Synthetic method of difluopyrazole acid, ester thereof and intermediate thereof

Abstract

The invention belongs to the technical field of organic synthesis of pesticides, and discloses a synthesis method of difluopyrazole acid, ester thereof and an intermediate of the difluopyrazole acid. The synthesis method of the intermediate of the difluopyrazole acid or ester comprises the following steps: reacting a compound I shown in a formula (I) with a chlorinating agent to obtain a compound II shown in a formula (II); taking the compound II and formaldehyde, and adding an alkaline reagent to react to obtain a compound III as shown in a formula (III); and taking the compound III and hydrogen, and adding a catalyst to react to obtain the intermediate of the difluopyrazole acid or ester as shown in the formula (IV). The intermediate of the difluropyrazole acid or the difluropyrazole ester is used in a synthesis method of the difluropyrazole acid and the difluropyrazole ester, and efficient synthesis of the difluropyrazole acid and the difluropyrazole ester is achieved. The synthesis method disclosed by the invention is simple and convenient to operate, can still obtain higher product quality and has high conversion rate through multi-step continuous feeding, generates few three wastes, is environment-friendly, and is suitable for green large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis of pesticides, and in particular to a method for synthesizing difluoropyrazole acid, its ester and its intermediates. Background Art

[0002] In recent years, people's in-depth exploration of fluorine- and nitrogen-containing heterocyclic compounds has not only enriched the field of chemical synthesis, but also brought revolutionary changes to the pharmaceutical, pesticide and other industries. In this series of compounds, difluoromethyl-substituted compounds have become important molecules in the research and development of new pharmaceuticals, pesticides and other fields due to their unique structure, activity and mechanism of action, especially compounds containing difluoromethyl, which have shown unparalleled advantages and potential in the creation of new pesticides. 3-Difluoromethyl-1H-methylpyrazole-4-carboxylic acid, as a difluoromethyl-substituted compound, can be used as a succinate dehydrogenase inhibitor (SDHI) fungicide, which plays an important role in controlling crop diseases and increasing crop yields.

[0003] There are four main methods for synthesizing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid in the prior art:

[0004] (1) Using ethyl difluoroacetate as the key raw material, 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid is obtained through a series of chemical reaction steps such as Claisen condensation, ethoxymethylation, cyclization, saponification, and acidification (see the schematic diagram of the reaction flow chart). Figure 1 ). This synthetic route occupies a dominant position in current industrial production, mainly due to its low raw material cost and suitability for large-scale production. However, in the ring-closing step with methylhydrazine, this synthetic route produces a large amount of isomers that are difficult to separate as by-products, which not only reduces the purity of the product, but also has an adverse effect on the subsequent use effect.

[0005] (2) 4,4-dichloroacetic acid is first converted into 4,4-dichloroacetyl chloride, and then the dichloroacetyl chloride is used as the starting material to obtain the target product 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid through a series of chemical reaction steps such as coupling, cyclization, fluorination, saponification, and acidification. However, this synthetic route faces challenges in industrial production. Its reaction conditions are relatively harsh, and the requirements for production equipment and pipeline systems are high. At the same time, the operation steps are also relatively complicated, which increases the difficulty and cost of production.

[0006] (3) 4,4-difluoroacetic acid is converted into 4,4-difluoroacetyl chloride, and difluoroacetyl chloride is used as a raw material, coupled with ethyl 3-dimethylaminoacrylate, and then cyclized with methyl hydrazine, and finally saponified and acidified to obtain 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid. The reaction temperature required for this synthetic route is relatively low (-20°C). When it is carried out in industrial production, a precise temperature control system is required to ensure that the reaction is carried out within the required temperature range. At the same time, the reaction product needs to be separated and purified multiple times during the reaction process, which increases the complexity and cost of the production equipment.

[0007] (4) 1,1-difluoroacetone is used as a raw material to react with methyl hydrazine, and then reacts with phosphorus oxychloride and N,N-dimethylformamide to undergo a cyclization reaction, and then is oxidized with hydrogen peroxide under alkaline conditions to obtain 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid. However, the 1,1-difluoroacetone used in this route is relatively expensive, and the yield of this reaction is low, which is not suitable for industrial-scale production.

[0008] In summary, the above-mentioned different difluoropyrazole acid synthesis methods all have the problems of cumbersome synthesis steps, low reaction yield, high raw material cost or difficulty in synthesis, and are not conducive to industrial production. At the same time, in the synthesis process of difluoropyrazole acid, a large amount of isomers that are difficult to separate are easily produced as by-products, resulting in a significant decrease in product yield and insufficient purity. Therefore, it is urgent to develop a more efficient, stable, green and environmentally friendly synthesis method for difluoropyrazole compounds that is easy to control. Summary of the invention

[0009] The object of the present invention is to overcome the deficiencies of the prior art and provide a method for synthesizing difluoropyrazole acid, its esters and their intermediates.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] In a first aspect, the present invention provides a method for synthesizing an intermediate of a difluoropyrazole acid or ester, characterized in that the method comprises the following steps:

[0012] (1) reacting a compound I represented by formula (I) with a chlorinating agent to obtain a compound II represented by formula (II);

[0013]

[0014] (2) taking the compound II and formaldehyde, adding an alkaline reagent to react to obtain a compound III represented by formula (III);

[0015]

[0016] (3) taking the compound III and hydrogen, adding a catalyst to react, and obtaining the intermediate of the difluoropyrazole acid or ester represented by formula (IV);

[0017]

[0018] In the synthesis method of the intermediate of difluoropyrazole acid or ester of the present invention, the intermediate 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-methanol of difluoropyrazole acid or ester is continuously synthesized through the three key steps of chlorination, hydroxymethylation and hydrogenation reduction. The reaction operation of the present invention is greatly simplified, and the multi-step intermediates are not separated separately and are directly added to the next step reaction without purification, which significantly reduces the post-processing process, shortens the production cycle, and improves the reaction efficiency. At the same time, although the process is added in multiple steps, it can still obtain a higher product quality and has a high conversion rate. The method of the present invention generates less three wastes during the synthesis process, is environmentally friendly, and is suitable for green large-scale production.

[0019] As a preferred embodiment of the synthesis method of the intermediate of difluoropyrazole acid or ester of the present invention, the compound I is obtained by reacting ethyl difluoroacetoacetate and methylhydrazine.

[0020] Preferably, in the method for preparing compound I, the reaction temperature is 50°C to 100°C, and the reaction time is 2h to 10h.

[0021] More preferably, the reaction temperature is 60° C. to 90° C., and the reaction time is 5 h to 8 h.

[0022] More preferably, the reaction temperature is 70°C to 80°C.

[0023] Preferably, the molar ratio of the ethyl difluoroacetoacetate to the methylhydrazine is 1:(1-5).

[0024] More preferably, the molar ratio of the ethyl difluoroacetoacetate to the methylhydrazine is 1:(2-4).

[0025] More preferably, the molar ratio of the ethyl difluoroacetoacetate to the methylhydrazine is 1:(2-3).

[0026] Preferably, the methylhydrazine is added dropwise; the temperature of the addition is -10°C to 10°C.

[0027] More preferably, the dropping temperature is -5°C to 5°C.

[0028] More preferably, the dropping temperature is 0°C.

[0029] As a preferred embodiment of the method for synthesizing the intermediate of difluoropyrazole acid or ester of the present invention, in step (1), the chlorinating agent is at least one of chlorine, thionyl chloride, oxalyl chloride, sulfonyl chloride, benzoyl chloride, phosphorus pentachloride, and phosphorus oxychloride.

[0030] Preferably, the chlorinating agent is phosphorus oxychloride.

[0031] As a preferred embodiment of the method for synthesizing the intermediate of the difluoropyrazole acid or ester of the present invention, in step (1), the molar ratio of the compound I to the chlorinating agent is 1:(1-10).

[0032] More preferably, the molar ratio of the compound I to the chlorinating agent is 1:(2-8).

[0033] More preferably, the molar ratio of the compound I to the chlorinating agent is 1:(3-5).

[0034] Most preferably, the molar ratio of the compound I to the chlorinating agent is 1:4.

[0035] As a preferred embodiment of the method for synthesizing the intermediate of the difluoropyrazole acid or ester of the present invention, in step (1), a solvent is further added to the reaction; the solvent is at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, toluene, and 1,4-dioxane.

[0036] Preferably, the solvent is toluene or 1,2-dichloroethane.

[0037] Preferably, the mass ratio of the chlorinating agent to the solvent is 1:(1-20).

[0038] Further preferably, the mass ratio of the chlorinating agent to the solvent is 1:(5-15).

[0039] More preferably, the mass ratio of the chlorinating agent to the solvent is 1:(5-10).

[0040] Most preferably, the mass ratio of the chlorinating agent to the solvent is 1:6.

[0041] As a preferred embodiment of the method for synthesizing the intermediate of difluoropyrazole acid or ester of the present invention, in step (1), the reaction temperature is 50° C. to 120° C., and the reaction time is 1 h to 10 h.

[0042] Preferably, the reaction temperature is 100° C., and the reaction time is 1 h to 5 h.

[0043] More preferably, the reaction time is 3 h.

[0044] As a preferred embodiment of the method for synthesizing the intermediate of the difluoropyrazole acid or ester of the present invention, in step (2), the alkaline reagent is at least one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.

[0045] Preferably, the alkaline agent is sodium hydroxide.

[0046] As a preferred embodiment of the method for synthesizing the intermediate of the difluoropyrazole acid or ester of the present invention, in step (2), the molar ratio of the compound II to the alkaline reagent is 1:(0.5-10).

[0047] Preferably, the molar ratio of the compound II to the alkaline agent is 1:(1-5).

[0048] Further preferably, the molar ratio of the compound II to the alkaline agent is 1:1.5.

[0049] As a preferred embodiment of the method for synthesizing the intermediate of the difluoropyrazole acid or ester of the present invention, in step (2), the molar ratio of the compound II to the formaldehyde is 1:(1-10).

[0050] Preferably, the molar ratio of the compound II to the formaldehyde is 1:(1-5).

[0051] Further preferably, the molar ratio of the compound II to the formaldehyde is 1:1.5.

[0052] As a preferred embodiment of the method for synthesizing the intermediate of difluoropyrazole acid or ester of the present invention, in step (2), the formaldehyde is a formaldehyde aqueous solution with a mass concentration of 30% to 45%.

[0053] Preferably, the formaldehyde is a formaldehyde aqueous solution with a mass concentration of 37%.

[0054] As a preferred embodiment of the method for synthesizing the intermediate of difluoropyrazole acid or ester of the present invention, in step (2), a solvent is further added to the reaction; the solvent is at least one of water, acetonitrile, tetrahydrofuran, toluene, dichloromethane, and 1,2-dichloroethane.

[0055] Preferably, the solvent is acetonitrile.

[0056] As a preferred embodiment of the method for synthesizing the intermediate of difluoropyrazole acid or ester of the present invention, in step (2), the reaction temperature is -10°C to 50°C, and the reaction time is 1h to 10h.

[0057] Preferably, the reaction temperature is 0°C to 40°C, and the reaction time is 1h to 5h.

[0058] More preferably, the reaction temperature is 10°C to 30°C, and the reaction time is 2 hours.

[0059] As a preferred embodiment of the method for synthesizing the intermediate of the difluoropyrazole acid or ester of the present invention, in step (3), the catalyst is at least one of Raney nickel, palladium carbon, palladium hydroxide carbon, platinum carbon, ruthenium carbon and rhodium carbon.

[0060] Preferably, the catalyst is palladium on carbon.

[0061] As a preferred embodiment of the method for synthesizing the intermediate of the difluoropyrazole acid or ester of the present invention, in step (3), a solvent is further added to the reaction; the solvent is at least one of water, methanol, ethanol, ethyl acetate, acetonitrile, tetrahydrofuran, toluene, dichloromethane, and 1,2-dichloroethane.

[0062] Preferably, the solvent is methanol.

[0063] As a preferred embodiment of the method for synthesizing the intermediate of difluoropyrazole acid or ester of the present invention, in step (3), the reaction temperature is 30° C. to 80° C. and the reaction time is 1 h to 10 h.

[0064] Preferably, the reaction temperature is 50° C. and the reaction time is 1 h to 5 h.

[0065] More preferably, the reaction time is 4 hours.

[0066] In a second aspect, the present invention provides a method for synthesizing difluoropyrazole acid, comprising the following steps: reacting the difluoropyrazole acid or ester intermediate with an oxidant to obtain difluoropyrazole acid represented by formula (V);

[0067]

[0068] As a preferred embodiment of the synthesis method of difluoropyrazole acid of the present invention, the oxidant is at least one of oxygen, hydrogen peroxide, perborate, hypochlorite, chlorite, manganese dioxide, ferrate, permanganate, high-valent chromium salt, chromic acid, dichromic acid, OXONE, periodate, dichromate, sodium peroxide, Jones reagent, 2-iodoacylbenzoic acid, and Dess-Martin reagent.

[0069] Preferably, the oxidant is oxygen.

[0070] As a preferred embodiment of the synthesis method of difluoropyrazole acid of the present invention, a solvent is further added to the reaction; the solvent is at least one of water, bis(methoxypropyl) ether, PEG400, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, and N-methylpyrrolidone.

[0071] Preferably, the solvent is water or bis(methoxypropyl) ether.

[0072] As a preferred embodiment of the method for synthesizing difluoropyrazole acid of the present invention, the reaction temperature is 30° C. to 180° C., and the reaction time is 1 h to 24 h.

[0073] Preferably, the reaction temperature is 60°C to 120°C, and the reaction time is 12h to 18h.

[0074] More preferably, the reaction temperature is 60° C. and the reaction time is 12 h.

[0075] In a third aspect, the present invention provides a method for synthesizing difluoropyrazole esters, comprising the following steps: taking the difluoropyrazole acid or ester intermediate V and an oxidant, adding alcohol to react, and obtaining a difluoropyrazole ester represented by formula (VI);

[0076]

[0077] Wherein, the R is any one of methyl, ethyl, isopropyl, phenyl and benzyl.

[0078] As a preferred embodiment of the synthesis method of difluoropyrazole esters of the present invention, the oxidant is at least one of oxygen, hydrogen peroxide, perborate, hypochlorite, chlorite, manganese dioxide, ferrate, permanganate, high-valent chromium salts, chromic acid, dichromic acid, OXONE, periodate, dichromate, sodium peroxide, Jones reagent, 2-iodoacylbenzoic acid, and Dess-Martin reagent.

[0079] Preferably, the oxidizing agent is pyridinium dichromate.

[0080] As a preferred embodiment of the synthesis method of difluoropyrazole esters of the present invention, the alcohol is at least one of methanol, ethanol, isopropanol, butanol, benzyl alcohol and phenol.

[0081] Preferably, the alcohol is methanol and / or ethanol.

[0082] Compared with the prior art, the beneficial effects of the present invention are as follows: first, the synthetic method reaction operation of the intermediate of difluoropyrazole acid or ester of the present invention is greatly simplified, and multi-step intermediates are not separated separately and are directly added to the next step reaction without purification, which significantly reduces the post-processing process, shortens the production cycle, and improves reaction efficiency. Secondly, the raw materials used in the synthetic method of the present invention are cheap and easy to obtain, and the reaction conditions are mild. Although the synthetic method is added through multi-step continuous casting, higher product quality can still be obtained and has a high conversion rate, which not only improves the process safety of difluoropyrazole acid production, but also makes the three wastes (waste gas, waste water and solid waste) produced in the whole process less, and is environmentally friendly and suitable for green large-scale production. In addition, the synthetic method of difluoropyrazole acid and difluoropyrazole ester of the present invention realizes the continuous reaction of multi-step intermediates by optimizing reaction steps and conditions, and can realize the efficient synthesis of difluoropyrazole acid and difluoropyrazole ester, while maintaining higher product quality and conversion rate, not only reducing operation complexity, but also reducing material loss and energy consumption, and improving overall reaction efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The schematic diagram of the reaction process of difluoropyrazole acid of the background technology of the present invention;

[0084] Figure 2 The schematic diagram of the reaction process of difluoropyrazole acid of the background technology of the present invention;

[0085] Figure 3 The schematic diagram of the reaction process of difluoropyrazole acid of the background technology of the present invention;

[0086] Figure 4 The schematic diagram of the reaction process of difluoropyrazole acid of the background technology of the present invention;

[0087] Figure 5 is the structural formula of difluoropyrazole acid of the present invention;

[0088] Figure 6 The schematic diagram of the reaction process of difluoropyrazole acid and difluoropyrazole ester of the present invention;

[0089] Figure 7 HPLC spectrum of Compound I (1-methyl-5-hydroxy-3-difluoromethylpyrazole) in Example 1 of the present invention;

[0090] Figure 8 HPLC spectrum of Compound II (5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole) of Example 1 of the present invention;

[0091] Fig. 9 HPLC spectrum of Compound V (1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid) in Example 1 of the present invention;

[0092] Fig.10 This is the HPLC spectrum of Compound VI (ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate) of Example 1 of the present invention. DETAILED DESCRIPTION

[0093] To better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. It should be understood by those skilled in the art that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0094] The following is an elaboration in conjunction with specific embodiments to illustrate the practical effects of the solutions of the present invention.

[0095] Unless otherwise specified, the experimental methods used in the examples are all conventional methods; the materials, reagents, equipment, etc. used, unless otherwise specified, can be obtained from commercial sources.

[0096] Example 1: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0097] (a) Synthesis of 1-methyl-5-hydroxy-3-difluoromethylpyrazole (Compound I):

[0098] Add 50g (0.3mol) of ethyl difluoroacetoacetate to the reaction bottle and stir at 25°C, add 38.2g of methylhydrazine aqueous solution (methylhydrazine mass concentration is 40%, methylhydrazine 0.33mol) dropwise to the bottle, heat to 80°C and react for 5h. After the reaction is completed, cool down and stir at 10°C for crystallization for 1h, filter by suction, rinse the filter cake with water and then air dry to obtain 1-methyl-5-hydroxy-3-difluoromethylpyrazole shown in formula (I). Purity 99%, yield 96.7%.

[0099] The data of the H NMR spectrum of the obtained product 1-methyl-5-hydroxy-3-difluoromethylpyrazole are as follows:

[0100] 1 H-NMR(d6-acetone):3.78(s,3H),5.90(s,1H),7.03(t,1H,J=54Hz).10.05(brs.1H).

[0101] The reaction structure is shown below:

[0102]

[0103] (b) Synthesis of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole (Compound II):

[0104] Add 70g (0.47mol) 1-methyl-5-hydroxy-3-difluoromethylpyrazole, 69g (0.94mol) DMF and 500mL toluene to the reaction bottle and stir evenly in an ice-water bath, then drop 288.3g (1.88mol) phosphorus oxychloride. After the addition, slowly warm to room temperature and stir. After the reaction is completed, concentrate to remove excess phosphorus oxychloride, add 2L ice water to the concentrate, stir and then add ethyl acetate to extract, wash the obtained organic phase with sodium bicarbonate solution, and concentrate under reduced pressure to obtain 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole shown in formula (II). Purity 98.4%, yield 95.3%.

[0105] The reaction structure is shown below:

[0106]

[0107] (c) Synthesis of (5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methanol (Compound III):

[0108] Add 45g (0.27mol) 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole, 16.2g (0.405mol) sodium hydroxide, 150mL water and 200mL acetonitrile to the reaction bottle and stir to dissolve, then add 32.9g formaldehyde aqueous solution (mass concentration of formaldehyde is 37%, formaldehyde 0.41mol) at below 15°C and stir at 25°C for 2h. After the reaction is complete, separate the phases, dry with sodium sulfate, and concentrate the organic phase to obtain (5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methanol shown in formula (III). Directly put it into the next step without purification.

[0109] The data of the hydrogen nuclear magnetic resonance spectrum of the obtained product (5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methanol are as follows:

[0110] 1 H NMR (CDCl3, δ (ppm)): 6.70 (1H, t, J = 40.8 Hz), 4.63 (2H, s), 3.86 (3H, s), 1.79 (1H, br).

[0111] The reaction structure is shown below:

[0112]

[0113] (d) Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-methanol (Compound IV):

[0114] Add 27g (0.14mol) (5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl) methanol, 100mL methanol and 1.35g palladium carbon to the reaction bottle, stir evenly, replace with hydrogen three times, and stir rapidly at 50°C for 4h. After the reaction is complete, filter and remove palladium carbon, concentrate the organic phase under reduced pressure and spin dry to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-methanol shown in formula (IV). Use it directly in the next step without purification.

[0115] The reaction structure is shown below:

[0116]

[0117] (e) Synthesis of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (Compound V):

[0118] Add 55g (0.34mol) 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-methanol and 165.5g (1.02mol) bis(methoxypropyl) ether to the reaction bottle, connect an oxygen bag to the reaction bottle, and then place it at 60°C for 8h of heating and stirring. After the sample is qualified, reduce the evaporation concentration to obtain a crude product. Add 20.4g sodium hydroxide and 100mL water to the crude product, stir at room temperature to dissolve. Extract the aqueous phase with ethyl acetate, separate the aqueous phase, add concentrated hydrochloric acid to the aqueous phase, stir and filter to obtain 51.4g of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid shown in formula (V) as a white solid, with a yield of 87.1% and a purity of 99.6%.

[0119] The data of the H NMR spectrum of the obtained product 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid are as follows:

[0120] 1 H NMR (400MHz, DMSO-d6) δ: 8.32 (s, 1H), 7.19 (t, J = 53.8Hz, 1H), 3.90 (s, 3H).

[0121] The reaction structure is shown below:

[0122]

[0123] (f) Synthesis of ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (Compound VI):

[0124] Add 40g (0.25mol) of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-methanol to the reaction bottle and dissolve it with 100mL of ethanol, then add 110g (0.37mol) of pyridinium dichromate, stir at room temperature for 8h, add 200mL of ethyl acetate after sampling, and wash with saturated brine. The organic phase is concentrated and cooled to obtain a solid crude product, which is recrystallized from n-hexane to obtain a pale yellow solid to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester shown in formula (VI). The yield is 85.9% and the purity is 98.8%.

[0125] The data of the H NMR spectrum of the obtained product 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester are as follows:

[0126] 1 H NMR (500MHz, CDCl3) δ: 7.89 (s, 1H), 7.09 (t, J = 53.8Hz, 1H), 4.32 (q, J = 7.0Hz, 2H), 3.96 (s, 3H), 1.35 (t, J = 7.0Hz, 3H).

[0127] The reaction structure is shown below:

[0128]

[0129] Example 2: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0130] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that the phosphorus oxychloride in step (b) is replaced by thionyl chloride, and the purity of the obtained product 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole is 85.1% and the yield is 77.3%.

[0131] Example 3: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0132] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that phosphorus oxychloride in step (b) is replaced by benzoyl chloride, and the purity of the obtained product 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole is 84.4% and the yield is 74.6%.

[0133] Example 4: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0134] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that the molar ratio of 1-methyl-5-hydroxy-3-difluoromethylpyrazole to phosphorus oxychloride in step (b) is 1:2, and the purity of the obtained product 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole is 94.7%, and the yield is 86.3%.

[0135] Example 5: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0136] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that the molar ratio of 1-methyl-5-hydroxy-3-difluoromethylpyrazole to phosphorus oxychloride in step (b) is 1:3, and the purity of the obtained product 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole is 95.9% and the yield is 83.5%.

[0137] Example 6: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0138] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that the molar ratio of 1-methyl-5-hydroxy-3-difluoromethylpyrazole to phosphorus oxychloride in step (b) is 1:5, and the purity of the obtained product 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole is 95.3%, and the yield is 75.6%.

[0139] Example 7: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0140] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that the molar ratio of 1-methyl-5-hydroxy-3-difluoromethylpyrazole to phosphorus oxychloride in step (b) is 1:8, and the purity of the obtained product 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole is 98.2% and the yield is 78.3%.

[0141] Example 8: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0142] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that the sodium hydroxide in step (c) is replaced by sodium carbonate, and the purity of the obtained product 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is 83.1% and the yield is 84.7%.

[0143] Example 9: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0144] The only difference between the synthesis method of difluoropyrazole acid described in this example and that in Example 1 is that the sodium hydroxide in step (c) is replaced by potassium bicarbonate, and the purity of the obtained product 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is 79.3% and the yield is 81.6%.

[0145] Example 10: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0146] The only difference between the synthesis method of difluoropyrazole acid described in this embodiment and that in Example 1 is that the mass concentration of the formaldehyde aqueous solution in step (c) is 30%, the amount of formaldehyde added is maintained at 0.41 mol, and the purity of the obtained product 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is 97.4%.

[0147] Example 11: Synthesis of difluoropyrazole acid and difluoropyrazole ester

[0148] The only difference between the synthesis method of difluoropyrazole acid described in this embodiment and that in embodiment 1 is that the mass concentration of the formaldehyde aqueous solution in step (c) is 45%, the amount of formaldehyde added is maintained at 0.41 mol, and the purity of the obtained product 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is 98.1%.

[0149] It can be seen from the above examples that the yield of the synthesis method of difluoropyrazole acid and difluoropyrazole ester of the present invention is greater than 86%, and the purity of the obtained difluoropyrazole acid and difluoropyrazole ester is greater than 99%.

[0150] The synthesis method of difluoropyrazole acid and difluoropyrazole ester of the present invention reduces the reaction steps, and the intermediates in multiple steps are not separated separately and can be directly added to the next reaction without purification, which greatly shortens the process time and production cycle; the raw materials used are cheap and easy to obtain, and the reaction conditions are mild; at the same time, less three wastes are generated in the process, which is friendly to the environment, and the obtained product has high yield and high purity, is suitable for green large-scale production, and is an efficient, environmentally friendly and easy-to-control green synthesis method.

[0151] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing an intermediate of a difluoropyrazole acid or ester, characterized in that: The following steps are involved: (1) reacting a compound I represented by formula (I) with a chlorinating agent to obtain a compound II represented by formula (II); (2) taking the compound II and formaldehyde, adding an alkaline reagent to react to obtain a compound III represented by formula (III); (3) taking the compound III and hydrogen, adding a catalyst to react, and obtaining the intermediate of the difluoropyrazole acid or ester represented by formula (IV); 2. The method for synthesizing an intermediate of a difluoropyrazole acid or ester according to claim 1, characterized in that: The compound I is obtained by reacting methylhydrazine with ethyl difluoroacetoacetate.

3. The method for synthesizing an intermediate of a difluoropyrazole acid or ester as claimed in claim 2, characterized in that: The reaction temperature is 50°C to 100°C, and the reaction time is 2h to 10h.

4. The method for synthesizing an intermediate of a difluoropyrazole acid or ester according to claim 1, characterized in that: In step (1), the chlorinating agent is at least one of chlorine, thionyl chloride, oxalyl chloride, sulfonyl chloride, benzoyl chloride, phosphorus pentachloride, and phosphorus oxychloride.

5. The method for synthesizing an intermediate of a difluoropyrazole acid or ester according to claim 1, characterized in that: In step (1), the reaction temperature is 50°C to 120°C, and the reaction time is 1 h to 5 h.

6. The method for synthesizing an intermediate of a difluoropyrazole acid or ester according to claim 1, characterized in that: In step (1), the molar ratio of the compound I to the chlorinating agent is 1:(1-10).

7. The method for synthesizing an intermediate of difluoropyrazole acid or ester according to claim 1, characterized in that: In step (2), the alkaline reagent is at least one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.

8. The method for synthesizing an intermediate of a difluoropyrazole acid or ester according to claim 1, characterized in that: In step (2), the formaldehyde is a formaldehyde aqueous solution with a mass concentration of 30% to 45%.

9. A method for synthesizing difluoropyrazole acid, characterized in that: The method comprises the following steps: reacting the intermediate of the difluoropyrazole acid or ester according to any one of claims 1 to 8 with an oxidant to obtain the difluoropyrazole acid represented by formula (V); 10. A method for synthesizing difluoropyrazole ester, characterized in that: The method comprises the following steps: taking the intermediate of the difluoropyrazole acid or ester according to any one of claims 1 to 8 and an oxidant, adding alcohol to react, and obtaining the difluoropyrazole ester represented by formula (VI); Wherein, the R is any one of methyl, ethyl, isopropyl, phenyl and benzyl.

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