Preparation method of flurbiprofen and preparation method of flurbiprofen axetil

A technology of flurbiprofen axetil and flurbiprofen, which is applied in the field of preparation of flurbiprofen and flurbiprofen axetil, can solve the problems of low industrial reproducibility and low yield, and achieve human environmental hazards low cost, low raw material cost and short preparation process

Inactive Publication Date: 2018-09-21
上海峰林生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other existing methods that adopt biphenyl to synthesize flurbiprofen have a relatively low overall yield, the highest being no more than 85%, and the industrial reproducibility is low

Method used

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  • Preparation method of flurbiprofen and preparation method of flurbiprofen axetil
  • Preparation method of flurbiprofen and preparation method of flurbiprofen axetil
  • Preparation method of flurbiprofen and preparation method of flurbiprofen axetil

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] 1, the preparation method of flurbiprofen

[0065] 1) Put a 500mL three-necked flask equipped with a condenser (with a calcium chloride drying tube), a constant pressure dropping funnel and a thermometer on a magnetic stirrer, and add 1.9g (80.0mmol) of magnesium chips and tetrahydrofuran (THF) 100mL, 2 iodine capsules, nitrogen gas;

[0066] 2) Move to an oil bath, and when heated to 70°C (internal temperature 62-68°C), add 4-bromo-2-fluorobiphenyl (20.0g, 80.0mmol) dropwise in THF (100mL ) solution 3.0-5.0mL, about 35min, the color of reaction iodine disappears gradually;

[0067] 3) Lower the temperature to 62°C, add 4-bromo-2-fluorobiphenyl solution dropwise, drop the solution for about 2 hours, then raise the temperature to 72°C and stir the reaction until the magnesium disappears, and the magnesium chips basically react completely;

[0068] 4) Cool to room temperature 25°C, add 11.0mL (84.0mmol) ethyl 2-bromopropionate dissolved in 50mL THF solution (add 2ml tit...

Embodiment 2

[0116] 1, prepare flurbiprofen axetil with the flurbiprofen prepared in embodiment one as raw material, concrete method is as follows:

[0117] 1) Dissolve flurbiprofen in 600ml THF (three-neck flask, insert a thermometer in the left mouth, insert a dropping funnel in the middle mouth, and plug the bottle stopper in the right mouth), add 27.6g potassium carbonate, and stir at room temperature (25°C) for 30 min;

[0118] 2) Control the temperature at 15-25°C, and add bromoethyl acetate dropwise with a dropping funnel;

[0119] 3) After the dropwise addition, reflux reaction at 66-70°C for 4-5h, monitored by TLC;

[0120] 4) Cool to room temperature (25°C), evaporate THF under reduced pressure, and the yield of THF is above 90%, add 300mL ethyl acetate to dissolve, add 300mL water, separate the organic phase, extract the aqueous phase twice with 300mL ethyl acetate, and combine Organic phase 600ml, washed twice with sodium carbonate, washed twice with water, dried over anhydrou...

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Abstract

The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of flurbiprofen and a preparation method of flurbiprofen axetil. The preparation method of the flurbiprofen comprises the steps of carrying out a Grignard reaction by using 4-bromine-2-fluorine biphenyl as a raw material, carrying out a coupling reaction, and acidizing to obtain the flurbiprofen; the yield is 90%, and the purity is 99.5%; then, the flurbiprofen axetil is prepared by using the flurbiprofen, obtained by the method, as a raw material, the yield reaches up to 90%, and thepurity reaches up to 99.5%. The preparation methods are high in quality controllability and industrial reproducibility.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, more specifically, it relates to a preparation method of flurbiprofen and flurbiprofen axetil. Background technique [0002] The chemical name of flurbiprofen is (±)-2-(2-fluoro-4-biphenyl)-propionic acid, white or off-white crystalline powder. Flurbiprofen is a non-steroidal anti-inflammatory drug propionate, which has analgesic, anti-inflammatory and antipyretic effects. Its anti-inflammatory effect is 250 times that of aspirin, and its analgesic effect is 50 times that of aspirin. Flurbiprofen has low toxicity and is well tolerated. Clinically, it is mainly suitable for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc. It can also be used for the symptomatic treatment of soft tissue diseases (such as sprains and strains) and mild to moderate pain (such as dysmenorrhea, postoperative pain, toothache, etc.) . [0003] Flurbiprofen axetil is the prodrug of flu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C57/58C07C51/09C07C27/02C07C51/41C07C67/343C07C69/616C07F3/02C07C67/11C07C67/56C07C69/65
CPCC07C51/02C07C51/09C07C51/412C07C67/11C07C67/343C07C67/56C07F3/02C07C69/616C07C57/58C07C69/65
Inventor 郑玉林陈玉双刘丽娟于曜荧
Owner 上海峰林生物科技有限公司
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