder solid, namely 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionic acid eth