A series of 4-pentenyliminosulfonyl amidines and preparation method and application thereof

Abstract

The application discloses a 4-pentene imino sulfone-based amidine series compound and a preparation method and application thereof. The method uses commercially available imino sulfone and N-allyl alkynyl sulfonamide as reaction substrates, and uses a cheap palladium salt as a catalyst, so that the 4-pentene imino sulfone-based amidine series compound is efficiently synthesized and prepared under a catalytic condition without strict water and oxygen, and at room temperature. The product obtained by the application has novel structure, high production efficiency, wide compatibility of substrate functional groups, conforms to green reaction characteristics, is suitable for large-scale preparation, has excellent industrial application prospect, is an environment-friendly green chemical technology, has wide compatibility of substrate functional groups, conforms to green reaction characteristics, is suitable for large-scale preparation, and is also an environment-friendly green chemical synthesis drug technology.

Description

Technical Field

[0001] This invention relates to the field of derivatives containing imino sulfone and enamide drug skeletons, specifically to a series of 4-pentene imino sulfone amidine compounds, their preparation methods, and applications. Background Technology

[0002] Imino sulfone compounds are important pharmacophores in many drugs on the market. They are a class of bioactive molecular fragments widely found in pesticides and pharmaceuticals. Imino sulfones are isosteric sulfones, with the nitrogen atom providing a modifiable site, making them a focus of drug development. Simultaneously, imino sulfones can also serve as chiral cofactors, ligands for asymmetric catalysis, and directing groups for hydrocarbon activation. In recent years, by introducing imino sulfone structures into existing drug molecules or highly active compound molecules, many highly active molecules and marketed drug molecules have emerged. As early as the 1970s, imino sulfone (sulfoximine) was used as a pharmacophore in clinical drug development research. Currently, drugs containing this type of imino sulfone skeleton that have been successfully marketed and applied clinically include: NSC 287474, a lymphocyte HIV reverse transcriptase inhibitor [P. Stoss, G. Satzinger, Chem. Ber. 1972, 105, 2575]; and the CDK9 inhibitor BAY1251152, which has shown high anti-tumor efficacy. It is a ternary cyclic drug molecule used as an anticonvulsant and anti-anxiety drug [Bartoszyk, GJPharm.Pharmacol.1987,39,407.]; Suloxifen can be used to treat asthma; Pfizer is a drug used to treat osteoporosis; AZD6738 is an ATR inhibitor; HE-HK 52 is a drug used to relieve spasms [(a)Satzinger, G.Drug News Perspect.2001,14,197.(b)Pothmann, R.Drugs Future 1982,7,478.]; Prazosine derivatives are effective antihypertensive drugs, etc.

[0003] Sulfonamides have been used clinically as antibacterial drugs for decades due to their broad antibacterial spectrum, stability, ease of use, and low cost. With in-depth research on sulfonamides, their broader biological activities have been discovered, such as diuresis, antithyroid activity, antidiabetic activity, antihyperglycemic activity, and cataract treatment. In recent years, numerous sulfonamides with antitumor activity have been reported, some of which have entered clinical trials. Currently, drugs containing this sulfonamide skeleton that have been successfully marketed and used clinically include: Prontosil's sulfonamides, which have certain antibacterial effects and can be used to treat sepsis caused by Staphylococcus aureus; E7010 (ABT-751), a microtubule inhibitor with antitumor activity, which, when combined with other drugs in chemotherapy, is effective in treating acute leukemia; and enamides, an important intermediate in organic reactions, also possess a wide range of biological activities.

[0004] Currently, there is no efficient method for the one-step synthesis of 4-pentene imine sulfone amidine series compounds. Based on the potent biological or pharmaceutical activities of imine sulfones and enamide derivatives, we anticipate that developing efficient methods to synthesize compounds containing this structural feature will have strong convertibility and broad application prospects.

[0005] Based on this, the present invention aims to use inexpensive and low-toxicity palladium as a catalyst and structurally inexpensive and readily available small molecule compounds as raw materials to efficiently and chemoselectively synthesize a series of compounds containing 4-pentene imine sulfone amidines under simple reaction conditions. The method of the present invention has good compatibility with various sensitive groups such as halogens (fluorine, chlorine, bromine, iodine), unsaturated groups (alkenyl, alkynyl), cyano, ester, and nitro groups. These groups themselves have good reactivity, so the obtained products can undergo further transformation through other organic chemical reactions, thereby introducing more functional groups into the skeleton, and simultaneously constructing other novel compounds. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing 4-pentene imine sulfone-amidine series compounds. This method has high chemical selectivity, wide substrate applicability, simple operation, few byproducts, and is suitable for large-scale preparation.

[0007] This invention is achieved by using imino sulfone and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide as reaction substrates in an organic solvent, and reacting at room temperature for a period of time under the combined action of a metal catalyst, a phosphorus ligand, and a base to obtain the product series of 4-pentene imino sulfone amidine compounds. The general reaction formula is as follows:

[0008]

[0009] The R mentioned therein 1 R 2 R 3 R 4 It is H, alkyl, alkoxy, and phenyl, or aryl, furanyl, thiophene, or pyridyl with an electron-donating group or an electron-withdrawing group; the electron-donating group is alkyl, alkoxy, or cycloalkyl; the electron-withdrawing group is fluorine, chlorine, bromine, iodine, ester, nitro, cyano, or amide.

[0010] R in Formula III 1 R 2 With R in Equation I 1 R 2 Having the same meaning, R in the structure of Equation III 3 R 4 With R in Equation II 3 R 4 They have the same meaning.

[0011] The metal catalyst is palladium triphenylphosphine dichloride, palladium acetate, palladium dichloride phenylacetonitrile, palladium chloride, palladium trifluoroacetate, palladium acetonitrile chloride, bis(dibenzylideneacetone)palladium or tri(dibenzylideneacetone)dipalladium, with palladium acetate being the most preferred.

[0012] The phosphorus ligands are tris(3-methylphenyl)phosphine, 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, triphenylphosphine, tris(4-fluorophenyl)phosphine, and tricyclohexylphosphine. Among them, triphenylphosphine is the best.

[0013] The alkali is cesium carbonate, potassium carbonate, sodium methoxide, lithium methoxide, lithium hydroxide, and potassium phosphate, with cesium carbonate being the best.

[0014] The organic solvent is acetonitrile, dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide. Among them, 1,4-dioxane is preferred.

[0015] The reaction does not require heating; room temperature (10–35°C) serves as the reaction environment.

[0016] In the 4-pentene imine sulfone amidine series compounds prepared by the above method, the aryl group at the 1-position of the skeleton can be any aryl group with an electron-donating group, any aryl group with an electron-withdrawing group, furanyl, thiophene, or pyridyl; the electron-donating group can be alkyl, alkoxy, or cycloalkyl; the electron-withdrawing group can be fluorine, chlorine, bromine, iodine, ester, nitro, cyano, or amide; the substituent at the 3-position of the skeleton can be any alkyl, alkoxy, cycloalkyl, aryl, naphthyl, furanyl, thiophene, pyridyl, silyl, or halogen group.

[0017] The 4-pentene imine sulfone amidine series compounds obtained in this invention have good anti-tumor activity and can exert a positive inhibitory effect on the A549 lung cancer cell line. At the same time, some compounds have a certain growth inhibitory effect on the phosphorylated protein CDC25B, which has a broader research prospect in the treatment of tumors.

[0018] Compared with the prior art, the beneficial effects of the present invention are:

[0019] In this invention, the reaction proceeds smoothly with a reactant-catalyst ratio of 1:0.1, producing no byproducts. This facilitates product separation and purification and demonstrates excellent environmental friendliness. The reaction exhibits high chemoselectivity, broad substrate applicability, and high product yield. No heating is required; room temperature serves as the reaction environment, making operation simple, reaction time short, and cost-effective, suitable for large-scale preparation. Because the product exhibits good compatibility with sensitive groups such as halogens (fluorine, chlorine, bromine, iodine), unsaturated groups (alkenyl, alkynyl), cyano, ester, and nitro groups, and these groups themselves possess good reactivity, the resulting product can undergo further transformation through other organic chemical reactions to construct other novel compounds containing imino sulfone structures, possessing potential biological or pharmaceutical activities and showing excellent application prospects in the fields of biomedicine, pesticides, and materials science.

[0020] This invention utilizes commercially available iminosulfone and N-allylalkynylsulfonamide as reaction substrates and inexpensive palladium salt as a catalyst. Under conditions that do not require strict anhydrous and oxygen-free catalysis, the method efficiently synthesizes 4-pentene iminosulfone-amidine series compounds at room temperature for 1-3 hours. The synthetic method described in this invention does not require inert gas protection, has no special requirements for reaction equipment, is simple to operate, and employs a one-pot reaction, eliminating the need for preparing and separating intermediates, thus resulting in extremely low costs. The products obtained by this invention have novel structures, high production efficiency, broad substrate functional group compatibility, and conform to the characteristics of green reactions. It is suitable for large-scale preparation and has excellent industrial application prospects. This is an environmentally friendly green chemistry technology for the synthesis of pharmaceuticals. This invention introduces an amidine structural fragment onto the nitrogen atom of an imine sulfone, resulting in a series of 4-pentene imine sulfone amidine compounds with good antitumor activity. These compounds can exert a positive inhibitory effect on the A549 lung cancer cell line. At the same time, some compounds have a certain growth inhibitory effect on the phosphorylated protein CDC25B, showing broader research prospects in the treatment of tumors. Attached Figure Description

[0021] Figure 1The product of Example 1 of this invention is (E)-N-((4-methoxyphenyl)(methyl)(oxo)-λ 6 A schematic diagram of the single crystal structure of compound 3c (-sulfonamide subunit)-2-phenyl-N'-toluenesulfonylpent-4-enamide.

[0022] Figure 2 The product of Example 1 of this invention is (E)-N-((4-methoxyphenyl)(methyl)(oxo)-λ 6 The chemical structural formula of compound 3c is given by (-sulfonamide subunit)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Detailed Implementation

[0023] The following embodiments are further illustrations of the present invention, but not limitations on the scope of the invention. Embodiment 1:

[0024]

[0025] Under a nitrogen atmosphere, palladium acetate catalyst (4.6 mg), triphenylphosphine ligand (10.6 mg), cesium carbonate alkali (130.34 mg), reactants NH-methyl(phenyl)imino sulfone (31.0 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the purified product (E)-N-(methyl(oxo)(phenyl)-λ). 6 Compound 3a: (-sulfonamide group)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 85%.

[0026] The following are the NMR experimental data for product 3a:

[0027] 1 H NMR (400MHz, CDCl3) δ7.42(m,14H),5.79-5.68(m,1H),5.09-4.91(m,3H),3.14–2.71(m,5H),2.37(s,3H).

[0028] 13C NMR (100MHz, CDCl3) δ142.2,142.1,140.2,139.2,135.6,135.5,133.7,129.6,129.5,129.0,128 .9,128.7,128.4,128.2,127.2,127.1,126.9,126.6,116.9,77.4,77.1,76.8,46.3,29.7,21.5.

[0029] Example 2:

[0030]

[0031] Under a nitrogen atmosphere, the catalyst triphenylphosphine-palladium dichloride (9.6 mg), the ligand tris(3-methylphenyl)phosphine (11.4 mg), sodium methoxide (110.2 mg), the reactant methyltolylimino sulfone (33.8 mg), and N-allyl-4-methyl-N-(phenylethynyl)phenylethynylsulfonamide (93.4 mg) were dissolved in a mixed solvent acetonitrile (2.0 mL). The reaction was continued at room temperature (20 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the purified product (E)-N-(methyl(oxo)(p-tolyl)-λ). 6 Compound 3b is a sulfonamide (-sulfonamide group)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 88%. The following are the NMR experimental data for product 3b:

[0032] 1 H NMR (400MHz, CDCl3) δ7.64–7.34(m,5H),7.32–7.23(m,4H),7.18–7.11(m,4H) ,5.79-5.67(m,1H),5.13–4.91(m,3H),3.13–2.85(m,5H),2.44–2.36(m,6H).

[0033] 13 C NMR (100MHz, CDCl3) δ144.8,142.1,142.0,140.2,139.3,135.6,135.6,130.2,130.0,129.0,129 .0,128.8,128.3,128.1,128.3,127.2,126.9,126.6,116.9,77.4,77.1,76.8,21.6,21.6,21.5.

[0034] Example 3:

[0035]

[0036] Under a nitrogen atmosphere, the catalysts phenylacetonitrile palladium dichloride (5.6 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (12.8 mg), sodium methoxide (93.4 mg), reactants methylmethoxyphenyl imino sulfone (37.0 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent tetrahydrofuran (2.0 mL). The reaction was continued at room temperature (30 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the pure product (E)-N-(methyl(oxo)(p-methoxyphenyl)-λ 6 Compound 3c is a sulfonamide (-sulfonamide group)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 83%. The following are the NMR experimental data for product 3c:

[0037] 1 H NMR (400MHz, CDCl3) δ7.75–7.53(m,4H),7.38–7.17(m,7H),6.96-6.94(m,1H),6.76-6.74(m, 1H),5.80-5.65(m,1H),5.12–4.90(m,3H),3.86–3.80(m,3H),3.13–2.61(m,5H),2.37(s,3H).

[0038] 13 C NMR (100MHz, CDCl3) δ164.1,163.8,142.1,139.3,135.7,135.6,129.5,129.2,129.0,128.9,12 8.3,128.1,127.2,127.0,126.6,116.8,114.8,114.7,77.4,77.1,76.8,55.8,55.7,38.6,21.5.

[0039] Example 4:

[0040]

[0041] Under a nitrogen atmosphere, the catalysts palladium trifluoroacetate (4.9 mg), tris(4-fluorophenyl)phosphine, tricyclohexylphosphine (14 mg), lithium hydroxide (100.4 mg), reactants methyl-p-chlorophenylimino sulfone (37.8 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent toluene (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the purified product (E)-N-(methyl(oxo)(p-chlorophenyl)-λ). 6 Compound 3d (-sulfonamido)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 78%. The following are the NMR experimental data for product 3d:

[0042] 1 H NMR (400MHz, CDCl3) δ7.55 -7.45(m,4H),7.40–7.23(m,5H),7.19-7.17(m,4H),5.77(s,1H),5.21–4.65(m,6H),3.28–2.51(m,5H),2.40(s,3H).

[0043] 13 C NMR (100MHz, CDCl3) δ142.3,142.1,140.2,139.2,135.6,135.5,133.7,129.6,129.5,129.0,128 .9,128.7,128.4,128.2,127.2,127.1,126.9,126.6,116.9,77.4,77.1,76.8,46.3,29.7,21.5.

[0044] Example 5:

[0045]

[0046] Under a nitrogen atmosphere, the catalysts palladium chloride diacetonitrile (4.8 mg), tris(4-fluorophenyl)phosphine (11.2 mg), lithium methoxide (90.4 mg), reactants ethyl p-bromophenylimino sulfone (37.8 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (95.2 mg) were dissolved in a mixed solvent N,N-dimethylformamide (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the purified product (E)-N-(methyl(oxo)(p-bromophenyl)-λ. 6Compound 3e (-sulfonamido)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 70%. The following are the NMR experimental data for product 3e:

[0047] 1 H NMR (400MHz, CDCl3) δ7.55(s,6H),7.36-7.30(m,3H),7.27-7.17(m,4H),5.76(s,1H),5.25–4.66(m,3H),3.10(m,5H),2.92-2.90(m,1H),2.64-

[0048] 2.56(m,1H),2.40(s,3H),2.40(s,3H).

[0049] 13 C NMR (100MHz, CDCl3) δ142.3,139.1,135.7,132.9,132.8,132.6,129.1,129.0,129.0,128.9,12 8.7,128.4,128.3,127.3,126.7,126.5,117.1,116.9,77.5,77.2,76.9,46.7,44.0,38.3,21.5.

[0050] Example 6:

[0051]

[0052] Under a nitrogen atmosphere, the catalysts bis(di(di-benzylacetone)palladium) (5.7 mg), tricyclohexylphosphine (11.3 mg), potassium phosphate (100.6 mg), reactants diphenylimino sulfone (43.5 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (98.4 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the purified product (E)-N-(phenyl(oxo)(phenyl)-λ). 6 Compound 3f (-sulfonamido)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 88%. The following are the NMR experimental data for product 3f:

[0053] 1H NMR (400MHz, CDCl3) δ8.04-7.77(m,6H),7.55–7.31(m,9H),7.13(s,4H),5.85-5.56(m,1H),5.02(s,3H),3.07-2.89(m,2H),2.35(s,3H).

[0054] 13 C NMR (100MHz, CDCl3) δ142.1,140.1,135.5,133.6,133.2,129.6,129.4,129.2,129. 0,128.2,127.9,127.8,127.5,127.4,127.2,126.5,117.0,77.5,77.2,76.9,21.5.

[0055] Example 7:

[0056]

[0057] Under a nitrogen atmosphere, palladium acetate (4.6 mg), triphenylphosphine (10.6 mg), cesium carbonate (130.34 mg), ethylphenylimino sulfone (33.8 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the pure product (E)-N-(ethyl(oxo)(phenyl)-λ). 6 3 g of (-sulfonamide)-2-phenyl-N'-toluenesulfonylpent-4-enamide compound. Yield: 70%. The following are the NMR experimental data for 3 g of the product:

[0058] 1 H NMR(400MHz, CDCl3)δ7.78–7.41(m,6H),7.39–7.21(m,5H),7.17-7.15(m,3H),5 .77(s,1H),5.24–4.35(m,3H),3.65–2.49(m,4H),2.37(s,3H),1.2–0.98(m,3H).

[0059] 13C NMR (100MHz, CDCl3) δ142.1,140.2,139.4,135.6,133.7,129.6,129.3,129.0,129.0,12 8.9,128.3,128.1,127.6,127.2,127.1,126.5,116.8,77.5,77.2,76.9,21.5,6.7,6.6.

[0060] Example 8:

[0061]

[0062] Under a nitrogen atmosphere, the catalysts palladium trifluoroacetate (5.2 mg), tris(4-fluorophenyl)phosphine (10.6 mg), cesium carbonate (130.34 mg), reactant (cyclopropyl)phenylimino sulfone (36.3 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent acetonitrile (2.0 mL). The reaction was continued at room temperature for 2 hours, and TLC was used to detect complete reaction. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the pure product (E)-N-(cyclopropyl(oxo)(phenyl)-λ). 6 (-sulfonamide)-2-phenyl-N'-toluenesulfonylpent-4-enamide compound, 3 h. Yield: 80%. The following are the NMR experimental data of the product after 3 h:

[0063] 1 H NMR(400MHz, CDCl3)δ7.85(s,1H),7.61-7.44(m,4H),7.31-7.20(m,6H),7.13(s,3H),5.76 (s,1H),5.07–4.96(m,3H),2.92(s,1H),2.45–2.43(m,1H),2.36(s,3H),1.38–0.86(m,5H).

[0064] 13 C NMR (100MHz, CDCl3) δ142.0,140.3,135.6,133.3,129.5,129.3,129.0,128.9,1 28.3,128.1,127.1,126.5,116.9,116.8,77.5,77.2,76.9,21.5,7.2,7.1,5.8.

[0065] Example 9:

[0066]

[0067] Under a nitrogen atmosphere, the catalysts triphenylphosphine, palladium dichloride (6.8 mg), triphenylphosphine (10.6 mg), cesium carbonate (130.34 mg), the reactant methyl (2-bromophenyl)imino sulfone (46.8 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (102 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the purified product (E)-N-(methyl(oxo)(2-bromophenyl)-λ). 6 Compound 3i (-sulfonamido)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 76%. The following are the NMR experimental data for product 3i:

[0068] 1 H NMR(400MHz, CDCl3)δ7.79(s,1H),7.52–7.43(m,8H),7.31–7.15(m,7H),7.11–7.09(m,2H),5.84-5.73(m,1H),5.15–5.10(m,1H),5.02–

[0069] 4.99(m,1H),3.31(s,3H),3.02-2.94(m,1H),2.75(s,1H),2.37(s,3H).

[0070] 13 C NMR (100MHz, CDCl3) δ141.9,140.0,138.6,137.1,135.3,134.1,131.8,129.6,128 .8,128.0,127.9,127.1,126.5,118.7,117.1,77.4,77.0,76.7,51.0,38.2,21.4.

[0071] Example 10:

[0072]

[0073] Under a nitrogen atmosphere, the catalysts palladium chloride (3.9 mg), triphenylphosphine (10.6 mg), potassium carbonate (92.5 mg), reactant (2-bromophenyl)phenylimino sulfone (59.2 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent tetrahydrofuran (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the pure product (E)-N-(phenyl(oxo)(2-bromophenyl)-λ. 6 Compound 3j, a sulfonamide (-sulfonamide group)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 61%. The following are the NMR experimental data for product 3j:

[0074] 1 H NMR(400MHz, CDCl3)δ8.08–7.67(m,3H),7.64–7.26(m,10H),7.21–7.17(m,2H) ,7.13–7.11(m,3H),5.78(s,1H),4.98(s,3H),3.01(s,2H),2.38-2.37(m,3H).

[0075] 13 C NMR (100MHz, CDCl3) δ142.0,140.0,138.8,135.8,135.5,135.2,134.5,133.8,133.6,132.5,132. 0,129.1,129.0,128.9,128.8,128.2,128.1,127.2,127.1,126.6,117.1,77.4,77.1,76.8,21.5.

[0076] Example 11:

[0077]

[0078] Under a nitrogen atmosphere, palladium acetate (4.6 mg), triphenylphosphine ligand (10.6 mg), sodium methoxide (81.0 mg), phenyl(4-methylphenyl)imino sulfone (46.3 mg), and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.0 mL). The reaction was continued at room temperature for 2 hours, and TLC was used to detect complete reaction. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the pure product (E)-N-(phenyl(oxo)(4-methylphenyl)-λ). 6Compound 3k is a sulfonamide (-sulfonamide group)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 83%. The following are the NMR experimental data for product 3k:

[0079] 1 H NMR (400MHz, CDCl3) δ8.13-7.63(m,5H),7.52–7.29(m,6H),7.13–7.05(m,7H),5.85(s,1H),5.14–5.02(m,3H),3.07–2.82(m,2H),2.37–

[0080] 2.29 (m, 6H).

[0081] 13 C NMR (100MHz, CDCl3) δ144.4,142.0,140.2,135.5,133.4,133.0,130.2,130.0,129.5,129 .3,129.0,128.9,128.2,127.8,127.7,127.2,126.6,116.9,77.5,77.1,76.8,21.6,21.5.

[0082] Example 12:

[0083]

[0084] Under a nitrogen atmosphere, palladium acetate (4.6 mg), triphenylphosphine (10.6 mg), and cesium carbonate (130.34 mg) were reacted with the product 10-imino-4a,10a-dihydro-10H-10λ. 4 10-Oxyphenoxathiazine (46.7 mg) and N-allyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (93.4 mg) were dissolved in a mixed solvent of dichloromethane (2.0 mL), and the reaction was continued at room temperature (25 °C) for 2 hours. The reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the pure product (Z)-N-(10-oxy-4a,10a-dihydro-10λ). 4 -Phenoxythione-10-ylidene)-2-phenyl-N'-toluenesulfonylpent-4-enamide. Yield: 74%. The following are the NMR experimental data for product 3l:

[0085] 1H NMR (400MHz, CDCl3) δ7.84–7.82(m,1H),7.60–7.45(m,4H),7.33–7.27(m,4H),7.25–7.22(m,1H),7.11–7.04(m,5H),6.98–6.95(m, 2H),5.76–5.63(m,1H),5.19–5.08(m,1H),4.97–4.94(m,1H),4.79–4.75(m,1H),3.06–2.95(m,1H),2.75–2.65(m,1H),2.40(s,3H).

[0086] 13 C NMR (100MHz, CDCl3) δ174.0,151.6,151.3,142.1,139.6,139.0,135.6,134.9,134.8,128.9,128.8,128.2, 127.0,126.3,124.7,123.9,123.4,119.9,119.0,118.5,118.3,116.9,77.5,77.1,76.8,50.4,38.2,21.5.

[0087] Example 13:

[0088]

[0089] Under a nitrogen atmosphere, palladium acetate (4.6 mg), triphenylphosphine ligand (10.6 mg), cesium carbonate (130.34 mg), methyl (p-methylphenyl)imino sulfone (33.8 mg), and N-allyl-4-methyl-N-(4-methylphenylethynyl)benzenesulfonamide (97.6 mg) were dissolved in a mixed solvent of 1,2-dichloroethane (2.0 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the purified product (E)-N-(methyl(oxo)(p-tolyl)-λ. 6 Compound 3m is an amide compound consisting of (-sulfanyl)-2-(p-tolyl)-N'-tolyl-4-enamide. Yield: 88%. The following are the NMR experimental data for product 3m:

[0090] 1 H NMR (400MHz, CDCl3) δ7.82–7.56(m,2H),7.44-7.42(m,1H),7.32–7.30(m,3H),7.18–7.11(m,6H),5.78(s,1H),5.18–4.52(m,3H),3.25–

[0091] 2.55 (m, 5H), 2.43–2.32 (m, 9H).

[0092] 13 C NMR (101MHz, CDCl3) δ144.7,142.1,140.2,136.6,136.2,135.8,135.7,130.2,130.0,129.0,12 8.9,128.9,128.8,127.3,127.0,126.6,116.8,77.4,77.1,76.8,21.6,21.6,21.5,21.1,21.1.

[0093] Example 14:

[0094]

[0095] Under a nitrogen atmosphere, palladium acetate (4.60 g), triphenylphosphine (1.06 g), cesium carbonate (13.034 g), methyl (p-methylphenyl)imino sulfone (3.38 g), and N-allyl-4-methyl-N-(4-methylphenylethynyl)benzenesulfonamide (9.76 g) were dissolved in a mixed solvent of 1,2-dichloroethane (100 mL). The reaction was continued at room temperature (25 °C) for 2 hours, and the reaction was confirmed to be complete by TLC. For post-treatment, the catalyst was first removed by filtration through a silica gel-filled sintered funnel. The resulting filtrate was then separated by rapid column chromatography to obtain the pure product (E)-N-(methyl(oxo)(p-tolyl)-λ. 6 Compound 3m is an amide compound consisting of (-sulfanyl)-2-(p-tolyl)-N'-tolyl-4-enamide. Yield: 86%. The following are the NMR experimental data for product 3m:

[0096] 1 H NMR (400MHz, CDCl3) δ7.82–7.56(m,2H),7.44-7.42(m,1H),7.32–7.30(m,3H),7.18–7.11(m,6H),5.78(s,1H),5.18–4.52(m,3H),3.25–

[0097] 2.55 (m, 5H), 2.43–2.32 (m, 9H).

[0098] 13C NMR (101MHz, CDCl3) δ144.7,142.1,140.2,136.6,136.2,135.8,135.7,130.2,130.0,129.0,12 8.9,128.9,128.8,127.3,127.0,126.6,116.8,77.4,77.1,76.8,21.6,21.6,21.5,21.1,21.1.

[0099] The present invention conducted experiments on the antitumor activity of the target compound, and the specific methods are as follows:

[0100] This invention introduces an amidine structural fragment onto the nitrogen atom of an imine sulfone, resulting in a series of 4-pentene imine sulfone amidine compounds with good antitumor activity. These compounds can exert a positive inhibitory effect on the squamous A549 lung cancer cell line. At the same time, some compounds have a certain growth inhibitory effect on the phosphorylated protein CDC25B, showing broader research prospects in the treatment of tumors.

[0101] Logarithmic growth phase A549 lung cancer cell line (squamous cells) was seeded at a rate of 8000 cells / well in 96-well plates (90 μL / well). After culturing for 24 h, different concentrations of the target compound were added at 20 μL / well. After culturing for 24 h, 48 h, and 72 h, a 1 mg / mL solution was added. After another 4 h of culturing, the supernatant was discarded, and 100 μL LDMSO was added to each well. The cells were shaken for 15 min to dissolve the supernatant. The OD value was measured at 570 nm using a microplate reader. The cell inhibition rate was calculated using the following formula. The experiment was repeated three times. The cell proliferation inhibition rate was calculated using the following formula:

[0102]

[0103] Obtain OD through experiments 570 The OD values ​​were measured, and the corresponding cell inhibition rates were calculated. Then, SPSS software was used to calculate the IC50 values ​​of each target compound against the squamous A549 lung cancer cell line and the phosphorylated protein CDC25B cell line. 50 Values. Data is shown in Table I.

[0104] Table I. Results of bioactivity tests on compounds containing 4-pentene imine sulfonemidine.

[0105]

[0106] As shown in the table above, the 4-pentene imine sulfonemidane series compounds exhibit good inhibitory activity against the two enzymes or proteins mentioned above, and are expected to become a feasible approach for the prevention and treatment of malignant tumors. For example, compound 3i shows a half-maximal inhibitory concentration (IC50) for CDC25B. 50The half-maximal inhibitory concentration (WMC) for A549 was 3.19 μg / mL, and the half-maximal inhibitory concentration (WMC) for A549 was 6.50 μg / mL.

Claims

1. A method for preparing a series of 4-pentene imine sulfonemidane compounds, characterized in that: Includes the following steps: In an organic solvent, using compounds with structures of formula I and formula II as reaction substrates, under the combined action of a metal catalyst, a phosphorus ligand, and a base, the product series of 4-pentene imine sulfonemidine compounds with structure of formula III is obtained. I II III, Where R 1 R 2 It is an alkyl, phenyl, or aryl group with an electron-donating group or an electron-withdrawing group; the electron-donating group is an alkyl, alkoxy, or cycloalkyl group; the electron-withdrawing group is fluorine, chlorine, bromine, or iodine. R 3 It is a phenyl group or an aryl group with an electron-donating group or an electron-withdrawing group; the electron-donating group is an alkyl, alkoxy, or cycloalkyl group; the electron-withdrawing group is fluorine, chlorine, bromine, or iodine. R 4 It is H or alkyl; R in Formula III 1 R 2 With R in Equation I 1 R 2 Having the same meaning, R in the structure of Equation III 3 R 4 With R in Equation II 3 R 4 They have the same meaning; The metal catalyst is palladium dichloride of triphenylphosphine, palladium acetate, palladium dichloride of phenylacetonitrile, palladium chloride, palladium trifluoroacetate, palladium diacetonitrile, bis(dibenzylidene acetone)palladium, or tri(dibenzylidene acetone)dipalladium; The phosphorus ligand is tris(3-methylphenyl)phosphine, 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, triphenylphosphine, tris(4-fluorophenyl)phosphine, or tricyclohexylphosphine; The alkali is cesium carbonate, potassium carbonate, potassium phosphate, sodium methoxide, lithium methoxide, or lithium hydroxide.

2. The method for preparing the 4-pentene imine sulfonemidane series compounds according to claim 1, characterized in that: The organic solvent is acetonitrile, dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide.

3. The method for preparing the 4-pentene imine sulfonemidane series compounds according to claim 1, characterized in that: The reaction was carried out at 10~35℃.

4. The method for preparing the 4-pentene imine sulfonemidane series compounds according to claim 1, characterized in that: The molecular skeleton of the 4-pentene imine sulfone-amidine series compounds contains imine sulfone and alkenylamidine structural fragments.

5. A series of 4-pentene imine sulfonemidane compounds, characterized in that, It has the following structure: 3a; 3b; 3c; 3e; 3f; 3g; 3i; 3j; 3k.

6. The use of the 4-pentene imine sulfonemidane series compounds according to claim 5 in the preparation of antitumor drugs.

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