A process for the preparation of 4-trifluoromethyl substituted 1,2,3-triazole compounds

Abstract

This invention discloses a method for preparing 4-trifluoromethyl-substituted 1,2,3-triazole compounds, belonging to the field of compound synthesis technology. The method includes: under alkaline conditions, in a solvent, a trifluoromethyl ketone compound (Formula I) undergoes a deprotonation-enolization and [3+2] cycloaddition reaction with an organic azide compound (Formula II). After the reaction, the mixture is separated by extraction, rotary evaporation, and column chromatography to obtain a 4-trifluoromethyl-substituted 1,2,3-triazole compound (Formula III). This invention can be carried out smoothly under air conditions, without requiring an anhydrous or oxygen-free environment, and without using a metal catalyst. The reaction conditions are mild, the operation is simple, the substrate range is wide, and the yield is good. It provides an efficient, green, and economical new route for the synthesis of 4-trifluoromethyl-substituted 1,2,3-triazole compounds, and the obtained compound can serve as a key intermediate for the antithrombotic drug Asundexian, showing good prospects for industrial application.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and in particular to a method for preparing a 4-trifluoromethyl-substituted 1,2,3-triazole compound. Background Technology

[0002] 1,2,3-Triazoles are a class of aromatic five-membered heterocyclic compounds containing three nitrogen atoms. They possess good biological activity and are widely used in pharmaceuticals, pesticides, and other fields. Trifluoromethyl groups are among the most widely used fluorine-containing groups in pharmaceuticals, capable of improving the solubility, lipophilicity, pharmacokinetic characteristics, and binding selectivity of drug candidates. Splicing trifluoromethyl groups with 1,2,3-triazole structural units holds promise for obtaining novel molecules with even stronger biological activity.

[0003] Currently, the classic method for synthesizing 1,2,3-triazole compounds is the copper-catalyzed azido-yne cycloaddition reaction (CuAAC reaction). This reaction has the advantages of high efficiency and selectivity, but the use of copper catalysts has potential toxicity issues, and the removal of copper ions in the post-processing is relatively cumbersome. In addition, there are some metal-free catalytic methods, such as the azido-alkene cycloaddition reaction catalyzed by organic bases, but the reaction conditions are relatively harsh and the substrate applicability is narrow.

[0004] For trifluoromethyl-substituted 1,2,3-triazole compounds, the common methods involve introducing the trifluoromethyl group through multi-step reactions or using expensive trifluoromethylating reagents. However, these methods are lengthy and require multiple steps to construct the target compound structure, which not only increases the synthesis cost but also reduces the yield of the final product. Furthermore, the use of expensive and difficult-to-obtain reagents or catalysts limits their application in practical production and hinders large-scale industrial production.

[0005] Therefore, developing a method for preparing trifluoromethyl-substituted 1,2,3-triazole compounds that has mild reaction conditions, is simple to operate, and is green and efficient has important practical application value. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing 4-trifluoromethyl-substituted 1,2,3-triazole compounds. This method can be carried out under air conditions, without the need for an anhydrous or oxygen-free environment. It is simple to operate, low in cost, and suitable for green synthesis and industrial applications.

[0007] To achieve the above objective, the present invention provides a method for preparing a 4-trifluoromethyl-substituted 1,2,3-triazole compound, comprising the following steps: Under alkaline conditions, in a solvent, trifluoromethyl ketone compounds undergo deprotonation-enolization and [3+2] cycloaddition reactions with organic azide compounds. After the reaction is completed, the compounds are separated by extraction, rotary evaporation, and column chromatography to obtain 4-trifluoromethyl-substituted 1,2,3-triazole compounds. The structural formula of the trifluoromethyl ketone compound is: ; The structural formula of the organic azide compound is: ; The structural formula of the 4-trifluoromethyl-substituted 1,2,3-triazole compound is: ; R in the structural formula 1 The aromatic group, alkyl group, or alkoxy group may be substituted or unsubstituted; R in the structural formula 2 It can be a substituted or unsubstituted aromatic group, alkyl group, or alkoxy group.

[0008] Preferably, the R 1 The substituents are substituted or unsubstituted phenyl, naphthyl, thiophene, benzothiophene, or furanyl, and the number of substituents is 1 to 5.

[0009] Preferably, the substitution is mono- or di-substituted, and the substituent is at least one selected from halogen, alkyl, alkenyl, alkoxy, aryl, fluoroalkyl, and amide groups.

[0010] Preferably, the R 1 It is an alkyl group having 1 to 12 carbon atoms or an alkoxy group having 1 to 6 carbon atoms.

[0011] Preferably, the R 2 It is a substituted or unsubstituted phenyl or an alkyl group having 1 to 6 carbon atoms.

[0012] Preferably, the alkaline conditions are provided by one of the following alkaline agents: Cs₂CO₃, CsOH·H₂O, K₂CO₃, DBU, and t-BuOK. The alkaline agents such as Cs₂CO₃ used in this invention have good chemical selectivity and substrate compatibility, are free of heavy metals, and avoid toxicity and post-processing problems.

[0013] Preferably, the total reaction time for the protonation-enolization reaction and the [3+2] cycloaddition reaction is 30 min to 60 min, and the reaction temperature is 20 °C. o C~60 o C.

[0014] Preferably, the molar ratio of the trifluoromethyl ketone compound, the organic azide compound, and the alkali agent is 1:1.5 to 3:1 to 2.

[0015] Preferably, the solvent is dimethyl sulfoxide. N , N - One of dimethylformamide, acetonitrile, 1,4-dioxane and toluene.

[0016] This invention also provides a 4-trifluoromethyl-substituted 1,2,3-triazole compound, prepared by the method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to any one of claims 1 to 9; the 4-trifluoromethyl-substituted 1,2,3-triazole compound comprises: 1- N - p-Cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ; 1- N - p-Cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole, with the following structural formula: ; 1- N - p-Cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole, with the following structural formula: ; 1- N -m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ; 1- N -p-Nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ; 1- N - p-Aldehydephenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ; 1- N -(2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole, with the following structural formula: ; 1- N -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole, with the following structural formula: ; 1- N- p-Cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole, with the following structural formula: .

[0017] In summary, the method for preparing a 4-trifluoromethyl-substituted 1,2,3-triazole compound provided by this invention has the following advantages compared to traditional techniques: (1) The deprotonation-enolization reaction and [3+2] cycloaddition reaction in this invention are both carried out under air conditions. The reaction conditions are mild, the equipment requirements are low, the steps are simple, and the atom economy is high. It can effectively reduce the synthesis cost and improve the production efficiency. It provides a more efficient, green and economical new route for the synthesis of 4-trifluoromethyl substituted 1,2,3-triazole compounds. It has broad application prospects in the fields of drug development and material synthesis. (2) The 4-trifluoromethyl-substituted 1,2,3-triazole compounds prepared in this invention are suitable for a variety of substrates, have good yields, and can be used for the synthesis of key drug intermediates (such as Asundexian intermediates).

[0018] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0019] Figure 1 This is a reaction diagram of a method for preparing a 4-trifluoromethyl-substituted 1,2,3-triazole compound according to the present invention. Figure 2 The 1- prepared in Example 1 of the present invention N -1H NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 3 The 1- prepared in Example 1 of the present invention N - Carbon NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 4 1- prepared in Example 2 of the present invention N -1H NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole; Figure 5 1- prepared for Example 2 of the present invention N - Carbon NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole; Figure 6 1- prepared in Example 3 of the present invention N -1H NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole; Figure 7 1- prepared in Example 3 of the present invention N -C NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole; Figure 8 The 1- prepared in Example 4 of this invention N The proton NMR spectrum of 1-m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 9 The 1- prepared in Example 4 of this invention N Carbon NMR spectrum of m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 10 1- prepared in Example 5 of the present invention N -1H NMR spectrum of p-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 11 1- prepared in Example 5 of the present invention N -C NMR spectrum of p-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 12 1- prepared for Example 6 of the present invention N -1H NMR spectrum of p-aldehyde phenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 13 1- prepared in Example 6 of the present invention N - Carbon NMR spectrum of p-aldehyde phenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole; Figure 14 1- prepared for Example 7 of the present invention N The proton NMR spectrum of (2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole; Figure 15 1- prepared for Example 7 of the present invention N Carbon NMR spectrum of (2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole; Figure 16 The 1- prepared in Example 8 of this invention N The proton NMR spectrum of -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole; Figure 17 The 1- prepared in Example 8 of this invention N Carbon NMR spectrum of -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole; Figure 18 1- prepared for Example 9 of the present invention N -H NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole; Figure 19 1- prepared for Example 9 of the present invention N Carbon NMR spectrum of p-cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole. Detailed Implementation

[0020] The technical method of the present invention will be further described below with reference to the accompanying drawings and embodiments. It should be noted that, unless otherwise specifically stated, the relative arrangement of steps, numerical expressions, and values ​​in these embodiments do not limit the scope of this application.

[0021] The following description of at least one exemplary embodiment is merely illustrative and is not intended to limit the scope of this application or its application or use.

[0022] In all the examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0023] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0024] The present invention provides a method for preparing a 4-trifluoromethyl-substituted 1,2,3-triazole compound by reacting a trifluoromethyl ketone compound (Formula I) with an organic azide compound (Formula II) under alkaline conditions in a solvent via deprotonation-enolization and [3+2] cycloaddition. After the reaction, the 4-trifluoromethyl-substituted 1,2,3-triazole compound (Formula III) is obtained by extraction, rotary evaporation, and column chromatography. The reaction formula is as follows: Figure 1 As shown, R 1 The substituted or unsubstituted aromatic group, alkyl group, or alkoxy group; R in the structural formula 2 It can be a substituted or unsubstituted aromatic group, alkyl group, or alkoxy group.

[0025] The reaction mechanism is as follows: Deprotonation-enolization reaction The α-hydrogen of the trifluoromethyl ketone compound (Formula I) is activated by the double electron-withdrawing of the carbonyl group and the trifluoromethyl group, making it a strong acid. Under alkaline conditions, the base abstracts the α-hydrogen to generate an enol anion (enol salt) intermediate. The enol anion intermediate undergoes rapid isomerization to form a nucleophilic azo ylide precursor (α-trifluoromethylenamine type intermediate), providing an active substrate for the subsequent [3+2] cycloaddition reaction.

[0026] [3+2] Cycloaddition reaction The azide group (-N3) of the organic azide compound (Formula II) acts as a 1,3-dipolar body. It undergoes a regioselective [3+2] cycloaddition reaction (a special variant of azide-olefin cycloaddition) with the azo ylide precursor (α-trifluoromethylenol salt) generated by the deprotonation-enolization reaction, forming a 1,2,3-triazole ring structure. Finally, a trifluoromethyl-substituted 1,2,3-triazole compound is obtained, namely a 4-trifluoromethyl-substituted 1,2,3-triazole compound (Formula III).

[0027] The specific embodiments provided by this invention are as follows: Example 1 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N A method for preparing p-cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of trifluoromethyl-substituted acetophenone, 0.1 mmol of Cs₂CO₃, 0.2 mmol of p-cyanophenyl azide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0028] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N - p-Cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: .

[0029] After weighing, 1- was separated. N - 25.8 mg of p-cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, yield 83%.

[0030] Figure 2 and Figure 3 1- prepared in Example 1 respectively N -The 1H and 1C NMR spectra of p-cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (600 MHz, CDCl3) δ 7.71 (d, J= 8.46 Hz, 2H), 7.53 (t, J =7.46 Hz, 1H), 7.45 (q, J = 7.57 Hz, 4H), 7.28-7.25 (m, 2H). Carbon NMR spectrum: 13 C NMR (150 MHz, CDCl3) δ 138.8, 136.9 (q, J C-F = 38.5 Hz),133.4, 130.9, 129.7, 129.3, 125.4, 123.9, 120.5 (q, J C-F = 268.7 Hz), 118.6,117.3, 113.7. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 315.0852, and the measured value is 315.0847.

[0031] Nuclear magnetic resonance spectroscopy analysis showed that the target compound obtained in Example 1 was 1- N -p-Cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole.

[0032] Example 2 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N A method for preparing p-cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of trifluoromethyl-substituted p-fluoroacetophenone, 0.1 mmol of Cs₂CO₃, 0.2 mmol of p-cyanophenyl azide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0033] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N - p-Cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole, with the following structural formula: .

[0034] After weighing, 1- was separated. N- 21.1 mg of cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole, yield 63%.

[0035] Figure 4 and Figure 5 1- prepared in Example 2 respectively N The 1H and 1C NMR spectra of p-cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.77-7.71 (m, 2H), 7.48-7.41 (m, 2H), 7.29-7.24 (m, 2H), 7.20-7.14 (m, 2H). Carbon NMR spectrum: 13 C NMR (100 MHz, CDCl3) δ 165.2, 162.7, 138.6, 137.0 (q, J C-F =38.7 Hz), 133.5, 131.8 (d, J C-F = 8.71 Hz), 125.5, 120.4 (q, J C-F = 268.4 Hz), 119.8 (d, J C-F = 3.6 Hz), 117.2, 116.9, 116.7, 113.9. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 333.0758, and the measured value is 333.0753.

[0036] Nuclear magnetic resonance spectroscopy analysis showed that the target compound obtained in Example 2 was 1- N -p-Cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole.

[0037] Example 3 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N A method for preparing p-cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of trifluoromethyl-substituted acetone, 0.1 mmol of Cs₂CO₃, 0.2 mmol of p-cyanophenyl azide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0038] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N - p-Cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole, with the following structural formula: .

[0039] After weighing, 1- was separated. N - 17.3 mg of p-cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole, yield 69%.

[0040] Figure 6 and Figure 7 1- prepared in Example 3 respectively N -The 1H and 1C NMR spectra of p-cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 8.70 Hz, 2H), 7.66 (d, J =8.70 Hz, 2H), 2.55-2.48 (m, 3H). Carbon NMR spectrum: 13 C NMR (150 MHz, CDCl3) δ 138.5, 136.7 (q, J C-F = 38.5 Hz),133.7, 125.9, 120.8 (q, J C-F = 268.7 Hz), 117.2, 114.4, 9.0. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 253.0696, and the measured value is 253.0687.

[0041] Nuclear magnetic resonance spectroscopy analysis showed that the target compound obtained in Example 3 was 1-N -p-Cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole.

[0042] Example 4 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N The preparation method of (-m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole) includes the following steps: S1. Under air conditions, add 0.1 mmol of trifluoromethyl-substituted acetophenone, 0.1 mmol of Cs₂CO₃, 0.2 mmol of m-nitroazide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0043] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N -m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: .

[0044] After weighing, 1- was separated. N - m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole 23.1 mg, yield 69%.

[0045] Figure 8 and Figure 9 1- prepared in Example 4 N The proton and carbon NMR spectra of -m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (600 MHz, CDCl3) δ 8.32-8.29 (m, 1H), 8.22-8.19 (m, 1H),7.66-7.60 (m, 2H), 7.52 (t, J = 7.49 Hz, 1H), 7.46 (t, J = 7.46 Hz, 2H), 7.27 (d, J = 7.44 Hz, 2H). Carbon NMR spectrum: 13 C NMR (150 MHz, CDCl3) δ148.5, 137.5, 136.9 (q, J C-F = 37.7Hz), 136.4, 131.0, 130.5, 130.4, 129.6, 129.3, 124.3, 123.7, 120.5 (q, J C-F =269.2 Hz), 120.1. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 335.0750, and the measured value is 335.0746.

[0046] Nuclear magnetic resonance spectroscopy analysis revealed that the target compound obtained in Example 4 was 1- N -m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole.

[0047] Example 5 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N A method for preparing p-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of trifluoromethyl-substituted acetophenone, 0.1 mmol of Cs₂CO₃, 0.2 mmol of p-nitroazide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0048] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N -p-Nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: .

[0049] After weighing, 1- was separated. N - 27.1 mg of p-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, yield 81%.

[0050] Figure 10 and Figure 11 1- prepared in Example 5 N -The 1H and 1C NMR spectra of p-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (600 MHz, CDCl3) δ 8.27 (d, J = 9.0 Hz, 2H), 7.56-7.52 (m,1H), 7.52-7.49 (m, 2H), 7.47 (t, J = 7.72 Hz, 2H), 7.29-7.26 (m, 2H). Carbon NMR spectrum: 13 C NMR (150 MHz, CDCl3) δ 147.9, 140.2, 137.1 (q, J C-F = 39.1Hz), 131.0, 129.7, 129.4, 128.7, 125.5, 124.9, 123.9, 120.5 (q, J C-F = 267.5Hz). Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 335.0750, and the measured value is 335.0747.

[0051] Nuclear magnetic resonance spectroscopy analysis revealed that the target compound obtained in Example 5 was 1- N -p-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole.

[0052] Example 6 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N A method for preparing p-aldehyde phenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of trifluoromethyl-substituted acetophenone, 0.1 mmol of Cs₂CO₃, 0.2 mmol of p-aldehyde phenyl azide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0053] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N - p-Aldehydephenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: .

[0054] After weighing, 1- was separated. N - 22.2 mg of 4-aldeoxyphenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, yield 70%.

[0055] Figure 12 and Figure 13 1- prepared in Example 6 respectively N -The 1H and 1C NMR spectra of p-aldehyde phenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (600 MHz, CDCl3) δ 10.04 (s, 1H), 7.92 (d, J = 8.5 Hz,2H), 7.51-7.46 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), 7.29-7.25 (m, 2H). Carbon NMR spectrum: 13 C NMR (100 MHz, CDCl3) δ 190.6, 139.8, 136.8 (q, J C-F = 39.1Hz), 132.4, 130.8, 130.7, 129.7, 129.2, 128.8, 125.5, 124.6, 120.5 (q, J C-F =269.3 Hz), 111.7. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 318.0849, and the measured value is 318.0844.

[0056] Nuclear magnetic resonance spectroscopy analysis revealed that the target compound obtained in Example 6 was 1- N -p-Aldehydephenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole.

[0057] Example 7 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N The preparation method of (2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of 3,3,3-trifluoropropaldehyde, 0.1 mmol of Cs₂CO₃, 0.2 mmol of 2-bromo-4-nitrophenyl azide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0058] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N -(2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole, with the following structural formula: .

[0059] After weighing, 1- was separated. N -(2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole 13.8 mg, yield 40%.

[0060] Figure 14 and Figure 15 1- prepared in Example 7 N The proton and carbon NMR spectra of -(2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (600 MHz, CDCl3) δ 8.74-8.63 (m, 1H), 8.48-8.36 (m, 2H),7.87 (d, J = 8.6 Hz, 1H). Carbon NMR spectrum: 13 C NMR (150 MHz, CDCl3) δ 148.7, 140.1, 139.2 (q, J C-F = 38.2Hz), 129.4, 128.9, 125.1, 123.8, 119.8(q, J C-F = 269.2 Hz), 118.7. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 336.9542, and the measured value is 336.9536.

[0061] Nuclear magnetic resonance spectroscopy analysis showed that the target compound obtained in Example 7 was 1- N -(2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole.

[0062] Example 8 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N The preparation method of (4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of 1,1,1-trifluoro-3-(2-naphthyl)prop-2-one, 0.1 mmol of Cs₂CO₃, 0.2 mmol of p-cyanoazide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0063] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole, with the following structural formula: .

[0064] After weighing, 1- was separated. N -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole 32.9 mg, yield 90%.

[0065] Figure 16 and Figure 17 1- prepared in Example 8 N The proton and carbon NMR spectra of -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.93-7.87 (m, 2H), 7.87-7.81 (m,2H), 7.70-7.56 (m, 4H), 7.47 (d, J = 8.6 Hz, 2H), 7.24-7.15 (m, 1H). Carbon NMR spectrum: 13C NMR (100 MHz, CDCl3) δ 138.7, 137.3, 137.0 (q, J C-F = 38.4Hz), 133.7, 133.4 132.6, 132.3, 130.1, 129.2, 128.7, 128.3, 127.9, 127.4,125.4, 125.3, 120.9, 120.5 (q, J C-F = 269.9 Hz), 113.6 Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 365.1009, and the measured value is 365.1005.

[0066] Nuclear magnetic resonance spectroscopy analysis showed that the target compound obtained in Example 8 was 1- N -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole.

[0067] Example 9 A 4-trifluoromethyl-substituted 1,2,3-triazole compound (1- N A method for preparing p-cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole includes the following steps: S1. Under air conditions, add 0.1 mmol of 1,1,1-trifluoro-3-(4-methylphenyl)prop-2-one, 0.1 mmol of Cs₂CO₃, 0.2 mmol of p-cyanoazide, and 1.0 mL of DMF sequentially to the reaction tube, and freely heat to 60°C. o C, react for 15 min.

[0068] S2. After the reaction is complete, transfer the reaction solution from the reaction tube to a 50mL pear-shaped flask, add an appropriate amount of ethyl acetate, and extract 2-3 times each with saturated saline and deionized water. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a rotary evaporator to remove the solvent. Purify the residue by column chromatography to obtain 1- N - p-Cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole, with the following structural formula: .

[0069] After weighing, 1- was separated. N - 27.2 mg of p-cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole, yield 83%.

[0070] Figure 18 and Figure 19 1- prepared in Example 9 respectively N The proton and carbon NMR spectra of p-cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole are characterized by the following spectral data: 1H NMR spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.8 Hz, 2H), 7.44 (d, J =8.59 Hz, 2H), 7.25 (d, J = 8.69 Hz, 2H), 7.12 (d, J = 7.72 Hz (2H), 2.41 (s, 3H). Carbon NMR spectrum: 13 C NMR (100 MHz, CDCl3) δ 141.3, 138.8, 137.4, 136.7 (q, J C-F =36.5 Hz), 133.3, 129.9, 129.4, 125.3, 120.7, 120.4 (q, J C-F = 268.8 Hz), 117.3,113.5, 21.4. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 329.1009, and the measured value is 329.1003.

[0071] Nuclear magnetic resonance spectroscopy analysis showed that the target compound obtained in Example 9 was 1- N -p-cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole.

[0072] In summary, this invention provides a method for preparing 4-trifluoromethyl-substituted 1,2,3-triazole compounds. Using trifluoromethyl ketone compounds and organic azide compounds as raw materials, a one-pot reaction is carried out under alkaline conditions and in a solvent. The 4-trifluoromethyl-substituted 1,2,3-triazole compounds are obtained by extraction, rotary evaporation, and column chromatography. This invention can be carried out smoothly under air conditions, without requiring an anhydrous or oxygen-free environment, and without using a metal catalyst. The reaction conditions are mild, the operation is simple, the substrate range is wide, and the yield is good (40%~83%). The obtained compounds can serve as key intermediates for antithrombotic drugs such as Asundexian. This invention provides an efficient, green, and economical new route for the synthesis of 4-trifluoromethyl-substituted 1,2,3-triazole compounds, and has good prospects for industrial application.

[0073] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a 4-trifluoromethyl-substituted 1,2,3-triazole compound, characterized in that, Includes the following steps: Under alkaline conditions, in a solvent, trifluoromethyl ketone compounds undergo deprotonation-enolization and [3+2] cycloaddition reactions with organic azide compounds. After the reaction is completed, the compounds are separated by extraction, rotary evaporation, and column chromatography to obtain 4-trifluoromethyl-substituted 1,2,3-triazole compounds. The structural formula of the trifluoromethyl ketone compound is: ； The structural formula of the organic azide compound is: ； The structural formula of the 4-trifluoromethyl-substituted 1,2,3-triazole compound is: ； R in the structural formula 1 The aromatic group, alkyl group, or alkoxy group may be substituted or unsubstituted; R in the structural formula 2 It can be a substituted or unsubstituted aromatic group, alkyl group, or alkoxy group.

2. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 1, characterized in that, The R 1 The substituents are substituted or unsubstituted phenyl, naphthyl, thiophene, benzothiophene, or furanyl, and the number of substituents is 1 to 5.

3. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 2, characterized in that, The substitution is mono- or di-substituted, and the substituent is at least one selected from halogen, alkyl, alkenyl, alkoxy, aryl, fluoroalkyl, and amide groups.

4. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 3, characterized in that, The R 1 It is an alkyl group having 1 to 12 carbon atoms or an alkoxy group having 1 to 6 carbon atoms.

5. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 1, characterized in that, The R 2 It is a substituted or unsubstituted phenyl or an alkyl group having 1 to 6 carbon atoms.

6. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 1, characterized in that, The alkaline conditions are provided by one of the following alkaline agents: Cs2CO3, CsOH·H2O, K2CO3, DBU, and t-BuOK.

7. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 1, characterized in that, The total reaction time for the protonation-enolization reaction and the [3+2] cycloaddition reaction was 30 min to 60 min, and the reaction temperature was 20 °C. o C~60 o C.

8. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 1, characterized in that, The molar ratio of the trifluoromethyl ketone compound, the organic azide compound, and the alkali agent is 1:1.5~3:1~2.

9. The method for preparing the 4-trifluoromethyl-substituted 1,2,3-triazole compound according to claim 1, characterized in that, The solvent is one of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, and toluene.

10. A 4-trifluoromethyl-substituted 1,2,3-triazole compound, characterized in that, Prepared by the method for preparing 4-trifluoromethyl-substituted 1,2,3-triazole compounds according to any one of claims 1 to 9; wherein the 4-trifluoromethyl-substituted 1,2,3-triazole compounds comprise: 1- N - p-Cyanophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ； 1- N - p-Cyanophenyl-4-trifluoromethyl-5-(4-fluorophenyl)-1,2,3-triazole, with the following structural formula: ； 1- N - p-Cyanophenyl-4-trifluoromethyl-5-methyl-1,2,3-triazole, with the following structural formula: ； 1- N -m-nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ； 1- N -p-Nitrophenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ； 1- N - p-Aldehydephenyl-4-trifluoromethyl-5-phenyl-1,2,3-triazole, with the following structural formula: ； 1- N -(2-bromo-4-nitrophenyl)-4-trifluoromethyl-1,2,3-triazole, with the following structural formula: ； 1- N -(4-cyanophenyl)-4-(trifluoromethyl)-5-(2-naphthyl)-1,2,3-triazole, with the following structural formula: ； 1- N - p-Cyanophenyl-4-trifluoromethyl-5-(p-methylphenyl)-1,2,3-triazole, with the following structural formula: 。

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