Preparation method and control method of 2-[(N-p-chlorphenyl)-3-pyrazoloxymethyl] nitrobenzene isomer

Abstract

The invention discloses a preparation method and a control method of a 2-[(N-p-chlorphenyl)-3-pyrazoloxymethyl] nitrobenzene isomer, determines that the isomer is a compound shown as a formula I in the synthesis process of 2-[(N-p-chlorphenyl)-3-pyrazoloxymethyl] nitrobenzene (a compound shown as a formula II), and determines the structure of the isomer. Meanwhile, the invention provides a preparation method of the compound in the formula I. By controlling conditions in the reaction process, the high-purity compound in the formula I is obtained, the purity of the compound is larger than or equal to 99%, and the compound can be used as a standard substance. By controlling conditions, the generation of the compound shown in the formula I is reduced, and the content of the isomer compound shown in the formula I in the generated 2-[(N-p-chlorphenyl)-3-pyrazoloxymethyl] nitrobenzene is controlled to be 0.2% or below.

Description

Technical Field

[0001] The invention belongs to the field of drug quality control, and specifically relates to a preparation method of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene isomer and a control method thereof. Background Art

[0002] 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene is an important intermediate of the pesticide pyraclostrobin. Pyraclostrobin, also known as pyraclostrobin, is a broad-spectrum fungicide of the methoxyacrylate type with a pyrazole structure discovered by BASF of Germany in 1993. Pyraclostrobin is a mitochondrial respiration inhibitor. It inhibits mitochondrial respiration by blocking the electron transfer between cytochrome b and c1, making the mitochondria unable to produce and provide the energy (ATP) required for normal cell metabolism, and ultimately leading to cell death. It has protective and therapeutic effects, systemic conductivity and resistance to rain erosion, a long lasting effect and a wide range of applications. The structural formula of pyraclostrobin is as follows:

[0003]

[0004] The industrial synthesis route of pyraclostrobin is:

[0005]

[0006] 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene is a key compound in the synthesis of pyraclostrobin, and its purity will directly affect the synthesis yield and product quality of the entire pyraclostrobin.

[0007] The existing industrial production process steps of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene are as follows:

[0008] 1) Add o-nitrotoluene and AIBN to dichloroethane, chlorobenzene or chloroform, raise the temperature to 65-75°C, add 30% hydrogen peroxide and 48% hydrobromic acid dropwise, add dropwise for 1-2 hours, keep warm for 1 hour, cool to room temperature, separate the phases, and obtain an organic phase containing o-nitrobenzyl bromide.

[0009] 2) Using dichloroethane, chlorobenzene or chloroform as the reaction solvent (the same as the reaction solvent for the synthesis of o-nitrobenzyl bromide in the previous step), sodium hydroxide or potassium hydroxide as the acid-binding agent, and tetrabutylammonium bromide as the catalyst, 1-(4-chlorophenyl)-3-pyrazolol and o-nitrobenzyl bromide undergo a substitution reaction at 60-80° C. to generate 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene and hydrobromic acid. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene isomers and a control method thereof, so as to obtain a compound of formula I with higher purity for use as a standard product and reduce the content of the isomer compound of formula I in the generated 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene.

[0011] To achieve the above purpose, the technical solution of the present invention is as follows:

[0012] The inventors of the present invention have found through research that, in the synthesis process of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene, the reaction raw material 1-(4-chlorophenyl)-3-pyrazolol undergoes intramolecular structural transformation, and the enol structure is converted into a keto structure to form a compound of formula III, which further reacts with o-nitrobenzyl bromide to generate a compound of formula I. Experimental research shows that the compound of formula I is an isomer of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene, and the physical and chemical properties of the two are similar. If the content of the compound of formula I is too high, 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene needs to be recrystallized several times to reduce the content of the compound of formula I in 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene to less than 0.5%, resulting in a large amount of waste of raw materials.

[0013] Through research, the structure of the compound of formula I was determined. The structural formula of the compound of formula I is as follows:

[0014]

[0015] The process of converting 1-(4-chlorophenyl)-3-pyrazolol into the compound of formula I:

[0016]

[0017] If the content of the impurity compound of formula I is not effectively controlled during the synthesis process of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene, the compound of formula I will enter the subsequent reaction, resulting in a low yield and low content of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene, affecting the quality of the pyraclostrobin finally produced.

[0018] A method for preparing 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene isomers comprises the following steps:

[0019] 1) adding p-chlorophenylhydrazine hydrochloride to a solvent, adding a base under nitrogen protection and stirring uniformly to obtain a mixed solution, heating the mixed solution to 60-80° C., adding methyl acrylate dropwise to the mixed solution, and keeping the temperature to react for 2-4 hours to obtain a reaction solution containing 1-(4-chlorophenyl)pyrazolidine-3-one; wherein the molar ratio of p-chlorophenylhydrazine hydrochloride, the base and the methyl acrylate is 1:1.5-3.0:1.2-1.5;

[0020] 2) adding water to the reaction solution containing 1-(4-chlorophenyl)pyrazolidine-3-one, quenching, and distilling to remove water and methanol generated by the reaction, then cooling the reaction solution to 60-80° C., adding o-nitrobenzyl bromide dropwise, and keeping the temperature for reaction for 3-5 hours to obtain a reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one; wherein the molar ratio of o-nitrobenzyl bromide to p-chlorophenylhydrazine hydrochloride is 1.1-1.3:1;

[0021] 3) The reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one is cooled to 20-30° C., and air is continuously introduced until the complete conversion is completed. The solvent is recovered under reduced pressure, hot water is added, and the pH value of the system is adjusted to 1-2 with hydrochloric acid. The precipitated white solid is filtered and washed to obtain 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene isomer, whose structural formula is shown in Formula I:

[0022]

[0023] Preferably, the solvent is toluene, DMF or DMSO, preferably DMF.

[0024] Preferably, in step 1), the amount of the solvent is 5 to 10 times the mass of o-nitrotoluene.

[0025] Preferably, in step 1), the base is one or both of sodium methoxide and sodium ethoxide, preferably sodium methoxide.

[0026] The present invention uses a "one-pot method" to prepare the compound of formula I, and the specific reaction route is as follows:

[0027]

[0028] The compound of formula I with a higher purity, ≥99%, is obtained and can be used as a standard product to further help control the isomeric impurities in the actual production process.

[0029] A method for controlling the production of isomers of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene during its production process comprises the following steps:

[0030] 1) Add o-nitrotoluene and AIBN to a solvent and mix well to obtain a mixed solution, heat the mixed solution to 65-75°C, add hydrogen peroxide and hydrobromic acid dropwise to the mixed solution over a period of 1-2 hours, keep the mixture warm for 1-2 hours, cool the reaction solution to room temperature, separate the phases, and obtain an organic phase containing o-nitrobenzyl bromide;

[0031] The molar ratio of o-nitrotoluene, hydrogen peroxide and hydrobromic acid is 1:0.7-0.9:0.6-0.7; the amount of AIBN used is 20-30% of the mass of o-nitrotoluene;

[0032] 2) the obtained organic phase containing o-nitrobenzyl bromide is added dropwise to an alkaline salt solution containing 1-(4-chlorophenyl)-3-pyrazolol, and the reaction is carried out for 2 to 4 hours at a temperature of 20 to 30° C. After the reaction is completed, the mixture is filtered and rinsed to obtain a pure white bromide salt and a filtrate containing 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene; the molar ratio of 1-(4-chlorophenyl)-3-pyrazolol to o-nitrobenzyl bromide is 1:1.03 to 1.1;

[0033] The alkaline salt solution containing 1-(4-chlorophenyl)-3-pyrazolol is prepared by mixing 1-(4-chlorophenyl)-3-pyrazolol, a non-protonic polar solvent and a base, the molar ratio of 1-(4-chlorophenyl)-3-pyrazolol to the base is 1:1.1-1.5, and the amount of the non-protonic polar solvent is 4-10 times the mass of 1-(4-chlorophenyl)-3-pyrazolol;

[0034] 3) distilling the filtrate containing 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene, recovering the obtained solvent for reuse, cooling the material after the distillation to 0-5°C for crystallization, filtering, eluting and drying to obtain 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene.

[0035] Preferably, in step 1), the solvent is chlorobenzene, chloroform or dichloroethane.

[0036] Preferably, the aprotic polar solvent is DMF, DMSO or acetonitrile.

[0037] Preferably, the base is potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.

[0038] The reaction route for preparing 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene (compound of formula II) is as follows:

[0039]

[0040] Therefore, in the synthesis process of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene (compound of formula II), the formation of compound of formula I needs to be strictly controlled.

[0041] The existing industrial production process of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene (compound of formula II) uses dichloroethane, chlorobenzene or chloroform as a reaction solvent (consistent with the reaction solvent of the previous step of synthesizing o-nitrobenzyl bromide), sodium hydroxide, potassium hydroxide, potassium carbonate, etc. as an acid-binding agent, and tetrabutylammonium bromide as a catalyst. 1-(4-chlorophenyl)-3-pyrazolol and o-nitrobenzyl bromide undergo a substitution reaction under a relatively high temperature condition of 60 to 80° C. to generate 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene and hydrobromic acid.

[0042] Traditional technology can cause several problems:

[0043] ① The raw materials contain water and water is generated in the production process system. Under high temperature, o-nitrobenzyl bromide will be hydrolyzed to further generate o-nitrobenzyl alcohol. The generated o-nitrobenzyl alcohol will further react with o-nitrobenzyl bromide to generate ether impurities, resulting in increased raw material consumption;

[0044] ② The reaction system is a three-phase reaction of solid, water and oil, resulting in a slow reaction rate and the need to add an excess of alkali. As the reaction proceeds, the alkali will form a sandwich with the generated bromide salt and 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene, resulting in a long reaction time, high temperature and low yield; solid refers to the alkali added during the reaction, the bromide salt generated as the reaction proceeds, and 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene (2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene has poor solubility in dichloroethane, chlorobenzene or chloroform); water refers to the water generated by the reaction of the alkali with the generated hydrobromic acid; oil refers to the reaction solvent.

[0045] ③ In actual production, the proportion of the isomer compound of formula I in 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene is as high as 4-8%;

[0046] ④ Post-treatment requires adding water to dissolve excess alkali and bromide salts, and then adding a large amount of hydrobromic acid to neutralize them. The wastewater is reddish brown and the COD is as high as 150,000 mg / L or more. The treatment cost is extremely high, and the high-value-added by-product bromide salts are also difficult to recover.

[0047] Hydrolysis and etherification reaction process of o-nitrobenzyl bromide:

[0048]

[0049] The invention dissolves 1-(4-chlorophenyl)-3-pyrazolol in a non-protonic polar solvent, adds a quantitative amount of alkali (sodium hydroxide), reacts 1-(4-chlorophenyl)-3-pyrazolol with sodium hydroxide to generate 1-(4-chlorophenyl)-3-pyrazolol salt, and completely dissolves the salt in the non-protonic polar solvent, completely converts the R-OH structure into the R-ONa or R-OK structure, and thus prevents the intramolecular structural transformation, avoids the generation of the compound of formula III, thereby reducing the generation of the compound of formula I, and controls the content of the isomer compound of formula I in the generated 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene to be less than 0.2%.

[0050] The process of converting 1-(4-chlorophenyl)-3-pyrazolol into the compound of formula I:

[0051]

[0052] Aprotic polar solvents are miscible with water in any proportion and have good solubility in sodium hydroxide. The water generated by the reaction of 1-(4-chlorophenyl)-3-pyrazolol with sodium hydroxide is miscible with aprotic polar solvents, reducing the concentration of water in the system and reducing the hydrolysis of o-nitrobenzyl bromide. At the same time, the study found that the entire reaction process is carried out in the liquid phase (all the reaction raw materials are dissolved in the aprotic polar solvent), and the generated sodium bromide (sodium bromide precipitates in the aprotic polar solvent) has no effect on the reaction, which greatly reduces the reaction temperature. At low temperatures, o-nitrobenzyl bromide is almost not hydrolyzed, and the reaction time is greatly reduced, further improving the reaction yield.

[0053] The prepared 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene is monitored using the prepared high-purity standard of the compound of formula I, and the content of the isomer compound of formula I in the 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene is controlled to be below 0.2%, thereby preventing an excessive amount of the compound of formula I from entering the subsequent reaction, resulting in an incomplete reaction of the raw materials, or generating a large amount of over-reduced products, which affects the quality of the final pyraclostrobin product.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] The present invention has been found through research that in the synthesis process of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene (compound of formula II), the compound of formula I is an isomer of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene, and its structure is determined. At the same time, a preparation method of the compound of formula I is provided. By controlling the conditions in the reaction process, a compound of formula I with a higher purity is obtained, and its purity is ≥99%, which can be used as a standard product.

[0056] The present invention studies 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene, dissolves 1-(4-chlorophenyl)-3-pyrazolol in a non-protonic polar solvent, adds a quantitative amount of base, reacts 1-(4-chlorophenyl)-3-pyrazolol with the base to generate 1-(4-chlorophenyl)-3-pyrazolol salt, and completely dissolves in the non-protonic polar solvent, completely converts the R-OH structure into the R-ONa or R-OK structure, so that the intramolecular structure transformation does not occur, avoids the generation of the compound of formula III, thereby reducing the generation of the compound of formula I, and controls the content of the isomer compound of formula I in the generated 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene to be less than 0.2%. Thus, the purity of the final product pyraclostrobin is improved, and the quality of pyraclostrobin is prevented from being affected by excessive impurities in 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene during the synthesis of pyraclostrobin. The content of the compound of formula I in 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene synthesized by conventional technology is usually 4-8%, and the reaction yield is 80-85%. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 The compound of formula Ⅰ in Example 1 1 H-NMR spectrum;

[0058] Figure 2 For the compound of formula II in Example 3 1 H-NMR spectrum;

[0059] Figure 3 This is the HPLC-MS spectrum of the compound of formula Ⅰ in Example 1. DETAILED DESCRIPTION

[0060] The present invention will be further described below in conjunction with the examples and drawings. It should be understood by those skilled in the art that the examples are only used to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0061] Specific experimental methods not mentioned in the following examples are usually carried out according to conventional experimental methods. All raw materials, reagents, etc. used, unless otherwise specified, are commercially available products.

[0062] Example 1

[0063] Preparation of compounds of formula I

[0064] 1) p-Chlorophenylhydrazine hydrochloride (20 g, 0.111 mol) was added to DMF (120 g, 6.0 w / w), and under nitrogen protection, sodium methoxide (39.97 g, 0.222 mol, 30% content) was added, and the temperature was raised and controlled at 60-80° C., and then methyl acrylate (13.51 g, 0.155 mol) was added dropwise, and the reaction was kept warm for 3-5 hours to obtain a reaction solution containing 1-(4-chlorophenyl)pyrazolidin-3-one.

[0065] 2) The reaction solution containing 1-(4-chlorophenyl)pyrazolidine-3-one was cooled to 30-50°C, water (50 g) was added to quench the sodium methoxide, and the temperature was increased for rectification to remove water and react to generate methanol; after the distillation, the material was controlled at 60-80°C and o-nitrobenzyl bromide (25.43 g, 0.117 mol) was added dropwise, and the temperature was kept for reaction for 2-4 hours to obtain a reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one.

[0066] 3) The reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one was cooled to 20-30°C and air was continuously introduced until complete conversion. The solvent was recovered under reduced pressure, hot water (50 g) was added, and the pH value of the system was adjusted to 1-2 with hydrochloric acid. A large amount of white solid was precipitated, which was filtered, washed, and dried to obtain 29.6 g of compound of formula I with a content of 99.02% and a yield of 80.25%.

[0067] The present invention detects the compound structure of formula I obtained in Example 1.

[0068] The product obtained in the embodiment of the present invention is 1 H-NMR test (with Figure 1 ), the sample was scanned at 0ppm to 10ppm for hydrogen spectrum, with 8 peaks and 12 hydrogens in total, which are assigned as shown in Table 1:

[0069] Proton chemical shift Number of protons Attribution 1.168～4.074 Ethyl acetate 5.266 2H Methylene 5.728～5.736 1H Pyrazole ring hydrogen 7.269 Deuterated chloroform 7.399～7.407 1H Pyrazole ring hydrogen 6.919～7.200、7.290～7.378、7.495～7.922 8H Benzene ring hydrogen

[0070] The product obtained in the embodiment of the present invention was subjected to HPLC-MS spectrogram detection (attached Figure 3 ), the molecular weight is 329.8, which is consistent with the theoretical value.

[0071] Example 2

[0072] Preparation of compounds of formula I

[0073] 1) Add p-chlorophenylhydrazine hydrochloride (35 g, 0.194 mol) to DMF (175 g, 5.0 w / w), add sodium methoxide (76.89 g, 0.427 mol, 30% content) under nitrogen protection, raise the temperature and control the temperature at 60-80° C., add methyl acrylate (21.69 g, 0.252 mol) dropwise, and keep the temperature for 3-5 hours to obtain a reaction solution containing 1-(4-chlorophenyl)pyrazolidine-3-one.

[0074] 2) The reaction solution containing 1-(4-chlorophenyl)pyrazolidine-3-one was cooled to 30-50°C, water (90 g) was added to quench the sodium methoxide, the temperature was increased for distillation, water was removed, and methanol was generated by reaction; after the distillation, o-nitrobenzyl bromide (50.80 g, 0.233 mol) was added dropwise at a temperature of 60-80°C, and the reaction was kept warm for 2-4 hours to obtain a reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one.

[0075] 3) The reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one was cooled to 20-30°C and air was continuously introduced until complete conversion. The solvent was recovered under reduced pressure, hot water (100 g) was added, and the pH value of the system was adjusted to 1-2 with hydrochloric acid. A large amount of white solid was precipitated, which was filtered, rinsed, and dried to obtain 53.02 g of compound of formula I, with a content of 99.12% and a yield of 82.32%.

[0076] Example 3

[0077] Preparation of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene

[0078] 1) o-Nitrotoluene (27 g, 0.195 mol) and AIBN (6.8 g, 25.19% w / w) were added to chlorobenzene (100 g, 3.7 w / w), and the temperature was raised to 65-75° C., and 30% hydrogen peroxide (17.69 g, 0.156 mol) and 48% hydrobromic acid (21.41 g, 0.127 mol) were added dropwise for 1-2 h. The reaction was kept warm for 1-2 h, and the temperature was lowered to room temperature. The phases were separated to obtain 138.2 g of chlorobenzene oil phase containing o-nitrobenzyl bromide, wherein the o-nitrobenzyl bromide content was 25.12%, and the yield was 82.41%.

[0079] 2) 1-(4-chlorophenyl)-3-pyrazolol (30 g, 0.151 mol) was added to DMF (150 g, 5 w / w), and sodium hydroxide (7.88 g, 0.189 mol, 96% content) was added, and stirred to completely dissolve to prepare a DMF solution of sodium salt of 1-(4-chlorophenyl)-3-pyrazolol;

[0080] 3) To the DMF solution of the sodium salt of 1-(4-chlorophenyl)-3-pyrazolol, a self-made dichloroethane oil phase containing o-nitrobenzyl bromide (134.2 g, 0.156 mol, 25.12% content) was added dropwise, and the reaction was carried out at 20-30° C. for 2 h. The reaction was completed by high performance liquid chromatography monitoring, wherein the compound of formula I accounted for 0.16%. After filtration and elution, 15.32 g of pure white sodium bromide was obtained, with a content of 98.8% and a bromine recovery rate of 98.2%;

[0081] 4) The filtrate from the previous step was distilled and recovered, and chlorobenzene was used, and 120-130 g of DMF was recovered by distillation. The temperature was cooled to 0-5 ° C for crystallization, filtration, elution, and drying to obtain 47.83 g of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene, with a content of 99.20% and a yield of 95.49%, of which the compound of formula I accounted for 0.11%.

[0082] The present invention detects the compound structure of formula II obtained in Example 3.

[0083] The product obtained in the embodiment of the present invention is 1 H-NMR test (with Figure 2 ), the sample was scanned at 0ppm to 10ppm for hydrogen spectrum, with 8 peaks and 12 hydrogens in total, which are assigned as shown in Table 1:

[0084]

[0085]

[0086] Example 4

[0087] Preparation of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene

[0088] 1) o-Nitrotoluene (90 g, 0.65 mol) and AIBN (20 g, 22.22% w / w) were added to dichloroethane (350 g, 3.89 w / w), and the temperature was raised to 65-75° C., and 30% hydrogen peroxide (58.95 g, 0.52 mol) and 48% hydrobromic acid (72.82 g, 0.432 mol) were added dropwise for 1-2 h. The reaction was kept warm for 1-2 h, and the temperature was lowered to room temperature. The phases were separated to obtain 465.56 g of dichloroethane oil phase containing o-nitrobenzyl bromide, wherein the o-nitrobenzyl bromide content was 24.66%, and the yield was 81.76%.

[0089] 2) 1-(4-chlorophenyl)-3-pyrazolol (100 g, 0.505 mol) was added to DMF (600 g, 6 w / w), and sodium hydroxide (26.92 g, 0.646 mol, 96% content) was added, and stirred to dissolve completely to prepare a DMSO solution of sodium salt of 1-(4-chlorophenyl)-3-pyrazolol;

[0090] 3) Add dichloroethane oil phase containing o-nitrobenzyl bromide (455.53 g, 0.520 mol, 24.66% content) dropwise to the DMSO solution of sodium salt of 1-(4-chlorophenyl)-3-pyrazolol, react at 20-30° C. for 2 h, and monitor the completion of the reaction by high performance liquid chromatography, wherein the compound of formula I accounts for 0.19%, filter and rinse to obtain 51.5 g of pure white sodium bromide, with a content of 98.6% and a bromine recovery rate of 98.4%;

[0091] 4) The filtrate from the previous step was distilled and recovered, and dichloroethane was used, and 400-450 g of DMSO was recovered by distillation. The temperature was cooled to 0-5 ° C for crystallization, filtration, elution, and drying to obtain 159.72 g of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene with a content of 99.12% and a yield of 95.27%, of which the compound of formula X accounted for 0.13%.

[0092] Example 5

[0093] Preparation of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene

[0094] 1) o-Nitrotoluene (48 g, 0.35 mol) and AIBN (12 g, 25% w / w) were added to dichloroethane (180 g, 3.75 w / w), and the temperature was raised to 65-75° C., and 30% hydrogen peroxide (32.88 g, 0.29 mol) and 48% hydrobromic acid (40.79 g, 0.242 mol) were added dropwise for 1-2 h. The reaction was kept warm for 1-2 h, and the temperature was lowered to room temperature. The phases were separated to obtain 246.27 g of dichloroethane oil phase containing o-nitrobenzyl bromide, wherein the o-nitrobenzyl bromide content was 25.08%, and the yield was 81.69%.

[0095] 2) 1-(4-chlorophenyl)-3-pyrazolol (50 g, 0.253 mol) was added to DMF (250 g, 5 w / w), and sodium hydroxide (12.67 g, 0.304 mol, 96% content) was added, and stirred to completely dissolve to prepare an acetonitrile solution of the sodium salt of 1-(4-chlorophenyl)-3-pyrazolol;

[0096] 3) Add dichloroethane oil phase containing o-nitrobenzyl bromide (229.12 g, 0.266 mol, 25.08% content) dropwise to the acetonitrile solution of sodium salt of 1-(4-chlorophenyl)-3-pyrazolol, react at 20-30° C. for 3 h, and monitor the completion of the reaction by high performance liquid chromatography, wherein the compound of formula I accounts for 0.16%, filter and rinse to obtain 25.8 g of pure white sodium bromide, with a content of 98.8% and a bromine recovery rate of 97.92%;

[0097] 4) The filtrate from the previous step was distilled and recovered, and dichloroethane was used, and 200-220 g of acetonitrile was recovered by distillation. The temperature was cooled to 0-5 ° C for crystallization, filtration, elution, and drying to obtain 79.93 g of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene with a content of 99.07% and a yield of 95.12%, of which the compound of formula I accounted for 0.11%.

[0098] Comparative Example 1

[0099] Preparation of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene

[0100] 1) o-Nitrotoluene (25 g, 0.180 mol) and AIBN (5.2 g, 20.8% w / w) were added to dichloroethane (100 g, 4 w / w), and the temperature was raised to 65-75° C., and 30% hydrogen peroxide (16.44 g, 0.145 mol) and 48% hydrobromic acid (20.23 g, 0.12 mol) were added dropwise for 1-2 h. The reaction was kept warm for 1-2 h, and the temperature was lowered to room temperature. The phases were separated to obtain 128.92 g of dichloroethane oil phase containing o-nitrobenzyl bromide, wherein the o-nitrobenzyl bromide content was 24.66%, and the yield was 81.76%.

[0101] 2) 1-(4-chlorophenyl)-3-pyrazolol (25 g, 0.126 mol) was added to dichloroethane (125 g, 5 w / w), and sodium hydroxide (9.46 g, 0.227 mol, 96% content) and tetrabutylammonium bromide (0.3 g, 1.2% w / w) were added and stirred to form a slurry of solid and liquid phases.

[0102] 3) The dichloroethane oil phase (121.77 g, 0.139 mol, 24.66% content) prepared in step 1) and containing o-nitrobenzyl bromide was added dropwise to the material in step 2), and the reaction was carried out at 60-80° C. for 8 h. The reaction was completed by high performance liquid chromatography, wherein the compound of formula I accounted for 5.61%. 40 g of hot water was added to perform thermal phase separation. The dichloroethane oil phase was distilled to recover the dichloroethane, and the temperature was lowered to 0-5° C. for crystallization, filtration, elution, and drying to obtain 35.98 g of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene, with a content of 94.88%, a yield of 82.34%, and 4.12% of the compound of formula I.

[0103] 4) The pH of the wastewater from the previous step of thermal separation was adjusted to neutral using hydrobromic acid, and it appeared reddish brown, and the COD was detected to be about 152000 mg / L.

[0104] Comparative Example 2

[0105] Preparation of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene

[0106] 1) o-Nitrotoluene (40 g, 0.289 mol) and AIBN (10 g, 25% w / w) were added to dichloroethane (150 g, 3.75 w / w), and the temperature was raised to 65-75° C., and 30% hydrogen peroxide (28.46 g, 0.251 mol) and 48% hydrobromic acid (32.53 g, 0.193 mol) were added dropwise for 1-2 h. The reaction was kept warm for 1-2 h, and the temperature was lowered to room temperature. The phases were separated to obtain 207.3 g of dichloroethane oil phase containing o-nitrobenzyl bromide, wherein the o-nitrobenzyl bromide content was 24.79%, and the yield was 82.31%.

[0107] 2) 1-(4-chlorophenyl)-3-pyrazolol (40 g, 0.202 mol) was added to dichloroethane (200 g, 5 w / w), and sodium hydroxide (10.54 g, 0.253 mol, 96% content) and tetrabutylammonium bromide (0.4 g, 1% w / w) were added and stirred to form a slurry of solid-liquid two phases.

[0108] 3) The self-made dichloroethane oil phase containing o-nitrobenzyl bromide (190 g, 0.218 mol, 24.79% content) prepared in step 1) was added dropwise to the material of step 2), and the reaction was carried out at 60-80° C. for 8 h. The reaction was monitored by high performance liquid chromatography, wherein the compound of formula I accounted for 5.61%. 70 g of hot water was added to perform thermal phase separation. The dichloroethane oil phase was distilled to recover the dichloroethane, and the temperature was lowered to 0-5° C. for crystallization, filtration, elution, and drying to obtain 58.53 g of 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene, with a content of 95.12%, a yield of 83.76%, and 3.66% of the compound of formula I.

[0109] 4) The pH of the wastewater from the previous step of thermal separation was adjusted to neutral using hydrobromic acid, and it appeared reddish brown, and the COD was detected to be about 150,000 mg / L.

[0110] Comparative Examples 1 and 2 are conventional methods of directly adding 1-(4-chlorophenyl)-3-pyrazolol, and the content of the compound of formula I in the finally generated 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene is relatively high.

Claims

1. A method for preparing 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene isomers, characterized in that: The steps include: 1) adding p-chlorophenylhydrazine hydrochloride to a solvent, adding a base under nitrogen protection and stirring uniformly to obtain a mixed solution, heating the mixed solution to 60-80° C., adding methyl acrylate dropwise to the mixed solution, and keeping the temperature to react for 2-4 hours to obtain a reaction solution containing 1-(4-chlorophenyl)pyrazolidine-3-one; wherein the molar ratio of p-chlorophenylhydrazine hydrochloride, the base and the methyl acrylate is 1:1.5-3.0:1.2-1.5; 2) adding water to the reaction solution containing 1-(4-chlorophenyl)pyrazolidine-3-one, quenching, and distilling to remove water and methanol generated by the reaction, then cooling the reaction solution to 60-80° C., adding o-nitrobenzyl bromide dropwise, and keeping the temperature for reaction for 3-5 hours to obtain a reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one; wherein the molar ratio of o-nitrobenzyl bromide to p-chlorophenylhydrazine hydrochloride is 1.1-1.3:1; 3) The reaction solution containing 1-(4-chlorophenyl)-2-[(2-nitrophenyl)methyl]tetrahydro-1H-pyrazol-3-one is cooled to 20-30° C., and air is continuously introduced until the complete conversion is completed. The solvent is recovered under reduced pressure, hot water is added, and the pH value of the system is adjusted to 1-2 with hydrochloric acid. The precipitated white solid is filtered and washed to obtain 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene isomer, whose structural formula is shown in Formula I:

2. The preparation method according to claim 1, characterized in that: The solvent is toluene, DMF or DMSO, preferably DMF.

3. The preparation method according to claim 1, characterized in that: In step 1), the amount of the solvent is 5 to 10 times the mass of o-nitrotoluene.

4. The preparation method according to claim 1, characterized in that: In step 1), the base is one or both of sodium methoxide and sodium ethoxide, preferably sodium methoxide.

5. A method for controlling the production of isomers of 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene during its production process, characterized in that: The steps include: 1) Add o-nitrotoluene and AIBN to a solvent and mix well to obtain a mixed solution, heat the mixed solution to 65-75°C, add hydrogen peroxide and hydrobromic acid dropwise to the mixed solution over a period of 1-2 hours, keep the mixture warm for 1-2 hours, cool the reaction solution to room temperature, separate the phases, and obtain an organic phase containing o-nitrobenzyl bromide; The molar ratio of o-nitrotoluene, hydrogen peroxide and hydrobromic acid is 1:0.7-0.9:0.6-0.7; the amount of AIBN used is 20-30% of the mass of o-nitrotoluene; 2) the obtained organic phase containing o-nitrobenzyl bromide is added dropwise to an alkaline salt solution containing 1-(4-chlorophenyl)-3-pyrazolol, and the reaction is carried out for 2 to 4 hours at a temperature of 20 to 30° C. After the reaction is completed, the mixture is filtered and rinsed to obtain a pure white bromide salt and a filtrate containing 2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]nitrobenzene; the molar ratio of 1-(4-chlorophenyl)-3-pyrazolol to o-nitrobenzyl bromide is 1:1.03 to 1.1; The alkaline salt solution containing 1-(4-chlorophenyl)-3-pyrazolol is prepared by mixing 1-(4-chlorophenyl)-3-pyrazolol, a non-protonic polar solvent and a base, the molar ratio of 1-(4-chlorophenyl)-3-pyrazolol to the base is 1:1.1-1.5, and the amount of the non-protonic polar solvent is 4-10 times the mass of 1-(4-chlorophenyl)-3-pyrazolol; 3) distilling the filtrate containing 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene, recovering the obtained solvent for reuse, cooling the material after the distillation to 0-5°C for crystallization, filtering, eluting and drying to obtain 2-[(N-p-chlorophenyl)-3-pyrazolyloxymethyl]nitrobenzene.

6. The preparation method according to claim 5, characterized in that: In step 1), the solvent is chlorobenzene, chloroform or dichloroethane.

7. The preparation method according to claim 5, characterized in that: The aprotic polar solvent is DMF, DMSO or acetonitrile, preferably DMF.

8. The preparation method according to claim 5, characterized in that: The alkali is potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.

Images