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Preparation method of high-purity flurbiprofen known impurities

A flurbiprofen and impurity technology, which is applied in the preparation of organic compounds, carboxylates, carboxylates, etc., can solve problems such as no preparation impurities, and achieve improved drug safety, easy operation, and purity. high effect

Active Publication Date: 2018-04-20
北京茗泽中和药物研究有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 2-(2-fluoro-4-biphenyl)-2,3-dimethylsuccinic acid (commonly known as flurbiprofen impurity B, hereinafter referred to as this), because this compound is rarely found in the open literature report, there is no relevant report on the preparation of the impurity (formula B) in the prior art

Method used

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  • Preparation method of high-purity flurbiprofen known impurities
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  • Preparation method of high-purity flurbiprofen known impurities

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Embodiment 1

[0037] Magnesium powder (2.55g, 0.105mol) was added to the reaction flask, under nitrogen protection and stirring, a solution of 4-bromo-2-fluorobiphenyl (25.1g, 0.1mol) in anhydrous tetrahydrofuran (125ml) was added dropwise, and the temperature was controlled at 20 ~35°C, after the dropwise addition was completed, the temperature was raised to reflux (65°C) for 2 hours, and the reaction was monitored by TLC; the temperature was lowered to room temperature under the protection of nitrogen, and 2-bromo-2,3-dimethylsuccinate sodium (26.9g, 0.1mol), the addition was completed, and the temperature was raised to 65°C for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and toluene (125ml) and dilute hydrochloric acid (125ml) were added, stirred and heated to dissolve, then left to stand, the organic phase was separated, and the aqueous phase was used Extract once with toluene (50ml), combine the organic phases, wash with purified water u...

Embodiment 2

[0039] Take 10g of the crude product of 2-(2-fluoro-4-biphenyl)-2,3-dimethylsuccinic acid, 70ml of methanol and water (1:1, v / v), heat and dissolve under stirring, add activated carbon 0.2g, reflux and decolorize for 0.5h, heat filter, stir the filtrate to cool down at 0-10°C, crystallize for 1h, filter, and dry the filter cake under vacuum at 45°C to get 2-(2-fluoro-4-biphenyl)- The refined product of 2,3-dimethylsuccinic acid was 7.72g, the HPLC purity was 99.1%, and the yield was 77.2%.

Embodiment 3

[0041] Take 10g of the crude product of 2-(2-fluoro-4-biphenyl)-2,3-dimethylsuccinic acid, 50ml of ethanol and water (2:1, v / v), heat and dissolve under stirring, add activated carbon 0.5g, decolorized under reflux for 0.5h, hot filtered, the filtrate was stirred and cooled down to 0-10°C, crystallized for 1h, filtered, and the filter cake was dried under vacuum at 45°C to obtain 2-(2-fluoro-4-biphenyl)- The refined product of 2,3-dimethylsuccinic acid was 7.55g, the HPLC purity was 99.4%, and the yield was 75.5%.

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Abstract

The invention discloses a preparation method of high-purity flurbiprofen known impurities B. The preparation method comprises the following steps: enabling a tetrahydrofuran solution of 4-bromine-2-fluorobiphenyl as a starting material to perform Grignard reaction with magnesium, acidifying after coupled docking with side chain 2-bromo-2,3-sodium dimethyl succinate, preparing crude products of flurbiprofen impurities and performing re-crystallization on the high-purity flurbiprofen known impurities B, namely 2-(2-fluoro-4-biphenyl)-2,3-dimethylidene succinic acids. The preparation method disclosed by the invention is simple and convenient to operate, short in reaction time, high in product purity, high in yield and suitable for industrial production. The synthesized impurities B can be used for the qualitative and quantitative analysis on the impurities, so that the drug use safety of flurbiprofen is improved.

Description

technical field [0001] The invention belongs to the field of medical technology and drug analysis, and more specifically relates to a method for preparing a known impurity of high-purity flurbiprofen, and the impurity 2-(2-fluoro-4-biphenyl)-2,3- Use of dimethylsuccinic acid as flurbiprofen quality control standard. Background technique [0002] The chemical name of flurbiprofen is (±)-2-(2-fluoro-4-biphenyl)-propionic acid, white or off-white crystalline powder. Soluble in methanol, ethanol, acetone or ether, soluble in acetonitrile, almost insoluble in water. Molecular formula is C 15 h 13 FO 2 . The molecular formula of flurbiprofen (CAS: 5104-49-4, flurbiprofen) is as follows: [0003] [0004] Flurbiprofen is a fluorine-containing non-steroidal anti-inflammatory drug, which is mainly used clinically for rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. It can also be used for symptomatic treatment of soft tissue diseases (such as sprains and st...

Claims

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Application Information

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IPC IPC(8): C07F3/02C07C51/41C07C51/353C07C57/58C07C51/42C07C51/02
Inventor 杨红伟李斐菲姚永波
Owner 北京茗泽中和药物研究有限公司
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