A kind of preparation method of bromfenac sodium dimer impurity

Abstract

The invention belongs to the technical field of medicine, and provides a preparation method of a bromfenac sodium dimer impurity, which comprises the following steps: hydrolyzing 7-(4-bromobenzoyl)-1,3-dihydro-indolyl-2-one to obtain bromfenac, adding bromfenac into an alkali metal hydroxide solution, crystallizing to obtain a bromfenac sodium dimer impurity crude product, and adding the bromfenac sodium dimer impurity crude product into ethyl acetate to obtain the bromfenac sodium dimer impurity. The method can precipitate the impurity in the bromfenac sodium dimer impurity crude product by salification, simply and efficiently implements refinement and purification of the bromfenac sodium dimer impurity, enhances the purity to 99% above, is simple and convenient, and has the advantages of favorable environmental benefit and high yield.

Description

technical field

[0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of bromfenac sodium dimer impurities. Background technique

[0002] Bromfenac sodium is one of the derivatives of 2-amino-3-benzoylphenylacetic acid, its chemical name is 2-amino-3-(4-bromobenzoyl)sodium phenylacetic acid, its structure is similar to that of ketoprofen and diclofenac Similarly, it can inhibit the synthesis of prostaglandin inflammatory mediators mediated by cyclooxygenase, and is the most effective cyclooxygenase inhibitor. It has a strong anti-inflammatory and analgesic effect, and its strength is 10 times that of other non-steroidal anti-inflammatory drugs. times.

[0003] The disclosed bromfenac sodium preparation method mainly comprises following two kinds: 1. take 2-amino-4-bromobenzophenone and 2-methylthio ethyl acetate as raw materials, use aluminum chloride as catalyst, carry out Friedel -crafts acylation, followed by ...

Examples

Embodiment 1

[0038] The preparation of embodiment 1 bromfenac

[0039] In a 50L reactor, add 1.80kg of 7-(4-bromobenzoyl)-1,3-dihydro-indol-2-one, add 20L of 20% by mass aqueous sodium hydroxide solution, and heat to reflux for reaction 2 -h, cool down, add dichloromethane for extraction, adjust the pH of the aqueous layer to 7.0 with acetic acid, filter, and dry at 50°C to obtain 1.46kg of bromfenac, the purity of bromfenac is 82.99%, and the bromfenac sodium dimer impurities The content is 13.3%.

Embodiment 2

[0040] The preparation of embodiment 2 bromfenac sodium dimer impurity crude product

[0041] Take 100g of bromfenac prepared in Example 1, add 400mL of 50% by mass sodium hydroxide aqueous solution, heat up to 75°C for 2 hours, then continue to heat up to reflux for 3 hours, drop to room temperature, add acetic acid to adjust the pH to 6.5 , crystallization, filtration, the filter cake was washed with 100mL of water, added to 200mL of ethyl acetate for beating for 1h, filtered, the filtrate was collected, concentrated under reduced pressure at 50°C, added acetonitrile and stirred for crystallization, filtered, and dried at 50°C to obtain 40.2g bromine Bromfenac sodium dimer impurity crude product, the purity of bromfenac sodium dimer impurity is 77.05%, the HPLC figure of related substance is as follows figure 1 shown.

Embodiment 3

[0042] The preparation of embodiment 3 bromfenac sodium dimer impurity crude product

[0043] Take 100 g of bromfenac prepared in Example 1, add it to 350 mL of 45% by mass aqueous sodium hydroxide solution, heat up to 70°C for 3 hours, then continue to heat up to reflux for 4 hours, cool down to room temperature, and add acetic acid to adjust the pH to 5.5 , crystallization, filtration, the filter cake was washed with 100mL of water, added to 150mL of ethyl acetate for beating for 1h, filtered, the filtrate was collected, concentrated under reduced pressure at 50°C, added acetonitrile and stirred for crystallization, filtered, and dried at 50°C to obtain 39.6g of bromine Bromfenac sodium dimer impurity crude product, the purity of bromfenac sodium dimer impurity is 75.81%.

technical field

[0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of bromfenac sodium dimer impurities. Background technique

[0002] Bromfenac sodium is one of the derivatives of 2-amino-3-benzoylphenylacetic acid, its chemical name is 2-amino-3-(4-bromobenzoyl)sodium phenylacetic acid, its structure is similar to that of ketoprofen and diclofenac Similarly, it can inhibit the synthesis of prostaglandin inflammatory mediators mediated by cyclooxygenase, and is the most effective cyclooxygenase inhibitor. It has a strong anti-inflammatory and analgesic effect, and its strength is 10 times that of other non-steroidal anti-inflammatory drugs. times.

[0003] The disclosed bromfenac sodium preparation method mainly comprises following two kinds: 1. take 2-amino-4-bromobenzophenone and 2-methylthio ethyl acetate as raw materials, use aluminum chloride as catalyst, carry out Friedel -crafts acylation, followed by ...

Examples

Embodiment 1

[0038] The preparation of embodiment 1 bromfenac

[0039] In a 50L reactor, add 1.80kg of 7-(4-bromobenzoyl)-1,3-dihydro-indol-2-one, add 20L of 20% by mass aqueous sodium hydroxide solution, and heat to reflux for reaction 2 -h, cool down, add dichloromethane for extraction, adjust the pH of the aqueous layer to 7.0 with acetic acid, filter, and dry at 50°C to obtain 1.46kg of bromfenac, the purity of bromfenac is 82.99%, and the bromfenac sodium dimer impurities The content is 13.3%.

Embodiment 2

[0040] The preparation of embodiment 2 bromfenac sodium dimer impurity crude product

[0041] Take 100g of bromfenac prepared in Example 1, add 400mL of 50% by mass sodium hydroxide aqueous solution, heat up to 75°C for 2 hours, then continue to heat up to reflux for 3 hours, drop to room temperature, add acetic acid to adjust the pH to 6.5 , crystallization, filtration, the filter cake was washed with 100mL of water, added to 200mL of ethyl acetate for beating for 1h, filtered, the filtrate was collected, concentrated under reduced pressure at 50°C, added acetonitrile and stirred for crystallization, filtered, and dried at 50°C to obtain 40.2g bromine Bromfenac sodium dimer impurity crude product, the purity of bromfenac sodium dimer impurity is 77.05%, the HPLC figure of related substance is as follows figure 1 shown.

Embodiment 3

[0042] The preparation of embodiment 3 bromfenac sodium dimer impurity crude product

[0043] Take 100 g of bromfenac prepared in Example 1, add it to 350 mL of 45% by mass aqueous sodium hydroxide solution, heat up to 70°C for 3 hours, then continue to heat up to reflux for 4 hours, cool down to room temperature, and add acetic acid to adjust the pH to 5.5 , crystallization, filtration, the filter cake was washed with 100mL of water, added to 150mL of ethyl acetate for beating for 1h, filtered, the filtrate was collected, concentrated under reduced pressure at 50°C, added acetonitrile and stirred for crystallization, filtered, and dried at 50°C to obtain 39.6g of bromine Bromfenac sodium dimer impurity crude product, the purity of bromfenac sodium dimer impurity is 75.81%.

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