Preparation and application of hesperetin derivative with antioxidant activity

Abstract

The invention belongs to the field of natural products and medicinal chemistry, and discloses a compound taking hesperetin as a mother nucleus as well as a preparation method and application of the compound. The preparation method of the compound taking hesperetin as the mother nucleus comprises the following steps: (1) weighing hesperidin, adding methanol and concentrated sulfuric acid for dissolving, heating and stirring at high temperature, and hydrolyzing hesperidin to remove glycosyl so as to generate hesperetin; (2) adding 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 4-dimethylaminopyridine (DMAP) and organic acid into a solvent, mixing, then adding hesperetin, and stirring at room temperature until the reaction is finished; and (3) taking the reaction liquid obtained in the step (1), extracting, carrying out reduced pressure distillation to recover the solvent, and purifying to obtain the hesperetin cinnamic acid derivative with the structural general formula as shown in the formula I. The preparation method is simple, raw materials are easy to obtain, the flavonoid derivative prepared through the method has good antioxidant activity, and a new thought can be provided for development of antioxidant drugs.

Description

Technical Field

[0001] The present invention belongs to the field of natural products and medicinal chemistry, and relates to a compound with hesperetin as the core, its preparation method and application. Background Art

[0002] In the normal physiological metabolism process, the body will produce various highly active free radicals. When stimulated by the outside world, it will lead to the imbalance of antioxidant substances, and then cause the state of oxidative stress, resulting in the loss of the structure and function of some macromolecules in the body, and triggering adverse consequences such as the disorder of the physiological functions of organelles. Research shows that excessive oxidative stress is closely related to the poor prognosis of cardiovascular diseases, cancers and neurodegenerative diseases, etc.

[0003] Hesperidin and hesperetin are widely present in citrus fruits and belong to dihydroflavonoids. Hesperetin has the effects of anti-inflammatory, antibacterial, antioxidant, and inhibiting fibrosis, and has low toxicity; in recent years, there have been literature reports that hesperetin also has the effects of treating related diseases such as cancer, cardiovascular system, and central nervous system, and has broad development and application prospects; however, due to its defects of poor water solubility, low bioavailability and insufficient pharmacological activity, its further clinical application is affected.

[0004] Aiming at the problems of low bioavailability and insufficient pharmacological activity of hesperetin, current researchers have carried out a large number of related studies, such as using nanotechnology to prepare hesperetin nanoparticles to improve the stability and bioavailability of hesperetin. However, nanomaterials still have limitations in biocompatibility and safety; this patent can effectively improve the pharmacological activity and safety of hesperetin through the strategy of chemical structure modification, and is expected to further improve the application value and development prospects of hesperetin, providing theoretical support for its clinical application. Summary of the Invention The primary object of the present invention is to provide a class of compounds with flavone as the core.

[0005] Another object of the present invention is to provide a preparation method for the above-mentioned class of compounds with flavone as the core.

[0006] Another object of the present invention is to provide the application of the above-mentioned class of compounds with flavone as the core.

[0007] The object of the present invention is achieved by the following technical solutions: The 7-O-cinnamic acid ester derivatives of flavone provided by the present invention contain the chemical structure shown in Formula 1:

[0008] Formula I In the formula, R is selected from organic acids, including cinnamic acid, substituted aromatic acids, fatty acids, etc.; n is a natural number from 0 to 20, and X is a -CH2- or -CO- group; A method for preparing a 7-O-cinnamic acid esterified derivative of flavonoid, comprising the following steps: (1) Weigh hesperidin into a reaction vessel, add methanol and a small amount of concentrated sulfuric acid to dissolve, heat and stir to promote the hydrolysis of hesperidin into hesperetin, and obtain hesperetin through extraction and purification; (2) Add EDCI, organic acid derivative, DMAP into the reaction vessel, then add dichloromethane, stir at room temperature, wait for activation and then add hesperetin, continue to stir and react at room temperature, and after the reaction stops, obtain the hesperetin H1-14 derivative through purification.

[0009] Preferably, the molar ratio of hesperetin, organic acid derivative, EDCI, and DMAP is 1:1-1.2:1-1.2:0.1.

[0010] Preferably, the organic acid includes cinnamic acid or cinnamic acid monosubstituted or disubstituted by methyl, methoxy, halogen, or nitro; benzoic acid, phenylacetic acid, or benzoic acid and phenylacetic acid monosubstituted or disubstituted by methyl, methoxy, halogen, or nitro; nicotinic acid, isonicotinic acid, or nicotinic acid and isonicotinic acid monosubstituted by halogen or methyl; fatty acids such as adamantaneformic acid and acetic acid; heterocyclic organic acids such as pyrimidinecarboxylic acid, pyrimidineacetic acid, indolecarboxylic acid, indoleacetic acid, pyridinecarboxylic acid, and pyridineacetic acid; and amino acids such as alanine, phenylalanine, valine, and leucine.

[0011] More preferably, the organic acid derivative includes p-bromocinnamic acid; 3-trifluoromethylcinnamic acid; 3,4-dimethoxycinnamic acid; 3-chlorocinnamic acid; 2-methylcinnamic acid; trans-cinnamic acid; pyridine-4-acrylic acid; 2,5-dimethoxycinnamic acid; trans-2,4-dimethoxycinnamic acid; 2-methoxycinnamic acid; 3,4-(methylenedioxy)cinnamic acid; 3-(trifluoromethoxy)cinnamic acid; 2-nitrocinnamic acid; 3-(3-thienyl)acrylic acid; 3-(3-furyl)acrylic acid; 3,4,5-trifluorocinnamic acid; trans-2,3,4-trimethoxycinnamic acid; 3,4,5-trimethoxycinnamic acid; Preferably, the dosage of dichloromethane is 2-4 ml.

[0012] Preferably, in step (1), the heating temperature is 70-80°C, the hydrolysis time is 5-7 h, in step (2), the activation time is 15-20 min, and the reaction time is 0.5-1 h.

[0013] Preferably, the room temperature is 20-30°C.

[0014] The synthetic method route of the flavonoid derivative can be expressed by the following reaction formula:

[0015] Another aspect of the present invention is a hesperetin derivative prepared by a method for preparing a compound having a flavone nucleus, and the hesperetin derivative is selected from any one of the compounds in Table 1: Table 1 Structural formulas of preferred derivatives

[0016] The present invention relates to the use of the hesperetin derivative in the preparation of a drug for treating antioxidant, and the dosage form of the drug is tablet, powder, capsule, pill, injection, solution or suspension.

[0017] Another aspect of the present invention is to provide an antioxidant comprising the hesperetin derivative. The antioxidant achieves antioxidant properties by scavenging DPPH free radicals.

[0018] The beneficial effects obtained by the present invention are as follows: the chemical structures of hesperetin analogs and the corresponding synthetic routes are provided. More importantly, their scavenging ability for DPPH free radicals was detected by an enzyme-linked immunosorbent assay. At the same time, the structure-activity relationship of the derivatives was obtained, lead compounds with significant free radical scavenging effects were screened out, and it was found that hesperetin cinnamic acid derivatives have the potential to be developed into antioxidants. Detailed implementation manners

[0019] The following further illustrates the present invention in conjunction with embodiments, but the present invention is not limited to these embodiments. The experimental methods described in the following embodiments are all conventional methods unless otherwise specified; the reagents and raw materials can be obtained from commercial sources and / or prepared according to known methods unless otherwise specified. Example 1

[0020] Compound H1 Add 1-adamantanecarboxylic acid (14.7 mg) and catalyst 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (18.49 mg) into a reaction flask, completely dissolve them in 3 mL of dichloromethane, add 1 mg of 4-dimethylaminopyridine (DMAP) under stirring conditions, add 30 mg of hesperetin after stirring at room temperature for 20 minutes. Monitor the reaction by thin-layer chromatography plate (PE:EA = 3:1), and add 3 mL of water to quench the reaction. Add 20 mL of dichloromethane, wash the reaction system three times with saturated sodium bicarbonate solution (10 ml * 3), combine the aqueous layers and back-extract once with 20 ml of dichloromethane, separate and combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate under vacuum. Purify by column chromatography to obtain a light yellow solid product (Compound H1), with a yield of 21.4%. Perform nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (13 It was detected by 13C-NMR to determine its structural formula. The nuclear magnetic resonance data are as follows: 1 1H NMR (400 MHz, CDCl3) δ H 11.88 (s, 1H), 7.05 (d, J J = 2.0 Hz, 1H), 6.98 – 6.87 (m, 2H), 6.27 (q, J J = 2.2 Hz, 2H), 5.38 (dd, J J = 13.1, 3.0 Hz, 1H), 3.94 (s, 4H), 3.13 (dd, J J = 17.2, 13.1 Hz, 1H), 2.86 (dd, J J = 17.2, 3.0 Hz, 1H), 2.14 – 1.89 (m, 15H). 13 13C NMR (101 MHz, CDCl3) δ C 197.17, 175.08, 163.28, 162.30, 159.20, 147.05, 145.95, 131.20, 118.14, 112.62, 110.68, 106.08, 103.26, 101.80, 78.98, 56.06, 43.41, 41.22, 38.61, 36.40, 29.72, 27.83. Example 2

[0021] Compound H2 Cinnamic acid (30.0 mg) and catalyst 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (17.3 mg) were weighed into a reaction flask and completely dissolved in 3 mL of dichloromethane. 1 mg of 4-dimethylaminopyridine (DMAP) was added under stirring. After stirring at room temperature for 20 minutes, 43.0 mg of hesperetin was added. The reaction was monitored by thin-layer chromatography plate (PE:EA = 2:1), and 3 mL of water was added to quench the reaction. Subsequently, 20 mL of dichloromethane was added, and the reaction system was washed three times with saturated sodium bicarbonate solution (10 ml * 3). The aqueous layer was combined and back-extracted once with 20 ml of dichloromethane. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Column chromatography purification gave H2, a pale yellow solid product, with a yield of 32%; 1 1H NMR(400 MHz, CDCl3) δ H11.92 (s, 1H), 8.22 – 8.11 (m, 1H), 7.68 – 7.61 (m, 1H), 7.35 (td, J J = 7.4, 1.4 Hz, 1H), 7.28 (d, J J = 5.9 Hz, 2H), 7.07 (d, J J = 2.1 Hz, 1H), 6.96 (dd, J J = 8.3, 2.2 Hz, 1H), 6.91 (d, J J = 8.3 Hz, 1H), 6.53 (d, J J = 15.9 Hz, 1H), 6.47 – 6.39 (m, 2H), 5.41 (dd, J J = 13.1, 2.9 Hz, 1H), 3.94 (s, 3H), 3.16 (dd, J J = 17.2, 13.1 Hz, 1H), 2.88 (dd, J J = 17.2, 3.0 Hz, 1H), 2.50 (s, 3H). 13 13C NMR(101 MHz, CDCl3) δ C 197.22, 164.27, 163.32, 162.38, 158.64, 147.08, 145.96, 145.19, 138.15, 132.88, 131.16, 131.00, 130.73, 126.66, 126.50, 118.20, 117.53, 112.65, 110.70, 103.28, 101.81, 79.05, 77.05, 76.73, 56.07, 43.42, 29.72, 19.85. Example 3

[0022] Compound H4 The implementation method is the same as that in Example 2, and the yield is 45%; 1 1H NMR (400 MHz, CDCl3) δ H 11.91 (s, 1H), 8.17 (d, J J = 16.1 Hz, 1H), 7.58 (dd, J J = 7.8, 1.7 Hz, 1H), 7.42 (ddd, J= 8.9, 7.3, 1.7 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.99 – 6.95 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 16.1 Hz, 1H), 6.42 (q, J = 2.1 Hz, 2H), 5.40 (dd, J = 13.1, 2.9 Hz, 1H), 3.94 (s, 6H), 3.89 (t, J = 4.1 Hz, 1H), 3.16 (dd, J = 17.2, 13.1 Hz, 1H), 2.87 (dd, J = 17.2, 3.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ C 197.21, 164.78, 163.30, 162.36, 158.86, 158.71, 147.07, 145.95, 143.11, 132.25, 131.21, 129.55, 122.92, 120.82, 118.22, 117.08, 112.65, 111.26, 110.70, 106.16, 103.34, 101.89, 79.04, 56.07, 55.54, 43.44, 29.72. Example 4

[0023] Compound H4 The implementation method is the same as that of Example 2, and the yield is 43%; 1 H NMR (400 MHz, CDCl3) δ H 11.92 (s, 1H), 7.71 (d, J = 15.9 Hz, 1H), 7.23 (dd, J = 7.8, 6.3 Hz, 2H), 7.07 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.3, 2.1 Hz, 1H), 6.91 (d,J = 8.3 Hz, 1H), 6.53 (d, J = 15.9 Hz,1H), 6.42 – 6.37 (m, 2H), 5.41 (dd, J = 13.1, 3.0 Hz, 1H), 3.95 (s, 3H), 3.52(s, 1H), 3.17 (dd, J = 17.2, 13.1 Hz, 1H), 2.88 (dd, J = 17.2, 3.0 Hz, 1H). 13 C NMR(101 MHz, CDCl3) δ C 197.22, 163.35, 162.42, 158.18, 147.11, 145.98, 143.99,131.05, 119.16, 118.21, 112.81, 110.68, 106.34, 103.13, 101.64, 79.13, 56.07,43.41, 29.72. Example 5

[0024] Compound H5 The implementation method is the same as that in Example 2, and the yield is 61%; 1 H NMR (400 MHz, DMSO) δ H 12.00 (s, 1H), 9.17(s, 1H), 7.96 – 7.84 (m, 3H), 7.59 (t, J = 8.0 Hz, 1H), 7.51 – 7.43 (m, 1H),7.02 (d, J = 16.0 Hz, 1H), 6.98 – 6.94 (m, 1H), 6.91 (dd, J = 8.3, 2.1 Hz, 1H),6.49 – 6.42 (m, 2H), 5.59 (dd, J = 12.7, 3.0 Hz, 1H), 3.79 (s, 3H), 3.45 – 3.40(m, 1H), 3.38 (s, 1H), 2.83 (dd, J = 17.2, 3.0 Hz, 1H). 13 C NMR (101 MHz, DMSO)δ C198.58, 164.18, 162.70, 158.35, 149.27, 148.52, 146.97, 145.76, 136.68, 131.43, 131.11, 128.26, 123.66, 121.64, 119.28, 118.33, 114.63, 112.40, 106.42, 103.12, 102.20, 79.15, 56.10, 42.81. Example 6

[0025] Compound H6 The implementation method is the same as that in Example 2, and the yield is 46%; 1 H NMR (400 MHz, DMSO-d6) δ H 9.18 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 16.1 Hz, 1H), 7.85–7.78 (m, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 16.1 Hz, 1H), 7.01 – 6.87(m, 3H), 6.48 – 6.41 (m, 2H), 5.58 (dd, J = 12.8, 2.9 Hz, 1H), 3.78 (s, 3H), 3.40 (s, 1H), 2.82 (dd, J = 17.2, 3.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ C 198.57, 164.20, 162.70, 158.34, 148.52, 146.97, 145.81, 135.38, 132.74, 131.10, 130.54, 127.65, 125.90, 119.43, 118.32, 114.64, 112.40, 106.42, 103.11, 102.19, 79.15, 56.11, 42.81. Example 7

[0026] Hesperetin (2, 10.0 g) and potassium carbonate catalyst (17.3 g) were weighed into a reaction flask and completely dissolved in 20 mL of DMF solution. The reaction was carried out at room temperature for 30 minutes, and then 1,5-dibromopentane was added. The reaction was monitored by thin-layer chromatography plate (PE: EA = 2: 1), and the reaction was quenched by adding 3 mL of water. Subsequently, 20 mL of dichloromethane was added, and the reaction system was washed three times with saturated sodium bicarbonate solution (10 ml * 3). The aqueous layers were combined and back-extracted once with 20 ml of dichloromethane. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by column chromatography gave intermediate 3, a pale yellow liquid, with a yield of 31%; Intermediate 3 and substituted cinnamic acid were reacted at room temperature for 20 hours under the conditions of DMF and potassium carbonate, and were worked up in the same way as intermediate 3 to obtain hesperetin derivative H7-15, a white solid.

[0027]

[0028] Compound H7 1 H NMR (400 MHz, CDCl3) δ H 12.04 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.64(t, J = 8.0 Hz, 3H), 7.06 (d, J = 2.0 Hz, 1H), 6.98 – 6.87 (m, 2H), 6.54 (d, J =16.1 Hz, 1H), 6.09 – 6.02 (m, 2H), 5.76 (s, 1H), 5.34 (dd, J = 12.9, 2.9 Hz,1H), 4.27 (t, J = 6.4 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.09 (dd, J = 17.2, 12.9 Hz, 1H), 2.80 (dd, J = 17.2, 3.1 Hz, 1H), 1.83 (dp, J = 22.0, 6.6Hz, 4H), 1.59 (dt, J = 8.1, 4.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ C195.91, 167.38, 166.19, 164.12, 162.83, 147.03, 145.96, 142.31, 138.71, 132.65, 131.54, 128.41, 121.74, 118.14, 113.40, 112.67, 110.68, 103.10, 95.48, 94.61, 78.96, 68.12, 64.72, 56.08, 43.19, 28.52, 28.33, 22.54. Example 8

[0029] Compound H8 The implementation method is the same as that of Example 7, and the yield is 29%; 1 H NMR (400 MHz, CDCl3) δ H 12.03 (s, 1H), 8.68(s, 2H), 7.61 (d, J = 16.0 Hz, 1H), 7.40 (d, J = 5.6 Hz, 2H), 7.05 (d, J = 2.0 Hz,1H), 6.97 – 6.86 (m, 2H), 6.62 (d, J = 16.1 Hz, 1H), 6.11 – 5.94 (m, 3H), 5.33(dd, J = 12.9, 3.0 Hz, 1H), 4.28 (t, J = 6.5 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H),3.93 (s, 3H), 3.08 (dd, J = 17.2, 12.9 Hz, 1H), 2.80 (dd, J = 17.2, 3.1 Hz, 1H),1.82 (dt, J = 14.2, 6.8 Hz, 4H), 1.65 – 1.53 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ C195.91, 167.37, 166.04, 164.12, 162.83, 150.50, 147.10, 146.04, 141.79, 131.53, 122.85, 121.89, 118.07, 112.73, 110.73, 103.10, 95.47, 94.60, 78.94, 68.12, 64.76, 56.06, 43.18, 29.70, 28.53, 28.33, 22.54. Example 9

[0030] Compound H9 The implementation method is the same as that in Example 7, and the yield is 29%; 1 H NMR (400 MHz, CDCl3) δ H 12.03 (s, 1H), 7.64(d, J = 15.9 Hz, 1H), 7.12 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (dd, J = 6.0, 2.0 Hz,2H), 6.92 (d, J = 2.1 Hz, 1H), 6.91 – 6.85 (m, 2H), 6.33 (d, J = 15.9 Hz, 1H),6.09 – 6.01 (m, 2H), 5.83 (s, 1H), 5.38 – 5.28 (m, 1H), 4.24 (t, J = 6.5 Hz,2H), 4.00 (t, J = 6.4 Hz, 2H), 3.92 (s, 9H), 3.07 (dd, J = 17.2, 12.9 Hz, 1H),2.78 (dd, J = 17.1, 3.1 Hz, 1H), 1.91 – 1.71 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ C195.93, 167.42, 164.08, 162.84, 151.12, 149.21, 147.02, 145.95, 144.71, 131.56, 127.40, 122.66, 118.13, 115.78, 112.70, 111.05, 110.69, 109.61, 103.07, 95.52, 94.59, 78.93, 68.21, 64.21, 56.13, 55.82, 43.18, 28.46, 22.58. Example 10

[0031] Compound H10 The implementation method is the same as that of Example 7, and the yield is 35%; 1 H NMR (400 MHz, CDCl3) δ H 12.03 (s, 1H), 7.92(d, J = 16.1 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.98 – 6.85 (m, 2H), 6.52 (dd, J = 8.6, 2.4 Hz, 1H), 6.47 – 6.41 (m, 2H), 6.10 – 6.01(m, 2H), 5.37 – 5.29 (m, 1H), 4.23 (t, J = 6.5 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.83 (s, 1H), 3.15 – 3.02 (m, 1H), 2.79 (dd, J = 17.1, 3.0 Hz, 1H), 1.91 – 1.73 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ C195.91, 168.00, 167.47, 164.08, 162.77, 159.87, 146.99, 145.94, 140.15, 131.60, 130.49, 118.14, 116.61, 115.97, 112.69, 110.68, 105.24, 103.07, 98.43, 95.54, 94.60, 78.91, 68.24, 64.00, 56.06, 55.48, 43.20, 29.71, 28.49, 22.57. Example 11

[0032] Compound H11 The implementation method is the same as that of Example 7, and the yield is 17%; 1 H NMR (400 MHz, CDCl3) δ H 12.03 (s, 1H), 7.99(d, J = 16.1 Hz, 1H), 7.06 (t, J = 2.2 Hz, 2H), 6.96 – 6.90 (m, 3H), 6.89 – 6.85(m, 1H), 6.51 (d, J = 16.1 Hz, 1H), 6.10 – 6.01 (m, 2H), 5.79 (s, 1H), 5.33(dd, J = 12.8, 3.0 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H),3.93 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.08 (dd, J = 17.1, 12.9 Hz, 1H),2.79 (dd, J = 17.1, 3.1 Hz, 1H), 1.83 (dt, J = 14.3, 6.7 Hz, 4H), 1.65 – 1.52 (m,2H). 13 C NMR (101 MHz, CDCl3) δ C195.91, 167.46, 164.08, 162.84, 153.50, 152.85, 146.99, 145.94, 139.97, 131.59, 123.96, 118.80, 118.14, 117.16, 113.28, 112.69, 112.46, 110.68, 103.07, 95.54, 94.59, 78.91, 68.23, 64.23, 56.08, 55.80, 43.19, 28.59, 28.45, 22.56. Example 12

[0033] Compound H12 The implementation method is the same as that of Example 7, and the yield is 26%; 1 H NMR (400 MHz, CDCl3) δ H 12.03 (s, 1H), 7.89(d, J = 16.1 Hz, 1H), 7.28 (s, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.94 (dd, J = 8.3, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 16.1Hz, 1H), 6.09 – 6.01 (m, 2H), 5.84 (s, 1H), 5.33 (dd, J = 12.9, 3.0 Hz, 1H), 4.24 (t, J = 6.5 Hz, 2H), 4.00 (t, J = 6.4 Hz, 2H), 3.95 – 3.87 (m, 12H), 3.08(dd, J = 17.2, 12.9 Hz, 1H), 2.79 (dd, J = 17.2, 3.1 Hz, 1H), 1.93 – 1.72 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ C195.93, 167.61, 167.45, 164.08, 162.84, 155.52, 153.30, 147.02, 145.95, 142.35, 139.74, 131.57, 123.23, 121.49, 118.14, 116.98, 112.70, 110.70, 107.62, 103.07, 95.53, 94.59, 78.92, 68.23, 64.15, 61.44, 60.91, 56.06, 43.18, 28.60, 28.46, 22.58. Example 13

[0034] Compound H13 The implementation method is the same as that in Example 7, and the yield is 31%; 1 H NMR (400 MHz, CDCl3) δ H 12.02 (s, 1H), 8.13(d, J = 15.8 Hz, 1H), 8.06 (dt, J = 8.2, 0.9 Hz, 1H), 7.71 – 7.61 (m, 2H), 7.59 – 7.51 (m, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.99 – 6.86 (m, 2H), 6.38 (d, J = 15.8Hz, 1H), 6.09 – 6.01 (m, 2H), 5.80 (s, 1H), 5.37 – 5.29 (m, 1H), 4.27 (t, J =6.5 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.08 (dd, J = 17.2, 12.9 Hz,1H), 2.79 (dd, J = 17.2, 3.1 Hz, 1H), 1.82 (ddt, J = 21.5, 14.3, 6.9 Hz, 4H),1.65 – 1.53 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ C195.93, 167.43, 165.84, 164.06, 162.84, 148.30, 147.00, 145.93, 140.09, 133.54, 131.57, 130.62, 130.30, 129.17, 124.94, 123.18, 118.15, 112.69, 110.69, 103.07, 95.55, 94.59, 78.92, 68.18, 64.74, 56.07, 43.18, 28.55, 28.32, 22.55. Example 14

[0035] Compound H14 The implementation method is the same as that of Example 7, and the yield is 28%; 1 H NMR (400 MHz, CDCl3) δ H 12.02 (s, 1H), 7.61 (d, J = 15.9 Hz, 1H), 7.06 (dd, J = 4.3, 1.9 Hz, 2H), 7.02 (dd, J = 8.0, 1.7 Hz, 1H), 6.94 (dd, J = 8.3, 2.1 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.28 (d, J = 15.9 Hz, 1H), 6.10 – 6.03 (m, 2H), 6.02 (s, 2H), 5.75 (s, 1H), 5.38 – 5.29 (m, 1H), 4.24 (t, J = 6.5 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.09 (dd, J = 17.2, 12.9 Hz, 1H), 2.80 (dd, J = 17.2, 3.1 Hz, 1H), 1.81 (dq, J = 27.6, 6.8 Hz, 4H), 1.62 – 1.54 (m, 2H). 1313C NMR (101 MHz, CDCl3) δ C 195.90, 167.44, 167.23, 164.10, 162.84, 149.61, 148.35, 146.99, 144.47,131.61, 128.87, 124.43, 118.14, 116.07, 112.68, 110.68, 108.55, 106.53,103.09, 101.55, 95.55, 94.59, 78.92, 68.20, 64.22, 56.07, 43.20, 28.57,22.56. Example 15

[0036] Compound H15 The implementation method is the same as that in Example 7, and the yield is 17%; 1 1H NMR (400 MHz, CDCl3) δ H 12.03 (s, 1H), 7.82(t, J J = 1.7 Hz, 1H), 7.76 (dt, J J = 7.9, 1.5 Hz, 1H), 7.71 – 7.62 (m, 2H), 7.53(t, J J = 7.8 Hz, 1H), 7.06 (d, J J = 2.1 Hz, 1H), 6.98 – 6.87 (m, 2H), 6.51 (d, J J =16.0 Hz, 1H), 6.10 – 6.03 (m, 2H), 5.75 (s, 1H), 5.34 (dd, J J = 12.8, 3.0 Hz,1H), 4.27 (t, J J = 6.5 Hz, 2H), 4.01 (t, J J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.09 (dd, J J = 17.2, 12.9 Hz, 1H), 2.80 (dd, J J = 17.1, 3.1 Hz, 1H), 1.83 (ddt, J J = 22.0, 14.4,6.8 Hz, 4H), 1.61 – 1.55 (m, 2H). 1313C NMR (101 MHz, CDCl3) δ C 195.91, 167.39, 164.10, 162.84, 147.00, 145.95, 141.97, 135.71, 133.20, 131.93, 131.55, 131.33, 129.82, 120.88, 118.15, 113.39, 112.67, 110.68, 103.10, 95.52, 94.58, 78.95, 68.15, 64.70, 56.07, 43.19, 29.71, 28.54, 28.35, 22.55. Example 16 Dissolve and dilute the above derivatives to 100 μmol / L, and use 100 μmol / L vitamin C (VC) as the positive control. Divide into a sample group (100 μL DPPH solution + 100 μL sample, A), a negative control group (100 μL ethanol + 100 μL sample, A0), and a blank group (100 μL DPPH solution + 100 μL ethanol, B). Screen the sample to be tested. After adding the above samples to a 96-well plate and mixing well, place them in the dark at room temperature for 30 min, and then use an enzyme-labeled instrument to detect the absorbance value at a wavelength of 517 nm. Repeat 3 times in parallel, and use GraphPad Prism 5 software to calculate its IC 50 value. The formula for calculating the DPPH free radical scavenging rate of the compound is as follows: Scavenging rate (%) = [1 - (A - A0) / B] × 100. Where: A represents the absorbance of the sample to be tested; A0 represents the absorbance of the negative control; B represents the absorbance of the blank control. The DPPH free radical scavenging rate is shown in Table 2; Table 2 Scavenging activity of compound H1-15 on DPPH free radicals

[0037] Experimental results and analysis The DPPH free radical scavenging ability of the derivatives measured in the present invention is shown in Table 2. At the maximum initial concentration of 100 μM, compared with the parent nucleus derivatives hesperidin and hesperetin, most derivatives showed strong DPPH free radical scavenging ability, and the DPPH free radical scavenging ability of derivative H10 was comparable to that of Vc. Generally, hesperetin ether cinnamate has good DPPH free radical scavenging ability.

[0038] In the above embodiments, it is only used to illustrate the present invention but is not limited thereto. It should be understood that there can be various variations or alternative solutions without departing from the scope of the present invention. It is still possible to modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A compound with a flavonoid as the parent nucleus, characterized in that, It has the structure described by the following general formula I: Formula I In the formula, R is selected from organic acids, including cinnamic acid, substituted aromatic acids, fatty acids, etc.; n is a natural number from 0 to 20, and X is a -CH2- or -CO- group.

2. The preparation method of the compound with flavonoid as the parent nucleus according to claim 1, characterized in that: It includes the following steps: (1) Hesperidin is hydrolyzed under the action of an acid to generate hesperetin; (2) Add EDCI, organic acid derivative, DMAP to the reaction vessel, then add dichloromethane, stir at room temperature, wait for activation and then add hesperetin, continue stirring and reacting at room temperature, and obtain flavonoid derivative after the reaction stops.

3. The preparation method of the compound with flavone as the mother nucleus according to claim 2, characterized in that: The organic acid includes any one of cinnamic acid, substituted cinnamic acid, benzoic acid, substituted benzoic acid, phenylacetic acid, substituted phenylacetic acid, adamantane formic acid, adamantane formic acid, nicotinic acid, substituted nicotinic acid, isonicotinic acid, substituted isonicotinic acid, heterocyclic organic acid, amino acid.

4. The preparation method of the compound with flavone as the mother nucleus according to claim 2, characterized in that: The substituted cinnamic acid is any one of cinnamic acids monosubstituted or disubstituted by methyl, methoxy, halogen, nitro; The substituted benzoic acid is any one of benzoic acids monosubstituted or disubstituted by methyl, methoxy, halogen, nitro; The substituted phenylacetic acid is any one of phenylacetic acids monosubstituted or disubstituted by methyl, methoxy, halogen, nitro; The substituted nicotinic acid is any one of nicotinic acids monosubstituted by halogen, methyl; The substituted isonicotinic acid is any one of isonicotinic acids monosubstituted by halogen, methyl; The heterocyclic organic acid is any one of pyrimidinecarboxylic acid, pyrimidineacetic acid, indolecarboxylic acid, indoleacetic acid, pyridinecarboxylic acid, pyridineacetic acid; The amino acid is any one of alanine, phenylalanine, valine, leucine.

5. The preparation method of the flavonoid-based compound according to claim 2, characterized in that, The organic acid includes any one of p-bromocinnamic acid, 3-trifluoromethylcinnamic acid, 3,4-dimethoxycinnamic acid, 3-chlorocinnamic acid, 2-methylcinnamic acid, trans-cinnamic acid, pyridine-4-acrylic acid, 2,5-dimethoxycinnamic acid, trans-2,4-dimethoxycinnamic acid, 2-methoxycinnamic acid, 3,4-(methylenedioxy)cinnamic acid, 3-(trifluoromethoxy)cinnamic acid, 2-nitrocinnamic acid, 3-(3-thienyl)acrylic acid, 3-(3-furyl)acrylic acid, 3,4,5-trifluorocinnamic acid, trans-2,3,4-trimethoxycinnamic acid, 3,4,5-trimethoxycinnamic acid, adamantane formic acid or adamantane acetic acid.

6. The synthesis method of a flavonoid-based compound according to claim 2, characterized in that: The molar ratio of the hesperetin, cinnamic acid derivative, EDCI, DMAP is 1:1 - 1.2:1 - 1.2:0.

1.

7. The synthesis method of a flavone-based compound according to claim 2, characterized in that: The acid described in step (1) includes any one of sulfuric acid, nitric acid, hydrochloric acid; the hydrolysis temperature is 70 - 80 °C, and the hydrolysis time is 5 - 7 h; In step (2), the activation time is 15 - 20 min, and the reaction time at room temperature is 0.5 - 1 h.

8. An hesperetin derivative prepared by the preparation method of the compound with flavone as the parent nucleus according to any one of claims 3-7, characterized in that, The partial hesperetin derivatives are selected from any one of the compounds in Table 1: Table 1 Preferred derivative structural formula 。 9. Use of the hesperetin derivative according to claim 8 in the preparation of a medicament for preparing a medicament for treating antioxidation, characterized in that: The dosage form of the drug is tablet, powder, capsule, pill, injection, solution or suspension.

10. An antioxidant, characterized in that, It includes the hesperetin derivative described in claim 8.

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