A method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds

Abstract

The invention discloses a method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds, and synthesizes 3-fluoroalkyl-5-amino-1,2,4-triazole compounds by [3+2] cycloaddition reaction of fluoroalkyl bromohydrazone and carbodiimide. The present invention utilizes fluoroalkyl bromohydrazone to participate in [3+2] cycloaddition reaction, which is used to synthesize 3-fluoroalkyl-5-amino-1,2,4-triazole compounds, and provides a new method for the synthesis of 3-fluoroalkyl-5-amino-1,2,4-triazole. The synthesis method provided by the present invention has the advantages of short reaction steps, small number of reaction raw materials and easy availability, simple operation, mild reaction conditions, and good reaction yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds. Background Art

[0002] 1,2,4-Triazole is a very important class of nitrogen heterocyclic compounds, and its structural units are widely present in drugs, pesticides and functional material molecules. Many drug molecules containing 1,2,4-triazole skeletons have been marketed for the treatment of various diseases. Among 1,2,4-triazole derivatives, amino-1,2,4-triazole compounds have attracted extensive attention in the agricultural chemistry and pharmaceutical fields due to their good and diverse biological activities, such as the following compounds A to B (references: J.Med.Chem.2014,57,5664-5678; J.Med.Chem.2005,48,1540-1549.). At the same time, they are also multifunctional synthetic building blocks for synthesizing other molecules containing 1,2,4-triazole skeletons with potential biological activity (Mol. Diversity. 2022, 26, 717-739; Front. Chem. 2018, 6, 527; RSC Adv. 2012, 2, 6719-6728; Tetrahedron. 2008, 64, 11041-11049.). In addition, the introduction of trifluoromethyl groups into drug molecules can significantly improve the physicochemical properties of related drugs, such as metabolic stability, lipid solubility and bioavailability. Among the numerous trifluoromethyl compounds, trifluoromethyl-substituted 1,2,4-triazole compounds have attracted extensive attention from scientists in the field of medicine due to their good biological activity, such as the following compounds C to F (references: Org. Process Res. Dev. 2005, 9, 634-639; J. Med. Chem. 2011, 54, 387-391; J. Fluorine Chem. 2012, 135, 323-329; Bioorg. Med. Chem. Lett. 2004, 14, 2463-2467.). Therefore, it is of great significance to continue to explore efficient synthesis methods for trifluoromethyl-substituted 1,2,4-triazoles.

[0003]

[0004] On the other hand, 1,2,4-triazole derivatives are used as a new type of environmentally friendly energy storage material, zwitterionic material, and luminescent material, etc., because they exhibit high thermal sensitivity, good thermal stability, low impact sensitivity, and high heat of formation (references: Cryst. Growth. Des. 2019, 19, 5292-5307; Cryst. Growth. Des. 2019, 19, 7206-7216; ACS. Appl. Energy. Mater. 2020, 3, 6492-6500; ACS. Macro. Lett. 2019, 8, 1372-1377.). Therefore, 1,2,4-triazole derivatives have shown great value in the field of energy storage materials. In addition, 1,2,4-triazole compounds are also one of the important raw materials for the preparation of other nitrogen-containing heterocyclic compounds. They are effective single, double, and multiple nucleophiles that can react with different electrophiles in two, three or multiple components, "one pot" reactions. Moreover, 1,2,4-triazole compounds have multiple alternating reaction centers. Therefore, 1,2,4-triazole compounds are favorable reagents for controllable multidirectional reactions (Molecular Diversity.2022,26,717-739; Front.Chem.2018,6,527; RSC.Adv.2012,2,6719-6728; Tetrahedron.2008,64,11041-11049.). Therefore, in order to further expand new methods for synthesizing triazole skeletons and explore the potential application value of their derivatives, it will be very necessary to synthesize various triazole derivatives.

[0005] At present, trifluoromethyl-substituted 1,2,4-triazole compounds are mainly synthesized by using hydrazine, hydrazone, diazo and amidine compounds as raw materials. The specific method is as follows:

[0006] (1) Synthesis of trifluoromethyl-substituted 1,2,4-triazole compounds using hydrazine and its derivatives as substrates

[0007] In 1987, Tanaka's research group first disclosed that 3-trifluoromethyl-substituted 1,2,4-triazole compounds were generated at room temperature by intermolecular cycloaddition process using trifluoromethyl bromohydrazone and cyanamide as starting materials in tetrahydrofuran as solvent and base catalysis (J. Heterocyclic Chem, 1987, 24, 1391-1987). This method provides a convenient reference for the synthesis of trifluoromethyl 1,2,4-triazole compounds. The reaction route is:

[0008]

[0009] In 2005, Hansen's research group used chloropyrazine and hydrazine hydrate as starting materials and synthesized trifluoromethyl-substituted 1,2,4-triazole compounds through multi-step reactions. The possible mechanism is: first, chloropyrazine reacts with hydrazine hydrate to obtain a pyrazine hydrazine intermediate, then undergoes a nucleophilic addition reaction with trifluoroacetic anhydride to generate a hydrazide intermediate, and finally undergoes intramolecular cyclization to obtain the target product (Org. Proess. Res. Dev. 2005, 9, 634-639). This reaction also has certain limitations, namely: although the reaction is successful on a laboratory scale, due to certain problems in the post-processing of hydrazine, hydrazine cannot be prepared in large quantities. Therefore, this strategy cannot be used for large-scale synthesis of trifluoromethyl-substituted 1,2,4-triazole compounds.

[0010] The reaction route is:

[0011]

[0012] In 2010, Mykhailiuk's research group used commercially available trifluoroacetylhydrazine and acetic acid amidine as starting materials, refluxed in acetic acid for 4 hours, and successfully obtained trifluoromethyl-substituted 1,2,4-triazole compounds with a yield of 25%, which can be mass-produced (Synthesis. 2010, 7, 1075-1077.). Unfortunately, the yield of this method is low. The reaction route is:

[0013]

[0014] (2) Synthesis of trifluoromethyl-containing 1,2,4-triazole compounds using chloroimide as substrate

[0015] In 2019, Wu Xiaofeng's research group used industrially available trifluoromethyl chloroimide and hydrazone as starting materials and disclosed a metal-free catalytic method to quickly synthesize 5-trifluoromethyl-1,2,4-triazole compounds (Adv. Synth. Catal. 2019, 361, 4949-4954.). Compared with the traditional multi-step and cumbersome method for preparing perfluoroalkyl-1,2,4-triazole compounds, this method exhibits the following characteristics: mild reaction conditions, simple operation, wide substrate range, high efficiency, and easy to achieve gram-scale reactions. This method provides a simple and environmentally friendly strategy for the synthesis of trifluoromethyl-substituted 1,2,4-triazole compounds. The reaction route is:

[0016]

[0017] In 2021, Wu Xiaofeng's research group reported a method for synthesizing 3-trifluoromethyl-1,2,4-triazole compounds through a copper-mediated [3+2] cycloaddition reaction of trifluoroacetylaminohydrazine and triphenylphosphine isocyanate (NIITP) (Org. Chem. Front., 2021, 8, 5040-5044.). Among them, NIITP is a safe, industrially available solid isonitrile. Mo(CO)6 is an effective promoter for activating NIITP. This conversion method has the advantages of easy reagent availability, mild reaction conditions, a wide range of substrates and high reaction efficiency, providing an effective route for the synthesis of fluorinated 1,2,4-triazoles. The reaction route is:

[0018]

[0019] In the same year, Wu Xiaofeng's research group reported a low-cost FeCl3-mediated cyclization and intramolecular dehydration process of trifluoromethyl chloroimide and hydrazide, and efficiently synthesized 5-trifluoromethyl-1,2,4-triazole compounds (Adv. Synth. Catal. 2020, 362, 5130-5134.). The notable features of this scheme are relatively mild reaction conditions, low cost of iron catalysts, simple operation, and wide applicability of substrates. This transformation provides an effective way to quickly construct 5-trifluoromethyl-1,2,4-triazole derivatives. The reaction formula is:

[0020]

[0021] (3) Synthesis of trifluoromethyl-containing 1,2,4-triazole compounds using amidine as substrate

[0022] In 2021, Wu Xiaofeng's research group reported a method for synthesizing 5-trifluoromethyl-1,2,4-triazole compounds using trifluoromethyl-substituted amidines and methyl ketones as starting materials through an I2-mediated metal-free [4+1] cyclization reaction. The transformation process includes iodination / Kornblum oxidation, intermolecular dehydration condensation, and iodine-mediated intramolecular cyclization / aromatization process (Adv. Synth. Catal. 2021, 363, 3060-3069.). This method can be easily expanded to a scale of 3 mol without significantly reducing the yield, and can be carried out in a one-pot manner. This synthetic method is very practical and can obtain medically important functionalized 1,2,4-triazole derivatives. The reaction route is:

[0023]

[0024] In 2021, Wu Xiaofeng's research group reported a palladium-catalyzed three-component carbonylation reaction of trifluoromethyl-substituted amidines and aryl iodides to synthesize 5-trifluoromethyl-1,2,4-triazole compounds with medicinal value. In the conversion process, TFBen, as a safe and convenient solid CO substitute, avoids the use of toxic gas CO (Org. Chem. Front. 2021, 8, 6089-6094.). The reaction has the characteristics of low catalyst loading, wide substrate applicability, high efficiency and no CO gas participation in the reaction, and has good application prospects. In addition, this method has been successfully applied to the preparation of bioactive molecule GlyT1 inhibitors. The reaction route is:

[0025]

[0026] In 2021, Wu Xiaofeng's research group reported a method for the efficient synthesis of trifluoromethyl-1,2,4-triazole compounds by the metal-free oxidative cyclization reaction of trifluoromethyl-substituted amidines and imines (Org.Chem.Front.2021,8,4490-4495.). The notable feature of this method is the use of industrially available starting materials, which has a wide range of substrate applicability, high yield and scalability. This transformation provides a simple and easy way to prepare valuable multifunctional 1,2,4-triazole derivatives. And the reaction can be expanded to the gram level, providing the possibility for further large-scale application. The reaction route is:

[0027]

[0028] (4) Other methods for synthesizing fluorinated 1,2,4-triazole compounds

[0029] In 2004, the Balsells group disclosed a simple and novel synthetic building block, which uses highly reactive chloroalkyl diazoles and ethylenediamine as starting materials to synthesize 3-trifluoromethyl-substituted 1,2,4-triazoles in two steps (Org. Lett. 2005, 7, 1039-1042.). The core of this method is the condensation reaction of chloroalkyl diazoles with ethylenediamine to synthesize acyl amidine intermediates. Then, the acyl amidine intermediates undergo intramolecular cyclization to generate 3-trifluoromethyl-substituted 1,2,4-triazole compounds. The reaction route is:

[0030]

[0031] In 2020, Ma Junan's research group reported a copper-catalyzed three-component "one-pot" transformation of aryl diazonium salts with fluorinated diazonium reagents and nitriles. Through the [1+2+2] cycloaddition reaction, a series of trifluoromethylated 1,2,4-triazoles with different substituents were obtained. This method fills the gap in the synthesis of trifluoromethylated N-aryl-1,2,4-triazole compounds, and the applicability of this synthetic method to 1,2,4-triazole drugs has also been verified (Adv. Synth. Catal. 2020, 362, 4432-4437.). The reaction route is:

[0032]

[0033] In summary, in recent years, there have been more and more studies on the synthesis methods of 1,2,4-triazole compounds, including the synthesis of 1,2,4-triazole compounds using hydrazine, hydrazone, diazo and amidine compounds as raw materials. However, each method has its own defects and limitations. Trifluoromethyl is a common fluorine-containing group. The introduction of trifluoromethyl into organic compounds can significantly change the chemical, physical and biological properties of the parent compound, such as acidity and alkalinity, bioavailability, metabolic stability, lipid solubility and protein binding ability. Compared with trifluoromethyl, the introduction of difluoromethyl into drug and pesticide molecules has a significant effect on pharmacokinetic properties, namely membrane permeability, bioavailability, binding affinity, metabolic stability and lipophilicity, so difluoromethyl-substituted compounds are widely used in the design and development of new drugs and pesticides. Therefore, it is very necessary to explore a new, efficient and simple synthetic method to prepare fluoroalkyl-substituted 1,2,4-triazole compounds.

[0034] In the synthesis of nitrogen heterocyclic compounds containing difluoromethyl or trifluoromethyl groups, the cycloaddition reaction involving difluoromethyl or trifluoromethyl nitrile imine generated in situ by fluoroalkyl halide hydrazone under the action of base is one of the powerful methods. At present, among the cycloaddition reactions involving difluoromethyl nitrile imine, the cycloaddition reaction of difluoromethyl nitrile imine with carbon-carbon double bond or carbon-carbon triple bond has been studied, and difluoromethyl substituted pyrazole or pyrazoline compounds have been successfully obtained (references: J. Org. Chem. 2022, 87, 498. Asian J. Org. Chem. 2022, e202200438., Chin. J. Org. Chem. 2024, 44, 1226-1239, etc.), while the cycloaddition reaction of difluoromethyl nitrile imine with carbon-nitrogen double bond has been less studied. Summary of the invention

[0035] In order to solve the above technical problems, the present invention proposes a method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds. The present invention uses difluoromethyl or trifluoromethyl nitrile imine generated in situ by fluoroalkyl bromohydrazone (difluoromethyl bromohydrazone or trifluoromethyl bromohydrazone) in the presence of a base as a 1,3-dipole, and N,N-di-tert-butylcarbodiimide as a dipolephile, and realizes the synthesis of 3-fluoroalkyl-5-amino-1,2,4-triazole compounds through a [3+2] cycloaddition reaction between them. The results of the present invention show that difluoromethyl bromohydrazone can not only undergo a cycloaddition reaction with a carbon-carbon double bond or a carbon-carbon triple bond, but also undergo a cycloaddition reaction with a carbon-nitrogen double bond (electron-rich structure). This method provides a new method for the synthesis of difluoromethyl or trifluoromethyl substituted 1,2,4-triazole compounds. At the same time, the application range of difluoromethyl bromohydrazone in organic synthesis is expanded. The method has the characteristics of cheap and readily available raw materials, short reaction steps, small amount of raw materials and easy preparation, mild reaction conditions, easy purification of products and high yield.

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

[0037] A method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds comprises mixing fluoroalkyl bromohydrazone and carbodiimide, adding a base and an organic solvent, and synthesizing the 3-fluoroalkyl-5-amino-1,2,4-triazole compounds through a [3+2] cycloaddition reaction.

[0038] The general structural formula of the 3-fluoroalkyl-5-amino-1,2,4-triazole compound of the present invention is:

[0039]

[0040] Among them, R f is CF2H or CF3; Ar is any one of phenyl, 4-methoxyphenyl and 4-bromophenyl.

[0041] Preferably, 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 phenyl, 4-methoxyphenyl and 4-bromophenyl.

[0044] Preferably, the organic solvent includes any one of dichloromethane (DCM), 1,4-dioxane and acetonitrile (CH3CN), more preferably 1,4-dioxane. The type of organic solvent will affect the yield of the target product. When CH3CN is used as a solvent, the yield is 45%; when THF is used as a solvent, the yield is only 25%; but when 1,4-dioxane is used as a solvent, the yield can be quickly increased to 80%.

[0045] Preferably, the molar ratio of the carbodiimide, the fluoroalkyl bromohydrazone and the base is 1:(1-2.5):(1-2.5), more preferably 1:(1-1.2):(1-1.2), and most preferably 1:1.2:1.2.

[0046] Preferably, the fluoroalkyl hydrazone bromide is difluoromethyl hydrazone bromide or trifluoromethyl hydrazone bromide.

[0047] Preferably, the carbodiimide is N,N-di-tert-butylcarbodiimide. Difluoromethyl bromohydrazone or trifluoromethyl bromohydrazone undergoes a [3+2] cycloaddition reaction with N,N-di-tert-butylcarbodiimide. Taking difluoromethyl bromohydrazone as an example, first, difluoromethyl bromohydrazone generates a difluoromethyl nitrile imine intermediate in situ under the action of a base. Difluoromethyl nitrile imine is the real substrate for the cycloaddition reaction with carbodiimide (i.e., N,N-di-tert-butylcarbodiimide). Therefore, the molar ratio of difluoromethyl bromohydrazone to the base is always maintained at 1:1, but the molar ratio of fluoroalkyl bromohydrazone, carbodiimide and base has a greater influence on the yield. When the molar ratio of difluoromethyl bromohydrazone, base and N,N-di-tert-butylcarbodiimide is 1:1:1, the yield is 49%; when the molar ratio of difluoromethyl bromohydrazone, base and N,N-di-tert-butylcarbodiimide is increased to 1.2:1.2:1, the yield is significantly increased (to 65%), which shows that the nitrile imine is slightly excessive, which is beneficial to the reaction; when the molar ratio of difluoromethyl bromohydrazone, base and N,N-di-tert-butylcarbodiimide is increased to 2.5:2.5:1, the yield is reduced, which shows that the nitrile imine is greatly excessive and is not conducive to the reaction, and other side reactions may occur. Therefore, the present invention limits the molar ratio of carbodiimide, fluoroalkyl bromohydrazone and base to 1:(1-2.5):(1-2.5).

[0048] Preferably, the base includes any one of K2CO3, Na2CO3, Cs2CO3, NaHCO3 and Et3N, and more preferably K2CO3. When K2CO3 is used as the base, the yield is the highest (80%), and Cs2CO3 is more alkaline than K2CO3. When Cs2CO3 is used, the yield is reduced to a certain extent, and the yield is 46%.

[0049] Preferably, the reaction temperature of the [3+2] cycloaddition reaction is room temperature, and the reaction time is 7 to 18 hours, more preferably 10 hours.

[0050] Preferably, after the [3+2] cycloaddition reaction is completed, a column chromatography separation process is also included.

[0051] Preferably, during the column chromatography separation, the eluent is a mixture of petroleum ether (PE) and ethyl acetate (EA).

[0052] Preferably, the volume ratio of petroleum ether to ethyl acetate is (100-40):1.

[0053] More preferably, the reaction route of the synthesis method of the 3-fluoroalkyl-5-amino-1,2,4-triazole compound is:

[0054]

[0055] The specific method is: adding fluoroalkyl bromohydrazone (1.2-2.5 equiv.), N,N-di-tert-butylcarbodiimide (1 equiv.), base (1.2-2.5 equiv.) and 3 mL of organic solvent into a 50 mL Schlenk reaction tube to obtain a mixture, stirring the mixture at 25° C. for 7-18 h, and after the reaction is completed, drying the solvent by spin-drying, and performing column chromatography purification using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA=(100-40):1, volume ratio) to obtain the 3-fluoroalkyl-5-amino-1,2,4-triazole compound.

[0056] Compared with the prior art, the present invention has the following advantages and technical effects:

[0057] (1) The present invention discloses for the first time a new method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds by [3+2] cycloaddition reaction using N,N-di-tert-butylcarbodiimide and fluoroalkyl bromohydrazone as raw materials.

[0058] (2) The synthesis method provided by the present invention has the characteristics of short reaction steps, small amount of raw materials and easy availability, simple operation, mild reaction conditions and good reaction yield.

[0059] (3) The present invention uses N,N-di-tert-butylcarbodiimide for the synthesis of 3-fluoroalkyl-5-amino-1,2,4-triazole, and N,N-di-tert-butylcarbodiimide is a stable liquid at normal temperature and pressure. Therefore, these advantages of the raw material provide great possibilities for the further industrialization of the method.

[0060] (4) The 3-fluoroalkyl-5-amino-1,2,4-triazole compound synthesized by the present invention is 1 H NMR, 13 C NMR, 19FNMR high-resolution mass spectrometry detection, the product is a pure target compound with high product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] 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:

[0062] Figure 1 The N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a) synthesized in Example 1 1 HNMR spectra;

[0063] Figure 2 The N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a) synthesized in Example 1 13 CNMR images;

[0064] Figure 3 The N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a) synthesized in Example 1 19 FNMR images;

[0065] Figure 4 This is a high-resolution mass spectrum monitoring diagram of N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a) synthesized in Example 1;

[0066] Figure 5 The N-(tert-butyl)-1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3b) synthesized in Example 2 1 H NMR spectra;

[0067] Figure 6 The N-(tert-butyl)-1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3b) synthesized in Example 2 13 C NMR spectra;

[0068] Figure 7 The N-(tert-butyl)-1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3b) synthesized in Example 2 19 F NMR spectra;

[0069] Figure 8This is a high-resolution mass spectrometry monitoring diagram of N-(tert-butyl)-1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3b) synthesized in Example 2;

[0070] Fig. 9 The N-(tert-butyl)-1-(4-bromophenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3c) synthesized in Example 3 1 H NMR spectra;

[0071] Fig.10 The N-(tert-butyl)-1-(4-bromophenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3c) synthesized in Example 3 13 C NMR spectra;

[0072] Fig.11 The N-(tert-butyl)-1-(4-bromophenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3c) synthesized in Example 3 19 F NMR spectra;

[0073] Fig.12 This is a high-resolution mass spectrometry monitoring diagram of N-(tert-butyl)-1-(4-bromophenyl)-3-(difluoromethyl)-1H-1,2,4-triazol-5-amine (3c) synthesized in Example 3;

[0074] Fig.13 N-(tert-butyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine synthesized in Example 4

[0075] (3d) 1 H NMR spectra;

[0076] Fig.14 The N-(tert-butyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3d) synthesized in Example 4 13 C NMR spectra;

[0077] Fig.15 The N-(tert-butyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3d) synthesized in Example 4 19 F NMR spectra;

[0078] Fig.16 This is a high-resolution mass spectrum monitoring diagram of N-(tert-butyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3d) synthesized in Example 4;

[0079] Fig.17 The N-(tert-butyl)-1-(4-bromophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3e) synthesized in Example 5 1 H NMR spectra;

[0080] Fig.18 The N-(tert-butyl)-1-(4-bromophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3e) synthesized in Example 5 13 C NMR spectra;

[0081] Fig.19 The N-(tert-butyl)-1-(4-bromophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3e) synthesized in Example 5 19 F NMR spectra;

[0082] Fig. 20 This is a high-resolution mass spectrum monitoring chart of N-(tert-butyl)-1-(4-bromophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3e) synthesized in Example 5. DETAILED DESCRIPTION

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0088] Unless otherwise specified, the room temperature in the present invention is 25±3°C.

[0089] The raw materials used in the examples of the present invention were synthesized from literature or purchased from the market. Difluoromethyl bromohydrazone was prepared according to (J. Org. Chem. 2022, 87, 498.); trifluoromethyl bromohydrazone was prepared according to (J. Fluorine Chem. 2016.10.018.).

[0090] The technical solution of the present invention is further illustrated by the following embodiments.

[0091] Example 1

[0092] Synthesis of N-(tert-butyl)-1-phenyl 3-(difluoromethyl)-1H-1,2,4-triazol-5-amine (3a)

[0093]

[0094] The specific synthesis process is as follows:

[0095] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed with silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1, v:v, the same below) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): orange solid, 43.0 mg, yield 80%.

[0096] The N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a) synthesized above was 1 HNMR,13 CNMR, 19 FNMR high-resolution mass spectrometry detection (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:

[0097] 1 H NMR (400MHz, CDCl3): δ7.55-7.51(m,2H),7.48-7.42(m,3H),6.59(t,J=53.6Hz,1H),4.33(s,1H),1.45(s,9H).

[0098] 13 C{ 1 H}NMR(150MHz,CDCl3):δ154.9(t,J C-F =26.9Hz),154.0,136.3,130.0,128.6,124.1,109.6(t,J C-F =235.1Hz),52.8,29.0.

[0099] 19 F NMR (376MHz, CDCl3): δ-117.32 (d, J=54.1Hz).

[0100] HRMS(ESI):m / z calcd for C 13 H 17 F2N4[M+H] + 267.1416, found 267.1406.

[0101] Example 2

[0102] Synthesis of N-(tert-butyl)-1-(4-methoxyphenyl)3-(difluoromethyl)-1H-1,2,4-triazol-5-amine (3b)

[0103] The synthetic route is as follows:

[0104]

[0105] The specific synthesis process is as follows:

[0106] N′-p-methoxyphenyl difluoromethyl bromohydrazone (67.0 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-(4-methoxyphenyl)3-(difluoromethyl)-1H-1,2,4-triazol-5-amine (3b): orange solid, 41.0 mg, yield 69%.

[0107] The N-(tert-butyl)-1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3b) synthesized above was 1 HNMR, 13 CNMR, 19 FNMR high-resolution mass spectrometry detection (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:

[0108] 1 H NMR (400MHz, CDCl3): δ7.35 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.58 (t, J = 54.0 Hz, 1H), 4.16 (s, 1H), 3.86 (s, 3H), 1.43 (s, 9H).

[0109] 13 C{ 1 H}NMR (150MHz, CDCl3): δ159.8,154.6(t,J C-F =26.6Hz),154.4,128.8,126.2,115.1,109.6(t,J C-F =234.9Hz),55.5,52.6,29.1.

[0110] 19 F NMR (376MHz, CDCl3): δ-117.21 (d, J=53.8Hz);

[0111] HRMS(ESI):m / z calcd for C 14 H 19 OF2N4[M+H] +297.1521, found 297.1523.

[0112] Example 3

[0113] Synthesis of N-(tert-butyl)-1-(4-bromophenyl)-3-(difluoromethyl)-1H-1,2,4-triazol-5-amine (3c)

[0114] The synthetic route is as follows:

[0115]

[0116] The specific synthesis process is as follows:

[0117] N′-p-bromophenyl difluoromethyl bromohydrazone (78.7 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=80:1) to obtain N-(tert-butyl)-1-(4-bromophenyl)-3-(difluoromethyl)-1H-1,2,4-triazol-5-amine (3c): a red solid, 57.2 mg, and a yield of 82%.

[0118] The N-(tert-butyl)-1-(4-bromophenyl)-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3c) synthesized above was 1 H NMR, 13 C NMR, 19 F NMR high-resolution mass spectrometry detection (such as Figure 9-12 The results show that the product is a pure target compound. The characterization data of the corresponding product are:

[0119] 1 H NMR (400MHz, CDCl3): δ7.65(d,J=8.8Hz,2H),7.36(d,J=8.4Hz,2H),6.57(t,J=53.6Hz,1H),4.26(s,1H),1.44(s,9H);

[0120] 13 C{ 1 H}NMR(150MHz,CDCl3):δ155.1(t,J C-F=26.6Hz),153.9,135.3,133.1,125.6,122.3,109.4(t,J C-F =235.4Hz),53.0,29.0;

[0121] 19 F NMR (376MHz, CDCl3): δ-117.55 (d, J=53.8Hz);

[0122] HRMS(ESI):m / z calcd for C 13 H 16 F2N4Br[M+H] + 345.0521, found 345.0524.

[0123] Example 4

[0124] Synthesis of N-(tert-butyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (3d)

[0125] The synthetic route is as follows:

[0126]

[0127] The specific synthesis process is as follows:

[0128] N′-p-methoxyphenyl trifluoromethyl bromohydrazone (71.3 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed with silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3d): orange solid, 44 mg, yield 70%.

[0129] The N-(tert-butyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (3d) synthesized above was 1 HNMR, 13 C NMR, 19 F NMR high-resolution mass spectrometry detection (such as Figure 13-16The results show that the product is a pure target compound. The characterization data of the corresponding product are:

[0130] 1 H NMR (400MHz, CDCl3): δ7.36 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 9.2 Hz, 2H), 4.20 (s, 1H), 3.86 (s, 3H), 1.43 (s, 9H);

[0131] 13 C{ 1 H}NMR (150MHz, CDCl3): δ160.0,154.3,151.2(q,J C-F =38.1Hz),128.4,126.3,119.4(q,J C-F =268.8Hz),115.1,55.6,52.8,29.0;

[0132] 19 F NMR (376MHz, CDCl3): δ-66.2 (s);

[0133] HRMS(ESI):m / z calcd for C 14 H 18 OF3N4[M+H] + 315.1427, found 315.1427.

[0134] Example 5

[0135] Synthesis of N-(tert-butyl)-1-(4-bromophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (3e)

[0136] The synthetic route is as follows:

[0137]

[0138] The specific synthesis process is as follows:

[0139] N′-p-bromophenyl trifluoromethyl bromohydrazone (83.0 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=60:1) to obtain N-(tert-butyl)-1-(4-bromophenyl)--3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (3e): orange solid, 61.1 mg, yield 84%.

[0140] The N-(tert-butyl)-1-(4-bromophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (3e) synthesized above was 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry (such as Figure 17-20 The results show that the product is a pure target compound. The characterization data of the corresponding product are:

[0141] 1 H NMR (400MHz, CDCl3): δ7.66 (d, J = 8.4Hz, 2H), 7.37 (d, J = 8.8Hz, 2H), 4.29 (s, 1H), 1.44 (s, 9H);

[0142] 13 C{ 1 H}NMR (150MHz, CDCl3): δ153.9,151.7(q,J C-F =38.7Hz),135.0,133.2,125.7,122.7,119.3(q,J C-F =268.5Hz),53.1,28.9;

[0143] 19 F NMR (376MHz, CDCl3): δ-66.3 (s);

[0144] HRMS(ESI):m / z calcd for C 13 H 15 F3N4B r [M+H] + 363.0427, found 363.0425.

[0145] Example 6

[0146] N′-phenyldifluoromethyl bromohydrazone (124.5 mg, 0.50 mmol, 2.5 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (69.1 mg, 0.50 mmol, 2.5 equiv.), and 3 mL of DCM were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 18 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): an orange solid, 24.0 mg, and a yield of 45%.

[0147] Example 7

[0148] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of DCM were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): orange solid, 34.6 mg, and a yield of 65%.

[0149] Example 8

[0150] N′-phenyldifluoromethyl bromohydrazone (49.8 mg, 0.20 mmol, 1.0 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (27.6 mg, 0.20 mmol, 1.0 equiv.), and 3 mL of DCM were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 9 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): an orange solid, 26.1 mg, and a yield of 49%.

[0151] Example 9

[0152] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of CH3CN were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): an orange solid, 24.0 mg, and a yield of 45%.

[0153] Example 10

[0154] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), Na2CO3 (25.4 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 9 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): an orange solid, 27.7 mg, and a yield of 52%.

[0155] Embodiment 11

[0156] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), Cs2CO3 (78.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 7 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): an orange solid, 24.5 mg, and a yield of 46%.

[0157] Example 12

[0158] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), NaHCO3 (20.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): orange solid, 30.9 mg, and a yield of 58%.

[0159] Example 13

[0160] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), Et3N (24.3 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 9 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed with silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): orange solid, 30.9 mg, yield 58%.

[0161] Comparative Example 1

[0162] N′-phenyldifluoromethyl bromohydrazone (59.8 mg, 0.24 mmol, 1.2 equiv.), N,N-di-tert-butylcarbodiimide (30.9 mg, 0.20 mmol, 1.0 equiv.), K2CO3 (33.2 mg, 0.24 mmol, 1.2 equiv.), and 3 mL of THF were added to a 50 mL Schlenk reaction tube to obtain a mixture, which was stirred at 25° C. for 10 h. After the reaction, the solvent was dried by spin drying, and column chromatography was performed using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=100:1) to obtain N-(tert-butyl)-1-phenyl-3-(difluoromethyl)-1H-1,2,4-triazole-5-amine (3a): an orange solid, 13.3 mg, and a yield of 25%.

[0163] 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 method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds, characterized in that: The fluoroalkyl bromohydrazone and carbodiimide are mixed, a base and an organic solvent are added, and a 3-fluoroalkyl-5-amino-1,2,4-triazole compound is synthesized through a [3+2] cycloaddition reaction; The general structural formula of the fluoroalkyl bromohydrazone is: In the formula, R f is CF2H or CF3; Ar is any one of phenyl, 4-methoxyphenyl and 4-bromophenyl; The organic solvent includes any one of dichloromethane, 1,4-dioxane and acetonitrile; The carbodiimide is N,N-di-tert-butylcarbodiimide; The base includes any one of K2CO3, Na2CO3, Cs2CO3, NaHCO3 and Et3N.

2. The method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds according to claim 1, characterized in that: The molar ratio of the carbodiimide, the fluoroalkyl bromohydrazone and the base is 1:(1-2.5):(1-2.5).

3. The method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds according to claim 1, characterized in that: The reaction temperature of the [3+2] cycloaddition reaction is room temperature, and the reaction time is 7 to 18 hours.

4. The method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds according to claim 1, characterized in that: After the [3+2] cycloaddition reaction is completed, a column chromatography separation process is also included.

5. The method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds according to claim 4, characterized in that: During the column chromatography separation, the eluent is a mixture of petroleum ether and ethyl acetate.

6. The method for synthesizing 3-fluoroalkyl-5-amino-1,2,4-triazole compounds according to claim 5, characterized in that: The volume ratio of the petroleum ether to ethyl acetate is (100-40):1.

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