Preparation of bezafibrate

A technology of bezafibrate and chlorobenzamide, which is applied in the field of preparation of bezafibrate, can solve the problems of long time consumption, strong corrosion of personnel and equipment, difficult operation, etc., achieve short reaction cycle, reduce operation cost, Conducive to the effect of industrial production

Inactive Publication Date: 2011-05-11
HUAIYIN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] According to the above reaction formula, the reaction is currently carried out under anhydrous conditions with acetone as a solvent (a part of acetone is used as a reactant). Synthesis of bezafibrate" and "Synthesis of bezafibrate" in "Liaoning Chemical Industry" Volume 36, No. 11, pages 733-738. Anhydrous conditions are required. The disadvantage of this method is that the solid sodium hydroxide needs to be crushed to increase its solubility in acetone. After the reaction, the acetone needs to be distilled from the system, and then it can be recycled after rectification and dehydration.
Therefore, the process takes a long time, and it is difficult to operate in anhydrous conditions. When sodium hydroxide is crushed, it is highly corrosive to personnel and equipment.

Method used

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Experimental program
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Effect test

Embodiment 1

[0022] Add 20g (72.6mmol) of N-p-hydroxyphenethyl-4-chlorobenzamide, 300ml of methylene chloride, 50ml of acetone and 0.5g (2mmol) of triethylbenzyl ammonium chloride into the reaction flask. Install a reflux condenser, a mechanical stirring device, a dropping funnel and a thermometer on the bottle, stir at room temperature for 0.5 hour, add 100ml of 50% sodium hydroxide solution, heat up to 35°C, add 26ml of chloroform (323mmol) dropwise, and React for 1 hour; cool to room temperature, add 200ml of water to the reactant, let stand to separate layers, wash the organic layer twice with 100ml of water, combine the water layer, cool to below 20°C, add 15% hydrochloric acid dropwise under stirring to adjust p H to 3.5~4.5, a beige solid is precipitated, continue to stir at this temperature for 0.5 hours, then suction filter, and dry the filter cake to obtain 24.9g of beige powder, with a yield of 95%. The crude product is analyzed by high performance liquid chromatography and has a...

Embodiment 2

[0024] N-p-hydroxyphenethyl-4-chlorobenzamide 100g (363mmol), 1,1-dichloroethane 1500ml, acetone (200ml) and hexadecyltrimethylammonium chloride 0.57g (1.8mmol ) was added to the reaction flask, a reflux condenser, a mechanical stirring device, a dropping funnel and a thermometer were installed on the reaction flask, stirred at room temperature for 0.5 hour, 485ml of 30% sodium hydroxide solution was added, the temperature was raised to 40°C, and 29.3ml was added dropwise Chloroform (363mmol), heat up, control the reaction temperature to be 50~55 ℃ for 3 hours, cool to room temperature, add 800ml water to the reactant, let stand to separate the layers, wash the organic layer twice with 200ml water, combine the water layer, Cool to below 20°C, add 15% hydrochloric acid dropwise under stirring to adjust the pH to 3.5-4.5, a beige solid precipitates, continue to stir at this temperature for 1 hour, filter with suction, and dry the filter cake to obtain 128.6 g of beige powder with...

Embodiment 3

[0026] Add 25g (90.8mmol) of N-p-hydroxyphenethyl-4-chlorobenzamide, 750ml of toluene, acetone (100ml) and 1.4g (4.3mmol) of tetrabutylammonium bromide to the reaction flask, and in the reaction flask Install a reflux condenser, a mechanical stirring device, a dropping funnel and a thermometer on top, stir at room temperature for 0.5 hours, add 130ml of 70% sodium hydroxide solution, heat up to 40°C, add dropwise 58.5ml of chloroform (0.73mol), heat up, and control the reaction React at 55-60°C for 2 hours, cool to room temperature, add 300ml of water to the reactant, let stand to separate the layers, wash the organic layer twice with 100ml of water, combine the water layer, cool to below 20°C, stir and drop Add 15% hydrochloric acid to adjust the pH to 3.5-4.5, a beige solid is precipitated, continue to stir at this temperature for 1 hour, then filter with suction, and dry the filter cake to obtain 30.5 g of beige powder with a yield of 93%. The crude product is analyzed by hi...

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Abstract

The invention discloses a preparation method of bezafibrate. The preparation method is characterized in that N-p-hydroxybenzylethyl-4-chlorobenzamide, sodium hydroxide aqueous solution, acetone and a phase transfer catalyst are added to an organic solvent, chloroform is added dropwise to react, after the reaction is completed, water is added to the system to extract and stratify, the water layer is acidified, and the bezafibrate is obtained. In the preparation method, an organic solvent incompatible with water is added in the reaction, and the reaction is carried out in water condition, thus avoiding solvent distillation, rectification dehydration and the crushing of solid sodium hydroxide; and the preparation method shortens production cycle, reduces operation cost and improves operational safety, thus being favorable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of bezafibrate. Background technique [0002] Bezafibrate (bezafibrate), the chemical name is 2-[4-[4-chlorobenzoyl]aminoethyl]-phenoxy]-2-methylpropionic acid, the English name is 2-[4-[ 4-chlorobenzoyl]aminoethyl]-phenoxy]-2-methylpropanoic ac id, its structural formula is: [0003] [0004] Bezafibrate was developed by Boehringer Mannheim of Germany in 1972 (German Patent No. 2149070). It was launched in West Germany and Switzerland in 1979. It was imported in my country in 1988 and approved for production in 2000. This product is the second-generation phenoxyacetic acid lipid-lowering drug. It has obvious effects in reducing triacylglycerol and increasing high-density lipoprotein cholesterol. It is mainly used clinically for hypertriglyceridemia, hypercholesterolemia, and mixed type. Hyperlipidemia treatment. Bezafibrate sustained-release tablets have a long action time and are administered once a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/73C07C231/14
Inventor 吴洁固旭谷亚昕倪沛洲
Owner HUAIYIN INSTITUTE OF TECHNOLOGY
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