A method for the synthesis of a bifenasine intermediate
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHAOXING SHANGYU XINYINBANG BIOCHEMICAL CO LTD
- Filing Date
- 2023-11-30
- Publication Date
- 2026-05-12
AI Technical Summary
Existing methods for preparing 4-methoxy-3-aminobiphenyl have problems such as high requirements for production equipment, high energy consumption, high cost, significant safety hazards, and difficulty in separating by-products.
Using 4-methoxyaniline as the starting material, 4-methoxybenzene diazonium salt is generated through diazotization, followed by coupling with benzene, and then halogenation and amination reactions. This avoids dangerous reactions such as high-temperature alkaline fusion, nitration, and high-pressure catalytic hydrogenation reduction. The substitution reaction is carried out using halogenation reagents and metal amines, which reduces the requirements for equipment and safety hazards.
This method successfully reduced production costs, avoided safety hazards from dangerous reactions, improved reaction selectivity and product purity, and provided a green, environmentally friendly, and high-yield synthetic method.
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Abstract
Description
Technical Field
[0001] This application relates to the field of organic synthesis technology, and in particular to a method for synthesizing a biphenylhydrazine ester intermediate. Background Technology
[0002] Bifenazate is a novel selective foliar spray acaricide, chemically named isopropyl 3-(4-methoxybiphenyl-3-yl)hydrazinocarboxylate. It is effective against all life stages of mites, exhibiting knockdown and ovicidal activity against adult mites, and has a long effective period. It can be used to control two-spotted spider mites and apple pterocaryon on crops such as apples, grapes, peaches, strawberries, and stone fruits. At the same time, it is harmless to beneficial mites and insects, making it environmentally friendly and highly suitable for integrated insect management, which can strongly promote the development of the agricultural industry.
[0003] 4-Methoxy-3-aminobiphenyl is an important intermediate in the synthesis of biphenylhydrazine esters. The existing technologies mainly include the following methods for preparing 4-methoxy-3-aminobiphenyl:
[0004] Route 1:
[0005]
[0006] This route uses biphenyl as a raw material, which is sulfonated to produce 4-sulfonic acid biphenyl, then fused at high temperature to produce 4-hydroxybiphenyl, followed by nitration and methylation, and finally catalytic hydrogenation on palladium on carbon to reduce the nitro group to obtain 4-methoxy-3-aminobiphenyl. However, this process requires high-temperature alkali fusion, which places high demands on the production equipment. The nitration and high-pressure catalytic hydrogenation reduction reactions also pose significant safety hazards during production, and generate a large amount of strong alkali and strong acid waste liquid. It also has problems such as high energy consumption and harsh reaction conditions.
[0007] Route 2:
[0008]
[0009] This route uses 3-bromo-5-methoxyaniline as a raw material, and phenylboronic acid and inorganic base are coupled with a palladium ligand catalyst under nitrogen protection to generate 4-methoxy-3-aminobiphenyl. However, this route is a Suzuki coupling reaction, which requires the use of palladium catalyst, which is expensive and costly. In addition, the raw materials are expensive and difficult to obtain.
[0010] Route 3:
[0011]
[0012] This route involves reacting 4-methoxybromobenzene with dry tetrahydrofuran as a solvent under inert gas protection, with the substrate and magnesium powder reacting to obtain a Grignard reagent. This reagent then reacts with bromobenzene under catalysis to yield 4-methoxybiphenyl, followed by nitration and high-pressure palladium-carbon catalytic hydrogenation reduction to obtain 4-methoxy-3-aminobiphenyl. However, this method involves a Grignard reaction, requiring strict anhydrousness and nitrogen protection. Furthermore, it generates self-coupling byproducts that are difficult to separate, affecting product yield. The high-pressure catalytic hydrogenation reduction reaction also poses significant safety risks during production.
[0013] Based on the existing technologies described above, it has been found that the current methods for preparing 4-methoxy-3-aminobiphenyl suffer from technical challenges such as high requirements for production equipment and high energy consumption, high production costs, and difficulty in separating byproducts. Therefore, there is a need to find a new, green, environmentally friendly method with high yield and low production costs to meet the urgent market demand for this product. Summary of the Invention
[0014] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a method for synthesizing 4-methoxy-3-aminobiphenyl, which solves the problems of expensive raw materials, unstable raw material sources, high production costs, large equipment investment, high requirements for production equipment, and high energy consumption in the prior art.
[0015] This application provides a method for synthesizing a biphenylhydrazine ester intermediate, which employs the following technical solution:
[0016] A method for synthesizing a biphenylhydrazine ester intermediate includes the following steps:
[0017] S1. Add 4-methoxyaniline to hydrochloric acid, dissolve and clear the solution, cool the system to 0 degrees, slowly add sodium nitrite, and keep the system warm to carry out the reaction, to obtain a reaction solution containing 4-methoxyaniline.
[0018] S2. Add benzene and sodium carbonate to the reaction solution obtained in S1, control the reaction temperature, and keep the reaction at the temperature. After the reaction is completed, add water, stir evenly, let stand to separate the layers, remove the organic layer, remove the solvent by vacuum distillation, and obtain 4-methoxybiphenyl.
[0019] S3. The 4-methoxybiphenyl obtained in S2 is added to solvent A, a halogenation reagent is added, the temperature is lowered, and the reaction is carried out at this temperature. After the reaction is completed, the solvent is removed by vacuum distillation to obtain 4-methoxy-3-halobiphenyl.
[0020] S4. Add 4-methoxy-3-halobiphenyl to solvent B, stir until homogeneous, cool to 0°C, maintain constant temperature, and add metal amine. After addition, stir until homogeneous, then slowly heat and maintain the temperature for amination reaction. After the reaction is complete, drop the reaction solution into ice water, extract to separate the layers, dry the organic phase, and remove the solvent by vacuum distillation to obtain 4-methoxy-3-aminobiphenyl.
[0021] The synthesis route is as follows:
[0022]
[0023] Wherein, X is one of F, Cl, Br, and I.
[0024] By adopting the above technical solution, 4-methoxyaniline is used as the starting material, and 4-methoxybenzene diazonium salt is obtained through diazotization reaction; the 4-methoxybenzene diazonium salt is decomposed to form aryl free radicals, and a certain amount of benzene is added to carry out a coupling reaction to obtain 4-methoxybiphenyl; then, 4-methoxy-3-halobiphenyl is obtained through halogenation reaction with a halogenating reagent; finally, a metal amine is added for nucleophilic substitution to obtain 4-methoxy-3-aminobiphenyl. The amination reaction in the 4-methoxy-3-aminobiphenyl production reaction of this invention uses a substitution reaction between a haloaromatic hydrocarbon and a metal amine to generate aromatic amines and halides. This successfully avoids the dangerous reaction of first introducing a nitro group and then using palladium on carbon for catalytic hydrogenation reduction to obtain aromatic amines, greatly avoiding the huge safety hazards brought about by dangerous reactions in production. It also eliminates the need for a palladium on carbon catalyst, reducing production costs. Simultaneously, the diazotization coupling reaction in the 4-methoxy-3-aminobiphenyl production reaction of this invention uses 4-methoxyaniline to first prepare a 4-methoxybenzene diazonium salt, which is then coupled with benzene to obtain 4-methoxybiphenyl. This successfully avoids the biphenyl undergoing sulfonation followed by ultra-high temperature alkaline fusion and then methylation, reducing the requirements for production equipment and minimizing the huge safety hazards in production. It also avoids the problems of large amounts of byproducts, high energy consumption, and harsh reaction conditions, reducing waste treatment issues.
[0025] Preferably, the halogenated reagent is one of X2, hypohalite (MXO), N-halosuccinimide (NXS), dihalohaline (DXDMH), and thioyl halide (SO2X2); wherein X is one of F, Cl, Br, and I; and M is an alkali metal or alkaline earth metal.
[0026] Preferably, the metal amide is one of NaNH2, KNH2, LiNH2, and Ca(NH2)2.
[0027] Preferably, the molar ratio of the reactants 4-methoxyaniline, hydrochloric acid, sodium nitrite, benzene and sodium carbonate is 1:(2-8):(1-1.5):(4-6):(2-4).
[0028] By adopting the above technical solution and controlling the molar ratio between the reactants 4-methoxyaniline, hydrochloric acid, sodium nitrite, benzene, and sodium carbonate, it is beneficial to improve the selectivity of the reaction and the purity or quality of the reaction products.
[0029] Preferably, the heat preservation reaction time in S1 is 1-3 hours.
[0030] Preferably, the temperature of the reaction in S2 is 0-10℃ and the reaction time is 1-5h.
[0031] By adopting the above technical solutions and controlling the reaction temperature and time, it is beneficial to improve the selectivity of the reaction and the purity or quality of the reaction products.
[0032] Preferably, the molar ratio of the reactant 4-methoxybiphenyl, solvent A, and halogenated reagent in S3 is 1:(15-17):(1-1.5).
[0033] By adopting the above technical solution, and by controlling the molar ratio between the reactant 4-methoxybiphenyl, solvent A, and halogenated reagent, it is beneficial to improve the selectivity of the halogenation reaction and the purity or quality of the reaction product.
[0034] Preferably, the halogenation reaction in S3 is carried out at a temperature of 0-20°C for 2-5 hours.
[0035] By adopting the above technical solutions and controlling the reaction temperature and time, it is beneficial to improve the selectivity of the reaction and the purity or quality of the reaction products.
[0036] Preferably, the molar ratio of the reactant 4-methoxy-3-halobiphenyl, solvent B, and metal amine in S4 is 1:(15-19):(1-3).
[0037] By adopting the above technical solution, and by controlling the molar ratio between the reactant 4-methoxy-3-halobiphenyl, solvent B, and metal amine, it is beneficial to improve the selectivity of the substitution reaction and the purity or quality of the reaction product.
[0038] Preferably, the amination reaction in S4 is carried out at a temperature of 70-95°C for 2-6 hours.
[0039] By adopting the above technical solutions and controlling the reaction temperature and time, it is beneficial to improve the selectivity of the reaction and the purity or quality of the reaction products.
[0040] In summary, this application includes at least one of the following beneficial technical effects:
[0041] 1. Existing technologies require sulfonation and high-temperature alkaline fusion to prepare 4-hydroxybiphenyl. The technical solution of this invention successfully avoids the sulfonation and alkaline fusion route, reducing energy consumption and waste costs.
[0042] 2. Existing technologies require nitration to prepare 4-hydroxy-3-nitrobenzene, while the technical solution of this invention successfully avoids dangerous reactions such as nitration, greatly reducing safety risks;
[0043] 3. Existing technologies require catalytic hydrogenation reduction to prepare 4-methoxy-3-aminobiphenyl, while the technical solution of this invention successfully avoids the use of expensive palladium on carbon catalyst, greatly reducing production costs;
[0044] 4. Existing technologies require SUZUKI coupling reactions, while the technical solution of this invention successfully avoids the use of expensive raw materials and expensive catalysts, greatly reducing production costs;
[0045] 5. Existing technologies require a Grignard reaction followed by coupling to prepare 4-methoxybiphenyl. The technical solution of this invention successfully avoids the Grignard reaction, greatly reducing safety risks and production costs.
[0046] 6. The technical solution provided by this invention uses readily available and sufficient raw materials, has good economic efficiency, low raw material costs, high yield, high product quality, and low industrialization costs, making it a practical and feasible industrial production method. Detailed Implementation
[0047] The present application will be further described in detail below with reference to the embodiments.
[0048] Example
[0049] Example 1
[0050] S1. Add 50g of 4-methoxyaniline to a 500ml three-necked flask, followed by 109g of hydrochloric acid. After dissolving and clearing the solution, cool the system to 0 degrees Celsius and slowly add 36.4g of sodium nitrite. Keep the reaction at this temperature for 1 hour to obtain a reaction solution containing 4-methoxybenzene.
[0051] S2. Add 170g benzene and 129g sodium carbonate to the reaction solution obtained in S1, control the reaction temperature to 5℃, and keep the temperature for 3h. After the reaction is completed, add water, stir evenly, let stand for layering, remove the organic layer, remove the solvent by vacuum distillation, and obtain 4-methoxybiphenyl.
[0052] S3. Add 72g of 4-methoxybiphenyl obtained from S2, 740g of chloroform solvent, and 67.7g of N-chlorosuccinimide to a 1000ml three-necked flask in sequence. Lower the temperature to 0℃ and keep it at this temperature for 3h for halogenation reaction. After the reaction is completed, remove the solvent by vacuum distillation to obtain 4-methoxy-3-chlorobiphenyl.
[0053] S4. Take 1000 ml of a dry reaction flask, add 50 g of 4-methoxy-3-chlorobiphenyl obtained from S3 and 284.4 g of solvent DMF in sequence, stir evenly, cool down to 0℃, control the temperature to be constant, and add 18.8 g of sodium amino. After the addition is complete, stir for 30 minutes, then slowly raise the temperature to 80-85℃ and keep it at the temperature for 4 hours. After the reaction is completed, drop the reaction solution into ice water, extract and separate the layers, dry the organic phase, and remove the solvent by vacuum distillation to obtain 4-methoxy-3-aminobiphenyl.
[0054] Example 2
[0055] S1. Add 50g of 4-methoxyaniline to a 500ml three-necked flask, followed by 29.6g of hydrochloric acid. After dissolving and clearing the solution, cool the system to 0 degrees Celsius and slowly add 36.4g of sodium nitrite. Keep the reaction at this temperature for 2 hours to obtain a reaction solution containing 4-methoxybenzene.
[0056] S2. Add 170g benzene and 86.07g sodium carbonate to the reaction solution obtained in S1, control the reaction temperature to 5℃, and keep the temperature for 3h. After the reaction is completed, add water, stir evenly, let stand for layering, remove the organic layer, remove the solvent by vacuum distillation, and obtain 4-methoxybiphenyl.
[0057] S3. Add 72g of 4-methoxybiphenyl obtained from S2, 699.1g of chloroform solvent, and 145g of dibromohydantoin to a 1000ml three-necked flask in sequence. Lower the temperature to 0℃ and keep it at this temperature for 3h for halogenation reaction. After the reaction is completed, remove the solvent by vacuum distillation to obtain 4-methoxy-3-bromobiphenyl.
[0058] S4. Take 1000 ml of a dry reaction flask, add 50 g of 4-methoxy-3-bromobiphenyl obtained from S3 and 252.2 g of DMF solvent, stir evenly, cool to 0℃, control the temperature to be constant, and add 26.4 g of potassium amino. After the addition is complete, stir for 30 minutes, then slowly raise the temperature to 80-85℃ and keep it at the temperature for 4 hours. After the reaction is completed, drop the reaction solution into ice water, extract to separate the layers, dry the organic phase, and remove the solvent by vacuum distillation to obtain 4-methoxy-3-aminobiphenyl.
[0059] Example 3
[0060] S1. Add 50g of 4-methoxyaniline to a 500ml three-necked flask, followed by 118.42g of hydrochloric acid. After dissolving and clearing the solution, cool the system to 0 degrees Celsius and slowly add 36.4g of sodium nitrite. Keep the reaction at this temperature for 3 hours to obtain a reaction solution containing 4-methoxybenzene.
[0061] S2. Add 170g benzene and 172.14g sodium carbonate to the reaction solution obtained in S1, control the reaction temperature to 5℃, and keep the temperature for 3h. After the reaction is completed, add water, stir evenly, let stand for layering, remove the organic layer, remove the solvent by vacuum distillation, and obtain 4-methoxybiphenyl.
[0062] S3. Add 72g of 4-methoxybiphenyl obtained from S2, 792.3g of chloroform solvent, and 68.4g of thioyl chloride to a 1000ml three-necked flask in sequence. Lower the temperature to 0℃ and keep it at this temperature for 3h for halogenation reaction. After the reaction is completed, remove the solvent by vacuum distillation to obtain 4-methoxy-3-chlorobiphenyl.
[0063] S4. Take 1000 ml of a dry reaction flask, add 50 g of 4-methoxy-3-chlorobiphenyl obtained from S3 and 319.4 g of solvent DMF in sequence, stir evenly, cool down to 0℃, control the temperature to be constant, and add 34.56 g of aminocalcium; after the addition is complete, stir for 30 minutes, then slowly raise the temperature to 80-85℃ and keep it at the temperature for 4 hours; after the reaction is completed, drop the reaction solution into ice water, extract to separate the layers, dry the organic phase, remove the solvent by vacuum distillation, and obtain 4-methoxy-3-aminobiphenyl.
[0064] Example 4
[0065] The difference between Example 4 and Example 1 is that the mass of sodium nitrite used in S1 in Example 4 is 30.8g.
[0066] Example 5
[0067] The difference between Example 5 and Example 1 is that the mass of sodium nitrite used in S1 in Example 5 is 42g.
[0068] Example 6
[0069] The difference between Example 6 and Example 1 is that the mass of sodium nitrite used in S1 in Example 6 is 24g.
[0070] Example 7
[0071] The difference between Example 7 and Example 1 is that the mass of sodium nitrite used in S1 in Example 7 is 48g.
[0072] Example 8
[0073] The difference between Example 8 and Example 1 is that the mass of benzene used in S2 in Example 8 is 126.7g.
[0074] Example 9
[0075] The difference between Example 9 and Example 1 is that the mass of benzene used in S2 in Example 9 is 190g.
[0076] Example 10
[0077] The difference between Example 10 and Example 1 is that the mass of benzene used in S2 in Example 10 is 95g.
[0078] Example 11
[0079] The difference between Example 11 and Example 1 is that the mass of benzene used in S2 in Example 11 is 222g.
[0080] Example 12
[0081] The difference between Example 12 and Example 1 is that the reaction temperature in Example 12 is 0°C and the reaction time is 5h in S2.
[0082] Example 13
[0083] The difference between Example 13 and Example 1 is that the reaction temperature in Example 13 is 10°C and the reaction time is 1 hour in S2.
[0084] Example 14
[0085] The difference between Example 14 and Example 1 is that the mass of the halogenated reagent N-chlorosuccinimide used in S3 in Example 14 is 54.9g.
[0086] Example 15
[0087] The difference between Example 15 and Example 1 is that the mass of the halogenated reagent N-chlorosuccinimide used in S3 in Example 15 is 78g.
[0088] Example 16
[0089] The difference between Example 16 and Example 1 is that the mass of the halogenated reagent N-chlorosuccinimide used in S3 in Example 16 is 26g.
[0090] Example 17
[0091] The difference between Example 17 and Example 1 is that the mass of the halogenated reagent N-chlorosuccinimide used in S3 in Example 17 is 88.5g.
[0092] Example 18
[0093] The difference between Example 18 and Example 1 is that the halogenation reaction temperature used in Example 18 in S3 is 10°C and the reaction time is 5h.
[0094] Example 19
[0095] The difference between Example 19 and Example 1 is that the halogenation reaction temperature used in Example 19 in S3 is 20°C and the reaction time is 1 hour.
[0096] Example 20
[0097] The difference between Example 20 and Example 1 is that the mass of sodium amide used in S4 of Example 20 is 9g.
[0098] Example 21
[0099] The difference between Example 21 and Example 1 is that the mass of sodium amide used in S4 in Example 21 is 26.9g.
[0100] Example 22
[0101] The difference between Example 22 and Example 1 is that the mass of sodium amide used in S4 in Example 22 is 4.5g.
[0102] Example 23
[0103] The difference between Example 23 and Example 1 is that the mass of sodium amide used in S4 in Example 23 is 31.4g.
[0104] Example 24
[0105] The difference between Example 24 and Example 1 is that the amination reaction temperature in Example 24 is 70-75°C and the reaction time is 6 hours.
[0106] Example 25
[0107] The difference between Example 25 and Example 1 is that the amination reaction temperature used in S4 of Example 25 is 90-95°C and the reaction time is 2h.
[0108] Performance testing
[0109] 1. The mass of the product 4-methoxybiphenyl obtained in S2 in Examples 1-13 was measured, and its purity was tested by gas chromatography. The results are shown in Table 1.
[0110] 2. The mass of the product 4-methoxy-3-halobiphenyl obtained in S3 in Examples 1-3 and Examples 14-19 was measured, and its purity was tested by gas chromatography. The results are shown in Table 2.
[0111] 3. The mass of the product 4-methoxy-3-aminobiphenyl obtained in S4 in Examples 1-3 and Examples 20-25 was measured, and its purity was tested by gas chromatography. The results are shown in Table 3.
[0112] The specific test results are as follows:
[0113] Table 1 shows the quality and purity of the product obtained in step S2.
[0114]
[0115]
[0116] As can be seen from the test results in Table 1, when the content of sodium nitrite, a reactant raw material in S1, increases, the mass of the product 4-methoxybiphenyl shows a trend of first increasing and then decreasing. Therefore, the preferred molar ratio between 4-methoxyaniline and sodium nitrite is 1:(1.1-1.5), and at this time, the purity of the product 4-methoxybiphenyl can also reach more than 96%.
[0117] When the content of benzene, a reactant in S2, increases, the mass of the product 4-methoxybiphenyl also shows a trend of first increasing and then decreasing. Therefore, the preferred molar ratio between 4-methoxyaniline and benzene is 1:(4-6), and at this time the purity of the product 4-methoxybiphenyl can also reach more than 96%.
[0118] When the reaction temperature in S2 is 0-10℃ and the reaction time is 1-5h, it is beneficial to improve the quality and purity of the product 4-methoxybiphenyl.
[0119] Table 2 shows the quality and purity of the product obtained in step S3.
[0120] Detection object Mass of product obtained from S3 / g Purity of the product obtained from S3 / % Example 1 84.4 98.2 Example 2 82.1 97.8 Example 3 83.8 97.5 Example 14 80.7 98.1 Example 15 79.8 97.9 Example 16 66.1 88.9 Example 17 70.5 89.2 Example 18 79.7 96.9 Example 19 81.1 97.2
[0121] As can be seen from the test results in Table 2, when the content of the halogenated reagent in S3 increases, the mass of the product 4-methoxy-3-halobiphenyl shows a trend of first increasing and then decreasing. Therefore, the preferred molar ratio between 4-methoxybiphenyl and the halogenated reagent is 1:(1-1.5), and at this time the purity of the product 4-methoxy-3-halobiphenyl can also reach more than 96%.
[0122] When the halogenation reaction temperature in S3 is 0-20℃ and the reaction time is 2-5h, it is beneficial to improve the quality and purity of the product 4-methoxy-3-halobiphenyl.
[0123] Table 3 shows the quality and purity of the product obtained in step S4.
[0124]
[0125]
[0126] As can be seen from the test results in Table 2, when the content of the metal amine in the reactant raw material S4 increases, the mass of the product 4-methoxy-3-aminobiphenyl shows a trend of first increasing and then decreasing. Therefore, the preferred molar ratio between 4-methoxy-3-halobiphenyl and the metal amine is 1:(1-3), and at this time the purity of the product 4-methoxy-3-aminobiphenyl can also reach more than 96%.
[0127] When the halogenation reaction in S4 is carried out at a temperature of 70-95℃ and for a reaction time of 2-6h, it is beneficial to improve the quality and purity of the product 4-methoxy-3-aminobiphenyl.
[0128] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.
Claims
1. A method for synthesizing a biphenylhydrazine ester intermediate, characterized in that: Includes the following steps: S1. Add 4-methoxyaniline to hydrochloric acid, dissolve and clear the solution, cool the system to 0 degrees, slowly add sodium nitrite, and keep the system warm to carry out the reaction, to obtain a reaction solution containing 4-methoxyaniline. S2. Add benzene and sodium carbonate to the reaction solution obtained in S1, control the reaction temperature, and keep the reaction at the temperature. After the reaction is completed, add water, stir evenly, let stand to separate the layers, remove the organic layer, remove the solvent by vacuum distillation, and obtain 4-methoxybiphenyl. S3. The 4-methoxybiphenyl obtained in S2 is added to solvent A, a halogenation reagent is added, the temperature is lowered, and the reaction is carried out at this temperature. After the reaction is completed, the solvent is removed by vacuum distillation to obtain 4-methoxy-3-halobiphenyl. S4. Add 4-methoxy-3-halobiphenyl to solvent B, stir until homogeneous, cool to 0°C, maintain constant temperature, and add metal amine. After addition, stir until homogeneous, then slowly heat and maintain the temperature for amination reaction. After the reaction is complete, drop the reaction solution into ice water, extract to separate the layers, dry the organic phase, and remove the solvent by vacuum distillation to obtain 4-methoxy-3-aminobiphenyl. The synthesis route is as follows: Wherein, X is one of F, Cl, Br, and I; The halogenated reagent is one of X2, hypohalite MXO, N-halosuccinimide NXS, dihalohein DXDMH, and thioyl halide SO2X2; wherein X is one of F, Cl, Br, and I; and M is an alkali metal or alkaline earth metal. The metal amide is one of NaNH2, KNH2, LiNH2, and Ca(NH2)2.
2. The method for synthesizing a biphenylhydrazine ester intermediate according to claim 1, characterized in that: The molar ratio of the reactants 4-methoxyaniline, hydrochloric acid, sodium nitrite, benzene and sodium carbonate is 1:(2-8):(1-1.5):(4-6):(2-4).
3. The method for synthesizing a biphenylhydrazine ester intermediate according to claim 1, characterized in that: The heat preservation reaction time described in S1 is 1-3 hours.
4. The method for synthesizing a biphenylhydrazine ester intermediate according to claim 1, characterized in that: The reaction temperature described in S2 is 0-10℃, and the reaction time is 1-5h.
5. The method for synthesizing a biphenylhydrazine ester intermediate according to claim 1, characterized in that: The molar ratio of reactant 4-methoxybiphenyl, solvent A, and halogenated reagent in S3 is 1:(15-17):(1-1.5).
6. The method for synthesizing a biphenylhydrazine ester intermediate according to claim 1, characterized in that: The halogenation reaction described in S3 is carried out at a temperature of 0-20℃ for a time of 2-5 hours.
7. The method for synthesizing a biphenylhydrazine ester intermediate according to claim 1, characterized in that: The molar ratio of reactant 4-methoxy-3-halobiphenyl, solvent B, and metal amine in S4 is 1:(15-19):(1-3).
8. The method for synthesizing a biphenylhydrazine ester intermediate according to claim 1, characterized in that: The amination reaction described in S4 is carried out at a temperature of 70-95℃ for a reaction time of 2-6 hours.