Preparation method of novel COX-2 inhibitor and intermediate thereof

Abstract

The invention discloses a preparation method of a novel COX-2 inhibitor intermediate as shown in a chemical formula 3 in the specification. Comprising the following steps: generating novel COX-2 inhibitor intermediates 2-(p-tolyl) acetic acid and 2-[4-(methylsulfonyl) phenyl]-2-oxoethyl ester as shown in a chemical formula 3 from 2-bromo-1-(4-methylsulfonyl) acetophenone as shown in a chemical formula 1 and p-methylphenylacetic acid as shown in a chemical formula 2 under the action of methylbenzene and triethylamine; wherein the molar ratio of the 2-bromo-1-(4-methylsulfonyl) acetophenone to the p-methylphenylacetic acid is 1: (1.05 to 1.2); the solid-to-liquid ratio of the 2-bromo-1-(4-methylsulfonyl) acetophenone to the toluene is 1: (3-5). According to the preparation method disclosed by the invention, the yield and purity of the novel COX-2 inhibitor and the intermediate thereof are effectively ensured, and the preparation process is beneficial to large-scale production.

Description

Technical Field

[0001] The present application relates to a novel COX-2 inhibitor and a method for preparing an intermediate thereof. Background Art

[0002] Irecoxib is a pyrrole compound, with a chemical name of 1-n-propyl-3-(4-methylphenyl)-4-(4-methylsulfonylphenyl)-2,5-dihydro-1H-2-pyrrolone, and a chemical structure as shown in Chemical Formula 5. Irecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2) to reduce the production of prostaglandins at the site of inflammation, thereby achieving anti-inflammatory and analgesic effects.

[0003]

[0004] The method for preparing Errecoxib disclosed in Chinese invention patent CN102206178B adopts a synthetic route as shown in the following formula, which has a low yield and has problems such as complex process control and difficulty in separating and purifying the product, which is not conducive to large-scale production. The synthetic route is as follows:

[0005] Summary of the invention

[0006] In view of the deficiencies of the prior art, the present application provides, in a first aspect, a method for preparing a novel COX-2 inhibitor intermediate as shown in Chemical Formula 3, comprising the following steps:

[0007]

[0008] 2-bromo-1-(4-methylsulfonyl)acetophenone shown in Chemical Formula 1 and p-methylphenylacetic acid shown in Chemical Formula 2 are reacted with toluene and triethylamine to generate a novel COX-2 inhibitor intermediate 2-(p-methylphenyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester shown in Chemical Formula 3;

[0009] The molar ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to p-methylphenylacetic acid is 1:1.05-1.2; the solid-liquid ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to toluene is 1:3-5.

[0010] Further, the following steps are included:

[0011] 1) Condensation reaction: 2-bromo-1-(4-methylsulfonyl)acetophenone, p-methylphenylacetic acid and toluene are mixed to obtain a reaction mixture, nitrogen is replaced in a reaction container, and triethylamine is added dropwise to the reaction solution under light-proof conditions and with the internal temperature controlled at no more than 25° C. After the addition is completed, the reaction mixture is heated to 40° C. to 60° C. and reacted at this temperature for 1.5 to 2.5 hours;

[0012] 2) Post-treatment: The reaction mixture obtained in step 1) is cooled to 0° C. to 10° C., and after stirring and filtering, a filter cake is collected; the filter cake is slurried with purified water, filtered, rinsed and dried to obtain 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester.

[0013] In a second aspect, the present application provides a method for preparing a novel COX-2 inhibitor intermediate as shown in Chemical Formula 4, comprising the following steps:

[0014]

[0015] 2-(p-tolyl)acetic acid and 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester as shown in Chemical Formula 3 are condensed in the presence of DMF and diisopropylamine to obtain 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one as shown in Chemical Formula 4; wherein the 2-(p-tolyl)acetic acid and 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester are obtained by the first method of the present application.

[0016] Further, the following steps are included:

[0017] 1) Condensation reaction: 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester, DMF and diisopropylamine are mixed to obtain a reaction mixture, nitrogen is replaced in a reaction container, the reaction mixture is heated to 40° C. to 60° C., and reacted at this temperature for 16 to 18 hours;

[0018] 2) Post-treatment: cooling the reaction mixture obtained in step 1) to 20° C. to 30° C., adding hydrochloric acid dropwise to adjust the pH value, crystallizing with purified water, and collecting a filter cake; the filter cake is rinsed with purified water and then dried to obtain a crude product of 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one;

[0019] 3) Purification: The crude 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one obtained in step 2) is mixed with ethyl acetate and anhydrous ethanol to obtain a reaction mixture, and nitrogen is replaced in a reaction container. The reaction mixture is heated to 50° C. to 60° C. and stirred for 1 hour, then cooled to 0° C. to 10° C. and stirred for 1 hour, filtered, and the filter cake is rinsed with anhydrous ethanol and then dried to obtain 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one;

[0020] Furthermore, the molar ratio of the 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester and the diisopropylamine is 1:2.2-3.0.

[0021] Furthermore, in step 2) post-treatment, the pH value is 4-5.

[0022] On the other hand, the present invention provides a method for preparing a novel COX-2 inhibitor as shown in the following chemical formula 5, comprising the following steps:

[0023] 1) 2-bromo-1-(4-methylsulfonyl)acetophenone shown in Chemical Formula 1 and p-methylphenylacetic acid shown in Chemical Formula 2 are reacted with toluene and triethylamine to generate a novel COX-2 inhibitor intermediate 2-(p-methylphenyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester shown in Chemical Formula 3;

[0024] 2) 2-(p-tolyl)acetic acid and 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester shown in Chemical Formula 3 are condensed in the presence of DMF and diisopropylamine to obtain a novel COX-2 inhibitor intermediate 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one shown in Chemical Formula 4;

[0025] 3) 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one shown in Chemical Formula 4 is subjected to ammonolysis with n-propylamine and then reacted with glacial acetic acid to obtain a crude novel COX-2 inhibitor shown in Chemical Formula 5;

[0026] 4) Refining the crude product of the novel COX-2 inhibitor represented by Chemical Formula 5 with anhydrous ethanol to obtain the novel COX-2 inhibitor;

[0027]

[0028] Among them, the 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester is obtained by the first method of the present application; the 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one is obtained by the second method of the present application.

[0029] Furthermore, the molar ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to p-methylphenylacetic acid is 1:1.05-1.2; the solid-liquid ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to toluene is 1:3-5; the molar ratio of the 2-(p-methylphenyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester and the diisopropylamine is 1:2.2-3.0.

[0030] Furthermore, the solid-liquid ratio of the novel COX-2 inhibitor crude product and the anhydrous ethanol is 1:20-24.

[0031] Furthermore, the refining temperature in step 4) is 55°C to 75°C.

[0032] Compared with the prior art, the preparation method of the novel COX-2 inhibitor (i.e., erecoxib) and its intermediates of the present invention has the following advantages:

[0033] (1) The present invention optimizes the existing preparation process of Erelcoxib to ensure that the purity and yield of the final product reach high standards, which is crucial for the quality control of drugs.

[0034] (2) The preparation process of the present invention significantly improves the yield of each reaction step, reduces the waste of raw materials, reduces production costs, and ensures the purity of each intermediate.

[0035] (3) The present invention simplifies the process flow and reduces unnecessary operating steps, making the entire production process more efficient and convenient.

[0036] (4) The use of more environmentally friendly production methods reduces the generation of harmful by-products, helping to reduce the impact on the environment. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present application will be described clearly below. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0038] The terms "first", "second", etc. in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated before and after are in an "or" relationship.

[0039] The preparation method of Erelcoxib and its intermediates comprises the following steps:

[0040] Step 1: 2-bromo-1-(4-methylsulfonyl)acetophenone (hereinafter referred to as YAR-SM-A) and p-methylphenylacetic acid (hereinafter referred to as YAR-SM-B) are reacted with toluene and triethylamine to generate the etoricoxib intermediate 2-(p-methylphenyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester (hereinafter referred to as YAR-1);

[0041] Specifically, the steps include:

[0042] 1) Condensation reaction: YAR-SM-A, YAR-SM-B and toluene are mixed to obtain a reaction mixture, nitrogen replacement is performed at least three times in a reaction container, and triethylamine is added dropwise to the reaction solution under light-proof conditions and with the internal temperature controlled at no more than 25° C. After the addition is completed, the reaction mixture is heated to 40° C. to 60° C. and reacted at this temperature for 1.5 to 2.5 hours;

[0043] 2) Post-treatment: cooling the reaction mixture obtained in step 1) to 0°C to 10°C, stirring and filtering, and collecting the filter cake; the filter cake is slurried with purified water, filtered, rinsed and dried to obtain YAR-1;

[0044] Among them, the molar ratio of YAR-SM-A to YAR-SM-B is 1:1.05 to 1.2, for example 1:1.05, 1:1 or 1:2, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable; too little YAR-SM-B will result in incomplete reaction of YAR-SM-A, and too much YAR-SM-B will result in excessive impurities in the final product, low purity, and waste of resources.

[0045] The solid-liquid ratio of YAR-SM-A and toluene is 1:3-5, preferably 1:3-4, such as 1:3 or 1:4, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; in the prior art, a variety of solvents can be selected in the preparation process of YAR-1, and these solvents can achieve certain effects. However, after in-depth research and a large number of experimental verifications by the inventors, toluene is selected as a solvent and used within the specific dosage range described herein, which not only makes the entire preparation process simpler, but also significantly improves the yield and purity of the final product while ensuring product quality.

[0046] Step 2: YAR-1 is condensed with DMF and diisopropylamine to obtain the etoricoxib intermediate 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one (hereinafter referred to as YAR-2); the diisopropylamine information mentioned in the present invention is: CAS No. 108-18-9, molecular formula C6H 15 N, molecular weight is 101.19, structural formula is as follows:

[0047]

[0048] Specifically, the steps include:

[0049] 1) Condensation reaction: YAR-1, DMF and diisopropylamine are mixed to obtain a reaction mixture, nitrogen replacement is performed at least three times in a reaction container, the reaction mixture is heated to 40° C. to 60° C., and reacted at this temperature for 16 to 18 hours;

[0050] 2) Post-treatment: cooling the reaction mixture obtained in step 1) to 20° C. to 30° C., adding hydrochloric acid dropwise to adjust the pH value, crystallizing with purified water, and collecting the filter cake; the filter cake is rinsed with purified water, and then dried to obtain a crude YAR-2 product;

[0051] 3) Purification: The crude YAR-2 obtained in step 2), ethyl acetate and anhydrous ethanol are mixed to obtain a reaction mixture, nitrogen replacement is performed at least three times in a reaction container, the reaction mixture is heated to 50° C. to 60° C. and stirred for 1 hour, then cooled to 0° C. to 10° C. and stirred for 1 hour, filtered, the filter cake is rinsed with anhydrous ethanol, and then dried to obtain YAR-2;

[0052] Wherein, the molar ratio of YAR-1 to diisopropylamine is 1:2.2-3.0, such as 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9 or 1:3.0, but it is not limited to the listed values, and other values ​​not listed in the numerical range are also applicable; the selection and proportion of diisopropylamine have a significant impact on the purity and yield of the product of step 2. Other types of solvents, such as DBU as a catalyst, cannot precipitate solids during post-treatment and refining, triethylamine as a catalyst has a slow reaction rate, and the raw material YAR-1 has a large amount of residue, while diisopropylamine does not have these problems. Diisopropylamine has a significant impact on the reaction process. Too much or too little makes the yield and purity of the product obtained in step 2 poor.

[0053] In step 2) post-treatment, the pH value is 4 to 5, for example 4 or 5, but is not limited to the listed values, and other values ​​not listed in the numerical range are also applicable; after in-depth research, the inventors found that by accurately controlling the pH value in the post-treatment stage between 4 and 5, the purity and yield of the product can be significantly improved. When the pH value exceeds this range, the yield and purity of the product are significantly reduced.

[0054] Step 3: YAR-2 is subjected to ammonolysis with n-propylamine and then reacted with glacial acetic acid to obtain a crude product of Erelcoxib (hereinafter referred to as YAR-CP);

[0055] Step 4: YAR-CP is purified by anhydrous ethanol to obtain 1-n-propyl-3-(4-methylphenyl)-4-(4-methylsulfonylphenyl)-2,5-dihydro-1H-2-pyrrolidone (hereinafter referred to as YAR);

[0056] Wherein, the solid-liquid ratio of YAR-CP and anhydrous ethanol is 1:10-24, preferably 1:20-24, such as 1:20, 1:21, 1:22, 1:23 or 1:24, but not limited to the listed values, other unlisted values ​​in the numerical range are also applicable; the dissolution temperature during the refining process is 55°C-75°C, preferably 55°C-65°C, such as 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C or 65°C, but not limited to the listed values, other unlisted values ​​in the numerical range are also applicable; the inventors found that too low a solvent ratio or too high a dissolution temperature will make the purity and yield of the final product of step 4 poor. Therefore, the control of the solvent ratio and dissolution temperature is crucial.

[0057] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0058] Example 1

[0059] Step 1: Preparation of intermediate YAR-1

[0060] Reaction equation:

[0061]

[0062] Steps:

[0063] Condensation reaction: add 1000g (3.62mol) YAR-SM-A, 598.21g (3.99mol) YAR-SM-B, and 3000ml toluene to a 5L three-necked flask in sequence, replace nitrogen three times, protect from light, stir until it is not dissolved, control the internal temperature not to exceed 25℃, and add 403.37g (3.99mol) triethylamine dropwise. After the addition, heat to 55℃±5℃ and react for 1.5-2.5h.

[0064] Post-treatment: The reaction solution was cooled to 0℃~10℃, stirred for 1h, the reaction system was filtered, and the filter cake was transferred to a 20L reactor, 10L purified water was added to slurry for 30min, filtered, and the filter cake was rinsed with 2L purified water. The wet product was vacuum dried at 50℃±5℃ and vacuum degree ≤-0.085MPa for 26~28h. Brown powder YAR-1 was obtained: 1150.0g, the yield was 91.7%, and the purity was 99.82%.

[0065] Yield calculation formula:

[0066] m YAR-1- / M YAR-1 ×M YAR-SM-A / m YAR-SM-A ×100%

[0067] m YAR-1 is the mass of YAR-1, M YAR-1 is the molecular weight of YAR-1, M YAR-SM-A is the molecular weight of YAR-SM-A, m YAR-SM-A Quality of YAR-SM-A

[0068] Related substances and purity test methods:

[0069] The relevant substances were determined according to high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0070] Solvent water-acetonitrile (60:40)

[0071] Test solution Take an appropriate amount of the product, dissolve it in solvent and dilute it to make a solution containing about 0.5 mg per 1 ml, shake well, and use it as the test solution;

[0072] System suitability solution: Take appropriate amounts of impurities YAR-SM-A and YAR-1, dissolve and dilute with solvent to make a mixed solution containing about 2.5 μg of impurities YAR-SM-A and about 0.5 mg of YAR-1 per 1 ml, as the system suitability solution.

[0073] Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (recommended: WelchLP C18, 4.6×250mm, 5μm or chromatographic column with equivalent performance); use water-acetonitrile (75:25) as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0ml per minute, the column temperature is 35℃, the detection wavelength is 228nm, and the injection volume is 10μl.

[0074]

[0075]

[0076] System suitability requirements In the system suitability solution chromatogram, the peak order of each component is YAR-SM-A and YAR-1. The separation between the main peak and the adjacent impurity peaks should meet the requirements.

[0077] Determination method: Precisely measure the blank solvent and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0078] If there are impurity peaks in the chromatogram of the limit test solution, according to the area normalization method, YAR-SM-A shall not exceed 0.5%, the area of ​​other individual impurity peaks shall not exceed 0.5%, and the sum of the areas of all impurity peaks shall not exceed 1.0%.

[0079]

Purity

[0080] Step 2: Synthesis of intermediate YAR-2

[0081] Reaction equation:

[0082]

[0083] Steps:

[0084] Ring-closing reaction: Into a 20L glass reactor, add 1140.0g (3.29mol) of YAR-1 obtained in step 1, 5700ml of DMF and 833.28g (8.23mol) of diisopropylamine in sequence, replace nitrogen three times, raise the temperature to 45°C ± 5°C, and react for 16 to 18h until the reaction is complete.

[0085] Post-treatment: The reaction solution after the reaction is completed is cooled to 20°C-30°C, 3500ml of 2mol / L hydrochloric acid is added dropwise to adjust the pH to 4-5, and then 11.4L of purified water is added. After the solid is precipitated, it is stirred for 1h and filtered. The filter cake is rinsed with purified water and vacuum dried at 45°C±5°C and vacuum degree ≤-0.085MPa to obtain 1020.0g of crude YAR-2.

[0086] Refining: Add 1020.0g YAR-2 crude product, 2850ml ethyl acetate, 2850ml anhydrous ethanol to a 20L glass reactor, replace with nitrogen three times, heat to 50℃~60℃ and stir for 1h, cool to 0℃~10℃ and stir for 1h, filter, and rinse the filter cake with 1140ml anhydrous ethanol. The wet product is vacuum dried at 45℃±5℃ and vacuum degree ≤-0.085MPa for 18~20h. Yellow-green powdered YAR-2 is obtained: 645.50g, with a yield of 59.73% and a purity of 98.45%.

[0087] Yield calculation formula:

[0088] m YAR-2- / M YAR-2 ×M YAR-1 / m YAR-1 ×100%

[0089] m YAR-2 is the mass of YAR-2, M YAR-2 is the molecular weight of YAR-2, m YAR-1 is the mass of YAR-1, M YAR-1 is the molecular weight of YAR-1

[0090] Related substances and purity test methods:

[0091] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0092] Solvent water-acetonitrile (60:40)

[0093] Test solution Take an appropriate amount of the product, dissolve it in solvent and dilute it to make a solution containing about 0.5 mg per 1 ml, shake well, and use it as the test solution;

[0094] System suitability solution: Take appropriate amounts of NNN dimethylformamide, impurities YAR-SM-A, YAR-1 and YAR-2, dissolve in solvent and dilute to make a mixed solution containing approximately 0.75 μg of NNN dimethylformamide, impurities YAR-SM-A and YAR-1 and approximately 0.5 mg of YAR-2 per 1 ml, as the system suitability solution.

[0095] Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (recommended: WelchLP C18, 4.6×250mm, 5μm or chromatographic column with equivalent performance); use water-acetonitrile (75:25) as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0ml per minute, the column temperature is 35℃, the detection wavelength is 228nm, and the injection volume is 10μl.

[0096]

[0097] System suitability requirements In the system suitability solution chromatogram, the peak order of each component is YAR-SM-A, YAR-2 and YAR-1. The separation between the main peak and the adjacent impurity peaks should meet the requirements.

[0098] Determination method: Precisely measure the blank solvent and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0099] If there are impurity peaks in the chromatogram of the limit test solution, after deducting the solvent peak and N-N dimethylformamide peak, calculated by the area normalization method, YAR-SM-A shall not exceed 0.15%, YAR-1 shall not exceed 0.15%, the area of ​​other individual impurity peaks shall not exceed 1.0%, and the sum of the areas of all impurity peaks shall not exceed 5.0%.

[0100]

Purity

[0101] Step 3: Synthesis of crude YAR-CP

[0102] Reaction equation:

[0103]

[0104] Steps:

[0105] Ammonolysis reaction: Into a 3L three-necked flask, add 600.00 g (1.83 mol) of YAR-2 obtained in step 2 and 864.23 g (14.63 mol) of n-propylamine in sequence, and react at 50°C ± 5°C for 2 to 3 h.

[0106] Ring-closing reaction: The reaction solution after the reaction is completed is concentrated to dryness under reduced pressure, dried with dichloromethane twice, added with 3L glacial acetic acid, heated to 110℃~120℃, and reacted for 2~3h.

[0107] Post-treatment: The reaction solution after the reaction is completely cooled to 20℃~30℃, 6L purified water is added to the reaction solution, solids are precipitated, 1500ml dichloromethane is added and stirred for 15min, the liquid is separated, the organic phase is washed twice with purified water, the liquid is separated, 300.0g anhydrous sodium sulfate is added to the organic phase and dried for 1h, and filtered. The filtrate is concentrated to dryness under reduced pressure at 40℃±5℃ and vacuum degree ≤-0.085MPa. Anhydrous ethanol is added to the residue and evaporated twice, each time with an amount of 600ml. After concentration, 3L anhydrous ethanol is added to the pulp for 1h, filtered, and the filter cake is rinsed with anhydrous ethanol. The wet product is vacuum dried at 45℃±5℃ and vacuum degree ≤-0.085MPa for 16-18h. A light yellow to yellow powdered YAR-CP is obtained: 589.5g, with a yield of 87.24% and a purity of 99.40%.

[0108] Yield calculation formula:

[0109] m YAR-CP- / M YAR-CP ×M YAR-2 / m YAR-2 ×100%

[0110] m YAR-CP is the mass of YAR-CP, M YAR-CP is the molecular weight of YAR-CP, m YAR-1 is the mass of YAR-1, M YAR-1 is the molecular weight of YAR-1

[0111] Related substances and purity test methods:

[0112] The relevant substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). Operation was carried out in a dark place.

[0113] Solvent water-acetonitrile (60:40)

[0114] Test solution Take an appropriate amount of the product, dissolve it in solvent and dilute it to make a solution containing about 0.5 mg per 1 ml, shake well, and use it as the test solution;

[0115] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with a solvent to make a solution containing about 1 μg per 1 ml as the control solution;

[0116] System suitability solution: Take appropriate amounts of impurities YAR-2, YAR-IM-B and erlotinib, add solvent to dissolve and dilute to prepare a mixed solution containing about 1.5 μg of impurities YAR-2, about 2.5 μg of YAR-IM-B and about 0.5 mg of erlotinib per 1 ml, as the system suitability solution.

[0117] Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (recommended: WelchLP C18, 4.6×250mm, 5μm or chromatographic column with equivalent performance); use water-acetonitrile (75:25) as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0ml per minute, the column temperature is 35℃, the detection wavelength is 228nm, and the injection volume is 10μl.

[0118]

[0119] System suitability requirements In the system suitability solution chromatogram, the peak order of each component is YAR-2, erlotinib, and YAR-IM-B. The separation between the main peak and the adjacent impurity peaks should meet the requirements. The theoretical plate number of the erlotinib peak in the control solution should not be less than 2000.

[0120] Determination method: Precisely measure blank solvent, test solution and control solution, inject them into liquid chromatograph respectively, and record the chromatogram.

[0121] If there are impurity peaks in the chromatogram of the limit test solution, the impurity YAR-2 shall not be greater than 1.5 times (0.3%) the main peak area of ​​the control solution, the impurity YAR-IM-B shall not be greater than 2.5 times (0.5%) the main peak area of ​​the control solution, the other individual impurity peak area shall not be greater than 5 times (1.0%) the main peak area of ​​the control solution, and the sum of the impurity peak areas shall not be greater than 15 times (3.0%) the main peak area of ​​the control solution.

[0122] The structure of impurity YAR-IM-B is as follows:

[0123]

[0124] Purity: Calculated by self-control method, taking the purity of the main component measured under the relevant substance inspection item, including C 21 H 23 NO3S should not be less than 97.0%.

[0125] Step 4: Synthesis of Erelcoxib finished product YAR

[0126] Steps:

[0127] Dissolution: Add 13.2L of anhydrous ethanol to a 20L reactor, stir and heat to 60℃±5℃, then add 550.00g of YAR-CP obtained in step 3, stir to dissolve, add 27.5g of activated carbon after complete dissolution, stir for 10min, and pass through a precision filter (0.45μm filter membrane) to remove carbon.

[0128] Crystallization: Cool the filtrate of the reaction solution after the reaction is completed to 0-10°C and crystallize for 3 hours. Filter and rinse the filter cake with 1.1L of anhydrous ethanol. The wet product is vacuum dried at 45°C±5°C and vacuum degree ≤-0.085MPa for 18-20 hours. Obtain off-white powder solid YAR: 488.00g, yield 88.73%. , purity 99.60%.

[0129] Yield calculation formula:

[0130] m YAR / m YAR-CP ×100%

[0131] m YAR is the mass of YAR, m YAR-CP For the quality of YAR-CP

[0132] Related substances and purity test methods:

[0133] The relevant substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). Operation was carried out in a dark place.

[0134] Solvent water-acetonitrile (60:40)

[0135] Test solution Take an appropriate amount of the product, dissolve it in solvent and dilute it to make a solution containing about 0.5 mg per 1 ml, shake well, and use it as the test solution;

[0136] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with a solvent to make a solution containing about 1 μg per 1 ml as the control solution;

[0137] Sensitivity solution: Accurately measure an appropriate amount of the control solution and quantitatively dilute it with a solvent to prepare a solution containing approximately 0.2 μg per 1 ml, which is used as the sensitivity solution.

[0138] System suitability solution: Take appropriate amounts of impurities YAR-2, YAR-IM-B and erlotinib, add solvent to dissolve and dilute to prepare a mixed solution containing about 0.75 μg of impurities YAR-2, about 2.5 μg of YAR-IM-B and about 0.5 mg of erlotinib per 1 ml, which is used as the system suitability solution.

[0139] Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (recommended: WelchLP C18, 4.6×250mm, 5μm or chromatographic column with equivalent performance); use water-acetonitrile (75:25) as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0ml per minute, the column temperature is 35℃, the detection wavelength is 228nm, and the injection volume is 10μl.

[0140]

[0141]

[0142] System suitability requirements In the system suitability solution chromatogram, the order of the peaks of each component is YAR-2, erlotinib, and YAR-IM-B. The separation between the main peak and the adjacent impurities should meet the requirements. In the control solution, the number of theoretical plates should not be less than 2000 based on the erlotinib peak. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0143] Determination method: Precisely measure blank solvent, test solution and control solution, inject them into liquid chromatograph respectively, and record the chromatogram.

[0144] If there are impurity peaks in the chromatogram of the limit test solution, the impurity YAR-2 shall not be greater than 0.75 times (0.15%) the main peak area of ​​the control solution, the impurity YAR-IM-B shall not be greater than 2.5 times (0.5%) the main peak area of ​​the control solution, the other individual impurity peak area shall not be greater than 0.5 times (0.10%) the main peak area of ​​the control solution, and the sum of the impurity peak areas shall not be greater than 5 times (1.0%) the main peak area of ​​the control solution.

[0145] Purity: Calculated by self-control method, taking the purity of the main component measured under the relevant substance inspection item, including C 21 H 23 NO3S should not be less than 99.0%.

[0146] Example 2

[0147] The amount of YAR-SM-B in step 1 was adjusted to 652.6 g (4.35 mol), and the remaining steps and conditions were the same as in Example 1, to obtain 1132.5 g of YAR-1 with a yield of 90.3% and a purity of 99.46%.

[0148] Example 3

[0149] The amount of toluene in step 1 was adjusted to 4000 ml, and the remaining steps and conditions were the same as those in Example 1, to obtain 88.7 g of YAR-110 with a yield of 85.3% and a purity of 99.785%.

[0150] Example 4

[0151] The condensation reaction in step 1 was adjusted from heating to 55°C±5°C for 1.5-2.5h to heating to 45°C±5°C for 1.5-2.5h. The remaining steps and conditions were the same as those in Example 1 to obtain 952.2 g of YAR-1 with a yield of 76.0% and a purity of 99.82%.

[0152] Comparative Example 1

[0153] The amount of YAR-SM-B in step 1 was adjusted to 543.83 g (3.62 mol), and the remaining steps and conditions were the same as in Example 1, to obtain 854.4 g of YAR-1 with a yield of 68.2% and a purity of 97.52%.

[0154] Comparative Example 2

[0155] The amount of YAR-SM-B in step 1 was adjusted to 706.23 g (4.71 mol), and the remaining steps and conditions were the same as in Example 1, to obtain 1148.9 g of YAR-1 with a yield of 91.7% and a purity of 98.87%.

[0156] Comparative Example 3

[0157] The amount of toluene in step 1 was adjusted to 5000 ml, and the remaining steps and conditions were the same as those in Example 1, to obtain 8.5 g of YAR-1100 with a yield of 80.5% and a purity of 99.52%.

[0158] Comparative Example 4

[0159] The 3000 ml toluene in step 1 was adjusted to 3000 ml acetonitrile, and the remaining steps and conditions were the same as those in Example 1, to obtain 88.7 g of YAR-110 with a yield of 85.3% and a purity of 99.90%.

[0160] Comparative Example 5

[0161] The 3000 ml toluene in step 1 was adjusted to 3000 ml N,N-dimethylformamide (DMF), and the remaining steps and conditions were the same as those in Example 1 to obtain 1038.6 g of YAR-1 with a yield of 82.9% and a purity of 99.90%.

[0162] Comparative Example 6

[0163] The 3000 ml toluene in step 1 was adjusted to 5000 ml acetonitrile, and the remaining steps and conditions were the same as those in Example 1 to obtain 2.2 g of YAR-198 with a yield of 78.4% and a purity of 99.90%.

[0164] Comparative Example 7

[0165] The 3000 ml toluene in step 1 was adjusted to 5000 ml acetone, and the remaining steps and conditions were the same as those in Example 1 to obtain 3.9 g of YAR-160 with a yield of 48.2% and a purity of 99.80%.

[0166] Comparative Example 8

[0167] The condensation reaction in step 1 was adjusted from heating to 55°C±5°C for 1.5-2.5h to heating to 25°C±5°C for 1.5-2.5h. The remaining steps and conditions were the same as those in Example 1 to obtain 978.5g of YAR-1 with a yield of 78.1% and a purity of 97.1%.

[0168] The yield and purity information of YAR-1 prepared in Examples 1 to 4 and Comparative Examples 1 to 8 are summarized as follows:

[0169]

[0170]

[0171] It can be seen from Examples 1 to 4 and Comparative Examples 1 to 8 that in the process of preparing the intermediate YAR-1, the amount of YAR-SM-B, the selection and proportion of the solvent, and the reaction temperature are crucial to the conversion rate of the raw material YAR-SM-A, as well as the yield and purity of the intermediate YAR-1.

[0172] When the amount of YAR-SM-B is too low, such as in Comparative Example 1 (the molar ratio of YAR-SM-A to YAR-SM-B is 1:1), the yield of YAR-1 is 68.2%, and the purity is 97.52%, which is poor compared with Examples 1 and 2 in which the molar ratio of YAR-SM-A to YAR-SM-B is 1:(1.1-1.2); when the amount of YAR-SM-B is too high, such as in Comparative Example 2 (the molar ratio of YAR-SM-A to YAR-SM-B is 1:3), the yield of YAR-1 can be maintained at a level similar to that of Examples 1-2, but the impurity content in the obtained YAR-1 is relatively high, resulting in a purity of only 98.87%.

[0173] When other conditions are the same, such as Example 1, Comparative Example 4 and Comparative Example 5, when the solvent is selected toluene, acetonitrile and DMF, the yield and purity of the obtained YAR-1 are at a high level, but the YAR-1 obtained by selecting toluene (Example 1) is obviously of better quality and higher yield; when other conditions are the same, it is known that when the solvent is acetone, the yield of the obtained YAR-1 is low, only 48.2%. It can be seen that the type of solvent has a greater impact on YAR-1. However, although acetonitrile and DMF can provide a good yield and purity, the obvious yield is lower than Example 1, and acetonitrile and DMF are selected in addition. Water needs to be added to precipitate crystals during post-treatment, and other solvents need to be extracted, and this process will produce a large amount of waste water, which not only increases the processing cost, but also is difficult to achieve effective recovery and reuse of solvents. Therefore, from the perspective of industrialization, acetonitrile and DMF are not ideal solvent selections because they are not conducive to subsequent large-scale production.

[0174] The present application also verifies the dosage of toluene. By comparing Example 1, Example 3 and Comparative Example 3, it can be seen that when the dosage of toluene is too high (such as the solid-liquid ratio of YAR-SM-A and toluene in Comparative Example 3 is 1:5), the yield and purity of YAR-1 can also be maintained at a high level, but the quality is significantly reduced compared with Examples 1 and 3.

[0175] When the reaction temperature is 45°C±5°C (Example 4) and 55°C±5°C (Example 1), the purity of the obtained YAR-1 is better than that when the reaction temperature is 25±5°C (Comparative Example 8).

[0176] In summary, the amount of YAR-SM-B used in step 1, the choice and proportion of solvent, and the reaction temperature are crucial to the yield and purity of the intermediate YAR-1 and the difficulty of subsequent large-scale production.

[0177] Example 5

[0178] The DMF 5700ml and diisopropylamine 833.28g (8.23mol) in the ring-closing reaction of step 2 were adjusted to DMF 5700ml and diisopropylamine 732.62g (7.24mol), and the remaining steps and conditions were the same as those in Example 1 to obtain 602.2g of YAR-2 with a yield of 55.72% and a purity of 98.88%.

[0179] Example 6

[0180] The DMF 5700ml and diisopropylamine 833.28g (8.23mol) in the ring-closing reaction of step 2 were adjusted to DMF 5700ml and diisopropylamine 998.75g (9.87mol). The remaining steps and conditions were the same as those in Example 1 to obtain 670.5g of YAR-2 with a yield of 62.04% and a purity of 98.08%.

[0181] Comparative Example 9

[0182] The DMF 5700ml and diisopropylamine 833.28g (8.23mol) in the ring-closing reaction of step 2 were adjusted to acetonitrile 5700ml and triethylamine 732.62g (7.24mol), and the remaining steps and conditions were the same as those in Example 1 to obtain 459.3g of YAR-2 with a yield of 42.5% and a purity of 67.9%.

[0183] Comparative Example 10

[0184] The DMF 5700ml and diisopropylamine 833.28g (8.23mol) in the ring-closure reaction of step 2 were adjusted to acetonitrile 5700ml and 1103.02g (7.24mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The remaining steps and conditions were the same as those in Example 1 to obtain 422.6g of YAR-2 with a yield of 39.1% and a purity of 83.04%.

[0185] Comparative Example 11

[0186] The DMF 5700ml and diisopropylamine 833.28g (8.23mol) in the ring-closure reaction of step 2 were adjusted to acetonitrile 5700ml and diisopropylamine 732.62g (7.24mol), and the remaining steps and conditions were the same as those in Example 1 to obtain 574.9g of YAR-2 with a yield of 53.2% and a purity of 83.83%.

[0187] Comparative Example 12

[0188] The DMF 5700ml and diisopropylamine 833.28g (8.23mol) in the ring-closing reaction of step 2 were adjusted to DMF 5700ml and triethylamine 732.62g (7.24mol), and the remaining steps and conditions were the same as those in Example 1 to obtain 354.5g of YAR-2 with a yield of 32.8% and a purity of 72.12%.

[0189] Comparative Example 13

[0190] The DMF 5700ml and diisopropylamine 833.28g (8.23mol) in the ring-closing reaction of step 2 were adjusted to DMF 5700ml and DBU 1103.02g (7.24mol). The remaining steps and conditions were the same as those in Example 1 to obtain 400.9g of YAR-2 with a yield of 37.1% and a purity of 68.51%.

[0191] Comparative Example 14

[0192] The temperature in the ring-closing reaction in step 2 was adjusted from 45°C±5°C to 65°C±5°C. The remaining steps and conditions were the same as those in Example 1. 624.6 g of YAR-2 was obtained with a yield of 57.8% and a purity of 95.99%.

[0193] Comparative Example 15

[0194] The pH value adjusted from 4 to 5 in the post-treatment of step 2 was adjusted to pH value adjusted from 1 to 3. The remaining steps and conditions were the same as those in Example 1. 554.4 g of YAR-2 was obtained with a yield of 51.3% and a purity of 85.06%.

[0195] The yield and purity information of YAR-2 in Example 1, Implementation 5-6 and Comparative Examples 9-15 are summarized as follows:

[0196] YAR-2 Yield of YAR-2 Purity of YAR-2 (95%) Example 1 645.50g 59.73％ 98.45％ Example 5 602.2g 55.72％ 98.88％ Example 6 670.5g 62.04％ 98.08％ Comparative Example 9 459.3g 42.5％ 67.9％ Comparative Example 10 422.6g 39.1％ 83.04％ Comparative Example 11 574.9g 53.2％ 83.83％ Comparative Example 12 354.5g 32.8％ 72.12％ Comparative Example 13 400.9g 37.1％ 68.51％ Comparative Example 14 624.6g 57.8％ 95.99％ Comparative Example 15 554.4g 51.3％ 85.06％

[0197] The present invention verifies a variety of catalysts and solvents, including DBU and acetonitrile (Comparative Example 10) mentioned in the experimental condition E of patent CN102206178B. From the yield and purity of YAR-2, when other conditions are the same, DMF is used as the solvent and diisopropylamine is used as the catalyst (such as Example 5) compared with acetonitrile and triethylamine (such as Comparative Example 9), acetonitrile and DBU (such as Comparative Example 10), acetonitrile and diisopropylamine (such as Comparative Example 11), DMF and triethylamine (such as Comparative Example 12) and DMF and DBU (such as Comparative Example 13). In addition, the molar ratio of YAR-1 to diisopropylamine is 1:2.2-3.0, such as Examples 1, 5 and 6, which have better effects on the yield and purity of the intermediate YAR-2. In addition, we verified various ratios of DBU and acetonitrile, including 1.75 g DBU in experimental condition E of CN102206178B, but none of them could achieve a yield of 91%.

[0198] In step 2, if the reaction temperature is too high, for example, reaching 65±5° C. (as shown in Comparative Example 14), the impurity content in YAR-2 will increase significantly, resulting in a decrease in its purity compared to Example 1, to only 95.99%.

[0199] In the post-treatment process of step 2, if the pH value is low, such as in the range of 1 to 3 (as shown in Comparative Example 15), the yield and purity of the intermediate YAR-2 are significantly lower than those in Example 1, and the purity is only 85.06%.

[0200] Therefore, controlling the type and ratio of the appropriate solvent and catalyst, the reaction temperature and the pH value of the post-treatment in step 2 is crucial to the yield and purity of the intermediate YAR-2.

[0201] Example 7

[0202] The temperature during dissolution in step 4 was adjusted from 60°C±5°C to 70°C±5°C. The remaining steps and conditions were the same as those in Example 1 to obtain 495.0 g of YAR with a yield of 90.0% and a purity of 99.36%.

[0203] Comparative Example 16

[0204] The amount of anhydrous ethanol added in step 4 was adjusted from 13.2 L to 5.5 L, and the remaining steps and conditions were the same as those in Example 1 to obtain 512.6 g of YAR with a yield of 93.2% and a purity of 98.07%.

[0205] The yield and purity information of YAR in Example 1, Example 7 and Comparative Example 16 are summarized as follows:

[0206] YAR Yield of YAR Purity of YAR (99%) Example 1 488.00g 88.73％ 99.60％ Example 7 495.0g 90.0％ 99.36％ Comparative Example 16 512.6g 93.2％ 98.07％

[0207] From Example 1, Example 7 and Comparative Example 16, it can be seen that when the dissolution temperature is increased, such as 70°C ± 5°C (Example 7), under the premise of ensuring the yield, the purity of YAR still meets the requirements; when the ratio of the anhydrous ethanol ratio is reduced, such as Comparative Example 16, although the yield of YAR is improved, the purity of YAR is relatively low. It can be seen that in step 4, the dissolution temperature and the ratio of the solvent anhydrous ethanol have a significant impact on the purity and yield of YAR. The experimental results show that within the range of dissolution temperature of 55 to 75 degrees Celsius, selecting a suitable anhydrous ethanol ratio can effectively improve the purity and yield of YAR. Specifically, when the solid-to-liquid ratio of the crude product of Erexib to anhydrous ethanol is controlled between 1:20 and 1:24, the purity and yield of YAR can reach an ideal state.

[0208] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for preparing a novel COX-2 inhibitor intermediate as shown in Chemical Formula 3, It is characterized in that The steps include: 2-bromo-1-(4-methylsulfonyl)acetophenone shown in Chemical Formula 1 and p-methylphenylacetic acid shown in Chemical Formula 2 are reacted with toluene and triethylamine to generate a novel COX-2 inhibitor intermediate 2-(p-methylphenyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester shown in Chemical Formula 3; The molar ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to the p-methylphenylacetic acid is 1:1.05-1.2; the solid-liquid ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to the toluene is 1:3-5.

2. The preparation method according to claim 1, It is characterized in that The steps include: 1) Condensation reaction: 2-bromo-1-(4-methylsulfonyl)acetophenone, p-methylphenylacetic acid and toluene are mixed to obtain a reaction mixture, nitrogen is replaced in a reaction container, and triethylamine is added dropwise to the reaction solution under light-proof conditions and with the internal temperature controlled at no more than 25° C. After the addition is completed, the reaction mixture is heated to 40° C. to 60° C. and reacted at this temperature for 1.5 to 2.5 hours; 2) Post-treatment: The reaction mixture obtained in step 1) is cooled to 0° C. to 10° C., and after stirring and filtering, a filter cake is collected; the filter cake is slurried with purified water, filtered, rinsed and dried to obtain 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester.

3. A method for preparing a novel COX-2 inhibitor intermediate as shown in Chemical Formula 4, It is characterized in that The steps include: 2-(p-tolyl)acetic acid and 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester as shown in chemical formula 3 are condensed under the action of DMF and diisopropylamine to obtain a novel COX-2 inhibitor intermediate 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one as shown in chemical formula 4; wherein the 2-(p-tolyl)acetic acid and 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester are obtained by the method according to claim 1 or 2.

4. The preparation method according to claim 3, It is characterized in that The steps include: 1) Condensation reaction: 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester, DMF and diisopropylamine are mixed to obtain a reaction mixture, nitrogen is replaced in a reaction container, the reaction mixture is heated to 40° C. to 60° C., and reacted at this temperature for 16 to 18 hours; 2) Post-treatment: cooling the reaction mixture obtained in step 1) to 20° C. to 30° C., adding hydrochloric acid dropwise to adjust the pH value, crystallizing with purified water, and collecting a filter cake; the filter cake is rinsed with purified water and then dried to obtain a crude product of 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one; 3) Purification: The crude 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one obtained in step 2) is mixed with ethyl acetate and anhydrous ethanol to obtain a reaction mixture, and nitrogen is replaced in a reaction container. The reaction mixture is heated to 50°C to 60°C and stirred for 1 hour, then cooled to 0°C to 10°C and stirred for 1 hour, filtered, and the filter cake is rinsed with anhydrous ethanol and then dried to obtain 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one.

5. The preparation method according to claim 4, It is characterized in that The molar ratio of the 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester and the diisopropylamine is 1:2.2-3.

0.

6. The preparation method according to claim 4, It is characterized in that In step 2) post-treatment, the pH value is 4-5.

7. A method for preparing a novel COX-2 inhibitor as shown in Chemical Formula 5, It is characterized in that The steps include: 1) 2-bromo-1-(4-methylsulfonyl)acetophenone shown in Chemical Formula 1 and p-methylphenylacetic acid shown in Chemical Formula 2 are reacted with toluene and triethylamine to generate a novel COX-2 inhibitor intermediate 2-(p-methylphenyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester shown in Chemical Formula 3; 2) 2-(p-tolyl)acetic acid and 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester shown in Chemical Formula 3 are condensed in the presence of DMF and diisopropylamine to obtain 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one shown in Chemical Formula 4; 3) 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one shown in Chemical Formula 4 is subjected to ammonolysis with n-propylamine and then reacted with glacial acetic acid to obtain a crude novel COX-2 inhibitor shown in Chemical Formula 5; 4) Refining the crude product of the novel COX-2 inhibitor represented by Chemical Formula 5 with anhydrous ethanol to obtain the novel COX-2 inhibitor; Wherein, the 2-(p-tolyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester is obtained by the method described in claim 1 or 2; the 4-[4-(methylsulfonyl)phenyl]-3-(p-tolyl)furan-2(5H)-one is obtained by the method described in any one of claims 3 to 7.

8. The preparation method according to claim 7, It is characterized in that The molar ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to p-methylphenylacetic acid is 1:1.05-1.2; the solid-liquid ratio of the 2-bromo-1-(4-methylsulfonyl)acetophenone to toluene is 1:3-5; the molar ratio of the 2-(p-methylphenyl)acetic acid, 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl ester and the diisopropylamine is 1:2.2-3.

0.

9. The preparation method according to claim 8, It is characterized in that In step 4), the solid-to-liquid ratio of the crude novel COX-2 inhibitor to the anhydrous ethanol is 1:20-24.

10. The preparation method according to claim 8, It is characterized in that The refining temperature in step 4) is 55°C to 75°C.

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