Preparation process of bezafibrate compound

A preparation process and technology of bezafibrate, applied in the field of pharmaceutical synthesis and preparation of bezafibrate, can solve the problems of easy hygroscopicity of sodium hydroxide, many side reactions, affecting the progress of the reaction, etc., so as to avoid a large loss of products, overcome the Explosion hazard and the effect of improving product purity

Inactive Publication Date: 2018-09-25
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] 1. Since only water-soluble inorganic strong alkali sodium hydroxide is used, there are too many side reactions in the reaction process;
[0022] 2. CH must be used after the reaction 3 OH, H + Post-processing;
[0024] 1. The reaction must be carried out under anhydrous conditions. In order to increase the solubility of solid sodium hydroxide in acetone solution, the solid sodium hydroxide must first be crushed during production;
[0025] 2. The mixture of solid sodium hydroxide, acetone and chloroform can cause explosion under certain conditions, and there are serious safety hazards in industrial production;
[0026] 3. Sodium hydroxide solid is extremely hygroscopic and will bring in a small amount of water, which will affect the reaction;
[0028] 5. The quality of the product is unstable and easy to stick;
[0029] In summary, the existing preparation process is not suitable for the preparation of bezafibrate on a commercial scale, therefore, an improved and commercially feasible process is needed to solve the related problems in the prior art method and make it suitable for large-scale production. mass production

Method used

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  • Preparation process of bezafibrate compound
  • Preparation process of bezafibrate compound
  • Preparation process of bezafibrate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1: the preparation of N-p-hydroxyphenethyl-4-chlorobenzamide

[0061]

[0062] Add 250g of water and 40.0g of p-hydroxyphenylethylamine hydrochloride into a 500ml reaction bottle, add 30.7g of 30% sodium hydroxide under stirring, add 26.2g of sodium bicarbonate, cool down to 10-15°C, and dropwise add 42.0g of p-chloro Benzoyl chloride was dropped in about 3 hours. After the reaction was completed, it was filtered and dried to obtain the crude product of N-p-hydroxyphenethyl-4-chlorobenzamide with a yield of 97.6%.

Embodiment 2

[0063] Embodiment 2: the preparation of N-p-hydroxyphenethyl-4-chlorobenzamide

[0064]

[0065] Add 250g of water and 30.0g of p-hydroxyphenylethylamine into a 500ml reaction bottle, add with stirring, add 18.4g of sodium bicarbonate, cool down to 10-15°C, add 42.0g of p-chlorobenzoyl chloride dropwise, and drop it in about 3 hours , the reaction was completed, filtered and dried to obtain the crude product of N-p-hydroxyphenethyl-4-chlorobenzamide with a yield of 97.8%.

Embodiment 3

[0066] Embodiment 3: the preparation of bezafibrate

[0067]

[0068] Add 820g of acetone and 50.0g of acylate into a 2000ml reaction flask, raise the temperature to 50-60°C, stir to dissolve, add 129.6g of sodium hydroxide solution, add 64.9g of chloroform dropwise at 50-60°C, drop for about 1 hour After completion, keep warm for half an hour, distill at normal pressure, recover acetone, add 600g of water after distillation, dissolve, cool down to 0-5°C to crystallize, filter to get sodium salt wet product, add water to dissolve the wet product, add hydrochloric acid solution to adjust to acidity, Filter and dry to obtain the finished product of bezafibrate with a yield of 85%, a purity of 99.5%, and mp: 181-182°C.

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Abstract

The invention especially relates to preparation technology for a bezafibrate compound, belonging to the field of pharmaceutical synthesis. The invention provides a preparation process of the bezafibrate compound. The preparation process comprises the following steps: subjecting a compound with a structure as shown in a formula a or a' and a compound with a structure as shown in a formula b to an acylation reaction in an aqueous solution of inorganic base B so as to obtain a bezafibrate intermediate with a structure as shown in a formula c; and then subjecting the bezafibrate intermediate, R1COR2 and methyl halide to a condensation reaction in an aqueous solution of inorganic alkali A to obtain the bezafibrate compound with a structure as shown in a formula d, wherein process flow is as described in the specification, M is a water-soluble inorganic acid, X is a halogen or alkoxy group, and R1 and R2 are the same or different and are selected from a group consisting of H and C1-C3 alkylgroups.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to the technical field of preparation of bezafibrate. Background technique [0002] Bezafibrate, Bezafibrate, chemical name is 2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methylpropionic acid, its structural formula is as follows: [0003] [0004] It is a second-generation phenoxyacetic acid lipid-lowering drug developed and prepared by Boehringer Mannheim in Germany. It 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 to treat hypertriglyceridemia, hypercholesterolemia and mixed hyperlipidemia. Common adverse reactions include: loss of appetite, nausea, stomach discomfort, myositis-like syndrome, sexual dysfunction, hair loss, allergic r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C231/02C07C233/73A61K31/192A61P3/06A61P7/02
CPCC07C231/02C07C231/12
Inventor 翁海军高照波许营洲周良国叶美其郑辉马晓东
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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