Sulfonyl pyridazinone compound as well as preparation method and application thereof

Abstract

The invention discloses a sulfonyl pyridazinone compound as well as a preparation method and application thereof, and the compound is characterized in that sulfonyl is introduced into 4-position C of pyridazine-3 (2H) ketone, so that the compound has multiple functional groups such as sulfonyl, phenyl and pyridazinone. The sulfonyl pyridazinone compound disclosed by the invention has a certain antibacterial effect on escherichia coli / staphylococcus aureus, and can be used for preparing broad-spectrum antibacterial drugs. Due to the characteristic of multiple flame-retardant functional groups, the compound is expected to be applied to the field of flame retardance. The invention also provides a preparation method of the sulfonyl pyridazinone compound, the preparation method is realized through a dehalogenation sulfonylation reaction of 4, 5-dihalo-2-phenylpyridazine-3 (2H) ketone and sulfonyl hydrazine, the reaction process does not have transition metal catalysis and does not need to add an oxidizing agent or a reducing agent, and the preparation method also has the characteristics of simple reaction system, wide substrate application range and relatively high yield, and is suitable for industrial production. The industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a sulfonyl pyridazinone compound and a preparation method and application thereof. Background Art

[0002] The pyridazine ring is a special six-membered heterocyclic ring containing two adjacent nitrogen atoms, which is widely present in natural products and drug molecules. Compounds containing pyridazine ring structures usually have excellent biological activities and are also widely used in various functional materials, such as fluorescent probes and high-energy materials. Among them, pyridazine-3(2H)one is one of the important subtypes of this type of heterocyclic compound, which is widely present in various drug molecules and has anti-inflammatory, anticancer, antibacterial and other biological activities.

[0003] At the same time, since there are multiple reaction sites on the structure of pyridazin-3(2H)one that are prone to functionalization, this compound is also an important synthon in organic synthesis. In recent years, functionalization reactions of pyridazin-3(2H)one compounds have been reported continuously. The most common ones are electrophilic substitution reactions at the 2-position N or nucleophilic substitution reactions at the 5-position C (reaction formula (a)).

[0004] In contrast, due to the low activity of the 4-position C of pyridazin-3(2H)one, there are few reports on functionalization reactions at this position, and progress has been slow. Moreover, in early studies on the functionalization of the 4-position C, it is usually necessary to functionalize the 5-position C first, and then introduce a new functional group on the basis of compound A to obtain compound B (reaction formula (b)) in the following two ways: (1) coupling reaction under the action of a metal catalyst or metal reagent; (2) nucleophilic reaction with nitrogen-, oxygen- or sulfur-containing reagents. Although these methods are of great significance for the synthesis and modification of pyridazin-3(2H)one functional molecules, the use of transition metal catalysts, reducing agents, and harsh conditions need to be solved.

[0005]

[0006] On the other hand, sulfonyl (sulfone) is a common functional group, which exists in various natural products and drug molecules. Sulfonyl can effectively change the water solubility, acidity, polarity and other properties of the molecule, thereby regulating the activity of the drug molecule. Therefore, sulfonylation reaction is of great significance in the fields of synthetic chemistry and medicinal chemistry. However, there are few reports on the introduction of sulfonyl at the 4-C of pyridazine-3 (2H) ketone. The current few studies can only be synthesized by a two-step method, and the substrate range is limited. Therefore, it is necessary to develop a sulfonyl pyridazine-3 (2H) ketone with new functionalization and a preparation method thereof. Summary of the invention

[0007] In order to overcome the problems existing in the above-mentioned prior art, one of the purposes of the present invention is to provide a sulfonyl pyridazinone compound. The second purpose of the present invention is to provide a method for preparing the above-mentioned sulfonyl pyridazinone compound. The third and fourth purposes of the present invention are to provide the application of the above-mentioned sulfonyl pyridazinone compound.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is:

[0009] The first aspect of the present invention provides a sulfonyl pyridazinone compound, the general structural formula of the sulfonyl pyridazinone compound is shown in formula (I):

[0010]

[0011] Wherein, R is selected from substituted or unsubstituted aryl; the substituted aryl is monosubstituted or polysubstituted; the substituents on the substituted aryl are selected from nitro, trifluoromethyl, halogen, cyano, amine, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl or C1-C4 alkoxy.

[0012] Preferably, R is selected from one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methylphenyl, 2-thienyl, 2-naphthyl and 3-pyridyl.

[0013] The second aspect of the present invention provides a method for preparing the sulfonyl pyridazinone compound of the first aspect, comprising the following steps: in the presence of an aromatic heterocyclic organic base and a quaternary ammonium salt tetrabutylammonium iodide, 4,5-dihalo-2-phenylpyridazin-3(2H)-one Sulfonyl hydrazide Carrying out a reaction to obtain the sulfonyl pyridazinone compound;

[0014] Wherein, X is a halogen.

[0015] Preferably, X is Cl or Br.

[0016] Preferably, R in the sulfonyl hydrazide is selected from one of 4-phenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methylphenyl, 2-thienyl, 2-naphthyl and 3-pyridyl.

[0017] Preferably, the molar ratio of the 4,5-dihalo-2-phenylpyridazin-3(2H)one to the sulfonylhydrazide is 1:(2-3).

[0018] More preferably, the molar ratio of the 4,5-dihalo-2-phenylpyridazin-3(2H)one to sulfonylhydrazide is 1:(2.2-2.6).

[0019] Preferably, the molar ratio of the 4,5-dihalo-2-phenylpyridazin-3(2H)one to the aromatic heterocyclic organic base is 1:(3-5).

[0020] Preferably, the molar ratio of the 4,5-dihalo-2-phenylpyridazin-3(2H)one to the quaternary ammonium salt is 1:(0.1-0.5).

[0021] Preferably, the aromatic heterocyclic organic base is selected from 4-dimethylaminopyridine or 2-methylimidazole.

[0022] Preferably, the quaternary ammonium salt is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide and benzyltriethylammonium chloride.

[0023] Preferably, the reaction temperature is 50-70°C.

[0024] More preferably, the reaction temperature is 50-70°C.

[0025] Preferably, the reaction time is 7-10 hours.

[0026] More preferably, the reaction time is 7.5-8.5 h.

[0027] Preferably, the reaction is carried out in a solvent consisting of an aprotic polar solvent and water;

[0028] More preferably, the aprotic polar solvent is at least one selected from acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and acetone.

[0029] More preferably, the volume ratio of the aprotic polar solvent to water is (8-12):1.

[0030] More preferably, the ratio of the amount of 4,5-dihalo-2-phenylpyridazin-3(2H)one to the solvent is 1 mmol:(5-20) mL.

[0031] More preferably, the method further comprises the following steps: after the reaction is completed, transferring the reaction mixture to a separatory funnel for separation, extracting the aqueous phase with dichloromethane, combining the organic phases, washing with a saturated sodium chloride solution, and then drying the organic phase with anhydrous sodium sulfate and concentrating under reduced pressure, and separating by column chromatography to obtain the sulfonyl pyridazinone compound.

[0032] The third aspect of the present invention provides the use of the sulfonyl pyridazinone compound of the first aspect in the preparation of antibacterial drugs.

[0033] Preferably, the sulfonyl pyridazinone compound is used in the preparation of an anti-Escherichia coli drug.

[0034] Preferably, the sulfonyl pyridazinone compound is used in the preparation of an anti-Staphylococcus aureus drug.

[0035] The fourth aspect of the present invention provides use of the sulfonyl pyridazinone compound of the first aspect in the preparation of a flame retardant.

[0036] The beneficial effects of the present invention are:

[0037] (1) The present invention provides a sulfonyl pyridazinone compound, wherein a sulfonyl group is introduced into the 4-C of pyridazin-3(2H)one, so that the compound has multiple functional groups such as sulfone group, phenyl group, pyridazinone, etc. The sulfonyl pyridazinone compound of the present invention has a certain antibacterial effect on Escherichia coli / Staphylococcus aureus, and can be used to prepare a broad-spectrum antibacterial drug. In addition, the pyridazinone compound with an aromatic ring structure is an important flame retardant, and the sulfone group structure is also an important structural unit in the flame retardant. Therefore, the sulfonyl pyridazinone compound of the present invention is expected to have important applications in the fields of medicine, flame retardants, etc.

[0038] (2) The present invention also provides a method for preparing the above-mentioned sulfonyl pyridazinone compounds, which is achieved by the dehalogenation sulfonylation reaction of 4,5-dihalo-2-phenylpyridazin-3 (2H) ketone and sulfonylhydrazine at the C-4 site. The reaction process is not only transition metal-free, does not require the addition of oxidants or reductants, is green and efficient, and conforms to the development of green synthetic chemistry, but also has the characteristics of a simple reaction system, a wide range of substrate applications, and a high yield, which is conducive to industrial production. Since the C-4 position activity of pyridazin-3 (2H) ketone is relatively low, it is difficult to carry out functionalization reactions (especially sulfonylation reactions) at this position. The present invention adopts a one-step method to prepare the above-mentioned sulfonyl pyridazinone compounds. Therefore, the preparation method of the present invention is of great significance for expanding the synthesis range of functionalized pyridazin-3 (2H) ketones, especially for constructing sulfonylation reactions of CS bonds. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is the X-ray single crystal diffraction pattern of Compound 1 of Example 1. DETAILED DESCRIPTION

[0040] The present invention is further described in detail below through specific examples. The raw materials used in the following examples, unless otherwise specified, can be obtained from conventional commercial sources or prepared and separated by simple synthesis; the processes used, unless otherwise specified, are conventional processes in the art.

[0041] Example 1

[0042] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0043] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1339g) 4-methylbenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 1 as a white solid (0.0734g, 75%).

[0044] The structural formula and relevant characterization data of compound 1 are shown below:

[0045]

[0046] 1 H NMR (600MHz, CDCl3), δ, ppm: 2.43 (s, 3H, CH3-15), 7.35 (d, J = 7.8Hz, 2H, ArH-13, 16), 7.40 (t, J = 7.8Hz, 1H, ArH-1), 7.44-7.47 (m, 2H, Ar H-2,3),7.54(d,J=7.8Hz,2H,ArH-12,17),8.04(d,J=8.4Hz,2H,ArH-4,5),8.12(d,J=4.2Hz,1H,ArH-8);8.18(d,J=3.6Hz,1H,ArH-7);

[0047] 13C NMR (150MHz, CDCl3), δ, ppm: 21.8 (C-15), 125.3 (C-4,5), 128.9 (C-12,17), 129.0 (C-1), 129.7 (C-2,3), 129. 9(C-13,16),131.9(C-7),134.8(C-8),135.3(C-11),140.5(C-14),140.8(C-6),145.7(C-9),154.9(C-10);

[0048] ESI-HRMS, m / z: Calcd for C 17 H 15 N2O3S[M+H] + :327.0798,Found:327.0793.

[0049] The X-ray single crystal diffraction pattern of compound 1 is shown in the attached figure. Figure 1 shown.

[0050] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, high-resolution mass spectrometry and single crystal X-ray diffraction showed that the structure of compound 1 was consistent with expectations.

[0051] Example 2

[0052] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0053] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)one, 0.72mmol (0.1368g) 4-fluorobenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 2 as a white solid (0.0525g, 53%).

[0054] The structural formula and relevant characterization data of compound 2 are shown below:

[0055]

[0056] 1H NMR (600MHz, CDCl3), δ, ppm: 7.19-7.22(m,2H,ArH-2,3),7.40(t,J=7.8Hz,2H,ArH-1),7.44-7.47(m,2H,ArH-13,15),7. 51(d,J=7.8Hz,2H,ArH-4,5),8.13(d,J=4.2Hz,1H,ArH-8),8.16(d,J=3.6Hz,1H,ArH-7),8.17-8.20(m,2H,ArH-12,16);

[0057] 13 C NMR(150MHz, CDCl3), δ, ppm: 116.5(d,J=22.5Hz,C-13,15),125.4(C-4,5),129.1(C-2,3),129.2(C-1),132.2(C-6),133.2(d,J =10.5Hz,C-12,16),133.7(C-7),133.8(C-8),135.4(C-9),140.5(d,J=6.0Hz,C-11),155.0(C-10),166.5(d,J=256.5Hz,C-14);

[0058] 19 F NMR (564MHz, CDCl3), δ, ppm: -101.9;

[0059] ESI-HRMS, m / z: Calcd for C 16 H 12 FN2O3S,[M+H] + :331.0547,Found:331.0537.

[0060] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, fluorine nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 2 was consistent with expectations.

[0061] Example 3

[0062] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0063] The preparation method is as follows: 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3 (2H) ketone, 0.72mmol (0.1483g) 4-chlorobenzenesulfonyl hydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide were added to a Schlenk tube and dissolved in 2mL acetonitrile and 0.2mL water, and stirred at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 3 as a white solid (0.0571g, 55%).

[0064] The structural formula and relevant characterization data of compound 3 are shown below:

[0065]

[0066] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.41 (t, J = 7.2Hz, 1H, ArH-1), 7.44-7.47 (m, 2H, ArH-2, 3), 7.50-7.53 (m, 4H, ArH -12,13,15,16),8.09(d,J=8.4Hz,2H,ArH-4,5),8.13(d,J=4.2Hz,1H,ArH-8),8.16(d,J=4.2Hz,1H,ArH-7);

[0067] 13 C NMR(150MHz, CDCl3), δ, ppm: 125.3(C-4,5),129.1(C-2,3),129.3(C-1),129.5(C-12,16),131.6(C-13,15),132 .3(C-7),135.4(C-8),136.3(C-14),140.3(C-6),140.5(C-11),141.5(C-9),155.0(C-10); ESI-HRMS,m / z:Calcd for C 16 H 12 ClN2O3S,[M+H] + :347.0252,Found:347.0242.

[0068] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 3 was consistent with expectations.

[0069] Example 4

[0070] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0071] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1729g) 4-trifluoromethylbenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 4 as a white solid (0.0570g, 50%).

[0072] The structural formula and relevant characterization data of compound 4 are shown below:

[0073]

[0074] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.41 (t, J=7.2Hz, 1H, ArH-1), 7.44-7.47 (m, 2H, ArH-2,3), 7.51 (d, J=8.4Hz, 2H, ArH-4,5), 7.80 (d,J=8.4Hz,2H,ArH-12,17),8.16(d,J=4.2Hz,1H,ArH-8),8.20(d,J=4.2Hz,1H,ArH-7),8.29(d,J=8.4Hz,2H,ArH-13,16);

[0075] 13 C NMR (150MHz, CDCl3), δ, ppm: 123.2 (q, J=271.5Hz, C-15), 125.3 (C-4,5), 126.2 (q, J=3.0Hz, C-13,16), 129.1 (C-12,17), 129.3 (C -1),130.7(C-2,3),132.7(C-7),135.4(C-8),136.0(q,J=31.5Hz,C-14),139.8(C-6),140.4(C-11),141.4(C-9),154.9(C-10);

[0076] 19 F NMR (564MHz, CDCl3), δ, ppm: -63.3;

[0077] ESI-HRMS, m / z: Calcd for C 17 H 12 F3N2O3S,[M+H] + :381.0515,Found:381.0504.

[0078] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, fluorine nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 4 was consistent with expectations.

[0079] Example 5

[0080] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0081] In a Schlenk tube, 0.3 mmol (0.099 g) of 4,5-dibromo-2-phenylpyridazine-3 (2H) ketone, 0.72 mmol (0.1483 g) of 3-chlorobenzenesulfonyl hydrazide, 1.2 mmol (0.1464 g) of 4-dimethylaminopyridine and 0.009 mmol (0.0033 g) of tetrabutylammonium iodide were dissolved in 2 mL of acetonitrile and 0.2 mL of water, and stirred at 60 ° C for 8 h. After the reaction was completed, the reaction solution was completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 5 as a white solid (0.0508 g, 49%).

[0082] The structural formula and relevant characterization data of compound 5 are shown below:

[0083]

[0084] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.41 (t, J=7.8Hz, 1H, ArH-1), 7.44-7.50 (m, 3H, ArH-2, 3, 15), 7.52 (d, J=7.8Hz, 2H, ArH-4, 5), 7.61 (d, J =7.8Hz,1H,ArH-14),8.06(s,1H,ArH-12),8.09(d,J=8.4Hz,1H,ArH-16),8.14(d,J=4.2Hz,1H,ArH-8),8.17(d,J=4.2Hz,1H,ArH-7);

[0085] 13C NMR(150MHz, CDCl3), δ, ppm: 125.3(C-4,5),128.5(C-16),129.1(C-2,3),129.3(C-12),129.6(C-1),130.4(C-1 5),132.6(C-14),134.7(C-13),135.2(C-7),135.4(C-8),139.7(C-6),140.0(C-11),140.5(C-9),154.9(C-10);

[0086] ESI-HRMS, m / z: Calcd for C 16 H 12 ClN2O3S,[M+H] + :347.0252,Found:347.0242.

[0087] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 5 was consistent with expectations.

[0088] Example 6

[0089] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0090] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1454g) 4-methoxybenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand to separate. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 6 as a white solid (0.0841g, 82%).

[0091] The structural formula and relevant characterization data of compound 6 are shown below:

[0092]

[0093] 1H NMR (600MHz, CDCl3), δ, ppm: 3.85 (s, 3H, OCH3-1), 6.98 (d, J = 7.8Hz, 2H, ArH-13, 16), 7.39 (t, J = 7.2Hz, 1H, ArH-1), 7.43-7.46 (m, 2H, Ar H-2,3),7.52(d,J=7.8Hz,2H,ArH-12,17),8.08(d,J=8.4Hz,2H,ArH-4,5),8.10(d,J=3.6Hz,1H,ArH-8),8.14(d,J=4.2Hz,1H,ArH-7);

[0094] 13 C NMR(150MHz,CDCl3),δ,ppm:55.8(C-15),114.4(C-13,16),125.4(C-4,5),129.0(C-2,3),129.1(C-1, 11),131.6(C-7),132.5(C-12,17),135.5(C-8),140.7(C-6),141.2(C-9),155.1(C-11),164.6(C-10);

[0095] ESI-HRMS, m / z: Calcd for C 17 H 15 N2O4S[M+H] + :343.0747,Found:343.0742.

[0096] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 6 was consistent with expectations.

[0097] Example 7

[0098] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0099] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)one, 0.72mmol (0.1440g) 4-ethylbenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 7 as a white solid (0.0663g, 82%).

[0100] The structural formula and relevant characterization data of compound 7 are shown below:

[0101]

[0102] 1 H NMR (600MHz, CDCl3), δ, ppm: 1.23 (t, J = 7.8Hz, 3H, CH3-16), 2.70 (q, J = 7.8Hz, 2H, CH2-15), 7.35 (d, J = 8.4Hz, 2H, ArH-13, 17), 7.38 (t, J = 7.8Hz, 1H, ArH-1), 7.42-7.45(m,2H,ArH-2,3),7.52(d,J=8.4Hz,2H,ArH-12,18),8.05(d,J=8.4 Hz,2H,ArH-4,5),8.10(d,J=3.6Hz,1H,ArH-8),8.16(d,J=4.2Hz,1H,ArH-7);

[0103] 13 C NMR (150MHz, CDCl3), δ, ppm: 15.7 (C-16), 29.1 (C-15), 125.4 (C-4,5), 128.6 (C-12,18), 129.0 (C-13,17), 129.1 (C -1),130.1(C-2,3),132.0(C-7),135.0(C-11),135.4(C-8),140.6(C-6),140.8(C-9),151.8(C-14),155.0(C-10);

[0104] ESI-HRMS, m / z: Calcd for C 18 H 17 N2O3S[M+H] + :341.0954,Found:341.0945.

[0105] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 7 was consistent with expectations.

[0106] Example 8

[0107] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0108] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)one, 0.72mmol (0.1641g) 4-tert-butylbenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 8 as a white solid (0.0740g, 67%).

[0109] The structural formula and relevant characterization data of compound 8 are shown below:

[0110]

[0111] 1 H NMR (600MHz, CDCl3), δ, ppm: 1.31 (s, 9H, CH3-16, 17, 18), 7.39 (t, J = 7.2Hz, 1H, ArH-1), 7.43-7.45 (m, 2H, ArH-2, 3), 7.52-7 .55(m,4H,ArH-4,5,13,19),8.06(d,J=9.0Hz,2H,ArH-12,20),8.11(d,J=4.2Hz,1H,ArH-8),8.16(d,J=4.2Hz,1H,ArH-7);

[0112] 13 C NMR(150 MHz, CDCl3), δ, ppm: 31.1(C-16,17,18),35.4(C-15),125.4(C-4,5),126.2(C-13,19),129.0(C-12,20),129.1(C- 1),129.9(C-2,3),132.1(C-7),134.7(C-8),135.4(C-11),140.6(C-6),140.8(C-9),155.0(C-14),158.6(C-10);

[0113] ESI-HRMS, m / z: Calcd for C 20 H 21 N2O3S[M+H]+:369.1267,Found:369.1258.

[0114] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 8 was consistent with expectations.

[0115] Example 9

[0116] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0117] Add 0.3 mmol (0.099 g) of 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72 mmol (0.1238 g) of benzenesulfonyl hydrazide, 1.2 mmol (0.1464 g) of 4-dimethylaminopyridine and 0.009 mmol (0.0033 g) of tetrabutylammonium iodide to a Schlenk tube, dissolve in 2 mL of acetonitrile and 0.2 mL of water, and stir at 60°C for 8 h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 9 as a white solid (0.0599 g, 64%).

[0118] The structural formula and relevant characterization data of compound 9 are shown below:

[0119]

[0120] 1 H NMR (600 MHz, CDCl3), δ, ppm: 7.39 (t, J = 7.2 Hz, 1H, ArH-1), 7.42-7.45 (m, 2H, ArH-2, 3), 7.50-7.52 (m, 2H, ArH-13, 15), 7.54 (d, J = 8.4 Hz,2H,ArH-4,5),7.64(t,J=7.2Hz,1H,ArH-14),8.11(d,J=4.2 Hz,1H,ArH-8),8.15(d,J=7.2 Hz,2H,ArH-12,16),8.17(d,J=4.2 Hz,1H,ArH-7);

[0121] 13 C NMR(150 MHz, CDCl3), δ, ppm:125.3(C-4,5),128.9(C-12,16),129.0(C-2,3),129.1(C-1,14),130.0 (C-13,15),132.3(C-7),134.5(C-8),135.4(C-6),137.9(C-11),140.6(C-9),155.0(C-10);

[0122] ESI-HRMS, m / z: Calcd for C 16 H 13N2O3S[M+H]+:313.0641,Found:313.0636.

[0123] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 9 was consistent with expectations.

[0124] Example 10

[0125] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0126] Add 0.3 mmol (0.099 g) of 4,5-dibromo-2-phenylpyridazine-3 (2H) ketone, 0.72 mmol (0.1807 g) of 4-bromobenzenesulfonyl hydrazide, 1.2 mmol (0.1464 g) of 4-dimethylaminopyridine and 0.009 mmol (0.0033 g) of tetrabutylammonium iodide to a Schlenk tube, dissolve in 2 mL of acetonitrile and 0.2 mL of water, and stir at 60 ° C for 8 h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 10 as a white solid (0.0679 g, 58%).

[0127] The structural formula and relevant characterization data of compound 10 are shown below:

[0128]

[0129] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.41 (t, J=7.2Hz, 1H, ArH-1), 7.44-7.47 (m, 2H, ArH-2,3), 7.51 (d, J=7.8Hz, 2H, ArH-4,5), 7.67 (d,J=9.0Hz,2H,ArH-12,16),8.00(d,J=9.0Hz,2H,ArH-13,15),8.13(d,J=4.2Hz,1H,ArH-8),8.16(d,J=4.2Hz,1H,ArH-7);

[0130] 13C NMR (150MHz, CDCl3), δ, ppm: 125.3(C-4,5),129.1(C-2,3),129.3(C-1),130.3(C-14),131.6(C-12,1 6),132.3(C-7),132.4(C-13,15),135.4(C-8),136.8(C-6),140.3(C-11),140.5(C-9),154.9(C-10);

[0131] ESI-HRMS, m / z: Calcd for C 16 H 12 BrN2O3S,[M+H] + :390.9747,Found:390.9742.

[0132] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 10 was consistent with expectations.

[0133] Embodiment 11

[0134] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0135] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)one, 0.72mmol (0.2146g) 4-iodobenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 11 as a white solid (0.0815g, 62%).

[0136] The structural formula and relevant characterization data of compound 11 are shown below:

[0137]

[0138] 1H NMR (600MHz, CDCl3), δ, ppm: 7.40 (t, J=7.8Hz, 1H, ArH-1), 7.44-7.48 (m, 2H, ArH-2,3), 7.51 (d, J=7.8Hz, 2H, ArH-4,5), 7.84 (d,J=8.4Hz,2H,ArH-12,16),7.89(d,J=8.4Hz,2H,ArH-13,15),8.13(d,J=3.6Hz,1H,ArH-8),8.15(d,J=4.2Hz,1H,ArH-7);

[0139] 13 C NMR(150MHz,CDCl3),δ,ppm:103.2(C-14),125.3(C-4,5),129.1(C-2,3),129.2(C-1),131.3(C-12,1 6),132.3(C-7),135.4(C-8),137.5(C-6),138.4(C-13,15),140.2(C-11),140.5(C-9),154.9(C-10);

[0140] ESI-HRMS, m / z: Calcd for C 16 H 12 IN2O3S,[M+H] + :438.9608,Found:438.9596.

[0141] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 11 was consistent with expectations.

[0142] Example 12

[0143] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0144] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1562g) 4-nitrobenzenesulfonylhydrazine, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. After separation by column chromatography, compound 12 is obtained as a pink solid (0.0482g, 45%).

[0145] The structural formula and relevant characterization data of compound 12 are shown below:

[0146]

[0147] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.42 (t, J=7.2Hz, 1H, ArH-1), 7.44-7.47 (m, 2H, ArH-2.3), 7.50 (d, J=7.8Hz, 2H, ArH-4,5),8.18(d,J=4.2Hz,1H,ArH-8),8.21(d,J=4.2Hz,1H,ArH-7),8.33-8.37(m,4H,ArH-12,13,15,16);

[0148] 13 C NMR(150MHz, CDCl3), δ, ppm: 124.2(C-4,5),125.3(C-13,15),129.1(C-2,3),129.5(C-1),131.6(C-1 2,16),132.9(C-7),135.4(C-8),139.5(C-6),140.3(C-9),143.5(C-11),151.2(C-14),154.9(C-10);

[0149] ESI-HRMS, m / z: Calcd for C 16 H 12 N3O5S,[M+H] + :358.0492,Found:358.0480.

[0150] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 12 was consistent with expectations.

[0151] Embodiment 13

[0152] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0153] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1339g) 3-methylbenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 13 as a white solid (0.0606g, 62%).

[0154] The structural formula and relevant characterization data of compound 13 are shown below:

[0155]

[0156] 1 H NMR (600MHz, CDCl3), δ, ppm: 2.41 (s, 3H, CH3-1), 7.38 (t, J = 7.8Hz, 1H, ArH-1), 7.41-7.45 (m, 4H, ArH-2, 3, 15, 16), 7.52 (d, J = 7.8 Hz,2H,ArH-4,5),7.90(s,1H,ArH-12),7.95(d,J=7.2Hz,1H,ArH-17),8.11(d,J=4.2Hz,1H,ArH-8),8.17(d,J=3.6Hz,1H,ArH-7);

[0157] 13 C NMR(150MHz,CDCl3),δ,ppm:21.5(C-14),125.3(C-4,5),127.2(C-17),128.9(C-2,3),129.0(C-12),129.9(C-1) ,132.2(C-16),135.3(C-7),135.6(C-8),137.8(C-15),139.3(C-6),140.60(C-11),140.62(C-13),154.9(C-10);

[0158] ESI-HRMS, m / z: Calcd for C 17 H 15 N2O3S,[M+H] + :327.0798,Found:327.0788.

[0159] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 13 was consistent with expectations.

[0160] Embodiment 14

[0161] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0162] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1454g) 3-methoxybenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 14 as a white waxy solid (0.0718g, 70%).

[0163] The structural formula and relevant characterization data of compound 14 are shown below:

[0164]

[0165] 1 H NMR (600MHz, CDCl3), δ, ppm: 3.86 (s, 3H, OCH3-13), 7.40 (t, J = 7.8Hz, 1H, ArH-1), 7.42-7.46 (m, 4H, ArH-2, 3, 15, 16), 7.53 (d, J = 7. 8Hz,2H,ArH-4,5),7.64(s,1H,ArH-12),7.71(d,J=7.8Hz,1H,ArH-17),8.12(d,J=4.2Hz,1H,ArH-8),8.16(d,J=4.2Hz,1H,ArH-7);

[0166] 13 C NMR (150MHz, CDCl3), δ, ppm: 55.9 (C-13), 114.1 (C-12), 121.2 (C-15), 122.1 (C-17), 125.4 (C-4,5), 129.0 (C-2,3), 129 .2(C-1),130.2(C-16),132.3(C-7),135.3(C-8),139.1(C-9),140.5(C-6),140.6(C-11),155.0(C-14),159.8(C-10);

[0167] ESI-HRMS, m / z: Calcd for C 17 H 15 N2O4S,[M+H] + :343.0747,Found:343.0737.

[0168] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 14 was consistent with expectations.

[0169] Embodiment 15

[0170] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0171] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1368g) 3-fluorobenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 15 as a white solid (0.0505g, 70%).

[0172] The structural formula and relevant characterization data of compound 15 are shown below:

[0173]

[0174] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.33-7.36 (m, 1H, ArH-15), 7.41 (t, J=7.8Hz, 1H, ArH-1), 7.44-7.47 (m, 2H, ArH-2, 3), 7.51-7.54 (m, 3H, A rH-4,5,12),7.84(d,J=7.8Hz,1H,ArH-14),7.96(d,J=7.8Hz,1H,ArH-16),8.14(d,J=4.2Hz,1H,ArH-8),8.17(d,J=4.2Hz,1H,ArH-7);

[0175] 13C NMR (150MHz, CDCl3), δ, ppm: 117.3 (d, J=25.5Hz, C-12), 121.9 ((d, J=21.0H z,C-14),125.3(C-4,5),125.9(d,J=3.0Hz,C-16),129.1(C-2,3),129.3(C- 1),130.9(d,J=7.5Hz,C-15),132.6(C-7),135.4(C-8),139.4(d,J=6.0Hz, C-11),140.1(C-6),140.5(C-9),154.9(C-10),162.2(d,J=250.5Hz,C-13);

[0176] 19 F NMR (564MHz, CDCl3), δ, ppm: -109.3;

[0177] ESI-HRMS, m / z: Calcd for C 16 H 12 FN2O3S,[M+H] + :331.0547,Found:331.0537.

[0178] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, fluorine nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 15 was consistent with expectations.

[0179] Example 16

[0180] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0181] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1807g) 3-bromobenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 16 as a white solid (0.0620g, 53%).

[0182] The structural formula and relevant characterization data of compound 16 are shown below:

[0183]

[0184] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.39-7.43 (m, 2H, ArH-1,15), 7.44-7.47 (m, 2H, ArH-2, 3), 7.52 (d, J=8.4Hz, 2H, ArH-4, 5),7.76(d,J=7.8Hz,1H,ArH-16),8.13-8.15(m,2H,ArH-7,14),8.16(d,J=3.6Hz,1H,ArH-8),8.19(s,1H,ArH-12);

[0185] 13 C NMR(150MHz,CDCl3),δ,ppm:122.9(C-13),125.3(C-4,5),129.0(C-16),129.1(C-2,3),129.2(C-1),130.6(C-1 2),132.3(C-15),132.6(C-14),135.4(C-7),137.6(C-8),139.8(C-6),140.0(C-11),140.5(C-9),154.9(C-10);

[0186] ESI-HRMS, m / z: Calcd for C 16 H 12 BrN2O3S,[M+H] + :390.9747,Found:390.9734.

[0187] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 16 was consistent with expectations.

[0188] Embodiment 17

[0189] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0190] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1729g) 3-trifluoromethylbenzenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, the reaction solution is completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 17 as a white solid (0.0524g, 46%).

[0191] The structural formula and relevant characterization data of compound 17 are shown below:

[0192]

[0193] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.41 (t, J = 7.2Hz, 1H, ArH-1), 7.44-7.48 (m, 2H, ArH-2, 3), 7.52 (d, J = 7.8Hz, 2H, ArH-4, 5), 7.69-7.72 (m, 1H, ArH-16 ),7.91(d,J=7.8Hz,1H,ArH-17),8.16(d,J=4.2Hz,1H,ArH-8),8.21(d,J=4.2Hz,1H,ArH-7),8.30(s,1H,ArH-12),8.47(d,J=7.8Hz,1H,ArH-15);

[0194] 13 C NMR (150MHz, CDCl3), δ, ppm: 123.2 (q, J=271.5Hz, C-14), 125.3 (C-4,5), 126.6 (q, J=3.0Hz, C-12), 129.1 (C-2,3), 129.3 (C-1), 129.9 (C-16), 131 .2(q,J=4.5Hz,C-15),131.7(q,J=34.5Hz,C-13),132.7(C-7),134.1(C- 8),135.4(C-6),139.2(C-17),139.8(C-11),140.5(C-9),154.9(C-10);

[0195] 19 F NMR (564MHz, CDCl3), δ, ppm: -62.7;

[0196] ESI-HRMS, m / z: Calcd for C 17 H 12 F3N2O3S,[M+H] + :381.0515,Found:381.0511.

[0197] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, fluorine nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 17 was consistent with expectations.

[0198] Embodiment 18

[0199] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0200] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)-one, 0.72mmol (0.1282g) 2-thienylsulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand for stratification. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. After separation by column chromatography, compound 18 is obtained as a white waxy solid (0.0506g, 53%).

[0201] The structural formula and relevant characterization data of compound 18 are shown below:

[0202]

[0203] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.12-7.14 (m, 1H, ArH-13), 7.41 (t, J=7.2Hz, 1H, ArH-1), 7.56 (d, J=7.2Hz, 2H, ArH-4,5),7.75(d,J=3.6Hz,1H,ArH-12),8.06(d,J=3.6Hz,1H,ArH-14),8.11-8.13(m,2H,ArH-7,8);

[0204] 13 C NMR (150MHz, CDCl3), δ, ppm: 125.3 (C-4,5), 128.1 (C-14), 128.9 (C-2,3), 129.1 (C-11), 131. 6(C-12,13),135.4(C-1),136.1(C-7),137.5(C-8),140.4(C-6),140.5(C-9),154.9(C-10);

[0205] ESI-HRMS, m / z: Calcd for C 14 H 11 N2O3S2,[M+H] + :319.0206,Found:319.0196.

[0206] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 18 was consistent with expectations.

[0207] Embodiment 19

[0208] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0209] Add 0.3mmol (0.099g) 4,5-dibromo-2-phenylpyridazine-3(2H)one, 0.72mmol (0.1598g) 2-naphthalenesulfonylhydrazide, 1.2mmol (0.1464g) 4-dimethylaminopyridine and 0.009mmol (0.0033g) tetrabutylammonium iodide to a Schlenk tube, dissolve in 2mL acetonitrile and 0.2mL water, and stir at 60°C for 8h. After the reaction is completed, transfer the reaction solution completely to a separatory funnel with dichloromethane, wash with saturated sodium chloride solution, and stand to separate. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 19 as a white solid (0.0662g, 61%).

[0210] The structural formula and relevant characterization data of compound 19 are shown below:

[0211]

[0212] 1 H NMR (600MHz, CDCl3), δ, ppm: 7.37 (t, J = 7.8Hz, 1H, ArH-1), 7.41-7.43 (m, 2H, ArH-2, 3), 7.49 (d ,J=7.8Hz,2H,ArH-4,5),7.59-7.61(m,1H,ArH-19),7.64-7.67(m,1H,ArH-18),7.90(d,J=8.4H z,1H,ArH-20),7.96(d,J=8.4Hz,1H,ArH-17),8.01(d,J=8.4Hz,1H,ArH-12),8.07(d,J=8.4Hz ,1H,ArH-13),8.14(d,J=4.2Hz,1H,ArH-8),8.24(d,J=4.2Hz,1H,ArH-7),8.74(s,1H,ArH-14).

[0213] 13C NMR(150MHz,CDCl3),δ,ppm:124.1(C-1),125.4(C-4,5),127.7(C-18),128.1(C-19),129.0(C-2,3),129.1(C-17),129.3(C-20),129.8(C-1 2),130.0(C-14),132.1(C-13),132.2(C-7),132.5(C-8),134.8(C-15 ),135.4(C-6),135.9(C-16),140.6(C-11),140.8(C-9),155.1(C-10).

[0214] ESI-HRMS, m / z: Calcd for C 20 H 15 N2O3S,[M+H] + :363.0798,Found:363.0787.

[0215] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 19 was consistent with expectations.

[0216] Embodiment 20

[0217] This embodiment provides a sulfonyl pyridazinone compound, and the preparation method thereof is as follows:

[0218] The preparation method is as follows: 0.3 mmol (0.099 g) of 4,5-dibromo-2-phenylpyridazine-3 (2H) ketone, 0.72 mmol (0.1246 g) of 3-pyridinesulfonylhydrazine, 1.2 mmol (0.1464 g) of 4-dimethylaminopyridine and 0.009 mmol (0.0033 g) of tetrabutylammonium iodide were added to a Schlenk tube, dissolved in 2 mL of acetonitrile and 0.2 mL of water, and stirred at 60°C for 8 h. After the reaction was completed, the reaction solution was completely transferred to a separatory funnel with dichloromethane, washed with saturated sodium chloride solution, and allowed to stand for stratification. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and separated by column chromatography to obtain compound 20 as a white waxy solid (0.0338 g, 36%).

[0219] The structural formula and relevant characterization data of compound 20 are shown below:

[0220]

[0221] 1H NMR (600MHz, CDCl3), δ, ppm: 7.41 (t, J = 7.2 Hz, 1H, ArH-1), 7.45-7.47 (m, 2H, ArH-2, 3), 7.49-7.52 (m, 3H, ArH-4, 5, 14), 8.17 (d, J = 4 .2Hz,1H,ArH-8),8.20(d,J=4.2Hz,1H,ArH-7),8.57(d,J=8.4Hz,1H,ArH-15),8.85(d,J=6.0Hz,1H,ArH-13),9.22(s,1H,ArH-12);

[0222] 13 C NMR(150MHz,CDCl3),δ,ppm:123.7(C-14),125.3(C-4,5),128.9(C-11),129.1(C-2,3),129.4(C-1),132 .5(C-7),135.4(C-8),138.8(C-15),140.0(C-6),140.4(C-12),150.4(C-9),154.7(C-13),154.9(C-10);

[0223] ESI-HRMS, m / z: Calcd for C 15 H 12 N3O3S,[M+H] + :314.0584,Found:314.0594.

[0224] The results of hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry showed that the structure of compound 20 was consistent with expectations.

[0225] Experimental analysis

[0226] The antibacterial performance of the products of Examples 1-5 was tested, and the specific test methods and results are as follows:

[0227] 1. Experimental strains

[0228] The strains used in the experiment were: Escherichia coli ATCC 43894 and Staphylococcus aureus ATCC 25923.

[0229] 2. Experimental steps

[0230] 2.1 Activation of bacterial strains and preparation of bacterial solution

[0231] Escherichia coli ATCC 43894 and Staphylococcus aureus ATCC 25923 frozen at -80℃ were spread on LB agar medium by streaking method and cultured in a 37℃ biochemical incubator for 24 hours. A single colony on the medium was picked up with an inoculation loop and inoculated into 2mL of liquid broth culture medium for 12 hours. Then, 50μL of the bacterial solution was diluted 1:100 and expanded to the logarithmic growth phase.

[0232] 2.2 Minimum inhibitory concentration (MIC) test

[0233] The bacterial solution that has been cultured to logarithmic growth is diluted with LB culture medium to an OD of 600 =0.1 for standby use. Weigh 8 mg of compound to prepare a stock solution with a concentration of 4 mg / mL, dilute it continuously with LB broth culture medium in a 96-well plate, and prepare solutions of different concentrations (180 μL). Add equal amounts of diluted bacterial solution (20 μL) to a 96-well plate, and control the final concentration of the polymer to be 2000, 1000, 500, 250, 125, 62.5, 31.25, and 16.125 μg / mL. Then place it in a 37°C constant temperature incubator for culture (Escherichia coli culture for 18 hours, Staphylococcus aureus culture for 18-20 hours). If the bacteria do not significantly increase the minimum concentration, it is the MIC of the compound. A bacterial suspension without compound was used as a negative control, and LB broth without compound and bacteria was used as a positive control. Three parallel controls were set for each concentration, and three technical replicates were performed to confirm the MIC value of each bacterium (Table 1).

[0234] 3. Experimental results

[0235] As can be seen from Table 1, the selected compounds all have certain antibacterial properties. Compared with similar tests, the representative compounds in the present invention have better results than those reported in existing literature (Wang YL; Liu ZH, Liu T, et al. Chemistry select, 2024, 9, e202401299).

[0236] Table 1 Minimum inhibitory activity of some compounds

[0237]

[0238]

[0239] In addition, the compounds of Examples 6 to 20 also potentially have a certain antibacterial effect.

[0240] The above is a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the principle of the present invention. These improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A sulfonyl pyridazinone compound, characterized in that: The general structural formula of the sulfonyl pyridazinone compound is shown in formula (I): Wherein, R is selected from substituted or unsubstituted aryl; the substituted aryl is monosubstituted or polysubstituted; the substituents on the substituted aryl are selected from nitro, trifluoromethyl, halogen, cyano, amine, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl or C1-C4 alkoxy.

2. The sulfonyl pyridazinone compound according to claim 1, characterized in that The R is selected from one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methylphenyl, 2-thienyl, 2-naphthyl, and 3-pyridyl.

3. The method for preparing the sulfonyl pyridazinone compound according to claim 1 or 2, characterized in that: The method comprises the following steps: in the presence of an aromatic heterocyclic organic base and a quaternary ammonium salt, 4,5-dihalogen-2-phenylpyridazine-3(2H)-one Sulfonyl hydrazide Carrying out a reaction to obtain the sulfonyl pyridazinone compound; Wherein, X is a halogen.

4. The method for preparing a sulfonyl pyridazinone compound according to claim 3, characterized in that: The molar ratio of the 4,5-dihalo-2-phenylpyridazine-3(2H)one to sulfonylhydrazide is 1:(2-3).

5. The method for preparing a sulfonyl pyridazinone compound according to claim 3, characterized in that: The reaction temperature is 50-70°C; And / or, the reaction time is 7-10h.

6. The method for preparing a sulfonyl pyridazinone compound according to claim 3, characterized in that: The molar ratio of the 4,5-dihalo-2-phenylpyridazin-3(2H)one to the aromatic heterocyclic organic base is 1:(3-5); And / or, the molar ratio of the 4,5-dihalo-2-phenylpyridazine-3(2H)one to the quaternary ammonium salt is 1:(0.1-0.5).

7. The method for preparing a sulfonyl pyridazinone compound according to claim 3, characterized in that: The aromatic heterocyclic organic base is selected from 4-dimethylaminopyridine or 2-methylimidazole; And / or, the quaternary ammonium salt is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, and benzyltriethylammonium chloride.

8. The method for preparing a sulfonyl pyridazinone compound according to claim 3, characterized in that: The reaction is carried out in a solvent consisting of an aprotic polar solvent and water.

9. Use of the sulfonyl pyridazinone compound according to claim 1 or 2 in the preparation of antibacterial drugs.

10. Use of the sulfonyl pyridazinone compound according to claim 1 or 2 in the preparation of a flame retardant.

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