Process for the preparation of a diphenylhydrazine intermediate

Abstract

The present application relates to the field of miticides, and relates to a preparation method of bifenazate intermediate, comprising: (1) in the presence of a first solvent, a compound shown in formula (II) (referred to as formula (II)) and concentrated nitric acid are subjected to a first reaction to obtain formula (III); (2) in the presence of a second solvent, formula (III) and sodium methoxide are subjected to a second reaction to obtain formula (IV); (3) in the presence of a third solvent, formula (IV) and hydrogen are subjected to a third reaction in the presence of a first catalyst to obtain formula (V); (4) in the presence of a fourth solvent, formula (V), diazotization reagent and benzene are subjected to a fourth reaction in the presence of a second catalyst to obtain formula (VI); (5) formula (VI) and sodium hypochlorite are subjected to a fifth reaction in the presence of a third catalyst to obtain the bifenazate intermediate shown in formula (I).

Description

Technical Field

[0001] This invention relates to the field of acaricides, and more specifically to a method for preparing a biphenylhydrazine intermediate. Background Technology

[0002] Biphenylhydrazine (chemical name: 3-(4-methoxybiphenyl-3-yl)hydrazinocarbamate isopropyl ester) is a novel acaricide developed by UniRoyal Chemical Company (Compton Group). It primarily acts on the γ-aminobutyric acid (GABA) receptors in the central nervous system of mites, is effective at all life stages of mites, is non-systemic, and possesses ovicidal activity and knockdown activity against adult mites (48-72 hours). It has a long residual effect and is effective against phytophagous mites such as spider mites and pseudococcus mites, exhibiting contact action. It shows no cross-resistance with existing commercial acaricides and can be used to control two-spotted spider mites and pseudococcus mites on crops such as apples, peaches, grapes, stone fruits, strawberries, and hops. It is harmless to beneficial mites and insects. It has low toxicity, is environmentally friendly, and is well-suited for integrated insect management, exhibiting excellent control effects.

[0003] 2-Amino-4-phenylanisole is an important fine chemical intermediate for the synthesis of the acaricide biphenylhydrazine. The current synthesis route mainly uses 4-hydroxybiphenyl as a raw material through nitration, alkylation, and hydrogenation reduction. However, 4-hydroxybiphenyl is expensive, the production process is difficult, and it generates a lot of waste and has a low yield, which cannot meet the current production needs.

[0004] US4467123 and CN1093111A disclose a method for synthesizing 4-hydroxybiphenyl, which involves alkaline pressurized hydrolysis of biphenyl-4-sulfonic acid with excess alkali metal hydroxide at 310-330℃ and 1-4 MPa to obtain 4-phenylphenol salt, followed by acidification with excess dilute sulfuric acid solution to obtain 4-hydroxybiphenyl. However, this process involves extremely harsh reaction conditions such as high temperature and high pressure, which can easily lead to explosion hazards and generate a large amount of waste acid water, resulting in huge wastewater treatment costs. The obtained product also has a high moisture content and is difficult to dry, making it unsuitable for industrial production.

[0005] Therefore, a new method for preparing biphenylhydrazine ester intermediates is urgently needed. Summary of the Invention

[0006] The purpose of this invention is to overcome the problems of harsh reaction conditions, low reaction yield and purity, high production cost, and huge amount of waste in the existing preparation of biphenylhydrazine intermediates (i.e., 2-amino-4-phenylanisole), and to provide a method for preparing biphenylhydrazine intermediates.

[0007] To achieve the above objectives, the present invention provides a method for preparing a biphenylhydrazine ester intermediate, the method comprising the following steps:

[0008] (1) In the presence of a first solvent, the compound shown in formula (II) is reacted with concentrated nitric acid to obtain the compound shown in formula (III).

[0009]

[0010] (2) In the presence of a second solvent, the compound shown in formula (III) is reacted with sodium methoxide to give the compound shown in formula (IV).

[0011]

[0012] (3) In the presence of a third solvent, the compound shown in formula (IV) and hydrogen gas are subjected to a third reaction in the presence of a first catalyst to obtain the compound shown in formula (V).

[0013]

[0014] (4) In the presence of a fourth solvent, the compound shown in formula (V), the diazotizing agent, and benzene are subjected to a fourth reaction in the presence of a second catalyst to obtain the compound shown in formula (VI).

[0015]

[0016] (5) The compound shown in formula (VI) and sodium hypochlorite were reacted in the presence of a third catalyst to obtain the biphenylhydrazine ester intermediate shown in formula (I).

[0017]

[0018] Compared with existing technologies, this invention provides a novel method for preparing biphenylhydrazine ester intermediates (i.e., 2-amino-4-phenylanisole). This method uses the compound shown in formula (II) as the starting material and cleverly designs steps (1)-(5) to ultimately obtain the target product, i.e., the compound shown in formula (I). This method avoids the drawbacks of safety hazards, harsh process conditions, complex process flow, and high waste volume. It has the advantages of mild reaction conditions, high reaction yield and purity, and low cost, making it suitable for industrial production. Furthermore, the method provided by this invention yields biphenylhydrazine ester intermediates with a purity of over 98 wt% and a total yield as high as 80.45%. Detailed Implementation

[0019] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0020] In this invention, unless otherwise specified, the terms "first," "second," "third," "fourth," and "fifth" do not indicate a sequential order, nor do they limit the specific materials or steps; they are merely used to distinguish between different steps or materials. For example, in "first reaction," "second reaction," "third reaction," "fourth reaction," and "fifth reaction," "first," "second," "third," "fourth," and "fifth" are used only to indicate that these are not the same reaction; similarly, in "first solvent," "second solvent," "third solvent," and "fourth solvent," "first," "second," "third," and "fourth" are used only to indicate that these are not the same solvent.

[0021] This invention provides a method for preparing a biphenylhydrazine ester intermediate, the method comprising the following steps:

[0022] (1) In the presence of a first solvent, the compound shown in formula (II) is reacted with concentrated nitric acid to obtain the compound shown in formula (III).

[0023]

[0024] (2) In the presence of a second solvent, the compound shown in formula (III) is reacted with sodium methoxide to give the compound shown in formula (IV).

[0025]

[0026] (3) In the presence of a third solvent, the compound shown in formula (IV) and hydrogen gas are subjected to a third reaction in the presence of a first catalyst to obtain the compound shown in formula (V).

[0027]

[0028] (4) In the presence of a fourth solvent, the compound shown in formula (V), the diazotizing agent, and benzene are subjected to a fourth reaction in the presence of a second catalyst to obtain the compound shown in formula (VI).

[0029]

[0030] (5) The compound shown in formula (VI) and sodium hypochlorite were reacted in the presence of a third catalyst to obtain the biphenylhydrazine ester intermediate shown in formula (I).

[0031]

[0032] In some embodiments of the present invention, in step (1), the molar ratio of the compound represented by formula (II) to concentrated nitric acid is 1:1-1.5, for example, 1:1, 1:1.05, 1:1.06, 1:1.08, 1:1, 1:1.2, 1:1.5, and any value within the range of any two values, preferably 1:1.05-1.1. Using these preferred conditions is more advantageous for converting -H in the compound represented by formula (II) to -NO2 in the compound represented by formula (III), thereby improving the purity and yield of the compound represented by formula (III).

[0033] In this invention, unless otherwise specified, "molar ratio" refers to "feed molar ratio".

[0034] In some embodiments of the present invention, preferably, the conditions for the first reaction include: a reaction temperature of -10°C to 5°C, more preferably -5°C to 0°C; and a reaction time of 0.5-2 h, more preferably 0.5-1 h. Using these preferred conditions is more advantageous for improving the purity and yield of the compound represented by formula (III).

[0035] In some embodiments of the present invention, preferably, the weight ratio of the compound represented by formula (II) to the first solvent is 1:2-5, for example, 1:2, 1:3, 1:3.5, 1:4, 1:5, and any value within the range of any two values, preferably 1:3-4. Using these preferred conditions is more advantageous for improving the purity and yield of the compound represented by formula (III).

[0036] In this invention, unless otherwise specified, "weight ratio" refers to "material input weight ratio".

[0037] In this invention, the type of the first solvent is subject to a wide range of selection, as long as the first reaction is carried out in the presence of the first solvent. Preferably, the first solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetonitrile, and sulfuric acid, with sulfuric acid being the most preferred. Specifically, the dichloroethane is selected from at least one of 1,1-dichloroethane, 1,2-dichloroethane, and 2,2-dichloroethane, with 1,2-dichloroethane being the most preferred.

[0038] In some embodiments of the present invention, preferably, in step (2), the molar ratio of the compound represented by formula (III) to sodium methoxide is 1:1-1.1, for example, 1:1, 1:1.05, 1:1.06, 1:1.08, 1:1, and any value within the range of any two values, preferably 1:1.05-1.1. Using these preferred conditions is more advantageous for converting -Cl in the compound represented by formula (III) to -OCH3 in the compound represented by formula (IV), thereby improving the yield and purity of the compound represented by formula (IV).

[0039] In some embodiments of the present invention, preferably, in step (2), sodium methoxide is present as an alcoholic solution with a concentration of 20-40 wt%, more preferably as a methanolic solution with a concentration of 20-40 wt%, and even more preferably as a methanolic solution with a concentration of 25-35 wt%. This arrangement is intended to improve the yield and purity of the compound represented by formula (IV).

[0040] In some embodiments of the present invention, preferably, the conditions for the second reaction include: a reaction temperature of 10-65°C, more preferably 25-35°C; and a reaction time of 1-2 h, more preferably 1-1.5 h. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (IV).

[0041] In some embodiments of the present invention, preferably, the weight ratio of the compound represented by formula (III) to the second solvent is 1:2-5, for example, 1:2, 1:2.5, 1:3, 1:4, 1:5, and any value within the range of any two values, preferably 1:2-3. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (IV).

[0042] In this invention, a wide range of types of the second solvent can be selected, as long as the second reaction is carried out in the second solvent. Preferably, the second solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, toluene, tetrahydrofuran, and dioxane, with methanol being the most preferred.

[0043] In some embodiments of the present invention, preferably, in step (3), the conditions of the third reaction include: a hydrogen pressure of 1-3 MPa, preferably 1-1.5 MPa; a reaction temperature of 20-100°C, preferably 40-50°C; and a reaction time of 4-8 h, preferably 5-6 h. Using these preferred conditions is more conducive to converting -NO2 in the compound shown in formula (IV) to -NH2 in the compound shown in formula (V), thereby improving the yield and purity of the compound shown in formula (V).

[0044] In some embodiments of the present invention, preferably, the weight ratio of the compound represented by formula (IV) to the third solvent is 1:2-5, for example, 1:2, 1:2.5, 1:3, 1:4, 1:5, and any value within the range of any two values, preferably 1:2-3. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (V).

[0045] In this invention, the type of the third solvent is subject to a wide range of selection, as long as the third reaction is carried out in the third solvent. Preferably, the third solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, toluene, tetrahydrofuran, and dioxane, with methanol being the most preferred.

[0046] In some embodiments of the present invention, preferably, in step (3), the weight ratio of the compound represented by formula (IV) to the first catalyst is 1:0.02-0.05, for example, 1:0.02, 1:0.03, 1:0.035, 1:0.04, 1:0.05, and any value within the range of any two values, preferably 1:0.03-0.04. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (V).

[0047] In some embodiments of the present invention, preferably, the first catalyst is selected from at least one of Raney nickel, palladium on carbon, and platinum on carbon, and preferably Raney nickel.

[0048] In some embodiments of the present invention, preferably, in step (4), the molar ratio of the compound represented by formula (V) to the diazotizing agent is 1:1-1.5, for example, 1:1, 1:1.2, 1:1.24, 1:1.25, 1:1.26, 1:1.3, 1:1.5, and any value within the range of any two values, preferably 1:1.2-1.3. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (VI).

[0049] In some embodiments of the present invention, preferably, the diazotizing agent is selected from at least one of n-butyl nitrite, isobutyl nitrite, tert-butyl nitrite, n-pentyl nitrite, isopentyl nitrite, nitrososulfuric acid, propyl nitrite, isopropyl nitrite, and sodium nitrite, preferably n-butyl nitrite and / or n-pentyl nitrite, more preferably n-pentyl nitrite. Using the preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (VI).

[0050] In some embodiments of the present invention, preferably, in step (4), the molar ratio of the compound represented by formula (V) to benzene is 1:1-1.1, for example, 1:1, 1:1.05, 1:1.06, 1:1.08, 1:1.1, and any value within a range of any two values, preferably 1:1.05-1.1. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (VI).

[0051] In some embodiments of the present invention, preferably, the conditions for the fourth reaction include: a reaction temperature of 20-100°C, more preferably 30-40°C; and a reaction time of 2-4 h, more preferably 3-4 h. Using these preferred conditions is more advantageous for converting -NH2 in the compound represented by formula (V) to phenyl in the compound represented by formula (VI), thereby improving the yield and purity of the compound represented by formula (VI).

[0052] In some embodiments of the present invention, preferably, in step (4), the weight ratio of the compound represented by formula (V) and the second catalyst is 1:0.1-0.2, for example, 1:0.1, 1:0.12, 1:0.14, 1:0.16, 1:0.18, 1:0.2, and any value within the range of any two values, preferably 1:0.12-0.16. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (VI).

[0053] In some embodiments of the present invention, preferably, the second catalyst is selected from at least one of copper powder, iron powder, dicyclopentadiene iron, 1,1'-bis(diphenylphosphine)ferrocene, 1,1'-bis(diisopropylphosphine)ferrocene, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [(1,1'-bis(diphenylphosphine)ferrocene]nickel dichloride, [1,1′-bis(diphenylphosphine)ferrocene]cobalt dichloride, 1,3-bis(diphenylphosphinepropane)nickel dichloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, ferric chloride, and trichloroacetic acid, more preferably selected from at least one of copper powder, dicyclopentadiene iron, and trichloroacetic acid, more preferably dicyclopentadiene iron and / or trichloroacetic acid, and most preferably dicyclopentadiene iron and trichloroacetic acid. Using the preferred conditions is more conducive to improving the yield and purity of the compound shown in formula (VI).

[0054] In some embodiments of the present invention, preferably, in step (4), the weight ratio of the compound represented by formula (V) to the fourth solvent is 1:2-5, for example, 1:2, 1:3, 1:3.5, 1:4, 1:5, and any value in the range of any two values, preferably 1:3-4.

[0055] In this invention, a wide range of types of the fourth solvent can be selected, as long as the fourth reaction is carried out in the fourth solvent. Preferably, the fourth solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, tetraoxane, toluene, and benzene, with benzene being the most preferred. This arrangement aims to improve the yield and purity of the compound represented by formula (VI).

[0056] In some embodiments of the present invention, preferably, in step (5), the molar ratio of the compound represented by formula (VI) to sodium hypochlorite is 1:1-1.3, for example, 1:1, 1:1.15, 1:1.2, 1:1.25, 1:3, and any value within the range of any two values, preferably 1:1.1-1.2. Using these preferred conditions is more advantageous for converting -CN in the compound represented by formula (VI) to -NH2 in the compound represented by formula (I), thereby improving the yield and purity of the compound represented by formula (I).

[0057] In some embodiments of the present invention, preferably, the compound represented by formula (VI) is present in an aqueous solution with a concentration of 20-30 wt%, and sodium hypochlorite is present in an aqueous solution with a concentration of 8-12 wt%. This arrangement is intended to improve the yield and purity of the compound represented by formula (I).

[0058] In some embodiments of the present invention, preferably, the conditions for the fifth reaction include: a reaction temperature of -10°C to 100°C, more preferably -5°C to 95°C; and a reaction time of 4-8 hours, more preferably 5-7 hours. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (I).

[0059] In a preferred embodiment of the present invention, the process of the fifth reaction includes:

[0060] i. The compound shown in formula (VI) and a portion of sodium hypochlorite are subjected to an initial reaction to obtain the initial reaction product;

[0061] ii. The initial reaction product and the remaining sodium hypochlorite are reacted again to obtain the compound shown in formula (I). This arrangement is more conducive to improving the purity and yield of the compound shown in formula (I).

[0062] In some embodiments of the present invention, preferably, the molar ratio of the partial sodium hypochlorite to the remaining sodium hypochlorite is 1:1-2, for example, 1:1, 1:1.2, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2, and any value within any range of two such values, preferably 1:1.4-1.6. In the present invention, the sum of the moles of the partial sodium hypochlorite and the remaining sodium hypochlorite is equal to the mole of sodium hypochlorite.

[0063] In some embodiments of the present invention, preferably, the initial reaction conditions include: a reaction temperature of -10°C to 10°C, more preferably -5°C to 5°C; and a reaction time of 1-4 hours, more preferably 2-3 hours.

[0064] In some embodiments of the present invention, preferably, the conditions for the re-reaction include: a reaction temperature of 80-100°C, preferably 85-95°C; and a reaction time of 1-4 hours, preferably 3-4 hours.

[0065] In some embodiments of the present invention, preferably, in step (5), the weight ratio of the compound represented by formula (VI) to the third catalyst is 1:0.02-0.08, for example, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.055, 1:0.06, 1:0.08, and any value within the range of any two values, preferably 1:0.05-0.06. Using these preferred conditions is more conducive to improving the yield and purity of the compound represented by formula (I).

[0066] In some embodiments of the present invention, preferably, the third catalyst is selected from at least one of sodium tungstate, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltriethylammonium chloride, 18-crown ether, 15-crown ether, and polyethylene glycol, and preferably sodium tungstate. Using preferred conditions is more advantageous for improving the yield and purity of the compound represented by formula (I).

[0067] According to a particularly preferred embodiment of the present invention, a method for preparing a biphenylhydrazine ester intermediate includes the following steps:

[0068] (1) In the presence of a first solvent, the compound shown in formula (II) is reacted with concentrated nitric acid to obtain the compound shown in formula (III).

[0069]

[0070] (2) In the presence of a second solvent, the compound shown in formula (III) is reacted with sodium methoxide to give the compound shown in formula (IV).

[0071]

[0072] (3) In the presence of a third solvent, the compound shown in formula (IV) and hydrogen gas are subjected to a third reaction in the presence of a first catalyst to obtain the compound shown in formula (V).

[0073]

[0074] (4) In the presence of a fourth solvent, the compound shown in formula (V), the diazotizing agent, and benzene are subjected to a fourth reaction in the presence of a second catalyst to obtain the compound shown in formula (VI).

[0075]

[0076] (5) The compound shown in formula (VI) and sodium hypochlorite were reacted in the presence of a third catalyst to obtain the biphenylhydrazine ester intermediate shown in formula (I).

[0077]

[0078] In step (4), the molar ratio of the compound shown in formula (V), the diazotizing agent, and benzene is 1:1.2-1.3:1.05-1.1; the diazotizing agent is selected from n-butyl nitrite and / or n-pentyl nitrite; the fourth solvent is selected from benzene.

[0079] The present invention will be described in detail below through embodiments.

[0080] Example 1

[0081] (1) In a 500 mL four-necked flask equipped with a condenser, thermometer and mechanical stirrer, add 68.78 g (0.5 mol) of the compound shown in formula (II) and 275.12 g (4 eq) of sulfuric acid. After stirring to dissolve, cool to -5℃ to 0℃ and slowly add 33.4 g (0.53 mol) of concentrated nitric acid. After the addition is complete, keep the reaction at the temperature for 0.5-1 h. Take a sample for analysis. After the reaction is complete, after post-processing, the compound shown in formula (III) is obtained, namely, 4-chloro-3-cyanonitrobenzene, with a purity of 99.13 wt% and a yield of 98.52% (based on the compound shown in formula (II)).

[0082] (2) In a 500 mL four-necked flask equipped with a condenser, thermometer and mechanical stirrer, add 91.28 g (0.5 mol) of the compound shown in formula (III) above and 273.84 g (3 eq) of methanol. After stirring to dissolve, cool to 25-35 °C and slowly add 95.44 g (0.53 mol) of a 30 wt% methanol solution of sodium methoxide. After the addition is complete, keep the reaction at the temperature for 1-1.5 h. Take a sample for analysis. After the reaction is complete, after post-processing, the compound shown in formula (IV) is obtained, namely, 2-cyano-4-nitrobenzene ether, with a purity of 98.56 wt% and a yield of 97.64% (based on the compound shown in formula (III)).

[0083] (3) In a 500 mL autoclave, add 89.07 g (0.5 mol) of the compound shown in formula (IV), 267.21 g (3 eq) of methanol and 3.56 g (0.04 eq) of Raney nickel catalyst, seal and pressurize with hydrogen to 1-1.5 MPa, slowly heat to 40-50 °C, keep the reaction at this temperature for 5-6 h, take a sample for analysis, and after the reaction is completed, after post-processing, obtain the compound shown in formula (V), namely, 2-cyano-4-aminoanisole, with a purity of 99.49 wt% and a yield of 97.16% (based on the compound shown in formula (IV));

[0084] (4) In a 500 mL four-necked flask equipped with a condenser, thermometer and mechanical stirrer, add 74.08 g (0.5 mol) of the compound shown in formula (V) above, 296.32 g (4 eq) of benzene, 5.18 g (0.07 eq) of iron dicyclopentadiene catalyst and 5.18 g (0.07 eq) of trichloroacetic acid catalyst, stir to dissolve and heat to 30-40 °C, slowly add 76.15 g (0.65 mol) of n-amyl nitrite and 41.4 g (0.53 mol) of benzene, keep the reaction at the temperature for 3-4 h after the addition is complete, take a sample for analysis, and after the reaction is completed, after post-processing, obtain the compound shown in formula (VI), namely, 2-cyano-4-phenylanisole, with a purity of 94.56 wt% and a yield of 91.81% (based on the compound shown in formula (V)).

[0085] (5) In a 1000 mL four-necked flask equipped with a condenser, thermometer, and mechanical stirrer, add 104.62 g (0.5 mol) of the compound shown in formula (VI) above and 244.11 g of water to prepare a 30 wt% aqueous solution. Add 6.28 g (0.06 eq) of sodium tungstate catalyst, stir and cool to -5°C to 5°C, then add 178.65 g (0.24 mol) of a 10 wt% sodium hypochlorite aqueous solution dropwise. After the addition is complete, maintain the temperature for 2- After 3 hours, samples were taken for analysis. If the reaction was complete, the reaction solution was added to the remaining 267.98 g (0.36 mol) of 10 wt% sodium hypochlorite aqueous solution. The temperature was slowly raised to 85-95 °C and kept at this temperature for 3-4 hours. Samples were taken for analysis. After the reaction was complete, the compound shown in formula (I), namely 2-amino-4-phenylanisole, was obtained after post-processing. The purity was 99.73 wt% and the yield was 93.76% (based on the compound shown in formula (VI)).

[0086] The overall yield of the above steps (1)-(5) was 80.45%.

[0087] Example 2

[0088] The method is the same as in Example 1, except that in step (4),

[0089] Replacing 76.15 g (0.65 mol) of n-amyl nitrite with 67.03 g (0.65 mol) of n-butyl nitrite, under the same conditions, yielded the compound shown in formula (VI), namely, 2-cyano-4-phenylanisole, with a purity of 93.18 wt% and a yield of 88.24% (based on the compound shown in formula (V)).

[0090] The remaining steps are the same, and the overall yield of the reaction in steps (1)-(5) above is 77.33%.

[0091] Example 3

[0092] The method is the same as in Example 1, except that in step (4),

[0093] Replacing 5.18 g (0.07 eq) of dicyclopentadiene iron catalyst and 5.18 g (0.07 eq) of trichloroacetic acid catalyst with 3.7 g (0.05 eq) of dicyclopentadiene iron catalyst and 3.7 g (0.05 eq) of trichloroacetic acid catalyst under the same conditions, the compound shown in formula (VI), namely 2-cyano-4-phenylanisole, was obtained with a purity of 92.19 wt% and a yield of 87.06% (based on the compound shown in formula (V)).

[0094] The remaining steps are the same, and the overall yield of the reaction in steps (1)-(5) above is 76.29%.

[0095] Example 4

[0096] The method is the same as in Example 1, except that in step (4),

[0097] Replacing 5.18 g (0.07 eq) of dicyclopentadiene iron catalyst and 5.18 g (0.07 eq) of trichloroacetic acid catalyst with 3.7 g (0.05 eq) of dicyclopentadiene iron catalyst and 3.7 g (0.05 eq) of trichloroacetic acid catalyst; replacing 76.15 g (0.65 mol) of n-amyl nitrite with 67.03 g (0.65 mol) of n-butyl nitrite, under the same conditions, yielded the compound shown in formula (VI), namely, 2-cyano-4-phenylanisole, with a purity of 92.09 wt% and a yield of 85.46% (based on the compound shown in formula (V));

[0098] The remaining steps are the same, and the overall yield of the reaction in steps (1)-(5) above is 74.89%.

[0099] Example 5

[0100] The method is the same as in Example 1, except that in step (1),

[0101] Replacing 33.4 g (0.53 mol) of concentrated nitric acid with 31.51 g (0.5 mol) of concentrated nitric acid, with the other conditions remaining the same, yielded the compound shown in formula (III), namely, 4-chloro-3-cyanonitrobenzene, with a purity of 97.73 wt% and a yield of 96.21% (based on the compound shown in formula (II)).

[0102] The remaining steps are the same, and the overall yield of the reaction in steps (1)-(5) above is 78.57%.

[0103] Example 6

[0104] The method is the same as in Example 1, except that in step (2),

[0105] 95.44 g (0.53 mol) of 30 wt% sodium methoxide solution was replaced with 0.53 mol of sodium methoxide solid powder (solid powder is easily decomposed by absorbing water when exposed to air), and the other conditions were the same, to obtain the compound shown in formula (IV), namely, 2-cyano-4-nitrobenzene ether, with a purity of 93.29 wt% and a yield of 89.57% (based on the compound shown in formula (III));

[0106] The remaining steps are the same, and the overall yield of the reaction in steps (1)-(5) above is 73.80%.

[0107] Example 7

[0108] The method is the same as in Example 1, except that in step (3),

[0109] After sealing, the hydrogen pressure was adjusted to 1-3 MPa, and the other conditions were the same, to obtain the compound shown in formula (V), namely, 2-cyano-4-aminoanisole, with a purity of 95.37 wt% and a yield of 90.56% (based on the compound shown in formula (III)).

[0110] The remaining steps are the same, and the overall yield of the reaction in steps (1)-(5) above is 74.99%.

[0111] Example 8

[0112] The method is the same as in Example 1, except that in step (5),

[0113] 446.63 g (0.6 mol) of a 10 wt% sodium hypochlorite aqueous solution was added at once, and the temperature was slowly raised to 85-95 °C. The reaction was maintained at this temperature for 5-7 h, and the other conditions were the same, to obtain the compound shown in formula (I), namely, 2-cyano-4-aminoanisole, with a purity of 70.64 wt% and a yield of 61.73% (based on the compound shown in formula (VI)).

[0114] The remaining steps are the same, and the overall yield of the reaction in steps (1)-(5) above is 52.97%.

[0115] Compared to Example 2, Example 1 used a scheme where the type of diazotizing reagent was within the preferred protection range, resulting in a compound of formula (VI) with high yield and high purity, thereby improving the overall yield of the reaction.

[0116] Compared to Example 3, Example 1 uses a scheme where the weight ratio of the compound shown in Formula (V) and the second catalyst is within the preferred protection range, resulting in the compound shown in Formula (VI) with high yield and high purity, thereby improving the overall yield of the reaction.

[0117] Compared to Example 4, Example 1 uses a diazotizing agent of a specific type and a preferred weight ratio of the compound shown in Formula (V) and the second catalyst within the range of protection to obtain the compound shown in Formula (VI) with high yield and high purity, thereby improving the overall yield of the reaction.

[0118] Compared to Example 5, Example 1 uses a scheme where the molar ratio of the compound shown in Formula (II) and concentrated nitric acid is within the preferred protection range, resulting in the compound shown in Formula (III) with high yield and high purity, thereby improving the overall yield of the reaction.

[0119] Compared to Example 6, Example 1 used a specific concentration of sodium methoxide solution to obtain the compound shown in formula (IV) with high yield and high purity, thereby improving the overall yield of the reaction.

[0120] Compared to Example 7, Example 1 uses a scheme where the hydrogen pressure in the third reaction is within the preferred protection range, resulting in a compound with high yield and high purity as shown in formula (V), thereby improving the overall yield of the reaction.

[0121] Compared to Example 8, Example 1 uses a scheme with the fifth reaction within the preferred protection range to obtain the compound shown in formula (I) with high yield and high purity, thereby improving the overall yield of the reaction.

[0122] Comparative Example 1

[0123] The compound shown in formula (I) was prepared according to the following process route:

[0124]

[0125] 1) Preparative formula (2) compound

[0126] Add 384.38g (1.5mol) of formula (1) and 857.07g (15mol) of 70wt% sodium hydroxide solution to a 5L high-pressure reactor. Slowly raise the temperature to 300-320℃ and pressurize to 2-2.5MPa. After holding the reaction at this temperature for 8-10h, lower the temperature to 90-100℃ and slowly add 1000g of water for dilution. Then add the solution dropwise to a 5L reactor containing 1470g (7.5mol) of 50wt% sulfuric acid. After acidification, the product is post-processed to obtain the compound of formula (2), namely, 4-hydroxybiphenyl, with a purity of 98.57wt% and a yield of 92.79%.

[0127] 2) Preparative formula (3) compound

[0128] In a 1000 mL four-necked flask equipped with a thermometer, condenser and mechanical stirrer, 170.21 g (1 mol) of the above compound (2) and 380.84 g (4 eq) of toluene were added. The temperature was raised to 20-25 °C, and 101.79 g (1.05 mol) of 65 wt% nitric acid was slowly added dropwise. After the addition was completed, the reaction was kept at the temperature for 0.5-1 h. After the reaction was completed, the sample was analyzed. After post-processing, the compound of formula (3) was obtained, namely, 2-nitro-4-phenylphenol, with a purity of 96.57 wt% and a yield of 95.29%.

[0129] 3) Preparative formula (4) compound

[0130] In a 1000 mL four-necked flask equipped with a thermometer, condenser and mechanical stirrer, 107.60 g (0.5 mol) of compound (3) and 430.4 g (4 eq) of toluene were added. The temperature was raised to 70-75 °C, and 100.9 g (0.8 mol) of dimethyl sulfate and 146.65 g (1.1 mol) of 30 wt% sodium hydroxide solution were slowly added dropwise. After the addition was completed, the reaction was kept at the temperature for 1-2 h. After the reaction was completed, the compound (4), namely 2-nitro-4-phenylanisole, was obtained after post-processing. The purity was 97.89 wt% and the yield was 96.38%.

[0131] 4) Preparation of the compound shown in formula (I)

[0132] In a 1000 mL autoclave, 114.62 g (0.5 mol) of compound (4), 458.48 g (4 eq) of methanol and 2.29 g (0.02 eq) of Raney nickel were added. Hydrogen gas was introduced to make the internal pressure 2.5-3 MPa. The temperature was slowly raised to 60-65 °C and kept at that temperature for 5-6 h. After the reaction was completed, the compound shown in formula (I) was obtained after post-processing, namely, 2-amino-4-phenylanisole, with a purity of 95.67 wt% and a yield of 94.98%.

[0133] The overall yield of steps 1)-4) was 80.94%.

[0134] The comparative example 1 has the following problems: a) The preparation of 4-hydroxybiphenyl requires harsh conditions such as high temperature and high pressure, which places high demands on the material of the reaction vessel and makes it expensive; and a large amount of waste acid water will be generated during the post-processing, which greatly increases the production cost; b) The preparation of compound (4) requires the use of highly toxic dimethyl sulfate, which poses a great threat to the environment and operators, and the wastewater containing dimethyl sulfate needs to be treated to be non-toxic before it can be discharged to the wastewater treatment plant, which greatly increases the production cost.

[0135] Compared with Comparative Example 1, the method provided by the present invention, that is, using the compound shown in Formula (II) as the starting material, and finally obtaining the target product through steps (1)-(5), avoids defects such as harsh reaction conditions and high cost. It has advantages such as mild conditions, high reaction yield and purity, low cost, less waste, and less harm to the environment and operators, and is more suitable for industrial production.

[0136] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a diphenylhydrazine intermediate, the method comprising the following steps: (1) performing a first reaction of a compound of formula (II) with concentrated nitric acid in the presence of a first solvent to obtain a compound of formula (III), (2) performing a second reaction of the compound of formula (III) with sodium methoxide in the presence of a second solvent to obtain a compound of formula (IV), (3) performing a third reaction of the compound of formula (IV) with hydrogen in the presence of a third solvent and under the action of a first catalyst to obtain a compound of formula (V), wherein the third reaction is performed under the conditions of a hydrogen pressure of 1-1.5 MPa, a reaction temperature of 40-50 ℃, and a reaction time of 5-6 h, (4) performing a fourth reaction of the compound of formula (V) with a diazotization reagent and benzene in the presence of a fourth solvent and under the action of a second catalyst to obtain a compound of formula (VI), wherein the diazotization reagent is n-pentyl nitrite, the weight ratio of the compound of formula (V) to the second catalyst is 1:0.12-0.16, and the second catalyst is dicyclopentadiene iron and trichloroacetic acid, and (5) performing a fifth reaction of the compound of formula (VI) with sodium hypochlorite in the presence of a third catalyst to obtain the diphenylhydrazine intermediate of formula (I), wherein the fifth reaction comprises: i. performing a preliminary reaction of the compound of formula (VI) with a part of the sodium hypochlorite to obtain a preliminary reaction product; ii. performing a re-reaction of the preliminary reaction product with the remaining part of the sodium hypochlorite to obtain the compound of formula (I), wherein the molar ratio of the part of the sodium hypochlorite to the remaining part of the sodium hypochlorite is 1:1-2, the sodium hypochlorite is in the form of an aqueous solution with a concentration of 8-12 wt%, and the third catalyst is sodium tungstate. In step (1), the molar ratio of the compound of formula (II) to the concentrated nitric acid is 1:1-1.

5. (I), (III); The first reaction is performed under the conditions of a reaction temperature of-10 ℃ to 5 ℃ and a reaction time of 0.5-2 h. (IV); The weight ratio of the compound of formula (II) to the first solvent is 1:2-5. （V）； The first solvent is at least one selected from dichloromethane, dichloroethane, chloroform, acetonitrile, and sulfuric acid. (WE); In step (1), the molar ratio of the compound of formula (II) to the concentrated nitric acid is 1:1.05-1.

1. （I）。 2. The method of claim 1, wherein, The first reaction is performed under the conditions of a reaction temperature of-5 ℃ to 0 ℃ and a reaction time of 0.5-1 h. The weight ratio of the compound of formula (II) to the first solvent is 1:3-4. The first solvent is sulfuric acid. In step (2), the molar ratio of the compound of formula (III) to sodium methoxide is 1:1-1.

1.

3. The method of claim 2, wherein, The sodium methoxide is in the form of an alcoholic solution with a concentration of 20-40 wt%. The second reaction is performed under the conditions of a reaction temperature of 10-65 ℃ and a reaction time of 1-2 h. The weight ratio of the compound of formula (III) to the second solvent is 1:2-5. The second solvent is at least one selected from dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, toluene, tetrahydrofuran, and dioxane.

4. The method of claim 1, wherein, ​ ​ ​ ​ ​ 5. The method of claim 4, wherein, In step (2), the molar ratio of the compound of formula (III) to sodium methoxide is 1:1.05-1.1; The sodium methoxide is in the form of a methanol solution with a concentration of 20-40wt%; The conditions of the second reaction include: the reaction temperature is 25-35℃; and the reaction time is 1-1.5h. The weight ratio of the compound of formula (III) to the second solvent is 1:2-3; The second solvent is methanol.

6. The method of claim 5, wherein, In step (2), the sodium methoxide is in the form of a methanol solution with a concentration of 25-35wt%.

7. The method of claim 1, wherein, In step (3), the weight ratio of the compound of formula (IV) to the third solvent is 1:2-5; The third solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, toluene, tetrahydrofuran and dioxane.

8. The method of claim 7, wherein, In step (3), the weight ratio of the compound of formula (IV) to the third solvent is 1:2-3; The third solvent is methanol.

9. The method of claim 1, wherein, In step (3), the weight ratio of the compound of formula (IV) to the first catalyst is 1:0.02-0.05; The first catalyst is selected from at least one of Raney nickel, palladium on carbon and platinum on carbon.

10. The method of claim 9, wherein, In step (3), the weight ratio of the compound of formula (IV) to the first catalyst is 1:0.03-0.04; The first catalyst is Raney nickel.

11. The method of claim 1, wherein, In step (4), the molar ratio of the compound of formula (V) to the diazotization reagent is 1:1-1.5; The molar ratio of the compound of formula (V) to benzene is 1:1-1.1; The conditions of the fourth reaction include: the reaction temperature is 20-100℃; and the reaction time is 2-4h.

12. The method of claim 11, wherein, In step (4), the molar ratio of the compound of formula (V) to the diazotization reagent is 1:1.2-1.3; The molar ratio of the compound of formula (V) to benzene is 1:1.05-1.1; The conditions of the fourth reaction include: the reaction temperature is 30-40℃; and the reaction time is 3-4h.

13. The method of claim 1, wherein, In step (4), the weight ratio of the compound of formula (V) to the fourth solvent is 1:2-5; The fourth solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, tetraoxane and benzene.

14. The method of claim 13, wherein, In step (4), the weight ratio of the compound of formula (V) to the fourth solvent is 1:3-4; The fourth solvent is benzene.

15. The method of claim 1, wherein, In step (5), the molar ratio of the compound of formula (VI) to sodium hypochlorite is 1:1-1.3; The conditions of the fifth reaction include: the reaction temperature is -10℃ to 100℃; and the reaction time is 4-8h; The molar ratio of the partial sodium hypochlorite to the remaining partial sodium hypochlorite is 1:1.4-1.6; The conditions of the initial reaction include: the reaction temperature is -10℃ to 10℃; and the reaction time is 1-4h; The conditions of the re-reaction include: the reaction temperature is 80-100℃; and the reaction time is 1-4h.

16. The method of claim 15, wherein, In step (5), the molar ratio of the compound of formula (VI) to sodium hypochlorite is 1:1.1-1.2; The conditions of the fifth reaction include: the reaction temperature is -5℃ to 95℃; and the reaction time is 5-7h; The conditions of the first reaction include: the reaction temperature is -5-5℃; the reaction time is 2-3h. The conditions of the second reaction include: the reaction temperature is 85-95℃; the reaction time is 1-4h.

17. The method of claim 1, wherein, In step (5), the weight ratio of the compound of formula (VI) to the third catalyst is 1:0.02-0.

08.

18. The method of claim 17, wherein, In step (5), the weight ratio of the compound of formula (VI) to the third catalyst is 1:0.05-0.06.

Images