Preparation method of sulfonylated dihydropyrazole derivative

Abstract

The invention provides a preparation method of a sulfonylated dihydropyrazole derivative, and belongs to the field of organic synthesis. According to the invention, a (E)-N-allyl-N '-benzyl acethydrazide compound (compound 1), an aryl diazonium salt compound (compound 2) and DABSO (1, 4-diazabicyclo [2.2. 2] octane-1, 4-dionium-1, 4-disulfinic acid) are used as raw materials, and the sulfonylated dihydropyrazole derivative is prepared by a method of catalyzing insertion of sulfur dioxide. According to the preparation method, the problems of corrosion of reagents, expensive metals and excessive oxidizing agents during insertion of SO2 in the prior art are avoided.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to a method for preparing a sulfonated dihydropyrazole derivative. Background Technology

[0002] Dihydropyrazoles are an important class of nitrogen-containing heterocyclic compounds. Due to their unique five-membered nitrogen heterocyclic structure and good biological activity, they are widely used in medicinal chemistry, pesticide chemistry, and materials science. Numerous studies have shown that dihydropyrazoles and their derivatives have potential applications in anti-inflammatory, antibacterial, and anticancer activities, as well as as fluorescent probes and functional materials.

[0003] Existing methods for synthesizing dihydropyrazole compounds involve the use of corrosive agents (such as sulfonyl chloride), expensive metals, and excess oxidizing agents (such as tert-butyl hydroperoxide TBHP). Summary of the Invention

[0004] This invention provides a method for preparing sulfonated dihydropyrazole derivatives, which avoids the use of corrosive reagents, expensive metals and excessive oxidants.

[0005] This invention provides a method for preparing a sulfonated dihydropyrazole derivative, comprising the following steps: Compound 1, compound 2, 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid, a copper-based catalyst, and an organic solvent were mixed and subjected to a sulfonation cyclization reaction to obtain the sulfonated dihydropyrazole derivative. Compound 1 has the structural formula shown in Formula I; Compound 2 has the structural formula shown in Formula II; The sulfonated dihydropyrazole derivative has the structural formula shown in Formula III: Formula I; Formula II; Formula III; The R 2 Including one of hydrogen, a first halogen, a first alkyl group, a first alkoxy group, and a heterocyclic group; R 1 It includes one of the following: second halogen, second alkyl, substituted alkyl, and second alkoxy.

[0006] Preferably, the substituents in the substituted alkyl group include halogen or ester groups, and the alkyl group includes methyl; The first halogen and the second halogen independently include fluorine, chlorine, bromine or iodine; The first alkyl group and the second alkyl group include methyl groups; The first alkoxy group and the second alkoxy group include methoxy groups; The heterocyclic group includes thiophene or pyridinium.

[0007] Preferably, compound 1 has any of the structural formulas shown in (1a) to (1d): .

[0008] Preferably, the molar ratio of the copper-based catalyst to compound 1 is 1:1 to 3.

[0009] Preferably, the copper-based catalyst comprises one or more of copper chloride, copper bromide, copper trifluoromethanesulfonate, and copper acetate.

[0010] Preferably, the molar ratio of 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid to compound 1 is 3~5:2.

[0011] Preferably, the molar ratio of compound 2 to compound 1 is 3~5:2.

[0012] Preferably, the molar ratio of compound 1 to the volume of the organic solvent is 1 mmol: 10 mL; the organic solvent includes one or more of acetonitrile, dichloromethane, 1,2-dichloroethane, and tetrahydrofuran.

[0013] Preferably, the sulfonation cyclization reaction is carried out at a temperature of 30~80℃ for 10~18h.

[0014] Preferably, after the sulfonation cyclization reaction, the present invention further includes: cooling the system obtained from the sulfonation cyclization reaction to room temperature and mixing it with saturated brine, then extracting it with ethyl acetate, and then drying the obtained organic phase with a solid desiccant to obtain a dried organic phase; removing the solvent from the dried organic phase to obtain a crude product; and separating and purifying the crude product by column chromatography.

[0015] This invention uses (E)-N-allyl-N'-benzylacetylhydrazine (compound 1), aryl diazonium salt (compound 2), and DABSO (1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid) as raw materials to prepare sulfonated dihydropyrazole derivatives by catalytic sulfur dioxide insertion. This preparation method avoids the problems of using corrosive reagents, expensive metals, and excessive oxidants in current SO2 insertion methods.

[0016] This invention is characterized by its simple operation, environmental friendliness, and low cost. The sulfonated dihydropyrazole derivative prepared by this invention may possess potential biological activity and significant research value. It can be used as an intermediate in drug development and provide raw materials for the synthesis of some complex molecules, thus showing excellent application prospects. Furthermore, the preparation method of this invention is characterized by its simple operation, green economy, broad substrate coverage, and high yield. Attached Figure Description

[0017] Figure 1 The synthetic route diagram for the sulfonated dihydropyrazole derivative in the examples is shown. Figure 2 The 1H NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4a) prepared in Example 1; Figure 3 The carbon NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4a) prepared in Example 1; Figure 4 The 1H NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4b) prepared in Example 2; Figure 5 The carbon NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4b) prepared in Example 2; Figure 6 The 1H NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4c) prepared in Example 3; Figure 7 The carbon NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4c) prepared in Example 3; Figure 8 The 1H NMR spectrum of 1-(4-(((4-fluorophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4e) prepared in Example 5; Figure 9 The carbon NMR spectrum of 1-(4-(((4-fluorophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4e) prepared in Example 5; Figure 10 The 1H NMR spectrum of 1-(3-phenyl-4-(tortenylmethyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4f) prepared in Example 6; Figure 11The carbon NMR spectrum of 1-(3-phenyl-4-(tortenylmethyl)-4,5-dihydro-1H-pyrazol-1-yl) ethyl ketone (i.e., compound 4f) prepared in Example 6. Detailed Implementation

[0018] This invention provides a method for preparing a sulfonated dihydropyrazole derivative, comprising the following steps: Compound 1, compound 2, 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid, a copper-based catalyst, and an organic solvent were mixed and subjected to a sulfonation cyclization reaction to obtain the sulfonated dihydropyrazole derivative. Compound 1 has the structural formula shown in Formula I; Compound 2 has the structural formula shown in Formula II; The sulfonated dihydropyrazole derivative has the structural formula shown in Formula III: Formula I; Formula II; Formula III; The R 2 Including one of hydrogen, a first halogen, a first alkyl group, a first alkoxy group, and a heterocyclic group; R 1 It includes one of the following: second halogen, second alkyl, substituted alkyl, and second alkoxy.

[0019] In this invention, the substituents in the substituted alkyl group preferably include halogen or ester groups, and the alkyl group preferably includes methyl; The first halogen and the second halogen preferably independently comprise fluorine, chlorine, bromine or iodine; The first alkyl group and the second alkyl group preferably include methyl groups; The first alkoxy group and the second alkoxy group preferably include methoxy groups; The heterocyclic group preferably includes thiophene or pyridinium.

[0020] In this invention, compound 1 has any of the structural formulas shown in (1a) to (1d): .

[0021] In this invention, the molar ratio of the copper-based catalyst to compound 1 is 1:1 to 3, and in specific embodiments of this invention, it can be 1:1.5, 13:20, 1:1.8, 1:2, 1:2.5 or 1:2.8; the copper-based catalyst preferably includes one or more of copper chloride, copper bromide, copper trifluoromethanesulfonate and copper acetate.

[0022] In this invention, the molar ratio of 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid to compound 1 is 3~5:2, and in specific embodiments of this invention, it can be 3.2:2, 3.5:2, 3.6:2, 4:2, 4.2:2, 4.5:2 or 4.8:2.

[0023] In this invention, the molar ratio of compound 2 to compound 1 is 3~5:2, and in specific embodiments of this invention it can be 3.2:2, 3.5:2, 3.6:2, 4:2, 4.2:2, 4.5:2 or 4.8:2.

[0024] In this invention, the preferred molar ratio of compound 1 to the volume of the organic solvent is 1 mmol: 10 mL; the organic solvent preferably includes one or more of acetonitrile, dichloromethane, 1,2-dichloroethane, and tetrahydrofuran.

[0025] In this invention, the preferred temperature for the sulfonation cyclization reaction is 30-80°C, and the preferred time is 10-18 hours. In specific embodiments of this invention, the preferred temperature for the sulfonation cyclization reaction can be 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, or 75°C, and the preferred time can be 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, or 17 hours.

[0026] Following the sulfonation cyclization reaction, the present invention preferably further includes: cooling the system obtained from the sulfonation cyclization reaction to room temperature, mixing it with saturated brine, extracting it with ethyl acetate, and then drying the obtained organic phase with a solid desiccant to obtain a dried organic phase; removing the solvent from the dried organic phase to obtain a crude product; and separating and purifying the crude product by column chromatography.

[0027] In this invention, the solvent used for column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 1 to 5:1. In specific embodiments of this invention, it can be 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1 or 4.5:1.

[0028] The following detailed description of the preparation method of the sulfonated dihydropyrazole derivative provided by the present invention, with reference to the embodiments, should not be construed as limiting the scope of protection of the present invention.

[0029] Figure 1 The example shows the synthetic route of the sulfonated dihydropyrazole derivative.

[0030] Example 1 The specific synthetic route for preparing 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone, i.e., compound 4a, is as follows: Under N2 conditions, (E)-N-allyl-N'-benzylacetylhydrazine 1a (0.4 mmol, 80.9 mg), 4-bromophenyldiazotetrafluoroborate (1 mmol, 270.82 mg), DABSO (0.6 mmol, 144 mg), Cu(OAc)₂ (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC). Copper ions were washed away and the emulsion was demulsified with 6 mL of saturated brine, and the mixture was extracted with ethyl acetate (8 mL × 3). The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4a (121.8 mg, yield 72.9%). Its NMR spectrum and mass spectrometry results are as follows: Figure 2 and Figure 3 As shown.

[0031] Figure 2 The 1H NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4a) prepared in Example 1; Figure 3 The carbon NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4a) prepared in Example 1.

[0032] 1 H NMR (500 MHz, CDCl3) δ 7.86 – 7.67 (m, 4H), 7.61 (dq, J = 4.6, 2.7Hz, 2H), 7.42 (dt, J = 5.7, 2.9 Hz, 3H), 4.21 (ddt, J = 13.6, 10.3, 2.9 Hz, 2H), 4.04 (dd, J = 13.0, 10.9 Hz, 1H), 3.34 (dd, J = 14.3, 1.5 Hz, 1H), 3.23– 3.04 (m, 1H), 2.35 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.48, 154.08, 137.94, 133.02, 130.60, 129.85, 129.56, 129.26, 129.21, 126.59, 57.54, 50.46, 38.59, 21.38. Example 2 The specific synthetic route for preparing 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone, i.e., compound 4b, is as follows: Under N2 conditions, (E)-N-allyl-N'-(4-fluorobenzylimine)acetylhydrazine 1b (0.4 mmol, 88.1 mg), 4-bromophenyldiazotetrafluoroborate (1 mmol, 270.82 mg), DABSO (0.6 mmol, 144 mg), Cu(OAc)2 (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC), and 6 mL of saturated brine was added, followed by extraction with ethyl acetate (8 mL × 3). The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4b (135.3 mg, yield 77%). Its NMR spectrum and mass spectrometry results are as follows: Figure 4 and Figure 5 As shown.

[0033] Figure 4 The 1H NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4b) prepared in Example 2; Figure 5 The carbon NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4b) prepared in Example 2.

[0034] 1H NMR (500 MHz, CDCl3) δ 7.79 – 7.69 (m, 4H), 7.66 – 7.58 (m, 2H), 7.09 (t, J = 8.6 Hz, 2H), 4.25 – 4.13 (m, 2H), 4.10 – 3.94 (m, 1H), 3.28 (dd, J = 14.2, 1.4 Hz, 1H), 3.13 (dd, J = 14.4, 10.2 Hz, 1H), 2.32 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.50, 165.13, 163.12, 153.22, 137.95, 133.14, 130.01, 129.65, 128.80, 128.73, 125.66, 125.63, 116.62, 116.44, 57.58, 50.70, 38.71, 21.44 Example 3 The specific synthetic route for preparing 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone, i.e., compound 4c, is as follows: Under N2 conditions, (E)-N-allyl-N'-(4-methylstyryl)acetylhydrazine (0.4 mmol, 86.5 mg), 4-bromophenyldiazotetrafluoroborate (1 mmol, 270.82 mg), DABSO (0.6 mmol, 144 mg), Cu(OAc)₂ (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC). 6 mL of saturated brine was added, and the mixture was extracted with ethyl acetate (8 mL × 3). The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4c (114.9 mg, yield 66%). Its NMR and mass spectrometry results are shown below. Figure 6 and Figure 7 As shown.

[0035] Figure 6The 1H NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4c) prepared in Example 3; Figure 7 The carbon NMR spectrum of 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4c) prepared in Example 3.

[0036] 1 H NMR (500 MHz, CDCl3) δ 7.82 – 7.69 (m, 4H), 7.54 – 7.40 (m, 2H), 7.22 (d, J = 7.9 Hz, 2H), 4.27 – 4.12 (m, 2H), 4.09 – 3.97 (m, 1H), 3.33 (dd, J = 14.2, 1.4 Hz, 1H), 3.10 (dd, J = 14.3, 10.3 Hz, 1H), 2.37 (d, J = 15.1Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 169.44, 154.22, 141.10, 137.96, 133.01, 129.92, 129.84, 129.56, 126.57, 126.41, 57.62, 50.36, 38.62, 21.41, 21.39. Example 4 The specific synthetic route for preparing 1-(4-(((4-bromophenyl)sulfonyl)methyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-yl)acetyl, i.e., compound 4d, is as follows: Under N2 conditions, (E)-N-allyl-N'-(4-methoxybenzylimine)acetylhydrazine (0.4 mmol, 92.9 mg), 4-bromophenyldiazotetrafluoroborate (1 mmol, 270.82 mg), DABSO (0.6 mmol, 144 mg), Cu(OAc)₂ (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC), and 6 mL of saturated brine was added, followed by extraction with ethyl acetate (8 mL × 3). The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4d (110.1 mg, yield 61%).

[0037] 1 H NMR (500 MHz, CDCl3) δ 7.79 – 7.68 (m, 4H), 7.58 – 7.51 (m, 2H), 6.94 – 6.88 (m, 2H), 4.19 – 4.11 (m, 2H), 4.02 – 3.92 (m, 1H), 3.83 (s, 3H), 3.32 (dd, J = 14.2, 1.5 Hz, 1H), 3.11 (dd, J = 14.3, 10.2 Hz, 1H), 2.33 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.29, 161.60, 153.98, 137.98, 133.00, 129.80, 129.55, 128.23, 121.69, 114.71, 57.69, 55.42, 50.35, 38.66, 21.35. Example 5 The specific synthetic route for preparing 1-(4-(((4-fluorophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone, i.e., compound 4e, is as follows: Under N2 conditions, (E)-N-allyl-N'-benzylacetylhydrazine 1a (0.4 mmol, 80.9 mg), 4-fluorophenyldiazotetrafluoroborate (1 mmol, 209.9 mg), DABSO (0.6 mmol, 144 mg), Cu(OAc)2 (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC). 6 mL of saturated brine was added, and the mixture was extracted with ethyl acetate (8 mL × 3). The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4e (105.23 mg, yield 73%). Its NMR and mass spectrometry results are shown below. Figure 8 and Figure 9 As shown.

[0038] Figure 8 The 1H NMR spectrum of 1-(4-(((4-fluorophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4e) prepared in Example 5; Figure 9 The carbon NMR spectrum of 1-(4-(((4-fluorophenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4e) prepared in Example 5.

[0039] 1 H NMR (500 MHz, CDCl3) δ 7.99 – 7.91 (m, 2H), 7.63 (dq, J = 6.8, 2.7Hz, 2H), 7.42 (dd, J = 5.3, 2.0 Hz, 3H), 7.31 – 7.22 (m, 2H), 4.26 – 4.13 (m, 2H), 4.03 (dd, J = 12.8, 10.7 Hz, 1H), 3.36 (dd, J = 14.3, 1.5 Hz, 1H), 3.14 (dd, J = 14.3, 10.6 Hz, 1H), 2.36 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.44, 167.21, 165.16, 154.15, 135.04, 135.01, 131.05, 130.98, 130.57, 129.30, 129.19, 126.60, 117.12, 116.94, 57.67, 50.44, 38.69, 21.35. Example 6 The specific synthetic route for preparing 1-(3-phenyl-4-(tortenylmethyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone, i.e., compound 4f, is as follows: Under N2 conditions, (E)-N-allyl-N'-benzylacetylhydrazine 1a (0.4 mmol, 80.9 mg), 4-tolyldiazotetrafluoroborate (1 mmol, 205.95 mg), DABSO (0.6 mmol, 144 mg), Cu(OAc)2 (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC). 6 mL of saturated brine was added, and the mixture was extracted with ethyl acetate (8 mL × 3). The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4e (101.2 mg, yield 71%). Its NMR and mass spectrometry results are shown below. Figure 10 and Figure 11 As shown.

[0040] Figure 10 The 1H NMR spectrum of 1-(3-phenyl-4-(tortenylmethyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone (i.e., compound 4f) prepared in Example 6; Figure 11 The carbon NMR spectrum of 1-(3-phenyl-4-(tortenylmethyl)-4,5-dihydro-1H-pyrazol-1-yl) ethyl ketone (i.e., compound 4f) prepared in Example 6.

[0041] 1H NMR (500 MHz, CDCl3) δ 7.90 – 7.72 (m, 2H), 7.71 – 7.53 (m, 2H), 7.40 (ddd, J = 11.3, 5.9, 2.8 Hz, 5H), 4.17 (tdd, J = 10.7, 4.4, 1.5 Hz, 1H), 4.08 (dd, J = 12.9, 4.3 Hz, 1H), 3.98 (dd, J = 12.9, 10.7 Hz, 1H), 3.34 (dd, J = 14.4, 1.6 Hz, 1H), 3.09 (dd, J = 14.4, 10.7 Hz, 1H), 2.46 (s, 3H), 2.34 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.42, 154.42, 145.57, 135.93, 130.50, 130.29, 129.34, 129.15, 128.11, 126.65, 57.72, 50.48, 38.93, 21.63, 21.37. Example 7 4g of 1-(3-phenyl-4-(((4-(trifluoromethyl)phenyl)sulfonyl)methyl)-4,5-dihydro-1H-pyrazol-1-yl)acetone was prepared via the following synthetic route: Under N2 conditions, (E)-N-allyl-N'-benzylacetylhydrazine 1a (0.4 mmol, 80.9 mg), 4-trifluoromethylphenyldiazotetrafluoroborate (1 mmol, 259.9 mg), DABSO (0.6 mmol, 144 mg), Cu(OAc)2 (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC), and 6 mL of saturated brine was added, followed by extraction with ethyl acetate (8 mL × 3). The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4 g (129.6 mg, yield 79%).

[0042] 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.3Hz, 2H), 7.65 – 7.55 (m, 2H), 7.48 – 7.36 (m, 3H), 4.34 – 4.22 (m, 2H), 4.14– 4.02 (m, 1H), 3.36 (dd, J = 14.1, 1.5 Hz, 1H), 3.27 – 3.08 (m, 1H), 2.36 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.51, 153.89, 142.53, 136.25, 135.99, 130.63, 129.22, 128.74, 126.83, 126.80, 126.77, 126.74, 126.55, 124.04, 121.87, 57.36, 50.45, 38.35, 21.35. Example 8 The specific synthetic route for preparing 1-(4-(((4-methoxyphenyl)sulfonyl)methyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)acetone, i.e., compound 4h, is as follows: Under N2 conditions, (E)-N-allyl-N'-benzylacetylhydrazine 1a (0.4 mmol, 80.9 mg), 4-methoxyphenyldiazotetrafluoroborate (1 mmol, 259.9 mg), 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid (0.6 mmol, 144 mg), Cu(OAc)2 (0.25 mmol, 45.4 mg), and DCE (4 mL) were added sequentially to a 25 mL Schlenk tube fitted with a stir bar. The reaction mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the reaction was detected by column chromatography (TLC), and the mixture was extracted with ethyl acetate (8 mL × 3) after adding 6 mL of saturated brine. The combined organic extract was dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure to obtain the crude product, which was then rapidly separated and purified by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain the target product, compound 4h (111.7 mg, yield 75%).

[0043] 1H NMR (500 MHz, CDCl3) δ 7.89 – 7.78 (m, 2H), 7.66 – 7.57 (m, 2H), 7.47 – 7.35 (m, 3H), 7.07 – 7.01 (m, 2H), 4.17 (tdd, J = 10.7, 4.3, 1.5 Hz, 1H), 4.08 (dd, J = 12.8, 4.3 Hz, 1H), 3.98 (dd, J = 12.9, 10.7 Hz, 1H), 3.89 (s, 3H), 3.34 (dd, J = 14.4, 1.5 Hz, 1H), 3.08 (dd, J = 14.4, 10.7 Hz, 1H), 2.34 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.42, 164.34, 154.47, 130.49, 130.29, 129.37, 129.14, 126.66, 114.90, 57.90, 55.77, 50.49, 39.05, 21.35.

[0044] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a sulfonated dihydropyrazole derivative, characterized in that, Includes the following steps: Compound 1, compound 2, 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid, a copper-based catalyst, and an organic solvent were mixed and subjected to a sulfonation cyclization reaction to obtain the sulfonated dihydropyrazole derivative. Compound 1 has the structural formula shown in Formula I; Compound 2 has the structural formula shown in Formula II; The sulfonated dihydropyrazole derivative has the structural formula shown in Formula III: Formula I; Formula II; Formula III; The R 2 Including one of hydrogen, a first halogen, a first alkyl group, a first alkoxy group, and a heterocyclic group; R 1 It includes one of the following: second halogen, second alkyl, substituted alkyl, and second alkoxy.

2. The preparation method according to claim 1, characterized in that, The substituents in the substituted alkyl group include halogen or ester groups, and the alkyl group includes methyl; The first halogen and the second halogen independently include fluorine, chlorine, bromine or iodine; The first alkyl group and the second alkyl group include methyl groups; The first alkoxy group and the second alkoxy group include methoxy groups; The heterocyclic group includes thiophene or pyridinium.

3. The preparation method according to claim 1, characterized in that, Compound 1 has any of the structural formulas shown in (1a) to (1d): 。 4. The preparation method according to claim 1, characterized in that, The molar ratio of the copper-based catalyst to compound 1 is 1:1~3.

5. The preparation method according to claim 1 or 4, characterized in that, The copper-based catalyst includes one or more of copper chloride, copper bromide, copper trifluoromethanesulfonate, and copper acetate.

6. The preparation method according to claim 1, characterized in that, The molar ratio of 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid to compound 1 is 3~5:

2.

7. The preparation method according to claim 1, characterized in that, The molar ratio of compound 2 to compound 1 is 3~5:

2.

8. The preparation method according to claim 1, characterized in that, The molar ratio of compound 1 to the volume of the organic solvent is 1 mmol: 10 mL; the organic solvent includes one or more of acetonitrile, dichloromethane, 1,2-dichloroethane, and tetrahydrofuran.

9. The preparation method according to claim 1, characterized in that, The sulfonation cyclization reaction is carried out at a temperature of 30~80℃ for 10~18h.

10. The preparation method according to claim 1, characterized in that, After the sulfonation cyclization reaction, the present invention further includes: cooling the system obtained from the sulfonation cyclization reaction to room temperature and mixing it with saturated brine, then extracting it with ethyl acetate, and then drying the obtained organic phase with a solid desiccant to obtain a dried organic phase; removing the solvent from the dried organic phase to obtain a crude product; and separating and purifying the crude product by column chromatography.

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