Preparation method of fluorine-containing ester-containing triazole compound

Abstract

The invention discloses a preparation method of a fluorine-containing ester-containing triazole compound, which comprises the following steps of: reacting fluorine-containing ester-containing p-toluenesulfonylhydrazone prepared from cheap and easily available starting raw materials (ketone containing trifluoromethyl or difluoromethyl functional groups) with an aromatic amine compound in tert-butyl hydroperoxide and acetonitrile under the promotion condition of iodine to obtain the fluorine-containing ester-containing triazole compound. And the fluorine-containing ester-containing triazole compound is obtained by a cyclization reaction and a'one-pot method '. In the preparation process, an expensive metal catalyst or ligand does not need to be used, so that the problem of toxicity or use safety caused by metal residues or azide compounds in a pharmaceutical process does not exist; in addition, the raw materials used in the process are bulk, cheap and easily available, the reaction system is green and environment-friendly, and the method has the advantages of simple operation steps and post-treatment process and high yield; the subsequent conversion research of the process can be applied to the synthesis of medical intermediates or related similar compounds.

Description

Technical Field

[0001] This scheme belongs to the field of triazole compound synthesis technology, specifically involving a method for preparing a fluorine-containing and ester-containing triazole compound. Background Technology

[0002] Fluorinated heterocyclic skeletons are widely found in natural products, pharmaceuticals, and related bioactive molecules. For example, in the development of drug-active molecules of triazole compounds (examples below), the introduction of trifluoromethyl functional groups can significantly improve their lipophilicity, absorbability, and metabolic stability, thus making the study of their synthetic methods extremely important.

[0003]

[0004] Many methods for synthesizing fluorinated triazole compounds have been developed. Among them, the condensation of azide compounds to obtain the target compound is the most common (see: J. Fluor. Chem. 2011, 132, 166-174; Chem. Eur. J. 2011, 17, 3584-3587; Tetrahedron 2012, 68, 614-618. However, the safe use of azides is particularly dangerous. Another approach is to synthesize related triazole intermediates via transition metal-catalyzed coupling reactions as key steps, followed by the introduction of fluorine-containing groups. Most of these studies involve further introduction of relatively expensive fluorinating agents in subsequent processes, resulting in complex operational procedures and post-processing (see: Org. Process. Res. Dev. 2020, 24, 207-215; Org. Lett. (2021, 23, 5937-5941.). Furthermore, due to the use of metal catalysts, the final removal of metal residues from the target product is also very challenging in the pharmaceutical industry.

[0005] Therefore, developing new green synthesis processes and studying methods that are simple in operation and post-processing and have high yields to prepare triazole compounds containing trifluoromethyl and other types is of great academic significance and market potential. Summary of the Invention

[0006] This solution aims to overcome at least one defect in the existing technology and provide a method for preparing fluorinated and esterified triazole compounds. It avoids the use of toxic or easily explosive azide compounds and expensive metal catalysts or ligands, and obtains fluorinated and esterified triazole compounds in a "one-pot" process. It features simple operation steps and post-processing as well as high yield.

[0007] To solve the above-mentioned technical problems, the following technical solution is adopted: A one-pot cyclization reaction was conducted using fluorinated esterified p-toluenesulfonylhydrazones, prepared from inexpensive and readily available starting materials (ketones containing trifluoromethyl or difluoromethyl functional groups), and aromatic amines in peroxytert-butanol (TBHP) and acetonitrile (MeCN) under iodine (I2) promoting conditions, to yield fluorinated esterified triazole compounds. The ester groups in these compounds can undergo inversion reactions, allowing for the subsequent generation of more types of fluorinated triazole compounds.

[0008] The reaction route of the above preparation method can be represented as follows:

[0009] or

[0010] Wherein, Rf is trifluoromethyl or difluoromethyl, R 1 It can be methyl, hydrogen, tert-butyl, phenyl, methoxy, phenoxy, chlorine, bromine, iodine, trifluoromethyl, ethyl ester, benzoyl, cyano, methanesulfonyl, or nitro; R 2 It can be hydrogen, methyl, or chlorine.

[0011] The above preparation method can prepare any one of the following fluorine-containing and ester-containing triazole compounds: .

[0012] Accordingly, aromatic amine compounds can be selected from one of the following compounds: .

[0013] Accordingly, the fluorine-containing and ester-containing p-toluenesulfonylhydrazone can be selected from one of the following compounds: .

[0014] In the above preparation method, the molar amount of fluorine-containing and ester-containing p-toluenesulfonylhydrazone is 1.5 ± 0.2 times the molar amount of aromatic amine compounds, the molar amount of iodine is 0.2 ± 0.05 times the molar amount of aromatic amine compounds, and the molar amount of peroxytert-butanol is 2 ± 0.2 times the molar amount of aromatic amine compounds.

[0015] The above preparation method preferably includes the following steps: S1. Add a solution of fluorine-containing and ester-containing p-toluenesulfonylhydrazone, aromatic amine compounds, iodine, and peroxytert-butanol to acetonitrile; S2. Place the mixture obtained in step S1 at 85±5℃ and react with stirring until the reaction is complete; S3. Cool to room temperature, quench, extract, dry and purify the product obtained in step S2.

[0016] The concentration of the peroxide tert-butanol solution is preferably 70 ± 5 wt%. In step S2, the reaction is preferably carried out in an oil bath, and the reaction endpoint is preferably monitored by thin-layer chromatography (TLC). In step S3, the quenching operation is preferably performed using a saturated sodium thiosulfate solution to quench the product, the extraction operation is preferably performed using ethyl acetate to extract the quenched product, the drying operation is preferably performed using anhydrous sodium sulfate to dry the extracted product and evaporate the solvent, and the purification operation is preferably performed using column chromatography to purify the dried product.

[0017] Compared with existing technologies, this solution has the following advantages: (1) The reaction is promoted by green iodine, without the need for expensive metal catalysts or ligands, so there is no toxicity problem caused by heavy metal residues in the pharmaceutical process; (2) It does not require the use of toxic or easily explosive azide as a nitrogen source reagent, so there are no toxicity or safety issues caused by azide in the pharmaceutical process; (3) The raw materials used are abundant, inexpensive and easy to obtain, and the preparation is simple. The reaction system is green and environmentally friendly, and has the advantages of simple operation steps and post-processing as well as high yield. (4) Subsequent translational research can be applied to the synthesis of pharmaceutical intermediates or related analogues. Detailed Implementation

[0018] This scheme proposes a method for preparing fluorinated ester-containing triazole compounds: using fluorinated ester-containing p-toluenesulfonylhydrazone, which can be prepared from inexpensive and readily available starting materials (ketones containing trifluoromethyl or difluoromethyl functional groups), and aromatic amine compounds in peroxytert-butanol (TBHP) and acetonitrile (MeCN) under the promoting condition of iodine (I2), the fluorinated ester-containing triazole compounds are obtained in a "one-pot" cyclization reaction.

[0019] The reaction route of the above preparation method is as follows:

[0020] or

[0021] Wherein, Rf is trifluoromethyl or difluoromethyl, R 1 It can be methyl, hydrogen, tert-butyl, phenyl, methoxy, phenoxy, chlorine, bromine, iodine, trifluoromethyl, ethyl ester, benzoyl, cyano, methanesulfonyl, or nitro; R 2 It can be hydrogen, methyl, or chlorine.

[0022] It is important to note that this reaction requires the participation of tert-butanol peroxide and acetonitrile; otherwise, fluorinated triazole compounds containing ester groups cannot be obtained. The ester groups in fluorinated ester-containing triazole compounds can undergo inversion reactions, thus allowing for the subsequent generation of more types of fluorinated triazole compounds through these reactions.

[0023] To enable those skilled in the art to better understand this solution, the following detailed description is provided in conjunction with specific embodiments. Unless otherwise specified, the process methods used in the embodiments are conventional methods; and unless otherwise specified, the materials used are commercially available.

[0024] Example 1 In this embodiment, fluorine-containing esterified triazole compound 3a was synthesized via the following reaction route:

[0025] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2a (1.0 times, 0.3 mmol, 32.0 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2a was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3a (white solid, 61.5 mg, yield 68%).

[0026] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorinated esterified triazole compound 3a obtained above was confirmed by 18NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.37-7.32 (m, 4H), 4.33 (q, J = 7.2 Hz, 2H),2.45 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.74 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.6, 141.1, 139.0 (q, J = 39.5 Hz),133.2, 129.8, 128.4 (d, J = 2.0 Hz), 125.2, 119.8 (q, J = 267.6 Hz), 63.1, 21.3, 13.5. Example 2 In this embodiment, fluorine-containing esterified triazole compound 3b was synthesized via the following reaction route:

[0027] In a 35 mL reaction tube, add a magnetic stir bar and 3.0 mL of MeCN solvent. Weigh out fluorinated p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2b (1.0 times, 0.3 mmol, 28.0 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). Cap the reaction tube and transfer it to a 100 °C oil bath. React for 15 hours (monitored by thin-layer chromatography). After the reaction of raw material 2b was completed, the reaction tube was cooled to room temperature, and then saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was taken, dried with anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3b (pale yellow solid, 38.6 mg, yield 45%).

[0028] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 3b obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.62-7.54 (m, 3H), 7.50-7.47 (m, 2H), 4.33 (q, J= 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.73 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.6, 139.2 (q, J = 39.6 Hz), 135.7,130.8, 129.3, 128.6 (d, J = 2.0 Hz), 125.5, 119.8 (q, J = 267.6 Hz), 63.1, 13.5. Example 3 In this embodiment, the fluorine-containing esterified triazole compound 3c was synthesized via the following reaction route:

[0029] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2c (1.0 times, 0.3 mmol, 36.4 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2c was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3c (pale yellow solid, 59.6 mg, yield 63%).

[0030] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 3c obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d7.30-7.28 (m, 1H), 7.26-7.25 (m, 1H), 7.19-7.16 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 2.34 (s, 3H), 1.28 (t, J =7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.72 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.7, 139.8, 138.9 (q, J = 39.6 Hz),138.0, 133.3, 130.2, 128.5 (d, J = 2.0 Hz), 126.2, 122.6, 119.9 (q, J = 267.6Hz), 63.0, 19.7, 19.6, 13.5. Example 4 In this embodiment, the fluorine-containing esterified triazole compound 3d was synthesized via the following reaction route:

[0031] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2d (1.0 times, 0.3 mmol, 36.4 mg), iodine (0.5 times, 0.15 mmol, 38.1 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2d was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3d (pale yellow liquid, 54.5 mg, yield 58%).

[0032] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13The structure of the obtained fluorine-containing esterified triazole compound 3d was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.20 (s, 3H), 7.17-7.12 (m, 2H), 4.28 (q, J =7.2 Hz, 2H), 2.42 (s, 3H), 2.01 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.70 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.2, 141.3, 138.9 (q, J = 39.6 Hz),134.5, 132.7, 131.7, 129.1 (d, J = 2.0 Hz), 127.3, 126.5, 119.9 (q, J = 267.6Hz), 62.9, 21.3, 17.1, 13.5. Example 5 In this embodiment, the fluorine-containing esterified triazole compound 3e was synthesized via the following reaction route:

[0033] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2e (1.0 times, 0.3 mmol, 44.8 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2e was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3e (pale yellow liquid, 66.3 mg, yield 65%).

[0034] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 3e obtained above was confirmed by 1NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.58-7.54 (m, 2H), 7.41-7.38 (m, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.37 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.72 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.9, 154.5, 139.4 (q, J = 39.6 Hz), 133.4, 128.7 (d, J = 2.0 Hz), 126.5, 125.3, 120.1 (q, J = 267.6 Hz), 63.3, 35.2,31.4, 13.7. Example 6 In this embodiment, the fluorine-containing esterified triazole compound 3f was synthesized via the following reaction route:

[0035] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2f (1.0 times, 0.3 mmol, 50.8 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2f was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3f (pale yellow solid, 54.2 mg, yield 50%).

[0036] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 3f obtained above was confirmed by 18NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.78-7.75 (m, 2H), 7.65-7.62 (m, 2H), 7.58-7.54 (m, 2H), 7.52-7.48 (m, 2H), 7.45-7.40 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.68 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.6, 143.8, 139.3, 139.2 (q, J = 39.7Hz), 134.6, 129.0, 128.5 (d, J = 2.0 Hz), 128.3, 127.9, 127.2, 125.8, 119.8 (q, J= 267.6 Hz), 63.2, 13.6. Example 7 In this embodiment, 3g of a fluorine-containing esterified triazole compound was synthesized, and the reaction route is as follows:

[0037] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. The following were weighed: 1.5 g of fluorinated p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), 2 g of aromatic amine compound (1.0 times, 0.3 mmol, 43.3 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and 82 μL of TBHP aqueous solution (70 wt%, 2.0 times). The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the 2 g of starting material had completely reacted, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain 3 g of trifluoromethyltriazole compound (yellow solid, 56.0 mg, yield 55%).

[0038] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained 3g of fluorine-containing ester-containing triazole compound was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.03-9.02 (m, 1H), 8.26-8.23 (m, 2H), 8.02-8.01 (m, 1H), 7.76-7.72 (m, 1H), 7.54-7.50 (m, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.71 (s, 3F); 13 C{ 1H} NMR (100 MHz, CDCl3): 156.5, 152.4, 148.3, 139.5 (q, J = 39.8Hz), 136.7, 133.5, 131.1, 128.7 (d, J = 2.0 Hz), 127.7, 126.3, 125.0, 122.6,119.8 (q, J = 267.7 Hz), 63.4, 13.6. Example 8 In this embodiment, a fluorine-containing esterified triazole compound was synthesized over 3 hours. The reaction route is as follows:

[0039] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2h (1.0 times, 0.3 mmol, 37.0 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reactants had reacted completely for 2 hours, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3h (pale yellow solid, 61.0 mg, yield 64%).

[0040] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 3h obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.41-7.38 (m, 2H), 7.05-7.01 (m, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.75 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 161.2, 156.6, 139.1 (q, J = 39.6 Hz), 128.5(d, J = 2.0 Hz), 128.4, 126.9, 119.9 (q, J = 267.5 Hz), 114.3, 63.1, 55.6, 13.6. Example 9 In this embodiment, the fluorine-containing esterified triazole compound 3i was synthesized via the following reaction route:

[0041] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2i (1.0 times, 0.3 mmol, 55.5 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2i was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3i (pale yellow solid, 76.7 mg, yield 68%).

[0042] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 3i obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.44-7.38 (m, 4H), 7.23-7.19 (m, 1H), 7.13-7.08 (m, 4H), 4.36 (q, J= 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.73 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 159.7, 156.5, 155.5, 139.2 (q, J = 39.6Hz), 130.1, 130.0, 128.5 (d, J = 2.0 Hz), 127.1, 124.6, 120.0, 119.8 (q, J =267.6 Hz), 118.1, 63.1, 13.5. Example 10 In this embodiment, fluorine-containing esterified triazole compound 3j was synthesized, and the reaction route is as follows:

[0043] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2j (1.0 times, 0.3 mmol, 38.3 mg), iodine (0.5 times, 0.15 mmol, 38.1 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2j was complete, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3j (white solid, 34.7 mg, yield 36%).

[0044] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 3j obtained above was confirmed by 18NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.56-7.52 (m, 2H), 7.46-7.42 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.75 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.4, 139.4 (q, J = 39.6 Hz), 137.0,134.1, 129.5, 128.5 (d, J = 2.0 Hz), 126.9, 119.7 (q, J = 267.7 Hz), 63.3, 13.6. Example 11 In this embodiment, the fluorine-containing esterified triazole compound 3k was synthesized via the following reaction route:

[0045] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2k (1.0 times, 0.3 mmol, 51.6 mg), iodine (0.5 times, 0.15 mmol, 38.1 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reactant 2k had reacted completely, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3k (white solid, 55.0 mg, yield 50%).

[0046] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 3k obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.71-7.68 (m, 2H), 7.39-7.35 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.75 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.4, 139.4 (q, J = 39.9 Hz), 134.6,132.5, 128.4 (d, J = 2.0 Hz), 127.1, 125.1, 119.7 (q, J = 267.7 Hz), 63.3, 13.6. Example 12 In this embodiment, fluorine-containing esterified triazole compound 3l was synthesized via the following reaction route:

[0047] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2l (1.0 times, 0.3 mmol, 65.7 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2l was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3l (white solid, 77.8 mg, yield 63%).

[0048] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13The structure of the fluorine-containing ester-containing triazole compound 3l obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.92-7.88 (m, 2H), 7.25-7.21 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.73 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.4, 139.4 (q, J = 39.8 Hz), 138.5,135.3, 128.4 (d, J = 2.0 Hz), 127.2, 119.7 (q, J = 267.9 Hz), 96.8, 63.3, 13.6. Example 13 In this embodiment, the fluorine-containing esterified triazole compound 3m was synthesized via the following reaction route:

[0049] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2m (1.0 times, 0.3 mmol, 48.6 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reactant 2m had reacted completely, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3m (white solid, 49.8 mg, yield 47%).

[0050] Using H respectively 1 -NMR (Bruker FT-NMR), F19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 3m obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.66-7.64 (m, 2H), 7.38-7.35 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.77 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.2, 139.6 (q, J = 39.7 Hz), 135.6,134.5, 133.6, 130.9, 128.5 (d, J = 2.0 Hz), 127.4, 124.9, 119.6 (q, J = 268.1Hz), 63.5, 13.6. Example 14 In this embodiment, the fluorine-containing esterified triazole compound 3n was synthesized via the following reaction route:

[0051] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2n (1.0 times, 0.3 mmol, 48.3 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reactant 2n had reacted completely, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3n (white solid, 54.8 mg, yield 52%).

[0052] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorinated esterified triazole compound 3n obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.86-7.84 (m, 2H), 7.66-7.64 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.75 (s, 3F), -62.89 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.3, 139.7 (q, J = 39.7 Hz), 138.4, 132.9(q, J = 33.1 Hz), 128.5 (d, J = 2.0 Hz), 126.5 (q, J = 3.7 Hz), 126.2, 123.3 (q, J =271.2 Hz), 119.7 (q, J = 268.0 Hz), 63.5, 13.5. Example 15 In this embodiment, fluorine-containing esterified triazole compound 3o was synthesized via the following reaction route:

[0053] In a 35 mL reaction tube, add a magnetic stir bar and 3.0 mL of MeCN solvent. Weigh out fluorinated p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2o (1.0 times, 0.3 mmol, 49.6 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). Cap the reaction tube and transfer it to a 100 °C oil bath. React for 15 hours (monitored by thin-layer chromatography). After the reaction of raw material 2o was complete, the reaction tube was cooled to room temperature, and then saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was taken, dried with anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3o (pale yellow solid, 52.7 mg, yield 49%).

[0054] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 3o obtained above was confirmed by 18NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 8.26-8.23 (m, 2H), 7.59-7.56 (m, 2H), 4.43 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.29 (t, J =7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.73 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 165.1, 156.4, 139.5 (q, J = 39.9 Hz),138.9, 132.7, 130.6, 128.5 (d, J = 2.0 Hz), 125.5, 119.7 (q, J= 267.7 Hz), 63.4, 61.7, 14.3, 13.6. Example 16 In this embodiment, the fluorine-containing esterified triazole compound 3p was synthesized via the following reaction route:

[0055] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2p (1.0 times, 0.3 mmol, 59.2 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2p was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3p (white solid, 62.0 mg, yield 53%).

[0056] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 3p obtained above was confirmed by 18NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 8.00-7.97 (m, 2H), 7.84-7.82 (m, 2H), 7.66-7.62 (m, 3H), 7.54-7.50 (m, 2H), 4.38 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.70 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 195.0, 156.3, 139.6 (q, J= 39.7 Hz),139.5, 138.3, 136.6, 133.1, 130.8, 130.0, 128.5, 125.5, 119.7 (q, J = 267.7Hz), 63.4, 13.5. Example 17 In this embodiment, the fluorine-containing ester-containing triazole compound 3q was synthesized via the following reaction route:

[0057] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2q (1.0 times, 0.3 mmol, 35.5 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2q was complete, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3q (white solid, 47.5 mg, yield 51%).

[0058] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 3q obtained above was confirmed by 18NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.90-7.86 (m, 2H), 7.68-7.64 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.74 (s, 3F); 13 C{ 1H} NMR (100 MHz, CDCl3): 156.1, 139.8 (q, J = 39.9 Hz), 138.8,133.2, 128.5 (d, J = 2.0 Hz), 126.6, 119.6 (q, J = 268.1 Hz), 117.2, 114.9, 63.6,13.5. Example 18 In this embodiment, the fluorine-containing esterified triazole compound 3r was synthesized via the following reaction route:

[0059] In a 35 mL reaction tube, add a magnetic stir bar and 3.0 mL of MeCN solvent. Weigh out fluorinated p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2r (1.0 times, 0.3 mmol, 51.4 mg), iodine (0.5 times, 0.15 mmol, 38.1 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). Cap the reaction tube and transfer it to a 100 °C oil bath. React for 15 hours (monitored by thin-layer chromatography). After the reaction of the raw material 2r was complete, the reaction tube was cooled to room temperature, and then saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was taken, dried with anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3r (pale yellow solid, 45.7 mg, yield 42%).

[0060] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 3r obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 8.17-8.14 (m, 2H), 7.76-7.72 (m, 2H), 4.38 (q, J = 7.2 Hz, 2H), 3.14 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3): -60.71 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.2, 142.7, 139.8 (q, J = 39.9 Hz),139.6, 128.7, 128.5 (d, J = 2.0 Hz), 126.8, 119.6 (q, J = 267.9 Hz), 63.6, 44.4, 13.6. Example 19 In this embodiment, the fluorine-containing esterified triazole compound 3s was synthesized via the following reaction route:

[0061] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Fluorine-containing ester-containing p-toluenesulfonylhydrazone 1a (1.5 times, 0.45 mmol, 158.5 mg), aromatic amine compound 2s (1.0 times, 0.3 mmol, 41.4 mg), iodine (0.2 times, 0.06 mmol, 15.2 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL) were weighed. The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reactant 2s had reacted completely, the reaction tube was cooled to room temperature. Then, saturated sodium thiosulfate solution (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethyltriazole compound 3s (yellow solid, 46.8 mg, yield 47%).

[0062] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 3S obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 8.46-8.42 (m, 2H), 7.75-7.72 (m, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.33 (t,J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -60.74 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.2, 148.8, 140.2, 139.8 (q, J = 39.9Hz), 128.6 (d, J = 2.0 Hz), 126.8, 124.7, 119.6 (q, J = 267.8 Hz), 63.6, 13.6. Example 20 In this embodiment, fluorine-containing esterified triazole compound 4a was synthesized via the following reaction route:

[0063] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. The following were weighed: difluoromethylating reagent 1b (1.5 times, 0.45 mmol, 150.5 mg), aromatic amine compound 2a (1.0 times, 0.3 mmol, 32.0 mg), iodine (0.3 times, 0.09 mmol, 23.0 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of reactant 2a was complete, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain difluoromethyltriazole compound 4a (pale yellow solid, 40.7 mg, yield 48%).

[0064] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained fluorine-containing esterified triazole compound 4a was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.36–7.31 (m, 4H), 7.13 (t, J= 53.5 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 2.46 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -115.04 (s, 2F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.9, 143.5 (t, J = 26.9 Hz), 140.9,133.5, 129.6, 127.7 (t, J = 3.7 Hz), 125.6, 108.8 (t, J = 235.6 Hz), 62.7, 21.3, 13.7. Example 21 In this embodiment, fluorine-containing esterified triazole compound 4b was synthesized via the following reaction route:

[0065] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. The following were weighed: difluoromethylating reagent 1b (1.5 times, 0.45 mmol, 150.5 mg), aromatic amine compound 2c (1.0 times, 0.3 mmol, 36.4 mg), iodine (0.3 times, 0.09 mmol, 23.0 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of reactant 2c was complete, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain difluoromethyltriazole compound 4b (pale yellow solid, 35.4 mg, yield 40%).

[0066] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing ester-containing triazole compound 4b obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1H NMR (400 MHz, CDCl3): d 7.29-7.26 (m, 1H), 7.23-7.22 (m, 1H), 7.17-7.15 (m, 1H), 7.12 (t, J = 53.5 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -115.00 (s, 2F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.9, 143.4 (t, J = 26.9 Hz), 139.5,137.8, 133.7, 130.0, 127.6 (t, J = 3.7 Hz), 126.6, 122.9, 108.8 (t, J = 235.6Hz), 62.6, 19.7, 19.6, 13.7. Example 22 In this embodiment, the fluorine-containing esterified triazole compound 4c was synthesized via the following reaction route:

[0067] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. The following were weighed: difluoromethylating reagent 1b (1.5 times, 0.45 mmol, 150.5 mg), aromatic amine compound 2e (1.0 times, 0.3 mmol, 44.8 mg), iodine (0.3 times, 0.09 mmol, 23.0 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of starting material 2e was complete, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain difluoromethyltriazole compound 4c (pale yellow liquid, 32.4 mg, yield 33%).

[0068] Using H respectively1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 4c obtained above was confirmed by FT-NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.56-7.53 (m, 2H), 7.39-7.36 (m, 2H), 7.13 (t, J = 53.5 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.37 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -115.09 (s, 2F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.9, 153.9, 143.6 (t, J = 26.9 Hz), 133.4, 127.7 (t, J = 3.7 Hz), 126.0, 125.3, 108.7 (t, J = 235.6 Hz), 62.6, 34.9,31.2, 13.6. Example 23 In this embodiment, the fluorine-containing esterified triazole compound 4d was synthesized via the following reaction route:

[0069] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. The following were weighed: difluoromethylating reagent 1b (1.5 times, 0.45 mmol, 150.5 mg), aromatic amine compound 2f (1.0 times, 0.3 mmol, 50.8 mg), iodine (0.3 times, 0.09 mmol, 23.0 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). The reaction tube was capped and transferred to a 100 °C oil bath. The reaction was carried out for 15 hours (monitored by thin-layer chromatography). After the reaction of reactant 2f was complete, the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain difluoromethyltriazole compound 4d (pale yellow solid, 34.8 mg, yield 34%).

[0070] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained fluorine-containing esterified triazole compound 4d was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.77-7.74 (m, 2H), 7.65-7.62 (m, 2H), 7.56-7.52 (m, 2H), 7.51-7.47 (m, 2H), 7.44-7.40 (m, 1H), 7.16 (t, J = 53.5 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -115.05 (s, 2F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 156.9, 143.7 (t, J = 26.9 Hz), 143.6,139.4, 135.0, 129.0, 128.2, 127.7 (t, J= 3.7 Hz), 127.6, 127.2, 126.1, 108.8(t, J = 235.6 Hz), 62.8, 13.7. Example 24 In this embodiment, the fluorine-containing esterified triazole compound 4e was synthesized via the following reaction route:

[0071] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. The following were weighed: difluoromethylating reagent 1b (1.5 times, 0.45 mmol, 150.5 mg), aromatic amine compound 2h (1.0 times, 0.3 mmol, 37.0 mg), iodine (0.3 times, 0.09 mmol, 23.0 mg), and TBHP aqueous solution (70 wt%, 2.0 times, 82 μL). The reaction tube was capped and transferred to an 85 °C oil bath. The reaction was allowed to proceed for 15 hours (monitored by thin-layer chromatography). After the initial reaction was complete (2 hours), the reaction tube was cooled to room temperature. Then, 10 mL of saturated sodium thiosulfate solution and ethyl acetate (10 mL × 3) were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain difluoromethyltriazole compound 4e (pale yellow solid, 49.2 mg, yield 55%).

[0072] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the fluorine-containing esterified triazole compound 4e obtained above was confirmed by 1NMR (Bruker FT-NMR), and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.38–7.34 (m, 2H), 7.12 (t, J = 53.5 Hz, 1H),7.03-6.99 (m, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDCl3): -115.15 (s, 2F); 13 C{ 1H} NMR (100 MHz, CDCl3): 160.9, 156.8, 143.5 (t, J = 26.9 Hz), 128.8, 127.7 (t, J = 3.7 Hz), 127.1, 114.1, 108.7 (t, J = 235.5 Hz), 62.6, 55.6, 13.7. Example 25 In this embodiment, fluorinated triazole compound 5a was synthesized via the following reaction route:

[0073] Step 1: Under air atmosphere, trifluoromethyltriazole compound 3a (1.0x, 0.10 mmol, 30.0 mg) was added to a MeOH / H2O (v / v = 3 / 1, 2.0 mL) mixed solution containing LiOH (4.0x, 0.4 mmol, 9.6 mg) in a 35 mL reaction tube. The mixture was then heated at 45°C (oil bath) for 20 hours (monitored by thin-layer chromatography). After the reaction was complete, the mixture was cooled to room temperature. The mixture was acidified to pH 1 with HCl (1N, 5 mL), extracted with ethyl acetate (10 mL × 3), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the crude acid product, which can be directly used in the next reaction.

[0074] Step 2: Under air atmosphere, the above crude acid product was added to a 35 mL reaction tube into a mixed solution of NMP / quinoline (v / v = 3 / 1, 2.0 mL) containing Cu₂O (10 mol%, 1.4 mg) and 1,10-phenanthroline (1,10-phen, 15 mol%, 2.7 mg). The mixture was then heated at 150°C (oil bath) for 15 hours (monitored by thin-layer chromatography). After the reaction was completed, the mixture was cooled to room temperature. Quinoline was washed away with HCl (1N, 10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to give trifluoromethyltriazole compound 5a (white solid, 17.4 mg, yield 77%).

[0075] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained fluorotriazole compound 5a was confirmed by Bruker FT-NMR, and the results are as follows: 1H NMR (400 MHz, CDCl3): d 8.24 (d, J = 0.6 Hz, 1H), 7.62-7.59 (m, 2H), 7.36-7.34 (m, 2H), 2.44 (s, 3H); 19 F NMR (376 MHz, CDCl3): -61.16 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 140.1, 139.4 (q, J = 39.1 Hz), 133.9,130.5, 121.4 (q, J = 2.5 Hz), 120.8, 120.4 (q, J = 266.4 Hz), 21.1. Example 26 In this embodiment, the fluorinated triazole compound 5b was synthesized via the following reaction route:

[0076] CaCl2 (1.0-fold, 0.10 mmol, 11.1 mg) was added to anhydrous EtOH (2.0 mL) containing NaBH4 (2.0-fold, 0.2 mmol, 7.6 mg) in an ice bath at 0°C, and the reaction was stirred for 0.5 h in an ice bath at 0°C. 3a (1.0-fold, 0.10 mmol, 30.0 mg) was added to the above system, and the reaction was continued in an ice bath at 0°C for 3 h (monitored by thin-layer chromatography). After the reaction was complete, the reaction was quenched with ice water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic layer solution was dried over anhydrous sodium sulfate. The solvent was evaporated, and the crude product was then separated by column chromatography (eluent: petroleum ether: ethyl acetate) to give trifluoromethyltriazole compound 5b (white solid, 21.0 mg, yield 82%).

[0077] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained fluorotriazole compound 5b was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d7.53-7.50 (m, 2H), 7.37-7.35 (m, 2H), 4.75 (d, J = 5.0 Hz, 2H), 2.61 (t, J = 6.0 Hz, 1H), 2.45 (s, 3H); 19 F NMR (376 MHz, CDCl3): -60.13 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 140.9, 136.7 (q, J = 38.2 Hz), 135.6 (q, J =1.5 Hz), 132.5, 130.3, 124.9, 120.9 (q, J = 266.8 Hz), 51.6, 21.2. Obviously, the above embodiments of this solution are merely examples for clearly illustrating this solution, and are not intended to limit the implementation of this solution. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this solution should be included within the scope of protection of the claims of this solution.

Claims

1. A method for preparing a fluorine-containing, ester-containing triazole compound, characterized in that, Fluorinated triazole compounds are obtained by cyclization of fluorinated esterified p-toluenesulfonylhydrazone and aromatic amine compounds in tert-butanol and acetonitrile under iodine-promoting conditions.

2. The method for preparing fluorine-containing and ester-containing triazole compounds according to claim 1, characterized in that, The reaction route is as follows: or Wherein, Rf is trifluoromethyl or difluoromethyl, R 1 It can be methyl, hydrogen, tert-butyl, phenyl, methoxy, phenoxy, chlorine, bromine, iodine, trifluoromethyl, ethyl ester, benzoyl, cyano, methanesulfonyl, or nitro; R 2 It can be hydrogen, methyl, or chlorine.

3. The method for preparing fluorine-containing and ester-containing triazole compounds according to claim 1, characterized in that, The fluorine-containing triazole compound is selected from one of the following compounds: 。 4. The method for preparing fluorine-containing and ester-containing triazole compounds according to claim 3, characterized in that, The aromatic amine compound is selected from one of the following compounds: 。 5. The method for preparing fluorine-containing and ester-containing triazole compounds according to claim 3, characterized in that, The fluorine-containing ester-containing p-toluenesulfonylhydrazone is selected from one of the following compounds: 。 6. The method for preparing the fluorinated ester-containing triazole compound according to any one of claims 1 to 5, characterized in that, The molar amount of the fluorine-containing ester-containing p-toluenesulfonylhydrazone is 1.5 ± 0.2 times the molar amount of the aromatic amine compound, the molar amount of the iodine is 0.2 ± 0.05 times the molar amount of the aromatic amine compound, and the molar amount of the peroxytert-butanol is 2 ± 0.2 times the molar amount of the aromatic amine compound.

7. The method for preparing the fluorinated ester-containing triazole compound according to any one of claims 1 to 5, characterized in that, The preparation method includes the following steps: S1. Add a solution of fluorine-containing and ester-containing p-toluenesulfonylhydrazone, aromatic amine compounds, iodine, and peroxytert-butanol to acetonitrile; S2. Place the mixture obtained in step S1 at 85±5℃ and react with stirring until the reaction is complete; S3. Cool to room temperature, quench, extract, dry and purify the product obtained in step S2.

8. The method for preparing fluorine-containing and ester-containing triazole compounds according to claim 7, characterized in that, The concentration of the peroxide tert-butanol solution is 70±5wt%.

9. The method for preparing fluorine-containing and ester-containing triazole compounds according to claim 7, characterized in that, In step S2, the reaction is carried out in an oil bath, and the reaction endpoint is monitored by thin-layer chromatography.

10. The method for preparing fluorine-containing and ester-containing triazole compounds according to claim 7, characterized in that, In step S3, the product is quenched with saturated sodium thiosulfate solution, the quenched product is extracted with ethyl acetate, the extracted product is dried with anhydrous sodium sulfate and the solvent is evaporated, and the dried product is purified by column chromatography.

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