3-fluoroalkyl-fully substituted pyrazole compound and preparation method thereof

Abstract

The invention discloses a 3-fluoroalkyl-full-substituted pyrazole compound and a preparation method thereof, and belongs to the technical field of organic synthesis. According to the method, the 3-fluoroalkyl-fully-substituted pyrazole compound is synthesized through a series cyclization / desulfurization reaction of fluoroalkyl bromohydrazone and thiopyridine onium salt. According to the invention, the series cyclization / desulfurization reaction in which fluoroalkyl bromohydrazone participates is used for synthesizing the 3-fluoroalkyl-fully-substituted pyrazole compound for the first time, and a new method is provided for synthesizing the fully-substituted pyrazole compound containing fluoroalkyl. The method has the advantages of mild conditions, simplicity in operation, easiness in post-treatment, easiness in product purification, high reaction yield and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a 3-fluoroalkyl-fully substituted pyrazole compound and a preparation method thereof. Background Art

[0002] Around 2000, the success of trifluoromethyl-substituted pyrazole drugs Celebrex and difluoromethyl-substituted pyrazole fungicides launched by Bayer, BASF and Syngenta aroused researchers' interest in fluoropyrazoles. Currently, fluoropyrazole compounds play an important role in the fields of medicinal chemistry, pesticide chemistry, coordination chemistry and organometallic chemistry (references: Bioorg. Med. Chem. 2009, 17, 4127.; J. Med. Chem. 2008, 51, 4986.; Inorg. Chem. 2008, 47, 7154.; Aust. J. Chem. 2008, 61, 342.; J. A m.Chem.Soc.2007,129,11608.;J.Am.Chem.Soc.2017,139,9325-9332.;ACSMed.Chem.Lett.2015,6,392-396.;J.Chem.Soc.Rev.2011,40,3496-3508.;Chem.Rev.2021,121,1670-1715.). In fluorinated pyrazole compounds, in addition to fluorine atoms, common fluorine-containing groups include: difluoromethyl, trifluoromethyl, tetrafluoroethyl and pentafluoroethyl. It is worth noting that difluoromethyl and trifluoromethyl substituted pyrazole compounds are the most common and widely used compounds among fluorinated pyrazoles. Among the numerous fluoroalkyl pyrazole compounds, 3-difluoromethyl / trifluoromethyl fully substituted pyrazole compounds are very eye-catching and have been widely used in the fields of medicine and pesticides. For example, compounds AF have the following chemical structures:

[0003]

[0004] Studies have shown that compound A (Lenacapavir) is a 3-trifluoromethyl fully substituted pyrazole compound with anti-HIV activity reported by Gilead in 2020 (reference: Int. J. Antimicrob. 2024, 64, 3, 107254.). Compound B (SNX-5422) is an anticancer drug developed by the biotechnology company Serenex in 2018 (reference: J. Med. Chem. 2020, 63, 10, 5421-5441.). Compound C (Fluazolate) and compound D (Pyroxasulfone) can be used as herbicides (reference: Org. Lett. 2012, 14, 18, 4858-4861.; Plant. Mol. Biol. 2020, 102, 4-5, 403-416.). Compound E (Pydiflumetofen) and Compound F (Isoflucypram) are 3-difluoromethyl fully substituted pyrazole compounds, which are pesticides with antifungal activity (CN 103313973 A; WO 2017 / 072166 Al). Therefore, the development of a method for efficiently synthesizing 3-difluoromethyl / trifluoromethyl fully substituted pyrazole compounds has important theoretical significance and practical application value.

[0005] At present, the preparation methods of 3-difluoromethyl / trifluoromethyl fully substituted pyrazole compounds mainly include the condensation cyclization reaction of 1,3-dicarbonyl compounds and their analogs, the [3+2] cycloaddition reaction of 1,3-dipole and the intramolecular tandem cyclization reaction of fluoroalkyl hydrazone compounds. The specific methods are as follows:

[0006] (I) Condensation cyclization reaction of 1,3-dicarbonyl compounds and their analogs with hydrazine

[0007] In 2020, the Rosa team reported the condensation cyclization reaction of trifluoromethylated β-enaminodione and phenylhydrazine, and synthesized trifluoromethyl-substituted fully substituted pyrazole compounds (reference: Org. Biomol. Chem. 2020, 18, 2524-2537.). The reaction uses boron trifluoride etherate as a carbonyl activation reagent and acetonitrile as a solvent, and the reaction is carried out at reflux temperature. Although the reaction can synthesize the target compound with a high yield and further expand its scope of application through transamination reactions, the reaction first requires the synthesis of β-enaminodione, which has the problem of cumbersome steps, and the phenylhydrazine part has not been widely expanded as a substrate, which limits the further application of this method. The reaction formula is as follows:

[0008]

[0009] In 2013, Leroux's research group reported the condensation cyclization reaction of fluorinated enaminones generated by the reaction of tetrafluoroethyldimethylamine with commercially available fluoroacetoacetate and hydrazine to synthesize a series of difluoromethyl-substituted fully substituted pyrazole compounds (reference: Eur. J. Org. Chem. 2013, 2013, 4249-4253.). This innovative one-pot method provides a method for synthesizing 3,5-bis(fluoroalkyl)pyrazole-4-carboxylic acid ethyl ester with a yield of 43%-85% and good regioselectivity. However, the preparation process is quite cumbersome and the reaction conditions are relatively harsh, which limits its application. The reaction formula is as follows:

[0010]

[0011] (II) [3+2] cycloaddition reaction involving 1,3-dipole

[0012] According to the different raw materials involved in the reaction, this [3+2] cycloaddition reaction can be divided into the following two types:

[0013] 1. [3+2] cycloaddition reaction involving diazoethane derivatives

[0014] In 2015, the Reissig group reported the [3+2] cycloaddition reaction of 2-diazo-3,3,3-trifluoropropionate with fluorinated alkyne derivatives (reference: Helv. Chim. Acta. 2014, 97, 808.). When 4,4,4-trifluoro-2-butynoic acid ethyl ester was used as a substrate, the reaction gave a mixture of 3,4(5)-bistrifluoromethyl fully substituted pyrazoles with yields of 15% and 75%, respectively. When 1,1,1,4,4,4-hexafluoro-2-butyne (HFB) was used as a substrate, the reaction gave 3,4,5-tristrifluoromethyl fully substituted pyrazoles with a yield of 76%. The biggest drawback of this method is the use of diazo compounds with potential safety hazards, a long reaction time, and regional selectivity in the reaction, which limits the practical application of this method. The reaction formula is as follows:

[0015]

[0016] In 2019, Yagupolskii's research group reported the synthesis of fully substituted pyrazole compounds substituted with ditrifluoromethyl groups by the [3+2] cycloaddition reaction of α-diazocarbonyl compounds and 1,1,1,4,4,4-hexafluorobut-2-yne, which are more stable than diazoalkanes (reference: Chemistry Select, 2019, 4, 4604-4610.). The reaction was carried out at room temperature using dimethyl ether as solvent to obtain the target compound with a yield of 90-97%. Although the reaction conditions of the reaction were mild and the yield of the target compound was higher than 90%, only three substrates were expanded and there were few examples. The reaction formula is as follows:

[0017]

[0018] 2. [3+2] Cycloaddition Reaction Involving Fluoroalkyl Halogenated Hydrazones

[0019] In 2022, the inventors' partnership team reported the [3+2] cycloaddition reaction of difluoromethyl bromohydrazone and alkynoic acid esters, and synthesized three 3-difluoromethyl fully substituted pyrazole compounds with yields of 89%, 66% and 87%, respectively (reference: J.Org.Chem.2022,87,498-511.). This method uses difluoromethyl bromohydrazone as a nitrile imine precursor, acetonitrile as a solvent, and sodium carbonate as a base, and reacts at room temperature. This method has the advantages of high regioselectivity and high yield. The disadvantage of this method is that the substrate applicability is relatively narrow. For non-terminal alkynoic acid esters, the reaction can only occur when dimethyl butynedioate is used as a substrate. The reaction formula is as follows:

[0020]

[0021] In 2022, Ma Junan's research group reported the [3+2] cycloaddition / decarboxylation reaction of trifluoromethyl chlorohydrazone and isoxazolidinone compounds to synthesize a series of 3-trifluoromethyl fully substituted pyrazole compounds (reference: Adv. Synth. Catal. 2021, 363, 2093-2097.). This method uses trifluoromethyl chlorohydrazone as the nitrile imine precursor, 1,2-dichloroethane as the solvent, potassium carbonate as the base, and reacts at 90°C for 12 hours. The reaction system is simple and the yield of most products is above 80%. The disadvantage of this method is that the preparation and processing of the substrate of the isoxazolidinone compound part is relatively complicated. The reaction formula is as follows:

[0022]

[0023] In 2022, the Kowalczyk team reported the [3+2] cycloaddition / oxidation reaction of trifluoromethyl bromohydrazone and enone compounds to synthesize a series of trifluoromethyl-substituted fully substituted pyrazole compounds (reference: Org. Lett. 2022, 24, 13, 2499-2503.). This method uses trifluoromethyl bromohydrazone as a nitrile imine precursor, tetrahydrofuran as a solvent, and triethylamine as a base. The trifluoromethyl-substituted fully substituted pyrazoline is first synthesized. After column chromatography separation and purification, manganese dioxide is used as an oxidant to synthesize 3-trifluoromethyl-1,4-disubstituted pyrazole compounds and 3-trifluoromethyl fully substituted pyrazole compounds under different solvents and temperatures. This reaction has the problem of cumbersome steps, and the second step oxidation reaction needs to be carried out at a higher temperature. The reaction formula is as follows:

[0024]

[0025] In 2023, the inventor's partnership team reported a method for synthesizing difluoromethyl-substituted fully substituted pyrazole compounds through the [3+2] cycloaddition reaction of trifluoromethyl bromohydrazone and acetonitrile ester derivatives (Chin. J. Org. Chem. 2023, 43, 3257-3267.). This method uses trifluoromethyl bromohydrazone as the nitrile imine precursor, acetonitrile as the solvent, and potassium carbonate as the base to obtain two target compounds at 25°C with yields of 63% and 39%, respectively. This method has the advantages of mild reaction conditions and simple operation. However, the disadvantage of this method is still that the substrate has a narrow range of applicability: for non-terminal acetylated esters, only dimethyl butynedioate (R 1 =CO2Me,R 2 =Me) and ethyl 4,4,4-trifluoro-2-butynoate (R 1 =CF3,R 2 =Et) reaction can occur. The reaction formula is as follows:

[0026]

[0027] In 2024, the inventors' partnership team reported the [3+2] cycloaddition reaction of difluoromethyl bromohydrazone with 2-acylacetonitrile or malononitrile, and synthesized a series of difluoromethyl-substituted fully substituted pyrazole compounds (reference: J.Org.Chem.2024,89,10591-10602.). This method uses difluoromethyl bromohydrazone as a nitrile imine precursor, and sodium carbonate is used as a base at room temperature. When methanol is used as a solvent, difluoromethyl bromohydrazone reacts with malononitrile to obtain 5-amino-3-difluoromethyl fully substituted pyrazole compounds with a yield of 47%-89%; when acetonitrile is used as a solvent, difluoromethyl bromohydrazone reacts with 2-acylacetonitrile to obtain 3-difluoromethyl-4-cyano fully substituted pyrazole compounds with a yield of 30%-88%. This method has the characteristics of mild reaction conditions and simple operation. The disadvantage of this method is that the substituent R in 2-acylacetonitrile 1 It can only be an aromatic group. When an aliphatic hydrocarbon group is used, the reaction does not occur. The reaction formula is as follows:

[0028]

[0029] (III) Intramolecular tandem cyclization reaction of fluoroalkyl hydrazone compounds

[0030] In 2018, Nenajdenko's research group reported the tandem cyclization reaction of fluoroalkyl alkynyl ketone hydrazones and synthesized a series of trifluoromethyl-substituted fully substituted pyrazole compounds (reference: Org. Biomol. Chem. 2018, 16, 7935-7946.). This method first prepared fluoroalkyl alkynyl ketone hydrazones by the reaction of phenylhydrazine hydrochloride and trifluoromethyl alkynyl ketone. Then, under the conditions of sodium bicarbonate as a base, acetonitrile as a solvent, and iodine as an additive, the fluoroalkyl alkynyl ketone hydrazone underwent self-tandem cyclization to obtain the target compound. This method has the characteristics of mild reaction conditions and high yield, and can be used for the synthesis of chloro, brominated and iodinated derivatives of Celebrex and SC-560. However, the reaction must first be carried out to prepare the alkynyl ketone hydrazone. The reaction formula is as follows:

[0031]

[0032] In summary, the existing technology can synthesize 3-difluoromethyl / trifluoromethyl fully substituted pyrazole compounds through condensation reactions of 1,3-dicarbonyl compounds and their analogs, [3+2] cycloaddition reactions involving 1,3-dipoles, and intramolecular tandem cyclization reactions of fluoroalkyl hydrazone compounds. However, each method has its own defects and limitations.

[0033] Thiopyridinium salt is a novel sulfur-containing synthetic building block. It can be stable in the air, has no odor, is easy to handle and easy to prepare (references: Org. Lett., 2022, 24, 5120-5125.; J. Org. Chem., 2021, 86, 15640-15647.; J. Org. Chem., 2021, 86, 18156-18163.; Adv. Synth. Catal., 2022, 364, 296-301.). As a multifunctional sulfur-containing synthetic building block, thiopyridinium salt is mainly used to synthesize a variety of heterocyclic compounds. There are two main types of cyclization reaction modes in which it participates. When the pyridine ring in the thiopyridinium salt molecule participates in the reaction, a [5+m] type cycloaddition reaction occurs through a two-step nucleophilic attack. In this reaction, thiopyridinium salt acts as a C5 synthon. On the other hand, when the pyridine ring in the thiopyridinium salt molecule acts as a leaving group, the thiopyridinium salt acts as a C3 synthon and undergoes a [3+m] type cycloaddition reaction (Org. Lett., 2022, 24, 5120-5125.; J. Org. Chem., 2021, 86, 18156-18163.; Eur. J. Org. Chem., 2020, 2020, 1896-1906.; Org. Lett., 2022, 24, 6024-6030.), and can further remove the sulfur atom to undergo a [3+m-1] type cycloaddition reaction (reference: Org. Biomol. Chem., 2020, 18, 2949-2955.).

[0034] On the other hand, difluoromethyl / trifluoromethyl halogenated hydrazones, as precursors of fluoroalkyl nitrile imines, can undergo [3+2] cycloaddition reactions with compounds with carbon-carbon triple bonds (alkynones, alkyne esters, alkyne amides, etc.), carbon-carbon double bonds (enones, isoxazolidinedione compounds, etc.) and 2-acyl acetonitrile or malononitrile, and have been successfully used to synthesize a series of 3-fluoroalkyl fully substituted pyrazole compounds. However, the reaction of difluoromethyl / trifluoromethyl halogenated hydrazones with thiopyridinium salts has not been reported so far. Summary of the invention

[0035] In order to solve the above technical problems, the present invention proposes a 3-fluoroalkyl-fully substituted pyrazole compound and a preparation method thereof. The present invention uses a fluoroalkyl bromohydrazone (difluoromethyl bromohydrazone or trifluoromethyl bromohydrazone) as a fluorine-containing building block, and in the presence of a base, a tandem cyclization / desulfurization reaction of a fluoroalkyl bromohydrazone and a thiopyridinium salt is carried out to achieve the synthesis of a 3-fluoroalkyl fully substituted pyrazole compound. The present invention provides a new method for the synthesis of a 3-fluoroalkyl fully substituted pyrazole compound for the first time through a tandem cyclization / desulfurization reaction of a thiopyridinium salt. Moreover, through the tandem cyclization / desulfurization reaction, the types of organic reactions in which fluoroalkyl bromohydrazones participate are expanded, further expanding the application of fluoroalkyl bromohydrazones in organic synthesis. The method has the characteristics of cheap, readily available, stable raw materials, mild reaction conditions, simple operation, easy purification of products, and high yield.

[0036] To achieve the above object, the present invention provides the following technical solutions:

[0037] Technical Solution 1: A 3-fluoroalkyl-fully substituted pyrazole compound having the general structure shown in Formula I:

[0038]

[0039] Among them, R f is CF2H or CF3; Ar is any one of Ph, 4-Me-C6H4, 4-COOMe-C6H4 and 4-F-C6H4.

[0040] Technical solution 2: A method for preparing a 3-fluoroalkyl-fully substituted pyrazole compound, comprising the following steps: mixing a fluoroalkyl bromohydrazone and a thiopyridinium salt, adding an organic solvent in the presence of a base, and synthesizing the 3-fluoroalkyl-fully substituted pyrazole compound by a tandem cyclization / desulfurization reaction;

[0041] The general structural formula of the fluoroalkyl bromohydrazone is:

[0042]

[0043] In the formula, R f is CF2H or CF3; Ar is any one of Ph, 4-MeC6H4, 4-COOMe-C6H4 and 4-F-C6H4.

[0044] The structural formula of the thiopyridinium salt is:

[0045]

[0046] Preferably, the molar ratio of the thiopyridinium salt, the fluoroalkyl bromohydrazone and the base is 1.0:(1.0-1.5):(1.0-2.0), and most preferably 1:1.2:1.5.

[0047] Preferably, the organic solvent includes any one of dichloromethane (DCM), tetrahydrofuran (THF), toluene and ethanol, more preferably dichloromethane.

[0048] Preferably, the fluoroalkyl hydrazone bromide is difluoromethyl hydrazone bromide or trifluoromethyl hydrazone bromide.

[0049] Preferably, the base includes any one of potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), sodium hydroxide (NaOH) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), more preferably potassium carbonate.

[0050] Preferably, the reaction temperature of the tandem cyclization / desulfurization reaction is 0-40°C, more preferably 25°C, and the reaction time is 7-12h; more preferably 7-10h.

[0051] Preferably, after the tandem cyclization / desulfurization reaction is completed, a column chromatography separation process is also included.

[0052] More preferably, during the column chromatography separation, the eluent is a mixture of petroleum ether (PE) and ethyl acetate (EA).

[0053] More preferably, the volume ratio of petroleum ether to ethyl acetate is (5-6):1, such as 5:1 or 6:1.

[0054] Taking dichloromethane as an organic solvent, the synthesis route of the 3-fluoroalkyl-fully substituted pyrazole compound is:

[0055]

[0056] The specific method is as follows: take a 10mL reaction tube, add fluoroalkyl bromohydrazone, thiopyridinium salt and base, then add 3mL of organic solvent, and stir the mixture at 0-40°C. Monitor the reaction by TLC, remove the solvent after the fluoroalkyl bromohydrazone is completely reacted, and quickly perform column chromatography separation using a mixed eluent of petroleum ether and ethyl acetate (volume ratio of PE:EA=(5-6):1) to obtain the target product.

[0057] Technical Solution Three: The use of the 3-fluoroalkyl-fully substituted pyrazole compound in the preparation of pesticide products, which include antifungal insecticides and herbicides. Pyrazole compounds are a class of compounds with important biological activity, and 3-fluoroalkyl pyrazole structural units are widely present in the molecules of compounds such as medicines and pesticides (Chem. Rev. 2021, 121, 1670-1715.). In particular, 3-difluoromethylpyrazole has antifungal activity and is widely used in pesticides and herbicides (Chin. J. Org. Chem. 2024, 44, 1226-1239.). In view of the aforementioned application of 3-fluoroalkyl pyrazole fully substituted pyrazole compounds as antifungal insecticides and herbicides in the field of pesticides, the 3-fluoroalkyl pyrazole fully substituted pyrazole compounds provided by the present invention can be used to prepare antifungal insecticides and herbicides.

[0058] The reaction principle of the present invention is:

[0059]

[0060] First, under the action of potassium carbonate, fluoroalkyl bromide hydrazone (R f CF2H or CF3) forms a nitrile imine intermediate A; then, the sulfur atom in the thiopyridinium salt attacks the carbon atom in the nitrile imine intermediate A to obtain a nitrogen anion intermediate B; then, intermediate B undergoes an intramolecular nitrogen-Michael addition reaction to generate an unstable 1,3,4-thiadiazine intermediate C; a molecule of pyridine is eliminated from intermediate C to obtain intermediate D; then, intermediate D undergoes a ring contraction reaction to obtain intermediate E; finally, intermediate E undergoes a desulfurization reaction to obtain the target product.

[0061] Compared with the prior art, the present invention has the following advantages and technical effects:

[0062] (1) The present invention discloses for the first time a new method for synthesizing 3-fluoroalkyl fully substituted pyrazole compounds by using thiopyridinium salt and fluoroalkyl bromohydrazone as raw materials through a tandem cyclization / desulfurization reaction.

[0063] (2) The present invention is the first to use fluoroalkyl bromohydrazone and thiopyridinium salt for the synthesis of 3-fluoroalkyl fully substituted pyrazole compounds. The thiopyridinium salt used in the reaction is an organic synthetic raw material that can exist stably, has no odor, and is easy to handle. The greatest advantage of the reaction is that the reaction yield is high and the product is easy to purify. Therefore, these advantages of the reaction provide great possibilities for the further industrialization of the method.

[0064] (3) The 3-fluoroalkyl fully substituted pyrazole compounds synthesized by the present invention can be used to prepare antifungal insecticides and herbicides.

[0065] (4) The synthesis method provided by the present invention has the characteristics of mild reaction conditions, simple operation, easy post-treatment and high reaction yield.

[0066] (5) The 3-fluoroalkyl fully substituted pyrazole compound synthesized by the present invention is 1 H NMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection, the product is a pure target compound with high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] The drawings constituting a part of the present application are used to provide a further understanding of the present application. The illustrative embodiments and descriptions of the present application are used to explain the present application and do not constitute an improper limitation on the present application. In the drawings:

[0068] Figure 1 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a) synthesized in Example 1 1 H NMR spectra;

[0069] Figure 2 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a) synthesized in Example 1 13 C NMR spectra;

[0070] Figure 3 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a) synthesized in Example 1 19 F NMR spectra;

[0071] Figure 4 This is a high-resolution mass spectrometry monitoring diagram of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a) synthesized in Example 1;

[0072] Figure 5 1-[4-(methyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3b) synthesized in Example 2 1 H NMR spectra;

[0073] Figure 6 1-[4-(methyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3b) synthesized in Example 2 13 C NMR spectra;

[0074] Figure 7 1-[4-(methyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3b) synthesized in Example 219 F NMR spectra;

[0075] Figure 8 This is a high-resolution mass spectrometry monitoring diagram of dimethyl 1-[4-(methyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3b) synthesized in Example 2;

[0076] Fig. 9 1-[4-(methoxycarbonyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3c) synthesized in Example 3 1 H NMR spectra;

[0077] Fig.10 1-[4-(methoxycarbonyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3c) synthesized in Example 3 13 C NMR spectra;

[0078] Fig.11 1-[4-(methoxycarbonyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3c) synthesized in Example 3 19 F NMR spectra;

[0079] Fig.12 This is a high-resolution mass spectrometry monitoring diagram of dimethyl 1-[4-(methoxycarbonyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3c) synthesized in Example 3;

[0080] Fig.13 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3d) synthesized in Example 4 1 HNMR spectra;

[0081] Fig.14 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3d) synthesized in Example 4 13 CNMR images;

[0082] Fig.15 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3d) synthesized in Example 4 19 FNMR images;

[0083] Fig.16 This is a high-resolution mass spectrum monitoring chart of dimethyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3d) synthesized in Example 4. DETAILED DESCRIPTION

[0084] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0085] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0086] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0087] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0088] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0089] Unless otherwise specified, the room temperature in the present invention is 25±3°C.

[0090] The raw materials used in the examples of the present invention are synthesized from literature or purchased from the market. Thiopyridinium salt is prepared according to (CN 110105269A), difluoromethyl bromohydrazone is prepared according to (J.Org.Chem.2022,87,498.), and trifluoromethyl bromohydrazone is prepared according to (Chin.J.Org.Chem.2023,43,3257-3267.). The influence of the raw material preparation method on the product is not used as a factor in evaluating the creativity of the present invention.

[0091] The technical solution of the present invention is further illustrated by the following embodiments.

[0092] Example 1

[0093] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0094] The specific synthesis process is as follows:

[0095]

[0096] Take a 10mL reaction tube, add thiopyridinium salt (0.2mmol, 50.6mg, 1.0equiv.), difluoromethylbromohydrazone (0.24mmol, 59.8mg, 1.2equiv.), potassium carbonate (0.3mmol, 41.5mg, 1.5equiv.), and then add 3mL of solvent dichloromethane. The mixture is stirred at 25°C. The reaction is monitored by TLC and is complete after 7 hours. After removing the solvent, a mixed eluent of petroleum ether and ethyl acetate (volume ratio of PE: EA = 6: 1) is used for rapid column chromatography separation to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 56.5mg, yield 91%.

[0097] The above-synthesized 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a) was 1 H NMR, 13 CNMR, 19 F NMR and high-resolution mass spectrometry (such as Figure 1-4 As shown), it can be concluded that the product is a pure target compound. The characterization data of the corresponding product are:

[0098] 1 H NMR (400MHz, CDCl3) δ7.49 (s, 5H), 7.10 (t, J = 54.0Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H);

[0099] 13 C NMR(150MHz,CDCl3)δ161.3,160.3,146.2(t,J C-F =25.4Hz),138.3,138.2,129.6,129.5,124.1,110.75,109.2(t,J C-F =236.7Hz),53.6,52.4;

[0100] 19 F NMR (376MHz, CDCl3) δ – 116.35 (d, J = 53.77Hz);

[0101] HRMS(ESI)m / z:calcd for C 14 H 13 F2N2O4[M+H] + 311.0838, found:311.0838.

[0102] Example 2

[0103] Synthesis of dimethyl 1-[4-(methyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3b)

[0104] The synthetic route is as follows:

[0105]

[0106] The specific synthesis process is as follows:

[0107] Take a 10mL reaction tube, add thiopyridinium salt (0.2mmol, 50.6mg, 1.0equiv.), p-methylphenyl difluoromethyl bromohydrazone (0.24mmol, 63.1mg, 1.2equiv.), potassium carbonate (0.3mmol, 41.5mg, 3.5equiv.), and then add 3mL of solvent dichloromethane. The mixture is stirred at 25°C. The reaction is monitored by TLC. After 10 hours, the reaction is complete. After removing the solvent, a mixed eluent of petroleum ether and ethyl acetate (volume ratio of PE: EA = 6: 1) is used for rapid column chromatography separation to obtain 1-[4-(methyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3b): yellow liquid, 55.1mg, yield 85%.

[0108] The above-synthesized 1-[4-(methyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3b) was reacted with 1 H NMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry (such as Figure 5-8 As shown), it can be concluded that the product is a pure target compound. The characterization data of the corresponding product are:

[0109] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),7.08(t,J=53.6Hz,1H),3.90(s,3H),3.87(s,3H),2.41(s,3H);

[0110] 13C NMR(150MHz,CDCl3)δ161.3,160.4,146.0(t,J C-F =25.5Hz),139.9,138.2,135.9,130.0,123.9,113.2,109.2(t,J C-F =236.7Hz),53.5,52.3,21.2;

[0111] 19 F NMR (376MHz, CDCl3) δ – 116.25 (d, J = 53.77Hz);

[0112] HRMS(ESI)m / z:calcd for C 15 H 15 F2N2O4[M+H] + 325.0994,found:.325.0994.

[0113] Example 3

[0114] Synthesis of dimethyl 1-[4-(methoxycarbonyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3c)

[0115] The synthetic route is as follows:

[0116]

[0117] The specific synthesis process is as follows:

[0118] Take a 10mL reaction tube, add thiopyridinium salt (0.2mmol, 50.6mg, 1.0equiv.), 4-(methoxycarbonyl)phenyldifluoromethylbromohydrazone (0.24mmol, 67.0mg, 1.2equiv.), potassium carbonate (0.3mmol, 41.5mg, 1.5equiv.), and then add 3mL of solvent dichloromethane. The mixture is stirred at 25°C. The reaction is monitored by TLC, and the reaction is complete after 7 hours. After removing the solvent, a mixed eluent of petroleum ether and ethyl acetate (volume ratio of PE: EA = 5: 1) is used for rapid column chromatography separation to obtain 1-[4-(methoxycarbonyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3c): yellow liquid, 69.2mg, yield 94%.

[0119] The above-synthesized 1-[4-(methoxycarbonyl)phenyl]-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3c) was reacted with 1 HNMR, 13 C NMR, 19F NMR and high-resolution mass spectrometry (such as Figure 9-12 The results show that the product is a pure target compound. The characterization data of the corresponding product are:

[0120] 1 H NMR (400MHz, CDCl3) δ8.16(d,J=8.4Hz,2H),7.59(d,J=8.4Hz,2H),7.09(t,J=53.6Hz,1H),3.95(s,3H),3.91(s,3H),3.89(s,3H);

[0121] 13 C NMR (150MHz, CDCl3) δ165.7,161.1,160.2,146.7(t,J C-F =25.4Hz),141.6,138.2,131.1,130.9,123.8,114.0,109.0(t,JC-F=237.2Hz),53.7,52.5,38.2;

[0122] 19 F NMR (376MHz, CDCl3) δ – 116.57 (d, J = 53.39Hz);

[0123] HRMS(ESI)m / z:calcd for C 16 H 15 F2N2O6[M+H] + ,346.0893,found:346.0891.

[0124] Example 4

[0125] Synthesis of dimethyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3d)

[0126] The synthetic route is as follows:

[0127]

[0128] The specific synthesis process is as follows:

[0129] Take a 10mL reaction tube, add thiopyridinium salt (0.2mmol, 50.6mg, 1.0equiv.), 4-fluorophenyl trifluoromethyl bromohydrazone (0.24mmol, 68.4mg, 1.2equiv.), potassium carbonate (0.3mmol, 41.5mg, 1.5equiv.), and then add 3mL of solvent dichloromethane. The mixture is stirred at 25°C. The reaction is monitored by TLC, and the reaction is complete after 12 hours. After removing the solvent, a mixed eluent of petroleum ether and ethyl acetate (volume ratio of PE: EA = 6: 1) is used for rapid column chromatography separation to obtain 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3d): yellow solid, 56.1mg, yield 81%.

[0130] The above-synthesized 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3d) was reacted with 1 HNMR, 13 CNMR, 19 F NMR and high-resolution mass spectrometry (such as Figure 13-16 The results show that the product is a pure target compound. The characterization data of the corresponding product are:

[0131] 1 H NMR (400MHz, CDCl3): δ7.48 (q, J = 4.4Hz, 2H), 7.19 (t, J = 8Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H);

[0132] 13 C NMR (150MHz, CDCl3): δ163.9,162.2,160.0(d,J C-F =190.1Hz),141.5(q,J C-F =39.0Hz),138.2,134.2(d,J C-F =3.5Hz),126.7(d,J C-F =9.0Hz),119.9(q,J C-F =268.8Hz),116.5(d,J C-F =23.3Hz),114.4,53.6,52.7;

[0133] 19 F NMR (376MHz, CDCl3): δ-62.11(s), –109.84––109.91(m);

[0134] HRMS(ESI)m / z:calcd for C 14H 11 F4N2O4[M+H] + ,347.0649,found:347.0640.

[0135] Example 5

[0136] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0137] The same as Example 1, except that potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) was replaced with cesium carbonate (0.3 mmol, 97.7 mg, 1.5 equiv.) to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 47.2 mg, yield 76%.

[0138] Example 6

[0139] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0140] The same as Example 1, except that potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) was replaced with sodium hydroxide (0.3 mmol, 12 mg, 1.5 equiv.) to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 49.7 mg, yield 80%.

[0141] Example 7

[0142] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0143] The same as Example 1, except that potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) was replaced with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mmol, 45.7 mg, 1.5 equiv.) to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 37.9 mg, yield 61%.

[0144] Example 8

[0145] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0146] The same as Example 1, except that the solvent dichloromethane was replaced by tetrahydrofuran in equal volume, to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 54.0 mg, yield 87%.

[0147] Example 9

[0148] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0149] The same as Example 1, except that the solvent dichloromethane was replaced by toluene in equal volume, to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 43.4 mg, yield 70%.

[0150] Example 10

[0151] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0152] The same as Example 1, except that the solvent dichloromethane was replaced with ethanol in equal volume to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 32.9 mg, yield 53%.

[0153] Embodiment 11

[0154] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0155] The same as Example 1, except that potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) was replaced with potassium carbonate (0.4 mmol, 55.3 mg, 2.0 equiv.) to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 45.9 mg, yield 74%.

[0156] Example 12

[0157] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0158] The same as Example 1, except that difluoromethylhydrazone bromide (0.24 mmol, 59.8 mg, 1.2 equiv.) and potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) were replaced by difluoromethylhydrazone bromide (0.30 mmol, 74.7 mg, 1.5 equiv.) and potassium carbonate (0.4 mmol, 55.3 mg, 2.0 equiv.), respectively, to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 39.1 mg, yield 63%.

[0159] Example 13

[0160] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0161] The same as Example 1, except that difluoromethyl bromohydrazone (0.24 mmol, 59.8 mg, 1.2 equiv.) was replaced with difluoromethyl bromohydrazone (0.20 mmol, 74.7 mg, 1.0 equiv.) to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 42.7 mg, yield 70%.

[0162] Embodiment 14

[0163] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0164] The same as Example 1, except that difluoromethylhydrazone bromide (0.24 mmol, 59.8 mg, 1.2 equiv.) and potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) were replaced by difluoromethylhydrazone bromide (0.20 mmol, 49.8 mg, 1.0 equiv.) and potassium carbonate (0.2 mmol, 27.6 mg, 1.0 equiv.), respectively, to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 46.5 mg, yield 75%.

[0165] Embodiment 15

[0166] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0167] The same as Example 1, except that difluoromethylhydrazone bromide (0.24mmol, 59.8mg, 1.2equiv.) and potassium carbonate (0.3mmol, 41.5mg, 1.5equiv.) were replaced by difluoromethylhydrazone bromide (0.40mmol, 99.6mg, 2.0equiv.) and potassium carbonate (0.5mmol, 69.0mg, 2.5equiv.), respectively, to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 31.7mg, yield 51%.

[0168] Example 16

[0169] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0170] The same as Example 1, except that "the mixed solution was stirred at 25°C" was replaced by "the mixed solution was stirred at 40°C", to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 39.7 mg, yield 64%.

[0171] Embodiment 17

[0172] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0173] The same as Example 1, except that "the mixed solution was stirred at 25°C" was replaced by "the mixed solution was stirred at 0°C", to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 44.1 mg, yield 71%.

[0174] Comparative Example 1

[0175] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0176] The same as Example 1, except that potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) was replaced with sodium carbonate (0.3 mmol, 31.8 mg, 1.5 equiv.) to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 18.6 mg, yield 30%.

[0177] Compared with Example 1, when only the base was changed to sodium carbonate, the yield was significantly reduced.

[0178] Comparative Example 2

[0179] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0180] The same as Example 1, except that potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) was replaced with triethylamine (0.3 mmol, 30.4 mg, 1.5 equiv.) to obtain dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a): yellow solid, 14.9 mg, yield 24%.

[0181] Compared with Example 1, when only the base was changed to triethylamine, the yield was significantly reduced.

[0182] Comparative Example 3

[0183] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0184] Same as Example 1, except that the solvent dichloromethane was replaced with carbon tetrachloride in equal volume. The mixed solution was stirred at 25° C. The reaction was monitored by TLC. No target product was detected after 24 hours.

[0185] Compared with Example 1, when only the solvent was changed to carbon tetrachloride, the yield was significantly reduced.

[0186] Comparative Example 4

[0187] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0188] Same as Example 1, except that the solvent dichloromethane was replaced with chloroform in equal volume. The mixture was stirred at 25° C. The reaction was monitored by TLC. No target product was detected after 24 hours.

[0189] Compared with Example 1, when only the solvent was changed to chloroform, the yield was significantly reduced.

[0190] Comparative Example 5

[0191] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0192] The same as Example 1, except that the solvent dichloromethane was replaced with 1,4-dioxane in equal volume. The mixed solution was stirred at 25° C. The reaction was monitored by TLC. After 24 hours, no target product was detected.

[0193] Compared with Example 1, when only the solvent was changed to 1,4-dioxane, the reaction did not occur.

[0194] Comparative Example 6

[0195] Synthesis of dimethyl 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylate (3a)

[0196] The same as Example 1, except that difluoromethylhydrazone bromide (0.24 mmol, 59.8 mg, 1.2 equiv.) and potassium carbonate (0.3 mmol, 41.5 mg, 1.5 equiv.) were replaced by difluoromethylhydrazone bromide (0.10 mmol, 24.9 mg, 0.5 equiv.) and potassium carbonate (0.1 mmol, 13.8 mg, 0.5 equiv.), respectively, to obtain 1-phenyl-3-(difluoromethyl)-1H-pyrazole-4,5-dicarboxylic acid dimethyl ester (3a): yellow solid, 21.2 mg, yield 34%.

[0197] Compared with Example 1, when only difluoromethyl bromohydrazone (0.10 mmol, 37.4 mg, 0.5 equiv.) and potassium carbonate (0.2 mmol, 13.8 mg, 0.5 equiv.) were changed, the yield was significantly reduced.

[0198] The above are only preferred specific implementations of the present application, but the protection scope of the present application is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed in the present application should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. A 3-fluoroalkyl-fully substituted pyrazole compound, characterized in that: It has the general structure shown in Formula I: Among them, R f is CF2H or CF3; Ar is any one of Ph, 4-MeC6H4, 4-COOMeC6H4 and 4-FC6H4.

2. A method for preparing a 3-fluoroalkyl-fully substituted pyrazole compound as claimed in claim 1, characterized in that: The following steps are involved: A base is added to a fluoroalkyl bromohydrazone and a thiopyridinium salt, and then an organic solvent is added to synthesize the 3-fluoroalkyl-fully substituted pyrazole compound through a tandem cyclization / desulfurization reaction: The general structural formula of the fluoroalkyl bromohydrazone is shown in Formula II: Among them, R f is CF2H or CF3; Ar is any one of Ph, 4-Me-C6H4, 4-COOMe-C6H4 and 4-F-C6H4; The structural formula of the thiopyridinium salt is shown in Formula III:

3. The method for preparing a 3-fluoroalkyl-fully substituted pyrazole compound according to claim 2, characterized in that: The molar ratio of the thiopyridinium salt, the fluoroalkyl bromohydrazone and the base is 1.0:(1.0-1.5):(1.0-2.0).

4. The method for preparing a 3-fluoroalkyl-fully substituted pyrazole compound according to claim 3, characterized in that: The fluoroalkyl hydrazone bromide is difluoromethyl hydrazone bromide or trifluoromethyl hydrazone bromide.

5. The method for preparing a 3-fluoroalkyl-fully substituted pyrazole compound according to claim 3, characterized in that: The base includes any one of potassium carbonate, cesium carbonate, sodium hydroxide and 1,8-diazabicyclo[5.4.0]undec-7-ene.

6. The method for preparing a 3-fluoroalkyl-fully substituted pyrazole compound according to claim 2, characterized in that: The organic solvent includes any one of dichloromethane, tetrahydrofuran, toluene and ethanol.

7. The method for synthesizing 3-fluoroalkyl fully substituted pyrazole compounds according to claim 2, characterized in that: The reaction temperature of the tandem cyclization / desulfurization reaction is 0-40° C., and the reaction time is 7-12 hours.

8. The method for synthesizing 3-fluoroalkyl-fully substituted pyrazole compounds according to claim 2, characterized in that: After the tandem cyclization / desulfurization reaction is completed, a column chromatography separation process is also included. During the column chromatography separation, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the two is (5-6):

1.

9. Use of the 3-fluoroalkyl-fully substituted pyrazole compound as claimed in claim 1 in the preparation of pesticide products.

10. The use according to claim 9, characterized in that: The pesticide products include antifungal insecticides and herbicides.

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