Preparation method of pyrazole ether compound

Abstract

The invention provides a preparation method of a pyrazole ether compound, which comprises the following steps: (1) carrying out condensation reaction on 1-chloro-2, 5-dimethyl-4-nitrobenzene and a pyrazole alcohol compound to obtain a nitro etherate with a structure as shown in a formula A1; (2) carrying out reduction reaction on the nitro etherate with the structure as shown in the formula A1 obtained in the step (1) to obtain amino etherate with a structure as shown in a formula B2; and (3) reacting the amino etherate with the structure as shown in the formula B2 obtained in the step (2) with N-ethyl-N-methyl-formamide, and synthesizing to obtain the pyrazole ether compound with the structure as shown in the formula I. According to the preparation method of the pyrazole ether compound provided by the invention, a process route for directly carrying out one-step reaction on the amino etherate and N-ethyl-N-methyl-formamide to obtain the target compound is designed, the reaction yield is improved (the highest single-step yield is 97.8%), the use of methylethyl amine as a raw material is avoided, and the industrialization cost is reduced.

Description

Technical Field

[0001] This invention belongs to the field of chemical product manufacturing technology and relates to a method for preparing pyrazole ether compounds. Background Technology

[0002] In recent decades, numerous publications have reported the bioactivity of pyrazole derivatives, and new pyrazole pesticides have been continuously commercialized. Among them, pyrazole ether compounds have become one of the focal points of herbicide research, and in recent years, pyrazole ether compounds with fungicidal activity have also been gradually discovered.

[0003] CN101631460A discloses a pyrazole ether compound with herbicidal activity (compound number 595-606, formula TM1). EP1150944B describes a method for preparing the compound of formula TM1, which uses a SnCl2 / HCl combination as a reducing agent. The post-processing generates a large amount of wastewater and is difficult to purify, which is not conducive to industrial production.

[0004]

[0005] The pyrazole ether compounds (shown as formula TM2) reported in CN116003322A have significant effects on the prevention and control of diseases in agriculture and forestry.

[0006]

[0007] Although CN116003322A synthesized this compound, the highest overall yield of the four-step reaction was only 36% (based on 1-chloro-2,5-dimethyl-4-nitrobenzene). The main synthetic route for pyrazole ether compounds published by CN116003322A is shown below:

[0008]

[0009] Specifically, this route uses iron powder as a reducing agent, which is difficult to recover, resulting in a lot of waste residue in the industrial process; the last two steps use triethyl orthoformate as a reaction reagent and solvent, which is used in large quantities and has low molecular utilization, resulting in an increase in waste liquid; in the final step of synthesizing the active ingredient, methyl ethylamine (4500 yuan / kg) is used, which is expensive and cannot be afforded relative to the cost of pesticide production.

[0010] As mentioned above, existing synthetic methods for preparing pyrazole ether compounds suffer from drawbacks such as being environmentally unfriendly, having low yields, and being difficult to purify, necessitating the development of more suitable synthetic processes. Therefore, providing a simple and high-yield method for preparing pyrazole ether compounds has become an urgent problem to be solved. Summary of the Invention

[0011] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing pyrazole ether compounds with the structure shown in Formula I. This method has a short route, high single-step yield, few by-products, avoids cryogenic and high-temperature processes, and is more suitable for industrial production.

[0012] To achieve this objective, the present invention adopts the following technical solution:

[0013] In a first aspect, the present invention provides a method for preparing a pyrazole ether compound having the structure shown in Formula I:

[0014]

[0015] In Formula I, R is selected from Where * represents the connection position of the group;

[0016] The preparation method includes:

[0017] (1) A condensation reaction is carried out between 1-chloro-2,5-dimethyl-4-nitrobenzene and a pyrazol alcohol compound to obtain a nitro ether with the structure shown in formula A1, as follows:

[0018]

[0019] (2) The nitro ether obtained in step (1) with the structure shown in formula A1 is reduced to obtain the amino ether with the structure shown in formula B2, as shown in the following reaction:

[0020]

[0021] (3) The amino ether compound with the structure shown in formula B2 obtained in step (2) is reacted with N-ethyl-N-methyl-formamide to synthesize a pyrazole ether compound with the structure shown in formula I. The reaction formula is as follows:

[0022]

[0023] In steps (1) to (3), R is selected from... The asterisk (*) represents the connection position of the functional group.

[0024] The preparation method provided by this invention uses 1-chloro-2,5-dimethyl-4-nitrobenzene as the starting material and proceeds sequentially through: condensation reaction with pyrazol alcohol compounds, reduction reaction, and reaction with N-ethyl-N-methyl-formamide. These three steps yield the target product, pyrazol ether compounds. This three-step reaction is almost quantitative, with few byproducts and high yield, achieving an overall yield of 87.5%-91.3% (based on 1-chloro-2,5-dimethyl-4-nitrobenzene; the overall yield here is calculated from the yields of the three steps. For example, in Example 1, the yield in step (1) is 96.3%; the yield in step (2) is 95.6%; and the yield in step (3) is 96.7%. The overall yield in this example is 96.3% * 95.6% * 96.7% = 89.1%). The process conditions are mild, and all three steps are easily purified, making it more suitable for industrial production.

[0025] In the existing technology CN116003322A, an amino ether is obtained through condensation and reduction reactions, followed by a two-step reaction with triethyl orthoformate and methyl ethylamine to obtain the target compound. Due to the low reactivity of triethyl orthoformate, the reaction time is long, resulting in a low yield (maximum only 78.3%) for the final reaction with methyl ethylamine. This invention designs a one-step process route for the direct reaction of the amino ether with N-ethyl-N-methyl-formamide to obtain the target compound, improving the reaction yield (maximum single-step yield of 97.8%), avoiding the use of methyl ethylamine as a raw material, and reducing industrialization costs.

[0026] Preferably, the pyrazole alcohol compound in step (1) includes any one of 1-(4-chlorophenyl)-1H-pyrazole-3-ol, 1-(4-fluorophenyl)-1H-pyrazole-3-ol, 1-(4-bromophenyl)-1H-pyrazole-3-ol or 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol.

[0027] Preferably, the molar ratio of the pyrazolol compound in step (1) to 1-chloro-2,5-dimethyl-4-nitrobenzene is (1.0-3.0):1, for example, it can be 1.1:1, 1.3:1, 1.5:1, 1.8:1, 2.0:1, 2.5:1 or 3:1, etc., and more preferably (1.0-2.0):1.

[0028] Preferably, the condensation reaction in step (1) is carried out in the presence of a basic compound.

[0029] Preferably, the alkaline compound includes any one or a combination of at least two of sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, or sodium hydride, with potassium carbonate being more preferred.

[0030] Preferably, the molar ratio of the basic compound to 1-chloro-2,5-dimethyl-4-nitrobenzene is (1.2-3.0):1, for example, it can be 1.2:1, 1.8:1, 2.0:1, 2.2:1, 2.5:1 or 3.0:1, etc., and more preferably (1.2-2.0):1.

[0031] Preferably, the condensation reaction in step (1) is carried out in the presence of a catalyst.

[0032] Preferably, the catalyst comprises potassium iodide.

[0033] Preferably, the catalyst comprises 0.1-5.0% by mass, based on 100% of 1-chloro-2,5-dimethyl-4-nitrobenzene, for example, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, etc., and more preferably 0.5-1.5%.

[0034] Preferably, the solvent for the condensation reaction in step (1) includes any one or a combination of at least two of 1,2-dichloroethane, toluene, acetonitrile, methanol, ethanol, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably N,N-dimethylacetamide.

[0035] Preferably, the mass ratio of the solvent to 1-chloro-2,5-dimethyl-4-nitrobenzene in the condensation reaction of step (1) is (0.5-5.0):1, for example, it can be 0.8:1, 1.0:1, 2.0:1, 3.0:1, 4.0:1, 5.0:1, etc., and more preferably (1-4):1.

[0036] Preferably, the temperature of the condensation reaction in step (1) is 140-160°C, for example, 140°C, 142°C, 145°C, 150°C, 155°C or 160°C, and more preferably 147-160°C.

[0037] Preferably, the condensation reaction time in step (1) is 1 to 24 hours, for example, 2 hours, 5 hours, 10 hours, 15 hours or 20 hours, and more preferably 4 to 10 hours.

[0038] Preferably, after the condensation reaction in step (1) is completed, a post-processing step is also included.

[0039] Preferably, the post-processing includes the following steps: adding water to the reaction system, cooling, filtering, obtaining a crude nitro ether product with the structure shown in Formula A1, and subjecting the crude product to solvent crystallization, solid-liquid separation, and drying to obtain a nitro ether product with the structure shown in Formula A1.

[0040] Preferably, the system temperature is cooled to 70-90°C before adding water to the reaction system, for example, 70°C, 75°C, 80°C, 85°C or 90°C.

[0041] Preferably, the cooling is to a temperature of 5-25°C, such as 5°C, 10°C, 20°C, or 25°C. At this temperature, a solid will precipitate, and the precipitation time is 1-3 hours, such as 1.3 hours, 1.5 hours, 2 hours, 2.3 hours, or 2.8 hours.

[0042] Preferably, the solid-liquid separation includes filtration.

[0043] Preferably, the solvent in the solvent crystallization process includes one or a combination of at least two of methanol, ethanol, isopropanol, and acetonitrile, with methanol or ethanol being the most preferred.

[0044] Preferably, the reaction yield of the nitro ether compound with the structure shown in Formula A1 is ≥94.2%, for example 94.3%, 95%, 96%, 97%, 97.5%, etc.

[0045] Preferably, the content of the nitro etherified compound with the structure shown in Formula A1 is ≥99.06%, such as 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, etc.

[0046] Preferably, the reducing agent used in the reduction reaction of step (2) includes hydrazine hydrate.

[0047] Preferably, the molar ratio of the nitro ether to the reducing agent is 1:(2.0-4.0), for example, it can be 1:2.2, 1:2.8, 1:3.0, 1:3.2, 1:3.5 or 1:4.0, and more preferably 1:(3.0-3.5).

[0048] Preferably, the reduction reaction in step (2) is carried out in the presence of a catalyst, which includes any one or a combination of at least two of palladium on carbon, platinum on carbon, palladium dioxide, Raney nickel, or ferric chloride, with Raney nickel being preferred.

[0049] Preferably, the mass of the catalyst is 12-18% based on 100% of the nitro ether, for example, 12.0%, 13.0%, 14.0%, 15.0%, 17.0% or 18.0%, and more preferably 13-15%.

[0050] Preferably, the solvent for the reduction reaction in step (2) includes any one or a combination of at least two of dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, toluene or chlorobenzene, preferably a combination of 1,2-dichloroethane and methanol.

[0051] Preferably, the mass ratio of the solvent to the nitro ether in the reduction reaction in step (2) is (0.5-4.0):1, for example, it can be 0.8:1, 1.0:1, 2.0:1, 3.0:1, 4.0:1, etc., and more preferably (2-4):1.

[0052] Preferably, the temperature of the reduction reaction in step (2) is 30-80℃, for example, it can be 30℃, 40℃, 50℃, 60℃, 70℃ or 80℃, and more preferably 50-60℃.

[0053] Preferably, the reduction reaction time in step (2) is 0.5 to 5 hours, for example, 0.5 hours, 2 hours, 4 hours, 4.5 hours or 5 hours, and more preferably 0.5 to 2 hours.

[0054] Preferably, after the reduction reaction in step (2) is completed, a post-processing step is also included. The post-processing method includes: filtering to recover the catalyst, retaining the filtrate, washing the filtrate with water, separating the liquid, retaining the organic phase, crystallizing or crystallizing the organic phase, separating the solid and liquid, drying, and obtaining the amino ether compound with the structure shown in B2.

[0055] Preferably, the crystallization temperature is -5 to 5°C, for example, it can be -5°C, 0.5°C, 2°C, 4°C or 4.5°C.

[0056] Preferably, the crystallization time is 2 to 5 hours, for example, it can be 1.5 hours, 2.0 hours, 3.0 hours, 4.0 hours or 4.5 hours.

[0057] Preferably, the solid-liquid separation method includes filtration.

[0058] Preferably, the reaction yield of the amino ether compound with the structure shown in Formula B2 is ≥95.0%, for example 95.0%, 96.0%, 97.0%, 98.0%, 98.2%, etc.

[0059] Preferably, the content of the amino ether compound with the structure shown in Formula B2 is ≥99.1%, such as 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.65%, etc.

[0060] In the preparation method provided by this invention, Raney nickel is used as a catalyst in the reduction reaction and hydrazine hydrate is used as a reducing agent. The catalyst can be recycled and reused, reducing the generation of industrial waste.

[0061] Preferably, the reaction in step (3) is carried out in the presence of a chlorinating agent.

[0062] Preferably, the chlorinating agent includes any one or a combination of at least two of thionyl chloride, triphosgene, oxaloyl chloride, phosphorus trichloride, and phosphorus pentachloride, and more preferably thionyl chloride and / or triphosgene.

[0063] Preferably, the molar ratio of the chlorinating agent to N-ethyl-N-methyl-formamide is (0.3-3.0):1, for example, it can be 0.3:1, 0.5:1, 1.0:1, 1.5:1, 2.0:1, 2.5:1 or 3.0:1, and more preferably (0.32-1.5):1.

[0064] Preferably, in step (3), the molar ratio of N-ethyl-N-methyl-formamide to amino ether is (1.05-3.0):1, for example, it can be 1.1:1, 1.3:1, 1.8:1, 2.1:1, 2.5:1 or 3.0:1, etc., and more preferably (1.1-2.0):1.

[0065] Preferably, the solvent for the reaction in step (3) includes any one or a combination of at least two of dichloromethane, 1,2-dichloroethane, chloroform, toluene or chlorobenzene, preferably 1,2-dichloroethane.

[0066] Preferably, the mass ratio of the solvent to the amino ether in step (3) is (0.5-4.0):1, for example, it can be 0.8:1, 1.0:1, 1.5:1, 2.0:1, 3.2:1, 3.8:1 or 4.0:1, and more preferably (1.0-3.0):1.

[0067] Preferably, the reaction temperature in step (3) is 20-80°C, for example, 25°C, 30°C, 40°C, 50°C or 60°C, and more preferably 25-50°C.

[0068] Preferably, the reaction time in step (3) is 1 to 4 hours, for example, 1 hour, 2 hours, 3 hours or 4 hours, and more preferably 2 to 3 hours.

[0069] Preferably, after the reaction in step (3) is completed, a post-processing step is also included. The post-processing method includes: adding an alkaline solution to adjust the pH value of the reaction solution to 8-10 (for example, it can be 8.2, 8.8, 9, 9.2 or 9.8, etc.), separating the liquid to obtain an organic layer, and then crystallizing or precipitating, separating the solid and liquid, and drying to obtain a pyrazole ether compound with the structure of formula I.

[0070] Preferably, the alkaline solution comprises any one or a combination of at least two of the following: an aqueous solution of an alkali metal or alkaline earth metal hydroxide, a carbonate, or a bicarbonate, preferably a sodium hydroxide solution or a sodium carbonate solution.

[0071] Preferably, the post-processing further includes recrystallization and / or washing steps to purify the product pyrazole ether compounds.

[0072] Preferably, the solvent for crystallization includes any one or a combination of at least two of dichloromethane, 1,2-dichloroethane, carbon tetrachloride, toluene, xylene, methanol, ethanol, and isopropanol, and more preferably 1,2-dichloroethane, methanol, and ethanol.

[0073] Preferably, the crystallization temperature is 0-5℃, for example, it can be 0.5℃, 2℃, 4℃ or 4.5℃, etc.

[0074] Preferably, the crystallization time is 2-5 hours, for example, it can be 1.5 hours, 2.0 hours, 3.0 hours, 4.0 hours or 4.5 hours.

[0075] Preferably, the solid-liquid separation method includes filtration.

[0076] Preferably, the reaction yield of the pyrazole ether compound with the structure shown in Formula I is ≥95.9%, for example 96.0%, 96.5%, 97.0%, 97.5%, 97.8%, etc.

[0077] Preferably, the content of the pyrazole ether compound with the structure shown in Formula I is ≥99.19%, such as 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.76%, etc.

[0078] As a preferred embodiment of the present invention, the preparation method includes:

[0079] (1) 1-Chloro-2,5-dimethyl-4-nitrobenzene and pyrazol alcohols are condensed in the presence of alkaline compounds, catalysts and solvents at 147-160°C for 4-10 hours. Then, the mixture is cooled to 70-90°C and water is added to the reaction system. The mixture is then cooled to 5-25°C and filtered to obtain a crude nitro ether product with the structure shown in Formula A1. The crude product is subjected to solvent crystallization, solid-liquid separation and drying to obtain a nitro ether product with the structure shown in Formula A1.

[0080] (2) The nitro ether obtained in step (1) with the structure shown in formula A1 is reduced at 50-60°C in the presence of solvent, catalyst and reducing agent for 0.5-2 hours. Then the catalyst is recovered by filtration, the filtrate is retained, the filtrate is washed with water, separated, the organic phase is retained, the organic phase is crystallized or crystallized, solid-liquid separation is performed, and dried to obtain the amino ether with the structure shown in formula B2.

[0081] (3) The amino ether obtained in step (2) with the structure shown in formula B2 is reacted with N-ethyl-N-methyl-formamide in the presence of solvent and chlorinating agent at 25-50°C for 2-3 hours. Then, an alkaline solution is added to adjust the pH of the reaction solution to 8-10. The organic layer is separated and then crystallized or precipitated, separated from the solid and liquid, and dried to synthesize the pyrazole ether compound with the structure shown in formula I.

[0082] Compared with the prior art, the present invention has at least the following beneficial effects:

[0083] The present invention provides a method for preparing pyrazole ether compounds, which designs a one-step process route for the direct reaction of amino ethers with N-ethyl-N-methyl-formamide to obtain the target compound. This improves the reaction yield (single-step yield up to 97.8%), avoids the use of methyl ethylamine as a raw material, and reduces industrialization costs. This three-step synthesis of pyrazole ether compounds is almost quantitative, with few byproducts, high yield (overall yield as high as 87.5%-91.3%), mild process conditions, recyclable catalyst, reduced industrial waste generation, and easy purification of all three steps, making it more suitable for industrial production. Detailed Implementation

[0084] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be considered as specific limitations thereof. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of raw materials for the product of the present invention, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of the present invention.

[0085] In the following specific embodiments of the present invention, all raw materials involved were purchased through market channels; the content of all intermediates and products was determined by high performance liquid chromatography (HPLC) external standard method, and the yield was molar yield.

[0086] Example 1

[0087] In this embodiment, R is used to prepare The product, namely (Hereinafter referred to as "Compound 1"), the reaction route is shown below:

[0088] The specific steps are as follows:

[0089] (1) 38.9 g of 1-(4-chlorophenyl)-1H-pyrazole-3-ol (purity 99.99%, 0.2 mol), 33.5 g of anhydrous potassium carbonate (purity 99.0%, 0.24 mol), KI (0.4 g, purity 99.5%) and 40 g of N,N-dimethylacetamide (DMA, purity 99.5%) were added sequentially to a 500 mL three-necked round-bottom flask. The temperature was raised to 120 °C, and 37.3 g of 1-chloro-2,5-dimethyl-4-nitrobenzene (purity 99.5%, 0.2 mol) was added in ten batches. The reaction solution was heated to 150 °C and reacted for 10 h. After cooling to 90 °C, 80 g of water was added. After cooling to room temperature, the mixture was filtered to obtain a wet filter cake. 80 g of ethanol was added to crystallize the mixture. After filtration and drying, 66.5 g of white solid compound 1A was obtained with a purity of 99.52% and a yield of 96.3%. LC / MS[M+1]: m / z=344.0796; 1 The following are the 1H NMR (400MHz, DMSO-d6) data (δ[ppm]): 8.58 (s, 1H), 8.05 (s, 1H), 7.81 (d, J = 8.4Hz, 2H), 7.56 (d, J = 8.4Hz, 2H), 7.14 (s, 1H), 6.34 (s, 1H), 2.50 (d, J = 14.8Hz, 3H), 2.32 (s, 3H).

[0090] (2) 51.8 g of nitro ether 1A (purity 99.52%, 0.15 mol), 52 g of 1,2-dichloroethane (purity 99.5%), 105 g of methanol (purity 99.9%), and 7.5 g of Raney nickel were added sequentially to a 500 mL four-necked round-bottom flask. The reaction solution was heated to 50 °C, and 32.8 g of hydrazine hydrate (purity 80%, 0.52 mol) was added dropwise. After reacting for 0.5 h, the mixture was cooled to room temperature. The catalyst was filtered off, and the filtrate was washed with 50 g of water and separated into layers. The organic phase was stirred and crystallized at 0 °C. After filtration and drying, 45.2 g of gray solid compound 1B was obtained, with a purity of 99.44% and a yield of 95.6%. LC / MS [M+1]: m / z = 314.1054; 1 The following are the 1H NMR (400MHz, DMSO-d6) data (δ[ppm]): 8.37 (s, 1H), 7.74 (d, J = 8.4Hz, 2H), 7.51 (d, J = 8.4Hz, 2H), 6.73 (s, 1H), 6.50 (s, 1H), 5.84 (s, 1H), 4.73 (s, 2H), 2.05 (d, J = 14.4Hz, 6H).

[0091] (3) Add 13.7g of N-ethyl-N-methyl-formamide (99.00%, 0.156mol) and 40g of 1,2-dichloroethane (99.5% purity) to a 500mL four-necked round-bottom flask in sequence. Control the temperature at 25℃ and slowly add 20g of triphosgene (99.00%, 15.4g, 0.0515mol) in dichloroethane. After reacting for 0.5h, add 37.8g of solid compound 1B (99.44% purity, 0.12mol) in ten batches. Heat the reaction solution to 35℃ and react for 2h. Add 40g of water and adjust the pH to 9.5 with 30% NaOH aqueous solution. After separation, cool the organic phase to 0℃ and stir to precipitate crystals. After filtration and drying, 44.5g of white solid compound 1 with a purity of 99.76% and a yield of 96.7% is obtained. LC / MS[M+1]: m / z=383.1633; 1 ¹H NMR (400MHz, DMSO-d6) data are as follows (δ [ppm]): 8.41 (d, J = 2.4Hz, 1H), 7.73 (d, J = 8.8Hz, 2H), 7.65 (s, 1H), 7.50 (d, J = 8.8Hz, 2H), 6.84 (s, 1H), 6.68 (s, 1H), 5.92 (d, J = 2.4Hz, 1H), 3.35 (s, 2H), 2.92 (s, 3H), 2.12 (d, J = 3.2Hz, 6H), 1.38–0.99 (m, 3H).

[0092] Example 2

[0093] In this embodiment, R is used to prepare The product, namely The preparation method includes the following steps:

[0094] (1) Add 46.8g of 1-chloro-2,5-dimethyl-4-nitrobenzene (99.0% purity, 0.25mol), 55.8g of anhydrous potassium carbonate (99.0% purity, 0.4mol), KI (0.5g, 99.5% purity) and 50g of [unspecified substance] to a 1L four-necked round-bottom flask in sequence. N,N-Dimethylacetamide (DMA, purity 99.5%) was heated to 130°C, and a DMA solution (145 g) of 1-(4-chlorophenyl)-1H-pyrazole-3-ol (purity 99.99%, 72.9 g, 0.375 mol) was slowly added dropwise over 1 hour. The reaction mixture was then heated to 147°C and reacted for 4 hours. After cooling to 90°C, 80 g of water was added, and the mixture was cooled to 10°C and filtered. The resulting wet filter cake was then crystallized with 100 g of methanol. After filtration and drying, 84.3 g of a white solid compound 1A was obtained, with a purity of 99.16% and a yield of 97.4%.

[0095] (2) 51.9 g of nitro ether 1A (purity 99.16%, 0.15 mol), 104 g of 1,2-dichloroethane (purity 99.5%), 52 g of methanol (purity 99.9%) and 7.2 g of Raney nickel were added sequentially to a 500 mL four-necked round-bottom flask. The reaction solution was heated to 55 °C, and 28.1 g of hydrazine hydrate (purity 80%, 0.45 mol) was added dropwise. After reacting for 1.5 h, the mixture was cooled to room temperature. The catalyst was filtered off, and the filtrate was washed with 55 g of water and separated into layers to obtain the organic phase. The solvent was removed under reduced pressure, and 50 g of methanol was added to crystallize the mixture. After filtration and drying, 45.6 g of gray solid compound 1B with a purity of 99.37% and a yield of 96.4% was obtained.

[0096] (3) Add 21.1 g of N-ethyl-N-methyl-formamide (99.00%, 0.24 mol) and 40 g of 1,2-dichloroethane (99.5% purity) to a 500 mL four-necked round-bottom flask in sequence. Control the temperature at 30 °C and slowly add 37.5 g of thionyl chloride (99.00%, 0.312 mol) dropwise. After the addition is completed in 30 min, continue stirring for 0.5 h. Then slowly add 37.8 g of a dichloroethane solution (40 g) of solid compound 1B (99.37% purity, 0.12 mol) dropwise. After the addition is completed in 1.5 h, raise the temperature of the reaction solution to 50 °C and react for 2 h. Add 40 g of water and adjust the pH to 8.5 with 30% NaOH aqueous solution. Separate the liquid to obtain the organic phase, remove the solvent, add 40 g of methanol to crystallize, filter and dry to obtain 44.9 g of white solid compound 1 with a purity of 99.37% and a yield of 97.2%.

[0097] Example 3

[0098] In this embodiment, R is used to prepare The product, namely The preparation method includes the following steps:

[0099] (1) 77.8 g of 1-(4-chlorophenyl)-1H-pyrazole-3-ol (purity 99.99%, 0.4 mol), 39.1 g of anhydrous potassium carbonate (purity 99.0%, 0.28 mol), KI (0.56 g, purity 99.5%) and 120 g of N,N-dimethylacetamide (DMA, purity 99.5%) were added sequentially to a 500 mL three-necked round-bottom flask. The temperature was raised to 140 °C, and 37.3 g of 1-chloro-2,5-dimethyl-4-nitrobenzene (purity 99.5%, 0.2 mol) was added in ten batches. The reaction solution was heated to 155 °C and reacted for 6 h. After cooling to 90 °C, 80 g of water was added, and the temperature was lowered to 10 °C and filtered. The wet filter cake was added to 80 g of ethanol to crystallize. After filtration and drying, 67.1 g of white solid compound 1A was obtained with a purity of 99.23% and a yield of 96.9%.

[0100] (2) 51.9 g of nitro ether 1A (purity 99.23%, 0.15 mol), 130 g of 1,2-dichloroethane (purity 99.5%), 78 g of methanol (purity 99.9%) and 7.0 g of Raney nickel were added sequentially to a 500 mL four-necked round-bottom flask. The reaction solution was heated to 60 °C, and 30.9 g of hydrazine hydrate (purity 80%, 0.49 mol) was added dropwise. After stirring for 1.5 h, the mixture was cooled to room temperature. The catalyst was filtered, and the filtrate was washed with 100 g of water. The layers were separated to obtain the organic phase. The solvent was removed under reduced pressure, and 52 g of ethanol was added to crystallize the mixture. After filtration and drying, 45.3 g of gray solid compound 1B with a purity of 99.50% and a yield of 95.9% was obtained.

[0101] (3) Add 11.6g of N-ethyl-N-methyl-formamide (99.00%, 0.132mol) and 60g of 1,2-dichloroethane (99.5% purity) to a 500mL four-necked round-bottom flask in sequence. Control the temperature at 25℃ and slowly add 60g of triphosgene (99.00%, 19.8g, 0.066mol) in dichloroethane solution. After the addition is completed in 30min, stir for 0.5h. Then add 37.8g of solid compound 1B (99.50%, 0.12mol purity) in ten batches. Heat the reaction solution to 40℃ and react for 3h. Add 40g of water and adjust the pH to 9.0 with 30% NaOH aqueous solution. Separate the liquid to obtain the organic phase. Remove 70g of solvent. Cool the remaining bottom of the flask to -5℃ to crystallize. After filtration and drying, obtain 44.9g of white solid compound 1 with a purity of 99.68% and a yield of 97.5%.

[0102] Examples 2 and 3 were characterized by the same mass spectrometry and NMR as Example 1, which verified the correctness of their product structures.

[0103] Example 4

[0104] In this embodiment, R is used to prepare The product, namely (Hereinafter referred to as "Compound 2"), the reaction route is shown below:

[0105]

[0106] The specific steps are as follows:

[0107] (1) Add 46.8g of 1-chloro-2,5-dimethyl-4-nitrobenzene (99.0% purity, 0.25mol), 69.7g of anhydrous potassium carbonate (99.0% purity, 0.5mol), KI (0.3g, 99.5% purity) and 100g of [unspecified substance] to a 1L four-necked round-bottom flask in sequence. N,N-Dimethylacetamide (DMA, purity 99.5%) was heated to 120°C, and a DMA solution (65 g) of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (purity 99.99%, 49.8 g, 0.3 mol) was slowly added dropwise over 1.5 h. The reaction mixture was then heated to 155°C and reacted for 8 h. After cooling to 90°C, 300 g of water was added, and the mixture was cooled to 5°C and filtered. A wet filter cake was obtained, and 45 g of methanol was added to crystallize the mixture. After filtration and drying, 75.8 g of a white solid compound 2A was obtained, with a purity of 99.46% and a yield of 95.7%. LC / MS [M+1]: m / z = 316.0903; 1 The following are the H NMR (400MHz, DMSO-d6) data (δ [ppm]): 8.07 (s, 1H), 7.16 (s, 1H), 6.40 (s, 1H), 3.80 (s, 3H), 2.48 (s, 3H), 2.35 (s, 3H).

[0108] (2) 47.5 g of nitro ether 2A (purity 99.46%, 0.15 mol), 100 g of 1,2-dichloroethane (purity 99.5%), 50 g of methanol (purity 99.9%), and 6.2 g of Raney nickel were added sequentially to a 500 mL four-necked round-bottom flask. The reaction solution was heated to 60 °C, and 31.0 g of hydrazine hydrate (purity 80%, 0.49 mol) was added dropwise. After reacting for 1.0 h, the mixture was cooled to room temperature, the catalyst was filtered, and the filtrate was washed with 30 g of water. The mixture was separated into layers to obtain an organic phase. The temperature was lowered to 5 °C to crystallize the mixture. After filtration and drying, 42.4 g of gray solid compound 2B was obtained, with a purity of 99.10% and a yield of 97.9%. LC / MS [M+1]: m / z = 286.1161; 1 The following are the H NMR (400MHz, DMSO-d6) data (δ [ppm]): 6.79 (s, 1H), 6.52 (s, 1H), 5.63 (s, 1H), 4.83 (s, 2H), 3.80 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H).

[0109] (3) Add 19.0g of N-ethyl-N-methyl-formamide (purity 99.00%, 0.216mol) and 88g of 1,2-dichloroethane (purity 99.5%) to a 500mL four-necked round-bottom flask in sequence. Control the temperature at 35℃ and slowly add 28.5g of thionyl chloride (purity 99.00%, 0.237mol). After the addition is completed in 30min, continue stirring for 0.5h. Then add 34.6g of solid compound 2B (purity 99.10%, 0.12mol) in ten batches. Heat the reaction solution to 45℃ and react for 1h. Add 80g of water and adjust the pH to 9.6 with 30% NaOH aqueous solution. Separate the liquid to obtain the organic phase. After removing the solvent, add 50g of ethanol to crystallize. After filtration and drying, 41.1g of white solid compound 2 with a purity of 99.19% and a yield of 95.9% is obtained. LC / MS[M+1]: m / z=355.1740; 1 ¹H NMR (400MHz, DMSO-d6) data are as follows (δ [ppm]): 6.90 (s, 1H), 6.72 (s, 1H), 5.74 (s, 1H), 3.80 (s, 3H), 3.34 (s, 3H), 2.92 (br s, 3H), 2.13 (s, 6H), 1.14–1.11 (m, 3H).

[0110] Example 5

[0111] In this embodiment, R is used to prepare The product, namely The preparation method includes the following steps:

[0112] (1) Add 53.1g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (99.99% purity, 0.32mol), 41.9g of anhydrous potassium carbonate (99.0% purity, 0.3mol), KI (0.4g, 99.5% purity) and 100g of N,N-dimethylacetamide (DMA, 99.5% purity) to a 500mL three-necked round-bottom flask in sequence. Heat to 135℃ and add 37.3g of the solution in ten batches. 1-Chloro-2,5-dimethyl-4-nitrobenzene (purity 99.5%, 0.2 mol) was reacted at 148°C for 10 h, cooled to 90°C, and 150 g of water was added. The mixture was then cooled to 10°C and filtered to obtain a wet filter cake. This cake was crystallized with 70 g of ethanol, filtered, and dried to obtain 60.4 g of a white solid compound 2A with a purity of 99.06% and a yield of 95.0%.

[0113] (2) 47.7 g of nitro ether 2A (purity 99.06%, 0.15 mol), 50 g of 1,2-dichloroethane (purity 99.5%), 72 g of methanol (purity 99.9%) and 6.6 g of Raney nickel were added sequentially to a 500 mL four-necked round-bottom flask. The reaction solution was heated to 50 °C, and 29.0 g of hydrazine hydrate (purity 80%, 0.46 mol) was added dropwise. After the addition was complete, the mixture was stirred for 1.5 h, then cooled to room temperature. The catalyst was filtered, and 80 g of solvent was removed from the filtrate under reduced pressure. The filtrate was washed with 30 g of water, and the layers were separated to obtain the organic phase. The temperature was lowered to 0 °C to crystallize, and after filtration and drying, 42.4 g of gray solid compound 2B with a purity of 99.36% and a yield of 98.2% was obtained.

[0114] (3) Add 12.7g of N-ethyl-N-methyl-formamide (purity 99.00%, 0.144mol) and 50g of 1,2-dichloroethane (purity 99.5%) to a 500mL four-necked round-bottom flask in sequence. Control the temperature at 30℃ and slowly add 20g of triphosgene (purity 99.00%, 17.3g, 0.057mol) in dichloroethane solution. After the addition is completed in 30min, stir for another 0.5h. Then add 34.5g of solid compound 2B (purity 99.36%, 0.12mol) in ten batches. Continue the reaction at 30℃ for 1.5h. Then add 80g of water and adjust the pH to 8.9 with 30% NaOH aqueous solution. Separate the liquid to obtain the organic phase, cool to -5℃ to crystallize, filter and dry to obtain 41.0g of white solid compound 2 with a purity of 99.51% and a yield of 96.0%.

[0115] Example 6

[0116] In this embodiment, R is used to prepare The product, namely The preparation method includes the following steps:

[0117] (1) Add 59.8 g of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (99.99% purity, 0.36 mol), 36.3 g of anhydrous potassium carbonate (99.0% purity, 0.26 mol), KI (0.48 g, 99.5% purity) and 130 g of N,N-dimethylacetamide (DMA, 99.5% purity) to a 500 mL three-necked round-bottom flask in sequence. Heat to 140 °C and add 37.3 g of KI in ten batches. 1-Chloro-2,5-dimethyl-4-nitrobenzene (purity 99.5%, 0.2 mol) was reacted at 160°C for 7 hours, cooled to 90°C, and 200 g of water was added. The mixture was then cooled to 15°C and filtered to obtain a wet filter cake. 40 g of ethanol was added to crystallize the mixture, and after filtration and drying, 59.8 g of a white solid compound 2A was obtained, with a purity of 99.23% and a yield of 94.2%.

[0118] (2) 47.6 g of nitro ether 2A (purity 99.23%, 0.15 mol), 96 g of 1,2-dichloroethane (purity 99.5%), 50 g of methanol (purity 99.9%) and 6.6 g of Raney nickel were added sequentially to a 500 mL four-necked round-bottom flask. The reaction solution was heated to 55 °C, and 31.9 g of hydrazine hydrate (purity 80%, 0.51 mol) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 0.5 h. The mixture was then cooled to room temperature, the catalyst was filtered, and the filtrate was washed with 50 g of water and separated into layers to obtain the organic phase. The temperature was lowered to -5 °C to crystallize the organic phase. After filtration and drying, 40.9 g of gray solid compound 2B with a purity of 99.65% and a yield of 95.0% was obtained.

[0119] (3) Add 15.8g of N-ethyl-N-methyl-formamide (purity 99.00%, 0.18mol) and 40g of [unclear text] to a 500mL four-necked round-bottom flask. 1,2-Dichloroethane (purity 99.5%) was used. A solution of 30 g of triphosgene (purity 99.00%, 24.3 g, 0.081 mol) in dichloroethane was slowly added dropwise at 25°C for 30 min. After the addition was complete, the mixture was stirred for another 0.5 h. Then, a solution of 35 g of solid compound 2B (purity 99.65%, 0.12 mol) in dichloroethane was slowly added dropwise for 1 h. After the addition was complete, the reaction was continued at 25°C for 2 h. Then, 80 g of water was added, and the pH was adjusted to 8.8 with a 30% NaOH aqueous solution. The organic phase was separated, the solvent was removed, and 52 g of methanol was added for crystallization. After filtration and drying, 41.7 g of white solid compound 2 was obtained, with a purity of 99.66% and a yield of 97.8%.

[0120] Examples 5 and 6 were characterized by the same mass spectrometry and NMR as Example 4, which verified the correctness of their product structures.

[0121] Example 7

[0122] In this embodiment, R is used to prepare The product, namely (Hereinafter referred to as "Compound 3"), the reaction route is shown below:

[0123]

[0124] The specific steps are as follows:

[0125] (1) Add 46.8g of 1-chloro-2,5-dimethyl-4-nitrobenzene (99.0% purity, 0.25mol), 69.7g of anhydrous potassium carbonate (99.0% purity, 0.5mol), KI (0.66g, 99.5% purity) and 60g of [unspecified substance] to a 1L four-necked round-bottom flask in sequence. N,N-Dimethylacetamide (DMA, purity 99.5%) was heated to 125°C, and a DMA solution (90 g) of 1-(4-fluorophenyl)-1H-pyrazole-3-ol (purity 99.99%, 57.9 g, 0.325 mol) was slowly added dropwise over 1 hour. The reaction mixture was then heated to 158°C and reacted for 5 hours. After cooling to 80°C, 100 g of water was added, and the mixture was cooled to 5°C and filtered. A wet filter cake was obtained, and 90 g of methanol was added to crystallize the mixture. After filtration and drying, 78.6 g of a white solid compound 3A was obtained, with a purity of 99.33% and a yield of 95.4%. LC / MS [M+1]: m / z = 328.1092; 1 The following are the 1H NMR (400MHz, DMSO-d6) data (δ[ppm]): 8.87 (s, 1H), 8.01 (s, 1H), 7.72 (d, J = 8.4Hz, 2H), 7.43 (d, J = 8.4Hz, 2H), 7.06 (s, 1H), 6.23 (s, 1H), 2.33 (d, J = 14.8Hz, 3H), 2.16 (s, 3H).

[0126] (2) 49.4 g of nitro ether 3A (purity 99.33%, 0.15 mol), 50 g of 1,2-dichloroethane (purity 99.5%), 50 g of methanol (purity 99.9%), and 7.4 g of Raney nickel were added sequentially to a 500 mL four-necked round-bottom flask. The reaction solution was heated to 55 °C, and 30 g of hydrazine hydrate (purity 80%, 0.48 mol) was added dropwise. After reacting for 1.0 h, the mixture was cooled to room temperature. The catalyst was filtered off, and the filtrate was washed with 55 g of water and separated into layers to obtain the organic phase. The solvent was removed under reduced pressure, and 90 g of ethanol was added to crystallize the mixture. After filtration and drying, 42.9 g of gray solid compound 3B was obtained, with a purity of 99.42% and a yield of 95.6%. LC / MS [M+1]: m / z = 298.1350; 1 The following are the 1H NMR (400MHz, DMSO-d6) data (δ[ppm]): 8.43 (s, 1H), 7.66 (d, J = 8.4Hz, 2H), 7.49 (d, J = 8.4Hz, 2H), 6.67 (s, 1H), 6.43 (s, 1H), 5.76 (s, 1H), 4.61 (s, 2H), 2.04 (d, J = 14.4Hz, 6H).

[0127] (3) Add 14.8 g of N-ethyl-N-methyl-formamide (purity 99.00%, 0.168 mol) and 54 g of 1,2-dichloroethane (purity 99.5%) to a 500 mL four-necked round-bottom flask in sequence. Control the temperature at 30 °C and slowly add 30.3 g of thionyl chloride (purity 99.00%, 0.252 mol). After the addition is completed in 30 min, continue stirring for 0.5 h. Add 35.9 g of solid compound 3B (purity 99.42%, 0.12 mol) in ten batches. After the addition is completed, heat the reaction solution to 50 °C and react for 2 h. Add 40 g of water and adjust the pH to 8.2 with 10% Na2CO3 aqueous solution. Separate the liquid to obtain the organic phase, remove the solvent, add 50 g of methanol to crystallize, filter and dry to obtain 42.8 g of white solid compound 3 with a purity of 99.03% and a yield of 96.4%. LC / MS[M+1]: m / z=367.1928; 1 HNMR (400MHz, DMSO-d6) data are as follows (δ [ppm]): 8.58 (d, J = 2.4Hz, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.67 (s, 1H), 7.43 (d, J = 8.8Hz, 2H), 6.77 (s, 1H), 6.56 (s, 1H), 5.87 (d, J = 2.4Hz, 1H), 3.39 (s, 2H), 2.87 (s, 3H), 2.19 (d, J = 3.2Hz, 6H), 1.34–1.09 (m, 3H).

[0128] Comparative Example 1

[0129] In this comparative example, R is used to prepare The product, namely The preparation method is described in Example 3 of CN116003322 A, and the specific steps are as follows:

[0130] (1) 1-Chloro-2,5-dimethyl-4-nitrobenzene (10 g, 53.9 mmol) and potassium carbonate (8.9 g, 64.65 mmol) were added to 80 mL of DMF, heated to reflux, and 1-(4-chlorophenyl)-1H-pyrazole-3-ol (10.5 g, 53.9 mmol) was added. The mixture was refluxed for 20 h, and the reaction solution was cooled to room temperature. 200 mL of water was added, and the mixture was filtered to obtain a yellow solid. The solid was washed with saturated sodium chloride water, dried in an oven, and the residue was purified by column chromatography (eluent:PE:EA = 5:1) to obtain 9.64 g of pale yellow solid, with a yield of 52.1%.

[0131] (2) 1-(4-chlorophenyl)-3-(2,5-dimethyl-4-nitrophenoxy)-1H-pyrazole (4.79 g, 13.96 mmol) was added to 30 mL of anhydrous ethanol, and reduced iron powder (2.35 g, 41.89 mmol) was added. 10 mL of saturated ammonium chloride aqueous solution was added dropwise and the mixture was refluxed. After 8 h, the reaction solution was cooled to room temperature, and 30 mL of water and 50 mL of ethyl acetate were added. The mixture was extracted by separation, and the organic layer was taken. It was washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent:PE:EA = 10:1) to give 3.91 g of brown solid, with a yield of 89.5%.

[0132] (3) 2,5-Dimethyl-4-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)aniline (2.49 g, 7.96 mmol), triethyl orthoformate (8.9 g, 60.05 mmol) and p-toluenesulfonic acid monohydrate (25 mg, 0.13 mmol) were added to the reaction flask, heated to reflux for 12 h, cooled to room temperature, and distilled under pressure until no more liquid dripped, yielding a brown oily substance, which was directly proceeded to the next step without separation.

[0133] (4) (E)-N-(4-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)-2,5-dimethylphenyl)formamidinyl ether (2.93 g, 7.96 mmol) was dissolved in 30 mL of dichloromethane, and methyl ethylamine (1.4 g, 23.88 mmol) was added. The mixture was heated to reflux and reacted for 4 h until the reaction was complete. The reaction solution was cooled to room temperature, and 30 mL of water was added. The mixture was extracted by separation, and the organic layer was washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent:PE:EA = 10:1) to give 2.38 g of white solid, with a yield of 78.3%.

[0134] As can be seen, in this method, an amino ether is obtained through condensation and reduction reactions, and then the target compound is obtained through a two-step reaction with triethyl orthoformate and methyl ethylamine. Due to the low reactivity of triethyl orthoformate, the reaction time is long (12 hours), and the yield of the final reaction with methyl ethylamine is low (only 78.3%), which is much lower than the yield of the preparation method provided by this invention. In addition, the cost of methyl ethylamine is also relatively expensive.

[0135] The applicant declares that the present invention illustrates the preparation method of the pyrazole ether compounds through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing a pyrazole ether compound, characterized in that, The preparation method includes: (1) A condensation reaction is carried out between 1-chloro-2,5-dimethyl-4-nitrobenzene and a pyrazol alcohol compound to obtain a nitro ether with the structure shown in formula A1, as follows: (2) The nitro ether obtained in step (1) with the structure shown in formula A1 is reduced to obtain the amino ether with the structure shown in formula B2, as shown in the following reaction: (3) The amino ether compound with the structure shown in formula B2 obtained in step (2) is reacted with N-ethyl-N-methyl-formamide to synthesize a pyrazole ether compound with the structure shown in formula I. The reaction formula is as follows: In steps (1) to (3), R is selected from... The asterisk (*) represents the connection position of the functional group.

2. The preparation method according to claim 1, characterized in that, The pyrazoloids in step (1) include any one of 1-(4-chlorophenyl)-1H-pyrazol-3-ol, 1-(4-fluorophenyl)-1H-pyrazol-3-ol, 1-(4-bromophenyl)-1H-pyrazol-3-ol or 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol; Preferably, the molar ratio of the pyrazolol compound in step (1) to 1-chloro-2,5-dimethyl-4-nitrobenzene is (1.0-3.0):1, and more preferably (1.0-2.0):1; Preferably, the condensation reaction in step (1) is carried out in the presence of a basic compound; Preferably, the alkaline compound includes any one or a combination of at least two of sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, or sodium hydride, with potassium carbonate being more preferred; Preferably, the molar ratio of the basic compound to 1-chloro-2,5-dimethyl-4-nitrobenzene is (1.2-3.0):1, more preferably (1.2-2.0):1; Preferably, the condensation reaction in step (1) is carried out in the presence of a catalyst; Preferably, the catalyst comprises potassium iodide; Preferably, the catalyst comprises 0.1-5.0% by mass, more preferably 0.5-1.5%, based on 100% of 1-chloro-2,5-dimethyl-4-nitrobenzene; Preferably, the solvent for the condensation reaction in step (1) includes any one or a combination of at least two of 1,2-dichloroethane, toluene, acetonitrile, methanol, ethanol, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably N,N-dimethylacetamide; Preferably, the mass ratio of the solvent to 1-chloro-2,5-dimethyl-4-nitrobenzene in the condensation reaction of step (1) is (0.5-5.0):1, and more preferably (1-4):

1.

3. The preparation method according to claim 1 or 2, characterized in that, The temperature of the condensation reaction in step (1) is 140-160℃, more preferably 147-160℃; Preferably, the condensation reaction in step (1) takes 1 to 24 hours, more preferably 4 to 10 hours; Preferably, after the condensation reaction in step (1) is completed, a post-processing step is also included; Preferably, the post-processing The process includes the following steps: adding water to the reaction system, cooling, filtering, and obtaining a crude nitro ether product with the structure shown in Formula A1; then, subjecting the crude product to solvent crystallization, solid-liquid separation, and drying to obtain a nitro ether product with the structure shown in Formula A1. Preferably, the reaction yield of the nitro ether compound with the structure shown in Formula A1 is ≥94.2%; Preferably, the content of the nitro ether compound with the structure shown in Formula A1 is ≥99.06%.

4. The preparation method according to any one of claims 1-3, characterized in that, The reducing agent used in the reduction reaction in step (2) includes hydrazine hydrate; Preferably, the molar ratio of the nitro ether to the reducing agent is 1:(2.0-4.0), more preferably 1:(3.0-3.5); Preferably, the reduction reaction in step (2) is carried out in the presence of a catalyst, which includes any one or a combination of at least two of palladium on carbon, platinum on carbon, palladium dioxide, Raney nickel or ferric chloride, preferably Raney nickel; Preferably, the catalyst comprises 12-18% by mass of 100% nitro ether, more preferably 13-15% by mass; Preferably, the solvent for the reduction reaction in step (2) includes any one or a combination of at least two of dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, toluene or chlorobenzene, preferably a combination of 1,2-dichloroethane and methanol; Preferably, the mass ratio of the solvent to the nitro ether in the reduction reaction of step (2) is (0.5-4.0):1, and more preferably (2-4):

1.

5. The preparation method according to any one of claims 1-4, characterized in that, The temperature of the reduction reaction in step (2) is 30-80℃, more preferably 50-60℃; Preferably, the reduction reaction in step (2) takes 0.5 to 5 hours, more preferably 0.5 to 2 hours; Preferably, after the reduction reaction in step (2) is completed, a post-processing step is also included. The post-processing method includes: filtering to recover the catalyst, retaining the filtrate, washing the filtrate with water, separating the liquid, retaining the organic phase, crystallizing or crystallizing the organic phase, separating the solid and liquid, drying, and obtaining the amino ether compound with the structure shown in B2.

6. The preparation method according to any one of claims 1-5, characterized in that, The reaction yield of the amino ether compound with the structure shown in Formula B2 is ≥95.0%; Preferably, the content of the amino ether compound with the structure shown in Formula B2 is ≥99.1%.

7. The preparation method according to any one of claims 1-6, characterized in that, The reaction described in step (3) is carried out in the presence of a chlorinating agent; Preferably, the chlorinating agent includes any one or a combination of at least two of thionyl chloride, triphosgene, oxaloyl chloride, phosphorus trichloride, and phosphorus pentachloride, and more preferably thionyl chloride and / or triphosgene; Preferably, the molar ratio of the chlorinating agent to N-ethyl-N-methyl-formamide is (0.3-3.0):1, more preferably (0.32-1.5):1; Preferably, in step (3), the molar ratio of N-ethyl-N-methyl-formamide to amino ether is (1.05-3.0):1, and more preferably (1.1-2.0):1; Preferably, the solvent for the reaction in step (3) includes any one or a combination of at least two of dichloromethane, 1,2-dichloroethane, chloroform, toluene, or chlorobenzene; Preferably, the mass ratio of the solvent to the amino ether in step (3) is (0.5-4.0):1, and more preferably (1.0-3.0):

1.

8. The preparation method according to any one of claims 1-7, characterized in that, The reaction temperature in step (3) is 20-80℃, more preferably 25-50℃; Preferably, the reaction time in step (3) is 1 to 4 hours, more preferably 2 to 3 hours; Preferably, after the reaction in step (3) is completed, a post-processing step is also included. The post-processing method includes: adding an alkaline solution to adjust the pH value of the reaction solution to 8-10, separating the liquid to obtain an organic layer, and then crystallizing or precipitating the liquid, separating the solid and liquid, and drying to obtain a pyrazole ether compound with the structure of formula I.

9. The preparation method according to any one of claims 1-8, characterized in that, The reaction yield of the pyrazole ether compounds with the structure shown in Formula I is ≥95.9%; Preferably, the content of the pyrazole ether compound with the structure shown in Formula I is ≥99.19%.

10. A preparation method according to any one of claims 1-9, characterized in that, The preparation method includes: (1) 1-Chloro-2,5-dimethyl-4-nitrobenzene and pyrazol alcohols are condensed in the presence of alkaline compounds, catalysts and solvents at 140-160°C for 1-24 hours. Then, the mixture is cooled to 70-90°C and water is added to the reaction system. The mixture is then cooled to 5-25°C and filtered to obtain a crude nitro ether product with the structure shown in Formula A1. The crude product is subjected to solvent crystallization, solid-liquid separation and drying to obtain a nitro ether product with the structure shown in Formula A1. (2) The nitro ether obtained in step (1) with the structure shown in formula A1 is reduced at 30-80°C in the presence of solvent, catalyst and reducing agent for 0.5-5 h. Then the catalyst is recovered by filtration, the filtrate is retained, the filtrate is washed with water, separated, the organic phase is retained, the organic phase is crystallized or crystallized, solid-liquid separation is performed, and dried to obtain the amino ether with the structure shown in formula B2. (3) The amino ether obtained in step (2) with the structure shown in formula B2 is reacted with N-ethyl-N-methyl-formamide in the presence of solvent and chlorinating agent at 20-80℃ for 1-4h. Then, an alkaline solution is added to adjust the pH of the reaction solution to 8-10. The organic layer is separated and then crystallized or precipitated, separated from the solid and liquid, and dried to synthesize the pyrazole ether compound with the structure shown in formula I.

Images