A method for industrial production of sulindac

Abstract

The application discloses a method for industrial production of sulindac. The method comprises the following steps: condensation reaction of compound 1 (5-fluoro-2-1-(4-methylthio benzyl) indene) and glyoxylic acid under catalysis of an organic base (benzyl trimethyl ammonium hydroxide) to generate compound 2, isomerization reaction of the compound 2 under hydrobromic acid-acetic acid solution to generate compound 3, which greatly improves reaction conversion rate and yield, reduces three waste problems, and finally obtains compound 4 (sulindac crude product) through oxidation of the obtained compound 3 by hydrogen peroxide, and high-purity sulindac is obtained through recrystallization of the crude product by isopropyl alcohol. The raw materials and reagents used in the preparation process of the sulindac are relatively cheap and low in cost, the whole preparation process is mild in reaction condition, simple and safe in operation, and convenient for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a method for industrial production of sulindac. BACKGROUND

[0002] Sulindac is a non-steroidal anti-inflammatory drug, mainly used for the treatment of pain, rheumatoid arthritis, ankylosing spondylitis and gouty arthritis. This drug is also used for the treatment of premature birth, diabetes and senile cataract. Further studies have shown that sulindac also has the ability to inhibit tumor cell growth, so the application of sulindac in tumor treatment has attracted widespread attention of the world scientific community and become a hot research field.

[0003] There are many reports on the synthesis of sulindac at home and abroad. The main method is to use 4-fluorobenzaldehyde as the starting material to undergo condensation, palladium-carbon hydrogenation reduction, ring formation with polyphosphoric acid, hydrolysis to obtain 5-fluoro-2-methyl-3-indenyl acetic acid, addition with p-sulfenyl benzaldehyde, and finally oxidation with sodium periodate to obtain sulindac:

[0004]

[0005] This method has obvious disadvantages. The second step uses noble metal catalytic hydrogenation, and the third step uses a large amount of polyphosphoric acid to form a ring. After the reaction is completed, water is added to quench the reaction, resulting in a large amount of phosphorus-containing wastewater, which pollutes the environment. The substrate reaction is not complete, a large amount of impurities is generated, and the product is not easy to purify. A large amount of sodium methoxide methanol solution is used in the fifth step, and a large amount of water is added to quench the reaction after the reaction is completed, resulting in a large amount of methanol that cannot be recovered, a large amount of waste solvent, and an increase in the difficulty of subsequent three waste treatment. An expensive sodium periodate is used as an oxidizing agent in the last step, which increases the production cost.

[0006] In 2006, Zeng et al. proposed a method for synthesizing sulindac using 4-methylsulfonyl benzyl bromide as the starting material:

[0007] The yield of this method reported in the literature is less than 30%. At the same time, due to the preparation and use of zinc Grignard reagent in this reaction, the problem of industrial production is difficult to solve.

[0008] In summary of the above, the current method for synthesizing sulindac can be achieved by different routes. However, as mentioned in the foregoing, each route has its own obvious disadvantages, such as low product purity, low yield, high process cost, large pollution, complex operation, harsh process conditions, and difficulty in industrial production, etc. SUMMARY

[0009] The technical problem solved by the present application is to overcome the technical defects of the prior art and provide a method for industrial production of sulindac with high yield and low cost.

[0010] The technical scheme adopted by the present application to solve the above technical problem is as follows:

[0011] A method for industrial production of sulindac comprises the following steps:

[0012] (1) Synthesis of compound 2:

[0013] Compound 1 (5-fluoro-2-1-(4-methylthiobenzyl) indene) is used as a starting material, methanol is used as a solvent, and glyoxylic acid is reacted under the catalysis of three-way B (benzyl trimethyl ammonium hydroxide) to obtain compound 2;

[0014] In the step (1), the molar ratio of the three-way B to the compound 1 is 1-3:1;

[0015] In the step (1), the reaction temperature is 0-50℃;

[0016] (2) Synthesis of compound 3:

[0017] Compound 2 is used as a starting material, acetic acid is used as a solvent, and isomerization is carried out under the catalysis of acetic acid hydrobromide, and compound 3 is obtained by toluene crystallization;

[0018] In the step (2), the mass ratio of the acetic acid to the compound 2 is 2-10:1;

[0019] In the step (2), the molar ratio of the acetic acid hydrobromide to the compound 2 is 0.03-1:1;

[0020] In the step (2), the reaction temperature is 25-110℃;

[0021] (3) Synthesis of compound 4:

[0022] Compound 3 is used as a starting material, dichloromethane is used as a solvent, and H2O2 is oxidized under the catalysis of acetic acid, and compound 4, i.e. sulindac crude product, is obtained by ethyl acetate crystallization;

[0023] In the step (3), the molar ratio of the H2O2 to the compound 3 is 1-5:1;

[0024] In the step (3), the reaction temperature is 25-80℃;

[0025] (4) Purification of compound 4:

[0026] The compound 4 prepared in step (3) is recrystallized with isopropanol to obtain high-purity sulindac product;

[0027] In step (4), the mass ratio of isopropanol to compound 4 is 1-10:1. Specifically, the method for industrial production of sulindac according to the present application comprises the following steps:

[0028] (1) Synthesis of compound 2:

[0029] In a container, compound 1 (5-fluoro-2-1-(4-methylthiobenzyl) indene), catalyst three-way B (benzyltrimethylammonium hydroxide), methanol are added, stirring is started, and then glyoxylic acid is added dropwise at room temperature. After the dropwise addition is completed, the reaction is carried out under heat preservation. After the reaction is completed, the pH is adjusted to 2-4 with an aqueous HCl solution, and then filtration is performed to obtain compound 2;

[0030] In step (1), the molar ratio of catalyst three-way B to compound 1 is 1-3:1;

[0031] In step (1), the mass ratio of methanol to compound 1 is 1-3:1;

[0032] In step (1), the molar ratio of glyoxylic acid to compound 1 is 1:1-2;

[0033] (2) Synthesis of compound 3:

[0034] In a container, compound 2 prepared in step (1) is added, followed by acetic acid. After the addition is completed, stirring is started, and then catalyst ethanolic hydrobromic acid is added. After the temperature is raised to 25-110°C, the reaction is carried out under heat preservation until the reaction is completed. Acetic acid is distilled out under reduced pressure, and then toluene is added for purification. After filtration and drying, compound 3 is obtained;

[0035] In step (2), the mass ratio of acetic acid to compound 2 is 2-10:1;

[0036] In step (2), the molar ratio of catalyst ethanolic hydrobromic acid to compound 2 is 0.03-1:1;

[0037] (3) Synthesis of compound 4:

[0038] In a container, add compound 3 prepared in step (2), catalyst acetic acid, dichloromethane, after feeding, open the stirring, add H2O2, heating to 25-80℃, keep the reaction until the reaction is completed, add aqueous sodium thiosulfate solution, quench the reaction, after quenching the reaction, add water, stirring, standing, separating the layers, the aqueous phase is extracted with dichloromethane, the organic phase is concentrated to remove dichloromethane, add ethyl acetate for purification, filter and dry to obtain compound 4, i.e. sulindac crude product;

[0039] In step (3), the mass ratio of acetic acid to compound 3 is 1-3:1;

[0040] In step (3), the mass ratio of dichloromethane to compound 3 during the synthesis of compound 4 is 4-8:1;

[0041] In step (3), the molar ratio of H2O2 to compound 3 is 1-5:1;

[0042] (4) Purification of compound 4:

[0043] In a container, add isopropyl alcohol, compound 4 prepared in step (3), heat to 75-85℃ under stirring, after the material is completely dissolved, slowly cool to 0-10℃ for recrystallization, filter and dry to obtain sulindac finished product;

[0044] In step (4), the mass ratio of isopropyl alcohol to compound 4 is 1-10:1.

[0045] Preferably, in step (1), the molar ratio of catalyst three-way B to compound 1 is 1.8-2.2:1.

[0046] Preferably, in step (1), the concentration of glyoxylic acid is 50%.

[0047] Preferably, in step (1), the temperature of the incubation reaction is 0-50℃.

[0048] More preferably, in step (1), the temperature of the incubation reaction is 30-40℃.

[0049] Preferably, in step (1), the incubation reaction time is 3-5 hours.

[0050] Preferably, in step (2), the mass ratio of acetic acid to compound 2 is 6-10:1.

[0051] Preferably, in step (2), the molar ratio of catalyst ethyl hydrobromate acetic acid to compound 2 is 0.1-0.3:1.

[0052] Preferably, in step (2), the concentration of catalyst ethyl hydrobromate acetic acid solution is 33%.

[0053] Preferably, in the step (2), the temperature of the incubation reaction is 70-100℃.

[0054] More preferably, in the step (2), the temperature of the incubation reaction is 85-95℃.

[0055] Preferably, in the step (2), the time of the incubation reaction is 3-5 hours.

[0056] Preferably, in the step (2), the mass ratio of the toluene to the compound 2 is 3-4:1.

[0057] Preferably, in the step (3), the molar ratio of the H2O2 to the compound 3 is 1-1.2:1.

[0058] Preferably, in the step (3), the concentration of the H2O2 is 30%.

[0059] Preferably, in the step (3), the temperature of the incubation reaction is 30-50℃.

[0060] More preferably, in the step (3), the temperature of the incubation reaction is 30-40℃.

[0061] Preferably, in the step (3), the time of the incubation reaction is 3-5 hours.

[0062] Preferably, in the step (3), the concentration of the aqueous sodium thiosulfate solution is 10%.

[0063] Preferably, in the step (3), the mass ratio of the aqueous sodium thiosulfate solution to the compound 3 is 0.2-1:1.

[0064] Preferably, in the step (3), the mass ratio of the water to the compound 3 is 1-3:1.

[0065] Preferably, in the step (3), the mass ratio of the dichloromethane to the compound 3 in the extraction is 0.5-1:1.

[0066] Preferably, in the step (3), the extraction is performed twice.

[0067] Preferably, in the step (3), the mass ratio of the ethyl acetate to the compound 3 is 3-6:1.

[0068] Preferably, in the step (4), the mass ratio of the isopropyl alcohol to the compound 4 is 4-7:1.

[0069] The basic principle of the present application is:

[0070] The process route for industrial production of sulindac according to the present application is shown in Figure 1

[0071] Specifically, the method for industrial production of sulindac according to the present application comprises the following steps:

[0072] (1) Compound 1 (5-fluoro-2-1-(4-methylthiobenzyl) indene) is condensed with glyoxylic acid under the catalysis of 1-3 times of three-way B (benzyl trimethyl ammonium hydroxide) at 0-50℃ to obtain compound 2, and the reaction formula is as follows:

[0073]

[0074] (2) Compound 2 is subjected to isomerization reaction in hydrobromic acid-acetic acid solution to obtain compound 3, and the reaction formula is as follows:

[0075]

[0076] (3) Compound 3 is subjected to oxidation reaction with hydrogen peroxide H2O2 to obtain compound 4, which is the crude sulindac, and the reaction formula is as follows:

[0077]

[0078] (4) Compound 4 is subjected to recrystallization with isopropyl alcohol to obtain high-purity sulindac.

[0079] Compared with the prior art, the present application has the following beneficial effects:

[0080] (1) The present application provides a method for industrial production of sulindac, which has simple synthesis process, safe and simple operation, and friendly production process environment, thereby achieving the purposes of reducing three wastes and reducing production cost;

[0081] (2) In the preparation of compound 2 according to the present application, three-way B is used for catalysis at 30-40℃, the purity of the main product is greater than 95%, the reaction condition is mild, the operation is simple, the process time is short, the purity of the material is high, and it can be used for the next step without purification;

[0082] ​(3) The present application is used to prepare compound 3 by using 33% HBr acetic acid solution to catalyze isomerization rearrangement reaction at 70-100 DEG C until the reaction is finished, recovering the solvent acetic acid for recycling; the solid is crystallized by toluene, the purity of the material is more than 98%, the material yield is 93%-95%, the operation is simple, the material yield is high, the waste is less, and the process production cost is reduced; the second step isomerization reaction in the present application comparative example 1 is catalyzed by using 30% hydrochloric acid solution, the purity of the intermediate is only 85.6%, and the yield is only 71.7%; compared with the present application, the HBr catalyzed isomerization reaction in acetic acid has obvious advantages in yield, intermediate purity, impurities and three wastes, and is more suitable for industrial production.

[0083] (4) The present application is used to prepare compound 3 by using 33% HBr acetic acid solution to catalyze isomerization rearrangement reaction at 70-100 DEG C until the reaction is finished, recovering the solvent acetic acid for recycling; the solid is crystallized by toluene, the purity of the material is more than 98%, the material yield is 93%-95%, the operation is simple, the material yield is high, the waste is less, and the process production cost is reduced; the second step isomerization reaction in the present application comparative example 1 is catalyzed by using 30% hydrochloric acid solution, the purity of the intermediate is only 85.6%, and the yield is only 71.7%; compared with the present application, the HBr catalyzed isomerization reaction in acetic acid has obvious advantages in yield, intermediate purity, impurities and three wastes, and is more suitable for industrial production.

[0084] (4) The present application is used to prepare compound 3 by using 33% HBr acetic acid solution to catalyze isomerization rearrangement reaction at 70-100 DEG C until the reaction is finished, recovering the solvent acetic acid for recycling; the solid is crystallized by toluene, the purity of the material is more than 98%, the material yield is 93%-95%, the operation is simple, the material yield is high, the waste is less, and the process production cost is reduced; the second step isomerization reaction in the present application comparative example 1 is catalyzed by using 30% hydrochloric acid solution, the purity of the intermediate is only 85.6%, and the yield is only 71.7%; compared with the present application, the HBr catalyzed isomerization reaction in acetic acid has obvious advantages in yield, intermediate purity, impurities and three wastes, and is more suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0085] Figure 1 The process route chart for industrial production of sulindac in the present application;

[0086] Figure 2 The HPLC spectrum of compound 2 prepared in example 3 of the present application;

[0087] Figure 3 The HPLC spectrum of compound 3 prepared in example 3 of the present application;

[0088] Figure 4 The HPLC spectrum of sulindac crude product prepared in example 3 of the present application;

[0089] Figure 5 The HPLC spectrum of sulindac finished product prepared in example 3 of the present application. DETAILED DESCRIPTION

[0090] For a better understanding of the present application, reference will be made to the following examples and accompanying drawings. It is to be understood that these examples are set forth by way of example and are not intended to limit the scope of the application. Furthermore, it is to be understood that the application can be carried out by specifically different embodiments and that numerous modifications can be made by those skilled in the art without departing from the spirit and scope of the application.

[0091] The compound 1 in Examples 1-3 and Comparative Example 1 is 5-fluoro-2-1-(4- methylthiobenzyl)indene, which is commercially available.

[0092] The three-way valve B in Examples 1-3 and Comparative Example 1 is benzyltrimethylammonium hydroxide.

[0093] Example 1

[0094] First Step: Synthesis of Compound 2

[0095] Into a 500ml flask was added compound 1 50g, three-way valve B 80g, and methanol 120g. After the addition was completed, stirring was started, and 50% glyoxylic acid 33.8g was added dropwise at room temperature. After the dropwise addition was completed, the reaction was allowed to proceed at 30-40°C for 3-5 hours. After the reaction was completed, the pH was adjusted to 2-4 with an aqueous HC1 solution, and filtration was performed to obtain compound 2 57.2g. The HPLC purity of the material was 95.3%, and the molar yield of the material was 95.58%.

[0096] Second Step: Synthesis of Compound 3

[0097] Into a 500ml flask was added compound 2 50g, and acetic acid 450g. After the addition was completed, stirring was started, and 33% HBr acetic acid solution 7.72g was added. After the temperature was raised to 85-95°C, the reaction was allowed to proceed for 3-5 hours. After the reaction was completed, acetic acid was distilled off under reduced pressure, and was reserved for use in the next batch. After the distillation of acetic acid was completed, toluene 200g was added for purification, and filtration and drying were performed to obtain compound 3 46.5g. The HPLC purity of the material was 98.6%, and the molar yield of the material was 93%.

[0098] Third Step: Synthesis of Compound 4

[0099] In 500 ml flask, add compound 340 g, acetic acid 100 g, dichloromethane 240 g, after adding, open stirring, add 30% H2O214.6 g, heat to 30-40 °C, keep reaction for 3-5 hours, after reaction, add 10% sodium thiosulfate aqueous solution 20 g, stirring to quench the reaction, after quenching the reaction, add 80 g water, stirring, standing, separating layers, water phase is extracted with 20 g dichloromethane twice, combined organic phase is concentrated to remove dichloromethane, which is used in the next batch. After concentrating dichloromethane, add ethyl acetate 160 g for purification, filter and dry to obtain compound 4, i.e. sulindac crude product 39.8 g, the material HPLC purity is 98.96%, the material molar yield is 95.03%.

[0100] Fourth step: purification of compound 4

[0101] In 250 ml flask, add isopropyl alcohol 150 g, compound 430 g, stirring, heat to 75-85 °C, after the material is completely dissolved, slowly cool to 0-10 °C for recrystallization, filter and dry to obtain sulindac finished product 28.7 g, the material HPLC purity is 99.54%, the material weight yield is 96.5%.

[0102] Example 2

[0103] First step: synthesis of compound 2

[0104] In 1000 ml flask, add compound 1 100 g, three-way valve B 160 g, methanol 240 g, after adding, open stirring, start dropping 50% glyoxylic acid 67.6 g at room temperature, after dropping, keep reaction for 3-5 hours at 30-40 °C, after reaction, adjust pH to 2-4 with HCl aqueous solution, filter to obtain compound 2 116.03 g, the material HPLC purity is 95.5%, the material molar yield is 97.11%.

[0105] Second step: synthesis of compound 3

[0106] In 1000 ml flask, add compound 2 100 g, acetic acid 900 g, after adding, open stirring, add 33% HBr acetic acid solution 77.2 g, heat to 85-95 °C, keep reaction for 3-5 hours, after reaction, distill acetic acid under reduced pressure, which is used in the next batch, after distillation of acetic acid, add toluene 400 g for purification, filter and dry to obtain compound 3 92.87 g, the material HPLC purity is 98.9%, the material molar yield is 92.87%.

[0107] Third step: synthesis of compound 4

[0108] In 1000 ml flask, add compound 380 g, acetic acid 200 g, dichloromethane 480 g, after adding, open the stirring, add 30% H2O 229.2 g, heat to 30-40 °C, keep the temperature for 3-5 hours, after the reaction is completed, add 10% sodium thiosulfate aqueous solution 40 g to quench the reaction, after quenching the reaction, add 160 g of water, stir and separate the layers, the aqueous phase is extracted with 40 g of dichloromethane twice, the organic phase is concentrated to remove dichloromethane, which is reserved for the next batch. After the concentration of dichloromethane, add ethyl acetate 320 g for purification, filter and dry to obtain compound 4, i.e. sulindac crude product 80.06 g, the material HPLC purity is 98.83%, the material molar yield is 95.5%.

[0109] Fourth step: purification of compound 4

[0110] In 1000 ml flask, add isopropyl alcohol 400 g, compound 480 g, stir and heat to 75-85 °C, after the material is completely dissolved, slowly cool to 0-10 °C for recrystallization, filter and dry to obtain sulindac finished product 76.6 g, the material HPLC purity is 99.68%, the material weight yield is 95.75%.

[0111] Example 3

[0112] First step: synthesis of compound 2

[0113] In 50 L reactor, add compound 15 kg, three-way valve B 8 kg, methanol 12 kg, after adding, open the stirring, start dropping 50% glyoxylic acid 3.38 kg at room temperature, after dropping, keep the temperature at 30-40 °C for 3-5 hours, after the reaction is completed, adjust the pH to 2-4 with HCl aqueous solution, filter to obtain compound 25.8 kg, the material HPLC purity is 98.26% (HPLC detection results see Figure 2 ), the material molar yield is 96.91%.

[0114] Second step: synthesis of compound 3

[0115] In 50 L reactor, add compound 25 kg, acetic acid 45 kg, after adding, open the stirring, add 33% HBr acetic acid solution 0.77 kg, heat to 85-95 °C, then keep the temperature for 3-5 hours, after the reaction is completed, distill acetic acid under reduced pressure, which is reserved for the next batch, after the distillation of acetic acid, add toluene 20 kg for purification, filter and dry to obtain compound 34.7 kg, the material HPLC purity is 98.94% (HPLC detection results see Figure 3 ), the material molar yield is 93%.

[0116] Third step: synthesis of sulindac crude product

[0117] In 50L reactor, add compound 34kg, acetic acid 10kg, dichloromethane 24kg, after adding, start stirring, add 30% H2O 21.46kg, heat to 30-40°C, keep reaction for 3-5h, after reaction, add 10% sodium thiosulfate aqueous solution 2kg, stirring to quench the reaction, after quenching reaction, add 8kg water, stirring, standing, separating layers, water phase is extracted with 2kg dichloromethane once, combine organic phase, concentrated dichloromethane, leave for next batch. After concentrating dichloromethane, add ethyl acetate 16kg for purification, filter and dry, get compound 4, i.e. sulindac crude product 4.02kg, material HPLC purity is 99.08%(HPLC detection results see Figure 4 ), material molar yield is 95.03%.

[0118] Fourth step: purification of compound 4

[0119] In 50L reactor, add isopropyl alcohol 20kg, compound 44kg, stirring, heat to 75-85°C, after material completely dissolves, slowly cool to 0-10°C for recrystallization, filter and dry, get sulindac finished product 3.86kg, material HPLC purity is 99.44%(HPLC detection results see Figure 5 ), material weight yield is 96.5%.

[0120] Comparative example 1

[0121] First step: synthesis of compound 2

[0122] In 500ml flask, add compound 150g, three-way B 88g, methanol 85g, after adding, start stirring, start dropping 50% glyoxylic acid 33.8g at room temperature, after dropping, keep reaction for 3-5h at 30-40°C, after reaction, adjust pH to 2-4 with HCl aqueous solution, filter, get compound 256.72g, material HPLC purity is 88.98%, material molar yield is 94.58%.

[0123] Second step: synthesis of compound 3

[0124] In 1000ml flask, add compound 250g, acetic acid 340g, after adding, start stirring, add 30% hydrochloric acid 210g, heat to 85-95°C, keep reaction until reaction is completed, distill acetic acid under reduced pressure, add toluene 200g for purification, filter and dry, get compound 335.85g, material HPLC purity is 85.6%, material molar yield is 71.7%.

[0125] Third step: synthesis of compound 4

[0126] In 500 ml flask, add compound 330 g, acetic acid 75 g, dichloromethane 180 g, after adding, open the stirring, add 30% H2O 210.38 g, heat to 30-40 °C, keep the reaction until the reaction is completed, add 10% sodium thiosulfate aqueous solution 15 g, stirring to quench the reaction, after quenching the reaction, add 60 g water, stirring, standing, separating the layers, the aqueous phase is extracted with 15 g dichloromethane once, the combined organic phase is concentrated to remove dichloromethane, which is used in the next batch. After the concentration of dichloromethane, add ethyl acetate 120 g for purification, filter and dry to obtain compound 4, i.e. sulindac crude product 26.88 g, the material HPLC purity is 97.93%, the material molar yield is 85.6%.

[0127] Fourth step: purification of compound 4

[0128] In 250 ml flask, add isopropyl alcohol 110 g, compound 420 g, heat to 75-85 °C under stirring, after the material is completely dissolved, slowly cool to 0-10 °C for recrystallization, filter and dry to obtain sulindac finished product 18.9 g, the material HPLC purity is 98.54%, the material weight yield is 94.5%.

[0129] The above description is not a limitation of the present application, and the present application is not limited to the above examples. Changes, modifications, additions or substitutions made by those skilled in the art within the scope of the present application should also be within the scope of the present application.

Claims

1. A process for the industrial production of sulindac, characterized in that, It comprises the following steps: (1) Synthesis of compound 2: In a container, add compound 1, catalyst tee B, methanol, start stirring after feeding is completed, start dropping glyoxylic acid at room temperature, and then perform incubation reaction after dropping is completed. After the reaction is completed, adjust pH to 2-4 with aqueous HCl solution, filter to obtain compound 2; In step (1), the compound 1 is 5-fluoro-2-1-(4-methylthiobenzyl) indene, and the tee B is benzyltrimethylammonium hydroxide; In step (1), the molar ratio of the catalyst tee B to compound 1 is 1-3:

1. In step (1), the mass ratio of methanol to compound 1 is 1-3:

1. In step (1), the molar ratio of glyoxylic acid to compound 1 is 1:1-2. (2) Synthesis of compound 3: In a container, add the compound 2 prepared in step (1), acetic acid, and start stirring after feeding is completed. Then, add the catalyst ethanolic hydrobromic acid, heat to 25-110 DEG C, and then incubate until the reaction is completed. Distill acetic acid under reduced pressure, add toluene for purification, filter and dry to obtain compound 3; In step (2), the mass ratio of acetic acid to compound 2 is 2-10:

1. In step (2), the molar ratio of the catalyst ethanolic hydrobromic acid to compound 2 is 0.03-1:

1. (3) Synthesis of compound 4: In a container, add the compound 3 prepared in step (2), catalyst acetic acid, dichloromethane, and start stirring after feeding is completed. Then, add H2O2, heat to 25-80 DEG C, and then incubate until the reaction is completed. Add aqueous sodium thiosulfate to quench the reaction, and then add water to stir and separate into layers after quenching the reaction. Extract the aqueous phase with dichloromethane, concentrate dichloromethane from the organic phase, add ethyl acetate for purification, filter and dry to obtain compound 4, i.e. sulindac crude product; In step (3), the mass ratio of acetic acid to compound 3 is 1-3:

1. In step (3), the mass ratio of dichloromethane to compound 3 for synthesizing compound 4 is 4-8:

1. In step (3), the molar ratio of H2O2 to compound 3 is 1-5:

1. (4) Purification of compound 4: In a container, add isopropyl alcohol and compound 4 prepared in step (3), heat to 75-85 DEG C under stirring, and then slowly cool to 0-10 DEG C for recrystallization. Filter and dry to obtain sulindac finished product; In step (4), the mass ratio of isopropyl alcohol to compound 4 is 1-10:

1. The tee B is benzyltrimethylammonium hydroxide.

2. A process for the industrial production of sulindac according to claim 1, characterized in that, In step (1), the molar ratio of the catalyst tee B to compound 1 is 1.8-2.2:

1.

3. A process for the industrial production of sulindac according to claim 1, characterized in that, In step (2), the mass ratio of acetic acid to compound 2 is 6-10:

1.

4. The process for the industrial production of sulindac according to claim 1, characterized in that, In step (2), the molar ratio of the catalyst ethanolic hydrobromic acid to compound 2 is 0.1-0.3:

1.

5. The method for industrial production of sulindac according to claim 1, wherein, In step (2), the concentration of the catalyst ethanolic hydrobromic acid solution is 33%. ​ 6. The method for industrial production of sulindac according to claim 1, wherein, In step (2), the mass ratio of toluene to compound 2 is 3-4:

1. ​ 7. The method for industrial production of sulindac according to claim 1, wherein, In the step (3), the molar ratio of H2O2 to compound 3 is 1-1.2:

1. ​ 8. The process for the industrial production of sulindac according to claim 1, characterized in that, In the step (3), the mass ratio of the aqueous sodium thiosulfate solution to compound 3 is 0.2-1:

1.

9. The method for industrial production of sulindac according to claim 1, wherein, In the step (3), the mass ratio of dichloromethane to compound 3 during extraction is 0.5-1:

1. ​ 10. The process for the industrial production of sulindac as claimed in claim 1 wherein, In the step (4), the mass ratio of isopropyl alcohol to compound 4 is 4-7:

1. ​

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