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Preparation method of bromfenac sodium

A technology of bromfenac sodium and phosphoric acid, which is applied in the field of medicinal chemistry, can solve the problems that the content of bromfenac sodium cannot be effectively controlled, the appearance and properties of the product are difficult to meet the standards, and the impurity content of the hydrolyzate is high, so as to achieve good appearance and properties, reduce the production, The effect of simple preparation method

Active Publication Date: 2014-12-03
GUANGDONG XIANQIANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Yet, use dichloromethane as reaction solvent in NBS or NCS halogenation step, cause the content of dichloro impurity in the halogenated product that this step prepares to be high, can be used for follow-up reaction after needing refining; The time of phosphoric acid hydrolysis is longer (18h ), resulting in a higher impurity content in the hydrolyzate, and the unknown impurity content with a relative retention time of about 1.95 is above 0.2%
[0011] In addition, the synthesis process of bromfenac sodium in the prior art all adopts a "one-step method", that is, hydrolysis and salt formation are carried out at the same time. On the one hand, the content of related substances in bromfenac sodium cannot be effectively controlled, and the appearance of the product is difficult to meet the standards; On the other hand, bromfenac sodium is prepared by the "one-step method" of 7-(4-bromobenzoyl)-1,3-dihydro-indol-2-one through sodium hydroxide hydrolysis to salt, which requires the use of toluene, Ethanol, isopropyl ether, ethylene glycol dimethyl ether and other organic solvents increase the environmental burden

Method used

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  • Preparation method of bromfenac sodium
  • Preparation method of bromfenac sodium
  • Preparation method of bromfenac sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0056] The investigation of reaction solvent in the preparation intermediate Ⅳ:

[0057] The present inventors used dichloromethane in the prior art as the reaction solvent to prepare intermediate IV, and found that the post-treatment process was cumbersome, so other reaction solvents were investigated, and the results are shown in Table 1. It can be seen from Table 1 that when dichloromethane is used as the reaction solvent, the reaction time is as long as 24h, and the unrefined purity of intermediate IV obtained is only 87.83%; while N,N-dimethylformamide (DMF) is used as the solvent , the reaction time can be shortened to 3.0h, and the unrefined purity can reach 93.61%, which is slightly higher than the purity of ethyl acetate after refining when using dichloromethane as a solvent; using dimethyl sulfoxide (DMSO) as a solvent, the reaction time can be Shortened to 5.0h, the unrefined purity can reach 92.37%, which is equivalent to the purity obtained when dichloromethane is...

Embodiment 2

[0062] The effect of the addition method of phosphoric acid on the preparation of intermediate III:

[0063] The present inventor investigates the way of adding phosphoric acid, and the results are shown in Table 2. As can be seen from Table 2, using dropwise addition of phosphoric acid, adding phosphoric acid at one time, adding phosphoric acid in two batches or adding phosphoric acid in three batches, the reaction time is longer, and the crystallization product is viscous and difficult to filter; while adding phosphoric acid in four batches When phosphoric acid is used, the reaction time is shortened to 11-12 hours, and the crystallization product is easy to filter; when phosphoric acid is added in five batches, although the crystallization product is easy to filter, the reaction time needs to be 17-18 hours.

[0064] Table 2: The effect of the addition method of phosphoric acid on the preparation of intermediate Ⅲ

[0065]

Embodiment 3

[0067] Effects of different recrystallization solvents on the product quality of intermediate Ⅲ and bromfenac sodium:

[0068] The inventor found through a large number of experiments that the content of unknown impurities with a relative retention time of about 2.1 in the bromfenac sodium prepared by the prior art is relatively high, which is caused by the unknown impurities with a relative retention time of about 1.95 in intermediate III. If intermediate III with relative retention time of about 1.95 and unknown impurity content above 0.2% is used for follow-up reaction, even if intermediate II and bromfenac sodium are refined using prior art, it cannot be used The content of unknown impurities with a relative retention time of about 2.1 in bromfenac sodium was reduced to below 0.1%. The inventors investigated various recrystallization solvents, and the results are shown in Table 3. As can be seen from Table 3, the impurity removal effect of single organic solvents such as ...

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Abstract

The invention relates to a preparation method of bromfenac sodium. The preparation method comprises the following steps of (a) reacting a compound represented by a formula (V) with an electrophilic substitutional reagent in the presence of N,N-dimethylformamide or dimethyl sulfoxide to obtain a compound represented by a formula (IV), (b) adding the compound represented by the formula (IV) into 2-methoxyethanol, adding phosphoric acid and carrying out acid hydrolysis to obtain a compound represented by a formula (III), (c) hydrolyzing the compound represented by the formula (III) with sodium hydroxide, extracting with dichloromethane and adding acetic acid to neutralize to obtain a compound represented by a formula (II) and (d) in the presence of an organic alcohol solvent, adding a sodium hydroxide solution, hydrolyzing the compound represented by the formula (II) to form a salt, adding the organic alcohol solvent, cooling and crystallizing to obtain bromfenac sodium. According to the preparation method disclosed by the invention, the reaction yield of the intermediate (IV) and the quality of the product are improved, high-purity bromfenac sodium can be obtained just by virtue of crystallizing with the organic alcohol solvent, the good environmental benefit is achieved and the generation of bromfenac sodium polymer impurity is reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of bromfenac sodium. 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 preparation of bromfenac sodium has the following two methods at present: [0004] Method 1: The literature (Journal of The American Chemical Society.1974.95: 5508~5517) reports that 2-amino-4-bromobenzophenone and 2-methylthioethyl acetate are used as raw materials, a...

Claims

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Application Information

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IPC IPC(8): C07C229/42C07C227/22
Inventor 谭珍友邓军邵广志黄爱君
Owner GUANGDONG XIANQIANG PHARMA
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