A 3-difluoromethyl-5-amino-1,2,4-triazole compound and a synthesis method thereof

Abstract

The invention discloses a 3-difluoromethyl-5-amino-1,2,4-triazole compound and a synthesis method thereof, belonging to the technical field of organic synthesis, and is prepared by a [3+2] cycloaddition reaction using difluoromethyl bromohydrazone or its derivatives and cyanamide as raw materials under alkaline conditions. The synthesis method provided by the invention has the characteristics of mild reaction conditions, wide substrate range and good functional group tolerance, and provides a new method for the synthesis of difluoromethyl-containing 1,2,4-triazole compounds.

Description

Technical Field

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

[0002] Fluorine is the most electronegative element in nature, and its atomic radius is close to that of hydrogen. In drug design, the unique electronic effects, pseudo-effects, and permeation effects of fluorine atoms and fluorine-containing substituents are often used to design and modify drugs. Therefore, fluorine-containing organic compounds are widely used in the fields of medicine, pesticides, veterinary drugs, and materials. As an important class of fluorine-containing compounds, difluoromethyl-containing 1,2,4-triazole compounds have attracted widespread attention from scientists due to their unique properties. There are currently many methods for synthesizing fluorine-containing 1,2,4-triazole compounds. In 1987, the Tanaka group (J. Heterocyclic Chem, 1987, 24, 1391-1987) first used trifluoromethyl bromohydrazone and cyanamide as starting materials, and synthesized 3-trifluoromethyl-5-amino-1.2.4-triazole compounds through an intermolecular cycloaddition process at room temperature. This method provides a reference for the preparation of difluoromethyl-substituted 5-amino-1,2,4-triazole compounds.

[0003] In the prior art, many methods for synthesizing fluorinated 1,2,4-triazole compounds have been reported. For example, in 2019, Wu Xiaofeng's group (Adv. Synth. Catal. 2019, 361, 4949-4954.) used trifluoromethyl chloroimide and hydrazone as starting materials to develop a fast and practical metal-free catalytic 5-trifluoromethyl-1,2,4-triazole compound. The disadvantage of this method is that toxic iodine is used as a catalyst. In 2021, Wu Xiaofeng's group (Adv. Synth. Catal. 2021, 363, 3060-3069.) used trifluoromethyl-substituted amidine and methyl ketone as starting materials, and synthesized 5-trifluoromethyl-1,2,4-triazole compounds through an I2-mediated metal-free catalytic [4+1] cyclization reaction. In 2004, the Balsells group (Org. Lett. 2005, 7, 1039-1042.) used highly reactive chloroalkyl oxadiazoles and ethylenediamine as starting materials to synthesize 3-trifluoromethyl-substituted 1,2,4-triazoles in two steps. However, the above prior art only reports the synthesis of trifluoromethyl-substituted 1,2,4-triazole compounds, and there are few reports on the synthesis of difluoromethyl-substituted 1,2,4-triazole compounds.

[0004] Compared with trifluoromethyl, difluoromethyl has weak acidity, and the hydrogen atom in it can participate in the formation of hydrogen bonds as a hydrogen bond donor, making difluoromethyl a lipophilic hydrogen bond donor, which can further form hydrogen bonds with biological macromolecules, which is beneficial for the binding of drugs to receptors, thereby improving drug activity. In addition, difluoromethyl-substituted nitrogen-containing heterocyclic compounds have very important applications in the fields of medicine, pesticides, and materials science in recent years.

[0005] Therefore, how to provide an efficient synthesis method for difluoromethyl substituted 1,2,4-triazole compounds is a technical problem that those skilled in the art need to solve urgently. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a 3-difluoromethyl-5-amino-1,2,4-triazole compound and a synthesis method thereof.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole compounds is prepared by a [3+2] cycloaddition reaction under alkaline conditions using difluoromethyl bromohydrazone or its derivatives and cyanamide as raw materials.

[0009] Preferably, the method specifically comprises the following steps:

[0010] Cyanamide, difluoromethyl bromohydrazone and a base are dissolved in an organic solvent and stirred for reaction. After the reaction is completed, the solvent is removed and then separated by column chromatography to obtain the 3-difluoromethyl-5-amino-1,2,4-triazole compound.

[0011] Beneficial effects: The present invention uses difluoromethyl bromohydrazone as a difluoromethyl synthetic building block to undergo a [3+2] cycloaddition reaction with cyanamide to synthesize 3-difluoromethyl-5-amino-1,2,4-triazole compounds. The reaction route is shown in the following formula (I): under the action of a base, difluoromethyl bromohydrazone removes a molecule of hydrogen bromide to obtain an intermediate A, and then the nitrogen anion on the intermediate A attacks the carbon atom in cyanamide to obtain an intermediate B, and the nitrogen anion in the intermediate B attacks the carbon cation to obtain the desired product 3-difluoromethyl-5-amino-1,2,4-triazole.

[0012]

[0013] Preferably, the ratio of the added amounts of cyanamide, difluoromethyl bromohydrazone and base is 0.5-2.5:0.5-2.5:0.5-3.5 (equivalent ratio).

[0014] Preferably, the base is any one of NaCO3, K2CO3, Cs2CO3, NaOH, KOH, Et3N, DBU or DABCO.

[0015] Preferably, the organic solvent is any one of methanol, tetrahydrofuran, toluene, acetonitrile, dichloromethane, ethanol or acetone.

[0016] Preferably, the stirring reaction is carried out at a temperature of -20 to 60°C and for a time of 2 to 8 hours.

[0017] Preferably, the reaction process is monitored by TLC.

[0018] Preferably, the eluent used in the column chromatography separation is a mixture of PE and EA in a ratio of 100:1 to 10:1.

[0019] A method for synthesizing difluoromethyl-5-amino-1,2,4-triazole compounds is provided to prepare 3-difluoromethyl-5-amino-1,2,4-triazole compounds, wherein bromohydrazone is used as a difluoromethyl synthetic building block to undergo a [3+2] cycloaddition reaction with cyanamide for the preparation.

[0020] Compared with the prior art, the present invention has the following advantages and technical effects:

[0021] The present invention uses difluoromethyl bromohydrazone or its derivatives and cyanamide as raw materials to undergo a [3+2] cycloaddition reaction to synthesize difluoromethyl-substituted 5-amino-1,2,4-triazole compounds. The method has the characteristics of mild reaction conditions, a wide substrate range, and good functional group tolerance, and provides a new method for the synthesis of difluoromethyl-containing 1,2,4-triazole compounds. A large number of experiments have shown that the present invention synthesizes 3-difluoromethyl-5-amino-1,2,4-triazole with a yield of up to 90%, and the present invention synthesizes 3-difluoromethyl-5-amino-1,2,4-triazole, through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry detection, the product is a pure target compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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:

[0023] Figure 1 3-difluoromethyl-5-amino-1-phenyl-1,2,4-triazole obtained in Example 1 of the present invention 1 HNMR test result diagram;

[0024] Figure 2 3-difluoromethyl-5-amino-1-phenyl-1,2,4-triazole obtained in Example 1 of the present invention 13 CNMR test result diagram;

[0025] Figure 3 3-difluoromethyl-5-amino-1-phenyl-1,2,4-triazole obtained in Example 1 of the present invention 19 FNMR test result diagram;

[0026] Figure 4 This is a diagram showing the high-resolution mass spectrometry detection result of 3-difluoromethyl-5-amino-1-phenyl-1,2,4-triazole obtained in Example 1 of the present invention;

[0027] Figure 5 3-difluoromethyl-5-amino-1-(p-tolyl)-1,2,4-triazole obtained in Example 9 of the present invention 1 H NMR test result diagram;

[0028] Figure 6 3-difluoromethyl-5-amino-1-(p-tolyl)-1,2,4-triazole obtained in Example 9 of the present invention 13 C NMR test result diagram;

[0029] Figure 7 3-difluoromethyl-5-amino-1-(p-tolyl)-1,2,4-triazole obtained in Example 9 of the present invention 19 F NMR test result diagram;

[0030] Figure 8 This is a diagram showing the high-resolution mass spectrometry detection result of 3-difluoromethyl-5-amino-1-(p-tolyl)-1,2,4-triazole obtained in Example 9 of the present invention;

[0031] Fig. 9 3-difluoromethyl-5-amino-1-(4-methoxyphenyl)-1,2,4-triazole obtained in Example 10 of the present invention 1 H NMR test result diagram;

[0032] Fig.10 3-difluoromethyl-5-amino-1-(4-methoxyphenyl)-1,2,4-triazole obtained in Example 10 of the present invention 13 C NMR test result diagram;

[0033] Fig.11 3-difluoromethyl-5-amino-1-(4-methoxyphenyl)-1,2,4-triazole obtained in Example 10 of the present invention 19 F NMR test result diagram;

[0034] Fig.12 This is a diagram showing the high-resolution mass spectrometry detection result of 3-difluoromethyl-5-amino-1-(4-methoxyphenyl)-1,2,4-triazole obtained in Example 10 of the present invention;

[0035] Fig.13 3-difluoromethyl-5-amino-1-(4-bromophenyl)-1,2,4-triazole obtained in Example 11 of the present invention 1 H NMR test result diagram;

[0036] Fig.14 3-difluoromethyl-5-amino-1-(4-bromophenyl)-1,2,4-triazole obtained in Example 11 of the present invention 13 C NMR test result diagram;

[0037] Fig.15 3-difluoromethyl-5-amino-1-(4-bromophenyl)-1,2,4-triazole obtained in Example 11 of the present invention 19 F NMR test result diagram;

[0038] Fig.16 This is a diagram showing the high-resolution mass spectrometry detection result of 3-difluoromethyl-5-amino-1-(4-bromophenyl)-1,2,4-triazole obtained in Example 11 of the present invention;

[0039] Fig.17 3-difluoromethyl-5-amino-1-(4-fluorophenyl)-1,2,4-triazole obtained in Example 12 of the present invention 1 H NMR test result diagram;

[0040] Fig.18 3-difluoromethyl-5-amino-1-(4-fluorophenyl)-1,2,4-triazole obtained in Example 12 of the present invention 13 C NMR test result diagram;

[0041] Fig.19 3-difluoromethyl-5-amino-1-(4-fluorophenyl)-1,2,4-triazole obtained in Example 12 of the present invention 19 F NMR test result diagram;

[0042] Fig. 20 This is a graph showing the high-resolution mass spectrometry detection results of 3-difluoromethyl-5-amino-1-(4-fluorophenyl)-1,2,4-triazole obtained in Example 12 of the present invention. DETAILED DESCRIPTION

[0043] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0045] All raw materials and reagents used in the examples of the present invention are purchased from the market or synthesized according to literature. As an example, difluoromethyl bromide hydrazone in the examples of the present invention is prepared according to J. Org. Chem. 2022, 87, 498. The remaining raw materials and reagents are obtained from commercial sources.

[0046] Example 1

[0047] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in the following formula (II):

[0048]

[0049] The specific steps include:

[0050] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethylhydrazone bromide (0.050 g, 0.20 mmol, 1.0 equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 25° C. and the reaction was monitored by TLC (PE: EA = 30: 1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE: EA = 40: 1) to obtain a yellow liquid with a yield of 90%.

[0051] The above-synthesized 3-difluoromethyl-5-amino-1-phenyl-1,2,4-triazole is 1 H NMR, 13 C NMR, 19 FNMR, high resolution mass spectrometry (eg: Figure 1-Figure 4 The product is a pure target compound.

[0052] 1H NMR (400MHz, Acetone-d6), δ7.44(d,J=68.2Hz,2H),7.56(t,J=8.4Hz,2H),7.46(t,J=7.2Hz,1H),6.70(t,J=53.2Hz,1H),6.15(s,1H);

[0053] 13 C NMR (150MHz, Acetone-d6), δ156.1,154.7(t,J C-F =27.0Hz),137.0,130.0,128.3,123.8,110.3(t,J C-F =232.5Hz),104.7;

[0054] 19 F NMR (376MHz, Acetone-d6): δ-115.43(d,J C-F =26.8Hz);

[0055] HRMS(ESI):m / z calcd for C9H8F2N4[M+H] + 211.07506, found 211.07901.

[0056] Example 2

[0057] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in formula (II) in Example 1, and specifically comprises the following steps:

[0058] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethylhydrazone bromide (0.050 g, 0.20 mmol, 1.0 equiv.), and sodium carbonate (0.021 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. The reaction was then stirred at 25° C. and the reaction was monitored by TLC (PE:EA=30:1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE:EA=40:1) to obtain a yellow liquid with a yield of 61%.

[0059] Example 3

[0060] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in formula (II) in Example 1, and specifically comprises the following steps:

[0061] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethylhydrazone bromide (0.050 g, 0.20 mmol, 1.0 equiv.), and potassium carbonate (0.027 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 25° C. and the reaction was monitored by TLC (PE: EA = 30: 1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h), the solvent was removed, and the product was separated by column chromatography (PE: EA = 40: 1) to obtain a yellow liquid with a yield of 20%.

[0062] Example 4

[0063] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in formula (II) in Example 1, and specifically comprises the following steps:

[0064] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethylhydrazone bromide (0.050 g, 0.20 mmol, 1.0 equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of tetrahydrofuran was added as a solvent to mix evenly with the above raw materials. The reaction was then stirred at 25° C. and the reaction was monitored by TLC (PE:EA=30:1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE:EA=40:1) to obtain a yellow liquid with a yield of 59%.

[0065] Example 5

[0066] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in formula (II) in Example 1, and specifically comprises the following steps:

[0067] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethyl bromohydrazone (0.050 g, 0.20 mmol, 1.0 equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of dichloromethane was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 25° C. and the reaction was monitored by TLC (PE: EA = 30: 1). The reaction was stopped after the difluoromethyl bromohydrazone reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE: EA = 40: 1) to obtain a yellow liquid with a yield of 34%.

[0068] Example 6

[0069] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in formula (I) in Example 1, and specifically comprises the following steps:

[0070] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethylhydrazone bromide (0.050 g, 0.20 mmol, 1.0 equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetone was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 25° C. and the reaction was monitored by TLC (PE: EA = 30: 1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE: EA = 40: 1) to obtain a yellow liquid with a yield of 40%.

[0071] Example 7

[0072] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in formula (II) in Example 1, and specifically comprises the following steps:

[0073] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethyl bromohydrazone (0.045 g, 0.18 mmol, 1.2 equiv.), and potassium hydroxide (0.061 g, 0.33 mmol, 2.2 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 0°C and monitored by TLC (PE: EA = 30: 1). The reaction was stopped after the difluoromethyl bromohydrazone reacted completely (4 h). After removing the solvent, the product was separated by column chromatography (PE: EA = 40: 1) to obtain a yellow liquid with a yield of 70%.

[0074] Example 8

[0075] A method for synthesizing 3-difluoromethyl-5-amino-1,2,4-triazole, wherein the synthesis process is shown in formula (II) in Example 1, and specifically comprises the following steps:

[0076] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), difluoromethyl bromohydrazone (0.045 g, 0.18 mmol, 1.2 equiv.), and potassium hydroxide (0.061 g, 0.33 mmol, 2.2 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 60° C. and the reaction was monitored by TLC (PE: EA = 30: 1). The reaction was stopped after the difluoromethyl bromohydrazone reacted completely (2 h). After removing the solvent, the product was separated by column chromatography (PE: EA = 40: 1) to obtain a yellow liquid with a yield of 76%.

[0077] Example 9

[0078] A method for synthesizing 3-difluoromethyl-5-amino-1-(p-tolyl)-1,2,4-triazole, wherein the synthesis process is shown in formula (III) in Example 1:

[0079]

[0080] The specific steps include:

[0081] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), 4-methylphenyldifluoromethylhydrazone bromide (0.056 g, 0.20 mmol, 1.0 equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 25° C. and the reaction was monitored by TLC (PE:EA=30:1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE:EA=40:1) to obtain a yellow liquid with a yield of 88%.

[0082] The above-synthesized 3-difluoromethyl-5-amino-1-(p-tolyl)-1,2,4-triazole is 1 H NMR, 13 CNMR, 19 F NMR, high resolution mass spectrometry (e.g. Figure 5-Figure 8 The product is a pure target compound.

[0083] 1 H NMR (400MHz, CDCl3), δ7.40 (d, J = 4Hz, 2H), 7.33 (d, J = 4.2Hz, 2H), 6.56 (t, J = 53.6Hz, 1H), 5.62 (s, 1H);

[0084] 13C NMR(150MHz,CDCl3)δ155.0,154.4(t,J C-F =27.0Hz),139.1,133.5,130.5,123.6,109.2(t,J C-F =235.5Hz),21.1.

[0085] 19 F NMR(376MHz, CDCl3): δ-117.25(d,J C-F =26.9Hz);

[0086] HRMS(ESI):m / z calcd for C 10 H 10 F2N4[M+H] + 225.09071, found 225.09459.

[0087] Example 10

[0088] A method for synthesizing 3-difluoromethyl-5-amino-1-(4-methoxyphenyl)-1,2,4-triazole, wherein the synthesis process is shown in formula (IV) of Example 1:

[0089]

[0090] The specific steps include:

[0091] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), 4-methoxyphenyl difluoromethyl hydrazone bromide (0.056 g, 0.20 mmol, 1.0 equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 30° C. and the reaction was monitored by TLC (PE: EA = 30: 1). The reaction was stopped after the difluoromethyl hydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE: EA = 50: 1) to obtain a yellow liquid with a yield of 84%.

[0092] The above-synthesized 3-difluoromethyl-5-amino-1-(4-methoxyphenyl)-1,2,4-triazole is 1 HNMR, 13 CNMR, 19 F NMR, high resolution mass spectrometry (e.g. Figure 9-12 The product is a pure target compound.

[0093] 1H NMR (400MHz, CDCl3), δ7.42 (d, J = 4.4Hz, 2H), 7.02 (d, J = 4.4Hz, 2H), 6.56 (t, J = 53.6Hz, 1H), 6.24 (s, 2H), 3.86 (s, 3H);

[0094] 13 C NMR (150MHz, CDCl3) δ160.0,154.9,154.4(t,J C-F =28.5Hz),128.7,125.7,115.1,109.2(t,J C-F =234.0Hz),55.6;

[0095] 19 F NMR(376MHz, CDCl3): δ-117.30(d,J C-F =26.9Hz);

[0096] HRMS(ESI):m / z calcd for C 10 H 10 F2N4O[M+H] + 241.08562,found

[0097] 241.08965.

[0098] Embodiment 11

[0099] A method for synthesizing 3-difluoromethyl-5-amino-1-(4-bromophenyl)-1,2,4-triazole, wherein the synthesis process is shown in formula (V) in Example 1:

[0100]

[0101] The specific steps include:

[0102] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), 4-bromophenyldifluoromethylhydrazone bromide (0.066 g, 0.20 mmol, 1.equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 25°C and monitored by TLC (PE:EA=30:1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE:EA=50:1) to obtain a yellow liquid with a yield of 73%.

[0103] The above-synthesized 3-difluoromethyl-5-amino-1-(4-bromophenyl)-1,2,4-triazole was 1 H NMR, 13 CNMR, 19 F NMR, high resolution mass spectrometry (e.g. Figure 13-Figure 16 The product is a pure target compound.

[0104] 1 H NMR (400MHz, CDCl3), δ7.67 (d, J = 4.4Hz, 2H), 7.43 (d, J = 4.4Hz, 2H), 6.56 (t, J = 54.0Hz, 1H), 5.56 (s, 1H), 2.34 (s, 3H);

[0105] 13 C NMR(150MHz,CDCl3)δ156.3,154.9(t,J C-F =27Hz),136.2,132.9,125.9,121.0,110.2(t,J C-F =234Hz);

[0106] 19 F NMR (376MHz, CDCl3): δ-117.51(d,J C-F =26.9Hz);

[0107] HRMS(ESI):m / z calcd for C 17 H 14 N2F2[M+H] + 287.98222, found 288.98945.

[0108] Example 12

[0109] A method for synthesizing 3-difluoromethyl-5-amino-1-(4-fluorophenyl)-1,2,4-triazole, wherein the synthesis process is shown in formula (VI) of Example 1:

[0110]

[0111] The specific steps include:

[0112] Cyanamide (0.009 g, 0.20 mmol, 1.0 equiv.), 4-fluorodifluoromethylhydrazone bromide (0.048 g, 0.20 mmol, 1.0 equiv.), and potassium hydroxide (0.011 g, 0.2 mmol, 1.0 equiv.) were added to the reaction tube, and 2 mL of acetonitrile was added as a solvent to mix evenly with the above raw materials. Then, the reaction was stirred at 25° C. and the reaction was monitored by TLC (PE:EA=30:1). The reaction was stopped after the difluoromethylhydrazone bromide reacted completely (3 h). After removing the solvent, the product was separated by column chromatography (PE:EA=50:1) to obtain a yellow liquid with a yield of 71%.

[0113] The above-synthesized 3-difluoromethyl-5-amino-1-(4-fluorophenyl)-1,2,4-triazole is 1 H NMR, 13 CNMR, 19 F NMR, high resolution mass spectrometry (e.g. Figure 17-Figure 20 The product is a pure target compound.

[0114] 1 H NMR (400MHz, CDCl3), δ7.52-7.48(m,2H),7.42-7.18(m,2H),6.54(t,J=53.6Hz,1H),5.67(s,2H);

[0115] 13 C NMR(150MHz,CDCl3)δ162.4(d,J C-F =123.8Hz),155.1,154.5(t,J C-F =27.0Hz),132.0,125.9(d,J C-F =4.5Hz),117.0(d,J C-F =11.25Hz),111.4(t,J C-F =235Hz),105.1;

[0116] 19 F NMR (376MHz, CDCl3): δ-111.01 (m), -117.39 (d, J=26.9Hz);

[0117] HRMS(ESI):m / z calcd for C9H7F3N4[M+H] + 228.06228,found:229.06972.

[0118] 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-difluoromethyl-5-amino-1,2,4-triazole compounds, characterized in that: Under alkaline conditions, it is prepared by a [3+2] cycloaddition reaction of difluoromethyl bromohydrazone derivatives and cyanamide as raw materials; The specific steps include: Dissolving cyanamide, difluoromethyl bromohydrazone derivative and alkali in an organic solvent and stirring for reaction, removing the solvent after the reaction is completed, and then separating by column chromatography to obtain the 3-difluoromethyl-5-amino-1,2,4-triazole compound; The molar ratio of cyanamide, difluoromethyl bromide hydrazone derivative and base is 1:1:1; The base is KOH; The organic solvent is acetonitrile; The stirring reaction temperature is 25°C and the time is 3h; The structure of the difluoromethyl bromide hydrazone derivative is:

2. The method for synthesizing a 3-difluoromethyl-5-amino-1,2,4-triazole compound according to claim 1, characterized in that: The reaction process was monitored by TLC.

3. The method for synthesizing a 3-difluoromethyl-5-amino-1,2,4-triazole compound according to claim 1, characterized in that: During the column chromatography separation, PE:EA=(100:1)-(10:1), v:v.

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