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Preparation method of bromfenac sodium sesquihydrate

A technology of sesquihydrate and bromfenac sodium, which is applied in the preparation of organic compounds, cyanide reaction preparation, chemical instruments and methods, etc., can solve the risk of inability to obtain bromfenac sodium sesquihydrate and organic solvent residues Large, unfavorable industrial production and other problems, to achieve the effect of simple and easy preparation method, lower production cost, and less discharge of three wastes

Active Publication Date: 2014-11-19
GUANGDONG ZHONGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, bromfenac sodium anhydrate can only be obtained by crystallization or recrystallization of bromfenac sodium using environmentally friendly solvents, namely water and organic alcohols, but bromfenac sodium sesquihydrate cannot be obtained
And prepare bromfenac sodium sesquihydrate in the prior art and all need to use ether organic solvents such as ethylene glycol dimethyl ether, environmental benefit is poor, organic solvent residue risk is bigger, is unfavorable for industrialized production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]In a 5L reaction flask, add 500g of bromfenac sodium anhydrate and 0.75g of sodium sulfite into a mixed solvent of 500mL of water and 500mL of ethanol. After heating and dissolving, add acetic acid to adjust the pH value to 9.0, then add 1500mL of ethanol, and cool to 30°C, add 15g of bromfenac sodium sesquihydrate as a seed crystal, stir evenly, cool to 5°C, stand for crystallization for 1h, collect crystals by centrifugation, and vacuum dry at 50°C, -0.095MPa~-0.090MPa After 15 hours, 341.5 g of bromfenac sodium sesquihydrate was obtained, with a mass yield of 68.3%, a purity of 99.69%, a single largest impurity content of 0.054%, and a moisture content of 6.97%.

[0045] The HPLC figure of the bromfenac sodium sesquihydrate related substance prepared by the present embodiment is as follows figure 1 shown.

[0046] The infrared spectrogram of the bromfenac sodium sesquihydrate prepared by the present embodiment is as follows figure 2 shown.

[0047] The X-ray powd...

Embodiment 2

[0051] In a 1L reaction flask, add 100g of bromfenac sodium anhydrate and 0.20g of sodium thiosulfate into a mixed solvent of 100mL of water and 100mL of methanol, heat to dissolve, add acetic acid to adjust the pH to 10.0, and then add 250mL of methanol , cooled to 35°C, added 3.0g of bromfenac sodium monohydrate as a seed crystal, stirred evenly, cooled to 15°C, stirred and crystallized for 2 hours, collected crystals by centrifugation, and kept at 47°C, -0.095MPa~-0.090MPa After vacuum drying for 14 hours, 67.2 g of bromfenac sodium sesquihydrate was obtained, with a mass yield of 67.2%, a purity of 99.67%, a single largest impurity content of 0.073%, and a water content of 7.04%.

Embodiment 3

[0053] In a 1L reaction flask, add 100g of bromfenac sodium monohydrate and 0.10g of sodium thiosulfate into a mixed solvent of 100mL of water and 100mL of isopropanol, heat to dissolve, add acetic acid to adjust the pH to 8.0, and then add 300mL isopropanol, cooled to 32°C, added 1.0g bromfenac sodium monohydrate and 1.0g bromfenac sodium sesquihydrate as seed crystals, stirred evenly, cooled to 0°C, stirred and crystallized for 1h, centrifuged The crystals were collected and dried under vacuum at 47°C and -0.095MPa to -0.090MPa for 16h to obtain 65.8g of bromfenac sodium sesquihydrate, with a mass yield of 65.8%, a purity of 99.75%, and a single largest impurity content of 0.048 %, the moisture content is 6.49%.

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Abstract

The invention aims at providing a preparation method of bromfenac sodium sesquihydrate. The preparation method comprises the following steps: (1) adding bromfenac sodium and an antioxidant into a mixed solvent of water and an organic alcohol, heating, dissolving and adding a pH adjustor to adjust the pH to 7.0-10.5; (2) adding an anti-solvent into a solution obtained in the step (1), cooling the solution to 30 DEG C to 35 DEG C, adding bromfenac sodium monohydrate, bromfenac sodium sesquihydrate or a mixture thereof as a seed crystal, and stirring; and (3) cooling, crystallizing, collecting crystals and drying to obtain the bromfenac sodium sesquihydrate. The preparation method avoids use of ether agents and is mild in reaction condition and good in environmental benefit. The prepared bromfenac sodium sesquihydrate is high in purity.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a preparation method of bromfenac sodium sesquihydrate. Background technique [0002] The chemical name of bromfenac sodium is 2-amino-3-(4-bromobenzoyl)sodium phenylacetate, which is one of the derivatives of 2-amino-3-benzoylphenylacetic acid, and its structure is similar to that of ketoprofen Similar to diclofenac, it can inhibit the synthesis of prostaglandin inflammatory mediators mediated by cyclooxygenase, and is the most effective cyclooxygenase inhibitor. 10 times. [0003] According to the data released by the Center for Drug Evaluation and Research (CDER) under the US FDA, the medicinal crystal form of bromfenac sodium (Application Number 21-664) is a sesquihydrate, that is, the crystal form I. [0004] Example 74 in the patent document EP0221753 and the Journal of China Pharmaceutical University (2003, 34 (5): 405-406) all reported that in a mixed solv...

Claims

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Application Information

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IPC IPC(8): C07C229/42C07C227/42
Inventor 谭珍友程志伟黄爱君贺忠玉
Owner GUANGDONG ZHONGSHENG PHARMA
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