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Method for synthesizing standard substance of degradation impurity of bromfenac sodium sesquihydrate

A synthesis method, the technology of bromfenac sodium, is applied in the field of medicine to achieve the effects of simple preparation process, low synthesis cost and short synthesis cycle

Active Publication Date: 2017-01-04
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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  • Method for synthesizing standard substance of degradation impurity of bromfenac sodium sesquihydrate
  • Method for synthesizing standard substance of degradation impurity of bromfenac sodium sesquihydrate
  • Method for synthesizing standard substance of degradation impurity of bromfenac sodium sesquihydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: Preparation of 7-(4-bromobenzoyl)indoline-2,3-dione

[0044] 7-(4-bromobenzoyl)indolin-2-one (CAS No. 91713-91-6) prepared by a general industrial method is used as a raw material.

[0045] 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

[0052] Example 2: Preparation of 2-(2-amino-3-(4-bromobenzoyl)phenyl)-2-oxoacetic acid

[0053]1. Add 8.25g (25mmol) of 7-(4-bromobenzoyl)indoline-2,3-dione into 75ml (75mmol) of 1N potassium hydroxide solution, stir and heat up to 50-60°C, Stir the reaction for 6h, stir and cool down to 20-30°C, filter, adjust the pH of the filtrate to 3-4 with dilute hydrochloric acid, stir for 0.5h, filter, wash with appropriate amount of water, and dry the solid at 50-60°C under reduced pressure for 4-6h to obtain 2- (2-Amino-3-(4-bromobenzoyl)phenyl)-2-oxoacetic acid crude product 7g, yield 80.5%;

[0054] 2. Add 7g of crude 2-(2-amino-3-(4-bromobenzoyl)phenyl)-2-oxoacetic acid into 100ml of ethanol, stir and heat up to 75-80°C to dissolve, and filter while hot. The filtrate was cooled to 0-10°C, stirred and crystallized for 3-4 hours, filtered, and the solid was dried under reduced pressure at 50-60°C for 4-6 hours to obtain 2-(2-amino-3-(4-bromobenzoyl)phenyl )-2-oxoacetic acid pure p...

Embodiment 3

[0064] Example 3: Preparation of 2-(2-amino-3-(4-bromobenzoyl)phenyl)-2-oxoacetic acid

[0065] 1. Add 10g (30.2mmol) of 7-(4-bromobenzoyl)indoline-2,3-dione into 120ml (120mmol) of 1N potassium hydroxide solution, stir and heat up to 50-60°C, Stir the reaction for 6h, stir and cool down to 20-30°C, filter, adjust the pH of the filtrate to 3-4 with dilute hydrochloric acid, stir for 0.5h, filter, wash with appropriate amount of water, and dry the solid at 50-60°C under reduced pressure for 4-6h to obtain 2- (2-Amino-3-(4-bromobenzoyl)phenyl)-2-oxoacetic acid crude product 8.3g, yield 78.9%;

[0066] 2. Add 8.3g of crude 2-(2-amino-3-(4-bromobenzoyl)phenyl)-2-oxoacetic acid into 160ml of acetonitrile, stir and heat up to 75-80°C to dissolve, and filter while hot , the filtrate was cooled to 0-10°C, stirred and crystallized for 3-4h, filtered, and the solid was dried under reduced pressure at 50-60°C for 4-6h to obtain 2-(2-amino-3-(4-bromobenzoyl)benzene Base)-2-oxoacetic aci...

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Abstract

The invention discloses a method for synthesizing a standard substance of a degradation impurity of bromfenac sodium sesquihydrate. 7-(4-bromobenzoyl)indoline-2,3-diketone is adopted as a raw material and subjected to hydrolysis and refining to obtain a purified product of 2-(2-amino-3-(4-bromobenzoyl)phenyl)-2-oxo-acetic acid, and content calibration of the purified product is realized by conventional analysis means. The method is simple in process and short in preparation cycle, and calibrated product content is higher than 97.0%. The bromfenac sodium sesquihydrate impurity synthesized according to the method can be used as a standard substance of the impurity and applied to qualitative and quantitative research and detection of impurities in raw materials and preparation of bromfenac sodium sesquihydrate.

Description

[0001] 1. Technical field [0002] The present invention relates to a kind of preparation method of drug impurity standard substance, specifically a kind of bromfenac sodium degradation impurity standard substance 2-(2-amino-3-(4-bromobenzoyl)phenyl)-2- A method for synthesizing oxoacetic acid belongs to the technical field of medicine. [0003] 2. Background technology [0004] 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. [0005] Bromfenac sodium raw materials and their preparations will prod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/22C07C227/38C07C227/42C07C229/42
CPCC07C227/22C07C227/38C07C227/42C07C229/42
Inventor 吴标佘文龙凌林
Owner HEFEI JIUNUO MEDICAL TECH
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