Purification method of bezafibrate in preparation process

Abstract

The invention discloses a purification method of bezafibrate in a preparation process. The purification method comprises the steps of evaporating and recycling solvent acetone after a synthesis reaction of the bezafibrate is finished, adding water to residues until the residues are clarified, adding hydrochloric acid to regulate the pH to be 11, introducing carbon dioxide into the water solution until no precipitate is generated, filtering, acidizing filter liquid until the pH of the filter liquid is 3-4, separating a product out, and filtering and washing to obtain a bezafibrate product. According to the purification method, unreacted raw materials are separated in an after-treatment stage of the synthesis reaction by virtue of acidity difference between the raw materials and the product, so that the content of the product is effectively increased, and the loss of the product caused by recrystallization is avoided.

Description

technical field

[0001] The invention relates to a purification method in the preparation process of bezafibrate. Background technique

[0002] Bezafibrate is a second-generation clofibrate derivative blood lipid regulating drug, which can significantly reduce the concentration of low-density lipoprotein, cholesterol, serum total cholesterol and triglyceride, increase high-density lipoprotein, and It has anti-platelet aggregation, lower blood viscosity and anti-thrombotic effects. Clinically, it is mainly used for the treatment of hypertriglyceridemia, hypercholesterolemia and mixed hyperlipidemia.

[0003] At present, the synthesis of bezafibrate mainly uses N-p-hydroxyphenethyl-4-chlorobenzamide (abbreviated as acylate) as raw material, and it is obtained through condensation reaction. The reaction formula is as follows:

[0004]

[0005] Due to the carbene reaction involved in the reaction process, the reaction conditions are difficult to control, which can easily cau...

Examples

Embodiment 1

[0012] Embodiment 1: Add 4 g of N-p-hydroxyphenylethyl-4-chlorobenzamide, 6 g of sodium hydroxide and 32 ml of acetone to the reaction flask, install a reflux condenser, a mechanical stirring device, and a dropper on the reaction flask Funnel and thermometer, stir at 20°C for 0.5h, add 6g of chloroform dropwise, control the temperature at 30°C, react at this temperature for 1h, then raise the temperature and reflux for 1h; cool to room temperature, add water to the reactant until it becomes clear, add dropwise under stirring Adjust the pH to 11 with 15% hydrochloric acid in mass concentration, pass carbon dioxide gas into the solution until no more precipitates appear, filter to remove the precipitates, continue to add 15% hydrochloric acid in the filtrate to pH 3, and precipitate a white solid, continue to stir for 1 hour Suction filtration, the filter cake was washed and dried to obtain 5 g of beige powder. The yield is 95%, and the content analyzed by high performance liqui...

Embodiment 2

[0013] Embodiment 2: Add 10 g of N-p-hydroxyphenylethyl-4-chlorobenzamide, 30 g of sodium hydroxide and 150 ml of acetone into the reaction flask, install a reflux condenser, a mechanical stirring device, and a dripping solution on the reaction flask Funnel and thermometer, stir at 40°C for 1h, add 25g of chloroform dropwise, react at this temperature for 1h, then raise the temperature and reflux for 2h; cool to room temperature, add water to the reactant until it becomes clear, add dropwise 15% hydrochloric acid under stirring to adjust the pH To 11, pass carbon dioxide gas into the solution until there is no more precipitate, filter to remove the precipitate, continue to dropwise add 15% hydrochloric acid to the filtrate to pH 4, and precipitate a white solid, continue to stir for 1 hour, then suction filter, and wash the filter cake After drying, 12.3 g of beige powder was obtained. The yield was 94%, and the content analyzed by high performance liquid chromatography was 98...

Embodiment 3

[0014] Embodiment 3: Add 25g of N-p-hydroxyphenylethyl-4-chlorobenzamide, 62.5g of sodium hydroxide and 375 ml of acetone to the reaction flask, install a reflux condenser, a mechanical stirring device, drop liquid funnel and thermometer, stirred at 30°C for 45 min, added dropwise 50g of chloroform, controlled the temperature at 35°C, reacted at this temperature for 1h, then raised the temperature and refluxed for 1.5h; cooled to room temperature, added water to the reactant until clear, stirred Add dropwise 15% hydrochloric acid to adjust the pH to 11, pass carbon dioxide gas into the solution until no precipitation occurs, filter to remove the precipitate, continue to dropwise add 15% hydrochloric acid to the filtrate to pH 3.5, and precipitate a white solid. Continue to stir for 1 hour, then filter with suction, wash and dry the filter cake to obtain 31 g of beige powder. The yield was 94.5%, and the content analyzed by high performance liquid chromatography was 99.1%.

technical field

[0001] The invention relates to a purification method in the preparation process of bezafibrate. Background technique

[0002] Bezafibrate is a second-generation clofibrate derivative blood lipid regulating drug, which can significantly reduce the concentration of low-density lipoprotein, cholesterol, serum total cholesterol and triglyceride, increase high-density lipoprotein, and It has anti-platelet aggregation, lower blood viscosity and anti-thrombotic effects. Clinically, it is mainly used for the treatment of hypertriglyceridemia, hypercholesterolemia and mixed hyperlipidemia.

[0003] At present, the synthesis of bezafibrate mainly uses N-p-hydroxyphenethyl-4-chlorobenzamide (abbreviated as acylate) as raw material, and it is obtained through condensation reaction. The reaction formula is as follows:

[0004]

[0005] Due to the carbene reaction involved in the reaction process, the reaction conditions are difficult to control, which can easily cau...

Examples

Embodiment 1

[0012] Embodiment 1: Add 4 g of N-p-hydroxyphenylethyl-4-chlorobenzamide, 6 g of sodium hydroxide and 32 ml of acetone to the reaction flask, install a reflux condenser, a mechanical stirring device, and a dropper on the reaction flask Funnel and thermometer, stir at 20°C for 0.5h, add 6g of chloroform dropwise, control the temperature at 30°C, react at this temperature for 1h, then raise the temperature and reflux for 1h; cool to room temperature, add water to the reactant until it becomes clear, add dropwise under stirring Adjust the pH to 11 with 15% hydrochloric acid in mass concentration, pass carbon dioxide gas into the solution until no more precipitates appear, filter to remove the precipitates, continue to add 15% hydrochloric acid in the filtrate to pH 3, and precipitate a white solid, continue to stir for 1 hour Suction filtration, the filter cake was washed and dried to obtain 5 g of beige powder. The yield is 95%, and the content analyzed by high performance liqui...

Embodiment 2

[0013] Embodiment 2: Add 10 g of N-p-hydroxyphenylethyl-4-chlorobenzamide, 30 g of sodium hydroxide and 150 ml of acetone into the reaction flask, install a reflux condenser, a mechanical stirring device, and a dripping solution on the reaction flask Funnel and thermometer, stir at 40°C for 1h, add 25g of chloroform dropwise, react at this temperature for 1h, then raise the temperature and reflux for 2h; cool to room temperature, add water to the reactant until it becomes clear, add dropwise 15% hydrochloric acid under stirring to adjust the pH To 11, pass carbon dioxide gas into the solution until there is no more precipitate, filter to remove the precipitate, continue to dropwise add 15% hydrochloric acid to the filtrate to pH 4, and precipitate a white solid, continue to stir for 1 hour, then suction filter, and wash the filter cake After drying, 12.3 g of beige powder was obtained. The yield was 94%, and the content analyzed by high performance liquid chromatography was 98...

Embodiment 3

[0014] Embodiment 3: Add 25g of N-p-hydroxyphenylethyl-4-chlorobenzamide, 62.5g of sodium hydroxide and 375 ml of acetone to the reaction flask, install a reflux condenser, a mechanical stirring device, drop liquid funnel and thermometer, stirred at 30°C for 45 min, added dropwise 50g of chloroform, controlled the temperature at 35°C, reacted at this temperature for 1h, then raised the temperature and refluxed for 1.5h; cooled to room temperature, added water to the reactant until clear, stirred Add dropwise 15% hydrochloric acid to adjust the pH to 11, pass carbon dioxide gas into the solution until no precipitation occurs, filter to remove the precipitate, continue to dropwise add 15% hydrochloric acid to the filtrate to pH 3.5, and precipitate a white solid. Continue to stir for 1 hour, then filter with suction, wash and dry the filter cake to obtain 31 g of beige powder. The yield was 94.5%, and the content analyzed by high performance liquid chromatography was 99.1%.

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