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Preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid

A biphenyl and propionic acid technology, applied in the preparation of carboxylate, the preparation of organic compounds, the preparation of carboxylate/lactone, etc., can solve the complex process of flurbiprofen, poor environmental safety, long reaction time, etc. problems, to achieve the effect of high product yield, high equipment utilization, and short reaction time

Active Publication Date: 2016-05-25
ZHENGZHOU SIGMA CHEM
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  • Abstract
  • Description
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Problems solved by technology

At present, the traditional synthesis of flurbiprofen generally has disadvantages such as complex process, long reaction time, low yield, and many by-products, which are not conducive to industrial scale-up production
A kind of method for preparing flurbiprofen disclosed in the patent of invention of publication number CN101585760A utilizes the improved Gomberg-bachmann reaction, with sodium nitrite or isoamyl nitrite as diazotization reagent, silica gel as dehydrating agent, make 2 -(4-Amino-3-fluorophenyl) ethyl propionate undergoes a coupling reaction with benzene to generate 2-(2-fluoro-4-biphenyl) ethyl propionate, which is hydrolyzed to obtain the target product fluorine ratio Profen, the method is easy to operate and low in production cost, but the reaction time is long, the product yield is low, and a highly toxic solvent is used in the reaction, and the environmental safety is poor

Method used

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  • Preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid
  • Preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid
  • Preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid

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Experimental program
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Effect test

Embodiment 1

[0024] The preparation steps of 2-(2-fluoro-4-biphenyl)propionic acid are as follows:

[0025] 1) Preparation of zinc reagent

[0026] Under the protection of nitrogen, 100g of zinc powder, 20g of trimethylsilylchloride and 100g of tetrahydrofuran were successively added to the reaction flask, stirred at room temperature for 15min, heated to reflux (temperature 65°C), and slowly added dropwise with ethyl 2-bromopropionate 500g of tetrahydrofuran solution (containing 200g of ethyl 2-bromopropionate, dripped over 2h), reflux at 65°C for 3.5h to obtain the zinc reagent for later use; the reaction formula is as follows:

[0027]

[0028] 2) Synthesis of ethyl 2-(2-fluoro-4-biphenyl)propionate

[0029] Add 206 g of 4-bromo-2-fluorobiphenyl, 3.1 g of nickel diacetylacetonate, 7.2 g of triphenylphosphine, and 731 g of tetrahydrofuran in the reaction flask, stir and mix at room temperature, and slowly add the above zinc reagent dropwise under nitrogen protection ( 2h), heat and r...

Embodiment 2

[0036] The preparation steps of 2-(2-fluoro-4-biphenyl)propionic acid are as follows:

[0037] 1) Preparation of zinc reagent

[0038] Under the protection of nitrogen, add 200g of zinc powder, 60g of trimethylchlorosilane, and 400g of tetrahydrofuran to the reaction flask in sequence, stir at room temperature for 15min, heat to reflux (temperature 66°C), and slowly add dropwise the solution of ethyl 2-bromopropionate 1100g of tetrahydrofuran solution (containing 500g of ethyl 2-bromopropionate, dripped in 2.5h), reflux at 66°C for 4h to obtain the zinc reagent for use;

[0039] 2) Synthesis of ethyl 2-(2-fluoro-4-biphenyl)propionate

[0040] Add 440g of 4-bromo-2-fluorobiphenyl, 11g of nickel chloride, 22g of terpyridine, and 1980g of tetrahydrofuran into the reaction flask in sequence, stir and mix well at room temperature, and slowly add the above zinc reagent dropwise under nitrogen protection (2.5h to finish) , heated under reflux at 60°C for 4 hours, after the reaction...

Embodiment 3

[0045] The preparation steps of 2-(2-fluoro-4-biphenyl)propionic acid are as follows:

[0046] 1) Preparation of zinc reagent

[0047] Under the protection of nitrogen, 350g of zinc powder, 35g of trimethylsilyl chloride, and 500g of tetrahydrofuran were successively added to the reaction flask, stirred at room temperature for 20min, heated to reflux (temperature 70°C), and slowly added dropwise with ethyl 2-bromopropionate 1950g of tetrahydrofuran solution (containing 1050g of ethyl 2-bromopropionate, dripped over 3h), reflux at 70°C for 3h to obtain the zinc reagent for later use;

[0048] 2) Synthesis of ethyl 2-(2-fluoro-4-biphenyl)propionate

[0049] Add 720g of 4-bromo-2-fluorobiphenyl, 21.6g of 1,2-bis(diphenylphosphine)ethane nickel chloride, 43.2g of triphenylphosphine, and 4200g of tetrahydrofuran in the reaction flask, and stir and mix at room temperature. Evenly, slowly add the above-mentioned zinc reagent dropwise under the protection of nitrogen (3h), heat and ...

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Abstract

The invention discloses a preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid, and belongs to the technical fields of chemical synthesis and medicines. A zinc reagent is prepared from trimethyl-chlorosilane as a zinc powder activating agent; with 4-bromo-2-fluoro biphenyl as a raw material, 2-(2-fluoro-4-biphenyl) ethyl propionate is obtained by reaction under the action of the zinc reagent and a catalyst-ligand; and the 2-(2-fluoro-4-biphenylyl) propionic acid is obtained through hydrolysis. The method is simple in process, simple and convenient to operate and short in reaction time; the product is high in yield, few in impurity, simple in post-treatment, high in equipment utilization rate and suitable for large-scale industrial production and application. Particularly, by a metal nickel-ligand catalyst system, the catalyst is high in activity and low in dosage; and the yield of the product can be effectively improved.

Description

technical field [0001] The invention relates to a preparation method of 2-(2-fluoro-4-biphenyl)propionic acid, which belongs to the technical fields of chemical synthesis and medicine. Background technique [0002] 2-(2-Fluoro-4-biphenyl)propionic acid is also known as flurbiprofen and benflubuprofen, molecular formula C 15 h 13 FO 2 , Molecular weight 244.3, white crystalline powder, slight odor and irritating taste, melting point 114.5-115.5°C, easily soluble in ethanol, ether, acetone, chloroform, almost insoluble in water. Flurbiprofen is a powerful phenylpropionic acid antipyretic, anti-inflammatory and analgesic drug. Its mechanism of action is to block the synthesis of prostaglandins by inhibiting the action of cyclooxygenase, so as to relieve pain, fever and inflammation. There is a carbon atom between the carboxyl group and the benzene ring in the flurbiprofen molecule, and there is a methyl group at the alpha position of the carboxyl group, which can limit the f...

Claims

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Application Information

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IPC IPC(8): C07C57/58C07C51/09
CPCC07C51/09C07C67/343C07F3/04C07C57/58C07C69/65
Inventor 杨勇王建莉赵萍萍郝家金胡孝伦杨广远武小军
Owner ZHENGZHOU SIGMA CHEM
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