CN112094235B - Preparation method of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole - Google Patents
Preparation method of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole Download PDFInfo
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Abstract
The invention provides a preparation method of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole. The preparation method takes p-trifluoromethylaniline as a raw material, and carries out diazotization reaction and cyclization with 2, 3-dicyanopropionic acid ethyl ester under a weak acidic condition; and introducing a proper amount of chlorine into the cyclic compound for chlorination, and regulating the pH value for decarboxylation to obtain the product 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole. The preparation method of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole has the advantages of simple operation, good chlorination selectivity, less side reaction, high product yield and mild reaction conditions, and is beneficial to realizing industrialization; the average yield of the method is not lower than 95%, and the product purity is more than 99.50%.
Description
Technical Field
The invention relates to a preparation method of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, belonging to the technical field of compound synthesis.
Background
The arylpyrazole nitrile is an important intermediate of N-phenylpyrazole pesticides such as fipronil, ethiprole, butene-fipronil and the like. The action principle of N-phenylpyrazole pesticides such as fipronil, ethiprole and the like is that chlorine channels regulated by gamma-aminobutyric acid interfere with chloride ion channels to destroy the activity of a normal central nervous system, so that insects die. Fipronil is popular with the albizzia due to the excellent insecticidal effect since entering the pesticide market, and the annual sale amount of fipronil in the first ten pesticide categories for years is within the middle level of pesticide in the world, so that fipronil becomes one of the most popular pesticide categories. Other insecticides such as ethiprole (ethiprole) and butene-fipronil are also excellent insecticides, and aryl pyrazolecarbonitriles are important intermediates for this class of insecticides.
5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole is a light tan solid, is soluble in methanol, ethanol, acetone, dichloroethane and ethyl acetate at m.p.141-142 ℃, and is an intermediate of the insecticide fipronil.
The synthesis methods of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole are more, 2, 6-dichloro-4-trifluoromethylaniline is mostly used as a raw material, and the methods all have certain technical problems.
For example, 2, 6-dichloro-4-trifluoromethylaniline is not easy to obtain, the synthesis method is complicated, most reactions need high temperature and high pressure, the yield is low, the requirement on equipment is high, and industrial production is difficult, or raw materials for synthesizing 2, 6-dichloro-4-trifluoromethylaniline are expensive and are not suitable for industrial mass production; similarly, 2, 6-dichloro-4-trifluoromethylaniline is directly synthesized by chlorination with chlorine, and the purity is only about 95-98 percent.
In CN200610040140.7, 2-chloro-4-trifluoromethyl-N, N-dimethylaniline is synthesized firstly; synthesizing an intermediate 2, 6-dichloro-4-trifluoromethylaniline; synthesizing an intermediate 2, 3-dicyanopropionic acid ethyl ester; and finally, taking concentrated sulfuric acid and sodium nitrite as initial raw materials, reacting in a glacial acetic acid solvent to generate nitrosyl sulfuric acid, then reacting with arylamine to generate diazonium salt, esterifying with dicyan ester, and finally performing rearrangement cyclization reaction with strong ammonia water in an ammonia water medium to obtain the finished product. However, the content of the product obtained by the process can only reach 98 percent, and the yield can only reach about 90 percent;
the main disadvantages of the process of CN201911238649.6, which uses 2, 6-dichloro-4-trifluoromethylaniline as the raw material, are that the reaction mechanism is complex, the side reactions are more, the content of the obtained product can only reach 95%, and the yield is lower, for example, considering the yield of 2, 6-dichloro-4-trifluoromethylaniline, the yield of the whole reaction will be lower.
In CN201911238649.6, 2, 6-dichloro-4-trifluoromethylaniline is used as a raw material, the raw material is salified with 2, 6-dichloro-4-trifluoromethylaniline in an acid solution, then 2, 3-dicyanopropionic acid ethyl ester is rapidly added, sodium nitrite is added at normal temperature, stirring is carried out, water is added for layering, and finally a cyclization reaction is carried out in an ammonia water medium to obtain a finished product, wherein the reaction time of the process is long, the product content reaches 96%, the yield reaches more than 83%, and if the yield of the 2, 6-dichloro-4-trifluoromethylaniline is considered, the yield of the whole reaction is lower.
CN101289401B proposes that 3,4, 5-trifluorotoluene is used as a raw material, and ammonia gas is directly introduced to prepare 2, 6-dichloro-4-trifluoromethylaniline, however, the ammonia introduction condition of the technical scheme is harsh, the reaction pressure is above 10MPa, the quantitative production risk coefficient is large, the chlorination selectivity is poor, side reactions are more, and the product is difficult to purify.
CN1137090C uses highly toxic sodium cyanide, which has great potential safety hazard in production.
Disclosure of Invention
In order to solve the above-mentioned technical problems, an object of the present invention is to provide a method for preparing 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, which has high yield and high product purity.
In order to achieve the technical object, the invention provides a preparation method comprising the following steps:
the method comprises the following steps: mixing ethyl 2, 3-dicyanopropionate, a solvent I and an acid, dropwise adding a mixture of p-trifluoromethylaniline and the solvent I, dropwise adding a sodium nitrite solution, carrying out a first heat preservation reaction, sampling and controlling, wherein the HPLC detection purity of the p-trifluoromethylaniline is less than 0.5%, adding a quenching agent, adjusting the pH to be =4-6, carrying out a second heat preservation reaction, sampling and controlling, the HPLC detection purity of the intermediate cyclic compound is more than 99%, stopping the reaction, recovering the solvent I under reduced pressure, adding water, stirring, standing and layering, wherein an oil phase is the intermediate cyclic compound, and the yield is not lower than 98.5%; the solvent I is a polar solvent, preferably the polar solvent is methanol or ethanol;
step two: adding a solvent II and a catalyst into the intermediate cyclic compound, introducing chlorine gas to carry out chlorination reaction, sampling, controlling, stopping the reaction, adjusting the pH =8-13, carrying out heat preservation reaction, after 8-12 hours, sampling, controlling, detecting the product HPLC, wherein the purity is more than 98%, decompressing, recovering the solvent II, adding a solvent III, and purifying to obtain 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole; the solvent II is an inert solvent, and the inert solvent is dichloroethane, chloroform or carbon tetrachloride; the solvent III is toluene, xylene or chlorobenzene.
According to the preparation method of the 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, p-trifluoromethylaniline is used as a raw material, diazotization is firstly carried out, then cyclization is carried out with 2, 3-dicyanopropionic acid ethyl ester under a weak acid condition, then a proper amount of chlorine is introduced into a cyclic compound for chlorination, and finally decarboxylation is carried out by adjusting pH to obtain the product 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, which is shown in figure 1.
The preparation method of the 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole has the advantages of good selectivity, less side reaction, high product yield and mild reaction conditions, and is beneficial to realizing industrialization; the average yield of the method is not lower than 95%, and the product purity is more than 99.50%; meanwhile, the solvent can be recycled, and the method is environment-friendly. The synthesis method is safe and simple to operate, has low requirements on equipment, and is suitable for industrial production.
In a specific embodiment of the invention, the acid used is one or a mixture of hydrochloric acid, acetic acid and sulfuric acid.
In one embodiment of the invention, the mass ratio of p-trifluoromethylaniline to acid is 1: (1.1-2.5).
In one embodiment of the present invention, in the step one, the time for the simultaneous dropping is 2 to 10 hours, and the dropping temperature is-5 ℃ to 10 ℃. The simultaneous dropwise addition refers to the simultaneous dropwise addition of a mixture of p-trifluoromethylaniline and the solvent I and a sodium nitrite solution.
In one embodiment of the invention, in the first step, the temperature of the first heat preservation reaction is-5 ℃ to 10 ℃; the temperature of the second incubation reaction is 5 ℃ to 20 ℃.
In a specific embodiment of the invention, in the step one, the mass ratio of p-trifluoromethylaniline, ethyl 2, 3-dicyanopropionate and sodium nitrite is 1: (1.01-1.50): (1.1-2); the mass ratio of the solvent I to the p-trifluoromethylaniline is (2-10): 1.
in a specific embodiment of the present invention, in the step one, the quenching agent used is one or a mixture of several of sulfamic acid and sodium bisulfite.
In one embodiment of the present invention, in the second step, the mass ratio of the solvent ii to the intermediate cyclic compound is (4-10): 1.
in one embodiment of the present invention, in the second step, the catalyst is azobisisobutyronitrile, dibenzoyl peroxide, or azobisisoheptonitrile.
In one embodiment of the present invention, in the second step, the molar equivalent ratio of the intermediate cyclic compound, the catalyst and the chlorine gas is 1: (0.01-0.1): (4.0-6.0).
In a specific embodiment of the invention, in the second step, the temperature of the chlorination reaction is 20 ℃ to 80 ℃, and the time of the chlorination reaction is 2h to 12 h.
In one embodiment of the present invention, in the second step, the mass ratio of the weight of the solvent iii to the solvent ii is (2-4): 1.
in one embodiment of the present invention, the preparation method of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole specifically comprises the following steps:
uniformly stirring ethyl 2, 3-dicyanopropionate, a solvent I and acid, cooling to 0 ℃, beginning to simultaneously dropwise add a mixed solution of p-trifluoromethylaniline and ethanol and a sodium nitrite solution, reacting for 4 hours at 5-10 ℃, sampling and controlling, wherein the HPLC detection purity of the p-trifluoromethylaniline is less than 0.5%, adding a sodium bisulfite solution after the reaction is finished to quench the reaction, adjusting the pH =5 by using dilute ammonia water after the reaction is finished, continuing to perform heat preservation reaction at 15-20 ℃, sampling and controlling, wherein the HPLC detection purity of an intermediate cyclic compound is more than 99%, stopping the reaction, beginning to recover the solvent ethanol under reduced pressure, adding water after the recovery is finished, standing and layering, wherein an oil phase is the intermediate cyclic compound;
adding a solvent II and a catalyst (azodiisobutyronitrile), introducing chlorine gas at 15-20 ℃, leading the temperature to be not more than 45 ℃ in the chlorine introduction process, reacting at the temperature below 45 ℃ for 2 hours after the chlorine introduction is finished, heating to 80 ℃, keeping the temperature for 4 hours continuously, sampling, controlling the temperature, stopping the reaction, adding water, stirring, standing for layering, adjusting the pH of an oil phase to be =10 by using dilute ammonia water, keeping the temperature for 4 hours continuously, controlling the sampling, controlling the product HPLC to be more than 98%, recovering dichloroethane by reducing the pressure, adding xylene and water as solvents, heating to reflux for 2 hours, layering, cooling the oil phase, crystallizing and filtering to obtain 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole; the yield is more than 95%, and the purity is not lower than 99.5% by HPLC detection. The recovered solvent is directly applied to the corresponding next batch.
According to the preparation method of the 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, p-trifluoromethylaniline is used as a starting material to prepare the 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, a cyclic compound is synthesized in a route, and then chlorination reaction is carried out, so that the selectivity is good, side reactions are fewer, and the yield is high.
According to the preparation method of the 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, adopted solvents are low in toxicity, so that great harm to human bodies is avoided, and the industrial production safety is high.
According to the preparation method of the 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, raw and auxiliary materials are all conventional compounds, solvents can be recycled, and the catalyst is single and environment-friendly.
According to the preparation method of the 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, the intermediate has high purity, the next reaction can be directly carried out without purification, and the productivity efficiency is improved; the product has high purity, and is favorable for sale; the process is simple to operate and is beneficial to industrial production.
Drawings
FIG. 1 is a reaction scheme of a method for preparing 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole according to the present invention.
FIG. 2 is a scheme showing the preparation of an intermediate cyclic compound of example 21H NMR 300MHz DMSO。
FIG. 3 is a drawing of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole from example 71H NMR 300MHz DMSO。
Detailed Description
Example 1
Synthesis of intermediate cyclic compounds
Adding 167.2g (1.1 mol) of ethyl 2, 3-dicyanopropionate, 500g of ethanol and 200g of 30% hydrochloric acid into a 2000mL four-mouth reaction bottle, starting stirring, cooling to 0 ℃, simultaneously dropwise adding a mixed solution of 161g (1.0 mol) of p-trifluoromethylaniline and 160g of ethanol and 195g (sodium nitrite: 79g and water: 116 g) of sodium nitrite solution, controlling the dropwise adding speed to about 6 hours, keeping the temperature at 8 ℃ for 4 hours after dropwise adding, controlling the sampling center, detecting the purity of 0.3% of the p-trifluoromethylaniline by HPLC, adding 50g (20 g of sodium bisulfite and 30g of water) of sodium bisulfite solution for quenching reaction, adjusting the pH =5 by 120g of 15% dilute ammonia water after the reaction is finished, adjusting the dropwise adding time to 4 hours and the temperature to 12 ℃, keeping the temperature at 15 ℃ for 2 hours, controlling the purity of a cyclic compound by HPLC to be 99.2%, recovering the ethanol under reduced pressure, after the recovery is finished, 500g of water is added under stirring, and then the mixture is kept stand for layering, so that 330g of intermediate cyclic compound is obtained, the detection content is 96.95%, the HPLC detection purity is 99.2%, and the yield is 98.75%.
Example 2
Synthesis of intermediate cyclic compounds
Adding 197.6g (1.3 mol) of ethyl 2, 3-dicyanopropionate, 500g of ethanol and 250g of 30% hydrochloric acid into a 2000mL four-mouth reaction bottle, starting stirring, cooling to-5 ℃, beginning to simultaneously dropwise add a mixed solution of 161g (1.0 mol) of p-trifluoromethylaniline and 160g of ethanol and 250g of sodium nitrite solution (100 g of sodium nitrite and 150g of water), controlling the dropwise adding speed to be about 8 hours, keeping the temperature at 5 ℃ for reaction for 4 hours after dropwise adding, sampling, controlling the sample to have a purity of 0.2% by HPLC (high performance liquid chromatography) of the p-trifluoromethylaniline, adding 50g (20 g of sodium bisulfite and 30g of water) of sodium bisulfite solution for quenching reaction, adjusting the pH to be 4 by using 110g of 15% dilute ammonia water after the reaction is finished, adjusting the dropwise adding time to be 3 hours, keeping the temperature to be 18 ℃, keeping the temperature at 15 ℃ for 2 hours, sampling and detecting the purity of 99.46% by HPLC of a cyclic compound, and recovering the solvent ethanol under reduced pressure, adding 500g of water while stirring after recovery, and standing for layering to obtain 335.5g of the intermediate cyclic compound, wherein the content is 95.44% by detection, the purity is 99.35% by HPLC detection, and the yield is 98.82%.
Of the intermediate Cyclic Compound of example 21H NMR 300MHz DMSO is shown in FIG. 2, δ =1.30 (t, 3H, CH)3），4.29（m,2H,CH2），6.27（s,2H,NH2），7.35（s,1H,ArH），7.48（s,1H,ArH），7.65（s,1H,ArH）。
Example 3
Synthesis of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole
Adding 330g (content: 96.95%), 1350g of dichloroethane and 8g (0.04878 mol) of azodiisobutyronitrile into a 2000mL four-mouth reaction bottle, stirring, introducing 281g (3.96 mol) of chlorine gas at 15 ℃, completing the introduction in about 4 hours, keeping the temperature at 45 ℃ or below during the chlorine introduction, then starting heating to 80 ℃, continuing to preserve heat for 4 hours, sampling and detecting, wherein the purity of the intermediate cyclic compound is 0.2% by HPLC (high performance liquid chromatography), stopping the reaction, adding 200g of water, stirring, standing and layering, adjusting the pH of an oil phase to be =10 by 150g of 15% dilute ammonia water, dropwise adding for 2 hours, keeping the temperature at 25 ℃, continuing to preserve heat for 4 hours at 25 ℃, sampling and detecting, wherein the purity of a product is 98.49% by HPLC, and starting to recover the dichloroethane under reduced pressure; after recovery, adding 650g of xylene solvent and 200g of water, heating to reflux, keeping the temperature for 2h in a reflux state, then cooling to 80 ℃ to begin layering, continuously cooling the oil phase to 0 ℃, crystallizing for 1h, and performing suction filtration to obtain a wet 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole product, drying by using an infrared lamp, weighing and detecting to obtain 306.0g of a finished product, wherein the purity is 99.55% by using HPLC (high performance liquid chromatography), the yield is 96.52%, and the total yield of the two-step reaction is: 95.31 percent.
Example 4
Synthesis of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole
Adding 335.5g (content: 95.44%) of the intermediate cyclic compound of example 2, 1500g of dichloroethane and 10g (0.061 mol) of azodiisobutyronitrile into a 2000mL four-mouth reaction bottle, stirring, introducing 426g (3.96 mol) of chlorine gas at 15-20 ℃, completing the chlorine introduction within about 6 hours, keeping the temperature not more than 45 ℃ in the chlorine introduction process, then starting to heat to 80 ℃, continuing to preserve heat for 2 hours, sampling and detecting, wherein the HPLC detection purity of the intermediate cyclic compound is 0.1%, stopping the reaction, adding 200g of water, stirring, standing and layering, adjusting the pH of an oil phase to be =8 by using 350g of 10% dilute ammonia water, dropwise adding the time to be 4 hours, the temperature to be 20 ℃, continuing to preserve heat for 4 hours at 25 ℃, sampling and detecting, wherein the HPLC detection purity of a product is 98.09%, and starting to recover the dichloroethane under reduced pressure; adding 650g of solvent xylene after recovery, heating to reflux, keeping the temperature for 2h in a reflux state, then cooling to 90 ℃ to begin layering, continuously cooling the oil phase to 5 ℃, crystallizing for 1h, and performing suction filtration to obtain a 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole wet product, drying by using an infrared lamp, weighing and detecting to obtain 306.5g of a finished product, wherein the HPLC detection purity is 99.51%, the yield is 96.63%, and the total yield of the two-step reaction is: 95.42 percent.
Example 5
Synthesis of intermediate cyclic compounds
Adding 155g (1.02 mol) of ethyl 2, 3-dicyanopropionate, 500g of ethanol and 200g of 30% hydrochloric acid into a 2000mL four-mouth reaction bottle, starting stirring, cooling to 5 ℃, simultaneously dropping a mixed solution of 161g (1.0 mol) of p-trifluoromethylaniline and 160g of ethanol and 195g (sodium nitrite: 79g, water: 116 g) of sodium nitrite solution, controlling the dropping speed for about 4 hours, keeping the temperature at 10 ℃ for 6 hours after dropping, sampling, controlling the purity of the p-trifluoromethylaniline by HPLC (high performance liquid chromatography) to be 0.52%, adding 50g (20 g of sodium bisulfite and 30g of water) of sodium bisulfite solution for quenching reaction, adjusting the pH to be =5 by 115g of 15% dilute ammonia water after the reaction is finished, keeping the temperature at 10 ℃ for 2 hours, controlling the purity of a cyclic compound by HPLC to be 99.08%, recovering the solvent ethanol under reduced pressure, after the recovery is finished, 500g of water is added under stirring, and then the mixture is kept stand for layering, so that 332g of intermediate cyclic compound is obtained, the detection content is 96.14%, the purity is 99.13% through HPLC detection, and the yield is 98.51%.
Example 6
Synthesis of intermediate cyclic compounds
Adding 228g (1.5 mol) of ethyl 2, 3-dicyanopropionate, 500g of ethanol and 240g of 30% hydrochloric acid into a 2000mL four-mouth reaction bottle, starting stirring, cooling to 0 ℃, simultaneously dropwise adding a mixed solution of 161g (1.0 mol) of p-trifluoromethylaniline and 160g of ethanol and 378g (sodium nitrite: 138g and water: 240 g) of sodium nitrite solution, controlling the dropwise adding speed to about 6 hours, keeping the temperature at 6 ℃ for 4 hours after dropwise adding, sampling, controlling the purity of the p-trifluoromethylaniline by HPLC (high performance liquid chromatography) to be 0.12%, adding 100g (40 g and 60 g) of sodium bisulfite solution for quenching reaction, adjusting the pH to be 4 by 180g of 10% dilute ammonia water after the reaction is finished, keeping the temperature at 15 ℃ for 2 hours, controlling the purity of a cyclic compound by HPLC to be 99.28%, recovering the solvent ethanol under reduced pressure, after the recovery is finished, 500g of water is added under stirring, and then the mixture is kept stand for layering, so that 340g of intermediate cyclic compound is obtained, the detection content is 94.12%, the HPLC detection purity is 99.13%, and the yield is 98.76%.
Example 7
Synthesis of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole
Adding 330g (content: 95.13%) of the mixed intermediate cyclic compound of example 5 and example 6, 1600g of dichloroethane and 8g (0.04878 mol) of azodiisobutyronitrile into a 2000mL four-mouth reaction bottle, stirring, introducing 320g (4.507 mol) of chlorine gas at 15-20 ℃, completing about 4 hours of introduction, keeping the temperature not more than 45 ℃ in the chlorine introduction process, then starting to heat to 80 ℃, continuing to preserve heat for 4 hours, sampling and detecting, wherein the purity of the intermediate cyclic compound is 0.25% by HPLC (high performance liquid chromatography), stopping the reaction, adding 200g of water, stirring, standing and layering, adjusting the pH of an oil phase to 12.5 by using 170g of 15% dilute ammonia water, dropwise adding the oil phase for 2 hours, keeping the temperature at 20 ℃, continuing to preserve heat for 4 hours, sampling and detecting, wherein the purity of a product is 98.32% by HPLC, and starting to recover dichloroethane under reduced pressure; and after the recovery is finished, adding 800g of solvent xylene and 200g of water, heating to reflux, keeping the temperature for 2h in a reflux state, then cooling to 85 ℃ to begin layering, continuously cooling the oil phase to 0 ℃, crystallizing for 2h, and performing suction filtration to obtain a wet 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole product, drying by using an infrared lamp, weighing and detecting to obtain 300g of a finished product, wherein the purity is 99.78% by HPLC (high performance liquid chromatography) and the yield is 96.43%.
Preparation of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, example 71H NMR 300MHz DMSO is shown in FIG. 3, δ =5.99 (s, 2H, NH)2），6.89（s,1H,CH），7.53（s,1H,ArH），7.53（s,1H,ArH）。
Comparative example 1
Synthesis of intermediate cyclic compounds
Adding 167.2g (1.1 mol) of ethyl 2, 3-dicyanopropionate, 500g of ethanol and 200g of 30% hydrochloric acid into a 2000mL four-mouth reaction bottle, starting stirring, cooling to 10 ℃, simultaneously dropping a mixed solution of 161g (1.0 mol) of p-trifluoromethylaniline and 160g of ethanol and 195g (sodium nitrite: 79g and water: 116 g) of sodium nitrite solution, controlling the dropping speed to about 6 hours, keeping the temperature at 15 ℃ for 4 hours after dropping, sampling, controlling the purity of the p-trifluoromethylaniline by HPLC (high performance liquid chromatography) to be 15.5%, adding 50g (20 g of sodium bisulfite and 30g of water) of sodium bisulfite solution for quenching reaction, adjusting the pH to be =8 by 120g of 15% dilute ammonia water after the reaction is finished, adjusting the dropping time to be 4 hours and the temperature to be 25 ℃, keeping the temperature at 30 ℃ for 4 hours, controlling the purity of a cyclic compound by HPLC to be 25.65%, recovering the solvent ethanol under reduced pressure, after the recovery is finished, 500g of water is added under stirring, and then the mixture is kept stand for layering, so that 55g of intermediate cyclic compound is obtained, the detection content is 45.65%, the purity is 58.45% by HPLC detection, and the yield is 7.75%.
Comparative example 2
Synthesis of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole
Adding 330g (content: 96.95%), 1350g of dichloroethane and 8g (0.04878 mol) of azodiisobutyronitrile into a 2000mL four-mouth reaction bottle, stirring, introducing 281g (3.96 mol) of chlorine gas at 30 ℃, completing about 4 hours, introducing the chlorine gas at 50 ℃ during the chlorine introduction process, then starting heating to 80 ℃, continuing to preserve heat for 4 hours, sampling and detecting, wherein the purity of the intermediate cyclic compound is 6.05% by HPLC (high performance liquid chromatography), stopping the reaction, adding 200g of water, stirring, standing and layering, adjusting the pH of an oil phase to be =5 by 150g of 15% dilute ammonia water, dropwise adding for 2 hours, keeping the temperature at 40 ℃, continuing to preserve heat for 4 hours at 25 ℃, sampling and detecting, and starting to decompress and recover the dichloroethane; after recovery, adding 650g of xylene solvent and 200g of water, heating to reflux, keeping the temperature for 2h in a reflux state, then cooling to 100 ℃ to begin layering, continuously cooling the oil phase to 10 ℃, crystallizing for 1h, and performing suction filtration to obtain a wet 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole product, drying by using an infrared lamp, weighing and detecting to obtain 280g of a finished product, wherein the detection content is 26.79%, the HPLC detection purity is 35.26%, the yield is 23.66%, and the total yield of the two-step reaction is as follows: 23.37 percent.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (3)
1. A process for the preparation of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole, which comprises:
the method comprises the following steps: mixing ethyl 2, 3-dicyanopropionate, a solvent I and an acid, dropwise adding a mixture of p-trifluoromethylaniline and the solvent I, dropwise adding a sodium nitrite solution, carrying out a first heat preservation reaction, sampling, controlling, and detecting the purity of the trifluoromethylaniline by HPLC<0.5 percent of quenching agent is added, the pH =4-6 is adjusted, the second continuous heat preservation reaction is carried out, the sampling is controlled in the middle, and the intermediate cyclic compound HPLC detects the purity>99 percent of the reaction is stopped, the solvent I is recovered under reduced pressure, water is added, the mixture is stirred and then is kept stand for layering, the oil phase is an intermediate cyclic compound, and the yield is not lower than 98.5 percent; the solvent I is a polar solvent, and the polar solvent is methanol or ethanol; the acid is one or a mixture of more of hydrochloric acid, acetic acid and sulfuric acid, and the mass ratio of the p-trifluoromethylaniline to the acid is 1: (1.1-2.5); the dropping time is 2-10 hours, the dropping temperature is-5 ℃ to 10 ℃, the temperature of the first heat preservation reaction is-5 ℃ to 10 ℃, and the temperature of the second heat preservation reaction is 5 ℃ to 20 ℃; p-trifluoromethylaniline, 2, 3-dicyanopropionic acid ethyl esterThe mass ratio of the ester to the sodium nitrite is 1: (1.01-1.50): (1.1-2); the mass ratio of the solvent I to the p-trifluoromethylaniline is (2-10): 1; the quenching agent is one or a mixture of more of sulfamic acid and sodium bisulfite; the chemical structural formula of the intermediate cyclic compound is as follows:
；
step two: adding a solvent II and a catalyst into the intermediate cyclic compound, introducing chlorine gas to carry out chlorination reaction, sampling, controlling, stopping the reaction, adjusting the pH to be =8-13, carrying out heat preservation reaction for 8-12 hours, sampling, controlling, detecting the product HPLC to be more than 98%, decompressing, recovering the solvent II, adding a solvent III, and purifying to obtain 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole; the solvent II is an inert solvent, and the inert solvent is dichloroethane, chloroform or carbon tetrachloride; the solvent III is toluene, xylene or chlorobenzene; the mass ratio of the solvent II to the intermediate cyclic compound is (4-10): 1, the catalyst is azodiisobutyronitrile, dibenzoyl peroxide or azodiisoheptadecylenide; the molar equivalent ratio of the intermediate cyclic compound to the catalyst to the chlorine gas is 1: (0.01-0.1): (4.0-6.0).
2. The preparation method according to claim 1, wherein in the second step, the temperature of the chlorination reaction is 20-80 ℃, and the time of the chlorination reaction is 2-12 h.
3. The preparation method according to claim 1, wherein in the second step, the mass ratio of the weight of the solvent III to the solvent II is (2-4): 1.
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