2-aryl-3-ketimino tetrahydrofuran compound as well as preparation method and application thereof

Abstract

The invention discloses a preparation method of a 2-aryl-3-ketimino tetrahydrofuran compound with a novel structure in the technical field of organic synthesis. The reaction general formula of the 2-aryl-3-ketimino tetrahydrofuran compound is as follows: # imgabs0, specifically, the 2-aryl-3-ketimino tetrahydrofuran compound is prepared from 4-aryl-3-butenol and diaryl ketimine in one step under the condition of organic electrochemical synthesis, the method is mild in condition, equivalent chemical oxidizing agents and additives do not need to be added additionally, and the yield is high. Reaction functional groups are good in compatibility, the product is easy to further derive and convert, and a green and efficient synthesis method is provided for the 2-aryl-3-amido substituted tetrahydrofuran compound.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a 2-aryl-3-ketoimino tetrahydrofuran compound, a preparation method and application thereof. Background Art

[0002] Amine-modified tetrahydrofuran is an important structural unit that is widely present in many natural products and bioactive molecules, such as Zidovudine, a drug used to treat AIDS or AIDS-related syndrome and HIV infection, and Zalcitabine, an antiviral and anticancer drug, all of which contain this type of heterocyclic skeleton. Therefore, the development of a new synthesis method for amine-modified tetrahydrofuran compounds is of great significance for further promoting the study of the biological activity of related molecules and the development of drugs based on this structure.

[0003] The intramolecular cyclofunctionalization reaction of unsaturated alcohols with the participation of intermolecular aminating agents can introduce additional amine functional groups while synthesizing the tetrahydrofuran ring, which is an important strategy for synthesizing amine-substituted tetrahydrofuran compounds. At present, the method of constructing diverse tetrahydrofuran compounds through this strategy often requires the participation of metals or oxidants (Org. Biomol. Chem. 2021, 19, 557; ChemCatChem. 2016, 8, 3720), and the amination products of the aminating agents used are not easy to be further derivatized and transformed. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention designs a method for preparing 2-aryl-3-ketoimino tetrahydrofuran compounds in one step under organic electrochemical synthesis conditions, so as to enrich the structural diversity of amine-modified tetrahydrofuran molecules.

[0005] One of the purposes of the present invention is to provide a 2-aryl-3-ketoimino tetrahydrofuran compound, the structural formula of which is as follows:

[0006]

[0007] Where: Ar 1 is selected from 4-methoxyphenyl, 4-n-butoxyphenyl, 4-propoxyphenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-methylphenyl, 3-methyl-4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 4-bromophenyl, 2-naphthyl, 2-furyl or 2-thienyl; Ar 2 ,Ar 3Each is independently selected from phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-bromophenyl, 4-fluorophenyl, 3-fluorophenyl, 3-methylphenyl or 3-chlorophenyl.

[0008] The second object of the present invention is to provide a method for preparing 2-aryl-3-ketoimino tetrahydrofuran compounds, the general reaction formula of which is as follows:

[0009]

[0010] 4-aryl-3-butene-1-ol, diaryl ketone imine, electrolyte and solvent are sequentially added into an electrolytic cell equipped with electrode materials, and 2-aryl-3-ketoimino tetrahydrofuran compounds are prepared in a one-pot method under constant current organic electrosynthesis conditions.

[0011] The working principle and beneficial effects of the present invention: Considering that diaryl ketone imine is a new type of aminating agent, the ketone imination product formed by it is easily further hydrolyzed into aminated molecules, the present invention innovatively develops a method for preparing tetrahydrofuran compounds modified by electro-oxidation ketone imine, using 4-aryl-3-butene-1-ol and diaryl ketone imine as raw materials, and preparing 2-aryl-3-ketoiminyl tetrahydrofuran compounds in one step under organic electrochemical synthesis conditions. The method has the characteristics of easy preparation of raw materials, mild reaction conditions, no need to add metals and oxidants, and easy derivatization and transformation of products, providing a green and efficient preparation method for 2-aryl-3-amine-substituted tetrahydrofuran compounds.

[0012] Furthermore, the molar ratio of each substance in the reaction is: 4-aryl-3-butenol: diaryl ketone imine: electrolyte = 1: 1 to 5: 0.2 to 5. Preferably, 4-aryl-3-buten-1-ol: diaryl ketone imine: electrolyte = 1: 3: 1.

[0013] Furthermore, the electrolyte is selected from tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate, tetra-n-butylammonium acetate, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetraethylammonium trifluoroacetate or lithium perchlorate, preferably tetra-n-butylammonium tetrafluoroborate.

[0014] Furthermore, the solvent is selected from one or more of acetonitrile, methanol, acetic acid, tetrahydrofuran, N,N-dimethylformamide, hexafluoroisopropanol and water, preferably acetonitrile.

[0015] Furthermore, the electrode material includes an anode electrode material and a cathode electrode material. The anode electrode material is selected from a carbon rod electrode, a glassy carbon electrode, carbon felt or carbon cloth, preferably a carbon rod electrode; the cathode electrode material is selected from a platinum sheet, an iron sheet, a copper sheet, a nickel sheet or a zinc sheet, preferably a platinum sheet.

[0016] Furthermore, the current is 2 mA to 20 mA, preferably 8 mA; the temperature is 5°C to 40°C, preferably 25°C; the reaction time is 1 h to 10 h, preferably 4 h; the gas atmosphere is selected from argon, nitrogen or air, preferably argon, and when the gas atmosphere is air, the electrolytic cell is not evacuated.

[0017] Furthermore, the electrolytic cell is selected from an integrated electrolytic cell and a separated electrolytic cell, and is preferably an integrated diaphragm-free electrolytic cell.

[0018] The third object of the present invention is to provide the use of 2-aryl-3-ketoiminotetrahydrofuran compounds in the preparation of anti-cancer drugs, specifically, the cancer is human breast cancer.

[0019] It has been verified that the 2-aryl-3-imino tetrahydrofuran compounds have drug activity against human breast cancer MCF-7 cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 A single crystal diagram of compound 1a prepared in Example 1;

[0021] Figure 2 Compound 1a prepared in Example 1 1 H NMR spectrum;

[0022] Figure 3 Compound 1a prepared in Example 1 13 C NMR spectrum;

[0023] Figure 4 Compound 1b prepared in Example 2 1 H NMR spectrum;

[0024] Figure 5 Compound 1b prepared in Example 2 13 C NMR spectrum;

[0025] Figure 6 The compound 1c prepared in Example 3 1 H NMR spectrum;

[0026] Figure 7 The compound 1c prepared in Example 3 13 C NMR spectrum;

[0027] Figure 8 Compound 1d prepared in Example 4 1 H NMR spectrum;

[0028] Fig. 9 Compound 1d prepared in Example 4 13 C NMR spectrum;

[0029] Fig.10 The compound 1e prepared in Example 5 1 H NMR spectrum;

[0030] Fig.11 The compound 1e prepared in Example 5 13 C NMR spectrum;

[0031] Fig.12 The compound 1f prepared in Example 6 1 H NMR spectrum;

[0032] Fig.13 The compound 1f prepared in Example 6 13 C NMR spectrum;

[0033] Fig.14 The compound 1f prepared in Example 6 19 F NMR spectrum;

[0034] Fig.15 1g of the compound prepared in Example 7 1 H NMR spectrum;

[0035] Fig.16 1g of the compound prepared in Example 7 13 C NMR spectrum;

[0036] Fig.17 Compound 1h prepared in Example 8 1 H NMR spectrum;

[0037] Fig.18 Compound 1h prepared in Example 8 13 C NMR spectrum;

[0038] Fig.19 Schematic diagram of the inhibitory effect of some compounds on the proliferation of human breast cancer cells (MCF-7 cells). DETAILED DESCRIPTION

[0039] The following is further described in detail through specific implementation methods:

[0040] Example 1: Using 4-(4-methoxy)phenyl-3-butene-1-ol as an olefin substrate and benzophenone imine as an amination reagent, a 2-aryl-3-ketoimine-substituted tetrahydrofuran molecule 1a was prepared (Reaction Formula 1)

[0041]

[0042] 4-(4-methoxy)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), benzophenone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and the reaction was stirred at 8mA constant current and room temperature for 4 hours. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA / Et3N=20:1:0.5-10:1:0.2) to obtain the target compound 1a (yellow oily liquid, dr>20:1, 44.3mg, 62%).

[0043] The NMR data of target compound 1a are as follows:

[0044] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=7.2Hz,2H),7.41–7.37(m,1H),7.37–7.32(m,3H),7.29(t,J=7.3Hz,2H),7.12(d,J=8.5Hz,2H),6.81(d,J=8.6Hz, 2H),6.74(d,J=7.1Hz,2H),4.92(d,J=6.8Hz,1H),4.29–4.22(m,1H),4.1 9–4.12(m,1H),3.83–3.78(m,4H),2.35–2.25(m,1H),2.19–2.10(m,1H).

[0045] 13 C NMR (101MHz, CDCl3) δ168.8,159.0,139.7,136.8,132.6,130.2,128.6,128.4,128.24,128.16,127.6,127.5,113.6,86.2,70.1,67.8,55.4,34.6.

[0046] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 24 H 24 NO2,400.2271; Found:358.1802.

[0047] The single crystal data of product 1a are shown in Table 1 below:

[0048]

[0049]

[0050] Example 2: Using 4-(3,4-dimethoxy)phenyl-3-butene-1-ol as a substrate and benzophenone imine as an amination reagent, a 2-aryl-3-ketoimine-substituted tetrahydrofuran molecule 1b was prepared (Reaction Formula 2)

[0051]

[0052] 4-(3,4-dimethoxy)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), benzophenone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and the reaction was stirred at 8mA constant current and room temperature for 4 hours. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA / Et3N=20:1:0.5-10:1:0.2) to obtain the target compound 1b (yellow oily liquid, dr>20:1, 56.6mg, 73%).

[0053] The NMR data of target compound 1b are as follows:

[0054] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=7.2Hz,2H),7.39–7.27(m,6H),6.75(s,2H),6.70(d,J=6.8Hz,2H),6.67(s,1H),4.86(d,J=6.9H z,1H),4.28–4.21(m,1H),4.19–4.13(m,1H),3.86(s,3H),3.83–3.77(m,1H),3.73(s,3H),2.36–2.26(m,1H),2.20–2.11(m,1H).

[0055] 13 C NMR (101MHz, CDCl3) δ169.0,148.9,148.4,139.7,136.9,132.8,130.2,128.6,128. 3,128.24,128.18,127.6,118.9,110.7,108.9,86.2,70.0,67.8,56.0,55.8,34.5.

[0056] HRMS (ESI, Q-TOF) m / z: [M+H +]Calcd for C 25 H 26 NO3,388.1907; Found:388.1908.

[0057] Example 3: 4-(3-bromo-4-methoxy)phenyl-3-butene-1-ol was used as an olefin substrate and benzophenone imine was used as an amination reagent to prepare a 2-aryl-3-imino-substituted tetrahydrofuran molecule 1c (Reaction Formula 3)

[0058]

[0059] 4-(3-bromo-4-methoxy)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), benzophenone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and the reaction was stirred at 8mA constant current and room temperature for 4 hours. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA / Et3N=20:1:0.5-10:1:0.2) to obtain the target compound 1c (yellow solid, dr>20:1, 53.2mg, 61%).

[0060] The NMR data of the target compound 1c are as follows:

[0061] 1 H NMR(400MHz, CDCl3) δ7.66(d,J=7.3Hz,2H),7.40–7.29(m,6H),7.17(d,J=8.7Hz,1H),7.01(d,J=2.4Hz,1H),6.91(d,J=6.5Hz,2H),6.76 (dd,J=8.7,2.4Hz,1H),5.35(d,J=4.7Hz,1H),4.37–4.30(m,1H),4.29–4.23(m,1H),3.92–3.86(m,1H),3.76(s,3H),2.19–2.13(m,2H).

[0062] 13 C NMR (101MHz, CDCl3) δ168.1,159.3,139.8,136.7,132.3,130.1,128.8,128.7,1 28.33,128.29,128.1,127.8,122.7,117.6,113.7,85.5,69.7,68.5,55.6,34.7.

[0063] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 24 H 23 BrNO2,436.0907; Found:436.0908.

[0064] Example 4: 4-(4-bromo)phenyl-3-butene-1-ol was used as an olefin substrate and benzophenone imine was used as an amination reagent to prepare 2-aryl-3-imino-substituted tetrahydrofuran molecule 1d (Reaction Formula 4)

[0065]

[0066] 4-(4-bromo)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), benzophenone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and stirred at 8mA constant current and room temperature for 5 hours. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA / Et3N=20:1:0.5-10:1:0.2) to obtain the target compound 1d (yellow oily liquid, dr>20:1, 27.6mg, 34%).

[0067] The target compound 1d NMR data are as follows:

[0068] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=7.3Hz,2H),7.42–7.28(m,8H),7.07(d,J=8.3Hz,2H),6.74(d,J=6.9Hz,2H),4.91 (d,J=6.7Hz,1H),4.29–4.23(m,1H),4.19–4.12(m,1H),3.77–3.71(m,1H),2.34–2.25(m,1H),2.17–2.09(m,1H).

[0069] 13 C NMR (101MHz, CDCl3) δ169.3,139.9,139.5,136.7,131.3,130.4,128.6,128.5,128.4,128.3,127.9,127.5,121.2,85.8,70.3,68.1,34.6.

[0070] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 23 H 21 BrNO,406.0801; Found:406.0802.

[0071] Example 5: Using 4-(4-butoxy)phenyl-3-butene-1-ol as an olefin substrate and bis(4-methoxy)phenylketone imine as an amination reagent, a 2-aryl-3-imino-substituted tetrahydrofuran molecule 1e was prepared (Reaction Formula 5)

[0072]

[0073] 4-(4-Butoxy)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), bis(4-methoxy)phenylmethanone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and stirred at 8mA constant current and room temperature for 4 hours. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA / Et3N=20:1:0.5-10:1:0.2) to obtain the target compound 1e (yellow oily liquid, dr>20:1, 68.9mg, 75%).

[0074] The NMR data of the target compound 1e are as follows:

[0075] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=8.7Hz,2H),7.10(d,J=8.4Hz,2H),6.84(d,J=8.7Hz,2H), 6.79(d,J=8.0Hz,4H),6.65(d,J=8.0Hz,2H),4.87(d,J=6.8Hz,1H),4.26–4.19(m,1H),4. 17–4.10(m,1H),3.94(t,J=6.5Hz,2H),3.81(d,J=1.9Hz,6H),3.79–3.74(m,1H),2.30–2. 21(m,1H),2.17–2.08(m,1H),1.79–1.72(m,2H),1.53–1.44(m,2H),0.97(t,J=7.3Hz,3H).

[0076] 13 C NMR (101MHz, CDCl3) δ168.1,161.2,159.3,158.6,133.1,132.6,130.2,129.3,129.1,12 7.5,114.3,113.6,113.4,86.2,69.9,67.84,67.77,55.4,55.3,34.8,31.4,19.4,14.0.

[0077] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 29 H 34 NO4,460.2482; Found:460.2481.

[0078] Example 6: Using 4-(4-butoxy)phenyl-3-butene-1-ol as an olefin substrate and bis(4-fluoro)phenylketone imine as an amination reagent, a 2-aryl-3-imino-substituted tetrahydrofuran molecule 1f is prepared (Reaction Formula 6)

[0079]

[0080] 4-(4-Butoxy)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), bis(4-fluoro)phenylmethanone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and stirred at 8mA constant current and room temperature for 4 hours. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA / Et3N=20:1:0.5-10:1:0.2) to obtain the target compound 1f (yellow oily liquid, dr>20:1, 60.1mg, 69%).

[0081] The target compound 1f NMR data are as follows:

[0082] 1H NMR(400MHz, CDCl3)δ7.60–7.53(m,2H),7.07(d,J=8.6Hz,2H),7.03–6.93(m,4H) ,6.79(d,J=8.6Hz,2H),6.67–6.59(m,2H),4.83(d,J=6.9Hz,1H),4.26–4.19(m,1 H),4.18–4.12(m,1H),3.94(t,J=6.6Hz,2H),3.74–3.68(m,1H),2.31–2.22(m,1H ),2.17–2.08(m,1H),1.78–1.72(m,2H),1.54–1.46(m,2H),0.97(t,J=7.4Hz,3H).

[0083] 13 C NMR (101MHz, CDCl3) δ166.7, 164.6 (d, J = 173.2Hz), 162.1 (d, J = 170.7Hz), 158.8, 135.8 (d, J = 3.2Hz), 132.4 (d, J = 3.6Hz), 132.2, 130.6 (d ,J=8.6Hz),129.5(d,J=8.1Hz),127.5,115.6(d,J=21.5Hz),115.2(d,J=21.6Hz),114.4,86.1,70.2,67.9,67.8,34.7,31.4,19.4,14.0.

[0084] 19 F NMR (376MHz, CDCl3) δ-110.71,-112.55.

[0085] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 27 H 28 F2NO2,436.2083; Found:436.2081.

[0086] Example 7: Using 4-(4-butoxy)phenyl-3-butene-1-ol as an olefin substrate and (4-bromophenyl)(phenyl)methanone imine as an amination reagent, 1 g of a 2-aryl-3-imino-substituted tetrahydrofuran molecule was prepared (Reaction Formula 7)

[0087]

[0088] 4-(4-Butoxy)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), 4-bromophenyl(phenyl)methanone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and stirred at 8mA constant current and room temperature for 4 hours. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EA / Et3N=20:1:0.5-10:1:0.2) to obtain 1g of the target compound (yellow oily liquid, dr>20:1, 50.7mg, 53%).

[0089] The NMR data of 1g of the target compound are as follows:

[0090] 1 H NMR (400MHz, CDCl3) δ7.49–7.42(m,4H),7.36–7.31(m,1H),7.29–7.26(m,2H),7.06(d, J=8.4Hz,2H),6.78(d,J=8.3Hz,2H),6.68(d,J=7.1Hz,2H),4.86(d,J=6.7Hz,1H),4.26 –4.19(m,1H),4.17–4.10(m,1H),3.93(t,J=6.5Hz,2H),3.78–3.72(m,1H),2.30–2.20( m,1H),2.16–2.08(m,1H),1.79–1.72(m,2H),1.53–1.45(m,2H),0.97(t,J=7.3Hz,3H).

[0091] 13 C NMR (101MHz, CDCl3) δ158.7,138.6,136.3,132.3,131.4,130.2,128.5,127.6,127.5,114.3,86.2,70.1,67.9,67.8,34.6,31.4,19.4,14.0.

[0092] HRMS (ESI, Q-TOF) m / z: [M+H + ]Calcd for C 27 H 29 BrNO2,478.1376; Found:478.1377.

[0093] Example 8: Using 4-(4-butoxy)phenyl-3-butene-1-ol as an olefin substrate and benzophenone imine as an amination reagent, 2-aryl-3-aminotetrahydrofuran molecule 1h was prepared (Reaction Formula 8)

[0094]

[0095] 4-(4-Butoxy)phenyl-3-butene-1-ol (0.2mmol, 1.0equiv.), benzophenone imine (0.6mmol, 3.0equiv.), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv.) and acetonitrile (12mL) were added to a 25mL three-necked electrochemical reaction bottle equipped with a stirrer. The electrochemical reaction bottle was then evacuated and filled with argon (repeated three times), and stirred for 4 hours at 8mA constant current and room temperature. After the reaction was completed, the crude reaction solution was extracted, dried, filtered and concentrated under reduced pressure by rotary evaporation. The crude reaction solution was purified by a short silica gel column (eluent: petroleum ether: ethyl acetate: triethylamine = 4:1:1), and the obtained liquid was further concentrated. The concentrate was dissolved in MeOH (10mL) and 2M HCl (5.0equiv.) was slowly added. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain the target compound 1h (colorless oily liquid product, 36.4 mg, 67%).

[0096] The 1h NMR data of the target compound are as follows:

[0097] 1 H NMR (400MHz, CD3OD) δ7.23(d,J=8.6Hz,2H),6.85(d,J=8.7Hz,2H),4.35(d,J=6.1Hz,1H),4.11–4.05(m,1H),4.04–3.98(m,1H),3.92( t,J=6.4Hz,2H),3.25–3.19(m,1H),2.29–2.20(m,1H),1.87–1.76(m,1H),1.74–1.67(m,2H),1.51–1.42(m,2H),0.95(t,J=7.4Hz,3H).

[0098] 13 C NMR (101MHz, CD3OD) δ160.3,133.7,128.5,115.4,88.7,68.7,67.8,60.4,35.1,32.5,20.3,14.2.

[0099] HRMS (ESI, Q-TOF) m / z: [M-HCl+H +]Calcd for C 14 H 22 NO2,236.1645; Found:236.1645.

[0100] Anti-tumor activity verification:

[0101] The 2-aryl-3-ketoiminotetrahydrofuran compounds prepared in the examples were selected and their in vitro antitumor activity (CCK-8 method) was tested using human breast cancer cells (MCF-7 cells) as receptors.

[0102] Taking compound 1e of Example 5 as an example, the specific operation is as follows:

[0103] (1) Collect logarithmic phase cells and add 100 μL to each well of a 96-well plate. Plate the cells to a density of 5000 cells / well. Incubate the cells at 5% CO2 and 37°C until the cell monolayer covers the bottom of the well. (2) Prepare compound 1e solutions with different concentration gradients (0.015 μM, 0.045 μM, 0.137 μM, 0.411 μM, 1.234 μM, 3.703 μM, 11.111 μM, 33.333 μM, 100.000 μM). (3) Remove the old culture medium from the 96-well plate and add new culture medium containing different compound concentrations. Add 100 μL to each well. Set up 3 replicate wells for each group. (4) Incubate the treated cells at 5% CO2 and 37°C for 48 hours and observe under an inverted microscope. (5) Add 10 μL to each well. CCK-8 solution, and continue to culture for 1-4h; (6) When the color of the solution in the 96-well plate gradually turns orange-red, an automatic microplate reader is used to detect the absorbance (OD) of each well at a wavelength of 450nm when a significant color change occurs; (7) Zero adjustment wells (culture medium, CCK-8 solution), positive control wells (cells, cisplatin dissolution medium of the same concentration, culture medium, CCK-8 solution), and blank control wells (no drug, only cells, culture medium and CCK-8 solution) are set at the same time; (8) The cell survival rate (%) is plotted against the logarithmic transformed drug concentration (such as log (drug concentration) and the data are fitted using a nonlinear regression curve (GraphPad Prism) to calculate the IC50 value of compound 1e; (9) The tumor inhibition experiment of the 2-aryl-3-ketoiminotetrahydrofuran compounds prepared in other embodiments and their cisplatin (CDDP) control group is performed according to a similar method as above.

[0104] Table 2 shows the inhibitory effects of some compounds in the examples on the proliferation of human breast cancer cells (MCF-7 cells).

[0105]

[0106] like Fig.19The results show that the 2-aryl-3-ketoimino tetrahydrofuran compounds prepared by the present invention have a certain inhibitory effect on human breast cancer cells.

[0107] The above is only an embodiment of the present invention, and the common knowledge such as the known specific structure and characteristics in the scheme is not described in detail here. It should be pointed out that for those skilled in the art, several deformations and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A 2-aryl-3-ketoimino tetrahydrofuran compound, characterized in that: Its structural formula is as follows: Where: Ar 1 is selected from 4-methoxyphenyl, 4-n-butoxyphenyl, 4-propoxyphenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-methylphenyl, 3-methyl-4-methoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 4-bromophenyl, 2-naphthyl, 2-furyl or 2-thienyl; Ar 2 ,Ar 3 Each is independently selected from phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-bromophenyl, 4-fluorophenyl, 3-fluorophenyl, 3-methylphenyl or 3-chlorophenyl.

2. The method for preparing the 2-aryl-3-ketoimino tetrahydrofuran compound according to claim 1, characterized in that: The general reaction formula is as follows: 4-aryl-3-butene-1-ol, diaryl ketone imine, electrolyte and solvent are sequentially added into an electrolytic cell equipped with electrode materials, and 2-aryl-3-ketoimino tetrahydrofuran compounds are prepared in a one-pot method under constant current organic electrosynthesis conditions.

3. The preparation method according to claim 2, characterized in that: The molar ratio of each substance in the reaction is: 4-aryl-3-butenol: diaryl ketone imine: electrolyte = 1:1-5:0.2-5.

4. The preparation method according to claim 3, characterized in that: The electrolyte is selected from tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate, tetra-n-butylammonium acetate, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetraethylammonium trifluoroacetate or lithium perchlorate.

5. The preparation method according to claim 2, characterized in that: The solvent is selected from one or more of acetonitrile, methanol, acetic acid, tetrahydrofuran, N,N-dimethylformamide, hexafluoroisopropanol and water.

6. The preparation method according to claim 2, characterized in that: The electrode materials include anode electrode materials and cathode electrode materials. The anode electrode materials are selected from carbon rod electrodes, glassy carbon electrodes, carbon felt or carbon cloth; the cathode electrode materials are selected from platinum sheets, iron sheets, copper sheets, nickel sheets or zinc sheets.

7. The preparation method according to claim 2, characterized in that: The current is 2 mA to 20 mA; the temperature is 5° C. to 40° C.; the reaction time is 1 h to 10 h; and the gas atmosphere is selected from argon, nitrogen or air.

8. The preparation method according to claim 2, characterized in that: The electrolytic cell is selected from an integrated diaphragmless electrolytic cell and a separated electrolytic cell.

9. Use of the compound according to claim 1 and / or the compound prepared by the method according to any one of claims 2 to 8 in the preparation of anticancer drugs.

10. The use according to claim 9, characterized in that: The cancer is human breast cancer.

Images