Preparation method of flurbiprofen axetil

Abstract

The invention relates to a preparation method of flurbiprofen axetil, and belongs to the technical field of medicine synthesis. In order to solve the problems of long synthetic route and low product yield in the prior art, the invention provides the flurbiprofen axetil preparation method, which comprises the following steps: in the presence of an acid-binding agent, carrying out alkylation reaction on ethyl 1-bromoacetate and 2-bromopropionic acid to obtain a compound shown as a formula IV; under the action of a coupling catalyst, a Grignard reagent and the compound shown in the formula IV are subjected to a coupling reaction, and the product flurbiprofen axetil is obtained. According to the method, the step of firstly synthesizing flurbiprofen ethyl ester and then hydrolyzing the flurbiprofen ethyl ester is not needed, the synthesis route is simplified, and the reduction of intermediate steps is beneficial to improving the yield and quality of the product.

Description

Technical Field

[0001] The invention relates to a method for preparing flurbiprofen axetil, and belongs to the technical field of drug synthesis. Background Art

[0002] Flurbiprofen axetil is a nonsteroidal anti-inflammatory analgesic that reduces the synthesis of prostaglandins by inhibiting cyclooxygenase (COX) in the spinal cord and periphery, thereby reducing the hyperalgesia caused by surgical trauma. It is clinically used to treat postoperative pain or pain caused by cancer. The structural formula of flurbiprofen axetil is as follows:

[0003]

[0004] The synthetic route of flurbiprofen axetil reported in existing literature is mainly synthesized by the following route:

[0005] Flurbiprofen is used as the starting material, and 1-haloethyl acetate is condensed under the catalysis of an acid-binding agent (such as potassium carbonate, etc.) to obtain a crude flurbiprofen axetil, and the product flurbiprofen axetil is prepared and separated. The synthetic route is as follows:

[0006]

[0007] Where: X = Cl, Br

[0008] Another synthetic route is to use flurbiprofen as a starting material, condense with 1,1-ethylene glycol diacetate or 1,1-ethylene glycol dipropionate and other similar ester compounds under the action of an acid catalyst to obtain a crude flurbiprofen axetil, and then column chromatography to obtain a pure flurbiprofen axetil. The synthetic route is as follows:

[0009]

[0010] The raw material 1,1-ethylene glycol diacetate used in this route is rarely sold commercially, and the homemade production requires the use of environmentally unfriendly raw material acetaldehyde, which is easy to cause environmental pollution and is not conducive to industrial production.

[0011] Some literature reports that the synthesis does not use flurbiprofen as the starting material, but rather reacts 4-bromo-2-fluorobiphenyl with magnesium chips to prepare a Grignard reagent, which is then coupled with ethyl 2-bromopropionate to obtain flurbiprofen ethyl ester, which is then hydrolyzed to generate flurbiprofen, which is then condensed with ethyl 1-bromoacetate to obtain the product flurbiprofen ester. The synthetic route is as follows:

[0012]

[0013] In the synthesis reaction process, flurbiprofen ethyl ester is first synthesized, and then the desired flurbiprofen is formed through a hydrolysis reaction. This has the problems of a long reaction route and a low product yield. Summary of the invention

[0014] The present invention aims at the defects existing in the above prior art and provides a method for preparing flurbiprofen axetil, in order to solve the problems of long synthesis route and low product yield.

[0015] The object of the present invention is achieved by the following technical scheme, a method for preparing flurbiprofen axetil, characterized in that the method comprises the following steps:

[0016] A. In the presence of an acid binding agent, ethyl bromoacetate of the compound of formula II and 2-bromopropionic acid of the compound of formula III are subjected to alkylation reaction to obtain a compound of formula IV;

[0017]

[0018] B. Under the action of a coupling catalyst, coupling the Grignard reagent compound of formula V with the compound of formula IV to obtain the product compound of formula I;

[0019]

[0020] The present invention adopts a new synthetic route, uses ethyl 1-bromoacetate of the compound of formula II as a raw material, synthesizes the compound of formula IV, and then directly reacts with a Grignard reagent to obtain a desired product. In particular, by adjusting and improving the synthetic route, it is achieved that there is no need to first synthesize flurbiprofen ethyl ester and then undergo a hydrolysis step, thereby simplifying the synthetic route. The reduction of intermediate steps is conducive to improving the yield and quality of the product, and then only needs to react with the Grignard reagent to obtain the final product. The raw materials used in the synthetic route of the present invention are easy to obtain, and the Grignard reagent can be obtained by purchasing or synthesizing, and there are no problems of excessively high raw material costs and difficulty in purchasing the raw materials in the market. The present invention is more conducive to industrial production, and the yield of the intermediate product in each step is relatively high, thereby achieving the final product yield and purity quality requirements of flurbiprofen axetil.

[0021] In the above-mentioned preparation method of flurbiprofen axetil, the presence of an acid-binding agent in step A can neutralize the small molecule acid formed during the reaction, promote the reaction, and also help to reduce the generation of impurities, improve the yield and quality requirements of the intermediate product. The acid-binding agent in step A is selected from an organic base or an inorganic base, and it is best that the organic base is selected from one or more of triethylamine, diisopropylethylamine, pyridine and pyrrole; the inorganic base is selected from one or more of sodium carbonate, potassium carbonate and cesium carbonate.

[0022] In the above-mentioned preparation method of flurbiprofen axetil, preferably, the alkylation reaction in step A is carried out in a polar organic solvent, and the polar organic solvent is selected from one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetone, 1,4-dioxane, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP). By carrying out the reaction in a polar organic solvent, the reaction temperature can be increased, which is more conducive to improving the purity and quality of the product. The amount of the polar organic solvent can be based on the conventional amount in the art, and it is best to make the amount of the added polar organic solvent 3 to 6 times the mass of the raw material formula II compound 1-ethyl bromoacetate.

[0023] In the above-mentioned preparation method of flurbiprofen axetil, preferably, the temperature of the alkylation reaction in step A is 30° C. to 50° C. By adjusting the starting raw materials of the reaction, the reaction temperature during the synthesis process is easier to control, and the operability is good, which is more conducive to industrial production. Moreover, the reaction is carried out at a mild reaction temperature to avoid the generation of unnecessary impurities, which is more conducive to ensuring the purity and quality of the product.

[0024] In the above-mentioned preparation method of flurbiprofen axetil, preferably, the coupling catalyst in step B is selected from one or more of nickel chloride, cobalt chloride and palladium chloride. Due to the adjustment of the reaction route, in order to allow the formed intermediate compound of formula IV to react directly with the Grignard reagent, the addition of a coupling catalyst in the reaction system can effectively promote the reaction, improve the reaction efficiency, and have the advantage of high product yield.

[0025] In the above-mentioned preparation method of flurbiprofen axetil, preferably, the coupling reaction in step B is carried out in an ether solvent one, and the ether solvent one is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ether and ethylene glycol dimethyl ether. The reaction can be carried out gently to ensure the quality of the product. It is best to use tetrahydrofuran or 2-methyltetrahydrofuran. The amount of the ether solvent can be based on the conventional reaction feed amount. Of course, it is best to make the amount of the ether solvent 1 to 4 times the mass of the Grignard reagent.

[0026] In the above-mentioned method for preparing flurbiprofen axetil, preferably, the temperature of the coupling reaction in step B is -10°C to 10°C.

[0027] In the above-mentioned preparation method of flurbiprofen axetil, the amount of each raw material in the synthesis route can be charged according to the molar equivalent of the reaction in the art, and the amount of the acid binding agent and the coupling catalyst can be charged according to the reaction, and the corresponding amount of the catalytic amount can be added. As a preference, it is best to make the molar ratio of the compound of formula II 1-ethyl bromoacetate: the compound of formula III 2-bromopropionic acid: the acid binding agent in step A be 1: 1.0-1.2: 1.0-1.5; the molar ratio of the Grignard reagent compound of formula V: the compound of formula IV: the coupling catalyst in step B be 1: 1.0-1.3: 0.01-0.1.

[0028] In the above-mentioned preparation method of flurbiprofen axetil, the Grignard reagent described in step B can be directly selected, or it can be synthesized from 4-bromo-2-fluorobiphenyl as a raw material to prepare a fresh Grignard reagent. Preferably, the Grignard reagent formula III compound described in step B is obtained by the following method:

[0029] In an aprotic solvent, 4-bromo-2-fluorobiphenyl and magnesium undergo a Grignard reaction to generate a Grignard reagent compound of formula V. By making the Grignard reagent by yourself, a fresher Grignard reagent can be provided, so that the effective components participating in the reaction can be better guaranteed, which is more conducive to reducing the presence of other impurities in the Grignard reagent, which is conducive to better improving the quality of the Grignard reagent, and is also conducive to improving the reaction efficiency and the quality of the intermediate product obtained.

[0030] In the above-mentioned preparation method of flurbiprofen axetil, preferably, the aprotic solvent is selected from ether solvent 2, and the ether solvent 2 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ether and ethylene glycol dimethyl ether. The reaction can be carried out more gently, and the use of an ether solvent can also make it better to be put into the next step of coupling reaction, so that the solvent does not need to be replaced. The above-mentioned ether solvent 1 and ether solvent 2 of the present invention are not the distinction and limitation of the solvent, but only for a clearer statement. Both refer to ether solvents, which can be the same ether solvent or different ether solvents. It is best to use the same ether solvent in the Grignard reaction and the coupling reaction, which is more conducive to operation. When using a homemade Grignard reagent, a convergent synthesis route is adopted, and the Grignard reagent and the IV compound are prepared separately, and then a coupling reaction occurs, which is equivalent to the first two steps. The method of synchronous synthesis can better improve the reaction efficiency.

[0031] The above-mentioned magnesium can be magnesium powder, magnesium strips or magnesium chips. The reaction process of magnesium powder is highly exothermic and has safety risks. It is difficult for magnesium strips to initiate the reaction. Therefore, magnesium chips are preferably used. It is further preferred that the molar ratio of the 4-bromo-2-fluorobiphenyl to magnesium is 1:1.05-1.20, preferably 1:1.15. The temperature of the Grignard reaction can also be further made to be 50°C to the reflux temperature, preferably reacting at the reflux temperature. The amount of the above-mentioned ether solvent II can be based on the conventional amount in the chemical field. Of course, it is best to make the amount of the ether solvent II 4-bromo-2-fluorobiphenyl The mass is 4 to 6 times.

[0032] The chemical reaction equation of the preparation method of the flurbiprofen axetil of the present invention is as follows:

[0033]

[0034] In summary, compared with the prior art, the present invention has the following advantages:

[0035] 1. The present invention achieves the purpose of simplifying the synthesis route by adjusting and improving the synthesis route, eliminating the need to first synthesize flurbiprofen ethyl and then undergoing a hydrolysis step. The reduction of intermediate steps is beneficial to improving the yield and quality of the product.

[0036] 2. The raw materials used are all easily available, and there is no problem of excessively high raw material costs and difficulty in purchasing them in the market, which is more conducive to industrial production, and the yield of the intermediate product in each step is relatively high, thereby achieving the final product yield and purity quality requirements of flurbiprofen axetil. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 It is the nuclear magnetic analysis spectrum of the intermediate compound of formula IV of the present invention. DETAILED DESCRIPTION

[0038] The technical solution of the present invention is further specifically described below through specific embodiments and drawings, but the present invention is not limited to these embodiments.

[0039] Example 1

[0040] 11.1g (0.46mol) of magnesium chips and 80.0g of anhydrous tetrahydrofuran were placed in a clean reaction bottle, and the reaction bottle was replaced with nitrogen. The temperature was raised to 60°C to 65°C, and a solution of 10g (0.04mol) of 4-bromo-2-fluorobiphenyl, 0.2g (0.0018mol) of bromoethane and 20.0g of tetrahydrofuran was added dropwise. The reaction liquid phenomenon was observed. The heat release was intense, the reflux rate was accelerated, and a large number of bubbles appeared on the liquid surface, indicating that the reaction was initiated. The temperature was then lowered to 55°C, and a mixed solution of 90g (0.36mol) of 4-bromo-2-fluorobiphenyl and 300g of tetrahydrofuran was added dropwise. The temperature was controlled at 60°C to 65°C during the addition process. After the addition was completed, the temperature was kept warm for 2h. After the reaction was completed, the temperature was lowered to room temperature to obtain a tetrahydrofuran solution containing a Grignard reagent compound of formula III, which was protected by nitrogen and allowed to stand for use.

[0041] Example 2

[0042] 81.8g (0.53mol) of 2-bromopropionic acid, 84.4g (0.61mol) of anhydrous potassium carbonate and 300g of acetone were placed in a clean reaction bottle, heated to 30℃~40℃, and a mixed solution of 85.0g (0.51mol) of ethyl 1-bromoacetate and 40.0g of tetrahydrofuran was added dropwise for about 1h. After the addition was completed, the reaction was continued for 2h. During the reaction, the sample was taken for central control. After the central control was qualified, the reaction was terminated, filtered, and the filtrate was concentrated to recover acetone. The concentrate was dissolved with 200g of dichloromethane, and washed with 100g of water, and then washed with 100g of sodium bicarbonate aqueous solution with a mass percentage of 5%, and then washed with 100g of water. The organic phase was concentrated to recover dichloromethane to obtain 105.0g of light yellow oily compound IV with a purity of 96.5%. The obtained compound IV was analyzed by nuclear magnetic resonance detection, and the specific spectrum is as follows Figure 1 shown.

[0043] Example 3

[0044] 105.0g (0.44mol) of compound IV, 8g of anhydrous cobalt chloride and 220g of anhydrous tetrahydrofuran were placed in a clean reaction bottle, cooled to 0-5°C, and the tetrahydrofuran solution of Grignard reagent compound III was slowly added dropwise, the temperature was controlled at 0-5°C, and the dropping time was about 1-2h. After the dropping was completed, the reaction was kept at 0-5°C for 5h, and the sample was taken for central control. After the central control was qualified, the tetrahydrofuran was recovered by vacuum concentration, and 250g of dichloromethane was added to the residue. 5% hydrochloric acid solution was added dropwise at room temperature, and the pH value was adjusted to 6-7. The mixture was allowed to stand for stratification, and the organic layer was washed twice with 100g of water. The mixture was concentrated under reduced pressure to dryness to obtain 105.5g of crude flurbiprofen axetil as a light yellow oil. Column chromatography was performed using ethyl acetate and n-heptane (3:17) and silica gel to obtain 80.18g of colorless to slightly yellow transparent liquid flurbiprofen axetil, with a yield of 76.0% and a purity of 99.98%.

[0045] Example 4

[0046] Place 11.5g (0.48mol) of magnesium chips and 80g of anhydrous tetrahydrofuran in a clean reaction bottle, replace the reaction bottle with nitrogen, heat it to 60℃~65℃, add dropwise a solution of 10g (0.04mol) of 4-bromo-2-fluorobiphenyl, 0.2g (0.0018mol) of ethyl bromide and 20g of tetrahydrofuran, observe the phenomenon of the reaction liquid, exotherm is intense, reflux rate is accelerated, and a large number of bubbles appear on the liquid surface, indicating that the reaction is initiated, then cool it to 50℃, add dropwise a mixed solution of 90.0g (0.36mol) of 4-bromo-2-fluorobiphenyl and 400g of tetrahydrofuran, control the temperature at 50℃~55℃ during the addition, continue to keep warm for 2.5h, the reaction is over, cool it to room temperature, fill it with nitrogen for protection, and let it stand for use.

[0047] Example 5

[0048] 93.3 g (0.61 mol) of 2-bromopropionic acid, 70.1 g (0.66 mol) of anhydrous sodium carbonate and 320 g of acetone are placed in a clean reaction bottle, the temperature is raised to 35°C-40°C, and a mixed solution of 85.0 g (0.51 mol) of ethyl 1-bromoacetate and 50 g of tetrahydrofuran is added dropwise. The addition time is about 1 hour. After the addition is completed, the reaction is continued for 2 hours of insulation. During the reaction, sampling is performed for central control. After the central control is qualified, the reaction is completed, the filtrate is filtered, and the acetone is concentrated to recover the acetone. The concentrate is dissolved with 200 g of dichloromethane, and 100 g of water is added for washing, and then 100 g of a 5% by mass sodium bicarbonate aqueous solution is added for washing, and then 100 g of water is added for washing. The organic phase is concentrated to recover dichloromethane to obtain 106 g of a light yellow oily compound of formula IV with a purity of 96.7%.

[0049] Example 6

[0050] Take 105g (0.44mol) of the compound of formula IV prepared by the method of Example 5, 4.3g of anhydrous nickel chloride and 200g of anhydrous 2-methyltetrahydrofuran and place them in a clean reaction bottle, cool to -5℃~0℃, slowly drip the 2-methyltetrahydrofuran solution of the Grignard reagent compound of formula III (the amount of the compound of formula III is 109.7g (0.4mol)), control the temperature at -5℃~0℃, and the dripping time is about 1.5h. After the dripping is completed, keep the temperature at -5℃~0℃ for 6h, take samples for central control, and after the central control is qualified, concentrate under reduced pressure to recover 2-methyltetrahydrofuran, add 250g of dichloromethane to the residue, drip 5% hydrochloric acid solution at room temperature, adjust the pH value to 6~7, let stand and separate, and wash the organic layer twice with 100g of water. Concentrate under reduced pressure to dryness to obtain 108.2g of crude flurbiprofen axetil as a light yellow oil. Column chromatography was then performed using ethyl acetate and n-heptane (3:17) and silica gel to obtain 84.6 g of colorless to slightly yellow transparent liquid flurbiprofen axetil with a yield of 78.2% and a purity of 99.97%.

[0051] Example 7

[0052] 85.7 g (0.56 mol) of 2-bromopropionic acid, 81.6 g (0.77 mol) of anhydrous sodium carbonate and 250 g of N,N-dimethylformamide were placed in a clean reaction bottle, heated to 45°C-50°C, and a mixed solution of 85.0 g (0.51 mol) of ethyl 1-bromoacetate and 40.0 g of 2-methyltetrahydrofuran was added dropwise for about 1 hour. After the addition was completed, the reaction was continued for 2 hours of insulation. During the reaction, sampling was performed for central control. After the central control was qualified, the reaction was completed, filtered, and the filtrate was concentrated to recover N,N-dimethylformamide. The concentrate was dissolved with 200 g of dichloromethane, and 100 g of water was added for washing, and then 100 g of a 5% by mass sodium bicarbonate aqueous solution was added for washing, and then 100 g of water was added for washing. The organic phase was concentrated to recover dichloromethane to obtain 108.2 g of a light yellow oily compound of formula IV with a purity of 96.7%.

[0053] Example 8

[0054] Take 124.3g (0.52mol) of compound IV, 7g of anhydrous palladium chloride and 220g of anhydrous 2-methyltetrahydrofuran and place them in a clean reaction bottle, cool to -10℃~0℃, slowly drip the 2-methyltetrahydrofuran solution of Grignard reagent compound III (the amount of compound III is 109.7g (0.4mol)), control the temperature at -10℃~0℃, and the dripping time is about 1~2h. After the dripping is completed, keep the temperature at -10℃~0℃ for 5h, take samples for central control, and after the central control is qualified, concentrate under reduced pressure to recover 2-methyltetrahydrofuran, add 250g of dichloromethane to the residue, drip 5% hydrochloric acid solution at room temperature, adjust the pH value to 6~7, let stand and separate, and wash the organic layer twice with 100g of water. Concentrate under reduced pressure to dryness to obtain 106.8g of crude flurbiprofen axetil as a light yellow oil. Column chromatography was then performed using ethyl acetate and n-heptane (3:17) and silica gel to obtain 82.66 g of colorless to slightly yellow transparent liquid flurbiprofen axetil with a yield of 77.4% and a purity of 99.95%.

[0055] Example 9

[0056] 90.3 g (0.59 mol) of 2-bromopropionic acid, 66.7 g (0.66 mol) of triethylamine and 350 g of 1,4-dioxane were placed in a clean reaction bottle, the temperature was raised to 40°C-45°C, and a mixed solution of 85.0 g (0.51 mol) of ethyl 1-bromoacetate and 35 g of anhydrous tetrahydrofuran was added dropwise. The addition time was about 1 hour. After the addition was completed, the reaction was continued for 2 hours of insulation. During the reaction, sampling was performed for central control. After the central control was qualified, the reaction was completed, the filtrate was filtered, and the 1,4-dioxane was recovered by concentration. The concentrate was dissolved with 200 g of dichloromethane, and 100 g of water was added for washing. Then 100 g of a 5% by mass sodium bicarbonate aqueous solution was added for washing, and then 100 g of water was added for washing. The organic phase was concentrated to recover dichloromethane to obtain 107.1 g of a light yellow oily compound of formula IV with a purity of 97.1%.

[0057] Example 10

[0058] Take 105g (0.44mol) of compound IV, 7.6g of anhydrous cobalt chloride and 320g of anhydrous 1,4-dioxane in a clean reaction bottle, cool to 0-5°C, slowly drop a 1,4-dioxane solution of Grignard reagent compound III (the amount of compound III is 109.7g (0.4mol)), control the temperature at 0-5°C, the dropping time is about 2h, and after the dropping is completed, keep the reaction at 5°C-10°C for 4h, take a sample for central control, and after the central control is qualified, concentrate under reduced pressure to recover 1,4-dioxane, add 250g of dichloromethane to the residue, add 5% hydrochloric acid solution at room temperature, adjust the pH to 6-7, let stand for stratification, wash the organic layer twice with 100g of water, and concentrate the collected organic phase under reduced pressure to dryness to obtain 107.3g of crude flurbiprofen axetil as a light yellow oil. Column chromatography was then performed using ethyl acetate and n-heptane (3:17) and silica gel to obtain 82.4 g of colorless to slightly yellow transparent liquid flurbiprofen axetil with a yield of 76.8% and a purity of 99.96%.

[0059] Embodiment 11

[0060] 10g (0.42mol) of magnesium chips and 90g of anhydrous 2-methyltetrahydrofuran were placed in a clean reaction bottle, and the reaction bottle was replaced with nitrogen. The temperature was raised to 50°C to 55°C, and a solution of 10g (0.04mol) of 4-bromo-2-fluorobiphenyl, 0.22g (0.002mol) of ethyl bromide and 25g of 2-methyltetrahydrofuran were added dropwise. The reaction liquid was observed to release heat violently, and the temperature and reflux speed were accelerated. A large number of bubbles appeared on the liquid surface, indicating that the reaction was initiated. , then cool to 60°C, add dropwise a mixed solution of 90g (0.36mol) of 4-bromo-2-fluorobiphenyl and 300g of anhydrous 2-methyltetrahydrofuran, control the temperature at 60°C to 65°C during the dropwise addition, raise the temperature to reflux and continue to keep warm for 1.5h, the reaction is completed, cool to room temperature, and obtain a 2-methyltetrahydrofuran solution containing a Grignard reagent compound of formula III (the amount of the compound of formula III is 110.2g), fill with nitrogen for protection, and stand for use.

[0061] The solvent 2-methyltetrahydrofuran in this embodiment can be replaced by an ether solvent such as 1,4-dioxane, diethyl ether or ethylene glycol dimethyl ether, which can also enable the reaction to proceed, and the content of the Grignard reagent formula III compound can also reach a considerable level.

[0062] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

[0063] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

1. A method for preparing flurbiprofen axetil, characterized in that, The method comprises the following steps: A. In the presence of an acid binding agent, ethyl bromoacetate of the compound of formula II and 2-bromopropionic acid of the compound of formula III are subjected to alkylation reaction to obtain a compound of formula IV; B. Under the action of a coupling catalyst, coupling the Grignard reagent compound of formula V with the compound of formula IV to obtain the product compound of formula I; 2. The method for preparing flurbiprofen axetil according to claim 1, wherein In step A, the acid-binding agent is selected from an organic base or an inorganic base, the organic base is selected from one or more of triethylamine, diisopropylethylamine, pyridine and pyrrole; the inorganic base is selected from one or more of sodium carbonate, potassium carbonate and cesium carbonate.

3. The method for preparing flurbiprofen axetil according to claim 1, wherein The alkylation reaction in step A is carried out in a polar organic solvent, and the polar organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetone, 1,4-dioxane, dimethyl sulfoxide and N-methylpyrrolidone.

4. The method for preparing flurbiprofen axetil according to claim 1, 2 or 3, characterized in that: The temperature of the alkylation reaction in step A is 30°C to 50°C.

5. The method for preparing flurbiprofen axetil according to claim 1, 2 or 3, characterized in that: The coupling catalyst in step B is selected from one or more of nickel chloride, cobalt chloride and palladium chloride.

6. The method for preparing flurbiprofen axetil according to claim 1, 2 or 3, characterized in that: The coupling reaction in step B is carried out in an ether solvent 1, and the ether solvent 1 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether and ethylene glycol dimethyl ether.

7. The method for preparing flurbiprofen axetil according to claim 6, characterized in that: The temperature of the coupling reaction in step B is -10°C to 10°C.

8. The method for preparing flurbiprofen axetil according to claim 1, 2 or 3, characterized in that: The molar ratio of the compound of formula II, 1-ethyl bromoacetate: the compound of formula III, 2-bromopropionic acid: the acid binding agent in step A is 1:1.0-1.2:1.0-1.5; the molar ratio of the Grignard reagent, compound of formula V: the compound of formula IV: the coupling catalyst in step B is 1:1.0-1.3:0.01-0.

1.

9. The method for preparing flurbiprofen axetil according to claim 1, 2 or 3, characterized in that: The Grignard reagent compound of formula V in step B is obtained by the following method: In an aprotic solvent, 4-bromo-2-fluorobiphenyl and magnesium undergo a Grignard reaction to generate the Grignard reagent compound of formula V.

10. The method for preparing flurbiprofen axetil according to claim 9, characterized in that: The aprotic solvent is selected from ether solvent II, and the ether solvent II is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether and ethylene glycol dimethyl ether.

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