Preparation method of trifluoromethylpyridazine compound

Abstract

The invention belongs to the technical field of synthesis of pyridazine compounds, and discloses a preparation method of a trifluoromethyl pyridazine compound. Trifluoromethyl p-toluenesulfonylhydrazone which is easy to prepare is adopted as a trifluoromethyl nitrogen source reagent, and the trifluoromethyl p-toluenesulfonylhydrazone and enaminone compounds are subjected to cyclization reaction under the promotion condition of alkali, so that the trifluoromethyl pyridazine compounds are obtained through a one-pot method. In the preparation process, only alkali is needed to promote the reaction, the reaction can be completed under the mild condition from the room temperature to 45 DEG C, an expensive metal catalyst or ligand does not need to be used, and toxic or easily exploded hydrazine hydrate does not need to be used as a nitrogen source reagent, so that the problem of toxicity or use safety caused by heavy metal residues or hydrazine hydrate in a pharmaceutical process does not exist; besides, the raw materials used in the process are bulk, cheap, easy to obtain and easy to prepare and purify, the reaction system is green and environment-friendly, the method has the advantages of simple operation steps and post-treatment process and high yield, and the obtained trifluoromethylpyridazine compound can be applied to synthesis of medical intermediates or analogues.

Description

Technical Field

[0001] This scheme belongs to the field of pyridazine compound synthesis technology, specifically involving a method for preparing a trifluoromethylpyridazine compound. Background Technology

[0002] Introducing trifluoromethyl functional groups into drug development can significantly improve physiological activities such as lipophilicity, absorbability, and metabolic stability, and this structure has a significant impact on drug efficacy. For example, many well-known drug molecules currently reported on the market contain trifluoromethyl structures, such as Celebrex, a highly effective drug for treating arthritis, Januvia, a drug for treating type II diabetes, and the active pharmaceutical ingredient BMS-911278 (structural formulas shown below). Therefore, how to introduce trifluoromethyl functional groups into organic molecular structures has attracted increasing interest and attention from researchers.

[0003]

[0004] On the other hand, pyridazine compounds, as bioisosteres of the benzene ring, have been identified as potential anticancer agents with high selectivity and low toxicity in drug development. Therefore, developing green synthetic processes and researching methods with simple operation steps and post-processing, as well as high yields, to prepare trifluoromethyl-containing pyridazine heterocyclic compounds has extremely important academic significance and market prospects. Summary of the Invention

[0005] This solution aims to overcome at least one defect in the prior art and provides a method for preparing trifluoromethylpyridazine compounds, which has the advantages of simple operation steps and post-processing and high yield.

[0006] To solve the above-mentioned technical problems, the following technical solution is adopted: Using readily prepared trifluoromethyl-p-toluenesulfonylhydrazone as the trifluoromethyl nitrogen source, trifluoromethylpyridazine compounds can be obtained in one step via a cyclization reaction with enaminoketone compounds under alkaline-promoted conditions, through a "one-pot" method.

[0007] The reaction route of the above preparation method can be represented as follows: .

[0008] Wherein, Formula 1a is trifluoromethyl-p-toluenesulfonylhydrazone, Formula 2 is an enaminoketone compound, and Formula 3 is a trifluoromethylpyridazine compound; in Formulas 2 and 3, R is aryl, heteroaryl, or alkenyl.

[0009] The above preparation method can prepare any one of the following trifluoromethylpyridazine compounds: .

[0010] Accordingly, any one of the following compounds can be selected from the enamine ketone compounds: .

[0011] In the above preparation method, the molar amount of trifluoromethyl p-toluenesulfonylhydrazone is preferably 1.2 ± 0.1 times the molar amount of enamine ketone in enamine ketone compounds; the base is preferably sodium carbonate (Na2CO3), and the molar amount of the base is preferably 2 ± 0.2 times the molar amount of enamine ketone in enamine ketone compounds.

[0012] The above preparation method preferably includes the following steps: S1. Add trifluoromethyl p-toluenesulfonylhydrazone, enamino ketone compounds, and a base to the solvent; S2. Place the mixture obtained in step S1 at 20~45℃ and react until the reaction is complete; S3. Extract, dry, and purify the product obtained in step S2.

[0013] In step S1, the solvent is preferably acetonitrile (MeCN) or N,N-dimethylformamide (DMF). In step S2, the reaction endpoint is preferably monitored by thin-layer chromatography (TLC), and the reaction is preferably quenched with purified water. In step S3, the extraction operation preferably uses ethyl acetate as the extractant to perform three extractions on the product; the drying operation preferably uses anhydrous sodium sulfate as a drying agent to dry the extracted product first, and then evaporates the solvent; the purification operation preferably uses column chromatography to purify the dried product.

[0014] Compared with existing technologies, this solution has the following advantages: (1) Only base is needed to promote the reaction, 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) There is no need to use toxic or easily explosive hydrazine hydrate as a nitrogen source reagent, so there are no toxicity or safety issues caused by hydrazine hydrate in the pharmaceutical process; (3) The raw materials used in the preparation process are abundant, inexpensive and easy to obtain and prepare and purify. 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) The obtained trifluoromethylpyridazine compounds can be used in the synthesis of pharmaceutical intermediates or analogs. Detailed Implementation

[0015] This scheme proposes a new method for preparing trifluoromethylpyridazine compounds: using readily prepared trifluoromethyl-p-toluenesulfonylhydrazone as the trifluoromethyl nitrogen source reagent, and reacting it with enaminoketone compounds under alkaline (Na2CO3) conditions, the trifluoromethylpyridazine compounds can be obtained in one step via a cyclization reaction in a "one-pot" method.

[0016] The reaction route of the above preparation method is as follows: .

[0017] Wherein, Formula 1a is trifluoromethyl-p-toluenesulfonylhydrazone, Formula 2 is an enaminoketone compound, and Formula 3 is a trifluoromethylpyridazine compound; in Formulas 2 and 3, R is aryl, heteroaryl, or alkenyl.

[0018] It is worth noting that the above preparation method uses an alkali, especially sodium carbonate (Na2CO3), to promote the reaction, allowing the reaction to produce pyridazine compounds, rather than dihydropyridazine compounds, under mild conditions ranging from room temperature (20°C) to 45°C. Furthermore, trifluoromethyl dihydropyridazine compounds can be obtained in a single "one-pot" reaction from trifluoromethyl p-toluenesulfonylhydrazone and enaminoketone compounds at room temperature via cyclization, without the need for any reaction-promoting additives.

[0019] 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.

[0020] Example 1 In this embodiment, trifluoromethylpyridazine compound 3a was synthesized via the following reaction route:

[0021] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2a (1.0 times, 0.3 mmol, 56.8 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2a had completely reacted, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 3a (pale yellow solid, 70.3 mg, yield 88%).

[0022] Using H respectively1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3a was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.58 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz,1H), 7.71-7.69 (m, 2H), 7.37-7.35 (m, 2H), 2.47 (s, 3H); 19 F NMR (376 MHz, CDCl3): -66.94 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.0, 152.2 (q, J = 35.2 Hz), 151.4,146.3, 135.9, 131.8, 130.2, 129.9, 122.8 (q, J = 2.2 Hz), 121.0 (q, J = 273.2Hz), 21.8. Example 2 In this embodiment, trifluoromethylpyridazine compound 3b was synthesized via the following reaction route:

[0023] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2b (1.0 times, 0.3 mmol, 52.6 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After reacting with starting material 2b completely, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 3b (pale yellow solid, 65.2 mg, yield 86%).

[0024] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3b was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.61 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 1.8 Hz,1H), 7.82-7.80 (m, 2H), 7.76-7.72 (m, 1H), 7.60-7.57 (m, 2H); 19 F NMR (376 MHz, CDCl3): -66.93 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.5, 152.3 (q, J = 35.2 Hz), 151.4,135.5, 134.8, 134.4, 130.0, 129.2, 122.8 (q, J = 2.3 Hz), 121.0 (q, J = 273.4Hz). Example 3 In this embodiment, trifluoromethylpyridazine compound 3c 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2c (1.0 times, 0.3 mmol, 62.9 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reaction of starting material 2c was complete, 10 mL of purified water 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 trifluoromethylpyridazine compound 3c (white solid, 78.0 mg, yield 91%).

[0026] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3c was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.60 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 1.8 Hz,1H), 7.78-7.76 (m, 2H), 7.58-7.55 (m, 2H); 19 F NMR (376 MHz, CDCl3): -66.93 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 190.3, 152.4 (q, J = 35.4 Hz), 151.1,141.7, 135.2, 132.7, 131.3, 129.7, 122.7 (q, J = 2.3 Hz), 120.9 (q, J = 273.4Hz). Example 4 In this embodiment, trifluoromethylpyridazine compound 3d was synthesized via the following reaction route:

[0027] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2d (1.0 times, 0.3 mmol, 76.2 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2d had reacted completely, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 3d (white solid, 89.2 mg, 90% yield).

[0028] Using H respectively 1-NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3d was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.60 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 1.8 Hz,1H), 7.75-7.73 (m, 2H), 7.69-7.67 (m, 2H); 19 F NMR (376 MHz, CDCl3): -66.92 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 190.6, 152.4 (q, J = 35.3 Hz), 151.1,135.1, 133.1, 132.7, 131.3, 130.5, 122.7 (q, J = 2.3 Hz), 120.9 (q, J = 273.4Hz). Example 5 In this embodiment, trifluoromethylpyridazine compound 3e 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2e (1.0 times, 0.3 mmol, 90.3 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2e had completely reacted, 10 mL of purified water 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 trifluoromethylpyridazine compound 3e (pale yellow solid, 95.0 mg, yield 84%).

[0030] Using H respectively 1-NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3e was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.58 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.0 Hz,1H), 7.97-7.93 (m, 2H), 7.53-7.50 (m, 2H); 19 F NMR (376 MHz, CDCl3): -66.90 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 190.9, 152.3 (q, J = 35.2 Hz), 151.1,138.6, 135.0, 133.6, 131.1, 122.7 (q, J = 2.3 Hz), 120.9 (q, J = 273.4 Hz). Example 6 In this embodiment, trifluoromethylpyridazine compound 3f 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2f (1.0 times, 0.3 mmol, 73.0 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reaction of starting material 2f was complete, 10 mL of purified water 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 trifluoromethylpyridazine compound 3f (pale yellow solid, 81.4 mg, yield 85%).

[0032] Using H respectively 1 -NMR (Bruker FT-NMR), F19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3f was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.63 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz,1H), 7.96-7.94 (m, 2H), 7.87-7.85 (m, 2H); 19 F NMR (376 MHz, CDCl3): -63.36 (s, 3F), -66.98 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 190.7, 152.5 (q, J = 35.5 Hz), 151.1,137.2, 135.9 (q, J = 32.9 Hz), 134.5, 130.3, 126.3 (q, J = 3.7 Hz), 123.1 (q, J =271.5 Hz), 122.8 (q, J = 2.3 Hz), 120.9 (q, J = 273.4 Hz). Example 7 In this embodiment, 3g of a trifluoromethylpyridazine compound was synthesized, and the reaction route is as follows:

[0033] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2 g (1.0 times, 0.3 mmol, 69.4 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the 2 g of starting material had completely reacted, 10 mL of purified water 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 trifluoromethylpyridazine compound (white solid, 83.4 mg, 90% yield).

[0034] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3g was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.62 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 1.8 Hz,1H), 7.77-7.75 (m, 2H), 7.61-7.58 (m, 2H), 1.37 (s, 9H); 19 F NMR (376 MHz, CDCl3): -66.90 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.0, 159.1, 151.4, 152.3 (q, J = 35.4Hz), 135.9, 131.8, 130.1, 126.3, 122.8 (q, J = 2.2 Hz), 121.0 (q, J = 273.3 Hz), 35.4, 30.9. Example 8 In this embodiment, the trifluoromethylpyridazine compound was synthesized over 3 hours, and the reaction route is as follows:

[0035] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2h (1.0 times, 0.3 mmol, 75.4 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the starting materials had reacted completely for 2 hours, 10 mL of purified water 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 trifluoromethylpyridazine compound 3h (pale yellow solid, 82.3 mg, yield 84%).

[0036] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3h was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.67 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 1.8 Hz,1H), 7.92-7.89 (m, 2H), 7.82-7.80 (m, 2H), 7.68-7.65 (m, 2H), 7.54-7.50 (m,2H), 7.48-7.43 (m, 1H); 19 F NMR (376 MHz, CDCl3): -66.86 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.0, 152.3 (q, J = 35.2 Hz), 151.3,147.6, 139.0, 135.7, 133.0, 130.7, 129.1, 128.8, 127.8, 127.3, 122.8 (q, J =2.3 Hz), 121.0 (q, J = 273.4 Hz). Example 9 In this embodiment, trifluoromethylpyridazine compound 3i was synthesized via the following reaction route:

[0037] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2i (1.0 times, 0.3 mmol, 56.8 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reaction of starting material 2i was complete, 10 mL of purified water 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 trifluoromethylpyridazine compound 3i (pale yellow liquid, 65.9 mg, yield 82%).

[0038] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3i was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.61 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 1.8 Hz,1H), 7.63 (s, 1H), 7.57-7.53 (m, 2H), 7.48-7.44 (m, 1H), 2.45 (s, 3H); 19 F NMR (376 MHz, CDCl3): -66.93 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.7, 152.4 (q, J = 35.7 Hz), 151.4,139.4, 135.7, 135.6, 134.5, 130.4, 129.0, 127.4, 122.8 (q, J = 2.4 Hz), 121.0(q, J= 273.4 Hz), 21.3. Example 10 In this embodiment, trifluoromethylpyridazine compound 3j was synthesized, and 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2j (1.0 times, 0.3 mmol, 56.8 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2j had completely reacted, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 3j (pale yellow liquid, 65.0 mg, yield 81%).

[0040] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3j was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.58 (d, J = 1.0 Hz, 1H), 8.06 (d, J = 2.0 Hz,1H), 7.56-7.52 (m, 1H), 7.42-7.40 (m, 1H), 7.36-7.30 (m, 2H), 2.48 (s, 3H); 19 F NMR (376 MHz, CDCl3): -66.91 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 193.3, 152.5 (q, J = 35.3 Hz), 151.6,139.4, 135.6, 134.0, 133.0, 132.4, 130.2, 125.9, 122.8 (q,J = 2.5 Hz), 121.0(q, J = 273.4 Hz), 20.6. Example 11 In this embodiment, trifluoromethylpyridazine compound 3k 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2k (1.0 times, 0.3 mmol, 67.6 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the starting material 2k had reacted completely, 10 mL of purified water 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 trifluoromethylpyridazine compound 3k (yellow solid, 69.0 mg, yield 76%).

[0042] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3k was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.64 (d, J = 1.8 Hz, 1H), 8.43-8.41 (m, 1H), 8.20-8.16 (m, 1H), 8.15 (d, J = 1.8 Hz, 1H), 8.01-7.97 (m, 1H), 7.69-7.62 (m, 2H), 7.61-7.55 (m, 2H); 19 F NMR (376 MHz, CDCl3): -66.85 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 192.8, 152.6 (q, J= 35.0 Hz), 151.7,136.3, 134.7, 134.0, 131.8, 130.9, 130.6, 128.9, 128.8, 127.4, 125.1, 124.2,123.0 (q, J = 2.3 Hz), 121.0 (q, J = 273.3 Hz). Example 12 In this embodiment, trifluoromethylpyridazine compound 3l was synthesized via the following reaction route:

[0043] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2l (1.0 times, 0.3 mmol, 67.6 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the initial reaction of 2l of reactants was complete, 10 mL of purified water 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 3l of trifluoromethylpyridazine compound (pale yellow solid, 73.6 mg, yield 81%).

[0044] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3l was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.68 (d, J = 1.8 Hz, 1H), 8.22-8.21 (m, 1H),8.15 (d, J = 2.0 Hz, 1H), 8.03-8.01 (m, 1H), 7.96-7.93 (m, 3H), 7.72-7.68 (m,1H), 7.64-7.60 (m, 1H); 19 F NMR (376 MHz, CDCl3): -66.86 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.4, 152.4 (q, J = 35.4 Hz), 151.4,136.1, 136.0, 133.0, 132.1, 131.8, 129.8, 129.7, 129.5, 128.0, 127.6, 124.3,122.9 (q, J = 2.2 Hz), 121.0 (q, J = 273.3 Hz). Example 13 In this embodiment, trifluoromethylpyridazine compound 3m was synthesized, and the reaction route is as follows:

[0045] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2m (1.0 times, 0.3 mmol, 61.6 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2m had reacted completely, 10 mL of purified water 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 trifluoromethylpyridazine compound 3m (pale yellow solid, 78.4 mg, yield 93%).

[0046] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3m was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.57 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 1.8 Hz,1H), 7.82-7.78 (m, 2H), 7.05-7.01 (m, 2H), 3.92 (s, 3H); 19F NMR (376 MHz, CDCl3): -66.94 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 189.7, 165.0, 151.4, 152.2 (q, J = 35.1Hz), 136.4, 132.7, 127.2, 122.7 (q, J = 2.5 Hz), 121.0 (q, J = 273.4 Hz), 114.5, 55.7. Example 14 In this embodiment, trifluoromethylpyridazine compound 3n 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2n (1.0 times, 0.3 mmol, 61.6 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2n had completely reacted, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 3n (pale yellow solid, 71.0 mg, yield 84%).

[0048] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3n was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.63–9.62 (m, 1H), 8.10 (d, J = 1.8 Hz, 1H),7.51-7.47 (m, 1H), 7.39-7.38 (m, 1H), 7.30-7.26 (m, 2H), 3.90 (s, 3H); 19 F NMR (376 MHz, CDCl3): -66.98 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.3, 160.2, 152.2 (q, J = 35.2 Hz),151.3, 135.7, 135.6, 130.1, 122.9, 122.7 (q, J = 2.4 Hz), 121.3, 121.0 (q, J =273.3 Hz), 113.9, 55.5. Example 15 In this embodiment, trifluoromethylpyridazine compound 3o 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2o (1.0 times, 0.3 mmol, 70.6 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2o had completely reacted, 10 mL of purified water 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 trifluoromethylpyridazine compound 3o (white solid, 69.4 mg, yield 74%).

[0050] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3o was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.57 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.49 (d, J= 2.0 Hz, 1H), 7.25-7.22 (m, 1H), 6.94-6.92 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H); 19 F NMR (376 MHz, CDCl3): -66.96 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 189.7, 154.9, 152.1 (q, J = 35.2 Hz),151.3, 149.8, 136.5, 127.4, 126.2, 122.7 (q, J = 2.3 Hz), 121.0 (q, J = 273.4Hz), 110.9, 110.1, 56.3, 56.1. Example 16 In this embodiment, the trifluoromethylpyridazine compound 3p 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2p (1.0 times, 0.3 mmol, 65.8 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2p had completely reacted, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 3p (pale yellow solid, 77.4 mg, yield 87%).

[0052] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3p was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d9.55-9.54 (m, 1H), 8.02 (d, J = 1.8 Hz, 1H),7.78-7.75 (m, 2H), 7.00-6.98 (m, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.45 (t, J = 7.0Hz, 3H); 19 F NMR (376 MHz, CDCl3): -67.00 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 189.6, 164.4, 152.1 (q, J = 35.3 Hz),151.3, 136.5, 132.6, 127.0, 122.6 (q, J = 2.4 Hz), 121.0 (q, J = 273.3 Hz),114.9, 64.1, 14.5. Example 17 In this embodiment, trifluoromethylpyridazine compound 3q was synthesized via the following reaction route:

[0053] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2q (1.0 times, 0.3 mmol, 65.8 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2q had completely reacted, 10 mL of purified water 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 trifluoromethylpyridazine compound 3q (yellow solid, 74.0 mg, yield 83%).

[0054] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3q was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.58 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.31-7.28 (m, 1H), 6.96-6.94 (m, 1H), 6.16 (s, 2H); 19 F NMR (376 MHz, CDCl3): -66.95 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 189.4, 153.6, 152.2 (q, J = 35.2 Hz),151.2, 149.0, 136.4, 129.1, 127.9, 122.6 (q, J = 2.3 Hz), 121.0 (q, J = 273.3Hz), 108.9, 108.3, 102.5. Example 18 In this embodiment, trifluoromethylpyridazine compound 3r 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2r (1.0 times, 0.3 mmol, 70.0 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2r had completely reacted, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 3r (white solid, 78.2 mg, yield 84%).

[0056] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13The structure of the obtained trifluoromethylpyridazine compound 3r was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.63 (d, J = 1.8 Hz, 1H), 8.23-8.21 (m, 2H), 8.09 (d, J = 1.8 Hz, 1H), 7.88-7.86 (m, 2H), 3.97 (s, 3H); 19 F NMR (376 MHz, CDCl3): -66.93 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.1, 165.6, 152.5 (q, J = 35.4 Hz),151.2, 137.6, 135.3, 134.8, 130.3, 129.9, 122.8 (q, J = 2.2 Hz), 120.9 (q, J =273.4 Hz), 52.8. Example 19 In this embodiment, trifluoromethylpyridazine compound 3S 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2s (1.0 times, 0.3 mmol, 60.1 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2s had completely reacted, 10 mL of purified water and 3 x 10 mL of ethyl acetate were added for extraction. The organic layer was 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 give trifluoromethylpyridazine compound 3s (white solid, 56.0 mg, yield 67%).

[0058] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C13 The structure of the obtained trifluoromethylpyridazine compound 3S was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.62 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.95-7.93 (m, 2H), 7.92-7.90 (m, 2H); 19 F NMR (376 MHz, CDCl3): -66.89 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 190.4, 152.6 (q, J = 35.6 Hz), 150.9,137.5, 134.2, 133.0, 130.3, 122.7 (q, J = 2.1 Hz), 120.9 (q, J = 273.5 Hz), 118.0, 116.8. Example 20 In this embodiment, trifluoromethylpyridazine compound 3t was synthesized, and the reaction route is as follows:

[0059] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2t (1.0 times, 0.3 mmol, 66.1 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the initial 2t of reactants had completely reacted, 10 mL of purified water 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 3t of trifluoromethylpyridazine compound (yellow solid, 68.0 mg, yield 76%).

[0060] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13The structure of the obtained trifluoromethylpyridazine compound 3t was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.65 (d, J = 2.0 Hz, 1H), 8.46-8.42 (m, 2H),8.11 (d, J = 2.0 Hz, 1H), 8.04-8.01 (m, 2H); 19 F NMR (376 MHz, CDCl3): -66.90 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 190.2, 152.6 (q, J = 35.4 Hz), 151.0,150.9, 139.0, 134.1, 131.0, 124.4, 122.7 (q, J = 2.3 Hz), 120.8 (q, J = 273.4Hz). Example 21 In this embodiment, trifluoromethylpyridazine compound 3u was synthesized via the following reaction route:

[0061] In a 35 mL reaction tube, add a magnetic stir bar and DMF solvent (3.0 mL). Weigh out trifluoromethyl p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2u (1.0 times, 0.3 mmol, 70.4 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg). Cap the reaction tube and incubate at 45 °C. o The reaction was carried out at C for 20 hours (monitored by thin-layer chromatography). After the reaction of 2u of raw material was complete, purified water (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain 3u of trifluoromethylpyridazine compound (pale yellow solid, 70.2 mg, yield 75%).

[0062] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13The structure of the obtained trifluoromethylpyridazine compound 3u was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.63 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.94-7.92 (m, 1H), 7.79-7.76 (m, 1H); 19 F NMR (376 MHz, CDCl3): -66.86 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 189.3, 152.7 (q, J = 35.5 Hz), 150.7,138.6, 138.5, 134.8, 133.7, 130.8, 127.9, 122.7, 120.8 (q, J = 273.6 Hz), 118.7, 114.6. Example 22 In this embodiment, trifluoromethylpyridazine compound 3v 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. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2v (1.0 times, 0.3 mmol, 69.4 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2v had completely reacted, 10 mL of purified water 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 trifluoromethylpyridazine compound 3v (yellow solid, 75.0 mg, yield 81%).

[0064] Using H respectively 1 -NMR (Bruker FT-NMR), F 19-NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3v was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.75 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 1.8 Hz,1H), 7.96-7.92 (m, 2H), 7.88 (s, 1H), 7.59-7.55 (m, 1H), 7.50-7.46 (m, 1H); 19 F NMR (376 MHz, CDCl3): -66.84 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 184.4, 152.4 (q, J = 35.4 Hz), 150.8,143.5, 140.4, 138.6, 135.6, 134.1, 129.0, 126.8, 125.8, 123.0, 122.4 (q, J =2.2 Hz), 121.0 (q, J = 273.5 Hz). Example 23 In this embodiment, trifluoromethylpyridazine compound 3w was synthesized, and the reaction route is as follows:

[0065] In a 35 mL reaction tube, a magnetic stir bar and 3.0 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminophen 2w (1.0 times, 0.3 mmol, 49.6 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg) were weighed. The reaction tube was capped and the reaction was allowed to proceed at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2w had reacted completely, 10 mL of purified water and 10 mL × 3 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 trifluoromethylpyridazine compound 3w (pale yellow solid, 45.2 mg, yield 62%).

[0066] Using H respectively1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3w was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.88 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 1.8 Hz,1H), 7.83-7.82 (m, 1H), 7.52 (dd, J = 3.8 Hz, 0.7 Hz, 1H), 6.75 (dd, J = 3.6 Hz, 1.6 Hz, 1H); 19 F NMR (376 MHz, CDCl3): -66.95 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 176.7, 152.4 (q, J = 35.2 Hz), 151.4,151.1, 148.8, 134.3, 122.8 (q, J = 2.5 Hz), 122.3, 121.0 (q, J = 273.2 Hz), 113.7. Example 24 In this embodiment, trifluoromethylpyridazine compound 3x was synthesized via the following reaction route:

[0067] In a 35 mL reaction tube, add a magnetic stir bar and DMF solvent (3.0 mL). Weigh out trifluoromethyl p-toluenesulfonylhydrazone 1a (1.2x, 0.36 mmol, 130.0 mg), enaminone 2x (1.0x, 0.3 mmol, 52.9 mg), and sodium carbonate (2.0x, 0.6 mmol, 64.0 mg). Cap the reaction tube and incubate at 45 °C. oThe reaction was carried out at C for 20 hours (monitored by thin-layer chromatography). After the reaction of the starting material 2x was complete, pure water (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethylpyridazine compound 3x (pale yellow solid, 48.2 mg, yield 63%).

[0068] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3x was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.97 (d, J = 1.8 Hz, 1H), 8.75-8.74 (m, 1H),8.52 (d, J = 1.8 Hz, 1H), 8.25-8.23 (m, 1H), 8.02-7.98 (m, 1H), 7.65-7.61 (m,1H); 19 F NMR (376 MHz, CDCl3): -66.95 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 189.0, 152.4, 152.1 (q, J = 35.1 Hz),151.8, 149.1, 137.8, 134.2, 128.3, 124.6, 124.3 (q, J = 2.3 Hz), 121.1 (q, J =273.2 Hz). Example 25 In this embodiment, trifluoromethylpyridazine compound 3y was synthesized, and the reaction route is as follows:

[0069] In a 35 mL reaction tube, add a magnetic stir bar and 3.0 mL of DMF solvent. Weigh out trifluoromethyl p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2y (1.0 times, 0.3 mmol, 53.2 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg). Cap the reaction tube and incubate at 45 °C. o The reaction was carried out at C for 20 hours (monitored by thin-layer chromatography). After the reaction of the starting material 2y was complete, pure water (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethylpyridazine compound 3y (yellow liquid, 44.3 mg, yield 58%).

[0070] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3y was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 10.02 (d, J = 1.8 Hz, 1H), 9.46 (d, J = 1.2 Hz, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.77-8.76 (m, 1H), 8.55 (d, J = 2.0 Hz, 1H); 19 F NMR (376 MHz, CDCl3): -66.93 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 188.1, 152.4 (q, J = 35.3 Hz), 151.9,148.9, 146.6, 146.1, 143.3, 133.1, 124.0 (q, J = 2.3 Hz), 121.1 (q, J = 273.2Hz). Example 26 In this embodiment, trifluoromethylpyridazine compound 3z was synthesized via the following reaction route:

[0071] In a 35 mL reaction tube, add a magnetic stir bar and 3.0 mL of MeCN solvent. Weigh out trifluoromethyl p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2z (1.0 times, 0.3 mmol, 60.4 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg). Cap the reaction tube and incubate at 45 °C. o The reaction was carried out for 20 hours (monitored by thin-layer chromatography). After the reaction of the starting material 2z was complete, pure water (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethylpyridazine compound 3z (yellow solid, 60.5 mg, yield 72%).

[0072] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3z was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.81 (d, J = 1.4 Hz, 1H), 8.24 (d, J = 1.8 Hz,1H), 7.94-7.91 (m, 1H), 7.69-7.67 (m, 2H), 7.52-7.43 (m, 4H); 19 F NMR (376 MHz, CDCl3): -66.90 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 186.4, 152.7 (q, J = 35.0 Hz), 150.4,149.1, 135.0, 133.5, 132.1, 129.2, 129.1, 121.6 (q, J = 2.2 Hz), 121.1 (q, J =273.3 Hz), 119.6. Example 27 In this embodiment, trifluoromethylpyridazine compound 3aa was synthesized via the following reaction route:

[0073] In a 35 mL reaction tube, add a magnetic stir bar and 3.0 mL of MeCN solvent. Weigh out trifluoromethyl p-toluenesulfonylhydrazone 1a (1.2 times, 0.36 mmol, 130.0 mg), enaminone 2aa (1.0 times, 0.3 mmol, 74.2 mg), and sodium carbonate (2.0 times, 0.6 mmol, 64.0 mg). Cap the reaction tube and incubate at 45 °C. o The reaction was carried out for 20 hours (monitored by thin-layer chromatography). After the reaction of the starting material 2aa was complete, pure water (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethylpyridazine compound 3aa (yellow solid, 40.9 mg, yield 42%).

[0074] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3aa was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.73 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 16.0 Hz, 1H), 6.88 (d, J = 16.0 Hz, 1H), 2.19-2.16 (m, 2H), 1.91 (s, 3H), 1.67-1.64 (m, 2H), 1.54-1.51 (m, 2H), 1.15 (s, 6H); 19 F NMR (376 MHz, CDCl3): -66.97 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 186.5, 152.7 (q, J= 35.0 Hz), 150.5,148.7, 143.2, 136.6, 135.5, 123.0, 121.6 (q, J = 2.3 Hz), 121.1 (q, J = 273.4Hz), 40.0, 34.4, 34.2, 28.8, 22.1, 18.6. Example 28 In this embodiment, the trifluoromethylpyridazine compound 3ab was synthesized via the following reaction route:

[0075] In a 35 mL reaction tube, add a magnetic stir bar and 3.0 mL of DMF solvent. Weigh out trifluoromethyl p-toluenesulfonylhydrazone 1a (2.4 times, 0.72 mmol, 260.0 mg), enaminophen 2ab (1.0 times, 0.3 mmol, 82.0 mg), and sodium carbonate (4.0 times, 1.2 mmol, 128.0 mg). Cap the reaction tube and incubate at 45 °C. o The reaction was carried out for 20 hours (monitored by thin-layer chromatography). After the reaction of the starting material 2ab was complete, pure water (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The organic layer solution was dried over anhydrous sodium sulfate, the solvent was evaporated, and the crude product was separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain trifluoromethylpyridazine compound 3ab (yellow solid, 65.5 mg, yield 51%).

[0076] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 3ab was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.73 (s, 2H), 8.63-8.61 (m, 2H), 8.43-8.39 (m,1H), 8.27 (s, 2H); 19 F NMR (376 MHz, CDCl3): -67.37 (s, 6F); 13 C{ 1H} NMR (100 MHz, CDCl3): 187.7, 151.5, 151.0, 140.4, 133.1, 129.0,123.7, 120.8 (q, J = 273.3 Hz). Example 29 In this embodiment, trifluoromethylpyridazine compound 4a was synthesized via the following reaction route:

[0077] Under an ice bath at 0°C, 3a (1.0x, 0.5 mmol, 133.0 mg) was added to anhydrous EtOH (3.0 mL) containing NaBH4 (2.0x, 1.0 mmol, 38.0 mg), and then... o The reaction was stirred in an ice bath for 1 hour, and then continued at room temperature for 4 hours (monitored by thin-layer chromatography). After the reaction was completed, 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 4a (white solid, 107.7 mg, yield 80%).

[0078] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethylpyridazine compound 4a was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 9.17 (d, J = 1.8 Hz, 1H), 7.95-7.94 (m, 1H), 7.19-7.15 (m, 4H), 5.87 (s, 1H), 3.62 (br, s, 1H), 2.33 (s, 3H); 19 F NMR (376 MHz, CDCl3): -67.01 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 152.0, 151.5 (q, J= 34.6 Hz), 145.8,139.1, 137.8, 129.9, 126.8, 121.2 (q, J = 273.0 Hz), 120.9 (q, J = 2.3 Hz), 72.6,21.1. Example 30 In this embodiment, trifluoromethyldihydropyridazine compound 5a was synthesized via the following reaction route:

[0079] In a 100 mL reaction flask, a magnetic stir bar and 20 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 2.4 mmol, 862.0 mg) and enaminophen 2a (1.0 times, 2.0 mmol, 378.5 mg) were weighed. The flask was capped, and the reaction was carried out at room temperature for 20 hours (monitored by thin-layer chromatography). After the reaction of starting material 2a was complete, 50 mL of purified water and 3 x 50 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 5a (white solid, 2.0 mmol scale, 0.72 g, yield 85%).

[0080] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethyldihydropyridazine compound 5a was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.79-7.77 (m, 2H), 7.68 (s, 1H), 7.51-7.49 (m,2H), 7.38-7.36 (m, 2H), 7.31-7.29 (m, 2H), 3.26 (s, 2H), 2.46 (s, 3H), 2.45(s, 3H); 19 F NMR (376 MHz, CDCl3): -73.28 (s, 3F); 13 C{ 1H} NMR (100 MHz, CDCl3): 192.5, 146.2, 143.2, 142.6 (q, J = 36.4Hz), 134.1, 133.6, 132.3, 130.1, 129.4, 128.8, 128.4, 119.6 (q, J = 273.4 Hz),111.6, 21.7, 21.6, 19.7. Example 31 In this embodiment, trifluoromethyldihydropyridazine compound 5c was synthesized via the following reaction route:

[0081] In a 50 mL reaction flask, a magnetic stir bar and 5 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.6 mmol, 216.0 mg) and enaminophen 2c (1.0 times, 0.5 mmol, 104.8 mg) were weighed. The flask was capped, and the reaction was carried out at room temperature for 20 hours (monitored by thin-layer chromatography). After the reaction of starting material 2c was complete, 20 mL of purified water and 3 x 20 mL of ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 5c (white solid, 0.5 mmol scale, 180.5 mg, yield 82%).

[0082] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethyldihydropyridazine compound 5c was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.78-7.76 (m, 2H), 7.65 (s, 1H), 7.55-7.52 (m,2H), 7.49-7.45 (m, 2H), 7.37-7.35 (m, 2H), 3.25 (s, 2H), 2.45 (s, 3H); 19 F NMR (376 MHz, CDCl3): -73.31 (s, 3F); 13 C{ 1H} NMR (100 MHz, CDCl3): 191.4, 146.3, 142.6 (q, J = 36.5 Hz),138.7, 135.1, 133.8, 132.1, 130.1, 130.0, 129.1, 128.4, 119.5 (q, J = 273.5Hz), 111.3, 21.7, 19.5. Example 32 In this embodiment, trifluoromethyldihydropyridazine compound 5f was synthesized via the following reaction route:

[0083] In a 50 mL reaction flask, a magnetic stir bar and 5 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.6 mmol, 216.0 mg) and enaminophen 2f (1.0 times, 0.5 mmol, 121.6 mg) were weighed. The flask was capped, and the reaction was carried out at room temperature for 20 hours (monitored by thin-layer chromatography). After the reaction of starting material 2f was complete, 20 mL of purified water and 3 x ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 5f (white solid, 0.5 mmol scale, 189.0 mg, yield 79%).

[0084] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethyldihydropyridazine compound 5f was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.78-7.76 (m, 4H), 7.70-7.68 (m, 2H), 7.66 (s,1H), 7.38-7.36 (m, 2H), 3.28 (s, 2H), 2.46 (s, 3H); 19 F NMR (376 MHz, CDCl3): -63.03 (s, 3F), -73.42 (s, 3F); 13 C{ 1H} NMR (100 MHz, CDCl3): 191.5, 146.4, 142.8 (q, J = 36.6 Hz),140.0, 134.4, 133.7 (q, J = 32.7 Hz), 132.1, 130.1, 128.9, 128.4, 125.8 (q, J =3.7 Hz), 123.5 (q, J = 271.0 Hz), 119.5 (q, J = 273.5 Hz), 111.2, 21.7, 19.4. Example 33 In this embodiment, trifluoromethyldihydropyridazine compound 5m was synthesized, and the reaction route is as follows:

[0085] In a 50 mL reaction flask, a magnetic stir bar and 5 mL of MeCN solvent were added. Trifluoromethyl-p-toluenesulfonylhydrazone 1a (1.2 times, 0.6 mmol, 216.0 mg) and enaminophen 2m (1.0 times, 0.5 mmol, 102.6 mg) were weighed. The flask was capped, and the reaction was carried out at room temperature for 20 hours (monitored by thin-layer chromatography). After the reactant 2m had reacted completely, 20 mL of purified water and 3 x ethyl acetate were added for extraction. The organic layer was 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 trifluoromethylpyridazine compound 5m (white solid, 0.5 mmol scale, 167.0 mg, yield 76%).

[0086] Using H respectively 1 -NMR (Bruker FT-NMR), F 19 -NMR (Bruker FT-NMR) and C 13 The structure of the obtained trifluoromethyldihydropyridazine compound 5m was confirmed by Bruker FT-NMR, and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.78-7.76 (m, 2H), 7.65 (s, 1H), 7.63-7.59 (m,2H), 7.37-7.35 (m, 2H), 6.99-6.96 (m, 2H), 3.89 (s, 3H), 3.25 (s, 2H), 2.44(s, 3H); 19 F NMR (376 MHz, CDCl3): -73.22 (s, 3F); 13 C{ 1 H} NMR (100 MHz, CDCl3): 191.3, 163.1, 146.1, 142.4 (q, J = 36.4Hz), 132.9, 132.3, 131.0, 130.0, 129.2, 128.3, 119.6 (q, J = 273.4 Hz), 114.0,111.6, 55.4, 21.6, 19.8. 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 trifluoromethylpyridazine compound, characterized in that, Trifluoromethylpyridazine compounds are obtained by cyclization of trifluoromethyl-p-toluenesulfonylhydrazone with enamino ketone compounds under alkaline-promoted conditions.

2. The method for preparing trifluoromethylpyridazine compounds according to claim 1, characterized in that, The reaction route is as follows: Wherein, Formula 1a is the trifluoromethyl-p-toluenesulfonylhydrazone, Formula 2 is the enaminoketone compound, and Formula 3 is the trifluoromethylpyridazine compound; in Formulas 2 and 3, R is aryl, heteroaryl, or alkenyl.

3. The method for preparing trifluoromethylpyridazine compounds according to claim 1, characterized in that, The trifluoromethylpyridazine compound is selected from any one of the following compounds: 。 4. The method for preparing trifluoromethylpyridazine compounds according to claim 3, characterized in that, The enaminoketone compound is selected from any one of the following compounds: 。 5. The method for preparing trifluoromethylpyridazine compounds according to claim 1, characterized in that, The structural formula of the trifluoromethyl-p-toluenesulfonylhydrazone is: 。 6. The method for preparing trifluoromethylpyridazine compounds according to claim 1, characterized in that, The alkali is sodium carbonate.

7. The method for preparing trifluoromethylpyridazine compounds according to any one of claims 1 to 6, characterized in that, The molar amount of the trifluoromethyl-p-toluenesulfonylhydrazone is 1.2 ± 0.1 times the molar amount of the enamine ketone in the enamine ketone compound; and / or the molar amount of the base is 2 ± 0.2 times the molar amount of the enamine ketone in the enamine ketone compound.

8. The method for preparing trifluoromethylpyridazine compounds according to claim 7, characterized in that, The preparation method includes the following steps: S1. Add trifluoromethyl p-toluenesulfonylhydrazone, enamino ketone compounds, and a base to the solvent; S2. Place the mixture obtained in step S1 at 20~45℃ and react until the reaction is complete; S3. Extract, dry, and purify the product obtained in step S2.

9. The method for preparing trifluoromethylpyridazine compounds according to claim 1, characterized in that, The solvent in step S1 is acetonitrile or N,N-dimethylformamide; and / or, the reaction endpoint in step S2 is monitored by thin-layer chromatography; and / or, the reaction is quenched with pure water in step S2.

10. The method for preparing trifluoromethylpyridazine compounds according to claim 1, characterized in that, Step S3 involves extracting the product with ethyl acetate; and / or, step S3 involves drying the extracted product with anhydrous sodium sulfate and then evaporating the solvent; and / or, step S3 involves purifying the dried product by column chromatography.

Images