Process for the preparation of an intermediate of irrexio

Abstract

The application provides a preparation method of an intermediate of irbesartan, adopts DMTMM as a condensing agent and TEMPO / sodium hypochlorite as an oxidizing agent, saves production cost, greatly reduces the security risk possibly introduced in the drug production process, and is more simple, safer, higher in yield, higher in product purity and more suitable for industrial production compared with the prior art.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a method for preparing an intermediate of etoricoxib. Background Technology

[0002] Imrecoxib is a highly selective COX-2 inhibitor developed by Jiangsu Hengrui Medicine Co., Ltd., used to treat and relieve pain symptoms in osteoarthritis and postoperative inflammation. The chemical name of imrecoxib is (N-n-propyl-3-(4-methylphenyl)-4-(4-methanesulfonylphenyl)-2,5-dihydropyrrole-2-one), and its structure is shown in formula (I).

[0003]

[0004] CN1134413C discloses a method for preparing etoricoxib, which uses 4-methanesulfonyl styrene oxide as a raw material and prepares etoricoxib through nucleophilic ring opening with n-propylamine, amidation with p-methylphenylacetyl chloride, hydroxyl oxidation, and condensation cyclization. The synthetic route is shown below:

[0005]

[0006] In the above route, the amidation step uses p-methylphenylacetyl chloride. Acyl chloride reacts not only with the amino group in intermediate (IV) but also with the hydroxyl group, generating esterification impurities, increasing purification difficulty, and thus affecting the yield. Patent CN107586268A optimizes and modifies the above route by replacing p-methylphenylacetyl chloride with p-methylphenylacetic acid. The amide intermediate (II) is prepared under the promotion of condensing agents such as CDI and EDCI, which improves the reaction yield and product purity of this step. However, condensing agents such as CDI and EDCI are sensitive to moisture in the reaction system, and industrial scale-up requires controlling the moisture content to a low level, increasing production difficulty.

[0007] Patents CN1134413C and CN107586268A use Jones' reagent or chromic anhydride pyridine as oxidants in their oxidation steps. Oxidation reaction systems containing chromium oxidants are viscous, resulting in high costs, low yields, and difficulty in product separation, which is detrimental to industrial scale-up. Furthermore, the residue of the heavy metal chromium can affect the quality of the active pharmaceutical ingredient, chromium-containing wastewater is difficult to treat, poses significant environmental pollution risks, and also presents considerable risks to the safety and health of personnel during the production process. Summary of the Invention

[0008] The present invention aims to overcome the shortcomings of the prior art. The technical problem to be solved by the present invention is to provide a method for preparing intermediate N-n-propyl-N-[2-oxo-2-(4'-methanesulfonylphenyl)]ethyl-4-methylphenylacetamide (II). This method uses DMTMM, which does not require hydrophobicity, as a condensing agent. Intermediate IV and 4-methylphenylacetic acid can react simply and rapidly to obtain intermediate (III) with high yield and purity. Subsequently, TEMPO / 5%-10% sodium hypochlorite is used as an oxidant to efficiently oxidize intermediate (III) to intermediate II.

[0009] To address the above problems, the technical solution provided by this invention is as follows:

[0010] A method for preparing an intermediate of etoricoxib, wherein the intermediate is N-n-propyl-N-[2-oxo-2-(4'-methanesulfonylphenyl)]ethyl-4-methylphenylacetamide (Formula II), characterized in that the method for preparing the intermediate comprises the following steps:

[0011] Step (1): Compound (IV), 4-methylphenylacetic acid, and a condensing agent are added to the reaction solvent and stirred at a certain temperature. After the reaction is complete, post-processing is performed to obtain an oily intermediate (III). The reaction formula is as follows:

[0012]

[0013] The condensing agent is DMTMM;

[0014] Step (2): Add intermediate (III), TEMPO and catalyst to the reaction solvent, and slowly add 5%-10% sodium hypochlorite aqueous solution dropwise under an ice-water bath until no raw material remains, to obtain compound (formula II), the reaction formula is as follows:

[0015]

[0016] The catalyst is sodium bromide or potassium bromide.

[0017] Further, the amount of condensing agent DMTMM used in step (1) is intermediate (IV):DMTMM molar ratio of 1:1.00 to 1.20 equivalents, preferably 1.05 equivalents;

[0018] Further, the solvent selected in step (1) includes one or more of N,N-dimethylformamide, N-methylpyrrolidone, toluene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, and water, preferably toluene; the amount of solvent used is 3 to 50 times the mass of intermediate (IV).

[0019] Furthermore, the reaction temperature in step (1) is 0–50°C, preferably 10–40°C.

[0020] Furthermore, the solvent selected in step (2) includes one or more of dichloromethane and toluene, preferably toluene; the amount of solvent used is 2 to 35 times the mass of intermediate (III); in the continuous addition step, the amount of solvent used is 3 to 50 times the mass of intermediate (IV).

[0021] Furthermore, the weight ratio of TEMPO / 5%-10% sodium hypochlorite solution used in step (2) is 1:100 to 1:85, and the amount of sodium hypochlorite used is 2.5 to 3.5 times the mass of intermediate (III); during continuous addition operation, the amount of sodium hypochlorite used is 3.75 to 5.25 times the mass of intermediate (IV).

[0022] Further, the catalyst used in step (2) is potassium bromide or sodium bromide, and the amount used is 3 to 10% of the weight of formula (III). In continuous addition operation, the amount of catalyst used is 4.5 to 15.0% of the weight of intermediate (IV). Further, the reaction temperature in step (2) is 0 to 50°C, preferably 10 to 40°C.

[0023] The intermediate (III) prepared by this invention has mild reaction conditions, high purity, and an esterification impurity (VI) content of less than 0.10%. The structural formula of the esterification impurity is as follows:

[0024]

[0025] Further research in this invention has shown that the yield and purity of intermediate (III) prepared by the condensation reaction are both high. The intermediate (II) can be prepared by a continuous two-step operation of condensation and oxidation, further optimizing the process. Specifically, 4-methylphenylacetic acid, compound (IV), and a condensing agent are added to a reaction solvent and stirred at a certain temperature. After the condensation reaction is complete, an aqueous solution of sodium bicarbonate is added. Water, a catalyst, and TEMPO are added to the organic layer after separation. A 5%-10% sodium hypochlorite solution is slowly added dropwise under an ice-water bath. After the reaction is complete, the product is processed to obtain compound (formula II). The condensing agent is DMTMM, and the catalyst is sodium bromide or potassium bromide.

[0026]

[0027] The beneficial effects of this invention are as follows: using DMTMM as a condensing agent makes the reaction operation simple, and the condensing agent does not react with the alcohol group in the etoricoxib intermediate (IV) to produce a large number of esters; using TEMPO / 5%-10% sodium hypochlorite as an oxidant makes the oxidation reaction green, mild, low-cost, and easy to process, and does not introduce heavy metals. While saving production costs, it also greatly reduces the safety risks that may be introduced in the drug production process. Compared with the prior art, the preparation method of intermediate (II) provided by this invention is simpler to operate, safer, has a higher yield, higher product purity, and is more suitable for industrial production. Attached Figure Description

[0028] Figure 1 The HPLC chromatogram of compound (III) prepared in Experiment 5 of Example 1;

[0029] Figure 2 The HPLC chromatogram of compound (II) prepared in Experiment 2 of Example 2 is shown below.

[0030] Figure 3 The HPLC chromatogram of etoricoxib prepared in Experiment 2 of Example 4 is shown. Detailed Implementation

[0031] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0032] Comparative Example:

[0033] 1) Preparation of compound (III) using thionyl chloride

[0034] 4-Methylphenylacetic acid (0.6 g, 4.0 mmol) and thionyl chloride (4 ml) were heated to reflux for 1.5 h. The thionyl chloride was removed by evaporation, and tetrahydrofuran (5 ml) was added to obtain a tetrahydrofuran solution of 4-methylphenylacetyl chloride.

[0035] Compound (IV) (1.0 g, 3.9 mmol) was dissolved in tetrahydrofuran (4 ml) and pyridine (1.6 ml). The above-mentioned tetrahydrofuran solution of 4-methylphenylacetyl chloride was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was continued for 1 hour. After the solvent was removed by vacuum distillation, dichloromethane (10 ml) was added. The mixture was washed with 10 ml each of 1N hydrochloric acid, saturated sodium carbonate solution, and water. The organic layer was dried with anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain 1.8 g of compound (III) as an oil, with a yield of 70%, a purity of 84.2%, and esterification impurities of 13.2%.

[0036] 2) Compound (III) was prepared using CDI / DCC / DIC / EDCI.

[0037] 4-Methylphenylacetic acid (0.6 g, 4.0 mmol) was added to anhydrous tetrahydrofuran (10 ml), followed by CDI (0.7 g, 4.4 mmol). The mixture was heated to 50 °C and reacted for 1 hour. Then, compound (IV) (1.0 g, 3.9 mmol) was heated and reacted for another hour. The solvent was removed under reduced pressure, and dichloromethane (10 ml) was added. The mixture was washed with 10 ml each of 1N hydrochloric acid, saturated sodium carbonate solution, and water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 1.4 g of compound (III) as an oil, with a yield of 95%, a purity of 98.2%, and esterification impurities of 1.1%.

[0038] Using the same material proportions and post-processing procedures as described above, the condensing agents selected were DCC, DIC, and EDCI. When DCC was used as the condensing agent, DMAP was added as a catalyst at a rate of 0.1 equivalents relative to the amount of 4-methylphenylacetic acid. When EDCI was used as the condensing agent, HOBT was added as a catalyst at a rate of 0.1 equivalents relative to the amount of 4-methylphenylacetic acid. The results are summarized in the table below:

[0039]

[0040]

[0041] 3) Compound (III) was oxidized with Jones' reagent to prepare compound (II).

[0042] To prepare Jones' reagent: Dissolve 4.4g CrO3 in 7.2g water by stirring, and slowly add 8.3g concentrated sulfuric acid dropwise in an ice-water bath.

[0043] Compound (III) (10.0 g, 25.6 mmol) was dissolved in acetone (150 ml). Jones' reagent prepared above was slowly added dropwise under an ice-water bath. After reacting for 1 hour, isopropanol (30 ml) was added and the reaction was continued for 2 hours. The solvent was removed by concentration under reduced pressure. Water (100 ml) was added to the concentrated residue, and the mixture was extracted twice with dichloromethane (100 ml). The organic layers were combined and washed with 100 ml each of saturated sodium bicarbonate solution and water, respectively. The mixture was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give 6.8 g of solid compound (II), with a yield of 68% and a purity of 94.7%.

[0044] Example 1: Preparation of compound (III)

[0045] 1) Prepared using DMTMM, with DMF as the solvent.

[0046] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to N,N-dimethylformamide (100 ml), followed by DMTMM (11.3 g, 41.0 mmol). The reaction was carried out at 20-30 °C for 1 hour until complete. Dichloromethane (100 ml) and 5% sodium bicarbonate (100 ml) were added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (100 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 14.8 g of the oily compound (III), with a yield of 97.8%, purity of 98.9%, content of 97.7%, and esterification impurities of 0.08%. [M+H] + 390.5, C 21 H 27 O4NS.

[0047] 2) Prepared using DMTMM, with methanol as the solvent.

[0048] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to methanol (100 ml), followed by DMTMM (11.3 g, 41.0 mmol). The reaction was carried out at 20-30 °C for 1 hour until complete. The solvent was removed by vacuum distillation. Dichloromethane (100 ml) and 5% sodium bicarbonate (100 ml) were added. The organic layer was separated and washed twice with water (100 ml). The organic layer was dried with anhydrous sodium sulfate and the solvent was removed by vacuum distillation to obtain 13.0 g of compound (III) as an oil, with a yield of 85.9%, purity of 98.6%, content of 98.3%, and esterification impurity content of 0.07%.

[0049] 3) Prepared using DMTMM, with dichloromethane as the solvent.

[0050] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to dichloromethane (100 ml), followed by the addition of DMTMM (11.3 g, 41.0 mmol). The reaction was carried out at 20-30 °C for 1 hour until complete. 5% sodium bicarbonate (100 ml) was added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (100 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 14.9 g of the oily compound (III), with a yield of 98.4%, purity of 99.7%, content of 98.5%, and esterification impurity content of 0.04%.

[0051] 4) Prepared using DMTMM, with water as the solvent.

[0052] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to water (100 ml), followed by the addition of DMTMM (11.3 g, 41.0 mmol). The reaction was carried out at 20-30 °C for 1 hour until complete. Dichloromethane (100 ml) and 5% sodium bicarbonate (100 ml) were added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (100 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 14.6 g of compound (III) as an oil, with a yield of 96.5%, purity of 96.8%, content of 96.8%, and esterification impurity content of 0.09%.

[0053] 5) Prepared using DMTMM, with toluene as the solvent.

[0054] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to toluene (100 ml), followed by the addition of DMTMM (11.3 g, 41.0 mmol). The reaction was carried out at 20-30 °C for 1 hour until complete. 5% sodium bicarbonate (100 ml) was added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (100 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 15.1 g of the oily compound (III), with a yield of 99.8%, purity (RT: 20.35 min) of 99.8%, content of 98.9%, and esterification impurity (RT: 22.43 min) content of 0.07%.

[0055] Example 2: Preparation of compound (II)

[0056] 1) TEMPO oxidation, using dichloromethane as a solvent.

[0057] Compound (III) (10.0 g, 25.6 mmol), TEMPO (0.3 g, 3% based on the weight of compound III), and potassium bromide (0.3 g, 3% based on the weight of compound III) were added to dichloromethane (100 ml) and water (20 ml). A 10% sodium hypochlorite solution (28.6 g, 38.4 mmol) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was continued for 5 hours until complete. Sodium sulfite solution (100 ml) was added to the reaction solution, and the aqueous layer was separated. The organic layer was washed with sodium sulfite solution (100 ml) and water (100 ml), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 10.0 g of solid compound (II) (RT: 18.91 min, consistent with the RT obtained in the comparative example), yield 100%, purity 98.7%.

[0058] 1H NMR (600MHz, CDCl3) δ8.12(d,J=8.3Hz,2H),8.03(d,J=8.3Hz,2H),7.15(q,J=8.1Hz,4H),4.72(s,2H) ,3.77(s,2H),3.44-3.29(m,2H),3.07(s,3H),2.33(s,3H),1.63-1.46(m,2H),0.90(t,J=7.4Hz,3H). [M+H] + 388.0. C 21 H 25 O4NS.

[0059] 2) TEMPO oxidation, with toluene as the solvent.

[0060] Compound (III) (10.0 g, 25.6 mmol), TEMPO (0.3 g, 3% based on the weight of compound III), and potassium bromide (0.3 g, 3% based on the weight of compound III) were added to toluene (100 ml) and water (20 ml). A 10% sodium hypochlorite solution (28.6 g, 38.4 mmol) was slowly added dropwise under an ice-water bath. After the addition was completed, the reaction was continued for 5 hours until the reaction was complete. A sodium sulfite solution (100 ml) was added to the reaction solution, and the mixture was filtered and dried to give 9.5 g of solid compound (II), with a yield of 95.5% and a purity of 99.7%.

[0061] Example 3: Continuous addition preparation of compound (II)

[0062] 1) Dichloromethane as a solvent in continuous addition

[0063] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to dichloromethane (150 ml), followed by the addition of DMTMM (11.3 g, 41.0 mmol). The reaction was carried out at 20-30 °C for 1 hour until complete. 5% sodium bicarbonate (100 ml) was added to the reaction solution. After separating the organic layer, it was washed twice with water (100 ml). Water (30 ml) and potassium bromide (0.45 g) were added to the organic layer. TEMPO (0.45 g) was added dropwise with 10% sodium hypochlorite solution (44.6 g, 60.0 mmol) under an ice-water bath. After the addition was complete, the reaction was continued for 5 hours until the reaction was complete. Sodium sulfite solution (150 ml) was added to the reaction solution, and the aqueous layer was separated. The organic layer was washed with sodium sulfite solution (150 ml) and water (150 ml), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to give 15.0 g of solid compound (II), with a yield of 99.6% and a purity of 97.8%.

[0064] 2) Toluene as a solvent in continuous addition

[0065] 4-Methylphenylacetic acid (6.0 g, 40.0 mmol) and compound (IV) (10.0 g, 39.0 mmol) were added to toluene (60 ml), followed by DMTMM (11.3 g, 41.0 mmol). The reaction was carried out at 20-30 °C for 1 hour until complete. 5% sodium bicarbonate (100 ml) was added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (100 ml). Water (30 ml), potassium bromide (0.45 g), and TEMPO (0.45 g) were added to the organic layer. 10% sodium hypochlorite solution (44.6 g, 60.0 mmol) was slowly added dropwise under an ice-water bath. After the addition was completed, the reaction was continued for 5 hours until complete. Sodium sulfite solution (150 ml) was added to the reaction solution. The mixture was filtered to obtain 14.3 g of solid compound (II), with a yield of 95.0% and a purity of 99.2%.

[0066] Example 4: Kilogram-scale preparation of etoricoxib

[0067] 1) Preparation of compound (II)

[0068] 2.1 kg (14.0 mol) of 4-methylphenylacetic acid and 3.5 kg (13.6 mol) of compound (IV) were added to toluene (20 L), followed by the addition of DMTMM (3.9 kg, 14.0 mol). The reaction was carried out at 20-30 °C for 1 hour until complete. 20 L (5% sodium bicarbonate) was added to the reaction solution. After separating the organic layer, the organic layer was washed twice with water (20 L). 10 L (water), 0.2 kg (potassium bromide), and 0.2 kg (TEMPO) were added to the organic layer. 17.8 kg (23.9 mol) of sodium hypochlorite solution was slowly added dropwise under an ice-water bath. After the addition was completed, the reaction was continued for 5 hours until complete. Sodium sulfite solution was added to the reaction solution, and the mixture was filtered to obtain 5.02 kg (95.3%) of solid compound (II) with a purity of 99.1%.

[0069] 2) Preparation of etoricoxib

[0070] Compound (II) (5.0 kg, 12.9 mol) and potassium carbonate (3.6 kg, 25.8 mol) were added to ethanol (100 L) and water (100 L), and heated to reflux. After 2 hours, the reaction was complete. After cooling, ice water (100 L) was added, and the pH was adjusted to 6.5-7.0 using 1 N hydrochloric acid in an ice water bath. After filtration, a solid was obtained. The wet product was added to ethanol (100 L) and neutral activated carbon (0.5 kg), and heated to 70 °C for decolorization. After hot filtration, crystallization was observed, filtered, and dried to obtain 3.81 kg of white solid, with a yield of 80.0% and a purity of 99.9%.

[0071] 1H NMR (600MHz, CDCl3) δ7.85(d,J=8.3Hz,2H),7.48(d,J=8.3Hz,2H),7.27(d,J=3.0Hz,2H),7.16(d,J=7.9Hz,2H),4 .30(s,2H),3.56(t,J=7.4Hz,2H),3.05(s,3H),2.36(s,3H),1.71(dd,J=14.7,7.4Hz,2H),0.99(t,J=7.4Hz,3H).

[0072] The English abbreviations used in the specification and claims have the following meanings.

[0073] abbreviation Full name CDI N,N'-Carbonyldiimidazole <![CDATA[CrO3]]> Chromium trioxide DMTMM 4-(4,6-Dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride TEMPO 2,2,6,6-Tetramethylpiperidine oxide DMF N,N-Dimethylformamide

[0074] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing an intermediate of etoricoxib, characterized in that, The intermediate is N-n-propyl-N-[2-oxo-2-(4'-methanesulfonylphenyl)]ethyl-4-methylphenylacetamide (II), and the preparation method of the intermediate includes the following steps: Step (1): Compound (IV), 4-methylphenylacetic acid, and condensing agent are added to the reaction solvent and stirred at 0–50 °C. After the reaction is complete, post-processing is performed to obtain an oily intermediate (III). The reaction formula is as follows: The condensing agent is DMTMM; Step (2): Add intermediate (III), TEMPO and catalyst to the reaction solvent, and slowly add 5%-10% sodium hypochlorite aqueous solution dropwise under an ice-water bath until no raw material remains. After post-treatment, compound (II) is obtained. The reaction formula is as follows: The catalyst is sodium bromide or potassium bromide.

2. A method for preparing an intermediate of etoricoxib, characterized in that, The intermediate is N-n-propyl-N-[2-oxo-2-(4'-methanesulfonylphenyl)]ethyl-4-methylphenylacetamide (II), and the preparation method of the intermediate includes the following steps: 4-Methylphenylacetic acid, compound (IV), and condensing agent were added to the reaction solvent and stirred at 0–50 °C. After the reaction was complete, an aqueous sodium bicarbonate solution was added. The mixture was separated, and water, catalyst, and TEMPO were added to the organic layer. A 5%–10% sodium hypochlorite solution was slowly added dropwise under an ice-water bath. After the reaction was completed, the mixture was treated to obtain compound (II). The condensing agent was DMTMM, and the catalyst was sodium bromide or potassium bromide.

3. The preparation method according to claim 1, characterized in that, The post-processing of step (1) includes adding an aqueous solution of sodium bicarbonate after the reaction is complete, separating, washing, drying, and concentrating to obtain an oily intermediate (III).

4. The preparation method according to claim 1, characterized in that, The reaction solvent in step (1) is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, toluene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, and water; the reaction solvent in step (2) is selected from dichloromethane and toluene.

5. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound (IV), 4-methylphenylacetic acid and condensing agent is 1:1.00-1.20:1.00-1.

20.

6. The preparation method according to claim 1, characterized in that, The reaction temperature in step (2) is 0 to 50°C.

7. The preparation method according to claim 1, characterized in that, The weight ratio of TEMPO / 5%-10% sodium hypochlorite solution used is 1:100 to 1:85, and the combined mass of TEMPO and 5%-10% sodium hypochlorite solution is 2.5 to 3.5 times the mass of intermediate (III).

8. The preparation method according to claim 1, characterized in that, The amount of catalyst used is 3 to 10% of the weight of intermediate (III).

9. The preparation method according to claim 2, characterized in that, The weight ratio of TEMPO / 5%-10% sodium hypochlorite solution used is 1:100 to 1:

85. The total mass of TEMPO and 5%-10% sodium hypochlorite solution used is 3.75 to 5.25 times the mass of compound (IV). The amount of catalyst used is 4.5 to 15.0% of the weight of compound (IV).

10. The preparation method according to claim 2, characterized in that, The molar ratio of compound (IV), 4-methylphenylacetic acid and condensing agent is 1:1.00-1.20:1.00-1.20; the reaction solvent is selected from toluene and dichloromethane.

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