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Synthesis method of Nepafenac

A technology for nepafenamide and a synthesis method, which is applied in the field of nepafenamide synthesis, can solve problems such as difficulty in ensuring anhydrous conditions, and achieve the effect of reducing excessive chlorination

Inactive Publication Date: 2010-12-08
SHANGHAI HUIKU BIOLOGY TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the literature, methylthioacetamide is dissolved in tetrahydrofuran for feeding. Since tetrahydrofuran is very easy to absorb water in humid air, it is difficult to ensure anhydrous conditions for the reaction.

Method used

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  • Synthesis method of Nepafenac

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preparation example Construction

[0026] Preparation 1 Preparation of tert-butyl hypochlorite

[0027] 500 milliliters of sodium hypochlorite solution with a weight concentration of 10% was stirred and cooled to 10°C, 75 milliliters of tert-butanol was added, and 60 milliliters of glacial acetic acid was added, stirred for 3 minutes, and the layers were separated. Wash with 100 ml of sodium solution for 3 times, and then wash with saturated sodium chloride solution for several times until the content detected by GC is higher than 95%. Avoid light and add desiccant to refrigerate.

[0028] Preparation of 2-methylthioacetamide

[0029] 108g methyl chloroacetate, add 0.6g tetramethylammonium bromide and stir, dropwise add 420g weight concentration of 10% sodium methyl mercaptide solution, stir and heat up to 48°C after the dropwise addition, control this temperature and stir for 40 minutes, Then add 3×100ml dichloromethane for extraction, combine the organic layers, add anhydrous magnesium sulfate to dry, and r...

Embodiment 1

[0030] Example 12-Amino-3-benzoyl-α-methylthiophenylacetamide

[0031] 20.0g (0.115mol) of 2-aminobenzophenone was dissolved in 300ml of dry dichloromethane, cooled to -70°C, and another 11.5g (0.10mol) was prepared in Preparation 1 with a weight concentration of 95%. Tert-butyl chlorate was mixed with 30ml of dichloromethane, and added dropwise to the 2-aminobenzophenone solution under nitrogen protection. After the reaction is complete, connect another flask containing 10.5 g (0.1 mol) of dry methylthioacetamide powder to the reaction flask with a rubber tube, and slowly add methylthioacetamide. The temperature should be maintained at -55°C during addition, and react at -60°C for another hour, then warm to room temperature, and collect the precipitate by filtration. Slurry the precipitate into 200ml of dichloromethane, add 11g (0.11mol) of triethylamine, and stir for 5min. The resulting solution was washed twice with 100 ml of water, the organic phase was separated, dried ...

Embodiment 2

[0032] Example 22-Amino-3-benzoyl-α-methylthiophenylacetamide

[0033] 19.7g (0.1mol) of 2-aminobenzophenone was dissolved in 300ml of undried dichloromethane, cooled to -70°C, and another 11.5g (0.10mol) of the newly prepared 95% by weight concentration in Preparation 1 Tert-butyl hypochlorite was mixed with 30ml of dichloromethane, and added dropwise to the 2-aminobenzophenone solution under nitrogen protection. After the reaction was complete, another flask containing 10.5 g (0.1 mol) of dry methylthioacetamide powder was connected to the reaction flask with a rubber tube. Slowly add methylthioacetamide. The temperature should be maintained at -55°C during feeding. The reaction was carried out at -60°C for another hour, then warmed to room temperature, and the precipitate was collected by filtration. Slurry the precipitate into 200ml of dichloromethane, add 11g (0.11mol) of triethylamine, and stir for 5min. The resulting solution was washed twice with 100 ml of water, t...

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Abstract

The invention discloses a synthesis method of Nepafenac, which comprises the steps of: (1) in reaction solvent, firstly using tert-butyl hypochlorite for carrying out amino chlorination on 2-aminoben-zophenone; then, condensing with methylthio-acetamide and rearranging for transforming into alpha-methylmercapto-(2-amino-3-benzoyl) phenylacetamide; (2) reducing by reducing agent, and preparing crude product of the Nepafenac; and (3) preparing pure product of the Nepafenac by ODS reverse-phase repaid chromatography. The invention strictly controls the condition of the synthesis process, and the obtained product has the purity higher than 99% through HPLC detection.

Description

technical field [0001] The invention relates to a synthesis method of napafenamide. Background technique [0002] Nepafenac is an ophthalmic non-hormonal anti-inflammatory prodrug used in the treatment of pain and inflammation associated with cataract surgery. The chemical name is 2-amino-3-benzoyl-phenylacetamide, GB2071086, GB2059963, JMC, 33, 2296-2304 (1990) reported its synthetic route, as shown in the following formula: [0003] [0004] However, the literature does not clarify the preparation method and quality requirements of the raw materials used, the key control factors of the main reaction and side reactions, and does not solve the purification of the product. The product prepared by the method described in the literature contains a large amount of excessively chlorinated impurities, which cannot be separated and removed, so that high-purity qualified products cannot be obtained. [0005] The applicant has done careful research on this reaction route, and fo...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12A61P29/00
Inventor 陈岱岭郭廷翘郭雪飞
Owner SHANGHAI HUIKU BIOLOGY TECH
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