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Preparation method of high-purity nepafenac intermediate

An intermediate, acetamide technology, applied in the field of pharmaceutical synthesis, can solve the problems of defective refining methods, harsh reaction conditions, low reaction temperature, etc., and achieve the effects of easy control, rapid reaction and high product purity

Pending Publication Date: 2021-05-14
NANJING GRITPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] In order to solve the problems of low reaction temperature, harsh reaction conditions, defects in the refining method, and low yield in the existing nepafenac synthesis process, and further improve the yield and quality of nepafenac, the invention provides a nepafenac The preparation method of the pufenac intermediate 2-amino-3-benzoyl-α-(methylthio)phenylacetamide formula (I), the preparation method improves the reaction temperature, reduces energy consumption, and improves the refining method , using safer reagents and increasing the yield

Method used

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  • Preparation method of high-purity nepafenac intermediate

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Experimental program
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Effect test

Embodiment 1

[0050]S1: 2-amino-3-benzoyl-α- (methylthio) phenylacetamide synthesis

[0051]67.70 g of N-chlorobutylimide was dissolved in 1000 ml of dichloromethane, and then 100 g 2-aminobenzophenone was dissolved in 1000 ml of dichloromethane. The dichloromethane solution of 2-aminobenzodone was slowly added dropwise to the dichloromethane solution of 2-aminobenzodone at -35 ° C ~ -25 ° C. After the dropwise addition was completed, the reaction was maintained at -35 ° C ~ -25 ° C for 0.5 h. After the time, 53.32 g 2- (methylthio) acetamide was slowly added to the reaction system, raised the temperature, and the control temperature was reacted at 0 ° C to 10 ° C for 2 h. TLC determines the end point of the reaction, the expander is VPetroleum ether : VEthyl acetate = 2: 1. After the reaction was completed, 56.43 g of triethylamine was slowly added dropwise at temperatures at 0 ° C ~ 10 ° C. After the dropwise addition, the entire system became a white turbidity into orange red clarified and transp...

Embodiment 2

[0056]S1: 2-amino-3-benzoyl-α- (methylthio) phenylacetamide synthesis

[0057]67.70 g of N-chloroimide was dissolved in 1000 ml of tetrahydrofuran in 1000 ml of tetrahydrofuran, and then dissolved in 1000 ml of tetrahydrofuran. At -35 ° C ~ -25 ° C, 2-aminobenzophenone tetrahydrofuran solution was slowly added to the tetrahydrofuran of N-chloroimide. After the dropwise addition was completed, the reaction was maintained at -35 ° C ~ -25 ° C for 0.5 h. After the time, 53.32 g 2- (methylthio) acetamide was slowly added to the reaction system, raised the temperature, and the control temperature was reacted at 0 ° C to 10 ° C for 2 h. TLC determines the end point of the reaction, the expander is VPetroleum ether : VEthyl acetate = 2: 1. After the reaction was completed, 56.43 g of triethylamine was slowly added dropwise at temperatures at 0 ° C ~ 10 ° C. After the dropwise addition, the entire system became a white turbidity into orange red clarified and transparent solution. Add pure wate...

Embodiment 3

[0061]S1: 2-amino-3-benzoyl-α- (methylthio) phenylacetamide synthesis

[0062]67.70 g of N-chlorobutyimide was dissolved in 1000 ml of ethyl acetate, and 100 g 2-aminobenzophenone was taken from 1000 ml of ethyl acetate. At -35 ° C ~ -25 ° C, 2-amino diphenyl acetate solution slowly droplets in ethyl acetate solution of N-chloroimide. After the dropwise addition was completed, the reaction was maintained at -35 ° C ~ -25 ° C for 0.5 h. After the time, 53.32 g 2- (methylthio) acetamide was slowly added to the reaction system, raised the temperature, and the control temperature was reacted at 0 ° C to 10 ° C for 2 h. TLC determines the end point of the reaction, the expander is VoilEther: VEthyl acetate = 2: 1. After the reaction was completed, 56.43 g of triethylamine was slowly added dropwise at temperatures at 0 ° C ~ 10 ° C. After the dropwise addition, the entire system became a white turbidity into orange red clarified and transparent solution. Add pure water 500 ml to the reaction...

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Abstract

The invention provides a preparation method of a high-purity nepafenac intermediate, which belongs to the technical field of medicine synthesis. The preparation method comprises the following steps of dissolving a chlorinating agent in an organic solvent, reacting with 2-aminobenzophenone at low temperature, carrying out heating reaction on the generated intermediate and 2-(methylthio)acetamide, after the reaction is finished, carrying out post-treatment, separating to obtain a 2-amino-3-benzoyl-alpha-(methylthio)phenylacetamide crude product, and recrystallizing the crude product to obtain a refined product of the 2-amino-3-benzoyl-alpha-(methylthio)phenylacetamide.

Description

Technical field[0001]The present invention belongs to the field of drug synthesis, and more particularly to a method of preparing a high-purity nappermine intermediate 2-amino-3-benzoyl-α-(methylthio) phenylthylethylidemide.Background technique[0002]Naphemine is a novel eye to non-steroidal antipyretic town pain resistant anti-inflammatory drugs. Treatment of inflammation. At present, the results show that Nai Phene is better than traditional non-steroidal antipyretic impections and is good safe. On August 19, 2005, the US Food and Drug Administration allowed its eyes to use the suspension (trade name Nevanac, Alton) to clinically, making it a first ophthalmic anti-hormone precision precursor approved by FDA drug.[0003]Naphifen amine, chemically called 2-amino-3-benzoyl phenylacetamide, the structural formula is as follows:[0004][0005]In 1981, the preparation method of Naphen is first disclosed in 1981, the patented, the patented patentol, the secondchlorite, tert-butyl hypochlorite...

Claims

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Application Information

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IPC IPC(8): C07C319/20C07C319/28C07C323/58
CPCC07C319/20C07C319/28C07C323/58
Inventor 杨建楠曹颖陆滢炎朱丽君魏伟业周静赵卿霍立茹李战
Owner NANJING GRITPHARMA CO LTD
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