A method for synthesizing robecoxib

Abstract

This invention belongs to the field of chemistry or medicinal chemistry, specifically relating to a method for synthesizing robecoxib. The method uses 2,3,5,6-tetrafluoroaniline and phthalic acid as raw materials, reacting them under alkaline conditions and with a catalyst to generate 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid. This benzoic acid is then reacted sequentially with an acyl chloride reagent and a diazotizing reagent to prepare 5-chloro-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one. Following a coupling reaction with an ethyl compound, 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one is synthesized, and finally, robecoxib is obtained after hydrolysis. In this invention, the starting materials 2,3,5,6-tetrafluoroaniline and phthalic acid are widely available. 2,3,5,6-tetrafluoroaniline is the direct structural fragment of robecoxib, while phthalic acid can be converted into the important functional groups of robecoxib, ethyl and acetic acid groups, through simple functional group transformation. This invention avoids the use of raw materials such as AlCl3, which easily generate corrosive and irritating acidic gases, thus providing a new route for the preparation of robecoxib.

Description

Technical Field

[0001] This invention belongs to the field of chemistry or medicinal chemistry, and specifically relates to a method for synthesizing robecoxib. Background Technology

[0002] Robecoxib is a novel, non-serotonin-selective cyclooxygenase 2 inhibitor that relieves pain by inhibiting cyclooxygenase 2. It is primarily used to treat arthritis, with fewer gastrointestinal side effects and a lower risk of gastrointestinal ulcers and bleeding. Robecoxib also demonstrates good efficacy and tolerability for single migraine attacks and is available in injectable and oral formulations. It can be used to treat inflammation, pain, and fever in cats and dogs, exhibiting rapid onset of action and enhanced safety across both feline and canine blood-brain barriers. Its chemical structure is as follows:

[0003]

[0004] Currently, there are several main methods for synthesizing robecoxib:

[0005] Chinese patent CN1140500C uses a 2-iodophenylacetic acid derivative coupled with 2,3,5,6-tetrafluoroaniline to prepare a diarylamine compound, followed by acylation, reduction, and hydrolysis to prepare robecoxib. Although this route involves only four steps, the starting material, the 2-iodophenylacetic acid derivative, is unavailable and must be prepared in-house, making the reaction route too long and increasing costs. The synthetic route is as follows:

[0006]

[0007] Chinese patents CN109503399A and CN112679410A use similar synthetic routes, both obtaining a key intermediate for the synthesis of robecoxib through Friedel-Crafts alkylation of starting materials, followed by hydrolysis to obtain robecoxib. The starting materials in this route are all unavailable and must be manufactured in-house, resulting in a long route, increased costs, and the use of AlCl3 in multiple steps generates large amounts of aluminum salts and acidic gases with strong corrosiveness, making post-processing difficult. The synthetic routes are as follows:

[0008]

[0009] Patent CN111807978A reports a method for synthesizing robecoxib. This method uses benzocyclopentamide through Friedel-Crafts acylation, reduction, and Ullmann reaction to obtain a key intermediate, which is then hydrolyzed to prepare robecoxib. However, this route lacks a supplier for the starting material benzocyclopentamide, and the raw material tetrafluoroiodobenzene is difficult to obtain, hindering production. The synthetic route is as follows:

[0010]

[0011] Patents CN102311355A and CN109694330A use p-ethylaniline as a starting material. After amidation, alkylation, and rearrangement to obtain the same intermediate, they undergo amidation reactions with chloroacetyl chloride and oxalyl chloride, respectively. Following cyclization via Friedel-Crafts reaction, the amide is hydrolyzed to obtain the product. CN109694330A further requires reduction with hydrazine hydrate. These two synthetic routes are similar, with lengthy synthetic steps, cumbersome operations, and low yields in the key rearrangement reaction. Furthermore, CN109694330A uses hydrazine hydrate for reduction, posing certain production safety concerns. The specific reaction routes are as follows:

[0012]

[0013] Patent CN115433117A discloses a method for synthesizing robecoxib, using 1-(2,3,5,6-tetrafluorophenyl)-4-ethylaniline or 1-(2,3,5,6-tetrafluorophenyl)-4-acetylaniline as starting materials to prepare robecoxib via a Sandmeier reaction, hydrolysis reaction, and reduction reaction. This route lacks commercially available starting materials, requiring in-house production, which lengthens the synthetic route and increases costs. Furthermore, the Sandmeier reaction involves concentrated sulfuric acid or concentrated phosphoric acid at temperatures reaching 200°C, posing a high risk and hindering production.

[0014]

[0015] Therefore, exploring a synthetic route for producing high-quality robecoxib that uses readily available raw materials, is simple to operate, and is convenient to produce is a problem that needs to be solved. Summary of the Invention

[0016] The purpose of this invention is to overcome the shortcomings of existing process routes and provide a simple and efficient synthetic method for preparing robecoxib. This method uses readily available raw materials, has a short route, and is easy to operate.

[0017] The method for synthesizing robecoxib according to the present invention includes the following steps:

[0018] Step 1: 2,3,5,6-Tetrafluoroaniline (raw material 1) and 5-chloro-2-halobenzoic acid (raw material 2) are synthesized into 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid (intermediate 1) via palladium-catalyzed coupling reaction;

[0019]

[0020] Step 2: 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid (intermediate 1) and acyl chloride reagent (preferably thionyl chloride) are refluxed in the presence of organic solvent 2 for 1-3 h (preferably at a reaction temperature of 80°C), cooled to room temperature, and a diazotizing reagent is added and reacted for 6-12 h (preferably 8 h). Then, under alkaline conditions (preferably with the addition of an organic base, more preferably with the addition of triethylamine) and catalyzed by a silver catalyst, the mixture is refluxed for 1-4 h (preferably 2 h) to prepare 5-chloro-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 2).

[0021]

[0022] Step 3: 5-chloro-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 2) is coupled with an ethyl compound under the action of a catalyst to synthesize 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 3).

[0023]

[0024] Step 4: 5-Ethyl-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 3) is dissolved in organic solvent 4 and then refluxed under alkaline conditions (preferably with the addition of sodium hydroxide solution) for 2-6 hours (preferably at 100°C for 4 hours). After purification, robecoxib is obtained.

[0025]

[0026] In a preferred embodiment of the present invention, step 1 is specifically performed as follows:

[0027] 2,3,5,6-Tetrafluoroaniline (starting material 1), 5-chloro-2-halobenzoic acid (starting material 2), palladium catalyst, ligand, base, and organic solvent 1 are added to a reaction vessel. Then, a coupling reaction is carried out under inert gas protection to synthesize 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid (intermediate 1). The coupling reaction is carried out at a temperature of 80-120°C for a reaction time of 6-16 hours (preferably 8 hours at 120°C).

[0028] In a preferred embodiment of the present invention, the organic solvent 1 in step 1 is dioxane, tetrahydrofuran, toluene or N,N-dimethylformamide, more preferably N,N-dimethylformamide; the ratio of its amount to 2,3,5,6-tetrafluoroaniline is (10-20) mL:1 g, more preferably 10 mL:1 g.

[0029] In a preferred embodiment of the present invention, the alkali used in step 1 is sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, or sodium tert-butoxide.

[0030] In a preferred embodiment of the present invention, the palladium catalyst used in step 1 is palladium acetate, Pd(dppf)Cl2, PdCl2, Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, Pd G4 Xphos, or Pd G4Sphos.

[0031] In a preferred embodiment of the present invention, the ligand used in step 1 is Xphos, Sphos, CyPF-t-Bu, JosiPhos, Binap, XantPhos, DPPF, BrettPhos, RuPhos, or BippyPhos.

[0032] In a preferred embodiment of the present invention, the molar ratio of raw material 1, raw material 2, alkali, palladium catalyst and ligand in step 1 is 1:(1.0~1.3):(1~4):(0.01~0.2):(0.01~0.2); more preferably it is 1:1:2.5:0.01:0.015.

[0033] In a preferred embodiment of the present invention, the organic solvent 2 used in step 2 is dichloromethane, dioxane, tetrahydrofuran, toluene or 1,2-dichloroethane, more preferably dichloromethane or tetrahydrofuran, and the ratio of its amount to intermediate 1 is (9-15) mL:1g, more preferably 9.4 mL:1g.

[0034] In a preferred embodiment of the present invention, the diazotizing reagent used in step 2 is either diazomethane or trimethylsilyl diazomethane, both of which are added in solution form. When trimethylsilyl diazomethane is selected, the addition temperature is room temperature, and when diazomethane is selected, the addition temperature is -20 to 0°C.

[0035] In a preferred embodiment of the present invention, the silver catalyst in step 2 is silver oxide, silver benzoate, or silver trifluoroacetate.

[0036] In a preferred embodiment of the present invention, the molar ratio of intermediate 1, acyl chloride reagent, diazotizing reagent and silver catalyst in step 2 is 1:(1.1-1.5):(2.5-5):(0.05-0.2); more preferably it is 1:1.31:3.59:0.12.

[0037] In a preferred embodiment of the present invention, the ethyl compound used in step 3 is EtX, EtMgX or EtBF3K, wherein Et is ethyl and X is Cl, Br or I. More preferably, the ethyl compound is EtBr, EtMgBr or EtBF3K.

[0038] In a preferred embodiment of the present invention, when the ethyl compound in step 3 is EtX or EtMgX, the catalyst used is a mixture of MnCl2 and LiCl in a molar ratio of 1:2; the coupling reaction temperature is -80 to -30°C, and the reaction time is 1 to 3 hours, preferably 1 hour at -30°C; the molar ratio of intermediate 2, ethyl compound, and catalyst is 1:(1.0 to 3):(2 to 4), preferably 1:1.2:3.6;

[0039] In a preferred embodiment of the present invention, when the ethyl compound in step 3 is EtBF3K, the reaction is carried out under a protective gas atmosphere, and a base and a ligand are added. The catalyst used is a Pd catalyst, preferably Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, PdG4Xphos, or PdG4. Sphos; the ligand is Xphos, Sphos, CyPF-t-Bu, JosiPhos, Binap, XantPhos, DPPF, BrettPhos, RuPhos, or BippyPhos; the base is sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, or sodium tert-butoxide; the coupling reaction temperature is 80-120°C, and the reaction time is 6-12 hours, preferably 8 hours at 120°C; the molar ratio of intermediate 2, ethyl compound, base, Pd catalyst, and ligand is 1:(1.5-3):(2-4):(0.01-0.2):(0.01-0.2); more preferably, the ratio is 1:3:2:0.1:0.1.

[0040] In a preferred embodiment of the present invention, in step 3, both 5-chloro-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 2) and the catalyst are dissolved in organic solvent 3 before being used. The organic solvent 3 used is tetrahydrofuran, dioxane, toluene, or N,N-dimethylacetamide.

[0041] In a preferred embodiment of the present invention, the organic solvent 4 used in step 4 is dichloromethane, dioxane, tetrahydrofuran, toluene, or 1,2-dichloroethane.

[0042] Compared with the prior art, the advantages and beneficial effects of the present invention include:

[0043] (1) Compared to most of the reported preparations of robecoxib in the literature, where the starting materials are difficult to obtain, the starting materials 2,3,5,6-tetrafluoroaniline and 5-chloro-2-halobenzoic acid in this invention are widely available, and all other reagents are commercially available, which is beneficial for production. 2,3,5,6-tetrafluoroaniline is the direct structural fragment of robecoxib, while 5-chloro-2-halobenzoic acid can be converted through simple functional group transformations, converting the 2-halogen and carboxylic acid into the ethyl and acetic acid groups, which are important functional groups of robecoxib.

[0044] (2) The reagents used in this invention are all relatively safe. It does not use raw materials such as AlCl3 that are prone to producing corrosive and irritating acidic gases, and has the advantages of less pollution and easy production.

[0045] (3) The present invention has a short synthetic route, mild reaction conditions, no special high temperature and high pressure reaction, safe and controllable reaction, and simple post-processing operation, providing a new way for the preparation of robecoxib. Attached Figure Description

[0046] Figure 1 This is the HNMR nuclear magnetic resonance image of robecoxib obtained in Example 4. 1 H NMR (400MHz, CDCl3): δ=7.02-6.95(d,2H),6.78-6.73(d,1H),6.73-6.68(s,1H ),6.62-6.54(m,1H),3.74-3.67(s,2H),2.56-2.50(q,2H),1.17-1.11,(t,3H);

[0047] Figure 2 This is the CNMR image of robecoxib obtained in Example 4. 13 C NMR (100MHz, CDCl3): 180.40, 139.54, 137.49, 130.45, 127.91, 123.34, 119.18, 97.15, 97.00, 96.85, 38.69, 28.06, 15.53;

[0048] Figure 3 This is the mass spectrum of robecoxib obtained in Example 4 (calcd.For C 16 H 13 F4NO2[M+H] + 328.0956, found: 328.1693);

[0049] Figure 4 This is the HPLC chromatogram of robecoxib obtained in Example 4 (RT = 17.160 min, 98.56% purity). Detailed Implementation

[0050] The beneficial effects of the present invention will now be illustrated through the following specific embodiments, but this should not be construed as limiting the scope of the subject matter to the following embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0051] In the following examples, "water" refers to pure water; yield refers to the percentage of the actual mass of the substance obtained in this step and the theoretical yield when the reactants react at 100%.

[0052] Example 1: Preparation of 2-(2,3,5,6-tetrafluorophenylamino)benzoic acid (intermediate 1)

[0053]

[0054] Weigh out 2,3,5,6-tetrafluoroaniline (raw material 1) (50.00 g, 302.86 mmol), 5-chloro-2-iodobenzoic acid (raw material 2) (85.55 g, 302.86 mmol), tris(dibenzylacetone)palladium Pd2(dba)3 (2.78 g, 3.04 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl Xphos (2.17 g, 4.55 mmol), and cesium carbonate (246.7 g, 757.17 mmol) and add them to a 2 L reaction flask. Add 500 mL of anhydrous N,N-dimethylformamide and react under nitrogen atmosphere. The reaction was carried out at 120℃ for 8 hours under protection. After the reaction was completed, the mixture was cooled to room temperature and filtered. 1.5L of water was added to the obtained solid, and the pH was adjusted to about 5 with 0.2M dilute hydrochloric acid. The solid was then extracted twice with ethyl acetate (500ml each time). The organic phases after the two extractions were combined and washed twice with 500ml of saturated sodium chloride solution, and then washed twice with 500ml of water. The washed organic phases were dried with anhydrous sodium sulfate and concentrated by rotary evaporation at 45℃ to obtain crude 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid (intermediate 1, yellow solid, 89.66g, yield: 86.6%, purity: 93.5%).

[0055] Example 2: Preparation of 5-chloro-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 2)

[0056]

[0057] Crude 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid (intermediate 1) (85 g, 248.64 mmol) was added to a 2 L reaction flask, followed by 800 mL of anhydrous tetrahydrofuran. Then, thionyl chloride (38.88 g, 326.80 mmol) was added with stirring. The mixture was heated to 80 °C and refluxed for 1 hour. Subsequently, the mixture was cooled to room temperature, and trimethylsilyldiazomethane (101.81 g, 891.4 mmol, 2.0 mol / L n-hexane solution) was added to the reaction system. The mixture was reacted at room temperature for 8 hours. Then, catalytic amounts of silver benzoate (6.81 g, 29.71 mmol) and triethylamine (45.10 g, 445.70 mmol) were added, and the mixture was heated to 80 °C and refluxed for another 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and 200 mL of 0.5 M hydrochloric acid solution was added to quench the reaction. Then, 1 L of water was added for dilution, and the mixture was extracted three times with ethyl acetate (500 mL each time). The organic phases from the three extractions were combined, washed twice with 500 mL of saturated sodium chloride aqueous solution, and then twice with 500 mL of pure water. The washed organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation at 45 °C to obtain a solid. Purification was performed using silica gel column chromatography under the following conditions: hexane / ethyl acetate = 1:0–1:1 (referring to the volume ratio range of the solvent gradient during column chromatography, the same below), TLC; hexane / ethyl acetate = 3:1 (referring to the volume ratio of the solvent for TLC spotting, the same below); rf = 0.63, yielding 5-chloro-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 2, white solid, 68.7 g, yield: 87.53%, purity: 96.7%).

[0058] Example 3: Preparation of 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 3)

[0059]

[0060] Anhydrous MnCl2 (30.87 g, 245.3 mmol) and anhydrous LiCl (20.75 g, 489.5 mmol) were weighed into a reaction flask and dissolved in 200 mL of anhydrous tetrahydrofuran. The solution was stirred until homogeneous. Ethyl magnesium bromide (EtMgBr) (123.6 mL, 2.0 M, 247.2 mmol) was added dropwise at -30 °C. Subsequently, 5-chloro-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 2) (65 g, 205.92 mmol) was dissolved in 250 mL of anhydrous tetrahydrofuran. The solution of intermediate 2 was added dropwise to the reaction flask at -30 °C. After stirring for 1 hour, 1 mol / L HCl (500 mL) was added dropwise and stirred for 15 min. The reaction solution was extracted three times with ethyl acetate, each time using 300 mL. The combined organic phases from the three extractions were washed twice with 500 ml of saturated brine, then twice with 500 ml of water, and dried over anhydrous sodium sulfate. The solvent was then evaporated to obtain the crude product. Purification was performed using silica gel column chromatography (n-hexane / ethyl acetate = 1:0–2:1, TLC, n-hexane / ethyl acetate = 3:1, rf = 0.7) to give 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)indololin-2-one (intermediate 3, white solid, 55.6 g, yield: 87.31%, purity: 97.8%).

[0061] Example 4: Synthesis of Robecoxib

[0062]

[0063] 50 g of 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 3) was dissolved in 200 mL of anhydrous tetrahydrofuran, and then 200 mL of 1 M sodium hydroxide solution was added. The mixture was heated to 100 °C and refluxed for 4 hours. After the reaction was complete, the pH was slowly adjusted to about 7 using 0.2 M dilute hydrochloric acid, and then extracted three times with 300 mL of ethyl acetate each time. The organic phases from the three extractions were combined and washed twice with 500 mL of saturated brine. The washed organic phase was dried over anhydrous sodium sulfate and filtered. The organic phase was then evaporated to dryness to obtain a solid. The crude product was recrystallized from 100 mL of a toluene / n-hexane (5 / 3 v / v) mixture to obtain robecoxib (white powder, 41.3 g, yield: 78.05%, purity: 98.56%).

[0064] The aforementioned intermediate 3 can also be prepared in the following manner:

[0065] Example 5: Preparation of 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)indoline-2-one (intermediate 3)

[0066]

[0067] Intermediate 2 (2.0 g, 6.34 mmol) and EtBF3K (2.58 g, 18.97 mmol) were dissolved in 20 mL of dioxane. Under nitrogen protection, Cs2CO3 (4.13 g, 12.68 mmol), Pd2(dba)3 (580 mg, 0.63 mmol), and Brettphos (340 mg, 0.63 mmol) were added. The mixture was then heated to 120 °C and reacted under nitrogen protection for 8 hours. After the reaction was complete, the mixture was cooled to room temperature. The sample was filtered through diatomaceous earth. 40 ml of water was added to the filtrate, and the sample was extracted three times with ethyl acetate (30 ml each time). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. Purification was performed using silica gel column chromatography (n-hexane / ethyl acetate = 1:0–2:1, TLC, n-hexane / ethyl acetate = 3:1, rf = 0.7) to give 5-ethyl-1-(2,3,5,6-tetrafluorophenyl)indololin-2-one (intermediate 3, white solid, 1.56 g, yield: 79.61%, purity: 98.5%).

[0068] The structural formulas of the intermediates and robecoxib obtained above were verified by NMR and other detection results.

Claims

1. A method for synthesizing robenacoxib, comprising the following steps in particular: Step 1: adding 2, 3, 5, 6-tetrafluoroaniline, 5-chloro-2-halobenzoic acid, a palladium catalyst tris (dibenzylideneacetone) dipalladium, a ligand 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl, a base cesium carbonate and an organic solvent 1 into a reaction container, and then performing a coupling reaction under inert gas protection to synthesize 5-chloro-2- (2, 3, 5, 6-tetrafluoroanilino) benzoic acid, wherein the coupling reaction is performed at a temperature of 80-120 ℃ for 6-16 hours; Step 2: refluxing 5-chloro-2- (2, 3, 5, 6-tetrafluoroanilino) benzoic acid and a chlorosulfonic reagent thionyl chloride in the presence of an organic solvent 2 for 1-3 hours, cooling to room temperature, adding a diazotization reagent trimethylsilyl diazomethane and reacting for 6-12 hours, and then refluxing in the presence of triethylamine and under the catalysis of a silver catalyst benzoic acid silver for 1-4 hours to prepare 5-chloro-1- (2, 3, 5, 6-tetrafluorophenyl) indolin-2-one; Step 3: performing a coupling reaction of 5-chloro-1- (2, 3, 5, 6-tetrafluorophenyl) indolin-2-one and an ethyl compound under the action of a catalyst to synthesize 5-ethyl-1- (2, 3, 5, 6-tetrafluorophenyl) indolin-2-one; and Step 4: dissolving 5-ethyl-1- (2, 3, 5, 6-tetrafluorophenyl) indolin-2-one in an organic solvent 4, performing a reflux reaction in the presence of a sodium hydroxide solution for 2-6 hours, and then purifying to obtain robenacoxib; wherein Et is ethyl, and X is Cl, Br or I; when the ethyl compound in Step 3 is EtX or EtMgX, the catalyst used is a mixture of MnCl2 and LiCl in a molar ratio of 1:2; the coupling reaction is performed at a temperature of-80--30 ℃ for 1-3 hours; and the molar ratio of 5-chloro-1- (2, 3, 5, 6-tetrafluorophenyl) indolin-2-one, the ethyl compound and the catalyst is 1: (1.0-3) : (2-4) ; when the ethyl compound in Step 3 is EtBF3K, the reaction is performed under a protective gas, and a base and a ligand are added thereto; the catalyst used is tris (dibenzylideneacetone) dipalladium; the ligand is Brettphos; the base is Cs2CO3; the coupling reaction is performed at a temperature of 80-120 ℃ for 6-12 hours; and the molar ratio of 5-chloro-1- (2, 3, 5, 6-tetrafluorophenyl) indolin-2-one, the ethyl compound, the base, tris (dibenzylideneacetone) dipalladium and the ligand is 1: (1.5-3) : (2-4) : (0.01-0.2) : (0.01-0.2) ; and the organic solvent 1 in Step 1 is dioxane, tetrahydrofuran, toluene or N, N-dimethylformamide, and the use amount ratio of the organic solvent 1 to 2, 3, 5, 6-tetrafluoroaniline is (10-20) mL:1 g. ​ ​ ​ ​ The ethyl compound used in step 3 is EtX, EtMgX or EtBF3K, wherein, ​ ​ ​ 2. The method of synthesis of claim 1, wherein, ​ The molar ratio of 2,3,5,6-tetrafluoroaniline, 5-chloro-2-halobenzoic acid, cesium carbonate, tris(dibenzylideneacetone)dipalladium and ligand 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl in step 1 is 1: (1.0-1.3): (1-4): (0.01-0.2): (0.01-0.2).

3. The method of synthesis of claim 1, wherein, The organic solvent 2 used in step 2 is dichloromethane, dioxane, tetrahydrofuran, toluene or 1,2-dichloroethane, and the ratio of the amount used to 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid is (9-15) mL: 1 g; the diazotization reagent used in step 2 is added in the form of a solution; The molar ratio of 5-chloro-2-(2,3,5,6-tetrafluorophenylamino)benzoic acid, acylating reagent, diazotization reagent and silver catalyst in step 2 is 1: (1.1-1.5): (2.5-5): (0.05-0.2).

4. The method of synthesis of claim 1, wherein, 5-Chloro-1-(2,3,5,6-tetrafluorophenyl)indolin-2-one and catalyst in step 3 are each dissolved in organic solvent 3 before being used, and the organic solvent 3 used is tetrahydrofuran, dioxane, toluene or N,N-dimethylacetamide.

5. The method of synthesis of claim 1, wherein, The organic solvent 4 used in step 4 is dichloromethane, dioxane, tetrahydrofuran, toluene or 1,2-dichloroethane.

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