Synthesis method of emodin amide derivatives containing coumarin thiazole and use thereof against marine Vibrio

Abstract

The present invention relates to a rhamnamide derivative containing coumarin thiazole and also relates to a synthesis method of the derivative. The method specifically comprises the following steps: firstly reacting rhamnamide, tetrabutylammonium bromide, anhydrous potassium carbonate and dimethyl carbonate to generate 1,3,8-trimethoxy-6-methylanthracene-9,10-dione; then reacting 1,3,8-trimethoxy-6-methylanthracene-9,10-dione with tetrabutylammonium permanganate to generate 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid; and finally reacting with substituted 3-(2-aminothiazol-4-yl)coumarin to generate 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide. The raw materials of the invention are readily available, the reaction conditions are mild, the synthesis method is simple and safe to operate, the environmental pollution is small, the yield is high, and the post-processing is convenient. The synthesized compounds have a certain inhibitory effect on Vibrio harveyi.

Description

Technical Field

[0001] The present invention relates to the field of drug preparation, and in particular to a method for preparing emodin amide derivatives containing coumarin thiazole and the use of the emodin amide derivatives in inhibiting Vibrio harveyi. Background Art

[0002] In recent years, my country's mariculture industry has developed rapidly, with fishery production increasing significantly and ranking among the highest in the world. However, as the scale and intensification of aquaculture continue to increase, the aquaculture environment has deteriorated. Diseases caused by various aquatic pathogens have become increasingly common, severely hindering the breeding and development of marine fish and causing significant losses to the mariculture industry. Over 100 diseases are common in my country's mariculture, with bacterial diseases being the most common, frequent, and most detrimental. Dozens of pathogens representing over a dozen genera and species are known to cause these diseases, with Vibrio harveyi being a major opportunistic pathogen.

[0003] Therefore, the demand for safe and effective new antibiotics in aquaculture production is increasing. Finding new lead compounds or modifying, simplifying and developing new aquatic antibiotics has become a hot topic in current research on aquatic disease prevention and control.

[0004] With the continuous research on the pharmacological effects and biological activities of emodin, many researchers have devoted themselves to the study of emodin. They use emodin as the parent substance and chemically modify it to improve its properties and obtain emodin derivatives with certain biological activities. Studies have shown that the introduction of some new groups into emodin can significantly improve its biological activity, water solubility and bioavailability.

[0005] Research has shown that the main active ingredients in antibacterial and bactericidal activities include nitrogen- and sulfur-containing compounds, alkaloids, amides, coumarins, and quinone compounds. Using promising compounds as active leads, modifying and simplifying their structures, and identifying more active, safer, and more effective drug candidates has great research value and significance. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a new emodin amide derivative containing coumarin thiazole.

[0007] The technical problem to be solved by the present invention is to provide a method for rapidly and efficiently synthesizing emodin amide derivatives containing coumarin thiazole.

[0008] Another object of the present invention is to provide the use of the above-mentioned emodin amide derivatives containing coumarin thiazole in inhibiting Vibrio harveyi.

[0009] The technical problem to be solved by the present invention is achieved by the following technical solution. The present invention is a morphine amide derivative containing coumarin thiazole, which is characterized by: its structural formula is as shown in the formula:

[0010]

[0011] Wherein: R is selected from H-, 3-OCH3-, -OC2H5-, 5-F-, 5-OCH3-, 6-Cl-.

[0012] The technical problem to be solved by the present invention can be further achieved by the following technical solution. The present invention also discloses a method for synthesizing the eucomicamide derivatives containing coumarin thiazole as described in the above technical solution, which is characterized by the following steps:

[0013] (1) First, emodin, tetrabutylammonium bromide, anhydrous potassium carbonate, and dimethyl carbonate are reacted to generate 1,3,8-trimethoxy-6-methylanthracene-9,10-dione;

[0014] (2) reacting 1,3,8-trimethoxy-6-methylanthracene-9,10-dione with tetrabutylammonium permanganate to generate 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid;

[0015] (3) 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid reacts with substituted 3-(2-aminothiazol-4-yl)coumarin to generate 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide; the substituted 3-(2-aminothiazol-4-yl)coumarin is selected from H-, 3-OCH3-, -OC2H5-, 5-F-, 5-OCH3-, 6-Cl-.

[0016] The above-mentioned synthesis method, further preferred technical solutions are as follows:

[0017] 1. In step (1): N,N-dimethylformamide (DMF) and dimethyl carbonate are used as a mixed solvent, the molar ratio of emodin, tetrabutylammonium bromide and anhydrous potassium carbonate is (1-1.2):(0.5-0.8):(1.5-2.0), the reaction temperature is 105-115°C, and the reaction time is 10-12h.

[0018] 2. In step (2): the reaction solvent is pyridine, the molar ratio of 1,3,8-trimethoxy-6-methylanthracene-9,10-dione and tetrabutylammonium permanganate is (1.5-1.8):(8-9), the reaction temperature is 75°C-85°C, and the reaction time is 2.5-4h;

[0019] 3. In step (3): the reaction solvent is dichloromethane, the molar ratio of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid to substituted 3-(2-aminothiazol-4-yl)coumarin is 1:(1.2-1.5), the reaction temperature is 20-30°C, and the reaction time is 10-12h.

[0020] 4. In step (1): after the reaction is completed, water and hydrochloric acid are added to the reaction solution to adjust the pH, the crude product is filtered off, and the crude product is purified by column chromatography to obtain 1,3,8-trimethoxy-6-methylanthracene-9,10-dione; the molar ratio of emodin, tetrabutylammonium bromide and anhydrous potassium carbonate is 1:0.6:1.5.

[0021] 5. In step (2): After the reaction is completed, cool the mixture and transfer it to an ice-water bath. After adding sodium metabisulfite and continuing to stir for a certain period of time, add water and adjust the pH with hydrochloric acid. The solution changes from purple to yellow and a large amount of solid precipitates. Filter the mixture and wash it with water three times to obtain a yellow solid 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid.

[0022] 6. In step (3): the preparation method of the substituted 3-(2-aminothiazol-4-yl) coumarin compound is as follows: first, ethyl acetoacetate is reacted with a salicylaldehyde compound to obtain a 3-(acetyl) coumarin compound, then reacted with bromoketone to obtain a 3-(bromoacetyl) coumarin compound, and finally reacted with thiourea to obtain a 3-(2-aminothiazol-4-yl) coumarin compound; the molar ratio of ethyl acetoacetate to salicylaldehyde is (1-1.5):1, and the solvent is The reaction mixture is anhydrous ethanol, the reaction temperature is 20-25°C, and the reaction time is 6-8h; the molar ratio of brominated ketone and 3-(acetyl)coumarin compound is (1.5-2):1, the solvent is ethyl acetate, the reaction temperature is 50-60°C, and the reaction time is 10-12h; the molar ratio of thiourea and 3-(2-aminothiazol-4-yl)coumarin compound is (0.9-1.4):1, the solvent is ethanol, the reaction temperature is 70-80°C, and the reaction time is 1-2h.

[0023] The present invention also discloses the use of the coumarin thiazole-containing emodin amide derivatives or the coumarin thiazole-containing emodin amide derivatives synthesized by any one of the above synthesis method technical schemes. The use is the use of the coumarin thiazole-containing emodin amide derivatives in the preparation of antibacterial drugs, and the antibacterial bacteria is Vibrio harveyi.

[0024] The route of the synthetic method of the present invention is as follows:

[0025]

[0026] Compared with the prior art, the present invention has the following significant effects:

[0027] 1. The present invention provides a compound with antibacterial activity against Vibrio harveyi, a thiazole-containing eugenamide derivative of coumarin. It has higher biological activity and exhibits a better inhibitory effect against Vibrio harveyi.

[0028] 2. The synthesis method of the present invention is simple and safe to operate, and the reaction conditions are mild; the raw materials are readily available, the reaction adopts traditional temperature control, the experimental steps are simple, the post-processing is convenient, and the scope of application is broadened. DETAILED DESCRIPTION

[0029] The specific technical solutions of the present invention are further described below to facilitate a better understanding of the present invention, but do not constitute a limitation on the rights thereof.

[0030] Example 1, a method for synthesizing emodin amide derivatives containing coumarin thiazole, the steps are as follows:

[0031] (1) Preparation of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid: First, emodin, tetrabutylammonium bromide, anhydrous potassium carbonate, and dimethyl carbonate were reacted to generate 1,3,8-trimethoxy-6-methylanthracene-9,10-dione; N,N-dimethylformamide (DMF) and dimethyl carbonate were used as a mixed solvent for the reaction; the molar ratio of emodin, tetrabutylammonium bromide, and anhydrous potassium carbonate was 1:0.8:1.5; the reaction temperature was 105°C; and the reaction time was 10 h.

[0032] 1,3,8-trimethoxy-6-methylanthracene-9,10-dione is reacted with tetrabutylammonium permanganate to produce 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid; the reaction solvent is pyridine, the molar ratio of 1,3,8-trimethoxy-6-methylanthracene-9,10-dione and tetrabutylammonium permanganate is 1.5:8, the reaction temperature is 75°C, and the reaction time is 3 hours.

[0033] (2) Preparation of 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide compounds: 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide was obtained by reacting 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide with substituted 3-(2-aminothiazol-4-yl)coumarin. The reaction solvent was dichloromethane. The molar ratio of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide to substituted 3-(2-aminothiazol-4-yl)coumarin was 1:1.2. The reaction temperature was 20°C and the reaction time was 10 h. The substituted 3-(2-aminothiazol-4-yl)coumarin is selected from H-, 3-OCH3-, -OC2H5-, 5-F-, 5-OCH3-, 6-Cl-.

[0034] Example 2, a method for synthesizing emodin amide derivatives containing coumarin thiazole, the steps are as follows:

[0035] (1) Preparation of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid: Rhamnosine, tetrabutylammonium bromide, anhydrous potassium carbonate, and dimethyl carbonate were first reacted to generate 1,3,8-trimethoxy-6-methylanthracene-9,10-dione; N,N-dimethylformamide (DMF) and dimethyl carbonate were used as a mixed solvent for the reaction; the molar ratio of Rhamnosine, tetrabutylammonium bromide, and anhydrous potassium carbonate was 1:0.6:1.5; the reaction temperature was 105°C; and the reaction time was 10 h.

[0036] 1,3,8-trimethoxy-6-methylanthracene-9,10-dione is reacted with tetrabutylammonium permanganate to produce 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid; the reaction solvent is pyridine, the molar ratio of 1,3,8-trimethoxy-6-methylanthracene-9,10-dione and tetrabutylammonium permanganate is 1.5:9, the reaction temperature is 80°C, and the reaction time is 4 hours.

[0037] (2) Preparation of 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide compounds: 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide was obtained by reacting 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide with substituted 3-(2-aminothiazol-4-yl)coumarin. The reaction solvent was dichloromethane. The molar ratio of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide to substituted 3-(2-aminothiazol-4-yl)coumarin was 1:1.5. The reaction temperature was 23°C and the reaction time was 11 h. The substituted 3-(2-aminothiazol-4-yl)coumarin is selected from H-, 3-OCH3-, -OC2H5-, 5-F-, 5-OCH3-, 6-Cl-.

[0038] Example 3, a method for synthesizing emodin amide derivatives containing coumarin thiazole, the steps are as follows:

[0039] (1) Preparation of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid: First, emodin, tetrabutylammonium bromide, anhydrous potassium carbonate, and dimethyl carbonate were reacted to generate 1,3,8-trimethoxy-6-methylanthracene-9,10-dione; N,N-dimethylformamide (DMF) and dimethyl carbonate were used as a mixed solvent for the reaction; the molar ratio of emodin, tetrabutylammonium bromide, and anhydrous potassium carbonate was 1.2:0.8:1.5; the reaction temperature was 105°C; and the reaction time was 12 h.

[0040] 1,3,8-trimethoxy-6-methylanthracene-9,10-dione is reacted with tetrabutylammonium permanganate to produce 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid; the reaction solvent is pyridine, the molar ratio of 1,3,8-trimethoxy-6-methylanthracene-9,10-dione to tetrabutylammonium permanganate is 1.6:8.5, the reaction temperature is 80°C, and the reaction time is 2.5 hours.

[0041] (2) Preparation of 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide compounds: 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide was obtained by reacting 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide with substituted 3-(2-aminothiazol-4-yl)coumarin. The reaction solvent was dichloromethane. The molar ratio of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide to substituted 3-(2-aminothiazol-4-yl)coumarin was 1:1.3. The reaction temperature was 25°C and the reaction time was 12 h. The substituted 3-(2-aminothiazol-4-yl)coumarin is selected from H-, 3-OCH3-, -OC2H5-, 5-F-, 5-OCH3-, 6-Cl-.

[0042] Example 4, in the synthesis method of the emodin amide derivatives containing coumarin thiazole described in Examples 1-3: the preparation method of the substituted 3-(2-aminothiazol-4-yl)coumarin described in step (2) is as follows:

[0043] First, ethyl acetoacetate is weighed and reacted with salicylaldehyde compounds to obtain 3-(acetyl)coumarin compounds; the molar ratio of ethyl acetoacetate to salicylaldehyde compounds is 1:1, the solvent is anhydrous ethanol, the reaction temperature is 20°C, and the reaction time is 6 hours; then, it is reacted with ketone bromide to obtain 3-(bromoacetyl)coumarin compounds; the molar ratio of ketone bromide to 3-(acetyl)coumarin compounds is 1.5:1, the solvent is ethyl acetate, the reaction temperature is 50°C, and the reaction time is 10 hours; finally, it is reacted with thiourea to obtain 3-(2-aminothiazol-4-yl)coumarin compounds; the molar ratio of thiourea to 3-(2-aminothiazol-4-yl)coumarin compounds is 0.9:1, the solvent is ethanol, the reaction temperature is 75°C, and the reaction time is 1 hour.

[0044] Example 5, in the synthesis method of the emodin amide derivatives containing coumarin thiazole described in Examples 1-3: the preparation method of the substituted 3-(2-aminothiazol-4-yl)coumarin described in step (2) is as follows:

[0045] First, ethyl acetoacetate is weighed and reacted with salicylaldehyde compounds to obtain 3-(acetyl)coumarin compounds; the molar ratio of ethyl acetoacetate to salicylaldehyde compounds is 1.2:1, the solvent is anhydrous ethanol, the reaction temperature is 25°C, and the reaction time is 7h; then, it is reacted with ketone bromide to obtain 3-(bromoacetyl)coumarin compounds; the molar ratio of ketone bromide to 3-(acetyl)coumarin compounds is 2:1, the solvent is ethyl acetate, the reaction temperature is 60°C, and the reaction time is 11h; finally, it is reacted with thiourea to obtain 3-(2-aminothiazol-4-yl)coumarin compounds; the molar ratio of thiourea to 3-(2-aminothiazol-4-yl)coumarin compounds is 1.2:1, the solvent is ethanol, the reaction temperature is 80°C, and the reaction time is 2h.

[0046] Example 6, Synthesis Test 1 of Coumarin Thiazole-Containing Emodinamide Derivatives:

[0047] To a 25 mL round-bottom flask were added 0.21 g of compound 3 (compound code consistent with the preceding reaction scheme, hereinafter the same), 0.34 g of (HATU), 248 μL of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (DIEA), and 12 mL of dichloromethane. After stirring at room temperature for 0.5 h, compound 7 was weighed and added to the reaction solution. Stirring was continued at room temperature overnight. Upon completion of the reaction, a solid precipitated and was filtered. The resulting solid was washed several times with saturated sodium bicarbonate, dilute hydrochloric acid, and distilled water to obtain compound 8, 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide, as a yellow solid in 62% yield. mp>310°C; IR (KBr), ν / cm -1 :3421,2848,1727,1662,1599,1466,1317,1276,1072,1009,876; 1H NMR (500MHz, CDCl3), δ = 9.92 (s, 1H, NH), 8.57 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H, Ar -H),8.03(s,1H,Ar-H),7.36(d,J=2.0Hz,1H,Ar-H),7.24(s,1H,Ar-H),7.20(d,J= 7.7Hz,1H,Ar-H),7.10(d,J=7.9Hz,1H,Ar-H),6.81(d,J=1.8Hz,1H,Ar-H),4.11( s,3H,OCH3),4.00(s,3H,OCH3),3.98(d,J=1.7Hz,6H,OCH3); HRMS(ESI):m / z[M+H] + calcd for:C 31 H 23 N2O9S+ :599.11188;Found:599.11121.

[0048] Example 7, Synthesis Test 2 of Coumarin Thiazole-Containing Emodinamide Derivatives:

[0049] To a 25 mL round-bottom flask were added 0.21 g of compound 3 (compound code consistent with the preceding reaction scheme, the same below), 0.34 g of (HATU), 248 μL of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (DIEA), and 12 mL of dichloromethane. After stirring at room temperature for 1 hour, compound 7 was weighed and added to the reaction solution. Stirring was continued at room temperature overnight. Upon completion of the reaction, a solid precipitated and was filtered. The resulting solid was washed several times with saturated sodium bicarbonate, dilute hydrochloric acid, and distilled water to obtain compound 8, 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide, as a yellow solid in 68% yield. mp>310°C; IR (KBr), ν / cm -1 :3421,2848,1727,1662,1599,1466,1317,1276,1072,1009,876; 1H NMR (500MHz, CDCl3), δ = 9.92 (s, 1H, NH), 8.57 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H, Ar -H),8.03(s,1H,Ar-H),7.36(d,J=2.0Hz,1H,Ar-H),7.24(s,1H,Ar-H),7.20(d,J= 7.7Hz,1H,Ar-H),7.10(d,J=7.9Hz,1H,Ar-H),6.81(d,J=1.8Hz,1H,Ar-H),4.11( s,3H,OCH3),4.00(s,3H,OCH3),3.98(d,J=1.7Hz,6H,OCH3); HRMS(ESI):m / z[M+H] + calcd for:C 31 H 23 N2O9S + :599.11188;Found:599.11121.

[0050] Example 8, Synthesis of Coumarin Thiazole-Containing Rhamnamide Derivatives Experiment 3: The synthesis method refers to Examples 6 and 7. The substituent structures, reaction times, and product yields of the prepared compounds are shown in the following table:

[0051]

[0052]

[0053] Example 9, Antibacterial Activity Test of Coumarin Thiazole-Containing Emodinamide Derivatives:

[0054] The antibacterial activity test substance is a synthesized target compound, a morphine amide derivative containing coumarin thiazole; the antibacterial activity test strain is Vibrio harveyi.

[0055] The Oxford cup assay is used to determine the antibacterial activity of test compounds. This is a diffusion method in which an antimicrobial compound diffuses through a medium, killing or inhibiting surrounding bacteria, thereby creating a zone of inhibition. The size of this zone reflects the degree of inhibition against the indicator bacteria. For compounds with significant activity, the minimum inhibitory concentration (MIC) is further determined.

[0056] Determination of the antimicrobial activity of the test article: Under a sterile environment, pour approximately 20 mL of sterilized beef extract peptone agar medium onto a plate. After solidification, add 200 μL of the bacterial suspension and spread evenly with a spreader. Let it stand for 10 minutes. Place an Oxford cup vertically and evenly on the medium. Add 200 μL of the test sample to the cup. Perform three replicates for each sample. After incubation at 37°C for 18 hours, measure the diameter of the inhibition zone using an electronic digital caliper. The average of these three measurements is used.

[0057] This series of compounds has poor solubility and the concentration cannot reach 1 mg / mL. Therefore, this series of compounds were prepared into 0.25 mg / mL solution with DMSO. The MIC of the compounds with inhibition zone diameter greater than 13 mm was further determined. The specific test results are shown in the table below:

[0058]

[0059]

[0060] The results showed that the synthesized target compound 1, a chrysinamide derivative containing coumarin thiazole, had varying degrees of inhibitory effect on Vibrio harveyi. When the substituent of the compound was 3-OC2H5-, the inhibition rate was the best, and the MIC was further determined to be 0.25 (mg / mL).

[0061] In summary, the method of the present invention is simple, safe, economical, and widely applicable. It also features simple post-processing, making it a rapid and efficient synthesis method. The raw materials are readily available and affordable. Furthermore, the synthesized compounds exhibit varying degrees of inhibitory activity against Vibrio harveyi. Therefore, these structural compounds have significant practical value and potential socioeconomic value.

Claims

1. A morphinamide derivative containing coumarin thiazole, characterized in that: Its structural formula is as follows: ； Wherein: R is selected from H-, 3-OCH3-, 3-OC2H5-, 5-F-, 5-OCH3-, 6-Cl-.

2. A method for synthesizing the emodin amide derivatives containing coumarin thiazole according to claim 1, characterized in that: The steps are as follows: (1) First, emodin, tetrabutylammonium bromide, anhydrous potassium carbonate, and dimethyl carbonate are reacted to generate 1,3,8-trimethoxy-6-methylanthracene-9,10-dione; (2) reacting 1,3,8-trimethoxy-6-methylanthracene-9,10-dione with tetrabutylammonium permanganate to generate 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid; (3) 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid reacts with substituted 3-(2-aminothiazol-4-yl)coumarin to generate 4,5,7-trimethoxy-N-(4-(coumarin-3-yl)thiazol-2-yl)-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxamide; the substituent of the substituted 3-(2-aminothiazol-4-yl)coumarin is selected from H-, 3-OCH3-, 3-OC2H5-, 5F-, 5-OCH3-, 6-Cl-.

3. The synthesis method according to claim 2, wherein: In step (1): N,N-dimethylformamide (DMF) and dimethyl carbonate are used as a mixed solvent, the molar ratio of emodin, tetrabutylammonium bromide and anhydrous potassium carbonate is (1-1.2):(0.5-0.8):(1.5-2.0), the reaction temperature is 105°C-115°C, and the reaction time is 10-12h.

4. The synthesis method according to claim 2, wherein: In step (2): the reaction solvent is pyridine, the molar ratio of 1,3,8-trimethoxy-6-methylanthracene-9,10-dione and tetrabutylammonium permanganate is (1.5-1.8):(8-9), the reaction temperature is 75°C-85°C, and the reaction time is 2.5-4h.

5. The synthesis method according to claim 2, wherein: In step (3): the reaction solvent is dichloromethane, the molar ratio of 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid to substituted 3-(2-aminothiazol-4-yl)coumarin is 1:(1.2-1.5), the reaction temperature is 20-30°C, and the reaction time is 10-12h.

6. The synthesis method according to claim 2, characterized in that: In step (1): after the reaction is completed, water and hydrochloric acid are added to the reaction solution to adjust the pH, the crude product is filtered, and the crude product is purified by column chromatography to obtain 1,3,8-trimethoxy-6-methylanthracene-9,10-dione; the molar ratio of emodin, tetrabutylammonium bromide and anhydrous potassium carbonate is 1:0.6:1.

5.

7. The synthesis method according to claim 2, characterized in that: In step (2): after the reaction is completed, the mixture is cooled and placed in an ice-water bath. Sodium metabisulfite is added and stirred for a certain period of time. Water is then added and the pH is adjusted with hydrochloric acid. The solution changes from purple to yellow and a large amount of solid precipitates. The solution is filtered and washed with water three times to obtain a yellow solid 4,5,7-trimethoxy-9,10-dicarbonyl-9,10-dihydroanthracene-2-carboxylic acid.

8. The synthesis method according to claim 2, characterized in that: The preparation method of the substituted 3-(2-aminothiazole-4-yl)coumarin compound in step (3) is as follows: first, ethyl acetoacetate is reacted with a salicylaldehyde compound to obtain a 3-(acetyl)coumarin compound, then the compound is reacted with bromoketone to obtain a 3-(bromoacetyl)coumarin compound, and finally the compound is reacted with thiourea to obtain a 3-(2-aminothiazole-4-yl)coumarin compound; the molar ratio of ethyl acetoacetate to salicylaldehyde is (1-1.5):1, the solvent is anhydrous ethanol, the reaction temperature is 20-25°C, and the reaction time is 6-8h.

9. Use of the emodinamide derivative containing coumarin thiazole according to claim 1 or the emodinamide derivative containing coumarin thiazole synthesized by the method of any one of claims 2 to 8, characterized in that: The application is the application of the emodin amide derivatives containing coumarin thiazole in the preparation of antibacterial drugs, and the antibacterial bacteria is Vibrio harveyi.

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