A process for the preparation of sulindac

Abstract

This invention discloses a method for preparing sulindac. The method involves first performing an Arbuzov reaction and a Wittig-Horner reaction sequentially to obtain 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene. 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene undergoes a condensation dehydration reaction with glyoxylic acid, followed by double bond rearrangement under acidic conditions to obtain (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid. Finally, it undergoes a single oxidation reaction with an oxidant to obtain sulindac. The raw materials and excipients used in this invention are readily available, and the entire reaction route is short, the reaction conditions are mild, the operation is safe and simple, the yield is high, the purity is high, the production cost is low, and the emissions of waste are minimal, conforming to green industrial production standards. The total yield of the obtained sulindac product is over 75%, which is conducive to industrial production.

Description

Technical Field

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

[0002] Sulindac, chemically known as 5-fluoro-2-methyl-1-[(4-methylsulfinylphenyl)methylene]-1H-indene-3-acetic acid, is an important nonsteroidal anti-inflammatory drug (NSAID). Clinically, sulindac is widely used to treat various inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and acute gout. It effectively relieves symptoms such as joint pain, swelling, and stiffness, improves joint function, and enhances patients' quality of life. Its mechanism of action mainly involves inhibiting the activity of cyclooxygenase (COX), reducing prostaglandin synthesis, and thus exerting significant anti-inflammatory, analgesic, and antipyretic effects. Furthermore, recent studies have revealed its potential antitumor activity, showing promising applications in the prevention and treatment of colonic polyps and early-stage cancer, further expanding its clinical applications. The market demand for sulindac remains stable, and the optimization and innovation of its preparation methods have significant industrial and clinical value.

[0003] Currently, various methods for preparing sulinic acid have been reported in existing technologies. They can be mainly divided into two categories based on the different order of introduction of sulfur-containing phenyl side chains and acetic acid side chains. However, each method has certain defects and cannot simultaneously meet the requirements of high efficiency, low cost, safety and environmental protection, and high purity in large-scale industrial production.

[0004] The first type of preparation method uses p-fluorobenzyl chloride or p-fluorobenzaldehyde as starting materials, and obtains the key intermediate 6-fluoro-2-methyl-1-indanone through multiple chemical reactions. Then, it is condensed with cyanoacetic acid, hydrolyzed to introduce an acetic acid side chain, and finally condensed with p-methylthiobenzaldehyde and oxidized to obtain sulinic acid (reaction route shown below). This method has cumbersome reaction steps, and the yield loss in each step affects the overall yield of the final product. Furthermore, some routes use expensive metal catalysts, significantly increasing production costs. The multi-step reaction easily introduces impurities, making product separation and purification more difficult. Each step requires strict control of reaction conditions, resulting in high operational complexity and hindering continuous industrial production.

[0005]

[0006] The second preparation method uses fluorobenzene and 2-bromoisobutyryl bromide as starting materials. A one-step Friedel-Crafts intramolecular cyclization reaction yields the key intermediate 5-fluoro-2-methyl-1-indanone. This intermediate then undergoes a carbonyl addition dehydration reaction with a p-thiobenzyl Grignard reagent or a zinc reagent to give 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indanone. This is followed by condensation with glyoxylic acid to give 6-fluoro-2-methyl-3-(p-methylthiobenzyl)-1-indanone acetate. Under hydrochloric acid, a single Z-configuration (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indanone acetate is obtained. Finally, oxidation with an oxidizing agent yields sulindac (reaction route shown below). This method has a shorter procedure time, higher yield, and easier control of the Z-configuration of the finished product, making it more suitable for industrial production than the first method. However, the Grignard reagent and zinc reagent used in this method are difficult to prepare, and the byproducts are numerous and difficult to control. The preparation of the metal reagent and the subsequent addition reaction are both significantly exothermic, posing a great safety risk during production, which does not conform to the development concept of green chemistry.

[0007]

[0008] With the rapid development of the pharmaceutical industry, higher requirements have been placed on the efficiency, economy, environmental protection and product purity of drug preparation. The existing methods for preparing sulindac have problems such as complicated steps, low yield, high production cost, serious environmental pollution and high operational safety risks, which have become key bottlenecks restricting the large-scale production and application expansion of sulindac.

[0009] Therefore, developing a method for preparing sulindac and its intermediates that features simple reaction steps, mild reaction conditions, safe and convenient operation, high yield, high purity, low production cost, low emissions of waste, and meets the requirements of green industrial production, can overcome the above-mentioned defects in existing technologies and meet the market demand for large-scale, high-quality production of sulindac. This has significant practical significance and industrial application value. Summary of the Invention

[0010] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for preparing sulindac, which addresses the shortcomings of the prior art.

[0011] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:

[0012] In a first aspect, the present invention discloses a method for preparing 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene.

[0013] The method involves reacting 4-methylthiobenzyl halide with triethyl phosphite via an Arbuzov reaction, followed by a Wittig-Horner reaction with 5-fluoro-2-methyl-1-indone to produce 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indone.

[0014]

[0015] Among them, 4-methylthiobenzyl halide is 4-methylthiobenzyl chloride or 4-methylthiobenzyl bromide, preferably 4-methylthiobenzyl chloride.

[0016] The Arbuzov reaction is carried out in an organic solvent, which is any one or a combination of tetrahydrofuran, 1,4-dioxane and toluene, preferably tetrahydrofuran, and the mass of the organic solvent is 5 to 8 times the mass of 4-methylthiobenzyl halide.

[0017] The molar ratio of 4-methylthiobenzyl halide to triethyl phosphite is 1:(1.0~1.2).

[0018] The Arbuzov reaction is carried out at a temperature of 60-110°C, such as 100°C.

[0019] The reaction time of the Arbuzov reaction is 1-2 h.

[0020] The product obtained from the Arbuzov reaction is used directly in the Wittig-Horner reaction without separation and purification; the product obtained from the Arbuzov reaction is a reaction solution containing diethyl 4-methylthiobenzyl phosphate.

[0021] .

[0022] The Wittig-Horner reaction is carried out under the catalysis of a base, which is any one or a combination of sodium hydride, sodium methoxide and potassium tert-butoxide, preferably potassium tert-butoxide; in some embodiments, the sodium hydride is 60% sodium hydride.

[0023] The molar ratio of the 4-methylthiobenzyl halide to 5-fluoro-2-methyl-1-indanone and the base is 1:(1.0~1.1):(1.0~1.2).

[0024] The Wittig-Horner reaction is carried out at a temperature of 20-30°C for 2-4 hours.

[0025] After the Wittig-Horner reaction is completed, water or n-heptane is added to the reaction solution and stirred or slurryed. The mixture is then filtered, and the filter cake is dried to obtain 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene. The amount of water or n-heptane used is 3-5 mL / 1 g of 4-methylthiobenzyl halide.

[0026] Secondly, this invention discloses a method for preparing sulindac.

[0027] The method includes the following steps:

[0028] (1) 4-methylthiobenzyl halide is reacted with triethyl phosphite by Arbuzov reaction, and then reacted with 5-fluoro-2-methyl-1-indone by Wittig-Horner reaction to produce 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indone;

[0029] (2) The condensation and dehydration reaction of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene with glyoxylic acid and the rearrangement of the double bond under acidic conditions produce (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid;

[0030] (3) Oxidation of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid yields sulinic acid;

[0031] .

[0032] In step (1),

[0033] Among them, 4-methylthiobenzyl halide is 4-methylthiobenzyl chloride or 4-methylthiobenzyl bromide, preferably 4-methylthiobenzyl chloride.

[0034] The Arbuzov reaction is carried out in an organic solvent, which is any one or a combination of tetrahydrofuran, 1,4-dioxane and toluene, preferably tetrahydrofuran, and the mass of the organic solvent is 5 to 8 times the mass of 4-methylthiobenzyl halide.

[0035] The molar ratio of 4-methylthiobenzyl halide to triethyl phosphite is 1:(1.0~1.2).

[0036] The Arbuzov reaction is carried out at a temperature of 60-110°C, such as 100°C.

[0037] The reaction time of the Arbuzov reaction is 1-2 h.

[0038] The product obtained from the Arbuzov reaction is used directly in the Wittig-Horner reaction without separation and purification; the product obtained from the Arbuzov reaction is a reaction solution containing diethyl 4-methylthiobenzyl phosphate.

[0039] .

[0040] The Wittig-Horner reaction is carried out under the catalysis of a base, which is any one or a combination of sodium hydride, sodium methoxide and potassium tert-butoxide, preferably potassium tert-butoxide; in some embodiments, the sodium hydride is 60% sodium hydride.

[0041] The molar ratio of the 4-methylthiobenzyl halide to 5-fluoro-2-methyl-1-indanone and the base is 1:(1.0~1.1):(1.0~1.2).

[0042] The Wittig-Horner reaction is carried out at a temperature of 20-30°C for 2-4 hours.

[0043] After the Wittig-Horner reaction is completed, water or n-heptane is added to the reaction solution and stirred or slurryed. The mixture is then filtered, and the filter cake is dried to obtain 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene. The amount of water or n-heptane used is 3-5 mL / 1 g of 4-methylthiobenzyl halide.

[0044] In step (2),

[0045] Specifically, the reaction involves the condensation and dehydration of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene with glyoxylic acid in an organic solvent under alkaline catalysis to yield 6-fluoro-2-methyl-3-(p-methylthiobenzyl)-1-indeneacetic acid, followed by double bond rearrangement under acidic conditions to yield (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid.

[0046] .

[0047] The alkali is sodium methoxide and / or sodium ethoxide, preferably sodium methoxide.

[0048] The organic solvent is methanol and / or ethanol, preferably methanol; the amount of the organic solvent used is 5 to 8 times the mass of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene.

[0049] The acidic conditions are achieved by adding an acid, which is hydrochloric acid and / or hydrobromic acid, optionally 36% hydrochloric acid and / or 40% hydrobromic acid, preferably 40% hydrobromic acid; the amount of acid used is 3 to 5 times the mass of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene.

[0050] The molar ratio of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene to glyoxylic acid and alkali is 1:(1.5~2.0):(3.0~4.0).

[0051] The condensation dehydration reaction temperature is 20~30℃, and the reaction time is 2~3 h.

[0052] The double bond rearrangement temperature is 60~80℃, and the rearrangement time is 1~2 h.

[0053] In step (3),

[0054] The specific reaction involves the oxidation of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid in chloroform with an oxidizing agent to obtain crude sulinic acid, which is then purified by ethanol and crystallized to obtain sulinic acid.

[0055] The chloroform is 5 to 7 times the mass of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid, and 6 times in some embodiments.

[0056] The oxidant is hydrogen peroxide and / or m-chlorobenzoic acid peroxide, optionally 30% hydrogen peroxide and / or 85% m-chlorobenzoic acid peroxide, preferably 30% hydrogen peroxide.

[0057] The molar ratio of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid to the oxidant is 1:(1.0~1.3).

[0058] The oxidation reaction is carried out at a temperature of 20-30°C for 3-5 hours.

[0059] After the reaction is completed, the reaction solution is quenched with sodium thiosulfate solution, chloroform is removed by vacuum distillation, and ethanol is added to the residue.

[0060] The amount of ethanol used is 5 to 8 times the mass of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid.

[0061] In this process, after adding ethanol, the temperature is raised to reflux to dissolve the crystals and then crystallize.

[0062] The crystallization temperature is 10~20℃ and the crystallization time is 2~3 h.

[0063] In some embodiments, the preparation method of sulindac specifically includes the following steps:

[0064] (1) Arbuzov reaction of 4-methylthiobenzyl halide with triethyl phosphite, and Wittig-Horner reaction of 4-methylthiobenzyl phosphate with 5-fluoro-2-methyl-1-indanone:

[0065] 4-Methylthiobenzyl halide reacts with triethyl phosphite in an organic solvent via the Arbuzov reaction to give diethyl 4-methylthiobenzyl phosphate. Without separation and purification, it directly reacts with 5-fluoro-2-methyl-1-indanone in a base-catalyzed Wittig-Horner reaction to give 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indanone.

[0066]

[0067] (2) Condensation dehydration reaction of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene with glyoxylic acid:

[0068] 6-Fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene undergoes a condensation dehydration reaction with glyoxylic acid in an organic solvent under alkaline catalysis to give 6-fluoro-2-methyl-3-(p-methylthiobenzyl)-1-indeneacetic acid. Then, under acidic conditions, the double bond rearranges to give a single Z-configuration product (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid.

[0069]

[0070] (3) Preparation of sulindac

[0071] (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid was oxidized in chloroform to obtain crude sulinic acid, which was then purified with ethanol to obtain sulinic acid.

[0072]

[0073] Unless otherwise specified, the hydrochloric acid, hydrobromic acid, hydrogen peroxide, and m-chlorobenzoic acid mentioned in this invention are mass percentages. For example, 30% hydrogen peroxide means that the mass percentage is 30%.

[0074] Beneficial effects: Compared with the prior art, the advantages of the present invention are as follows:

[0075] This invention provides a method for preparing sulindac with low production cost, short reaction route, good reaction safety, and high-quality product. Furthermore, the raw materials and excipients used in this invention are readily available, the entire reaction route is concise, the reaction conditions are mild, the operation is safe and simple, the yield is high, the purity is high, the production cost is low, the emissions of waste are minimal, and it conforms to green industrial production. The resulting sulindac product has a high yield, with an overall yield of over 75%, which is conducive to industrial production. Attached Figure Description

[0076] Figure 1 The HRMS spectrum of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene obtained in Example 1.

[0077] Figure 2 The 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene obtained in Example 1 1 H-NMR spectrum.

[0078] Figure 3 The HRMS spectrum of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid obtained in Example 1.

[0079] Figure 4 The (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-inden-3-acetic acid obtained in Example 1 1 H-NMR spectrum.

[0080] Figure 5 The image shows the HRMS spectrum of sulindac obtained in Example 1.

[0081] Figure 6 The sulindac obtained in Example 1 1 H-NMR spectrum. Detailed Implementation

[0082] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0083] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0084] Example 1:

[0085] The preparation method of sulindac in this embodiment is as follows:

[0086] (1) Preparation of diethyl 4-methylthiobenzyl phosphate

[0087] At room temperature, 100.0 g (579.14 mmol) of 4-methylthiobenzyl chloride, 105.9 g (637.05 mmol) of triethyl phosphite and 500 g of tetrahydrofuran were added to a reaction vessel. After the addition was complete, the mixture was stirred at 65 °C for 2 h. No concentration or purification was required after the reaction was complete; the mixture was used directly for the next reaction.

[0088] (2) Preparation of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene

[0089] At room temperature, 95.1 g (579.14 mmol) of 5-fluoro-2-methyl-1-indanone and 71.5 g (637.07 mmol) of potassium tert-butoxide were added to a reaction vessel containing the intermediate solution from the previous step. After the addition was complete, the mixture was stirred at 20–30 °C for 4 h. After the reaction was complete, 36% hydrochloric acid was added to adjust the pH to 2–3, and the mixture was heated to reflux and stirred for 2 h. 300 g of water was added to the reaction solution, and the mixture was stirred at room temperature for 1 h. The mixture was then filtered, and the filter cake was dried to give 158.1 g of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indanone, with a yield of 96%.

[0090] like Figure 1 As shown, HRMS (ESI) found [MH]. - =283.0965.

[0091] like Figure 2 As shown, 1 H NMR (400 MHz, CDCl3): δ =2.12(s, 3H), 2.43(s, 3H), 3.33(s,2H), 3.81(s, 2H), 6.82-6.87(m, 1H), 6.93-6.96(m, 1H), 7.06-7.08(m, 1H), 7.10-7.17(m, 4H).

[0092] (3) Preparation of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-inden-3-acetic acid

[0093] 100.0 g (351.63 mmol) of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene and 39.1 g (527.44 mmol) of glyoxylic acid were added to 500 g of methanol. 57.0 g (1.05 mol) of sodium methoxide was added at a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at 20-30°C for 2 h. After the reaction was complete, 300 g of 40% hydrobromic acid was added, and the mixture was heated to 60-80°C and stirred for 1 h. 300 g of water was added, and the mixture was stirred for 30 min before filtration. The filter cake was purified according to the method described in patent CN117326991A. After drying, 107.7 g of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid was obtained, with a yield of 90%.

[0094] like Figure 3 As shown, HRMS (ESI) found [2M-H] - =679.1755.

[0095] like Figure 4As shown, 1 H NMR (400 MHz, CDCl3): δ =2.20(s, 3H), 2.55(s, 3H), 3.59(s,2H), 6.59(m, 1H), 6.88(m, 1H), 7.15(m, 1H), 7.28(m, 2H), 7.36(m, 1H), 7.44(m,2H).

[0096] (4) Preparation of sulindac

[0097] At room temperature, 100 g (293.76 mmol) of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid was added to 600 g of chloroform. 36.6 g (323.14 mmol) of 30% hydrogen peroxide was added dropwise while maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at 20-30°C for 3 h. After the reaction was complete, the reaction mixture was quenched with sodium thiosulfate solution, and the chloroform was removed by vacuum distillation. 600 g of ethanol was added to the residue, and the mixture was heated to reflux until dissolved. The temperature was then slowly lowered to 10-20°C and maintained at this temperature for 2-3 h to allow crystals to crystallize. The crystals were filtered, and the filter cake was dried to obtain 98.4 g of sulindac, with a yield of 94%.

[0098] like Figure 5 As shown, HRMS (ESI) found [2M-H] - =711.1627.

[0099] like Figure 6 As shown, 1 H NMR (400 MHz, CDCl3): δ =2.20(s, 3H), 2.84(s, 3H), 3.58(s, 2H), 6.54(m, 1H), 6.88(m, 1H), 7.12(m, 2H), 7.63-7.72(m, 4H).

[0100] Example 2:

[0101] The preparation method of sulindac in this embodiment is as follows:

[0102] (1) Preparation of diethyl 4-methylthiobenzyl phosphate

[0103] At room temperature, 100.0 g (579.14 mmol) of 4-methylthiobenzyl chloride, 96.2 g (579.14 mmol) of triethyl phosphite, and 500 g of 1,4-dioxane were added to a reaction vessel. After the addition was complete, the mixture was stirred at 100 °C for 1 h. No concentration or purification was required after the reaction was complete; the mixture was used directly for the next reaction.

[0104] (2) Preparation of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene

[0105] At room temperature, 104.6 g (637.07 mmol) of 5-fluoro-2-methyl-1-indanone and 27.8 g (694.98 mmol) of 60% sodium hydride were added to a reaction vessel containing the intermediate solution from the previous step. After the addition was complete, the mixture was stirred at 20–30 °C for 2 h. After the reaction was complete, 36% hydrochloric acid was added to adjust the pH to 2–3, and the mixture was heated to reflux and stirred for 2 h. 300 g of water was added to the reaction solution, and the mixture was stirred at room temperature for 1 h. The mixture was then filtered, and the filter cake was dried to give 156.5 g of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indanone, with a yield of 95%.

[0106] (3) Preparation of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-inden-3-acetic acid

[0107] 100.0 g (351.63 mmol) of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene and 52.1 g (703.25 mmol) of glyoxylic acid were added to 600 g of ethanol. 95.7 g (1.41 mol) of sodium ethoxide was added while maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at 20-30°C for 3 h. After the reaction was complete, 300 g of 36% hydrochloric acid was added, and the mixture was heated to 60-80°C and stirred for 2 h. 300 g of water was added, and the mixture was stirred for 30 min before filtration. The filter cake was purified according to the method described in patent CN117326991A. After drying, 105.3 g of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid was obtained, with a yield of 88%.

[0108] (4) Preparation of sulindac

[0109] At room temperature, 100 g (293.76 mmol) of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid was added to 600 g of chloroform. 71.6 g (352.51 mmol) of 85% m-chloroperoxybenzoic acid was added while maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at 20–30°C for 5 h. After the reaction was complete, the reaction mixture was quenched with sodium thiosulfate solution, filtered, and the filtrate was washed with saturated sodium bicarbonate solution. The organic phase was then evaporated under reduced pressure to remove chloroform. 800 g of ethanol was added to the residue, and the mixture was heated to reflux until dissolved. The temperature was then slowly lowered to 10–20°C and maintained at this temperature for 2–3 h to allow crystals to crystallize. The crystals were filtered, and the filter cake was dried to obtain 97.4 g of sulindac, with a yield of 93%.

[0110] Example 3:

[0111] The preparation method of sulindac in this embodiment is as follows:

[0112] (1) Preparation of diethyl 4-methylthiobenzyl phosphate

[0113] At room temperature, 100.0 g (579.14 mmol) of 4-methylthiobenzyl chloride, 115.5 g (694.97 mmol) of triethyl phosphite and 800 g of toluene were added to a reaction vessel. After the addition was complete, the mixture was stirred at 110 °C for 1 h. No concentration or purification was required after the reaction was complete; the mixture was used directly for the next reaction.

[0114] (2) Preparation of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene

[0115] At room temperature, 104.6 g (637.07 mmol) of 5-fluoro-2-methyl-1-indanone and 34.4 g (637.07 mmol) of sodium methoxide were added to a reaction vessel containing the intermediate solution from the previous step. After the addition was complete, the mixture was stirred at 20–30 °C for 4 h. After the reaction was complete, 36% hydrochloric acid was added to adjust the pH to 2–3, and the mixture was heated to reflux and stirred for 2 h. Toluene was removed by vacuum distillation, and the residue was slurried with 500 mL of n-heptane for 30 min and then filtered. The filter cake was dried to give 156.5 g of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indanone, with a yield of 95%.

[0116] (3) Preparation of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-inden-3-acetic acid

[0117] 100.0 g (351.63 mmol) of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene and 39.1 g (527.44 mmol) of glyoxylic acid were added to 600 g of ethanol. 71.8 g (1.05 mol) of sodium ethoxide was added while maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at 20–30°C for 3 h. After the reaction was complete, 300 g of 40% hydrobromic acid was added, and the mixture was heated to 60–80°C and stirred for 1 h. 300 g of water was added, and the mixture was stirred for 30 min before filtration. The filter cake was purified according to the method described in patent CN117326991A. After drying, 106.5 g of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid was obtained, with a yield of 89%.

[0118] (4) Preparation of sulindac

[0119] At room temperature, 100 g (293.76 mmol) of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid was added to 600 g of chloroform. 39.9 g (352.512 mmol) of 30% hydrogen peroxide was added dropwise while maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at 20–30°C for 3 h. After the reaction was complete, the reaction mixture was quenched with sodium thiosulfate solution, and the chloroform was removed by vacuum distillation. 600 g of ethanol was added to the residue, and the mixture was heated to reflux until dissolved. The mixture was then slowly cooled to 10–20°C and kept at this temperature for 2–3 h to allow crystals to crystallize. The crystals were filtered, and the filter cake was dried to obtain 96.3 g of sulindac, with a yield of 92%.

[0120] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene, characterized in that, 4-Methylthiobenzyl halide is reacted with triethyl phosphite via an Arbuzov reaction, followed by a Wittig-Horner reaction with 5-fluoro-2-methyl-1-indone to produce 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indone; 。 2. The preparation method according to claim 1, characterized in that, The Arbuzov reaction is carried out in an organic solvent, which is any one or a combination of tetrahydrofuran, 1,4-dioxane, and toluene, and the mass of the organic solvent is 5 to 8 times the mass of 4-methylthiobenzyl halide; the molar ratio of 4-methylthiobenzyl halide to triethyl phosphite is 1:(1.0 to 1.2); the Arbuzov reaction temperature is 60 to 110°C, and the Arbuzov reaction time is 1 to 2 h; optionally, the product obtained from the Arbuzov reaction is used directly in the Wittig-Horner reaction without separation and purification; optionally, the product obtained from the Arbuzov reaction is a reaction solution containing diethyl 4-methylthiobenzyl phosphate. 。 3. The preparation method according to claim 1, characterized in that, The Wittig-Horner reaction is carried out under the catalysis of a base, wherein the base is any one or a combination of several of sodium hydride, sodium methoxide, and potassium tert-butoxide; the molar ratio of the raw materials 4-methylthiobenzyl halide, 5-fluoro-2-methyl-1-indanone, and the base is 1:(1.0~1.1):(1.0~1.2); the temperature of the Wittig-Horner reaction is 20~30℃, and the reaction time is 2~4 h.

4. A method for preparing sulindac, characterized in that, Includes the following steps: (1) 4-methylthiobenzyl halide is reacted with triethyl phosphite by Arbuzov reaction, and then reacted with 5-fluoro-2-methyl-1-indone by Wittig-Horner reaction to produce 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indone; (2) The condensation and dehydration reaction of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene with glyoxylic acid and the rearrangement of the double bond under acidic conditions produce (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid; (3) Oxidation of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid yields sulinic acid; 。 5. The method according to claim 4, characterized in that, In step (1), the Arbuzov reaction is carried out in an organic solvent, which is any one or a combination of tetrahydrofuran, 1,4-dioxane and toluene, and the mass of the organic solvent is 5 to 8 times the mass of 4-methylthiobenzyl halide; the molar ratio of 4-methylthiobenzyl halide to triethyl phosphite is 1:(1.0 to 1.2); the temperature of the Arbuzov reaction is 60 to 110°C, and the reaction time of the Arbuzov reaction is 1 to 2 h; optionally, the product obtained from the Arbuzov reaction is used directly in the Wittig-Horner reaction without separation and purification; optionally, the product obtained from the Arbuzov reaction is a reaction solution containing diethyl 4-methylthiobenzyl phosphate. 。 6. The preparation method according to claim 4, characterized in that, In step (1), the Wittig-Horner reaction occurs under the catalysis of a base, which is any one or a combination of sodium hydride, sodium methoxide, and potassium tert-butoxide; the molar ratio of the raw materials 4-methylthiobenzyl halide, 5-fluoro-2-methyl-1-indanone, and the base is 1:(1.0~1.1):(1.0~1.2); the temperature of the Wittig-Horner reaction is 20~30℃, and the reaction time is 2~4 h.

7. The preparation method according to claim 4, characterized in that, In step (2), 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene undergoes a condensation dehydration reaction with glyoxylic acid in an organic solvent under alkaline catalysis to obtain 6-fluoro-2-methyl-3-(p-methylthiobenzyl)-1-indeneacetic acid, and then the double bond rearranges under acidic conditions to obtain (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid; 。 8. The preparation method according to claim 7, characterized in that, The alkali is sodium methoxide and / or sodium ethoxide; the organic solvent is methanol and / or ethanol; the amount of the organic solvent is 5 to 8 times the mass of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene; the acidic conditions are achieved by adding acid, which is hydrochloric acid and / or hydrobromic acid, optionally 36% hydrochloric acid and / or 40% hydrobromic acid; the amount of acid is 3 to 5 times the mass of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene; the molar ratio of 6-fluoro-3-(p-methylthiobenzyl)-2-methyl-1H-indene to glyoxylic acid and alkali is 1:(1.5 to 2.0):(3.0 to 4.0); the condensation dehydration reaction temperature is 20 to 30°C, and the reaction time is 2 to 3 h; the double bond rearrangement temperature is 60 to 80°C, and the rearrangement time is 1 to 2 h.

9. The preparation method according to claim 4, characterized in that, In step (3), (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylmethyl)-1H-indene-3-acetic acid is oxidized in chloroform to obtain crude sulinic acid, which is then purified by ethanol and crystallized to obtain sulinic acid.

10. The method according to claim 9, characterized in that, The oxidant is hydrogen peroxide and / or m-chlorobenzoic acid, optionally 30% hydrogen peroxide and / or 85% m-chlorobenzoic acid; the molar ratio of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid to the oxidant is 1:(1.0~1.3); the oxidation reaction temperature is 20~30℃, and the reaction time is 3~5 h; the amount of ethanol used is 5~8 times the mass of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzyl)-1H-indene-3-acetic acid; the crystallization temperature is 10~20℃, and the crystallization time is 2~3 h.

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