A kind of synthetic method of indobufen

Abstract

The invention belongs to the technical field of drug synthesis, and specifically discloses a synthetic method of indobufen, wherein the synthetic method of the present invention comprises: in an organic solvent, under the action of a catalyst, a base and a ligand, p-bromoiodobenzene reacts with isoindolin-1-one to obtain an intermediate I; under alkaline conditions, the intermediate I reacts with diethyl malonate to obtain an intermediate II, and the intermediate II directly reacts with bromoethane without separation to obtain an intermediate III, and the intermediate III is decarboxylated, refined and purified to obtain indobufen. The synthetic method of the present invention has a simple process, short preparation steps, is suitable for industrial production, does not need to carry out nitration reaction, overcomes the defect of using a large amount of sulfuric acid and nitric acid mixed acid, reduces the pressure on environmental protection, improves the safety of the reaction, and avoids the use of dangerous hydrogen and hydrogen chloride gas, avoids the excessive reduction or incomplete reduction impurities generated in the final zinc powder reduction process, and improves the product purity.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and specifically relates to a method for synthesizing indobufen. Background Art

[0002] Indobufen is a racemic compound developed by Pfizer, USA. It was first launched in Italy in 1984. As a new generation of non-steroidal potent antiplatelet aggregation drugs, it selectively acts on circulating platelets, blocks the formation of thrombi, and inhibits the release of platelet factors to block platelet aggregation. This inhibitory effect is reversible, does not damage the function of platelets, does not change plasma parameters, and restores abnormal platelets to normal function. Compared with similar drugs, indobufen's effect of inhibiting platelet factors and anti-platelet aggregation is 2 to 5 times that of salicylic acid. Clinical studies have shown that under normal circumstances, the human body can ingest 200 to 400 mg per day, and 100 to 200 mg per day is appropriate for elderly patients and those with renal insufficiency. This product is non-mutagenic, non-teratogenic, and non-toxic to the fetus.

[0003] The synthesis methods of indobufen reported in the literature are mainly the following:

[0004] 1. Hangzhou Zhongmei Huadong invention patent CN106631974A reported that organic acid was used as reaction solvent, 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid and zinc powder were added, hydrogen chloride gas was introduced under normal pressure, the reaction temperature was controlled at 82°C, the reaction time was 1 hour, and the reaction liquid was completely clear. Filter, wash the filter residue with acetic acid, combine the filtrate and washing liquid, recover the solvent under reduced pressure, pour the residual liquid into an appropriate amount of water, stir, adjust the pH to 5.5-6.5 with ammonia water, centrifuge and dry to obtain crude indobufen, and the crude product was purified by activated carbon according to conventional processes, and the purity was 99.6%. (1) This method requires hydrogen chloride gas to pass through at high temperature, which has higher requirements for equipment, not only polluting the environment but also posing safety risks; (2) The synthesis reaction is finally reduced using zinc powder, which is a product made from explosive tubes, which inevitably produces impurities that are over-reduced or incompletely reduced, and is difficult to remove, resulting in a low purity of the final product; (3) During post-treatment, the residue is poured into water for crystallization, but the concentrate has high viscosity and is difficult to transfer, making the operation inconvenient. Ammonia water is used to adjust the pH, and the amount of alkali used is large, which easily introduces ammonium salt impurities; (4) The synthesis reaction is prepared by condensing 2-(4-aminophenyl)butyric acid with o-cyanobenzyl bromide or o-phthalaldehyde. The o-cyanobenzyl bromide and o-phthalaldehyde used are expensive and not suitable for industrial production.

[0005] 2. The synthesis methods of indobufen reported by Gao Xuemin et al. in "Synthesis of the Anticoagulant Indobufen" (China Pharmaceutical Industry Journal, 1989, 20 (11)), Zheng Gengxiu et al. in "Preparation Process of Indobufen" (China Pharmaceutical Industry Journal, 1991, 27 (7)), invention patent CN110229075A, invention patent CN101914055A, Australian patent (AT1977, 337173), and German patent (GerOffen, 1988, 3807595) can be summarized as follows: 2-(4-nitrophenyl)butyric acid is used as the starting material, and is reduced to 2-(4-aminophenyl)butyric acid by iron powder reduction, catalytic hydrogenation or hydrazine hydrate reduction, which is then condensed with phthalic anhydride, and finally reduced with zinc powder and hydrogen chloride gas, and indobufen is obtained by recrystallization from ethanol. (1) The final step of the synthesis reaction is the use of zinc powder for reduction, which inevitably produces impurities due to over-reduction or incomplete reduction, and these impurities are difficult to remove. (2) In addition, the synthesis route of the starting material 2-(4-nitrophenyl)butyric acid involves a nitration reaction, so due to factors such as safety assessment and environmental assessment, the market supply is unstable, which affects the industrial production of indobufen.

[0006] 3. Beijing Zimeng Pharmaceutical Invention Patent CN 116554083 A prepares indobufen by reducing 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid. The reducing agent used is a mixture of anhydrous zinc chloride and zinc powder, which also inevitably produces impurities due to excessive reduction or incomplete reduction.

[0007] Fourth, Shanghai Gaozhun Pharmaceutical's invention patent CN 114685346 A uses reagents such as o-carboxybenzaldehyde and sodium borohydride to add to a methanol solution of 2-(4-nitrophenyl)butyric acid, and finally reacts to produce indobufen. Although the impurities produced by excessive reduction or incomplete reduction in the final zinc powder reduction reaction are avoided, the invention uses sodium borohydride, which is easy to make explosives, and the synthesis route of the starting material 2-(4-nitrophenyl)butyric acid involves nitration reaction, so the starting material is easily affected by safety assessment, environmental assessment and other factors, and the market supply is unstable, which affects the industrial production of indobufen.

[0008] 5. Shandong Jingwei Pharmaceutical's invention patent CN 115850154 A uses 2-(4-aminophenyl)butyric acid and 2-formylbenzoic acid to prepare indobufen imine through condensation reaction; then directly add a reducing agent, sodium borohydride, to the reaction system to prepare indobufenamine, and further add an acidic reagent to the reaction system to prepare indobufen through cyclization reaction. The reaction route uses easily explosive sodium borohydride, which poses a safety risk and is not conducive to industrial production and expansion.

[0009] Therefore, it is currently very necessary to develop a synthesis method of indobufen that is environmentally friendly, highly safe, has high product purity and is suitable for industrial production. Summary of the invention

[0010] In view of the above-mentioned deficiencies in the prior art, the present invention provides a method for preparing indobufen that is simple to operate, environmentally friendly, safe, and suitable for industrial production. The present invention uses p-bromoiodobenzene as a starting material, reacts with isoindolin-1-one to obtain intermediate I, intermediate I reacts with diethyl malonate to obtain intermediate II, intermediate II directly reacts with bromoethane without separation to obtain intermediate III, and intermediate III is subjected to decarboxylation reaction, refined and purified to obtain indobufen. The synthetic route is as follows:

[0011]

[0012] It is characterized in that the synthetic route comprises the following steps:

[0013] Step 1: In an organic solvent A, p-bromoiodobenzene reacts with isoindolin-1-one under the catalysis of a catalyst, a basic substance a, and a ligand to obtain an intermediate I;

[0014]

[0015] Step 2: In an organic solvent B, in the presence of an alkaline substance b, intermediate I reacts with diethyl malonate to obtain intermediate II, and intermediate II reacts with ethyl bromide without separation or purification to obtain intermediate III;

[0016]

[0017] Step 3: The intermediate III is hydrolyzed under alkaline substance c, and indobufen is obtained after post-treatment and purification;

[0018]

[0019] The above-mentioned method for preparing indobufen is characterized in that the molar ratio of p-bromoiodobenzene to isoindolin-1-one in step 1 is 1-1.3:1;

[0020] The above-mentioned method for preparing indobufen is characterized in that the catalyst described in step 1 comprises one of cuprous iodide, cuprous chloride, and cuprous oxide, and the molar ratio of the catalyst to p-bromoiodobenzene is 0.04-0.06:1;

[0021] The above-mentioned method for preparing indobufen is characterized in that the ligand described in step 1 includes one of N,N-diethylethylenediamine and trans-N,N-dimethylcyclohexanediamine, and the molar ratio of the ligand to p-bromoiodobenzene is 0.08-0.12:1;

[0022] The above-mentioned method for preparing indobufen is characterized in that the alkaline substance a described in step 1 comprises one of potassium carbonate and potassium phosphate, and potassium phosphate is further preferred, and the molar ratio of the alkaline substance a to p-bromoiodobenzene is 1.5-3:1;

[0023] The above-mentioned method for preparing indobufen is characterized in that the reaction temperature in step 1 is 70-90° C.;

[0024] The above-mentioned method for preparing indobufen is characterized in that the reaction solvent A described in step 1 comprises one of acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide;

[0025] The above-mentioned method for preparing indobufen is characterized in that the alkaline substance b used in the reaction in step 2 includes one of potassium carbonate, cesium carbonate, and sodium hydride, and potassium carbonate is further preferred; the molar ratio of intermediate I, diethyl malonate and alkaline substance b is 1: 1.1~2: 1.2~5; the above-mentioned method for preparing indobufen is characterized in that the molar ratio of bromoethane to intermediate II in step 2 is 1.1~2:1; the reaction solvent B described in step 2 includes one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide;

[0026] The above-mentioned method for preparing indobufen is characterized in that the reaction temperature of the intermediate II in step 2 is 60-95° C.;

[0027] The above-mentioned method for preparing indobufen is characterized in that the reaction temperature of the intermediate III in step 2 is 25-35° C.;

[0028] The above-mentioned method for preparing indobufen is characterized in that the alkaline substance c described in step 3 is one of sodium hydroxide and potassium hydroxide, and the molar ratio of the intermediate III to the base is 1:3-5;

[0029] The above-mentioned method for preparing indobufen is characterized in that the reaction temperature in step 3 is 40-60° C.;

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] 1. In the preparation process of the present invention, no nitration reaction is required to prepare 2-(4-nitrophenyl)butyric acid, which overcomes the defect of using a large amount of sulfuric acid and nitric acid mixed acid, reduces the pressure on environmental protection, and improves the safety of the reaction.

[0032] 2. The preparation method of the present invention avoids the use of dangerous hydrogen and hydrogen chloride gases and explosive reagents, and avoids the over-reduction or incomplete reduction impurities generated in the final zinc powder reduction process, thereby improving the purity of the product.

[0033] 3. A new indobufen preparation route has been developed. The raw materials used in the route are easily available, the process is simple, the preparation steps are short, the reaction process is easy to control, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Attached Figure 1 It is the synthetic route of indobufen;

[0035] Attached Figure 2 is the liquid phase spectrum of indobufen, the product in Example 1;

[0036] Attached Figure 3 is the peak result of the product indobufen in Example 1;

[0037] Attached Figure 4 is the liquid phase spectrum of indobufen, the product in Example 2;

[0038] Attached Figure 5 is the peak result of the product indobufen in Example 2;

[0039] Attached Figure 6 is the liquid phase spectrum of indobufen, the product in Example 3;

[0040] Attached Figure 7 is the peak result of the product indobufen in Example 3;

[0041] Attached Figure 8 is the liquid phase spectrum of indobufen, the product in Example 4;

[0042] Attached Fig. 9 This is the peak result of the product indobufen in Example 4. DETAILED DESCRIPTION

[0043] The present invention is further described below in conjunction with specific implementation methods. The following description is only for explaining the present invention. The protection scope of the present invention is not limited to these embodiments. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the contents of the present invention still fall within the protection scope of the present invention.

[0044] The following specific examples are provided to illustrate the present invention in detail, but are not intended to limit the present invention.

[0045] Example 1

[0046] 1. Preparation of intermediate I:

[0047] Place p-bromoiodobenzene (50 g, 1.0 eq), isoindolin-1-one (32 g, 0.83 eq), potassium phosphate (122 g, 2.0 eq), cuprous iodide (2.72 g, 0.05 eq), and N,N-diethylethylenediamine (3.25 g, 0.10 eq) in a reaction bottle, add 300 ml of acetonitrile, start stirring, replace nitrogen, and heat to 70 °C for reaction. After the reaction is completed by thin layer detection, cool to 5-10 °C, filter, add purified water to the filtrate, precipitate an off-white solid, filter and dry to obtain 74 g of intermediate I with a yield of 90.0%.

[0048] 2. Preparation of Intermediate II and Intermediate III:

[0049] The intermediate I (74 g, 1.0 eq), diethyl malonate (46 g, 1.1 eq) and potassium carbonate (178 g, 5.0 eq) obtained in the previous step were placed in a reaction bottle, 500 ml of acetonitrile was added, stirring was started, the temperature was raised to 95 °C for reaction, and after the reaction was completed by thin layer chromatography detection, the preparation of intermediate II was completed, the temperature was lowered to 25 °C, ethyl bromide (42 g, 1.5 eq) was added to continue the reaction, and after the reaction was completed by thin layer chromatography detection, 2000 ml of purified water was added to the reaction solution, and an off-white solid was precipitated under stirring. After drying, 87 g of intermediate III was obtained, and the yield was 85.0%.

[0050] 3. Preparation of Indobufen:

[0051] The intermediate III (87 g, 1.0 eq) and sodium hydroxide (45 g, 5.0 eq) obtained in the previous step were placed in a reaction bottle, 800 ml of purified water were added, stirring was started, and the temperature was raised to 40°C for reaction. After the solid in the reaction solution was completely dissolved, the reaction was continued. After the reaction was completed by thin layer detection, the temperature was lowered to 5-10°C, and the reaction solution was neutralized with hydrochloric acid. A large amount of solid precipitated in the reaction solution, which was filtered to obtain a wet product of crude indobufen.

[0052] The wet product was placed back in a reaction bottle, ethanol (9V / W) was added, and the temperature was raised to reflux. After the solid was completely dissolved, activated carbon was added, refluxed and stirred for 1 hour, filtered while hot, and the filtrate was cooled to 0-5°C. A white solid gradually precipitated in the filtrate. The stirring was continued for 1 hour, and suction was filtered. The filter cake was rinsed with a small amount of ethanol and dried at 60°C to obtain 62 g of indobufen with a yield of 95.0% and a purity of 99.68%.

[0053] Example 2

[0054] 1. Preparation of intermediate I:

[0055] Place p-bromoiodobenzene (50 g, 1.0 eq), isoindolin-1-one (39 g, 1.0 eq), potassium carbonate (36.8 g, 1.5 eq), cuprous chloride (1.13 g, 0.04 eq), and trans-N,N-dimethylcyclohexanediamine (6.40 g, 0.08 eq) in a reaction bottle, add 300 ml of N,N-dimethylformamide, start stirring, replace nitrogen, heat to 80 °C for reaction, and after the reaction is completed by thin layer detection, cool to 5-10 °C, filter, add purified water to the filtrate, precipitate an off-white solid, filter and dry to obtain 78 g of intermediate I with a yield of 95.0%.

[0056] 2. Preparation of Intermediate II and Intermediate III:

[0057] The intermediate I (78 g, 1.0 eq), diethyl malonate (53.7 g, 1.3 eq) and cesium carbonate (265 g, 3 eq) obtained in the previous step were placed in a reaction bottle, 500 ml of dimethyl sulfoxide was added, stirring was started, the temperature was raised to 60 °C for reaction, and after the reaction was completed by thin layer chromatography detection, the preparation of intermediate II was completed, the temperature was lowered to 35 °C, ethyl bromide (31 g, 1.1 eq) was added and the reaction was continued for 20 hours. After the reaction was completed by thin layer chromatography detection, 2000 ml of purified water was added to the reaction solution, and an off-white solid was precipitated under stirring. The solid was dried to obtain 80 g of intermediate III with a yield of 75%.

[0058] 3. Preparation of Indobufen:

[0059] The intermediate III (80 g, 1.0 eq) and sodium hydroxide (33 g, 4.0 eq) obtained in the previous step were placed in a reaction bottle, 800 ml of purified water were added, stirring was started, and the temperature was raised to 40°C for reaction. After the solid in the reaction solution was completely dissolved, the reaction was continued. After the reaction was completed by thin layer detection, the temperature was lowered to 5-10°C, and the reaction solution was neutralized with hydrochloric acid. A large amount of solid precipitated in the reaction solution, which was filtered to obtain a wet product of crude indobufen.

[0060] The wet product was placed back in a reaction bottle, ethanol (9V / W) was added, and the temperature was raised to reflux. After the solid was completely dissolved, activated carbon was added, refluxed and stirred for 1 hour, filtered while hot, and the filtrate was cooled to 0-5°C. A white solid gradually precipitated in the filtrate. The stirring was continued for 1 hour, filtered with suction, and the filter cake was rinsed with a small amount of ethanol. Drying at 60°C gave 56 g of indobufen with a yield of 95.0% and a purity of 99.68%.

[0061] Example 3

[0062] 1. Preparation of intermediate I:

[0063] Place p-bromoiodobenzene (50 g, 1.0 eq), isoindolin-1-one (30 g, 0.77 eq), potassium phosphate (183 g, 3.0 eq), cuprous oxide (2.45 g, 0.06 eq), and N,N-diethylethylenediamine (3.90 g, 0.12 eq) in a reaction bottle, add 300 ml of dimethyl sulfoxide, start stirring, replace nitrogen, heat to 90 °C for reaction, and after the reaction is completed by thin layer detection, cool to 5-10 °C, filter, add purified water to the filtrate, precipitate an off-white solid, filter and dry to obtain 70 g of intermediate I with a yield of 85.0%.

[0064] 2. Preparation of Intermediate II and Intermediate III:

[0065] The intermediate I (70 g, 1.0 eq), diethyl malonate (78 g, 2.0 eq) and sodium hydride (15 g, 1.2 eq) obtained in the previous step were placed in a reaction bottle, 500 ml of N, N-dimethylformamide was added, stirring was started, the temperature was raised to 70 ° C for reaction, and after the reaction was completed by thin layer chromatography detection, the preparation of intermediate II was completed, the temperature was lowered to 30 ° C, ethyl bromide (56 g, 2.0 eq) and sodium hydride (15 g, 1.2 eq) were added to continue the reaction, and after the reaction was completed by thin layer chromatography detection, 2000 ml of purified water was added to the reaction solution, and an off-white solid was precipitated under stirring. After drying, 87 g of intermediate III was obtained, and the yield was 90.0%.

[0066] 3. Preparation of Indobufen:

[0067] The intermediate III (87 g, 1.0 eq) and potassium hydroxide (37.5 g, 3.0 eq) obtained in the previous step were placed in a reaction bottle, 800 ml of purified water was added, stirring was started, and the temperature was raised to 40°C for reaction. After the solid in the reaction solution was completely dissolved, the reaction was continued. After the reaction was completed by thin layer detection, the temperature was lowered to 5-10°C, and the reaction solution was neutralized with hydrochloric acid. A large amount of solid precipitated in the reaction solution, which was filtered to obtain a wet product of crude indobufen.

[0068] The wet product was placed back in a reaction bottle, ethanol (9V / W) was added, and the temperature was raised to reflux. After the solid was completely dissolved, activated carbon was added, refluxed and stirred for 1 hour, filtered while hot, and the filtrate was cooled to 0-5°C. A white solid gradually precipitated in the filtrate. The stirring was continued for 1 hour, and suction was filtered. The filter cake was rinsed with a small amount of ethanol and dried at 60°C to obtain 62 g of indobufen with a yield of 95.0% and a purity of 99.70%.

[0069] Example 4

[0070] 1. Preparation of intermediate I:

[0071] Place p-bromoiodobenzene (500 g, 1.0 eq), isoindolin-1-one (320 g, 0.83 eq), potassium phosphate (1220 g, 2.0 eq), cuprous iodide (27.2 g, 0.05 eq), and N,N-diethylethylenediamine (32.5 g, 0.10 eq) in a reaction bottle, add 3000 ml of acetonitrile, start stirring, replace nitrogen, heat to 70-80 °C for reaction, and after the reaction is completed by thin layer detection, cool to 5-10 °C, filter, add purified water to the filtrate, precipitate an off-white solid, filter and dry to obtain 750 g of intermediate I with a yield of 90.0%.

[0072] 2. Preparation of Intermediate II and Intermediate III:

[0073] The intermediate I (750 g, 1.0 eq), diethyl malonate (540 g, 1.3 eq) and potassium carbonate (1100 g, 3.0 eq) obtained in the previous step were placed in a reaction bottle, 5000 ml of N, N-dimethylacetamide was added, stirring was started, the temperature was raised to 60 °C for reaction, and after the reaction was completed by thin layer chromatography detection, the preparation of intermediate II was completed, the temperature was lowered to 25-35 °C, ethyl bromide (420 g, 1.5 eq) was added to continue the reaction, and after the reaction was completed by thin layer chromatography detection, 2000 ml of purified water was added to the reaction solution, and an off-white solid was precipitated under stirring, which was dried to obtain 875 g of intermediate III with a yield of 85.0%.

[0074] 3. Preparation of Indobufen:

[0075] The intermediate III (875 g, 1.0 eq) and sodium hydroxide (360 g, 4.0 eq) obtained in the previous step were placed in a reaction bottle, 8000 ml of purified water were added, stirring was started, and the temperature was raised to 60°C for reaction. After the solid in the reaction solution was completely dissolved, the reaction was continued. After the reaction was completed by thin layer detection, the temperature was lowered to 5-10°C, and the reaction solution was neutralized with hydrochloric acid. A large amount of solid precipitated in the reaction solution, which was filtered to obtain a wet product of crude indobufen.

[0076] The wet product was placed back in a reaction bottle, ethanol (9V / W) was added, and the temperature was raised to reflux. After the solid was completely dissolved, activated carbon was added, refluxed and stirred for 1 hour, filtered while hot, and the filtrate was cooled to 0-5°C. A white solid gradually precipitated in the filtrate. The stirring was continued for 1 hour, and suction was filtered. The filter cake was rinsed with a small amount of ethanol and dried at 60°C to obtain 621 g of indobufen with a yield of 95.0% and a purity of 99.76%.

[0077] The above descriptions are only the best embodiments of the present invention, and the protection scope of the present invention is not limited to these embodiments. Those skilled in the art should understand that equivalent replacements or corresponding improvements made to the contents of the present invention still fall within the protection scope of the present invention.

Claims

1. A method for synthesizing indobufen, characterized in that: The method comprises the following steps: Step 1: In solvent A, p-bromoiodobenzene and isoindolin-1-one react under the catalysis of a catalyst, a basic substance a, and a ligand to obtain an intermediate I. The reaction formula is: ； The reaction temperature is 70~90℃. The reaction solvent A is selected from one of acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide, The catalyst is selected from cuprous iodide, cuprous chloride, and cuprous oxide. The ligand is selected from one of N,N-diethylethylenediamine and trans-N,N-dimethylcyclohexanediamine. The molar ratio of 4-bromoiodobenzene to isoindolin-1-one is 1-1.3:

1. The molar ratio of catalyst to p-bromoiodobenzene is 0.04-0.06:

1. The molar ratio of ligand to p-bromoiodobenzene is 0.08~0.12:

1. The molar ratio of alkaline substance a to p-bromoiodobenzene is 1.5-3:1; Step 2: In solvent B, under the action of alkaline substance b, intermediate I reacts with diethyl malonate to obtain intermediate II, and then ethyl bromide is added to react without separation and purification to obtain intermediate III. The reaction formula is: ； Wherein, the reaction temperature of the intermediate II is 60-95°C, the reaction temperature of the intermediate III is 25-35°C, the molar ratio of the intermediate I, diethyl malonate and the alkaline substance b is 1:1.1-2:1.2-5, and the molar ratio of ethyl bromide to the intermediate II is 1.1-2:1; The reaction solvent B is selected from one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; Step 3, the intermediate III is hydrolyzed under alkaline substance c, and indobufen is obtained after acid adjustment, crystallization and purification. The reaction formula is: ； The reaction temperature is 40-60°C, and the molar ratio of the intermediate III to the alkaline substance c is 1:3-5.

2. The method for synthesizing indobufen according to claim 1, characterized in that: The alkaline substance a described in step 1 is selected from one of potassium carbonate and potassium phosphate.

3. The method for synthesizing indobufen according to claim 1, characterized in that: The alkaline substance a described in step 1 is potassium phosphate.

4. The method for synthesizing indobufen according to claim 1, characterized in that: The alkaline substance b described in step 2 is selected from one of potassium carbonate, cesium carbonate and sodium hydride.

5. The method for synthesizing indobufen according to claim 1, characterized in that: The alkaline substance b described in step 2 is potassium carbonate.

6. The method for synthesizing indobufen according to claim 1, characterized in that: The alkaline substance c described in step 3 is selected from one of sodium hydroxide and potassium hydroxide.

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