A process for the preparation of a fluoxastrobin intermediate, 3',4',5'-trifluorobiphenyl-2-amine

Abstract

The present application relates to a kind of preparation method of flubendiamide intermediate 3 ', 4 ', 5 '-trifluorobiphenyl-2-amine, belong to the technical field of pesticide.The present application with common industrial product acetanilide as starting material, with boron tribromide to generate 2-acetamidobenzoic acid, then with 3, 4, 5-trifluorobromobenzene through nickel catalyst coupling reaction to obtain N-(3 ', 4 ', 5 '-trifluoro [1, 1 '-biphenyl] -2-yl) acetamide, finally through acid or base hydrolysis reaction to obtain flubendiamide key intermediate 3 ', 4 ', 5 '-trifluorobiphenyl-2-amine.The intermediate 2-acetamidobenzoic acid of preparation in the present application does not use palladium catalyst to prepare boric acid, also need not add phase transfer catalyst, reaction does not use polar organic solvent, can be continuous production, suitable for industrial scale production, with the advantages such as simple process, high yield, high production efficiency and green environmental protection.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticides, in particular to a preparation method of 3',4',5'-trifluorobiphenyl-2-amine, an intermediate of fluoxastrobin. BACKGROUND

[0002] Fluoxastrobin is an amide fungicide developed by BASF, which is also a succinate dehydrogenase inhibitor (SDHI). The success of fluoxastrobin is first attributed to its unique molecular structure, and secondly to its wide application in crops. On the one hand, fluoxastrobin is the most optimized variety in the SDHI class, which can quickly and effectively inhibit the activity of succinate dehydrogenase in the mitochondria of fungi. Before reaching the target enzyme, fluoxastrobin needs to pass through multiple barriers such as the cell wall and cell membrane of crops, the cell membrane of fungi, etc. Usually, under the action of multiple lipophilic and hydrophilic barriers, many drugs cannot quickly reach the target enzyme, but the fluoxastrobin molecule can present different spatial conformations, which can be converted between the two different molecular spatial conformations at the interface of lipophilicity or hydrophilicity, helping the drug to quickly pass through multiple biological membrane barriers and reach the succinate dehydrogenase action site, with both preventive and therapeutic effects. It can inhibit spore germination, germ tube elongation, mycelial growth and spore formation, and can effectively prevent and control the main diseases of crops such as cereals, soybeans, corn, rapeseed, fruit trees, vegetables, sugar beets, peanuts, cotton, lawns and special crops, etc.

[0003] Fluoxastrobin is a white to beige solid, and its chemical name is: 3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide; CAS registration number: 907204-31-3; molecular formula: C 18 H 12 F5N3O; relative molecular mass: 381.31. The chemical structural formula is as follows:

[0004] .

[0005] 3',4',5'-trifluorobiphenyl-2-amine (CAS: 915416-45-4) is an important precursor of fluoxastrobin. The traditional preparation method of 3',4',5'-trifluorobiphenyl-2-amine takes o-chloronitrobenzene and 3,4,5-trifluorobenzeneboronic acid as starting materials, and is obtained after transition metal catalytic Suzuki coupling and reduction of nitro group. The specific reaction route is as follows:

[0006] .

[0007] The 3,4,5-trifluorobenzoic acid in the method generally needs to be synthesized from halobenzene through a Grignard reagent, a borate ester and hydrolysis in three steps, the synthetic route is complex, the cost is high, the Grignard reaction has relatively harsh requirements for reaction conditions, industrialization is difficult, and more waste is generated. The synthetic route of 3,4,5-trifluorobenzoic acid is as follows:

[0008] .

[0009] Moreover, borate esters are a kind of relatively expensive chemical raw materials, which need to be synthesized from 3,4,5-trifluorobromobenzene raw materials, and the 3,4,5-trifluorobromobenzene raw materials also need to be obtained through a multi-step synthetic process route. If the 3,4,5-trifluorobromobenzene raw materials are obtained by purchase, the industrial production cost will be greatly increased.

[0010] Patent WO2009156359A2 discloses a method for synthesizing 3',4',5'-trifluorobiphenyl-2-amine using 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (CAS: 80326-98-3) as a ligand and PdCl2 as a catalyst at high temperature and high pressure. 2,2-dimethyl-1,3-bis(diphenylphosphino)propane has no commercial product for sale, PdCl2 powder is difficult to recover, and the reaction requires high temperature and high pressure equipment, which is difficult to apply in factory production.

[0011] Patent WO2018035685A1 discloses a method for synthesizing 3',4',5'-trifluorobiphenyl-2-amine using palladium acetate as a catalyst and 4-(9-anthryl)-3-tert-butyl-2,3-dihydrobenzo[d][1,3]oxaphospholane (CAS: 1268693-24-8) as a ligand at 110°C. Although 4-(9-anthryl)-3-tert-butyl-2,3-dihydrobenzo[d][1,3]oxaphospholane has been commercialized, its price is high and it is difficult to be industrialized.

[0012] Patent CN105399635B discloses a method for synthesizing 2-nitro-3',4',5'-trifluoro-1,1'-biphenyl using palladium / graphene as a catalyst at 100°C under microwave promotion. In this reaction, the catalyst used has not been commercialized, and the amount used is large. In addition, at present, it is basically not realistic to realize industrial production with a microwave reactor. Similarly, patent CN104529786B uses a 4A molecular sieve supported palladium catalyst to catalytically synthesize 3',4',5'-trifluorobiphenyl-2-amine. This catalyst also has not been commercialized and is difficult to be applied in industrialization.

[0013] Patent CN105218378A uses tetrahydrofuran as a solvent to synthesize 3', 4', 5'-trifluorobiphenyl-2-amine under high temperature and high pressure conditions. High temperature and high pressure reactions have certain safety hazards, and there are many unfavorable factors in industrial production. Patent CN109956871B makes improvements by using green and environmentally friendly water as a solvent, but the addition of a complex and expensive phase transfer catalyst increases the cost.

[0014] There are still several other methods for synthesizing 3', 4', 5'-trifluorobiphenyl-2-amine:

[0015] Patent WO2013132006A1 discloses the following synthesis route:

[0016] ;

[0017] This method uses 3, 4, 5-trifluorophenylhydrazine and aniline as raw materials to synthesize 3', 4', 5'-trifluorobiphenyl-2-amine. In this method, the raw material 3, 4, 5-trifluorophenylhydrazine is scarce and not easy to obtain, and a large excess of aniline (20 eq) and oxidant MnO2 (5 eq) are used in the reaction, which is high in cost. Secondly, this method produces about 16% of by-product 3', 4', 5'-trifluoro-[1, 1'-biphenyl]-4-amine, which is difficult to separate from the product. In the presence of an oxidant, aniline is easily destroyed, making it difficult to recover aniline and producing a large amount of solid waste, which does not meet the requirements of green production.

[0018] Patent CN107488113A uses o-nitrobenzoic acid and 3, 4, 5-trifluorobromobenzene as raw materials to synthesize 3', 4', 5'-trifluorobiphenyl-2-amine by decarboxylation coupling and then reduction, and the synthesis method is as follows:

[0019] ;

[0020] This reaction route uses an expensive catalyst Pd(acac)2, resulting in high overall cost, and requires a reaction temperature of 190°C for 22h, so it is not suitable for industrial production.

[0021] Patent CN109761820A uses o-chlorobenzonitrile and 3, 4, 5-trifluorobenzeneboronic acid to couple under palladium catalysis, hydrolyzes with hydrogen peroxide and sodium hydroxide, and then Hofmann degradation with sodium hypochlorite to obtain 3', 4', 5'-trifluorobiphenyl-2-amine, and the synthesis route is as follows:

[0022]

[0023] The route needs to use hydrogen peroxide, sodium hypochlorite and other strong oxidants, the use of strong oxidants will cause uncontrollable exothermic reaction in production, unpredictable explosion risk, production accident, high risk, and quality production control difficulty.

[0024] Patent WO2010102980A9 discloses a method for preparing 3,4,5-trifluoro-2'-nitro biphenyl by using a non-coupling method, which takes 3,4,5-trifluorobromobenzene as raw material, and prepares the target compound through formylation, Aldol condensation reaction, Dieis-Alder reaction, oxidative aromatization and other multi-step reactions, the method is complex in steps, low in yield, and the reagents used are flammable and explosive, high in danger. SUMMARY

[0025] In view of the problems of high price of raw materials, unsuitable production process for industrial production and the like in the prior art, the application provides a preparation method of a fluazinam intermediate 3',4',5'-trifluorobiphenyl-2-amine.

[0026] The technical scheme of the application is as follows:

[0027] A preparation method of a fluazinam intermediate 3',4',5'-trifluorobiphenyl-2-amine, and a reaction formula is as follows:

[0028] ;

[0029] The specific method is:

[0030] (1) taking acetanilide and boron tribromide as raw materials, reacting to obtain 2-acetamidobenzenboronic acid under an argon atmosphere in a water-free solvent;

[0031] (2) coupling 2-acetamidobenzenboronic acid and 3,4,5-trifluorobromobenzene under the action of a catalyst to obtain N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide;

[0032] (3) hydrolyzing N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide to obtain 3',4',5'-trifluorobiphenyl-2-amine.

[0033] Further, step (1) is to dissolve acetanilide in anhydrous solvent, drop boron tribromide under argon protection, add potassium carbonate aqueous solution to quench after a period of reaction, separate, concentrate the organic phase, and obtain 2-acetamidobenzenboronic acid after slurry of the concentrate.

[0034] Further, in step (1), the anhydrous solvent is selected from at least one of dichloromethane, dichloroethane, trichloromethane or carbon tetrachloride, preferably dichloromethane.

[0035] Further, in step (1), when dropping boron tribromide, the temperature of the reaction solution is controlled at 10-50℃, preferably 25-35℃.

[0036] Further, in step (1), the concentration of potassium carbonate aqueous solution is 0.5-2.5 mol / L, preferably 2.0 mol / L; when quenching the reaction with potassium carbonate aqueous solution, the temperature of the reaction solution is controlled at 0-30℃, preferably 0-5℃.

[0037] Further, step (2) is to add a catalyst and a ligand to the solvent under nitrogen protection, dissolve 2-acetamidobenzenboronic acid prepared in step (1) and 3,4,5-trifluorobromobenzene, add a base under stirring, and heat to react; after the reaction is completed, the temperature is lowered to room temperature, water and methyl tert-butyl ether are added, and the organic phase is concentrated to obtain N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide crude product, which is slurry with methyl tert-butyl ether to obtain fine product.

[0038] Further, in step (2), the catalyst is nickel chloride hexahydrate;

[0039] The ligand is DPPF (1,1'-bis(diphenylphosphino)ferrocene) or Ph-Xphos (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl), preferably Ph-XPhos;

[0040] The solvent is selected from one of DMF (N,N-dimethylformamide), DMAC (dimethylacetamide), 2-methyltetrahydrofuran, and tetrahydrofuran, preferably DMAC;

[0041] The base is DBU (1,8-diazabicyclo[5.4.0]undec-7-ene);

[0042] The heating reaction temperature is controlled at 80-90℃.

[0043] Further, in step (2), the catalyst is palladium acetate;

[0044] The ligand is n-butyl bis(1-adamantyl)phosphine;

[0045] The solvent is one of 1,4-dioxane or cyclopentyl methyl ether, preferably cyclopentyl methyl ether;

[0046] The alkali is potassium carbonate;

[0047] The heating reaction temperature is controlled between 95-105℃.

[0048] Further, step (3) involves taking the N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide prepared in step (2), adding an organic solvent and stirring to dissolve it, then adding an acid or alkali solution to carry out a hydrolysis reaction. After the reaction is completed, the pH of the reaction solution is adjusted to 6-8, the organic solvent is concentrated under reduced pressure, and then ethyl acetate is added for extraction. The extract is concentrated to obtain 3',4',5'-trifluorobiphenyl-2-amine.

[0049] Furthermore, in step (3), the acid solution is selected from hydrochloric acid or sulfuric acid, and the hydrolysis temperature of the acid solution is 20-100℃, preferably 100℃.

[0050] Furthermore, in step (3), the alkaline solution is selected from one of sodium hydroxide solution, potassium hydroxide solution, and lithium hydroxide solution, preferably a 30% sodium hydroxide aqueous solution, and the alkaline hydrolysis is carried out under reflux conditions at 100°C.

[0051] Furthermore, in step (3), the organic solvent is selected from methanol, ethanol or isopropanol, preferably ethanol.

[0052] The beneficial effects of this invention are as follows:

[0053] The raw materials used in the preparation method of this invention are all selected from common industrial raw materials, which are readily available and inexpensive. The preparation method of this invention has the advantages of simple process, high yield, high production efficiency and green environmental protection. The preparation of intermediate 2-acetamidophenylboronic acid does not use palladium catalyst to prepare boric acid, nor does it require the addition of phase transfer catalyst. The reaction does not use polar organic solvents, and it can be continuously produced, making it suitable for industrial scale-up.

[0054] The 3',4',5'-trifluorobiphenyl-2-amine intermediate produced by the method of this invention can be used to synthesize the novel fungicide fluopyram. Detailed Implementation

[0055] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions in the embodiments of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0056] Example 1: Preparation of 2-acetamidophenylboronic acid

[0057] In a 50 L double layer glass reactor with magnetic stirring, constant pressure dropping funnel, 540.65 g (4 mol, 1 eq) of acetanilide was dissolved in 1700 g of anhydrous dichloromethane solution, and 4.4 L of 1 mol / L boron tribromide (4.4 mol, 1.1 eq) in dichloromethane was slowly added dropwise at room temperature under magnetic stirring. The temperature of the reaction solution was maintained at 25-35°C. After the addition was completed, the mixture was continuously stirred at room temperature for 1 h. The reaction solution was cooled to 0-5°C, and 10 L of 2 mol / L potassium carbonate aqueous solution (2764.1 g, 20 mol, 5.0 eq) was slowly added dropwise. The temperature of the mixture was maintained at 0-5°C, and then slowly warmed to room temperature and continuously stirred for 1 h. The dichloromethane organic phase was obtained by filtration and extraction. The crude product was concentrated under reduced pressure. The crude product was slurried with 2100 mL of a mixture of ethyl acetate / petroleum ether (1:5 by volume) to obtain 558.42 g of white solid 2-acetamidobenzenboronic acid with a yield of 78%.

[0058] 1 H-NMR (300MHz, DMSO-d 6 ,) δ 11.79 (brs,1H), 7.58 (d, J = 3 Hz, 1H), 7.42 (d, J = 3 Hz, 1H), 7.25 (dd, J1= 3 Hz, J2= 6 Hz, 1H), 7.10 n(dd, J1= 3 Hz, J2= 6 Hz, 1H), 2.10 (s, 3H) ppm.

[0059] Example 2 Preparation of 2-acetamidobenzenboronic acid

[0060] In a 3 L four-necked flask with magnetic stirring, constant pressure dropping funnel, 32.44 g (0.24 mol, 1 eq) of acetanilide was dissolved in 425 g of anhydrous dichloroethane solution, and 0.24 L of 1 mol / L boron tribromide in dichloromethane (0.24 mol, 1 eq) was slowly added dropwise at room temperature under magnetic stirring. The temperature of the reaction solution was maintained at 30-45°C. After the addition was completed, the mixture was continuously stirred at room temperature for 1 h. The reaction solution was cooled to 0-25°C and 1.2 L of 1 mol / L potassium carbonate aqueous solution (165.84 g, 1.2 mol, 5.0 eq) was slowly added dropwise. The temperature of the mixture was maintained at 0-5°C, and then slowly warmed to room temperature and continuously stirred for 1 h. The dichloromethane organic phase was obtained by filtration and extraction. The crude product was concentrated under reduced pressure. The crude product was slurried with 420 mL of a mixture of ethyl acetate / petroleum ether (1:5 by volume) to obtain 25.57 g of white solid 2-acetamidobenzenboronic acid with a yield of 65%.

[0061] Example 3 Preparation of N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide

[0062] Into a 3 L reaction flask, NiCl2 . 6H2O (10.69 g, 0.045 mol, 0.045 eq) and Ph-XPhos (41.81 g, 0.09 mol, 0.09 eq) were dissolved with 900 mL DMAC under magnetic stirring and the mixed solution was stirred at room temperature for 1 hour in a nitrogen-filled glove box. To the reaction, 2-acetamidobenzoic acid (178.98 g, 1 mol, 1.0 eq) and 3,4,5-trifluorobromobenzene (210.98 g, 1 mol, 1.0 eq) prepared in Example 1 were added, followed by stirring for 20 minutes. To the reaction, DBU (456.7 g, 3 mol, 3.0 eq) was added, and the reaction flask was taken out of the glove box and stirred at 80-90 °C for 20 hours in an oil bath. After cooling to room temperature, 4500 mL of water and 5 L of methyl tert-butyl ether were added, and the organic phase was separated by extraction. The organic phase was concentrated under reduced pressure, and the crude product was slurried with 650 mL of methyl tert-butyl ether at room temperature to obtain 241.1 g of N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide at a yield of 91%.

[0063] 1 H-NMR (CDCl3, 300 MHz): δ = 8.08 (d, J = 8.1 Hz, 1H), 7.40 (ddd, J = 8.5,5.9, 3.1 Hz, 1H), 7.24-7.17 (m, 2H), 7.06-6.97 (m, 2H), 6.93 (s, 1H), 2.07(s, 3H) ppm.

[0064] Example 4 Preparation of N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide

[0065] Into a 3 L reaction flask, NiCl2 .6H2O (10.69 g, 0.045 mol, 0.045 eq) and DPPF (49.89 g, 0.09 mol, 0.09 eq) were dissolved in 1200 mL of 2-methyltetrahydrofuran under magnetic stirring and the mixture was stirred at room temperature for 1 hour in a nitrogen-filled glove box. To the reaction was added 2-acetamidobenzoic acid (178.98 g, 1 mol, 1.0 eq) and 3,4,5-trifluorobromobenzene (210.98 g, 1 mol, 1.0 eq) prepared in Example 1, and then stirred for 20 minutes. DBU (456.7 g, 3 mol, 3.0 eq) was added to the reaction, which was sealed and stirred at 80-85°C for 24 hours in an oil bath. After cooling to room temperature, 4500 mL of water and 5 L of methyl tert-butyl ether were added, and the organic phase was separated by extraction. The organic phase was concentrated under reduced pressure, and the crude product was slurried with 650 mL of methyl tert-butyl ether at room temperature to obtain 220.14 g of N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide at a yield of 83%.

[0066] Example 5 Preparation of N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide

[0067] In a 500 mL four-necked flask, 2-acetamidobenzoic acid (44.75 g, 0.25 mol, 1.0 eq) and 3,4,5-trifluorobromobenzene (52.75 g, 0.25 mol, 1.0 eq) prepared in Example 1 were sequentially added, and then cyclopentyl methyl ether 300 mL was added and dissolved with stirring. Then, palladium acetate (0.566 g, 0.0025 mol, 0.01 eq), n-butyl bis(1-adamantyl)phosphine (1.79 g, 0.005 mol, 0.02 eq), potassium carbonate (0.691 g, 0.005 mol, 0.02 eq), and water (0.18 g, 0.01 mol, 0.04 eq) were added, and the mixture was vacuumed and replaced with nitrogen three times with stirring. The mixture was heated to 95-105°C using an oil bath, and then stirred for 16 hours. After cooling to room temperature, 450 mL of water and 500 mL of cyclopentyl methyl ether were added, and the organic phase was separated by extraction. The organic phase was concentrated under reduced pressure, and the crude product was slurried with 650 mL of methyl tert-butyl ether at room temperature to obtain 61.66 g of N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide at a yield of 93%.

[0068] Example 6 Preparation of 3',4',5'-trifluorobiphenyl-2-amine

[0069] N-(3',4',5'-trifluoro[l,l'-biphenyl]-2-yl)acetamide (16.0 g, 0.06 mol) prepared in example 3 was taken in a four necked flask fitted with magnetic stirrer, reflux condenser and 160 mL of ethanol was added. The mixture was stirred at room temperature to dissolve. To this, 40 mL of 6 M hydrochloric acid solution was added and refluxed for 20 h maintaining the oil bath temperature at 100 °C. After cooling to room temperature, 50 mL of water was added to dilute the solution. After removing ethanol under reduced pressure, the solution was neutralized with 4.5 mL of concentrated ammonia solution. The mixture was extracted with ethyl acetate (2 x 50 mL) and the combined organic layer was washed with 30 mL of ammonium chloride solution, 20 mL of saturated sodium bicarbonate solution and 20 mL of brine. The solution was dried over anhydrous Na2SO4and concentrated under reduced pressure to get 3',4',5'-trifluorobiphenyl-2-amine 12.84 g in 96% yield.

[0070] 1 H-NMR (300 MHz, CDCl3): δ 7.17 (td, J = 7.9 Hz and 1.4 Hz, 1H), 7.13-7.07 (m, 2H), 7.05 (dd, J = 7.9 Hz and 1.1 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H),6.75 (d, J = 8.3 Hz, 1H), 3.72 (br. s, 2H) ppm.

[0071] Example 7 Preparation of 3',4',5'-trifluorobiphenyl-2-amine

[0072] N-(3',4',5'-trifluoro[l,l'-biphenyl]-2-yl)acetamide (31.8 g, 0.12 mol) prepared in example 5 was taken in a four necked flask fitted with magnetic stirrer and 380 mL of ethanol was added. The mixture was stirred at room temperature to dissolve. To this, 100 mL of 30% sodium hydroxide solution was added and stirred for 24 h at reflux maintaining the oil bath temperature at 100 °C. After cooling to room temperature, 50 mL of water was added to dilute the solution. After neutralizing with 66.6 mL of 30% concentrated hydrochloric acid, ethanol was removed under reduced pressure. The mixture was extracted with ethyl acetate (3 x 60 mL) and the organic layer was washed with 60 mL of saturated sodium bicarbonate solution and 60 mL of brine. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get 3',4',5'-trifluorobiphenyl-2-amine 24.62 g in 92% yield.

[0073] Although the present application has been described in detail with reference to the preferred embodiments, the application is not limited to such but encompasses any modifications or alternatives within the scope of the application as disclosed in the appended claims.

Claims

1. A process for the preparation of a myclobutanil intermediate 3',4',5'-trifluorobiphenyl-2-amine, characterized in that, The reaction formula is as follows: ； The preparation method comprises the following steps: (1) acetoanilide is dissolved in anhydrous solvent, and boron tribromide is added dropwise under argon protection, after a period of reaction, potassium carbonate aqueous solution is added for quenching, and then the organic phase is concentrated, and the concentrate is pulped to obtain 2-acetamidobenzenboronic acid; (2) 2-acetamidobenzenboronic acid and 3,4,5-trifluorobromobenzene are coupled under the action of a catalyst to obtain N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide; (3) N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)acetamide is hydrolyzed to obtain 3',4',5'-trifluorobiphenyl-2-amine.

2. The production method according to claim 1, wherein In step (1), the anhydrous solvent is at least one selected from dichloromethane, dichloroethane, trichloromethane or carbon tetrachloride.

3. The production method according to claim 1, wherein In step (1), when the boron tribromide is added dropwise, the temperature of the reaction solution is controlled at 10-50 DEG C.

4. The production method according to claim 1, wherein In step (2), the catalyst is nickel chloride hexahydrate; 5. The production method according to claim 4, wherein the ligand is selected from 1,1'-bis(diphenylphosphino)ferrocene or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; the base is 1,8-diazabicyclo[5.4.0]undec-7-ene; the heating reaction temperature is controlled at 80-90 DEG C. In step (2), the catalyst is palladium acetate; 6. The production method according to claim 4, wherein the ligand is n-butylbis(1-adamantyl)phosphine; the base is potassium carbonate; the heating reaction temperature is controlled at 95-105 DEG C. In step (3), the acid liquid is selected from one of hydrochloric acid or sulfuric acid, and the acid liquid hydrolysis temperature is 20-100 DEG C; the base liquid is selected from one of sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution, and the base liquid hydrolysis is carried out under reflux condition.

7. The production method according to claim 1, wherein In step (3), the organic solvent is selected from one of methanol, ethanol or isopropanol.

8. The production method according to claim 7, wherein ​ 9. The production method according to claim 7, wherein ​

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