A kind of synthetic method of bromfenac sodium impurity standard product 2-amino-3-(4-bromobenzoyl) benzoic acid

A kind of technology of bromobenzoyl, bromfenac sodium

Active Publication Date: 2018-05-11
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In view of this impurity control is crucial to bromfenac sodium product quality, and it can be used as the preparation method and the quality detection method of the standard substance that those skilled in the art use as yet bibliographical information, so the obtaining of this impurity standard substance is very important for effectively controlling bromine. The quality of fenac sodium raw materials and its preparations is of great significance

Method used

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  • A kind of synthetic method of bromfenac sodium impurity standard product 2-amino-3-(4-bromobenzoyl) benzoic acid
  • A kind of synthetic method of bromfenac sodium impurity standard product 2-amino-3-(4-bromobenzoyl) benzoic acid
  • A kind of synthetic method of bromfenac sodium impurity standard product 2-amino-3-(4-bromobenzoyl) benzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Preparation of 7-(4-bromobenzoyl)indoline-2,3-dione

[0039] 7-(4-bromobenzoyl)indolin-2-one (CAS No. 91713-91-6) prepared by a general industrial method is used as a raw material.

[0040] Dissolve 25g (79mmol) of 7-(4-bromobenzoyl)indolin-2-one in 750ml of ethyl acetate with stirring, add 88.2g (395mmol) of copper bromide, and react under reflux at 78-85°C After 4 hours, the temperature was lowered to 20-30°C, the reaction solution was washed successively with water equal to the volume of ethyl acetate and saturated aqueous sodium chloride solution, the organic phase was concentrated to dryness at 50-60°C under reduced pressure, and methanol / water (volume ratio 4 : 1) 700ml of mixed solution, reflux at 70-80°C and stir for 3h, cool to 20-30°C, filter, wash the filter cake with appropriate amount of water and methanol successively, add 500ml of methanol to the solid, reflux at 65-70°C for 30min, Filtrate hot, cool the filtrate to -5~0°C, stir and crystalliz...

Embodiment 2

[0047] Embodiment 2: Preparation of 2-amino-3-(4-bromobenzoyl)benzoic acid

[0048]1. Put 12g (36.3mmol) of 7-(4-bromobenzoyl)indoline-2,3-dione into 180g (225mmol) of 5% sodium hydroxide aqueous solution, stir and dissolve at 50-60°C, drop Add 180ml (1.8mol) of 30% hydrogen peroxide, after the dropwise addition, stir and react at 50-60°C for 1 hour, stir and cool down to 20-30°C, filter, adjust the pH of the filtrate to 3-4 with 10% hydrochloric acid, filter, and water the filter cake Appropriate amount of washing was carried out, and the solid was dried under reduced pressure at 50-60°C for 4 hours to obtain 8.85 g of crude 2-amino-3-(4-bromobenzoyl)benzoic acid, with a yield of 76.1%.

[0049] 2. Add 450ml of ethyl acetate to 8.85g of crude 2-amino-3-(4-bromobenzoyl)benzoic acid, heat and stir at 75-85°C to dissolve, filter while hot, stir the filtrate to cool down to 0-5°C, Stir and crystallize for 2 hours, filter, and dry the solid under reduced pressure at 50-60°C for 4...

Embodiment 3

[0059] Embodiment 3: Preparation of 2-amino-3-(4-bromobenzoyl)benzoic acid

[0060] 1. Put 10.0g (30.3mmol) of 7-(4-bromobenzoyl)indoline-2,3-dione into 160g (200mmol) 5% sodium hydroxide aqueous solution, stir and dissolve at 50-60°C, Add 170ml (1.7mol) of 30% hydrogen peroxide dropwise, after the dropwise addition, stir and react at 50-60°C for 1 hour, stir and cool down to 20-30°C, filter, adjust the pH of the filtrate to 3-4 with 10% hydrochloric acid, filter, and filter the cake Wash with an appropriate amount of water, and dry the solid under reduced pressure at 50-60°C for 6 hours to obtain 7.5 g of crude 2-amino-3-(4-bromobenzoyl)benzoic acid, with a yield of 77.3%.

[0061] 2. Add 200ml of ethanol to 7.5g of crude 2-amino-3-(4-bromobenzoyl)benzoic acid, heat and stir at 75-85°C to dissolve, filter while hot, stir and cool the filtrate to 0-5°C, stir and analyze Crystallized for 3 hours, filtered, and the solid was dried under reduced pressure at 50-60°C for 6 hours t...

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Abstract

The invention discloses a synthesis method of a bromfenac sodium impurity standard substance 2-amino-3-(4-bromo benzoyl) benzoic acid. 7-(4-Bromobenzoyl)indoline-2,3-dione is taken as a material, the operations of decarboxylation and refining are carried out to prepare a pure product of 2-amino-3-(4-bromo benzoyl) benzoic acid, and the content of the pure product is calibrated through a conventional analysis means. The impurity preparation method provided by the invention is simple and convenient in process and short in preparation period, and calibration shows that the product content is higher than 99.0%. The bromfenac sodium impurity provided by the invention can serve as the impurity standard substance, and is applied to qualitative and quantitative researches and detection of the bromfenac sodium material and the preparation impurity.

Description

1. Technical field [0001] The invention relates to a preparation method of a drug impurity standard product, specifically a method for synthesizing a bromfenac sodium impurity standard product 2-amino-3-(4-bromobenzoyl)benzoic acid, belonging to the technical field of medicine . 2. Background technology [0002] Bromfenac sodium sesquihydrate, the chemical name is 2-amino-3-(4-bromobenzoyl) phenylacetic acid sodium salt sesquihydrate, is a non-steroidal anti-inflammatory drug, produced by Japan Chishou Developed by Pharmaceutical Co., Ltd., it was approved by Japan PMDA in March 2000. The product name is "BRONUCK", and the specification is 0.1% bromfenac sodium eye drops of 5ml / bottle. Symptomatic treatment of diseases, including blepharitis, conjunctivitis, dynasticitis (including superior dynasticitis), postoperative inflammation, etc. [0003] The bromfenac sodium raw material and its preparations will produce degradation impurities during storage and transportation: 2-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/22C07C227/42C07C229/66
CPCC07C227/22C07C227/42C07C229/66
Inventor 吴标凌林佘文龙
Owner HEFEI JIUNUO MEDICAL TECH
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