A method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

Abstract

This invention belongs to the field of compound synthesis, specifically relating to a method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The invention involves a condensation reaction of difluoroacetaldehyde half-ethanol and cyanoacetaldehyde under a catalyst; the resulting intermediate is then washed with water and reacted directly with hydrazine hydrate to obtain an intermediate product. Finally, the intermediate product is reacted with formaldehyde under a catalyst to undergo cyclization and aromatization, followed by hydrolysis to the final product. This invention provides a novel method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, using difluoroacetaldehyde half-ethanol as the fluorinating agent in the reaction process, resulting in a simple synthesis method. This invention is the first to use the less expensive hydrazine hydrate instead of methylhydrazine to synthesize 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, resulting in lower cost, simpler operation, and less waste generation, thus possessing higher economic and environmental value and being more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, specifically relating to a method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. Background Technology

[0002] Fluoropyrazole compounds are common intermediates in pharmaceuticals and pesticides. Among them, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is an important intermediate and is often used in the synthesis of fungicides such as pyraclostrobin, fluopyram, benzylfluopyram, bifenthiophanate, and fluopyram.

[0003] The reported synthesis methods mainly include: (1) Patent EP1997808A discloses a method that uses ethyl difluoroacetate as a raw material to react with methyl orthoformate and acetic anhydride to generate intermediate ethyl 4,4-difluoro-2-(ethoxymethylene)-3-oxobutyrate. Then, the intermediate is cyclized with methylhydrazine and hydrolyzed under alkaline conditions to generate 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. This method is simple and produces less waste, but the raw materials required are expensive and difficult to obtain, and the product has poor selectivity.

[0004] (2) Patent CN101687806A and patent CN101679282A disclose a five-step reaction to synthesize 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid using dichloroacetyl chloride and vinyl ether as raw materials, and methylhydrazine cyclization, bromination, potassium fluoride substitution, and carbonyl insertion. The process involves a large temperature range, and the carbonyl insertion process requires catalysis and pressure. The conditions are harsh, it is not easy to operate, and the cost is high, making it unsuitable for industrial production.

[0005] (3) Patent WO2012025469 discloses a method that uses difluorochloroacetyl chloride as a raw material, reacts with ketene to obtain ethyl difluorochloroacetoacetate, and after cyclization with methylhydrazine, it is dechlorinated by hydrogenation to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. Under alkaline conditions, it is hydrolyzed to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. This method has a long route, the raw materials are not easy to obtain, the hydrogenation dechlorination step is complicated to operate, the cost is high, and a lot of waste is generated. Summary of the Invention

[0006] In view of the fact that most existing technologies use methylhydrazine in the synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, and that the existing processes are expensive, have complex reaction steps, and generate a lot of waste, this invention provides a new method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. This method uses cheaper hydrazine hydrate to replace methylhydrazine, and has fewer steps, is simple, and is highly operable, thus having great industrial practical value.

[0007] The structural formula of the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid synthesized in this invention is as follows: .

[0008] The technical solution adopted by the present invention to achieve the above objectives is as follows: This invention provides a method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, comprising the following steps: (A) Condensation reaction: Difluoroacetaldehyde half-ethanol as shown in formula (II) and cyanoacetaldehyde as shown in formula (I) undergo brain condensation under the action of a catalyst to obtain intermediate formula (III); (B) Addition reaction: The reaction solution of the intermediate shown in formula (III) is washed with water and then reacted directly with hydrazine hydrate to obtain intermediate (IV); (C) Cycloary aromatization reaction: The intermediate shown in formula (IV) reacts with formaldehyde under the action of a catalyst to undergo cyclization aromatization and then hydrolyzes to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula (V); .

[0009] Furthermore, in step (A), the catalyst is a mixed catalyst of nitrogen-containing catalyst and acid catalyst; the molar ratio of cyanoacetaldehyde, nitrogen-containing catalyst and acid catalyst is 1:0.5 to 1:0.5 to 1; the molar ratio of cyanoacetaldehyde to difluoroacetaldehyde acetal condensate is 1:1.03 to 1.5.

[0010] Preferably, the nitrogen-containing catalyst includes, but is not limited to, at least one of: triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, piperidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, and 4-dimethylaminopyridine; the acid catalyst includes, but is not limited to, at least one of: acetic acid and formic acid.

[0011] In the synthesis method provided by this invention, in step (A), the condensation reaction is carried out in a solvent; the solvent includes, but is not limited to, benzene solvents, amide solvents, alcohol solvents, nitrile solvents, acid solvents, or ketone solvents; preferably, the solvent is toluene, N,N-dimethylformamide, ethanol, acetonitrile, acetic acid, acetone, or dichloromethane; the condensation reaction may be carried out by adding, but is not limited to, toluene, benzene, xylene, cyclohexane, petroleum ether, chloroform, or carbon tetrachloride organic solvents with azeotropic properties.

[0012] Furthermore, in step (B), the molar ratio of the intermediate shown in formula (III) to hydrazine hydrate is 1:1.03 to 1.5; the addition reaction is first carried out at -5 to 0°C with stirring for 1 hour, and then heated to room temperature with stirring for 1 hour.

[0013] Furthermore, in step (C), the molar ratio of the intermediate shown in formula (IV) to formaldehyde is 1:1.03 to 1.5; the catalyst is an acid catalyst; the molar ratio of the intermediate shown in formula (IV) to the acid catalyst is 1:1.03 to 1.5; the acid catalyst includes, but is not limited to, acetic acid, formic acid or phosphoric acid.

[0014] Preferably, in step (C), the hydrolysis is performed by hydrolyzing the 3-fluorocyanopyrazole generated by the cyclization aromatization reaction and an inorganic base solution; the molar ratio of the 3-fluorocyanopyrazole to the inorganic base is 1:1.03 to 1.5; the inorganic base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, or potassium carbonate.

[0015] The above hydrolysis is carried out in an aqueous phase or a water-oil two-phase system; the oil phase includes, but is not limited to, at least one of alkyl solvents, benzene solvents, ester solvents, and ether solvents; preferably, the oil phase is at least one of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, diethyl ether, and methyl tert-butyl ether.

[0016] Compared with the prior art, the present invention has the following advantages: 1. This invention provides a novel method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, in which difluoroacetaldehyde half-ethanol is used as the fluorinating agent during the reaction, and the synthesis method is simple.

[0017] 2. This invention is the first to use hydrazine hydrate, which is cheaper, to replace methylhydrazine in the synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. It is inexpensive, simple to operate, generates less waste, and has high economic and environmental value, making it more suitable for industrial production.

[0018] 3. Methylhydrazine is a highly toxic substance that poses a great threat to the environment and workers. This invention uses hydrated hydrazine instead of methylhydrazine, which has high environmental value and is a manifestation of green chemistry. Attached Figure Description

[0019] Figure 1 The hydrogen spectrum of the synthesized 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is shown.

[0020] Figure 2 The carbon spectrum of the synthesized 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is shown. Detailed Implementation

[0021] The present invention will be further described below with reference to specific embodiments. The following description is merely exemplary and does not limit the scope of protection. Other embodiments obtained by those skilled in the art without creative effort, without departing from the inventive concept of the present invention, are also within the scope of protection.

[0022] Unless otherwise specified, all raw materials used in the following embodiments are commercially available products.

[0023] Unless otherwise specified, all concentrations mentioned in the following embodiments are mass percentage concentrations.

[0024] In the following examples, yield = actual product mass × purity / theoretical product mass.

[0025] Example 1 Condensation reaction: At room temperature, 34.53 g (0.500 mol) of cyanoacetaldehyde, 103.59 g of toluene, 15.01 g (0.250 mol) of acetic acid, and 19.78 g (0.250 mol) of piperidine were added dropwise to a four-necked flask. At room temperature, 126.10 g (0.525 mol) of difluoroacetaldehyde half-ethanol was added dropwise. The mixture was stirred for 12 h, and 50 g of water was added. The mixture was separated to obtain the condensation reaction solution.

[0026] Addition reaction: 21.03 g (0.525 mol) of 80% hydrazine hydrate and 34.53 g of toluene were added to a four-necked flask and placed at -5 to 0°C. The condensation reaction solution was slowly added dropwise. After the addition was complete, the mixture was kept at -5 to 0°C and stirred for 1 hour, then heated to room temperature and stirred for 1 hour. The mixture was allowed to stand and separated to obtain the addition reaction solution.

[0027] Cycloary aromatization reaction: 39.41 g (0.525 mol) of 40% formaldehyde solution, 31.53 g (0.525 mol) of acetic acid, and 34.53 g of toluene were added to a four-necked flask. The flask was placed at -5 to 0 °C, and the addition reaction solution was added dropwise. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 1 h, then heated to room temperature and stirred for another 1 h. 50 g of water was added for washing. After separation, the organic phase was evaporated under reduced pressure to remove toluene, yielding 80.95 g of crude 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxynitrile with a purity of 87.5%. 80 g of n-hexane was added and heated to dissolve completely. The mixture was refluxed for 1 h, stirred, and cooled to room temperature to crystallize. Filtration yielded 64.57 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxynitrile with a purity of 98.8%.

[0028] Cycloarylation and hydrolysis: 67.77 g (0.427 mol) of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was added to a four-necked flask along with 210 g of toluene and 170 g (0.448 mol) of 10% NaOH solution. The mixture was heated to 60 °C and stirred for 3 h. After cooling to room temperature, the mixture was separated into liquid and aqueous phases. Hydrochloric acid was added dropwise to adjust the pH to 2-3, at which point a large amount of white solid precipitated. The solid was filtered, and the filter cake was washed with 30 g of water and dried to obtain 71.93 g of white solid, which was 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The purity was determined to be 98.6%, and the yield (based on cyanoacetaldehyde) was 80.58%.

[0029] The structural formula of the synthesized product 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is: 1 H NMR (400 MHz, DMSO- d 6) δ 12.82 (s, 1H), 8.33 (s, 1H), 7.20 (t, J =53.8 Hz, 1H), 3.91 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 163.0, 145.1 (t, J = 23.8 Hz), 136.2, 113.0(t, J= 3.3 Hz), 109.6 (t, J = 234.7 Hz). 39.3.

[0030] Example 2 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of Example 1, except that: 30g of toluene was added as a dehydrating agent in the condensation step, the mixture was heated to reflux, about 9g of water was separated, heating was stopped, the mixture was cooled to room temperature, 50g of water was added, and the mixture was separated to obtain the condensation reaction solution.

[0031] Cycloary aromatization reaction: 81.37 g of crude 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 90.7% was obtained. 80 g of n-hexane was added and heated to dissolve completely. The mixture was refluxed for 1 h, stirred, and cooled to room temperature to crystallize. After filtration, 68.03 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 99.1% was obtained.

[0032] Cycloary aromatization hydrolysis: 170 g (0.451 mol) of 10% NaOH solution was added dropwise to obtain 75.93 g of a white solid, which is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The purity was determined to be 98.9%, and the yield, based on cyanoacetaldehyde, was 85.32%.

[0033] Example 3 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method in Example 1, except that the cyclization, aromatization, and hydrolysis steps did not involve the addition of the organic solvent toluene. 170 g (0.427 mol) of 10% NaOH solution was added dropwise, the mixture was heated to 60°C and stirred for 3 h, cooled to room temperature, and separated. Hydrochloric acid was added dropwise to the aqueous phase to adjust the pH to 2-3, at which point a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with 30 g of water and dried to obtain 71.53 g of white solid, which was 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The purity was determined to be 98.0%, and the yield, based on cyanoacetaldehyde, was 79.64%.

[0034] Example 4 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of Example 1, except that in the condensation step, the alkaline catalyst was replaced with piperidine instead of 25.30 g (0.250 mol) of triethylamine.

[0035] Cycloary aromatization reaction: 81.79 g of crude 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 86.91% was obtained. 80 g of n-hexane was added and heated to dissolve completely. The mixture was refluxed for 1 h, stirred, and cooled to room temperature to crystallize. After filtration, 65.57 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 98.4% was obtained.

[0036] Cycloary aromatization hydrolysis: 173 g (0.431 mol) of 10% NaOH solution was added dropwise to obtain 70.97 g of a white solid, which is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The purity was determined to be 98.4%, and the yield, based on cyanoacetaldehyde, was 79.34%.

[0037] Example 5 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of Example 1, except that the alkaline catalyst in the condensation step was changed from piperidine to the addition of 19.78 g (0.250 mol) of pyridine.

[0038] Cycloary aromatization reaction: 79.87 g of crude 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 88.11% was obtained. 80 g of n-hexane was added and heated to dissolve completely. The mixture was refluxed for 1 h, stirred, and cooled to room temperature to crystallize. After filtration, 63.39 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 99.3% was obtained.

[0039] Cycloary aromatization hydrolysis: 168 g (0.421 mol) of 10% NaOH solution was added dropwise to obtain 70.53 g of a white solid, which is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The purity was determined to be 99.2%, and the yield, based on cyanoacetaldehyde, was 78.87%.

[0040] Example 6 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method of Example 1, except that the acidic catalyst in the condensation step was changed from acetic acid to the addition of 11.51 g (0.250 mol) of formic acid.

[0041] Cycloary aromatization reaction: 79.87 g of crude 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 88.11% was obtained. 80 g of n-hexane was added and heated to dissolve completely. The mixture was refluxed for 1 h, stirred, and cooled to room temperature to crystallize. After filtration, 63.39 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylonitrile with a purity of 99.3% was obtained.

[0042] Cycloary aromatization hydrolysis: 166 g (0.415 mol) of 10% NaOH solution was added dropwise to obtain 70.53 g of a white solid, which is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The purity was determined to be 99.2%, and the yield, based on cyanoacetaldehyde, was 78.87%.

[0043] Application Example 1 Synthesis of 3-monofluoromethyl-1-methyl-N-(9-isopropyl-1,2,3,4-tetrahydro-1,4-methylnaphthyl-5-yl)-1H-pyrazole-4-carboxamide (pyrazolenaphthylamine): According to the synthesis method described in CN 109970652 A patent: 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (96 mg, 0.55 mmol) and phosphorus pentachloride (125 mg, 0.6 mmol) were suspended in 2 L of diethyl ether solvent and stirred at room temperature under nitrogen protection until homogeneous and transparent. After removing the solvent and trace amounts of phosphorus pentachloride under reduced pressure, the pyrazole formyl chloride intermediate was dissolved in 2 mL of tetrahydrofuran, and pyridine (87 mg, 1.1 mmol) and 9-isopropyl-1,2,3,4-tetrahydro-1,4-methylbridged naphthyl-5-amine (110.7 mg, 0.55 mmol) were added. The mixture was stirred at room temperature for 2 hours. Add 5 mL of water and 15 mL of ethyl acetate to the reaction mixture, transfer to a separatory funnel, separate the organic phase, wash with 10 mL of 4% HCl, 10 mL of 5% NaHCO3 and 10 mL of saturated brine, dry with anhydrous magnesium sulfate to remove the solvent, and separate by rapid silica gel column chromatography (ethyl acetate as eluent) to give compound 3-monofluoromethyl-1-methyl-N-(9-isopropyl-1,2,3,4-tetrahydro-1,4-methylnaphthyl-5-yl)-1H-pyrazole-4-carboxamide (pyrazolenaphthylamine) (113 mg, yield 60%). Application Example 2 Synthesis of 3-monofluoromethyl-1-methyl-N-(9-dichloromethyleneenyl-1,2,3,4-tetrahydro-1,4-methylnaphthyl-5-yl)-IH-pyrazole-4-carboxamide (benzo[a]fluoroazole) According to the synthesis method of patent CN 109970652 A, similar to cited example 1, except that 9-isopropyl-1,2,3,4-tetrahydro-1,4-methylbridged naphthyl-5-amine is replaced with 9-dichloromethyleneenyl-1,2,3,4-tetrahydro-1,4-methylbridged naphthyl-5-amine, the compound 3-monofluoromethyl-1-methyl-N-(9-dichloromethyleneenyl-1,2,3,4-tetrahydro-1,4-methylbridged naphthyl-5-yl)-IH-pyrazole-4-carboxamide (115 mg, yield 55%) is obtained.

Claims

1. A method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, characterized in that, Includes the following steps: (A) Condensation reaction: Difluoroacetaldehyde half-ethanol as shown in formula (II) and cyanoacetaldehyde as shown in formula (I) undergo brain condensation under the action of a catalyst to obtain intermediate formula (III); (B) Addition reaction: The reaction solution of the intermediate shown in formula (III) is washed with water and then reacted directly with hydrazine hydrate to obtain intermediate (IV); (C) Cycloary aromatization reaction: The intermediate shown in formula (IV) reacts with formaldehyde under the action of a catalyst to undergo cyclization aromatization and then hydrolyzes to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula (V); 。 2. The synthesis method according to claim 1, characterized in that, In step (A), the catalyst is a mixed catalyst of nitrogen-containing catalyst and acid catalyst; the molar ratio of cyanoacetaldehyde, nitrogen-containing catalyst and acid catalyst is 1:0.5 to 1:0.5 to 1; the molar ratio of cyanoacetaldehyde to difluoroacetaldehyde acetal condensate is 1:1.03 to 1.5; the nitrogen-containing catalyst is at least one of triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, piperidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and 4-dimethylaminopyridine; the acid catalyst is at least one of acetic acid and formic acid.

3. The synthesis method according to claim 1 or 2, characterized in that, In step (A), the condensation reaction is carried out in a solvent; the solvent is a benzene-based solvent, an amide-based solvent, an alcohol-based solvent, a nitrile-based solvent, an acid-based solvent, or a ketone-based solvent; during the condensation reaction, toluene, benzene, xylene, cyclohexane, petroleum ether, chloroform, or carbon tetrachloride azeotropically mixed with water is added.

4. The synthesis method according to claim 3, characterized in that, The solvent is toluene, N,N-dimethylformamide, ethanol, acetonitrile, acetic acid, acetone, or dichloromethane.

5. The synthesis method according to claim 1, characterized in that, In step (B), the molar ratio of the intermediate shown in formula (III) to hydrazine hydrate is 1:1.03 to 1.5; the addition reaction is first carried out at -5-0℃ with stirring for 1 h, and then heated to room temperature with stirring for 1 h.

6. The synthesis method according to claim 1, characterized in that, In step (C), the molar ratio of the intermediate shown in formula (IV) to formaldehyde is 1:1.03 to 1.5; the catalyst is an acid catalyst; the molar ratio of the intermediate shown in formula (IV) to the acid catalyst is 1:1.03 to 1.5; the acid catalyst is acetic acid, formic acid or phosphoric acid.

7. The synthesis method according to claim 1 or 6, characterized in that, In step (C), the hydrolysis is the hydrolysis of 3-fluorocyanopyrazole generated by the cyclization aromatization reaction and an inorganic base solution; the molar ratio of the 3-fluorocyanopyrazole to the inorganic base is 1:1.03 to 1.5; the inorganic base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, and potassium carbonate.

8. The synthesis method according to claim 7, characterized in that, The hydrolysis is carried out in an aqueous phase or a water-oil two-phase system; the oil phase is at least one of alkyl, benzene, ester and ether solvents.

9. The synthesis method according to claim 8, characterized in that, The oil phase is at least one of dichloromethane, toluene, xylene, ethyl acetate, isopropyl acetate, diethyl ether, and methyl tert-butyl ether.

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