A 2-aryl-3-acyloxytetrahydrofuran compound, a preparation method thereof and an application thereof

Abstract

The present application discloses 2-aryl-3-acyloxytetrahydrofuran compounds in the field of organic synthesis technology, and their structural formula is as follows: These compounds are prepared through the following steps: Using 4-aryl-3-butenol and an alkyl or aryl carboxylic acid as raw materials, reacting in an electrolytic cell under a constant current electrolysis reaction mode, and obtaining 2-aryl-3-acyloxytetrahydrofuran compounds through further separation and purification. This method has mild conditions and does not require an external oxidant, providing a green and efficient preparation method for alkoxy-modified tetrahydrofuran compounds, and further promoting the research on the biological activities of related compounds.

Description

Technical Field

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

[0002] Tetrahydrofurans modified with oxygen-containing functional groups are widely present in natural products and bioactive molecules. For example, natural products with anti-tumor activity such as (+)-Varitriol, selective respiratory syncytial virus (RSV) polymerase inhibitor ALS-8122, and drugs such as afatinib used for the treatment of advanced non-small cell lung cancer all contain this type of heterocyclic structure. Therefore, the development of a variety of structurally diverse oxygen-containing functional group-substituted tetrahydrofuran compounds is of great significance for promoting the biological activity research of related molecules and the discovery of lead compounds. At present, the research on the direct one-step synthesis of tetrahydrofurans modified with oxygen-containing functional groups is relatively less, and mainly uses two-step reactions, namely the epoxidation reaction of the double bond of unsaturated alcohols and the subsequent intramolecular nucleophilic ring-opening reaction of alcohol hydroxyl groups (J. Org. Chem. 2002, 67, 3479; Tetrahedron Lett. 2002, 43, 1495).

[0003] The olefin epoxidation part often requires the use of excessive chemical oxidants, resulting in equivalent by-products and also affecting the compatibility of substrate functional groups. 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-acyl-oxy tetrahydrofuran compounds in one step under organic electrochemical synthesis conditions.

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

[0006]

[0007] Wherein: Ar is 4-methylphenyl, biphenyl, 2-naphthyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3-methyl-4-methoxyphenyl or 2,3-dihydrobenzofuran-5-yl; R is hydrogen, methyl, ethyl, propyl, cyclopropyl, butyl, phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, biphenyl, 2-naphthyl, 2-thienyl, 2-furyl or 2-benzofuryl.

[0008] The second object of the present invention is to provide a preparation method of 2-aryl-3-acyl-oxytetrahydrofuran compounds, and the reaction formula is as follows:

[0009]

[0010] 4-aryl-3-butenol, carboxylic acid, electrolyte and solvent are sequentially added into an electrolytic cell equipped with cathode and anode electrode materials, and the reaction is carried out under a constant current condition in the electrolytic cell, and 2-aryl-3-acyl-oxytetrahydrofuran compounds are obtained through subsequent separation and purification; the carboxylic acid is an alkyl carboxylic acid or an aryl carboxylic acid.

[0011] The working principle and beneficial effects of the present invention: The present invention innovatively uses 4-aryl-3-butenol and alkyl or aryl carboxylic acid as raw materials, and 2-aryl-3-acyl-oxytetrahydrofuran compounds are obtained through an organic electrochemical synthesis condition reaction and subsequent purification process. This reaction makes full use of the characteristics of organic electrochemical technology to develop a new reaction mode to synthesize 2-aryl-3-acyl-oxytetrahydrofuran compounds with novel and diverse structures.

[0012] The conditions of the present invention are mild, the raw materials are simple, the operation is convenient, and the product is easy to be further hydrolyzed, providing a green and efficient preparation method for 2-aryl-3-acyl-oxytetrahydrofuran compounds and their derivatives.

[0013] Furthermore, the molar ratio of each substance in the reaction: 4-aryl-3-butenol: electrolyte: carboxylic acid = 1: 0.5 - 5: 1 - 100.

[0014] Furthermore, when the carboxylic acid is a solid or a high-boiling liquid, 4-aryl-3-butenol: electrolyte: carboxylic acid = 1: 3: 2; when the carboxylic acid is a low-boiling liquid, 4-aryl-3-butenol: electrolyte: carboxylic acid = 1: 1: 30 - 100.

[0015] Further, the electrolyte is selected from tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate or lithium perchlorate. Preferably, it is tetrabutylammonium acetate.

[0016] Further, the solvent is selected from one or more of acetonitrile, dimethyl sulfoxide, dichloromethane, water, methanol or N,N-dimethylformamide. Preferably, it is acetonitrile.

[0017] Further, the electrode material includes an anode electrode material and a cathode electrode material. The anode electrode material is selected from a carbon rod, carbon felt, carbon cloth, platinum sheet or nickel sheet, and preferably a carbon rod electrode; the cathode electrode material is selected from a carbon rod, platinum sheet, nickel sheet, copper sheet, iron sheet or zinc sheet, and preferably a platinum sheet.

[0018] Further, the current is 1 - 30 mA, preferably 6 mA; the temperature used is 0 °C - 60 °C, preferably 25 °C; the reaction time is 0.5 - 20 hours, preferably 4 hours; the gas atmosphere is selected from air, argon, nitrogen and oxygen, preferably argon. When the gas atmosphere is air, the electrolytic cell is not evacuated. The separation and purification method is selected from column chromatography and recrystallization, preferably column chromatography.

[0019] Further, the electrolytic cell is selected from a diaphragm-free electrolytic cell and a separated electrolytic cell. Preferably, it is a diaphragm-free electrolytic cell.

[0020] The third object of the present invention is to provide the use of 2-aryl-3-acyloxytetrahydrofuran compounds in the preparation of anti-cancer drugs. Specifically, the cancer is human breast cancer.

[0021] It has been verified that the 2-aryl-3-acyloxytetrahydrofuran compounds have drug activity against human breast cancer MCF-7 cells. Description of the Drawings

[0022] Figure 1 Single crystal drawing of compound 1h prepared in Example 8;

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

[0024] Figure 3 For compound 1a prepared in Example 1 13 13C NMR spectrum;

[0025] Figure 4 For compound 1b prepared in Example 2 1 1H NMR spectrum;

[0026] Figure 5 For compound 1b prepared in Example 2 13 13C NMR spectrum;

[0027] Figure 6 1H NMR spectrum of compound 1c prepared in Example 3; 1 ;

[0028] Figure 7 13C NMR spectrum of compound 1c prepared in Example 3; 13 ;

[0029] Figure 8 1H NMR spectrum of compound 1d prepared in Example 4; 1 ;

[0030] Figure 9 13C NMR spectrum of compound 1d prepared in Example 4; 13 ;

[0031] Figure 10 1H NMR spectrum of compound 1e prepared in Example 5; 1 ;

[0032] Figure 11 13C NMR spectrum of compound 1e prepared in Example 5; 13 ;

[0033] Figure 12 19F NMR spectrum of compound 1e prepared in Example 5; 19 ;

[0034] Figure 13 1H NMR spectrum of compound 1f prepared in Example 6; 1 ;

[0035] Figure 14 13C NMR spectrum of compound 1f prepared in Example 6; 13 ;

[0036] Figure 15 1H NMR spectrum of compound 1g prepared in Example 7; 1 ;

[0037] Figure 16 13C NMR spectrum of compound 1g prepared in Example 7; 13 ;

[0038] Figure 17 1H NMR spectrum of compound 1h prepared in Example 8; 1 ;

[0039] Figure 18 13C NMR spectrum of compound 1h prepared in Example 8; 13 ;

[0040] Figure 19 1H NMR spectrum of compound 1i prepared in Example 9;1 1H NMR spectrum

[0041] Figure 20 For compound 1i prepared in Example 9 13 13C NMR spectrum

[0042] Figure 21 For compound 1j prepared in Example 10 1 1H NMR spectrum

[0043] Figure 22 For compound 1j prepared in Example 10 13 13C NMR spectrum

[0044] Figure 23 For compound 1k prepared in Example 11 1 1H NMR spectrum

[0045] Figure 24 For compound 1k prepared in Example 11 13 13C NMR spectrum

[0046] Figure 25 Schematic diagram of the inhibitory effect of some compounds on the proliferation of human breast cancer cells (MCF-7 cells). Detailed implementation mode

[0047] The following is a further detailed description through specific implementation modes:

[0048] Example 1: Using 4-(4-butoxyphenyl)-3-buten-1-ol as the olefin substrate and acetic acid as the acidifying reagent, prepare 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1a (Reaction Scheme 1)

[0049]

[0050] 4-(4-butoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), n Bu 4NOAc (0.2 mmol, 1.0 equiv.), MeCN (12 mL), acetic acid (2.0 mL) and a magnetic stir bar were successively added into a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rods and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon gas (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 5 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration processes to obtain the crude reaction product. The crude reaction product was purified by column chromatography (petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain a colorless oily liquid product 1a (dr > 20:1, 41.8 mg, 75%).

[0051] The detection data of product 1a are as follows:

[0052] 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.12 (d, J = 5.7 Hz, 1H), 4.95 (s, 1H), 4.27–4.21 (m, 1H), 4.10–4.03 (m, 1H), 3.94 (t, J = 6.5 Hz, 2H), 2.25–2.15 (m, 1H), 2.11 (s, 3H), 2.01–1.94 (m, 1H), 1.78–1.71 (m, 2H), 1.53–1.43 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0053] 13 C NMR (101 MHz, CDCl 3 ) δ 170.9, 158.7, 132.0, 126.8, 114.4, 85.2, 81.0, 67.72, 67.66, 31.4, 31.2, 21.3, 19.3, 14.0.

[0054] HRMS (ESI, Q-TOF) m / z: [M + H + Calcd for C 16 H 23 O 4 , 279.1591; Found: 279.1592.

[0055] Example 2: Using 4-(4-butoxyphenyl)-3-buten-1-ol as the olefin substrate and formic acid as the acidifying reagent, 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1b was prepared (Reaction Scheme 2)

[0056]

[0057] 4-(4-Butoxy)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), n Bu 4 NOAc (0.2 mmol, 1.0 equiv.) and MeCN (12 mL), formic acid (2.0 mL) and a magnetic stir bar were successively added to a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rods and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and argon gas was injected into the reaction system for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 5 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration processes to obtain the crude reaction product. The crude reaction product was purified by column chromatography (petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain a colorless oily liquid product 1b (dr > 20:1, 34.4 mg, 65%).

[0058] The detection data of product 1b are as follows:

[0059] 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.28 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.23 (d, J = 5.2 Hz, 1H), 4.96 (s, 1H), 4.28–4.21 (m, 1H), 4.10–4.03 (m, 1H), 3.93 (t, J = 6.5 Hz, 2H), 2.27–2.18 (m, 1H), 2.03–1.97 (m, 1H), 1.78–1.71 (m, 2H), 1.51–1.44 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0060] 13 C NMR (101 MHz, CDCl 3 ) δ 160.7, 158.8, 131.7, 126.8, 114.5, 85.1, 80.6, 67.7, 67.6, 31.4, 31.2, 19.3, 13.9.

[0061] HRMS (ESI, Q-TOF) m / z: [M+Na + Calcd for C 15 H 20 O 4 Na, 287.1254; Found: 287.1259.

[0062] Example 3: Using 4-(4-butoxy)phenyl-3-buten-1-ol compound as a substrate and cyclopropylformic acid as an acidifying reagent, 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1c was prepared (Reaction Scheme 3).

[0063]

[0064] 4-(4-Butoxy)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), n Bu 4 NOAc (0.2 mmol, 1.0 equiv.), MeCN (12 mL), cyclopropylformic acid (2.0 mL) and a magnetic stir bar were successively added into a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rod and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 5 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration to obtain the crude reaction product. The crude reaction product was purified by column chromatography (petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain a colorless oily liquid product 1c (dr > 20:1, 41.4 mg, 68%).

[0065] The detection data of product 1c are as follows:

[0066] 1 H NMR (400 MHz, CD 3 OD) δ 7.24 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.05–5.00 (m, 1H), 4.84 (s, 1H), 4.24–4.18 (m, 1H), 4.07–3.98 (m, 1H), 3.92 (t, J = 6.4 Hz, 2H), 2.23–2.12 (m, 1H), 2.00–1.93 (m, 1H), 1.75–1.64 (m, 3H), 1.51–1.42 (m, 2H), 0.98–0.88 (m, 7H).

[0067] 13 C NMR (101 MHz, CD 3 OD) δ 176.3, 160.1, 133.3, 127.9, 115.3, 86.6, 82.4, 68.64, 68.61, 32.5, 32.0, 20.3, 14.2, 13.7, 9.1, 9.0.

[0068] HRMS ESI, Q-TOF) m / z: [M+H + Calcd for C18 H 25 O 4 , 305.1747; Found: 305.1744.

[0069] Example 4: Using 4-(4-butoxy)phenyl-3-buten-1-ol compound as a substrate and benzoic acid as an acidifying reagent, 2-aryl-3-ester carbonyl substituted tetrahydrofuran molecule 1d was prepared (Reaction Formula 4)

[0070]

[0071] 4-(4-butoxy)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), benzoic acid (0.4 mmol, 2.0 equiv), n Bu 4 NOAc (0.2 mmol, 1.0 equiv.), MeCN (12 mL) and a magnetic stir bar were successively added into a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rod and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 5 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration to obtain the crude reaction product. The crude reaction product was purified by column chromatography (petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain a colorless oily liquid product 1d (dr > 20:1, 36.8 mg, 54%).

[0072] The detection data of product 1d are as follows:

[0073] 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.39 (d, J = 5.6 Hz, 1H), 5.14 (s, 1H), 4.37–4.30 (m, 1H), 4.23–4.16 (m, 1H), 3.96 (t, J = 6.5 Hz, 2H), 2.38–2.28 (m, 1H), 2.19–2.12 (m, 1H), 1.81–1.73 (m, 2H), 1.54–1.45 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0074] 13 C NMR (101 MHz, CDCl 3)δ166.3,158.7,133.3,132.1,130.0,129.7,128.5,126.8,114.4,85.3,81.6,67.8,67.7,31.37,31.35,19.3,14.0.

[0075] HRMS(ESI,Q - TOF)m / z: [M + H + Calcd for C 21 H 25 O 4 ,341.1747;Found:341.1746.

[0076] Example 5: Using 4-(4-butoxy)phenyl-3-buten-1-ol as the olefin substrate and p-fluorobenzoic acid as the acidifying reagent, 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1e was prepared (Reaction Scheme 5)

[0077]

[0078] 4-(4-butoxy)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), p-fluorobenzoic acid (0.4 mmol, 2.0 equiv), n Bu 4 NOAc (0.6 mmol, 1.0 equiv.), MeCN (12 mL) and a magnetic stir bar were successively added into a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rod and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 5 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration to obtain the crude reaction product. The crude reaction product was purified by column chromatography (petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain the product 1e as a colorless oily liquid (dr > 20:1, 43.0 mg, 60%).

[0079] The detection data of product 1e are as follows:

[0080] 1 H NMR(400MHz,CDCl 3)δ8.14–8.05(m,2H),7.35(d,J=8.4Hz,2H),7.13(t,J=8.5Hz,2H),6.90(d,J=8.4Hz,2H),5.37(d,J=5.1Hz,1H),5.11(s,1H),4.32(t,J=7.6Hz,1H),4.21–4.14(m,1H),3.96(t,J=6.4Hz,2H),2.37–2.27(m,1H),2.17–2.10(m,1H),1.80–1.74(m,2H),1.54–1.46(m,2H),0.97(t,J=7.3Hz,3H).

[0081] 13 C NMR(101MHz,CDCl 3 )δ166.0(d,J=254.4Hz),165.4,158.8,132.3(d,J=9.4Hz),132.0,126.8,126.4(d,J=2.9Hz),115.7(d,J=22.0Hz),114.5,85.3,81.8,67.83,67.78,31.42,31.39,19.4,14.0.

[0082] 19 F NMR(376MHz,CDCl3)δ-105.14.

[0083] HRMS(ESI,Q-TOF)m / z:[M+H + Calcd for C 21 H 24 FO 4 ,359.1653;Found:359.1657.

[0084] Example 6: Using 4-(4-butoxy)phenyl-3-buten-1-ol as the olefin substrate and 4-bromobenzoic acid as the acidifying reagent, 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1f was prepared (Reaction Scheme 6)

[0085]

[0086] 4-(4-butoxy)phenyl-3-buten-1-ol(0.2mmol, 1.0equiv.), 4-bromobenzoic acid(0.4mmol, 2.0equiv), n Bu 4NOAc (0.6 mmol, 1.0 equiv.), MeCN (12 mL), and a magnetic stir bar were successively added to a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rods and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and purged with argon (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 4 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration, and concentration to obtain the crude reaction product. The crude reaction product was purified by column chromatography (petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain the colorless oily liquid product 1f (dr > 20:1, 40.3 mg, 48%).

[0087] The detection data of product 1f are as follows:

[0088] 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 5.36 (d, J = 5.6 Hz, 1H), 5.11 (s, 1H), 4.35–4.29 (m, 1H), 4.21–4.14 (m, 1H), 3.95 (t, J = 6.5 Hz, 2H), 2.37–2.27 (m, 1H), 2.17–2.10 (m, 1H), 1.79–1.73 (m, 2H), 1.52–1.46 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H).

[0089] 13 C NMR (101 MHz, CDCl 3 ) δ 165.7, 158.8, 132.0, 131.9, 131.3, 129.0, 128.5, 126.8, 114.5, 85.3, 81.9, 67.84, 67.80, 31.43, 31.37, 19.4, 14.0.

[0090] HRMS (ESI, Q-TOF) m / z: [M + H + Calcd for C 21 H 24 BrO 4 , 419.0852; Found: 419.0846.

[0091] Example 7: Using 4-(4-butoxy)phenyl-3-buten-1-ol as the olefin substrate and 2-furoic acid as the acidifying reagent, 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1g was prepared (Reaction Scheme 7)

[0092]

[0093] 4-(4-Butoxy)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), 2-furoic acid (0.4 mmol, 2.0 equiv), n Bu 4 NOAc (0.6 mmol, 1.0 equiv.), MeCN (12 mL) and a magnetic stir bar were successively added into a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rod and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 4 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration processes to obtain the crude reaction product. The crude reaction product was purified by column chromatography (using petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain 1 g of a colorless oily liquid product (dr > 20:1, 45.6 mg, 69%).

[0094] The detection data of 1 g of the product are as follows:

[0095] 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 0.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 2.9 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.55–6.49 (m, 1H), 5.34 (d, J = 5.6 Hz, 1H), 5.12–5.08 (m, 1H), 4.33–4.26 (m, 1H), 4.19–4.11 (m, 1H), 3.94 (t, J = 6.5 Hz, 2H), 2.34–2.24 (m, 1H), 2.15–2.10 (m, 1H), 1.79–1.73 (m, 2H), 1.52–1.45 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0096] 13 C NMR (101 MHz, CDCl 3 ) δ 158.8, 158.4, 146.7, 144.5, 131.9, 126.8, 118.4, 114.5, 112.0, 85.2, 81.6, 67.7, 31.4, 31.3, 21.3, 19.3, 13.9.

[0097] HRMS (ESI, Q-TOF) m / z: [M+H +Calcd for C 19 H 23 O 5 , 331.1540; Found: 331.1538.

[0098] Example 8: Using 4-(4-butoxyphenyl)-3-buten-1-ol as the olefin substrate and benzofuran-2-carboxylic acid as the acidifying reagent, 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1h was prepared (Reaction Scheme 8)

[0099]

[0100] 4-(4-butoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), benzofuran-2-carboxylic acid (0.4 mmol, 2.0 equiv), n Bu 4 NOAc (0.6 mmol, 1.0 equiv.), MeCN (12 mL) and a magnetic stir bar were successively added to a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rod and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 5 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration to obtain the crude reaction product. The crude reaction product was purified by column chromatography (using petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain a colorless oily liquid product 1h (dr > 20:1, 50.2 mg, 66%).

[0101] The detection data of product 1h are as follows:

[0102] 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J = 7.9 Hz, 1H), 7.64–7.57 (m, 2H), 7.50–7.45 (m, 1H), 7.39–7.30 (m, 3H), 6.90 (d, J = 8.7 Hz, 2H), 5.42 (d, J = 5.7 Hz, 1H), 5.15 (s, 1H), 4.36–4.31 (m, 1H), 4.24–4.17 (m, 1H), 3.96 (t, J = 6.5 Hz, 2H), 2.40–2.29 (m, 1H), 2.22–2.15 (m, 1H), 1.80–1.72 (m, 2H), 1.54–1.44 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0103] 13 C NMR (101 MHz, CDCl3 )δ159.4,158.9,156.0,145.4,131.9,128.0,127.0,126.9,124.0,123.0,114.6,114.5,112.5,85.2,82.2,67.8,31.4,19.4,14.0.

[0104] HRMS(ESI,Q - TOF)m / z: [M + H + Calcd for C 23 H 25 O 5 ,381.1697;Found:381.1698.

[0105] The single crystal of product 1h is as Figure 1 shown, and the specific data are as follows in Table 1:

[0106]

[0107]

[0108] Example 9: Using 4-(4-butoxy)phenyl-3-buten-1-ol as the olefin substrate and 2,5-dichlorophenylacetic acid as the acidifying reagent, 2-aryl-3-ester carbonyl-substituted tetrahydrofuran molecule 1i was prepared (Reaction Scheme 9)

[0109]

[0110] 4-(4-butoxy)phenyl-3-buten-1-ol (0.2 mmol, 1.0 equiv.), 2,5-dichlorophenylacetic acid (0.4 mmol, 2.0 equiv), n Bu 4 NOAc (0.6 mmol, 1.0 equiv.), MeCN (12 mL) and a magnetic stir bar were successively added into a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rod and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 4 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration processes to obtain the crude reaction product. The crude reaction product was purified by column chromatography (using petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 10:1 - 5:1) to obtain a colorless oily liquid 1i (dr > 20:1, 32.2 mg, 38%).

[0111] The detection data of product 1i are as follows:

[0112] 1 H NMR(400MHz,CDCl3 ) δ 7.35–7.30 (m, 2H), 7.29 (s, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.25–7.20 (m, 1H), 6.86 (d, J = 8.7 Hz, 2H), 5.16 (d, J = 5.6 Hz, 1H), 4.97 (s, 1H), 4.28–4.21 (m, 1H), 4.08–4.01 (m, 1H), 3.94 (t, J = 6.5 Hz, 2H), 3.79 (s, 2H), 2.26–2.16 (m, 1H), 2.04–1.97 (m, 1H), 1.78–1.71 (m, 2H), 1.52–1.44 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0113] 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 169.9, 158.8, 133.9, 133.0, 132.8, 131.9, 131.5, 130.7, 129.0, 126.8, 114.4, 85.1, 82.0, 67.8, 67.7, 39.3, 31.4, 31.1, 19.4, 14.0.

[0114] HRMS (ESI, Q-TOF) m / z: [M + H + Calcd for C 22 H 25 Cl 2 O 4 , 423.1124; Found: 423.1121.

[0115] Example 10: Using (3,4-dimethoxyphenyl)-3-buten-1-ol as the olefin substrate and acetic acid as the acidifying reagent, 2-aryl-3-ester carbonyl substituted tetrahydrofuran molecule 1j was prepared (Reaction Scheme 10)

[0116]

[0117] (3,4-dimethoxyphenyl)-3-buten-1-ol substrate (0.2 mmol, 1.0 equiv.), n Bu 4NOAc (0.2 mmol, 1.0 equiv.), MeCN (12 mL), acetic acid (2.0 mL) and a magnetic stir bar were successively added into a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rod and platinum sheet electrodes. Subsequently, the reaction system was evacuated with an oil pump and then purged with argon (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 3 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration and concentration to obtain the crude reaction product. The crude reaction product was purified by column chromatography using a mixture of petroleum ether and ethyl acetate (PE / EA = 10:1 - 5:1) to obtain the colorless oily liquid product 1j (dr > 20:1, 33.5 mg, 63%).

[0118] The detection data of product 1j are as follows:

[0119] 1 H NMR (400 MHz, CDCl 3 ) δ 6.93–6.87 (m, 2H), 6.80 (d, J = 8.1 Hz, 1H), 5.10 (d, J = 5.7 Hz, 1H), 4.91 (s, 1H), 4.24–4.19 (m, 1H), 4.08–4.01 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.21–2.12 (m, 1H), 2.08 (s, 3H), 1.98–1.91 (m, 1H).

[0120] 13 C NMR (101 MHz, CDCl 3 ) δ 170.9, 148.9, 148.4, 132.7, 117.6, 110.9, 108.7, 85.2, 81.0, 67.7, 55.9, 55.8, 31.0, 21.2.

[0121] HRMS (ESI, Q-TOF) m / z: [M+H + Calcd for C 14 H 19 O 5 , 267.1227; Found: 267.1225.

[0122] Example 11: Using 4-(4-butoxyphenyl)-3-buten-1-ol as the olefin substrate and acetic acid as the acidifying reagent, 2-aryl-3-hydroxy-substituted tetrahydrofuran molecule 1k was prepared (Reaction Scheme 11)

[0123]

[0124] (3,4-Dimethoxyphenyl)-3-buten-1-ol (0.2 mmol, 1.0 equiv.), n Bu 4 NOAc (0.2 mmol, 1.0 equiv.) and MeCN (12 mL), acetic acid (2.0 mL) and a magnetic stir bar were successively added to a three-necked flask, and the reaction flask was sealed with a rubber stopper equipped with carbon rods and platinum plate electrodes. Subsequently, the reaction system was evacuated with an oil pump and then filled with argon for protection (this operation was repeated three times). Under stirring at room temperature, electrolysis was carried out for 5 hours with a constant current (direct current, output by a constant current potentiostat). After the reaction was completed, the reaction solution was subjected to extraction, drying, filtration, and concentration to obtain the crude reaction product. The crude product was dissolved in MeOH (10 mL), and then K 2 CO 3 (2.0 equiv.) was added, and the reaction was stirred at room temperature for 2 hours. After 2 hours, the reaction solution was subjected to extraction, drying, filtration, and concentration to obtain the crude reaction product. The crude reaction product was purified by column chromatography using a mixture of petroleum ether and ethyl acetate (PE / EA = 3:1 - 1:1) to obtain a colorless oily liquid product 1k (dr > 20:1, 31.2 mg, 66%).

[0125] The detection data of product 1l are as follows:

[0126] 1 H NMR (400 MHz, DMSO-d6) δ 7.04 (d, J = 8.2 Hz, 2H), 6.72 (d, J = 8.2 Hz, 2H), 5.10 (d, J = 3.9 Hz, 1H), 4.37 (d, J = 2.4 Hz, 1H), 3.91–3.82 (m, 2H), 3.80–3.72 (m, 3H), 1.91–1.81 (m, 1H), 1.67–1.60 (m, 1H), 1.56–1.48 (m, 2H), 1.32–1.22 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H).

[0127] 13 C NMR (101 MHz, DMSO-d6) δ 157.9, 133.8, 126.9, 114.1, 86.8, 77.7, 67.2, 66.7, 34.2, 30.9, 18.9, 13.8.

[0128] HRMS (ESI, Q-TOF) m / z: [M+H + Calcd for C 14 H 21 O 3 , 237.1485; Found: 237.1486.

[0129] Anti-tumor activity verification experiment:

[0130] Select the 2-aryl-3-acetyloxytetrahydrofuran compounds prepared in the examples, use human breast cancer cells (MCF-7 cells) as receptors, and use the CCK-8 method to test their in vitro anti-tumor activity.

[0131] Taking compound 1e of Example 5 as an example to illustrate the activity test process: (1) Collect cells in the logarithmic phase, adjust the cell suspension concentration, add 100 μL to each well, and plate to make the density of the cells to be tested 5000 cells / well; (2) 5% CO 2 , incubate at 37 °C until the cell monolayer covers the bottom of the 96-well flat bottom plate, and then add compound 1e with a concentration gradient (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), set 3 replicates; (3) 5% CO 2 , incubate at 37 °C for 48 hours, and observe under an inverted microscope; (4) Add 10 μL of CCK-8 solution to each well and continue to culture for 1-4 h; (4) Wait until the color of the solution in the 96-well plate gradually turns orange-red, and when there is an obvious color change, measure the absorbance value of each well at OD450nm on an automatic microplate reader; (5) At the same time, set a zero-adjustment well (culture 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); (6) 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 obtain the IC50 value of compound 1e; (7) The tumor inhibition experiments of the 2-aryl-3-acetyloxytetrahydrofuran compounds prepared in other examples and cisplatin are operated according to a similar method above.

[0132] Table 2 shows the inhibitory effects of some compounds in the examples on the proliferation of human breast cancer cells (MCF-7 cells).

[0133] Compound Human breast cancer cells (MCF-7 cells) [IC50 (μM)] Compound 1e of Example 5 67.09 Compound 1f of Example 6 54.00 Compound 1h of Example 8 42.97 Compound 1i of Example 9 18.18 Cisplatin 7.62

[0134] As Figure 25 shown, the results show that: the 2-aryl-3-acetyloxytetrahydrofuran compounds prepared by the present invention have a certain inhibitory effect on human breast cancer cells.

[0135] 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 practicality of the patent. The protection scope required by this application shall be subject to the content of its claims, and the specific implementation manners and the like recorded in the specification can be used to interpret the content of the claims.

Claims

1. A 2-aryl-3-acyloxytetrahydrofuran compound, characterized in that: Its structural formula is as follows: ， Wherein: Ar is p-4-methylphenyl, biphenyl, 2-naphthyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3-methyl-4-methoxyphenyl or 2,3-dihydrobenzofuran-5-yl; R is hydrogen, methyl, ethyl, propyl, cyclopropyl, butyl, phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, biphenyl, 2-naphthyl, 2-thienyl, 2-furyl or 2-benzofuranyl.

2. The method for preparing 2-aryl-3-acyloxytetrahydrofuran compounds according to claim 1, characterized in that: The reaction formula is as follows: ； 4-aryl-3-butenol, carboxylic acid, electrolyte and solvent are sequentially added into an electrolytic cell equipped with cathode and anode electrode materials, reacted in the electrolytic cell under constant current conditions, and 2-aryl-3-acyloxytetrahydrofuran compounds are subsequently separated and purified, wherein the electrolyte is selected from tetra-n-butylammonium tetrafluoroborate or tetra-n-butylammonium hexafluorophosphate.

3. The preparation method according to claim 2, characterized in that: The molar ratio of each substance in the reaction: 4-aryl-3-butenol: electrolyte: carboxylic acid = 1:0.5~5:1~100.

4. The preparation method according to claim 3, characterized in that: When the carboxylic acid is a solid or high-boiling point liquid, 4-aryl-3-butenol: electrolyte: carboxylic acid = 1:1:2; when the carboxylic acid is a low-boiling point liquid, 4-aryl-3-butenol: Electrolyte: carboxylic acid = 1:1:30~100.

5. The preparation method according to claim 2, characterized in that: The solvent is selected from one or more of acetonitrile, dimethyl sulfoxide, dichloromethane, water, methanol or N,N-dimethylformamide.

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 rods, carbon felt, carbon cloth, platinum sheets or nickel sheets; the cathode electrode materials are selected from carbon rods, platinum sheets, nickel sheets, copper sheets, iron sheets or zinc sheets.

7. The preparation method according to claim 2, characterized in that: The current is 1 mA to 30 mA; the temperature is 0°C to 60°C; the reaction time is 0.5 h to 20 h; the gas atmosphere is selected from air, argon, nitrogen and oxygen; and the separation and purification method is selected from column chromatography or recrystallization.

8. Use of the compound according to claim 1 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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