A process for the preparation of indobufen

Abstract

The application discloses a preparation method of indobufen, and belongs to the technical field of drug synthesis process, wherein the preparation method is as follows: dissolving ortho-carboxyl benzamide in an organic solvent, cooling to 2-8 DEG C, adding a reducing agent, and carrying out incubation reaction, post-treatment, and obtaining compound I; mixing the organic solvent, a catalyst and the compound I, carrying out reflux water separation reaction, post-treatment, and obtaining compound II; dissolving the compound II in an organic solvent, adding an alkaline reagent, heating to 40-50 DEG C, dropwise adding 2-(4-bromophenyl) butyric acid methyl ester, then carrying out reflux reaction, post-treatment, and obtaining compound III; dissolving the compound III in an organic solvent, adjusting the pH to 10.5-11.5, stirring and reacting at 40-50 DEG C, post-treatment, and obtaining indobufen. The preparation method improves the safety of preparation, and also improves the quality and yield of the product indobufen.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to a method for preparing indobufen. Background Technology

[0002] Indobufen is a racemic mixture developed by Pfizer Inc. in the United States and successfully developed by Farmfalia Carlo Erba, SPA in Italy. It was first launched in Italy in August 1984. As a non-steroidal antiplatelet aggregation drug, its mechanism of action includes: (1) inhibiting platelet COX in a reversible manner, thereby reducing the production of platelet activator TXA2, promoting the production of prostacyclin, and inhibiting platelet activation; (2) selectively inhibiting platelet aggregation mediated by platelet activating factor, ADP, collagen, adrenaline, and AA; (3) selectively downgrading the levels of platelet factor 3, platelet adenosine triphosphate, platelet factor 4, β-TG, and serotonin, thereby inhibiting platelet adhesion; (4) inhibiting platelet aggregation through platelet membrane glycoprotein receptors, blocking platelet aggregation mediated by multiple pathways. Indobufen is currently the only antithrombotic drug with reversible selective multi-target characteristics, and patients experience fewer adverse reactions after oral administration.

[0003] Currently, the reported methods for preparing indobufen mainly include the following two: Preparation method 1: Prepared by reduction of 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid; Preparation method 2: The isoindoline is coupled with ethyl 2-(4-bromophenyl)butyrate via palladium acetate catalysis, followed by CH2 oxidation of the isoindoline at the benzylic position, and finally hydrolysis of the ethyl ester to obtain the product.

[0004] Of the methods described above, the second preparation method involves high CN coupling production costs, cumbersome post-processing, and low oxidation reaction yield, making it unsuitable for industrial production. For the first preparation method, namely the reduction of 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid to prepare indobufen, the specific implementation schemes are as follows: Implementation Plan 1: Gao Xuemin et al. reported in "Synthesis of the anticoagulant indobufen" (China Pharmaceutical Industry Journal, 1989, 20(11): 486-487) that acetic acid was used as the reaction solvent, zinc powder was added and refluxed for reduction, filtration was performed, the solid was washed with acetic acid, the filtrate was concentrated and evaporated to dryness, the residue was added with water, neutralized with sodium carbonate, filtered, the solid was crystallized with ethanol, and dried to obtain indobufen. This method requires a large amount of solvent, a high reaction temperature, incomplete reaction, and many impurities. There is a lot of filter residue during post-processing filtration; the dispersion of crystals after filtrate concentration and addition of water is poor, and inorganic salts are easily encapsulated. Adjusting the pH with sodium carbonate easily introduces indobufen sodium salt impurities. The purity of the obtained crude product is low, and the yield is only 68.5%.

[0005] Implementation Plan 2: Zheng Gengxiu et al. reported in "Preparation Process of Indobufen" (China Pharmaceutical Industry Magazine, 1991, 22(7): 291-293) that diethyl ether was used as the reaction solvent, zinc powder was added, hydrogen chloride gas was passed through, and then 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid was added. Hydrogen chloride was passed through for another hour, filtered, the filter cake was washed with ethanol, the filtrate was concentrated under reduced pressure and evaporated to dryness, the residue was poured into water, filtered and dried. The obtained solid was crystallized with ethanol / petroleum ether to obtain indobufen, with a yield of 84%. This method requires the passage of hydrogen chloride gas, which has high requirements for the material of the equipment and relatively low safety; the use of low-boiling-point diethyl ether as the reaction solvent poses even greater safety risks.

[0006] Implementation Scheme 3: Chinese Patent CN101914055A discloses a method for preparing indomethacin by reduction. This patent reports the use of dioxane as a solvent, the addition of 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid and zinc powder, the purging of hydrogen chloride gas until the reaction is complete, the mixture being concentrated under reduced pressure and evaporated to dryness, water being added, stirring to induce crystallization, drying, and then crystallizing with anhydrous ethanol to obtain indobufen. This method also requires the purging of hydrogen chloride gas, placing high demands on the equipment materials; the solvent used, dioxane, is a Class II solvent, highly toxic, and prone to residue; the overall yield after recrystallization is low, only 65%.

[0007] Implementation Scheme 4: Chinese Patent CN106631974B discloses a method for preparing indobufen. This patent reports using an organic acid as a reaction solvent, adding 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid and zinc powder, passing hydrogen chloride gas under normal pressure, controlling the reaction temperature at 82℃, and reacting for 1 hour until the reaction solution is completely clear. The solution is filtered, the filter residue is washed with acetic acid, the filtrate and washings are combined, the solvent is recovered under reduced pressure, the residue is poured into an appropriate amount of water, stirred, and the pH is adjusted to 5.5-6.5 with ammonia. After centrifugation and drying, crude indobufen is obtained with a yield of 94.7% and a purity of 98%. After purification with activated carbon using conventional processes, the purity is 99.6%. This method involves passing hydrogen chloride gas at high temperature, which places higher demands on equipment and poses safety risks. In the post-processing, the residue is poured into water to crystallize, but the concentrate has high viscosity, making it difficult to transfer and inconvenient to operate. Using ammonia to adjust the pH results in a large amount of alkali being used, which can easily introduce ammonium salt impurities.

[0008] Given the problems with the above-mentioned synthesis processes, there is an urgent need to develop a simple, safe method for preparing indobufen that is suitable for industrial production. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention provides a method for preparing indobufen, using o-carboxybenzamide and methyl 2-(4-bromophenyl)butyrate as raw materials. Through reduction, cyclization, condensation, and hydrolysis reactions, the product indobufen is obtained. This method avoids the problems of zinc powder contamination and incomplete reduction in traditional processes, improves the safety of preparation, and also improves the quality and yield of the product indobufen, facilitating industrial production.

[0010] To solve the above technical problems, the technical solution adopted by the present invention is as follows: A method for preparing indobufen, the preparation route is as follows: .

[0011] A method for preparing indobufen includes the following steps: reduction, cyclization, condensation, and hydrolysis; The reduction involves dissolving o-carboxybenzamide in an organic solvent, cooling the solution to 2-8°C, adding a reducing agent, maintaining the temperature for the reaction, and then performing post-treatment to obtain compound I. The reduction reaction route is as follows: ;

[0012] In the reduction process, the structural formula of compound I is: ;

[0013] The organic solvent is tetrahydrofuran or methanol; The reducing agent is one or more of lithium aluminum hydride, borane-tetrahydrofuran complex, sodium borohydride, and boron trifluoride-tetrahydrofuran complex; When the reducing agent is sodium borohydride, aluminum chloride is required as an auxiliary agent, and the molar ratio of sodium borohydride to aluminum chloride is 0.18-0.19:0.39-0.4. The ratio of o-carboxybenzamide to organic solution is 60g:90-300mL; The molar ratio of o-carboxybenzamide to reducing agent is 0.363:0.182-0.726; When dissolving o-carboxybenzamide in an organic solvent, the dissolution temperature is 20-30℃; When adding the reducing agent, it should be added slowly, with each addition taking 1-1.5 hours. The heat preservation reaction is a heat preservation reaction at 2-8℃ or a reflux heat preservation reaction; The heat preservation reaction time is 4-5 hours; When the reducing agent used includes lithium aluminum hydride, the post-treatment is to add 8-12% sodium hydroxide solution at 0-5°C, control the ratio of o-carboxybenzamide to 8-12% sodium hydroxide solution to be 60g:28-32mL, stir, filter, adjust the pH of the filtrate to 5.5-6.5, stir, filter, and dry the filter residue. When the reducing agent used includes sodium borohydride, the post-treatment is as follows: at 0-5°C, water is added, the ratio of o-carboxybenzamide to water is controlled at 60g:25-35mL, the mixture is stirred, filtered, the pH of the filtrate is adjusted to 4.5-5.5, the mixture is stirred, filtered, and the filter residue is dried. The cyclization involves mixing an organic solvent, a catalyst, and compound I, followed by reflux to separate water, and then post-processing to obtain compound II. The cyclization reaction pathway is as follows: ;

[0014] In the cyclization, the structural formula of compound II is: ;

[0015] The organic solvent is toluene or xylene; The catalyst is concentrated sulfuric acid or p-toluenesulfonic acid monohydrate; The ratio of organic solvent to compound I is 200-220 mL: 50 g; The ratio of compound I to catalyst was 50 g: 0.016-0.017 mol; The reflux water separation reaction time is 3-3.5 hours; The post-treatment involves washing the organic solvent layer with water to remove the organic solvent, adding acetonitrile, controlling the ratio of o-carboxybenzylamine to acetonitrile to be 50g:100-120mL, stirring, and filtering. The condensation involves dissolving compound II in an organic solvent, adding a basic reagent, heating to 40-50°C, adding methyl 2-(4-bromophenyl)butyrate dropwise, then refluxing, followed by post-treatment to obtain compound III. The condensation reaction pathway is as follows: ;

[0016] The structural formula of the methyl 2-(4-bromophenyl)butyrate is: ;

[0017] In the condensation, the structural formula of compound III is: ;

[0018] The organic solvent is one of acetone, butanone, and methanol; The alkaline reagent is one of sodium hydroxide, potassium hydroxide, and potassium carbonate; The ratio of compound II to organic solvent is 40g:200-220mL; The molar ratio of compound II to the basic reagent is 0.3:0.33-0.45; The molar ratio of compound II to methyl 2-(4-bromophenyl)butyrate is 0.3:0.31-0.32; The dropping time for methyl 2-(4-bromophenyl)butyrate is 2-2.5 h; The reflux reaction time is 4-4.5 hours; The post-treatment involves adding water dropwise at 20-30°C for 1-1.5 hours, with a ratio of compound II to water of 40g:100-120mL. The mixture is then stirred, filtered, and the filter cake is washed with water. The hydrolysis involves dissolving compound III in an organic solvent, adjusting the pH to 10.5-11.5, stirring the reaction at 40-50°C, and then performing post-treatment to obtain indobufen. The hydrolysis reaction route is as follows: ;

[0019] In the hydrolysis, the organic solvent is one of methanol, ethanol, and acetone; The ratio of compound III to organic solvent is 80g:200-220mL; When adjusting the pH to 10.5-11.5, use an 8-12% sodium hydroxide solution. The stirring reaction time at 40-50℃ is 5-5.5 hours. The post-treatment involves adjusting the pH to 3-3.5 with 8-12% dilute hydrochloric acid, filtering, washing the filter cake with water, adding 95% ethanol to the filter cake, controlling the ratio of compound III to 95% ethanol to be 80g:800-820mL, heating to 70-80℃, stirring to dissolve, decolorizing with activated carbon, filtering while hot, cooling to 20-30℃, stirring, vacuum filtering, and drying.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) In the traditional preparation of indobufen, the raw material required is 2-(4-nitrophenyl)butyric acid. Since 2-(4-nitrophenyl)butyric acid contains a nitro group, a nitration reaction is required in the preparation process. The nitration reaction is highly dangerous. However, the preparation method of indobufen in this invention uses o-carboxybenzamide and methyl 2-(4-bromophenyl)butyrate as raw materials. After reduction, cyclization, condensation and hydrolysis reactions, indobufen is obtained, which avoids the use of 2-(4-nitrophenyl)butyric acid, improves the safety of raw materials, and improves product quality and yield, which is convenient for industrial production.

[0021] (2) The preparation method of indobufen of the present invention has mild reaction conditions, high raw material utilization, good repeatability, convenient operation, improved product quality and yield, and the purity of the prepared indobufen can reach 99.7-99.8%. Attached Figure Description

[0022] Figure 1 The 1H NMR spectrum of o-carboxybenzylamine prepared in Example 1; Figure 2 The proton NMR spectrum of compound III prepared in Example 8; Figure 3 The 1H NMR spectrum of indobufen prepared in Example 14; Figure 4 The mass spectrum of indobufen prepared in Example 14; Figure 5 The liquid chromatogram of indobufen prepared in Example 14 is shown. Detailed Implementation

[0023] To provide a clearer understanding of the technical features, objectives, and effects of the present invention, specific embodiments of the present invention are now described.

[0024] The structural formula of o-carboxybenzamide in Examples 1-18 is as follows: ;

[0025] The structural formula of compound I is: ;

[0026] The structural formula of compound II is: ;

[0027] The structural formula of methyl 2-(4-bromophenyl)butyrate is: ;

[0028] The structural formula of compound III is: ;

[0029] The structural formula of indobufen is: ;

[0030] The molecular weight of o-carboxybenzamide in Examples 1-18 is 165.15; The molecular weight of compound I (o-carboxybenzylamine) is 151; The molecular weight of compound II (isoindoline-1-one) is 133.15; The molecular weight of compound III is 309.13; The molecular weight of the product indobufen is 295.34.

[0031] Example 1 300 mL of tetrahydrofuran was added to a 500 mL four-necked flask, followed by 60 g (0.363 mol) of o-carboxybenzamide. The mixture was stirred and dissolved at 25 °C, then cooled to 5 °C. Lithium aluminum hydride (20.7 g, 0.544 mol) was slowly added over 1.5 h at 5 °C. After the addition was complete, the mixture was refluxed for 4 h. After the reaction was complete, the mixture was cooled to 0 °C, and 30 mL of purified water was slowly added dropwise to the reaction solution over 1 h. After the addition was complete, the mixture was stirred for 30 min. Then, 30 mL of 10% sodium hydroxide solution was slowly added over 0.5 h, and the mixture was stirred for 30 min. The mixture was filtered, and the pH of the filtrate was adjusted to 6 with 10% dilute hydrochloric acid. The mixture was stirred, filtered, and dried to obtain 51.36 g of compound I (o-carboxybenzamide), with a yield of 92.22% and a purity of 98.5%. Nuclear magnetic resonance (NMR) analysis of compound I was performed, and the resulting 1H NMR spectrum is shown below. Figure 1 . Figure 1 The analysis is as follows: 1 H NMR (500 MHz, DMSO- d6 ) δ 7.78 – 7.74 (m, 1H), 7.33 – 7.29 (m, 1H), 7.28 – 7.23 (m, 2H), 3.88 (td, J = 6.5, 1.0 Hz, 2H), 3.10 (dq, J = 29.7, 6.6 Hz, 2H). Example 2 Add 90 mL of tetrahydrofuran to a 500 mL four-necked flask, then add 60 g of o-carboxybenzamide (0.363 mol). Stir and dissolve at 25 °C, then cool to 5 °C. At 5 °C, slowly add a borane-tetrahydrofuran complex solution (BH3•THF) (1 mol / L, 0.726 mol) over 1.5 h. After the addition is complete, reflux for 5 h. After the reaction is complete, cool to 5 °C, then slowly add 90 mL of purified water dropwise over 1 h. Stir for 2 h, filter, and dry to obtain 49.8 g of compound I (o-carboxybenzamide), with a yield of 88.51% and a purity of 97.5%.

[0032] Example 3 90 mL of methanol was added to a 500 mL four-necked flask, followed by 60 g of o-carboxybenzamide (0.363 mol). The mixture was stirred and dissolved at 25 °C, then cooled to 5 °C. Sodium borohydride (6.86 g, 0.182 mol) was slowly added over 1.5 h at 5 °C. After the addition was complete, the mixture was stirred for 30 min. Then, a boron trifluoride-tetrahydrofuran complex solution (47% purity, 0.381 mol molar volume) was slowly added over 1 h at 5 °C. The mixture was then kept at 5 °C for 4 h. 90 mL of purified water was slowly added dropwise over 1.5 h, and the mixture was stirred for 2 h. The mixture was then filtered and dried to obtain 51.5 g of compound I (o-carboxybenzamide), with a yield of 92.00% and a purity of 98%.

[0033] Example 4 Add 90 mL of methanol to a 500 mL four-necked flask, then add o-carboxybenzamide (60 g, 0.363 mol). Stir and dissolve at 25 °C, then cool to 5 °C. At 5 °C, slowly add sodium borohydride (6.86 g, 0.182 mol) over 1.5 h, stirring for 30 min. At 5 °C, slowly add aluminum trichloride (53.2 g, 0.399 mol) over 1 h, then keep warm at 5 °C for 4 h. Slowly add 30 mL of purified water dropwise over 1 h, stirring for 30 min. Filter (to remove the hydrolysis products of aluminum trichloride). Adjust the pH of the filtrate to 5 with 10% dilute hydrochloric acid, stir, filter, and dry to obtain compound I (o-carboxybenzamide) 49.9 g, with a yield of 89.87% and a purity of 98.8%.

[0034] Example 5 200 mL of toluene was added to a 500 mL four-necked flask, followed by o-carboxybenzylamine (containing 50 g of o-carboxybenzylamine, 0.331 mol) prepared according to the method in Example 1. The mixture was stirred to dissolve, and then concentrated sulfuric acid (1.66 g, 0.0166 mol) was added. The mixture was heated to reflux and the water was removed for 3 h. After the reaction was complete, the toluene layer was washed with purified water, and the toluene was removed by vacuum distillation. 100 mL of acetonitrile was added, and the mixture was stirred at room temperature for 2 h. The mixture was then filtered to obtain 43.2 g of compound II (isoindoline-1-one), with a yield of 97.98%.

[0035] Example 6 200 mL of xylene was added to a 500 mL four-necked flask, followed by o-carboxybenzylamine (containing 50 g of o-carboxybenzylamine, 0.331 mol) prepared according to the method in Example 2. The mixture was stirred and dissolved, and then concentrated sulfuric acid (1.66 g, 0.0166 mol) was added. The mixture was heated to reflux and the water was removed for 3 h. After the reaction was complete, the toluene layer was washed with purified water, and the toluene was removed by vacuum distillation. 100 mL of acetonitrile was added, and the mixture was stirred at room temperature for 2 h. The mixture was then filtered to obtain 41.9 g of compound II (isoindoline-1-one), with a yield of 95.03%.

[0036] Example 7 200 mL of toluene was added to a 500 mL four-necked flask, followed by o-carboxybenzylamine (containing 50 g of o-carboxybenzylamine, 0.331 mol) prepared according to the method in Example 3. The mixture was stirred and dissolved, and then p-toluenesulfonic acid monohydrate (3.16 g, 0.0166 mol) was added. The mixture was heated to reflux and the water was removed for 3 h. After the reaction was complete, the toluene layer was washed with purified water, and the toluene was removed by vacuum distillation. 100 mL of acetonitrile was added, and the mixture was stirred at room temperature for 2 h. The mixture was then filtered to obtain 42.8 g of compound II (isoindoline-1-one), with a yield of 97.08%.

[0037] Example 8 200 mL of acetone was added to a 500 mL four-necked flask, followed by compound II (40 g, 0.3 mol) prepared according to the method in Example 5. The mixture was stirred until dissolved, and sodium hydroxide (13.2 g, 0.33 mol) was added. The mixture was heated to 45 °C, and methyl 2-(4-bromophenyl)butyrate (81 g, 0.315 mol) was slowly added dropwise over 2 h at 45 °C. After the addition was complete, the mixture was refluxed for 4 h. After the reaction was complete, the mixture was cooled, and 100 mL of purified water was added dropwise over 1 h at 25 °C. The mixture was stirred for 2 h, filtered, and the filter cake was washed with purified water and dried to obtain 83.6 g of compound III, with a yield of 90.02%.

[0038] The obtained compound III was subjected to nuclear magnetic resonance analysis, and the proton NMR spectrum is shown below. Figure 2 . Figure 2 The analysis is as follows: 1 H NMR (600 MHz, DMSO-d6) δ 7.96 (d, J = 8.0, 1.6 Hz, 1H), 7.36 (ddd,J = 8.2, 6.7, 1.5 Hz, 1H), 7.34 – 7.28 (m, 2H),7.21 (d, J = 8.8 Hz, 2H), 7.18(d, J = 8.9 Hz, 2H), 4.83 – 4.77 (m, 2H), 3.61 (s, 3H), 3.54 (t, J = 6.4 Hz,1H), 1.79 – 1.72 (m, 1H), 1.72 – 1.66 (m, 1H), 0.90 (t, 3H). Example 9 Add 200 mL of butanone to a 500 mL four-necked flask, then add compound II (40 g, 0.3 mol) prepared according to the method in Example 5, stir to dissolve, add potassium hydroxide (18.5 g, 0.33 mol), heat to 45 °C, and slowly add methyl 2-(4-bromophenyl)butyrate (81 g, 0.315 mol) dropwise over 2 h at 45 °C. After the addition is complete, reflux for 4 h. After the reaction is complete, cool down, and add 100 mL of purified water dropwise over 1 h at 25 °C, stir for 2 h, filter, wash the filter cake with purified water, and dry to obtain 85.1 g of compound III, with a yield of 91.64%.

[0039] Example 10 200 mL of methanol was added to a 500 mL four-necked flask, followed by compound II (40 g, 0.3 mol) prepared according to the method in Example 5. The mixture was stirred until dissolved, and potassium hydroxide (18.5 g, 0.33 mol) was added. The mixture was heated to 45 °C, and methyl 2-(4-bromophenyl)butyrate (81 g, 0.315 mol) was slowly added dropwise over 2 h at 45 °C. After the addition was complete, the mixture was refluxed for 4 h. After the reaction was complete, the mixture was cooled, and 100 mL of purified water was added dropwise over 1 h at 25 °C. The mixture was stirred for 2 h, filtered, and the filter cake was washed with purified water and dried to obtain 85.5 g of compound III, with a yield of 92.07%.

[0040] Example 11 Add 200 mL of butanone to a 500 mL four-necked flask, then add compound II (40 g, 0.3 mol) prepared according to the method in Example 5, stir to dissolve, add potassium carbonate (62.2 g, 0.45 mol), heat to 45 °C, and slowly add methyl 2-(4-bromophenyl)butyrate (81 g, 0.315 mol) dropwise over 2 h at 45 °C. After the addition is complete, reflux for 4 h. After the reaction is complete, cool down, and add 100 mL of purified water dropwise over 1 h at 25 °C, stir for 2 h, filter, wash the filter cake with purified water, and dry to obtain 82.7 g of compound III, with a yield of 89.05%.

[0041] Example 12 Add 200 mL of ethanol to a 500 mL four-necked flask, then add compound II (40 g, 0.3 mol) prepared according to the method in Example 5 and stir to dissolve. Add potassium hydroxide (18.5 g, 0.33 mol), heat to 45 °C, and slowly add methyl 2-(4-bromophenyl)butyrate (81 g, 0.315 mol) dropwise over 2 h at 45 °C. After the addition is complete, reflux the reaction for 4 h. After the reaction is complete, cool down and add 100 mL of purified water dropwise over 1 h at 25 °C. Stir for 2 h, filter, wash the filter cake with purified water, and dry to obtain 84.7 g of compound III, with a yield of 91.21%.

[0042] Example 13 200 mL of methanol was added to a 500 mL four-necked flask, followed by compound II (40 g, 0.3 mol) prepared according to the method in Example 5. The mixture was stirred and dissolved. Sodium hydroxide (13.2 g, 0.33 mol) was added, and the mixture was heated to 45 °C. Methyl 2-(4-bromophenyl)butyrate (81 g, 0.315 mol) was slowly added dropwise over 2 h at 45 °C. After the addition was complete, the mixture was refluxed for 4 h. After the reaction was complete, the mixture was cooled, and 100 mL of purified water was added dropwise over 1 h at 25 °C. The mixture was stirred for 2 h, filtered, and the filter cake was washed with purified water and dried to obtain 87.3 g of compound III, with a yield of 94.01%.

[0043] Example 14 Add 200 mL of methanol to a 500 mL four-necked flask, then add compound III (80 g, 0.259 mol) prepared according to the method of Example 8, stir to dissolve, add 10% sodium hydroxide solution to adjust the pH to 11, heat to 45 °C, and stir to react for 5 h at 45 °C. After the reaction is complete, adjust the pH to 3 with 10% dilute hydrochloric acid, filter, wash the filter cake with purified water, put the filter cake into a 1000 mL four-necked flask, add 800 mL of 95% ethanol, heat to 75 °C, stir to dissolve, decolorize with activated carbon, filter while hot, cool the filtrate to 25 °C, stir for 2 h, filter under vacuum, and dry to obtain 68.7 g of indobufen, with a yield of 89.63% and a purity of 99.72%.

[0044] The prepared product, indobufen, was analyzed by nuclear magnetic resonance (NMR). The resulting proton NMR spectrum is shown below. Figure 3 . Figure 3 The analysis is as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 12.33 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.78 (dt, J = 7.7, 1.0 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.54 (ddd, J = 8.1, 6.3, 1.9Hz, 1H), 7.38 – 7.32 (m, 2H), 5.01 (s, 2H), 3.42 (t, J = 7.6 Hz, 1H), 1.98 (dt, J = 13.4, 7.4 Hz, 1H), 1.68 (dt, J = 13.5, 7.3 Hz, 1H), 0.84 (t, J = 7.3Hz, 3H). Example 15 Add 200 mL of methanol to a 500 mL four-necked flask, then add compound III (80 g, 0.259 mol) prepared according to the method of Example 9, stir to dissolve, add 10% potassium hydroxide solution to adjust the pH to 11, heat to 45 °C, and stir to react for 5 h at 45 °C. After the reaction is complete, adjust the pH to 3 with 10% dilute sulfuric acid, filter, wash the filter cake with purified water, put the filter cake into a 1000 mL four-necked flask, add 800 mL of 95% ethanol, heat to 75 °C, stir to dissolve, decolorize with activated carbon, filter while hot, cool to 25 °C, stir for 2 h, filter and dry to obtain 66.4 g of product indobufen, yield 86.70%, purity 99.8%.

[0045] Example 16 Add 200 mL of ethanol to a 500 mL four-necked flask, then add compound III (80 g, 0.259 mol) prepared according to the method of Example 10, stir to dissolve, add 10% potassium hydroxide solution to adjust the pH to 11, heat to 45 °C, and stir to react for 5 h at 45 °C. After the reaction is complete, adjust the pH to 3 with 10% dilute sulfuric acid, filter, wash the filter cake with purified water, put the filter cake into a 1000 mL four-necked flask, add 800 mL of 95% ethanol, heat to 75 °C, stir to dissolve, decolorize with activated carbon, filter while hot, cool the filtrate to 25 °C, stir for 2 h, filter under vacuum, and dry to obtain 67.1 g of product indobufen, with a yield of 87.60% and a purity of 99.78%.

[0046] Example 17 Add 200 mL of acetone to a 500 mL four-necked flask, then add compound III (80 g, 0.259 mol) prepared according to the method of Example 11, stir to dissolve, add 10% sodium hydroxide solution to adjust the pH to 11, heat to 45 °C, and stir to react for 5 h at 45 °C. After the reaction is complete, adjust the pH to 3 with 10% dilute hydrochloric acid, filter, wash the filter cake with purified water, put the filter cake into a 1000 mL four-necked flask, add 800 mL of 95% ethanol, heat to 75 °C, stir to dissolve at 75 °C, decolorize with activated carbon, filter while hot, cool to 25 °C, stir for 2 h, filter and dry to obtain 65.6 g of product indobufen, yield 85.62%, purity 99.75%.

[0047] Example 18 Add 200 mL of ethanol to a 500 mL four-necked flask, then add compound III (80 g, 0.259 mol) prepared according to the method of Example 11, stir to dissolve, add 10% sodium hydroxide solution to adjust the pH to 11, heat to 45 °C, and stir to react for 5 h at 45 °C. After the reaction is complete, adjust the pH to 3 with 10% dilute acetic acid, filter, wash the filter cake with purified water, put the filter cake into a 1000 mL four-necked flask, add 800 mL of 95% ethanol, heat to 75 °C, stir to dissolve at 75 °C, decolorize with activated carbon, filter while hot, cool to 25 °C, stir for 2 h, filter under vacuum, and dry to obtain 69.3 g of indobufen, with a yield of 90.40% and a purity of 99.7%.

[0048] Unless otherwise stated, all percentages used in this invention are mass percentages.

[0049] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing indobufen, characterized in that, Includes the following steps: Reduction, cyclization, condensation, hydrolysis; The reduction involves dissolving o-carboxybenzamide in an organic solvent, cooling the solution to 2-8°C, adding a reducing agent, maintaining the temperature for the reaction, and then performing post-treatment to obtain compound I. The cyclization involves mixing an organic solvent, a catalyst, and compound I, followed by reflux to separate water, and then post-processing to obtain compound II. The condensation involves dissolving compound II in an organic solvent, adding a basic reagent, heating to 40-50°C, adding methyl 2-(4-bromophenyl)butyrate dropwise, then refluxing, followed by post-treatment to obtain compound III. The hydrolysis involves dissolving compound III in an organic solvent, adjusting the pH to 10.5-11.5, stirring the reaction at 40-50°C, and then performing post-treatment to obtain indobufen. The structural formula of compound I is: ； The structural formula of compound II is: ； The structural formula of compound III is: 。 2. The method for preparing indobufen according to claim 1, characterized in that, In the reduction process, the organic solvent is tetrahydrofuran or methanol; The reducing agent is one or more of lithium aluminum hydride, borane-tetrahydrofuran complex, sodium borohydride, and boron trifluoride-tetrahydrofuran complex; When the reducing agent is sodium borohydride, aluminum chloride is required as an auxiliary agent, and the molar ratio of sodium borohydride to aluminum chloride is 0.18-0.19:0.39-0.

4.

3. The method for preparing indobufen according to claim 1, characterized in that, In the reduction process, the ratio of o-carboxybenzamide to organic solution is 60g:90-300mL; The molar ratio of o-carboxybenzamide to reducing agent is 0.363:0.182-0.726; When adding the reducing agent, it should be added slowly, with each addition taking 1-1.5 hours. The heat preservation reaction is a heat preservation reaction at 2-8℃ or a reflux heat preservation reaction; The heat preservation reaction takes 4-5 hours.

4. The method for preparing indobufen according to claim 1, characterized in that, In the reduction process, when the reducing agent used includes lithium aluminum hydride, the post-treatment is to add sodium hydroxide solution at 0-5°C, stir, filter, adjust the pH of the filtrate to 5.5-6.5, stir, filter, and dry the filter residue. When the reducing agent used includes sodium borohydride, the post-treatment is to add water at 0-5°C, stir, filter, adjust the pH of the filtrate to 4.5-5.5, stir, filter, and dry the filter residue.

5. The method for preparing indobufen according to claim 1, characterized in that, In the cyclization, the organic solvent is toluene or xylene; The catalyst is concentrated sulfuric acid or p-toluenesulfonic acid monohydrate; The post-treatment involves washing the organic solvent layer with water to remove the organic solvent, adding acetonitrile, stirring, and then filtering.

6. The method for preparing indobufen according to claim 1, characterized in that, In the cyclization, the ratio of organic solvent to compound I is 200-220 mL: 50 g; The ratio of compound I to catalyst was 50 g: 0.016-0.017 mol; The reflux water separation reaction takes 3-3.5 hours.

7. The method for preparing indobufen according to claim 1, characterized in that, In the condensation, the organic solvent is one of acetone, butanone, and methanol; The alkaline reagent is one of sodium hydroxide, potassium hydroxide, and potassium carbonate; The post-treatment involves adding water dropwise at 20-30°C, then stirring, filtering, and washing the filter cake with water.

8. The method for preparing indobufen according to claim 1, characterized in that, In the condensation, the ratio of compound II to organic solvent is 40g:200-220mL; The molar ratio of compound II to the basic reagent is 0.3:0.33-0.45; The molar ratio of compound II to methyl 2-(4-bromophenyl)butyrate is 0.3:0.31-0.32; The dropping time for methyl 2-(4-bromophenyl)butyrate is 2-2.5 h; The reflux reaction time is 4-4.5 hours.

9. The method for preparing indobufen according to claim 1, characterized in that, In the hydrolysis, the organic solvent is one of methanol, ethanol, and acetone; The ratio of compound III to organic solvent is 80g:200-220mL.

10. The method for preparing indobufen according to claim 1, characterized in that, During the hydrolysis, an 8-12% sodium hydroxide solution was used to adjust the pH to 10.5-11.

5. The stirring reaction time at 40-50℃ is 5-5.5 hours. The post-treatment involves adjusting the pH to 3-3.5, filtering, washing the filter cake with water, adding 95% ethanol to the filter cake, heating to 70-80℃, stirring to dissolve, decolorizing with activated carbon, filtering while hot, cooling to 20-30℃, stirring, vacuum filtering, and drying.

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