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Method for preparing S-(+)-flurbiprofen axetil high in optical purity

A flurbiprofen axetil and optical purity technology, applied in the field of chemical drug preparation, can solve the problems of easy decomposition of products, high temperature requirements, and inability to purify

Active Publication Date: 2016-07-20
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of purification, since racemic flurbiprofen axetil is liquid, it cannot be purified by recrystallization
At present, the main purification method is silica gel column chromatography. In addition, there are also reports in the literature that the method of vacuum distillation or molecular distillation is used, but it will be accompanied by problems such as high temperature and easy decomposition of the product.

Method used

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  • Method for preparing S-(+)-flurbiprofen axetil high in optical purity
  • Method for preparing S-(+)-flurbiprofen axetil high in optical purity
  • Method for preparing S-(+)-flurbiprofen axetil high in optical purity

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the impact of different bases and solvents on the Dr value and yield.

[0038] Accurately weigh S-(+)-flurbiprofen (2.0g, 8.19mmol) into a 100mL three-necked bottle, add 50mL of acetone and stir to dissolve it completely, the reaction temperature is lowered to 0°C, and slowly add KHCO 3 Solid (410mg, 4.10mmol), then (2.1g, 12.29mmol) 10mL of acetone solution of ethyl 1-bromoacetate was added dropwise to the above-mentioned S-(+)-flurbiprofen in acetone solution at 0°C, And stirred at 25°C for 4 hours, then added 100mL of water at 25°C to quench the reaction, then extracted 3 times with ethyl acetate, 50mL each time, the combined organic phase was washed 2 times with saturated sodium chloride solution, 30mL each time, and used Sufficiently dried over sodium sulfate water, evaporated in vacuo and purified by flash chromatography (filler is neutral aluminum oxide, PE:EA=10:1) to obtain 860 mg of the target compound as light yellow oil with a yield of 63.5%. ...

Embodiment 2

[0042] Embodiment 2: the influence of charging mode on Dr value and yield.

[0043]Accurately weigh S-(+)-flurbiprofen (2.0g, 8.19mmol) and ethyl 1-bromoacetate (2.1g, 12.29mmol) in a 100mL there-necked flask, add 50mL of acetone and stir to make it all dissolve, react The temperature was lowered to 0°C, and 10 mL of acetone solution of DBU (624 mg, 4.10 mmol) was slowly added dropwise to the above solution, and the reaction was stirred at 20°C for 4 hours. After the reaction was completed, 100 mL of water was added at 25°C to quench the reaction, followed by acetic acid Ethyl ester was extracted 3 times, 50mL each time, the combined organic phase was washed 2 times with saturated sodium chloride solution, 30mL each time, fully dried with anhydrous sodium sulfate, evaporated in vacuo and passed flash chromatography (the filler was neutral trioxide Dialuminium, PE:EA=10:1) was purified to obtain 880 mg of the target compound as a pale yellow oil, with a yield of 65.1% and Dr=98...

Embodiment 3

[0044] Embodiment 3: the influence of the molar equivalent of alkali on Dr value and yield.

[0045] Accurately weigh S-(+)-flurbiprofen (2.0g, 8.19mmol) and ethyl 1-bromoacetate (2.1g, 12.29mmol) in a 100mL there-necked flask, add 50mL of acetone and stir to make it all dissolve, react The temperature was lowered to 0°C, a solution of DBU (1.2g, 8.19mmol) in acetone (2mL) was slowly added dropwise to the above solution, and the reaction was stirred at room temperature at 25°C for 4 hours, and 100mL of water was added at 25°C to quench the reaction, followed by acetic acid Ethyl ester was extracted 3 times, 50mL each time, the combined organic phase was washed 2 times with saturated sodium chloride solution, 30mL each time, fully dried with anhydrous sodium sulfate, evaporated in vacuo and passed flash chromatography (the filler was neutral trioxide Dialuminium, PE:EA=10:1) was purified to obtain 2.0 g of the target compound as a pale yellow oil with a yield of 80.0% and Dr=88...

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Abstract

The invention discloses a method for preparing S-(+)-flurbiprofen axetil high in optical purity.The method comprises the steps of 1, making S-(+)-flurbiprofen axetil react with 1-substituted ethyl acetate in the presence of alkali and organic solvent for 3-15 h at the temperature of 0-25 DEG C; 2, extracting and washing a reaction product, and separating out grease; 3, conducting column chromatographic purification on the grease; 4, removing organic solution residues with the solvent coevaporation method, and then conducting vacuum drying to obtain the target product.Inorganic base is not used, organic base highly intersoluble with organic solvent is adopted, a proper solvent ratio is selected to guarantee the proceeding of reaction, and racemization and product breakdown which occur often are avoided during preparation.The total yield of the prepared S-(+)-flurbiprofen axetil can be 80% or more, and optical purity is higher than 99%.

Description

technical field [0001] The invention belongs to the field of chemical medicine preparation, and in particular relates to a preparation method of S-(+)-flurbiprofen axetil with high optical purity. Background technique [0002] The chemical structure of S-(+)-flurbiprofen axetil is as follows: [0003] [0004] Flurbiprofen axetil is the prodrug of the non-steroidal targeted anti-inflammatory drug flurbiprofen, which can reduce hyperalgesia by inhibiting the synthesis of cyclooxygenase (COX) and prostaglandins in the spinal cord and periphery. Because it is insoluble in water, flurbiprofen axetil (lipid microspheres) injection was developed by Nippon Pharmaceutical Co., Ltd. and Green Cross Pharmaceutical Co., Ltd. in 1992. It is widely used clinically to treat postoperative pain or pain caused by cancer. . [0005] Studies have found that the active source of flurbiprofen axetil is mainly S-(+)-flurbiprofen axetil, while the enantiomer of R(-) flurbiprofen axetil lacks ...

Claims

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Application Information

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IPC IPC(8): C07C69/65C07C67/11C07C67/48C07B53/00A61K31/216A61P29/00
CPCA61K9/0019A61K31/216C07B53/00C07B2200/07C07C67/11C07C67/48C07C69/65
Inventor 李英富黄浩喜杜振军刘冠锋陈垌珲许阳潘小燕
Owner CHENGDU BRILLIANT PHARMA CO LTD
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