A 2-aryl-3-ketoimino tetrahydrofuran compound, preparation method and application

Abstract

The present application discloses a preparation method of 2-aryl-3-ketoimino tetrahydrofuran compounds with novel structures in the field of organic synthesis technology. The reaction general formula is as follows: Specifically, 2-aryl-3-ketoimino tetrahydrofuran compounds are prepared in one step from 4-aryl-3-butenol and diaryl ketimine under organic electrochemical synthesis conditions. This method has mild conditions, does not require additional equivalent chemical oxidants and additives, has good compatibility of reaction functional groups, and the products are easily further derivatized and transformed, providing a green and efficient synthesis method for 2-aryl-3-amino-substituted tetrahydrofuran compounds.

Description

Technical Field

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

[0002] Amino-modified tetrahydrofuran is an important structural unit, which widely exists in many natural products and bioactive molecules. For example, the therapeutic drug Zidovudine for the treatment of patients with AIDS or AIDS-related syndromes and human immunodeficiency virus (HIV) infection, and the antiviral and anticancer drug Zalcitabine both contain this kind of heterocyclic skeleton. Therefore, developing new synthetic methods for amino-modified tetrahydrofuran compounds is of great significance for further promoting the bioactivity research of related molecules and the drug development based on this structure.

[0003] The intramolecular cyclization functionalization reaction of unsaturated alcohols participated by intermolecular amination reagents introduces an amino functional group additionally while synthesizing the tetrahydrofuran ring, which is an important strategy for synthesizing amino-substituted tetrahydrofuran compounds. At present, the methods for constructing diverse tetrahydrofuran compounds through this strategy often require the participation of metals or oxidants (Org. Biomol. Chem. 2021, 19, 557; ChemCatChem. 2016, 8, 3720), and the amination products of the amination reagents used are not easily further derivatized and transformed. Summary of the Invention

[0004] Aiming at 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 to enrich the structural diversity of amino-modified tetrahydrofuran molecules.

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

[0006]

[0007] Wherein: 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 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 preparation method of 2-aryl-3-ketoimino tetrahydrofuran compounds, and the reaction general formula is as follows:

[0009]

[0010] 4-Aryl-3-buten-1-ol, diaryl ketimine, electrolyte and solvent are successively added into an electrolytic cell equipped with electrode materials, and 2-aryl-3-ketoimino tetrahydrofuran compounds are prepared by a one-pot method under the conditions of constant current organic electrosynthesis.

[0011] The working principle and beneficial effects of the present invention: Considering that diaryl ketimine is a novel amination reagent and the formed ketoimination product is prone to further hydrolysis into an aminated molecule, the present invention innovatively develops a preparation method for electro-oxidizing ketoimine-modified tetrahydrofuran compounds. Using 4-aryl-3-buten-1-ol and diaryl ketimine as raw materials, 2-aryl-3-ketoimino tetrahydrofuran compounds are prepared in one step under the conditions of organic electrochemical synthesis. This 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-amino-substituted tetrahydrofuran compounds.

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

[0015] Furthermore, the electrode materials include an anode electrode material and a cathode electrode material. The anode electrode material is selected from a carbon rod electrode, a glassy carbon electrode, a carbon felt or a 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] Further, 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. When the gas atmosphere is air, the electrolytic cell is not evacuated.

[0017] Further, the electrolytic cell is selected from an integrated electrolytic cell and a separated electrolytic cell. Preferably, it is an integrated diaphragmless electrolytic cell.

[0018] The third object of the present invention is to provide the use of 2-aryl-3-ketoimino tetrahydrofuran 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 anti-drug activity against human breast cancer MCF-7 cells. Description of the Drawings

[0020] Figure 1 Single crystal drawing of compound 1a prepared in Example 1;

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

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

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

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

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

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

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

[0028] Figure 9 For compound 1d prepared in Example 4 13 C NMR spectrum;

[0029] Figure 10 1H NMR spectrum of compound 1e prepared in Example 5; 1 H NMR spectrum;

[0030] Figure 11 1H NMR spectrum of compound 1e prepared in Example 5; 13 13C NMR spectrum;

[0031] Figure 12 1H NMR spectrum of compound 1f prepared in Example 6; 1 H NMR spectrum;

[0032] Figure 13 1H NMR spectrum of compound 1f prepared in Example 6; 13 13C NMR spectrum;

[0033] Figure 14 1H NMR spectrum of compound 1f prepared in Example 6; 19 19F NMR spectrum;

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

[0035] Figure 16 1H NMR spectrum of compound 1g prepared in Example 7; 13 13C NMR spectrum;

[0036] Figure 17 1H NMR spectrum of compound 1h prepared in Example 8; 1 H NMR spectrum;

[0037] Figure 18 1H NMR spectrum of compound 1h prepared in Example 8; 13 13C NMR spectrum;

[0038] Figure 19 Schematic diagram of the inhibitory effect of some compounds on the proliferation of human breast cancer cells (MCF-7 cells). Detailed description of the specific implementation

[0039] The following is a further detailed description through specific implementation methods:

[0040] Example 1: Using 4-(4-methoxyphenyl)-3-buten-1-ol as the olefin substrate and diphenylmethanimine as the amination reagent to prepare 2-aryl-3-ketoiminyl-substituted tetrahydrofuran molecule 1a (Reaction Scheme 1)

[0041]

[0042] To a 25 mL three-necked electric reaction flask equipped with a magnetic stir bar, 4-(4-methoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), benzophenone imine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were added successively. Subsequently, the reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred for 4 hours under a constant current of 8 mA and at room temperature. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (PE / EA / Et 3 N = 20:1:0.5 - 10:1:0.2) to obtain the target compound 1a (yellow oily liquid, dr > 20:1, 44.3 mg, 62%).

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

[0044] 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J = 7.2 Hz, 2H), 7.41–7.37 (m, 1H), 7.37–7.32 (m, 3H), 7.29 (t, J = 7.3 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 7.1 Hz, 2H), 4.92 (d, J = 6.8 Hz, 1H), 4.29–4.22 (m, 1H), 4.19–4.12 (m, 1H), 3.83–3.78 (m, 4H), 2.35–2.25 (m, 1H), 2.19–2.10 (m, 1H).

[0045] 13 C NMR (101 MHz, CDCl 3 ) δ 168.8, 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 NO 2 , 400.2271; Found: 358.1802.

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

[0048]

[0049]

[0050] Example 2: Using 4-(3,4-dimethoxyphenyl)-3-buten-1-ol compound as the substrate and benzophenone imine as the amination reagent, 2-aryl-3-ketoimine-substituted tetrahydrofuran molecule 1b was prepared (Reaction Scheme 2)

[0051]

[0052] To a 25 mL three-necked electric reaction flask equipped with a magnetic stirrer, 4-(3,4-dimethoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), benzophenone imine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were added successively. Subsequently, the reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred for 4 hours under a constant current of 8 mA and at room temperature. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (PE / EA / Et 3 N = 20:1:0.5 - 10:1:0.2) to obtain the target compound 1b (yellow oily liquid, dr > 20:1, 56.6 mg, 73%).

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

[0054] 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 7.2 Hz, 2H), 7.39–7.27 (m, 6H), 6.75 (s, 2H), 6.70 (d, J = 6.8 Hz, 2H), 6.67 (s, 1H), 4.86 (d, J = 6.9 Hz, 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 (101 MHz, CDCl 3)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 NO 3 ,388.1907;Found:388.1908.

[0057] Example 3: 4-(3-Bromo-4-methoxyphenyl)-3-buten-1-ol was used as the olefin substrate, and benzophenone imine was used as the amination reagent to prepare 2-aryl-3-imino-substituted tetrahydrofuran molecule 1c (Reaction Scheme 3)

[0058]

[0059] 4-(3-Bromo-4-methoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), benzophenone imine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were successively added to a 25 mL three-necked electric reaction flask equipped with a magnetic stir bar. Subsequently, the reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred for 4 hours under a constant current of 8 mA and at room temperature. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (PE / EA / Et 3 N = 20:1:0.5 - 10:1:0.2) to obtain the target compound 1c (yellow solid, dr > 20:1, 53.2 mg, 61%).

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

[0061] 1 H NMR(400MHz,CDCl 3) δ 7.66 (d, J = 7.3 Hz, 2H), 7.40–7.29 (m, 6H), 7.17 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 6.5 Hz, 2H), 6.76 (dd, J = 8.7, 2.4 Hz, 1H), 5.35 (d, J = 4.7 Hz, 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 (101 MHz, CDCl 3 ) δ 168.1, 159.3, 139.8, 136.7, 132.3, 130.1, 128.8, 128.7, 128.33, 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 BrNO 2 , 436.0907; Found: 436.0908.

[0064] Example 4: Using 4-(4-bromo)phenyl-3-buten-1-ol as the olefin substrate and benzophenone imine as the amination reagent, 2-aryl-3-imino-substituted tetrahydrofuran molecule 1d was prepared (Reaction Scheme 4)

[0065]

[0066] To a 25 mL three-necked electric reaction flask equipped with a stir bar, 4-(4-bromo)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), benzophenone imine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were added successively. Subsequently, the reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred at a constant current of 8 mA and room temperature for 5 hours. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (PE / EA / Et 3 N = 20:1:0.5 - 10:1:0.2) to obtain the target compound 1d (yellow oily liquid, dr > 20:1, 27.6 mg, 34%).

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

[0068] 1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )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-buten-1-ol as the olefin substrate and bis(4-methoxy)phenylketimine as the amination reagent, 2-aryl-3-imino-substituted tetrahydrofuran molecule 1e was prepared (Reaction Scheme 5)

[0072]

[0073] To a 25 mL three-necked electric reaction flask equipped with a magnetic stirrer, 4-(4-butoxy)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), bis(4-methoxy)phenylketimine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were added successively. Subsequently, the reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred at a constant current of 8 mA and room temperature for 4 hours. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (PE / EA / Et 3N = 20:1:0.5 - 10:1:0.2), the target compound 1e (yellow oily liquid, dr > 20:1, 68.9 mg, 75%) was obtained.

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

[0075] 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.0 Hz, 4H), 6.65 (d, J = 8.0 Hz, 2H), 4.87 (d, J = 6.8 Hz, 1H), 4.26–4.19 (m, 1H), 4.17–4.10 (m, 1H), 3.94 (t, J = 6.5 Hz, 2H), 3.81 (d, J = 1.9 Hz, 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 = 7.3 Hz, 3H).

[0076] 13 C NMR (101 MHz, CDCl 3 ) δ 168.1, 161.2, 159.3, 158.6, 133.1, 132.6, 130.2, 129.3, 129.1, 127.5, 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 NO 4 , 460.2482; Found: 460.2481.

[0078] Example 6: Using 4-(4-butoxyphenyl)-3-buten-1-ol as the olefin substrate and bis(4-fluoro)phenylketimine as the amination reagent, the 2-aryl-3-iminosubstituted tetrahydrofuran molecule 1f was prepared (Reaction Scheme 6)

[0079]

[0080] To a 25 mL three-necked electric reaction flask equipped with a magnetic stir bar, 4-(4-butoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), bis(4-fluorophenyl)methanimine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were added successively. Subsequently, the electric reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred for 4 hours under a constant current of 8 mA and at room temperature. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (PE / EA / Et 3 N = 20:1:0.5 - 10:1:0.2) to obtain the target compound 1f (yellow oily liquid, dr > 20:1, 60.1 mg, 69%).

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

[0082] 1 H NMR (400 MHz, CDCl 3 ) δ 7.60–7.53 (m, 2H), 7.07 (d, J = 8.6 Hz, 2H), 7.03–6.93 (m, 4H), 6.79 (d, J = 8.6 Hz, 2H), 6.67–6.59 (m, 2H), 4.83 (d, J = 6.9 Hz, 1H), 4.26–4.19 (m, 1H), 4.18–4.12 (m, 1H), 3.94 (t, J = 6.6 Hz, 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 = 7.4 Hz, 3H).

[0083] 13 C NMR (101 MHz, CDCl 3 ) δ 166.7, 164.6 (d, J = 173.2 Hz), 162.1 (d, J = 170.7 Hz), 158.8, 135.8 (d, J = 3.2 Hz), 132.4 (d, J = 3.6 Hz), 132.2, 130.6 (d, J = 8.6 Hz), 129.5 (d, J = 8.1 Hz), 127.5, 115.6 (d, J = 21.5 Hz), 115.2 (d, J = 21.6 Hz), 114.4, 86.1, 70.2, 67.9, 67.8, 34.7, 31.4, 19.4, 14.0.

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

[0085] HRMS(ESI, Q-TOF) m / z: [M + H + Calcd for C 27 H 28 F 2 NO 2 , 436.2083; Found: 436.2081.

[0086] Example 7: Using 4-(4-butoxyphenyl)-3-buten-1-ol as the olefin substrate and (4-bromophenyl)(phenyl)methanimine as the amination reagent, 1g of 2-aryl-3-iminosubstituted tetrahydrofuran molecules was prepared (Reaction Scheme 7)

[0087]

[0088] To a 25 mL three-necked electric reaction flask equipped with a magnetic stir bar, 4-(4-butoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), 4-bromophenyl(phenyl)methanimine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were added successively. Subsequently, the reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred for 4 hours under a constant current of 8 mA and at room temperature. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (PE / EA / Et 3 N = 20:1:0.5 - 10:1:0.2) to obtain the target compound 1g (yellow oily liquid, dr > 20:1, 50.7 mg, 53%).

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

[0090] 1 H NMR (400 MHz, CDCl 3)δ 7.49–7.42 (m, 4H), 7.36–7.31 (m, 1H), 7.29–7.26 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 7.1 Hz, 2H), 4.86 (d, J = 6.7 Hz, 1H), 4.26–4.19 (m, 1H), 4.17–4.10 (m, 1H), 3.93 (t, J = 6.5 Hz, 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 = 7.3 Hz, 3H).

[0091] 13 C NMR (101 MHz, CDCl 3 ) δ 158.7, 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 BrNO 2 , 478.1376; Found: 478.1377.

[0093] Example 8: Using 4-(4-butoxyphenyl)-3-buten-1-ol as the olefin substrate and diphenylketimine as the amination reagent, 2-aryl-3-aminotetrahydrofuran molecule 1h was prepared (Reaction Scheme 8)

[0094]

[0095] To a 25 mL three-necked electric reaction flask equipped with a magnetic stir bar, 4-(4-butoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), diphenylketimine (0.6 mmol, 3.0 equiv.), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv.) and acetonitrile (12 mL) were added successively. Subsequently, the reaction flask was evacuated and filled with argon (repeated three times), and the reaction was stirred for 4 hours under a constant current of 8 mA and at room temperature. After the reaction was completed, the crude reaction solution was obtained through extraction, drying, filtration and rotary evaporation under reduced pressure. The crude reaction solution was purified by a short silica gel column (eluent: petroleum ether: ethyl acetate: triethylamine = 4:1:1), and the resulting liquid was further concentrated. The concentrated solution was dissolved in MeOH (10 mL), and 2 M HCl (5.0 equiv.) was slowly added. It was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain the crude product. The crude product 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 NMR data of the target compound 1h are as follows:

[0097] 1 H NMR(400MHz,CD 3 OD)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,CD 3 OD)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 NO 2 ,236.1645;Found:236.1645.

[0100] Verification of anti-tumor activity:

[0101] Select the 2-aryl-3-ketoiminotetrahydrofuran compounds prepared in the examples, using human breast cancer cells (MCF-7 cells) as receptors, and test their in vitro anti-tumor activity (CCK-8 method).

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

[0103] (1) Collect cells in the logarithmic phase and add them to a 96-well plate, 100 μL per well, and plate to make the density of the cells to be tested 5000 cells / well. The cells are incubated at 5% CO 2 , 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 medium in the 96-well plate, add new medium containing different compound concentrations, 100 μL per well, and set 3 replicate wells for each group; (4) Incubate the treated cells at 5% CO 2 , 37 °C for 48 hours, and observe under an inverted microscope; (5) Add 10 μL of CCK-8 solution to each well and continue to culture for 1-4 h; (6) When the color of the solution in the 96-well plate gradually turns orange-red and there is an obvious color change, use an automatic microplate reader to detect the absorbance value (OD) of each well at a wavelength of 450 nm; (7) At the same time, set a zero-adjustment well (medium, CCK-8 solution), a positive control well (cells, cisplatin dissolution medium with the same concentration, culture solution, CCK-8 solution), and a blank control well (without drug, only cells, culture solution and CCK-8 solution); (8) Plot the cell survival rate (%) against the logarithmically transformed drug concentration (such as log(drug concentration)), and use non-linear regression curve fitting to fit the data (GraphPad Prism) to calculate the IC50 value of compound 1e; (9) The tumor inhibition experiments of the 2-aryl-3-ketoiminotetrahydrofuran compounds prepared in other examples and their cisplatin (CDDP) control groups are operated according to a similar method 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] As Figure 19 The results show that the 2-aryl-3-ketoiminotetrahydrofuran compounds prepared in the present invention have a certain inhibitory effect on human breast cancer cells.

[0107] The above are only embodiments of the present invention, and common knowledge such as specific structures and characteristics known in the art are not described in detail herein. It should be noted that for those skilled in the art, without departing from the structure of the present invention, several modifications and improvements can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the implementation effect of the present invention and the practicability of the patent. The protection scope claimed in this application shall be subject to the content of its claims, and the specific implementation manners described 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 or 2-naphthyl; 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; 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 or tetraethylammonium trifluoroacetate.

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

4. 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.

5. 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.

6. 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.

7. 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.

8. Use of the compound according to claim 1 and / or the compound prepared by the method according to any one of claims 2 to 7 in the preparation of an anti-human breast cancer drug.

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