Gallic acid derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of development of anti-inflammatory and antioxidant drugs, and discloses a gallic acid derivative as well as a preparation method and application thereof. The gallic acid derivative is a compound with a structure as shown in a formula 2 or a pharmaceutically acceptable salt or solvent compound thereof. The gallic acid derivative belongs to novel compounds, the compounds are designed and successfully synthesized for the first time, and meanwhile, the structures of the compounds are represented; the preparation method of the gallic acid derivative is simple and convenient to operate, and the compounds can be rapidly synthesized; research finds that the gallic acid derivative has good anti-inflammatory and antioxidant activity, and shows good application prospects in treatment of inflammation and oxidative stress. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of anti-inflammatory and antioxidant drug development, and particularly relates to a gallic acid derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Gallic acid is a polyphenolic organic compound with the chemical name of 3,4,5-trihydroxybenzoic acid, and the molecular formula of C7H6O5. The molecular weight is 170.12, and the CAS number is: 149-91-7. The structure is shown in Formula 1. Gallic acid widely exists in plants such as Rheum palmatum, Eucalyptus robusta, and Cornus officinalis, and has various application fields. It has wide applications in the fields of food, biology, medicine, and chemical industry, such as being used as an antioxidant, manufacturing dyes, food additives, etc. Trimethyl gallate (3,4,5-Trimethoxybenzoic acid), with the molecular formula of C 10 H 12 O5, the molecular weight is 212.2, and the CAS number is: 118-41-2. The structure is shown in Formula 1-1. This compound is used as a precursor for synthesizing gallic acid derivatives.

[0003]

[0004] Gallic acid has various biological activities such as anti-inflammatory, antimutagenic, antioxidant, and anti-free radical; at the same time, gallic acid has an antitumor effect, can inhibit the metastasis of mast cell tumors, thereby prolonging the survival period; it is also a relatively suitable candidate drug for killing trypanosomes; it has a protective effect on the liver and can resist the physiological and biochemical changes of the liver induced by carbon tetrachloride; it can induce endothelium-dependent contraction and endothelium-dependent relaxation by inhibiting the production of endothelial NO.

[0005] Molecular hybridization refers to connecting two active molecular fragments through chemical synthesis to form a new active compound. Molecular hybridization can enhance the pharmacological activity of active molecules and reduce their toxic side effects. Summary of the Invention

[0006] In order to overcome the disadvantages and deficiencies existing in the prior art, the primary object of the present invention is to provide a gallic acid derivative, which can enhance the anti-inflammatory and antioxidant activities of gallic acid.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned gallic acid derivative; based on the drug modification strategy of molecular hybridization, glycine is introduced as a linker at the carboxyl side chain end of gallic acid to connect gallic acid with different aniline compounds to form a new series of compounds, in order to improve their biological activity and drug-likeness.

[0008] Another object of the present invention is to provide the application of the above-mentioned gallic acid derivative. Since the gallic acid derivative has good in vitro anti-inflammatory and antioxidant activities, it is expected to be used as a novel lead compound for inflammatory or oxidative stress diseases.

[0009] The object of the present invention is achieved by the following technical solutions:

[0010] A gallic acid derivative, wherein the derivative is a compound of the structure shown in Formula 2 or a pharmaceutically acceptable salt or solvate thereof:

[0011]

[0012] Among them, R is one of the following groups:

[0013]

[0014] The specific groups of the above compounds are summarized in Table 1 as follows:

[0015] Table 1 Compound numbers and structures

[0016]

[0017]

[0018] The pharmaceutically acceptable salt is preferably a salt formed by the compound of the structure shown in Formula 2 and ions such as lithium ion, sodium ion, potassium ion, rubidium ion, cesium ion, francium ion, calcium ion, ammonium ion, etc., and the structure is as shown in Formula 2-1.

[0019]

[0020] The preparation method of the above-mentioned gallic acid derivative includes the following operation steps:

[0021] (1) Mix trimethyl gallate, glycine methyl ester hydrochloride, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) for reaction to obtain Intermediate I of the structure shown in Formula 3;

[0022]

[0023] (2) Using methanol and water as solvents, react the intermediate I obtained in step (1) with lithium hydroxide to obtain intermediate II with the structure shown in Formula 4;

[0024]

[0025] (3) Using dichloromethane as a solvent, react the intermediate II obtained in step (2), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), and amine compounds with different substituents to obtain intermediate III with the structure shown in Formula 5;

[0026]

[0027] (4) Using dichloromethane as a solvent, react the intermediate III obtained in step (3) with boron tribromide to obtain the gallic acid derivative with the structure shown in Formula 2.

[0028] In step (1), the molar ratio of trimethyl gallate, glycine methyl ester hydrochloride, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and N,N-diisopropylethylamine (DIPEA) is 1:1.2:1.5:1.5; in step (2), the molar ratio of intermediate I to lithium hydroxide is 1:3; in step (3), the molar ratio of intermediate II, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), and amine compounds with different substituents is 1:1.1:1.5:1.5; in step (4), the molar ratio of intermediate III to boron tribromide is 1:7.5.

[0029] The specific operation steps of step (1) are as follows: Using dichloromethane as a solvent, add trimethyl gallate under ice-salt bath stirring, then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA). After reacting for 10 minutes, add glycine methyl ester hydrochloride and stir for 4 h; after extraction with distilled water and ethyl acetate, collect the organic phase, wash with saturated sodium bicarbonate solution, dry, and evaporate the solvent with a rotary evaporator to obtain an oily crude product; dissolve the oily crude product in ethyl acetate, add silica gel and mix well, and purify and separate by column chromatography to obtain intermediate I.

[0030] Step (2) is specifically carried out according to the following operation steps: Add intermediate Ⅰ into a reaction flask, pour methanol and water with a volume ratio of 4:1 into it, add lithium hydroxide under ice bath stirring, then stir and react at room temperature for 3 hours, monitor by TLC until the reaction is completely converted, distill off methanol in the reaction system under reduced pressure, adjust the pH value to 6 - 7, precipitate a white solid, filter and dry to obtain intermediate Ⅱ.

[0031] Step (3) is specifically carried out according to the following operation steps: Using dichloromethane as a solvent, add intermediate Ⅱ under ice - salt bath stirring, then add 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N - diisopropylethylamine (DIPEA), react for 10 minutes, then add amine compounds with different substituents, stir and react for 4 h; After extraction with distilled water and ethyl acetate, collect the organic phase, wash with saturated sodium bicarbonate solution, dry, evaporate the solvent with a rotary evaporator to obtain an oily crude product; The oily crude product is redissolved in methanol, silica gel is added and mixed thoroughly, and column chromatography is used for separation to obtain a yellow - white solid. The yellow - white solid is added to a methanol solution and heated until the compound is completely dissolved. After waiting for the solution to cool, a white solid precipitates, filter and dry to obtain intermediate Ⅲ.

[0032] Step (4) is specifically carried out according to the following operation steps: Dissolve intermediate Ⅲ in dichloromethane, displace with nitrogen three times, add boron tribromide solution under the conditions of nitrogen protection and ice - salt bath stirring, react overnight, add methanol and triethylamine to quench, rotate and evaporate the obtained reaction solution, dissolve the obtained solid in ethyl acetate, after extraction with distilled water and ethyl acetate, collect the organic phase, alternately extract and wash with saturated sodium bicarbonate, brine, and dilute acid, then evaporate the solvent with a rotary evaporator to obtain a brown solid; The brown solid is added to an ethyl acetate solution and heated until the compound is completely dissolved. After waiting for the solution to cool, a yellow solid precipitates, filter and dry to obtain a yellow solid; The obtained yellow solid is dissolved in methanol, add dichloromethane until a small amount of solid precipitates, monitor by TLC until the impurities are completely removed, filter off the impurities, collect the filtrate, and evaporate the solvent with a rotary evaporator to obtain the gallic acid derivative.

[0033] The application of the above - mentioned gallic acid derivative in the preparation of drugs for preventing and treating inflammatory diseases and oxidative stress.

[0034] The synthetic route of the above - mentioned gallic acid derivative is shown in the following formula, and the R groups are all the groups in Table 1:

[0035]

[0036] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0037] (1) The gallic acid derivatives provided by the present invention are new types of compounds that have not been reported before. The present invention designed and successfully synthesized these compounds for the first time, and at the same time clarified the structural characterization.

[0038] (2) The preparation method of the gallic acid derivatives described in the present invention has the characteristics of simplicity and convenient operation, and can quickly synthesize the target compounds.

[0039] (3) Based on extensive and in-depth research, the present invention synthesized gallic acid derivatives with a brand-new structure and having anti-inflammatory and antioxidant activities, and carried out anti-inflammatory and antioxidant activity screening. It was found for the first time that this type of compound has good in vitro anti-inflammatory and antioxidant activities and is expected to be used as a new type of drug for the prevention and treatment of inflammatory diseases and oxidative stress. Description of the Drawings

[0040] Figures 1 to 11 It is the NMR spectrum diagram of Compounds 1-11.

[0041] Figure 12 It is the result of the cytotoxicity test of gallic acid and its derivatives on RAW 264.7 cells measured by the MTT method.

[0042] Figure 13 It is the inhibitory effect of gallic acid and its derivatives on the NO content in the inflammation of LPS-induced RAW 264.7 cells measured by the Griess method. Detailed Embodiments

[0043] The present invention will be further described in detail below in conjunction with the embodiments and the drawings, but the embodiments of the present invention are not limited thereto.

[0044] Example 1: Preparation of Intermediate I

[0045] Dissolve trimethyl gallate (4.22 g, 20 mmol) in 40 mL of dichloromethane, stir the solution under an ice-salt bath, then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (11.4 g, 30 mmol) and N,N-diisopropylethylamine (DIPEA) (3.88 g, 30 mmol). After reacting for 10 minutes, add glycine methyl ester hydrochloride (1.38 g, 22 mmol); monitor the reaction by TLC. After stirring the reaction for 4 h, transfer the reaction system from the eggplant-shaped flask to a separatory funnel, extract with distilled water and ethyl acetate, shake the separatory funnel up and down to fully extract, and after standing, discard the upper aqueous phase; collect the organic phase with a conical flask, wash with saturated sodium bicarbonate solution, dry, and evaporate the solvent with a rotary evaporator to obtain an oily crude product. Redissolve the oily crude product in 20 mL of ethyl acetate, add an appropriate amount of silica gel and mix well, and separate with a separation column to obtain Intermediate I with the structure shown in Formula 3, a white solid, with a yield of 92%.

[0046] Example 2: Preparation of Intermediate II

[0047] Add the Intermediate I (5.66 g, 20 mmol) obtained in Example 1 into a round-bottom flask, place a magnetic stir bar, and pour 25 ml of a methanol and water mixture with a volume ratio of 4:1 into the round-bottom flask. Slowly add lithium hydroxide (1.44 g, 60 mmol) under ice bath stirring, and then stir the reaction at room temperature for 3 hours. Monitor the reaction by TLC until the reaction is completely converted; evaporate the methanol in the reaction system under reduced pressure, slowly add 0.1 mol / L dilute hydrochloric acid to adjust the pH to 6 - 7, and a white solid precipitates. Filter and dry to obtain Intermediate II with the structure shown in Formula 4, with a yield of 93%.

[0048] Example 3: Preparation of Intermediates III1 - III11

[0049] Dissolve Intermediate II (5.36 g, 20 mmol) obtained in Example 2 in 40 mL of dichloromethane, stir the solution under ice-salt bath conditions, and then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (11.4 g, 30 mmol) and N,N-diisopropylethylamine (DIPEA) (3.88 g, 30 mmol). After reacting for 10 minutes, add amines with different substituents (22 mmol); monitor the reaction by TLC. After stirring the reaction for 4 h, transfer the reaction system from the eggplant-shaped flask to a separatory funnel, extract with distilled water and ethyl acetate, shake the separatory funnel up and down thoroughly for extraction, and after standing, discard the upper aqueous phase. Collect the organic phase in a conical flask, wash with saturated sodium bicarbonate solution, dry, and evaporate the solvent with a rotary evaporator to obtain an oily crude product. Redissolve the oily crude product in 25 - 35 mL of ethyl acetate, add an appropriate amount of silica gel and mix well, separate with a separation column to obtain a yellowish-white solid. Add the yellowish-white solid to 10 - 15 mL of methanol solution and heat until the compound is completely dissolved. Wait for the solution to cool and a white solid precipitates. Filter and dry to obtain Intermediates III1 - III11, with a yield of 64 - 87%.

[0050] Example 4: Synthesis of Compounds 1 - 11

[0051] The dried intermediates Ⅲ1-11 (0.345 g, 1 mmol) obtained in Example 3 were respectively dissolved in 10 mL of dichloromethane. After replacing the nitrogen three times, 7.5 mL of boron tribromide solution (1 mol / L) was slowly added under the conditions of nitrogen protection and stirring in an ice-salt bath, and the reaction was carried out overnight; 15 mL of methanol and 1 mL of triethylamine were added to quench. The obtained reaction solution was rotary evaporated, and the obtained solid was redissolved in ethyl acetate. After extraction with distilled water and ethyl acetate, the organic phase was collected. After alternately extracting and washing with saturated sodium bicarbonate, brine, and dilute acid, the solvent was evaporated with a rotary evaporator to obtain a brown solid. The obtained brown solid was added to 10 mL of ethyl acetate solution and heated until the compound was completely dissolved. After waiting for the solution to cool, yellow solid precipitated out. It was filtered and dried to obtain a yellow solid. The obtained yellow solid was dissolved in 5 mL of methanol, and 3 mL of dichloromethane was added until a small amount of solid precipitated out. TLC monitoring was carried out until the impurities were completely removed. The impurities were removed by filtration, the filtrate was collected, the solvent was evaporated with a rotary evaporator, and dried to obtain gallic acid derivatives, which were compounds 1-11. The yield was 30-47%. The NMR spectra of compounds 1-11 are respectively as shown in Figures 1 to 11 shown. The preparation yields of the above compounds 1-11 are summarized in Table 2 as shown in

[0052] Table 2 Yields of Compounds 1-11

[0053]

[0054] Effect Example

[0055] 1. Experimental Method

[0056] 1.1 DPPH Free Radical Scavenging Experiment

[0057] 190 μL of the prepared 100 μmol / L DPPH solution was added to each well of a 96-well plate, and then 10 μL of compounds 1-11 (gallic acid derivatives prepared in Example 4) with a final concentration of 5-50 μmol / L was added. A control group was set to keep their total volume at 200 μL. The reaction was allowed to stand in the dark at room temperature for 30 min, and then their absorbance values were measured at 517 nm. The DPPH free radical scavenging rate was calculated as follows: DPPH scavenging rate = [1 - (Am - An) / As] × 100%. Am represents the OD value of the sample group, An represents the OD value of the methanol solution, and As represents the OD value of the negative control group. The concentration of the gallic acid derivative was used as the abscissa, and the scavenging rates corresponding to the concentrations of the gallic acid derivatives were used as the ordinate to make a standard curve, and the linear regression equation and correlation coefficient (R 2 ) were obtained. The sample concentration measured when 50% of the DPPH free radicals were scavenged was denoted as IC 50The values are shown in Table 3. Compounds 1, 5, 9, 10 and 11 all showed stronger DPPH radical scavenging ability than gallic acid. Among them, compounds 10 and 11 had the strongest scavenging ability, and the IC 50 values were 12.4 and 11.9 μM, respectively.

[0058] 1.2 ABTS radical scavenging experiment

[0059] Prepare a 2.45 mmol / L K2S2O8 solution with a 7 mmol / L ABTS solution, and place it in the dark at room temperature for 12 - 16 h to obtain the ABTS radical stock solution. Dilute the stock solution with methanol solution (50:1) to make its absorbance value at 734 nm be 0.7 ± 0.02, and the ABTS+ working solution can be obtained. Add the prepared ABTS+ working solution, 195 μL per well, to a 96-well plate, and then add 5 μL of compounds 1 - 11 (gallic acid derivatives prepared in Examples 2 - 3) with a final concentration of 2.5 - 10 μmol / L. Set up a control group, and let it stand and react in the dark at room temperature for 20 min. Then measure their absorbance values at 734 nm. The ABTS cation radical scavenging rate is calculated by the following formula: ABTS scavenging rate = [1 - (Am - An) / As] × 100%. Am represents the OD value of the sample group, An represents the OD value of the methanol solution, and As represents the OD value of the negative control group. The measured sample concentration when 50% of the ABTS radicals are scavenged is represented by the IC 50 value, and the results are shown in Table 3. Among them, the ABTS radical scavenging ability of most compounds was enhanced compared with gallic acid. Among them, compounds 5 and 11 had the strongest scavenging ability, and the IC 50 values were 5.6 and 5.1 μM, respectively.

[0060] Table 3

[0061]

[0062] 1.3 Cytotoxicity experiment

[0063] Mouse mononuclear macrophages RAW 264.7 were passaged and cultured in DMEM medium containing 10% fetal bovine serum, 100 mg / L penicillin, and 100 mg / L streptomycin in a 37°C, 5% CO2 constant temperature incubator. Take RAW 264.7 cells in the logarithmic growth phase and adjust the cell density to 1 × 10 5cells / mL, inoculated into a 96-well plate, 100 μL per well. After the cells adhered for 12 h, the culture medium was replaced with DMEM without or containing 30 μmol / L of Compound 1-11 (gallic acid derivative prepared in Example 4), and 3 replicates were set for each concentration. After incubation for 24 h, 100 μL of MTT was added to each well and cultured for another 4 h. The supernatant was discarded, 150 μL of dimethyl sulfoxide (DMSO) was added to each well, and the plate was shaken on a shaker for 10 min until the crystals were fully dissolved. The absorbance A was measured at 490 nm. The experiment was repeated 3 times. The cell survival rate (%) was calculated as (A of the test well / A of the blank well) × 100%. The experimental results are as Figure 12 shown. At a concentration of 30 μM, none of the compounds showed significant inhibitory effects on RAW 264.7 cells. At a concentration of 60 μM, Compound 4 and gallic acid had certain inhibitory effects on RAW 264.7 cells.

[0064] 1.4 Effect of the compounds on the NO content

[0065] All the compounds were selected to study the effect of gallic acid derivatives on the NO release of LPS-induced RAW 264.7 cells: A suspension of RAW 264.7 cells in the logarithmic growth phase was taken, and the cell density was adjusted to 2×10 5 cells / mL, inoculated into a 96-well plate, 100 μL per well. After adhering for 12 h, 100 μL of Compound 1-11 (gallic acid derivative prepared in Example 4) with a concentration of 30 μmol / L was added and incubated for 3 h, then 100 ng / L LPS was added and incubated for 12 h. A blank group, an LPS group, and an LPS + drug administration group were set, with 3 replicates in each group. The content of NO in the supernatant was detected by the Griess method. Prism software was used for data analysis, and the t-test was used for comparison between groups. P < 0.05 was considered statistically significant. The results are as Figure 13 shown. The compounds of the present invention showed no obvious cell inhibitory effects on RAW 264.7, and at the same time, they could significantly reduce the release level of the inflammatory factor NO in LPS-induced RAW 264.7 cells. Among them, Compounds 5, 10, and 11 had the strongest inhibitory effects on the release of NO and had good anti-inflammatory and antioxidant activities, and could be used as active ingredients of anti-inflammatory and antioxidant drugs.

[0066] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A gallic acid derivative, characterized in that: The derivative is a compound of the structure shown in Formula 2 or a pharmaceutically acceptable salt or solvate thereof: wherein, R is one of the following groups:

2. The gallic acid derivative according to claim 1, characterized in that: The pharmaceutically acceptable salt is preferably a salt formed by the compound of the structure shown in Formula 2 and ions such as lithium ion, sodium ion, potassium ion, rubidium ion, cesium ion, francium ion, calcium ion, ammonium ion, etc.

3. The preparation method of a gallic acid derivative according to claim 1 or 2, characterized in that It includes the following operation steps: (1) Trimethyl gallate, glycine methyl ester hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine are mixed and reacted to obtain intermediate I of the structure shown in Formula 3; (2) Using methanol and water as solvents, intermediate I obtained in step (1) is reacted with lithium hydroxide to obtain intermediate II of the structure shown in Formula 4; (3) Using dichloromethane as a solvent, intermediate II obtained in step (2), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and amine compounds with different substituents are reacted to obtain intermediate III of the structure shown in Formula 5; (4) Using dichloromethane as a solvent, intermediate III obtained in step (3) is reacted with boron tribromide to obtain the gallic acid derivative of the structure shown in Formula 2.

4. The preparation method according to claim 3, wherein: In step (1), the molar ratio of trimethyl gallate, glycine methyl ester hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine is 1:1.2:1.5:1.5; in step (2), the molar ratio of intermediate I to lithium hydroxide is 1:3; in step (3), the molar ratio of intermediate II, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and amine compounds with different substituents is 1:1.1:1.5:1.5; in step (4), the molar ratio of intermediate III to boron tribromide is 1:7.

5.

5. The preparation method according to claim 3, characterized in that: The specific operation of step (1) is as follows: Using dichloromethane as a solvent, trimethyl gallate is added under ice-salt bath stirring, then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine are added. After reacting for 10 minutes, glycine methyl ester hydrochloride is added, and the reaction is stirred for 4 h; after extraction with distilled water and ethyl acetate, the organic phase is collected, washed with saturated sodium bicarbonate solution, dried, and the solvent is evaporated with a rotary evaporator to obtain an oily crude product; the oily crude product is redissolved in ethyl acetate, silica gel is added and mixed well, and purified by column chromatography to obtain intermediate I.

6. The preparation method according to claim 3, characterized in that: The specific operation of step (2) is as follows: Intermediate I is added to a reaction flask, and methanol and water with a volume ratio of 4:1 are poured into it, Lithium hydroxide is added under ice bath stirring, and then the reaction is stirred at room temperature for 3 hours. TLC is used to monitor until the reaction is completely converted. Methanol in the reaction system is removed by reduced pressure distillation, the pH value is adjusted to 6-7, a white solid is precipitated, and it is filtered and dried to obtain intermediate II.

7. The preparation method according to claim 3, characterized in that: The specific operation steps of step (3) are as follows: Using dichloromethane as a solvent, add intermediate II under stirring in an ice-salt bath, then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine. After reacting for 10 minutes, add amine compounds with different substituents and stir to react for 4 h; after extraction with distilled water and ethyl acetate, collect the organic phase, wash with saturated sodium bicarbonate solution, dry, and evaporate the solvent with a rotary evaporator to obtain an oily crude product; redissolve the oily crude product in methanol, add silica gel and mix well, separate by column chromatography to obtain a yellowish-white solid. Add the yellowish-white solid to a methanol solution and heat until the compound is completely dissolved. Wait for the solution to cool and white solid will precipitate. Filter and dry to obtain intermediate III.

8. The preparation method according to claim 3, characterized in that: The specific operation steps of step (4) are as follows: Dissolve intermediate III in dichloromethane, displace with nitrogen three times. Under the protection of nitrogen and stirring in an ice-salt bath, add boron tribromide solution and react overnight. Add methanol and triethylamine to quench. Rotate evaporate the obtained reaction solution. Redissolve the obtained solid in ethyl acetate, extract with distilled water and ethyl acetate, collect the organic phase, and alternately extract and wash with saturated sodium bicarbonate, brine, and dilute acid, then evaporate the solvent with a rotary evaporator to obtain a brown solid; add the brown solid to an ethyl acetate solution and heat until the compound is completely dissolved. Wait for the solution to cool and yellow solid will precipitate. Filter and dry to obtain a yellow solid; dissolve the obtained yellow solid in methanol, add dichloromethane until a trace amount of solid precipitates, monitor by TLC until the impurities are completely removed, filter to remove the impurities, collect the filtrate, and evaporate the solvent with a rotary evaporator to obtain the gallic acid derivative.

9. Use of the gallic acid derivative according to claim 1 or 2 in the preparation of drugs for preventing and treating inflammatory diseases and oxidative stress.

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