A protocatechu derivative and its synthesis method and application

Abstract

The present invention provides a protocatechuic acid derivative and its synthesis method and application. Derivative preparation method: First, the carboxyl group of protocatechuic acid is substituted with thiosemicarbazide, and the active group 1,3,4-thiadiazole is introduced to synthesize the intermediate 4-(5-amino-1,3,4-thiadiazole-2-yl) catechol. Then, the intermediate undergoes a nucleophilic addition reaction with a substituted benzaldehyde, and the active group Schiff base is introduced to obtain a protocatechuic acid derivative 4-{5-(substituted benzylamino)-1,3,4-thiadiazole-2-yl} catechol. The method for synthesizing the protocatechuic acid derivative is easy to operate, the raw material cost is low, and the obtained product is easy to purify. The protocatechuic acid derivative provided by the present invention can effectively inhibit the cabbage soft rot fungus and the potato ring rot fungus, and can be used in the prevention and treatment of cabbage soft rot and potato ring rot.

Description

Technical Field

[0001] The invention relates to a protocatechu derivative, in particular to a protocatechu derivative and a synthesis method thereof and application of the derivative in preventing and controlling cabbage soft rot and potato ring rot. Background Art

[0002] Cabbage soft rot bacteria are Gram-negative bacteria that can cause cabbage soft rot. When cabbage is infected with soft rot, it will rot regardless of whether it is in the growth period or in the storage period, and the incidence rate can reach 30% to 40%. When the disease is serious, the yield reduction will exceed 50%, and there will even be a total crop failure. Potato ring rot bacteria are Gram-positive bacteria that can cause potato ring rot. After the bacteria enter the plant through the vascular bundle, the underground tubers will gradually form ring rot. After infection, the potato yield will be reduced by 10% to 30%, and in severe plots it will be as high as 60%, and there will also be a total crop failure.

[0003] Protocatechuic acid is a phenolic acid compound widely distributed in vegetables, fruits and Chinese herbal medicines. Protocatechuic acid consists of a benzene ring, a phenolic hydroxyl group and a carboxyl group, and has a derivatizable structure. 1,3,4-thiadiazole is a five-membered aromatic heterocyclic compound that can be used as an important antibacterial active structure. Schiff base refers to a class of compounds containing an imine or azomethine characteristic group (-RC=N-) and having antibacterial, antiviral and other physiological activities.

[0004] Therefore, according to the active splicing principle, the present invention splices protocatechuic acid with 1,3,4-thiadiazole and then with different substituted benzaldehydes in a Schiff base structure, and designs and synthesizes a series of protocatechuic acid derivatives with 1,3,4-thiadiazole groups and Schiff base structures for the first time. The method for synthesizing the protocatechuic acid derivative is easy to operate, the raw material cost is low, and the obtained product is easy to purify. The protocatechuic acid derivative can significantly inhibit the cabbage soft rot bacteria and potato ring rot bacteria, can effectively prevent and treat the cabbage soft rot and potato ring rot, and is a new effective compound. Summary of the invention

[0005] The invention aims to provide a protocatechuic acid derivative resistant to Chinese cabbage soft rot bacteria and potato ring rot bacteria, and a synthesis method and use thereof.

[0006] The present invention provides a protocatechuic acid derivative resistant to Chinese cabbage soft rot bacteria and potato ring rot bacteria, and its structural formula is:

[0007]

[0008] Preferably R=2-F, 2-Cl, 2-NO2, 3-F, 3-Cl or 3-Br.

[0009] The present invention provides a method for preparing a protocatechuic acid derivative resistant to Chinese cabbage soft rot bacteria and potato ring rot bacteria, comprising the following steps:

[0010] (1) Weigh protocatechuic acid and thiosemicarbazide, add 20-50 mL of phosphorus oxychloride, stir thoroughly and heat to 60-100°C, and continue stirring for 4-8 hours. The molar ratio of protocatechuic acid to thiosemicarbazide is 1:(1-3), and the reaction is monitored by thin layer spot plate until it is complete. After cooling to room temperature, slowly add 40-80 mL of distilled water in an ice water bath, react at 80-120°C for 3-6 hours, and monitor by thin layer spot plate until the reaction is complete. After the reaction solution is cooled, pour it into ice water, adjust the pH with NaOH solution, and stir to produce precipitation. After filtering, the filter cake is recrystallized with a mixture [V(DMF):V(H2O)=1:(1-3)] to obtain a light pink powder 4-(5-amino-1,3,4-thiadiazole-2-yl) o-diphenol;

[0011] (2) Take the light pink powder obtained in step (1) and the substituted benzaldehyde in a molar ratio of 1:(1-2), dissolve them in anhydrous ethanol, add a small amount of acetic acid, stir and reflux for 3-6 hours, and monitor with a thin layer spot plate until the reaction is complete. Distill off most of the ethanol, cool and filter, wash the filter cake with distilled water and filter, and then recrystallize with ethanol to obtain a yellow or reddish brown solid protocatechuic acid derivative 4-(5-substituted phenylimino-1,3,4-thiadiazole-2-yl)catechol.

[0012] The substituted benzaldehydes are 2-fluorobenzaldehyde, 2-chlorobenzaldehyde, 2-bromobenzaldehyde, 2-methylbenzaldehyde, 2-methoxybenzaldehyde, 2-nitrobenzaldehyde, 2-hydroxybenzaldehyde, 3-fluorobenzaldehyde, 3-chlorobenzaldehyde, 3-bromobenzaldehyde, 3-methylbenzaldehyde, 3-methoxybenzaldehyde, 3-nitrobenzaldehyde, 3-hydroxybenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-methylbenzaldehyde, 4- Anisaldehyde, 4-nitrobenzaldehyde, 4-hydroxybenzaldehyde, 2,4-difluorobenzaldehyde, 2,4-dichlorobenzaldehyde, 2,4-dimethylbenzaldehyde, 3,4-difluorobenzaldehyde, 3,4-dibromobenzaldehyde, 3,4-dimethylbenzaldehyde, 3,4-dimethoxybenzaldehyde, 3,4-dihydroxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 3-methoxy-4-hydroxybenzaldehyde, 2-hydroxy-3-methoxybenzaldehyde.

[0013] In the step (1), the molar ratio of protocatechuic acid to thiosemicarbazide is preferably 1:1.

[0014] The molar ratio of the light pink powder to the substituted benzaldehyde in step (2) is preferably 1:1.25.

[0015] The protocatechuic acid derivative prepared by the invention has a strong bactericidal effect on cabbage soft rot bacteria and potato ring rot bacteria, and can be used for preventing and controlling cabbage soft rot and potato ring rot.

[0016] Compared with the prior art, the present invention has the following beneficial effects: in vivo experiments show that the protocatechuic acid derivatives have very obvious inhibitory activity against cabbage soft rot fungi and potato ring rot fungi, among which the derivatives 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazole-2-yl}catechol, 4-{5-[(3-fluorobenzyl)amino]-1,3,4-thiadiazole-2-yl}catechol, 4-{5-[(3-chlorobenzyl)amino]-1,3,4-thiadiazole-2-yl}catechol, The control effects of 4-{5-[(3-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol on the soft rot of cabbage were significantly higher than those of the positive control agent zinc thiazole (72.82%) and the therapeutic effects (68.24%). Among them, 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol had the best control effect (the preventive effect and therapeutic effect were 89.44% and 83.95%, respectively). The control effects of the derivatives 4-{5-[(2-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol, 4-{5-[(2-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol and 4-{5-[(2-nitrobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol on potato ring rot pathogen were significantly higher than the preventive effect (66.21%) and therapeutic effect (60.44%) of the positive control agent methyl thiophanate, among which 4-{5-[(2-nitrobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol had the best control effect (the preventive effect and therapeutic effect were 85.44% and 77.67%, respectively). In the potted experiment, the disease condition of cabbage seedlings was significantly improved after the treatment of 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol, and the control effect of 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (preventive effect 88.94%, therapeutic effect 83.27%) was better than that of zinc thiazol (preventive effect 77.10%, therapeutic effect 69.72%). After the treatment of 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazol-2-yl}catechol, the disease of potato seedlings was significantly improved, and the control effect of 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazol-2-yl}catechol (preventive effect 85.84%, therapeutic effect 76.62%) was better than that of methyl thiophanate (preventive effect 77.22%, therapeutic effect 71.91%). It can be seen that protocatechuic acid derivatives have excellent control effects on cabbage soft rot and potato ring rot.

[0017] In summary, the protocatechuic acid derivatives provided by the present invention have a strong bactericidal effect on cabbage soft rot bacteria and potato ring rot bacteria, and can be used for the prevention and treatment of cabbage soft rot and potato ring rot. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 1H, 1C and Mass Spectra of 4-{5-[(2-nitrobenzylidine)amino]-1,3,4-thiadiazol-2-yl}catechol(A6)

[0019] Figure 2 4-{5-[(3-Fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol(A8) 1H, 2C and 3D spectra DETAILED DESCRIPTION

[0020] Example 1 is the preparation of 4-{5-[(2-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 2 is the preparation of 4-{5-[(2-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 3 is the preparation of 4-{5-[(2-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 4 is the preparation of 4-{5-[(2-methylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 5 is the preparation of 4-{5-[(2-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 6 is the preparation of 4-{5-[(2- Example 7 is the preparation of 4-{5-[(2-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 8 is the preparation of 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 9 is the preparation of 4-{5-[(3-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol: Example 10 is the preparation of 4-{5-[(3-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 11 is the preparation of 4-{5-[(3-methylbenzylidene)amino]-1,3 ,4-thiadiazol-2-yl}catechol; Example 12 is the preparation of 4-{5-[(3-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 13 is the preparation of 4-{5-[(3-nitrobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 14 is the preparation of 4-{5-[(3-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 15 is the preparation of 4-{5-[(4-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 16 is the preparation of 4-{5-[(4-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl} Preparation of catechol; Example 17 is the preparation of 4-{5-[(4-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 18 is the preparation of 4-{5-[(4-methylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 19 is the preparation of 4-{5-[(4-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 20 is the preparation of 4-{5-[(4-nitrobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 21 is the preparation of 4-{5-[(4-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol;Example 22 is the preparation of 4-{5-[(2,4-difluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 23 is the preparation of 4-{5-[(2,4-dichlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 24 is the preparation of 4-{5-[(2,4-dimethylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 25 is the preparation of 4-{5-[(3,4-difluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 26 is the preparation of 4-{5-[(3,4-dibromobenzylidene)amino]- 1,3,4-thiadiazol-2-yl}catechol; Example 27 is 4-{5-[(3,4-dimethylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 28 is the preparation of 4-{5-[(3,4-dimethoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 29 is the preparation of 4-{5-[(3,4-dihydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 30 is the preparation of 4-{5-[(3,5-dimethoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 3 Example 1 is the preparation of 4-{5-[(3-methoxy-4-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 32 is the preparation of 4-{5-[(2-hydroxy-3-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol; Example 33 is the preventive effect of 32 protocatechuic acid derivatives on cabbage soft rot bacteria; Example 34 is the therapeutic effect of 32 protocatechuic acid derivatives on cabbage soft rot bacteria; Example 35 is the preventive effect of 32 protocatechuic acid derivatives on potato ring rot bacteria; Example 36 is the therapeutic effect of 32 protocatechuic acid derivatives on potato ring rot bacteria; Example 37 is 4 -{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol has a potted preventive effect on cabbage soft rot fungi; Example 38 is the potted therapeutic preventive effect of 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol on cabbage soft rot fungi; Example 39 is the potted preventive effect of 4-{5-[(2-nitrobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol on potato ring rot fungi; Example 40 is the potted therapeutic effect of 4-{5-[(2-nitrobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol on potato ring rot fungi. ;

[0021] Example 1

[0022] Preparation of 4-{5-[(2-fluorobenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A1):

[0023] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol

[0024] Add 50mmol protocatechuic acid and 50mmol thiosemicarbazide to a round-bottom flask, add 30mL phosphorus oxychloride in 5 times with stirring, reflux at 80℃ for 120min, and monitor the reaction with a thin layer plate until the reaction is complete. After cooling to room temperature, slowly add 60mL water to the reaction solution in 4 times in an ice-water bath, reflux at 110℃ for 5h, and monitor the reaction with a thin layer plate until the reaction is complete. After the reaction solution is cooled, pour it into 200mL ice water, adjust the pH to 8 with 40% NaOH, and stir to precipitate. Filter by suction, wash the filter cake twice with distilled water and dry to obtain a crude product. Recrystallize with a mixture [V(DMF):V(H2O)=1:2] to obtain a light pink solid.

[0025] (2) Synthesis of 4-{5-[(2-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A1)

[0026] Add 20mmol of the above-mentioned light pink solid 4-(5-amino-1,3,4-thiadiazole-2-yl) o-diphenol and 25mmol of 2-fluorobenzaldehyde (substituted benzaldehyde) and 20mL of anhydrous ethanol into a flask, and add 2-3 drops of acetic acid, heat under reflux for 5h under stirring, and monitor with a thin layer spot plate until the reaction is complete. Distill off most of the ethanol, cool and filter, wash the filter cake with distilled water and filter, and then recrystallize with ethanol to obtain a light yellow solid 4-{5-[(2-fluorobenzylidene)amino]-1,3,4-thiadiazole-2-yl} o-diphenol.

[0027] 1 H NMR(600MHz,DMSO-d6)δ:9.64(s,2H),9.09(s,1H),8.17(t,J=7.4Hz,1H),7.74(q,J=7.1Hz,1H) ,7.47–7.35(m,2H),7.27(dd,J=8.3,2.2Hz,1H),7.18(d,J=11.3Hz,1H),6.88(d,J=8.1Hz,1H); 13C NMR(151MHz,DMSO-d6)δ:172.62,168.03,167.90,166.95,149.47,147.66,146.40,146.07,133.11,133.02 ,122.86,121.66,120.26,118.87,117.03,116.81,116.73,116.39,114.39,113.65;ESI-HRMS(m / z),calcd for C 15 H 11 FN3O2S[M+H] + :316.05402,found:316.05505.

[0028] Example 2

[0029] Preparation of 4-{5-[(2-chlorobenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A2):

[0030] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0031] (2) Synthesis of 4-{5-[(2-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A2), wherein the substituted benzaldehyde is 2-chlorobenzaldehyde, and the rest is the same as in Example 1.

[0032] 1 H NMR(600MHz,DMSO-d6)δ:9.61(s,1H),9.23(s,2H),7.68(s,2H),7.56(s,1H),7.43(d,J =2.2Hz,1H),7.29(dd,J=8.2,2.2Hz,1H),7.19(d,J=6.2Hz,1H),6.89(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:172.34,167.62,164.27,149.61,146.42,136.78,135.40,13 1.72,130.98,129.63,128.52,121.51,120.45,116.72,114.40;ESI-HRMS(m / z),calcd for C 15 H 11 ClN3O2S[M+H] + :332.02444,found:332.02550.

[0033] Example 3

[0034] Preparation of 4-{5-[(2-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A3):

[0035] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0036] (2) Synthesis of 4-{5-[(2-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A3), wherein the substituted benzaldehyde is 2-bromobenzaldehyde, and the rest is the same as in Example 1.

[0037] 1 H NMR(600MHz, DMSO-d6)δ:10.23(d,J=0.7Hz,1H),9.17(s,1H),8.23(dd,J=6.0,3.6Hz,1H),7.87–7.81(m,1H),7.59( dd,J=5.9,3.5Hz,2H),7.44(d,J=2.2Hz,1H),7.29(dd,J=8.2,2.2Hz,1H),7.22–7.17(m,1H),6.90(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:172.18,167.66,166.51,149.63,146.43,135.56,134.24,13 3.04,130.01,129.01,127.19,121.48,120.44,116.74,114.44;ESI-HRMS(m / z),calcd for C 15 H 11 BrN3O2S[M+H] + :377.97113,found:377.97294.

[0038] Example 4

[0039] Preparation of 4-{5-[(2-methylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A4):

[0040] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0041] (2) Synthesis of 4-{5-[(2-methylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A4), wherein the substituted benzaldehyde is 2-methylbenzaldehyde, and the rest is the same as in Example 1.

[0042] 1 H NMR(600MHz,DMSO-d6)δ:10.18(d,J=0.8Hz,1H),9.41(d,J=70.7Hz,2H),7.67(d,J=8.6Hz,2H),7.19(d,J=2.2Hz,1H),7 .01(dd,J=8.2,2.2Hz,1H),6.80(d,J=8.2Hz,1H),6.69(d,J=2.3Hz,1H),6.65(ddd,J=8.7,2.3,0.8Hz,1H),3.91(s,3H); 13 C NMR(151MHz,DMSO-d6)δ:167.89,157.38,151.13,147.65,146.08,139.13,135.71,130.18, 129.53,127.37,118.83,116.74,116.41,113.67,112.44,21.18;ESI-HRMS(m / z),calcdfor C 16 H 14 N3O2S[M+H] + :312.07901,found:312.08012.

[0043] Example 5

[0044] Preparation of 4-{5-[(2-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A5):

[0045] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0046] (2) Synthesis of 4-{5-[(2-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A5), wherein the substituted benzaldehyde is 2-methoxybenzaldehyde, and the rest is the same as in Example 1.

[0047] 1 H NMR(600MHz, DMSO-d6)δ:9.64(s,2H),9.20(s,1H),8.09(dd,J=7.8,1.8Hz,1H),7.66(ddd,J=8.9,7.3,1.8Hz,1H) ,7.42(d,J=2.2Hz,1H),7.25(ddd,J=14.7,8.4,1.6Hz,2H),7.15–7.07(m,1H),6.89(d,J=8.2Hz,1H),3.95(s,3H); 13C NMR(151MHz,DMSO-d6)δ:173.32,166.73,163.43,160.93,149.44,146.38,136.19,128.1 0,122.74,121.68,121.52,121.10,120.32,116.68,114.36,56.53;ESI-HRMS(m / z),calcd for C 16 H 14 N3O3S[M+H] + :328.07385,found:328.07504.

[0048] Example 6

[0049] Preparation of 4-{5-[(2-nitrobenzylidine)amino]-1,3,4-thiadiazole-2-yl}catechol (A6):

[0050] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0051] (2) Synthesis of 4-{5-[(2-nitrobenzylethylene)amino]-1,3,4-thiadiazol-2-yl}catechol (A6), wherein the substituted benzaldehyde is 2-nitrobenzaldehyde, and the rest is the same as in Example 1, and finally a reddish brown solid is obtained.

[0052] 1 H NMR(600MHz,DMSO-d6)δ:9.74(s,2H),9.20(s,1H),7.66(td,J=7.9,7.4,1.8Hz,1H),7 .41(d,J=2.1Hz,1H),7.26–7.23(m,2H),7.13(t,J=7.5Hz,2H),6.87(d,J=8.2Hz,1H); 13 CNMR(151MHz,DMSO-d6)δ:171.36,163.98,149.93,149.84,146.47,134.08,132.11,13 1.97,129.06,128.68,120.82,120.65,120.22,116.79,114.58;ESI-HRMS(m / z),calcd for C 15 H 11 N4O4S[M+H] + :343.04807,found:343.04955.

[0053] Example 7

[0054] Preparation of 4-{5-[(2-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A7):

[0055] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0056] (2) Synthesis of 4-{5-[(2-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A7), wherein the substituted benzaldehyde is 2-hydroxybenzaldehyde, and the rest is the same as in Example 1.

[0057] 1 H NMR(600MHz, DMSO-d6)δ:10.27(s,1H),9.21(s,2H),7.91(dd,J=7.8,1.8Hz,1H),7.52(ddd,J=8.7,7.1 ,1.8Hz,1H),7.41(d,J=2.2Hz,1H),7.26(dd,J=8.2,2.2Hz,1H),7.19–7.18(m,1H),7.06–6.93(m,3H); 13 C NMR(151MHz,DMSO-d6)δ:172.24,167.14,149.48,147.64,146.40,146.07,130.95,12 1.62,120.32,120.29,117.44,116.72,116.39,114.36,113.64;ESI-HRMS(m / z),calcd for C 15 H 12 N3O3S[M+H] + :314.05826,found:314.05939.

[0058] Example 8

[0059] Preparation of 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A8):

[0060] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0061] (2) Synthesis of 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A8), wherein the substituted benzaldehyde is 3-fluorobenzaldehyde, and the rest is the same as in Example 1.

[0062] 1H NMR (600MHz, DMSO-d6) δ: 10.02 (d, J=1.8Hz, 1H), 9.05 (s, 2H), 7.81–7.78 (m, 1H), 7.67 (dtd, J= 21.6,8.5,8.0,5.9Hz,3H),7.19(d,J=2.2Hz,1H),6.90(d,J=8.2Hz,1H),6.79(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:172.29,167.33,149.58,146.43,131.98,131.84,122.05,12 1.91,121.54,120.30,116.76,116.41,115.97,114.45,113.67;ESI-HRMS(m / z),calcd for C 15 H 11 FN3O2S[M+H] + :315.05426,found:315.05505.

[0063] Example 9

[0064] Preparation of 4-{5-[(3-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A9):

[0065] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0066] (2) Synthesis of 4-{5-[(3-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A9), wherein the substituted benzaldehyde is 3-chlorobenzaldehyde, and the rest is the same as in Example 1.

[0067] 1 H NMR (600MHz, DMSO-d6) δ: 10.01 (s, 2H), 9.04 (s, 1H), 7.90–7.87 (m, 1H), 7.68–7.62 (m, 3H), 6.98 (dd, J = 8.2, 2.2Hz, 2H), 6.90 (d, J = 8.2Hz, 1H); 13 C NMR(151MHz,DMSO-d6)δ:192.63,167.89,157.36,147.65,146.07,138.37,134.67,13 1.66,129.50,128.85,128.42,122.84,118.85,116.40,113.65;ESI-HRMS(m / z),calcd for C15 H 11 ClN3O2S[M+H] + :332.02414,found:332.02550.

[0068] Example 10

[0069] Preparation of 4-{5-[(3-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A10):

[0070] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0071] (2) Synthesis of 4-{5-[(3-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A10), wherein the substituted benzaldehyde is 3-bromobenzaldehyde, and the rest is the same as in Example 1.

[0072] 1 H NMR(600MHz, DMSO-d6)δ:9.77(s,1H),9.55(s,1H),9.03(s,1H),8.24(t,J=1.8Hz,1H),8.07(dt,J=7.8,1.3Hz,1H),7.86(d dd,J=8.0,2.1,1.0Hz,1H),7.56(t,J=7.9Hz,1H),7.41(d,J=2.2Hz,1H),7.27(dd,J=8.2,2.2Hz,1H),6.90(d,J=8.2Hz,1H); 13 CNMR(151MHz,DMSO-d6)δ:172.26,167.94,167.34,149.57,146.42,137.24,136.35,13 2.63,131.82,129.18,122.82,121.55,120.33,116.75,114.43;ESI-HRMS(m / z),calcd forC 15 H 11 BrN3O2S[M+H] + :377.97134,found:377.97294.

[0073] Embodiment 11

[0074] Preparation of 4-{5-[(3-methylbenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A11):

[0075] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0076] (2) Synthesis of 4-{5-[(3-methylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A11), wherein the substituted benzaldehyde is 3-methylbenzaldehyde, and the rest is the same as in Example 1.

[0077] 1 H NMR(600MHz,DMSO-d6)δ:9.98(s,2H),8.97(s,1H),7.90–7.87(m,1H),7.85(td,J=4.7,1.7Hz,1H),7.48(dt ,J=3.9,0.8Hz,2H),7.42(d,J=2.2Hz,1H),7.26(dd,J=8.2,2.2Hz,1H),6.90(d,J=8.2Hz,1H),2.41(s,3H); 13 C NMR(151MHz,DMSO-d6)δ:172.79,169.37,166.90,149.47,146.41,139.05,134.98,134.7 4,130.47,129.55,128.04,121.65,120.22,116.74,114.42,21.27;ESI-HRMS(m / z),calcd for C 16 H 14 N3O2S[M+H] + :312.07892,found:312.08012.

[0078] Example 12

[0079] Preparation of 4-{5-[(3-methoxybenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A12):

[0080] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0081] (2) Synthesis of 4-{5-[(3-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A12), wherein the substituted benzaldehyde is 3-methoxybenzaldehyde, and the rest is the same as in Example 1.

[0082] 1H NMR(600MHz, DMSO-d6)δ:9.66(s,2H),9.00(s,1H),7.64(dt,J=7.7,1.3Hz,1H),7.61(dd,J=2.7,1.4Hz,1H),7.54–7.49(m,1 H),7.41(d,J=2.2Hz,1H),7.26(dd,J=8.1,2.2Hz,1H),7.24(ddd,J=8.2,2.7,1.0Hz,1H),6.90(d,J=8.2Hz,1H),3.86(s,3H); 13 CNMR(151MHz,DMSO-d6)δ:172.66,169.24,166.99,160.13,149.53,146.43,136.39,130.78 ,123.54,121.61,120.52,120.24,116.74,114.42,113.80,55.84;ESI-HRMS(m / z),calcdfor C 16 H 14 N3O3S[M+H] + :328.07397,found:328.07504.

[0083] Embodiment 13

[0084] Preparation of 4-{5-[(3-nitrobenzylidine)amino]-1,3,4-thiadiazole-2-yl}catechol (A13):

[0085] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0086] (2) Synthesis of 4-{5-[(3-nitrobenzylethylene)amino]-1,3,4-thiadiazol-2-yl}catechol (A13), wherein the substituted benzaldehyde is 3-nitrobenzaldehyde, and the rest is the same as in Example 1, and finally a reddish brown solid is obtained.

[0087] 1 H NMR(600MHz,DMSO-d6)δ:10.15(s,2H),9.21(s,1H),8.85(t,J=2.0Hz,1H),8.50–8.46(m,2H) ,7.91–7.88(m,1H),7.42(d,J=2.2Hz,1H),7.28(dd,J=8.2,2.2Hz,1H),6.90(d,J=8.2Hz,1H); 13C NMR(151MHz,DMSO-d6)δ:172.01,167.62,167.58,149.69,148.74,146.45,136.51,13 5.89,131.43,131.32,124.62,121.46,120.36,116.77,114.48;ESI-HRMS(m / z),calcd for C 15 H 11 N4O4S[M+H] + :343.04840,found:343.04955.

[0088] Embodiment 14

[0089] Preparation of 4-{5-[(3-hydroxybenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A14):

[0090] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0091] (2) Synthesis of 4-{5-[(3-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A14), wherein the substituted benzaldehyde is 3-hydroxybenzaldehyde, and the rest is the same as in Example 1.

[0092] 1 H NMR(600MHz,DMSO-d6)δ:9.71(s,3H),8.92(s,1H),7.49–7.35(m,4H),7.25(d d,J=8.2,2.2Hz,1H),7.06(ddd,J=8.1,2.6,1.0Hz,1H),6.88(d,J=8.1Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:193.60,172.75,169.44,166.88,158.34,136.29,130.78,13 0.73,122.26,121.54,121.40,120.24,116.70,115.52,114.32;ESI-HRMS(m / z),calcd forC 15 H 12 N3O3S[M+H] + :314.05820,found:314.05939.

[0093] Embodiment 15

[0094] Preparation of 4-{5-[(4-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A15):

[0095] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0096] (2) Synthesis of 4-{5-[(4-fluorobenzylidine)amino]-1,3,4-thiadiazol-2-yl}catechol (A15), wherein the substituted benzaldehyde is 4-fluorobenzaldehyde, and the rest is the same as in Example 1.

[0097] 1 H NMR (600MHz, DMSO-d6) δ: 9.75 (s, 2H), 9.03 (s, 1H), 8.14 (dd, J = 8.5, 5.5Hz, 2H), 7.26 ( dd,J=8.2,2.1Hz,2H),7.02–6.97(m,1H),6.89(d,J=8.3Hz,1H),6.79(d,J=8.1Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:168.03,149.47,147.66,146.40,146.07,133.11,133.02,12 0.26,118.87,117.03,116.81,116.73,116.39,114.39,113.65;ESI-HRMS(m / z),calcd for C 15 H 11 FN3O2S[M+H] + :316.05411,found:316.05515.

[0098] Example 16

[0099] Preparation of 4-{5-[(4-chlorobenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A16):

[0100] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0101] (2) Synthesis of 4-{5-[(4-chlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A16), wherein the substituted benzaldehyde is 4-chlorobenzaldehyde, and the rest is the same as in Example 1.

[0102] 1H NMR(600MHz,DMSO-d6)δ:9.75(d,J=315.4Hz,2H),9.04(s,1H),8.11–8.05(m,2H),7.70 –7.65(m,2H),7.41(d,J=2.2Hz,1H),7.26(dd,J=8.2,2.2Hz,1H),6.89(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:172.48,168.17,167.14,149.58,146.43,146.08,138.65,13 3.86,132.00,129.86,121.56,120.28,116.74,114.39,113.64;ESI-HRMS(m / z),calcd for C 15 H 11 ClN3O2S[M+H] + :332.02478,found:332.02550.

[0103] Embodiment 17

[0104] Preparation of 4-{5-[(4-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A17):

[0105] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0106] (2) Synthesis of 4-{5-[(4-bromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A17), wherein the substituted benzaldehyde is 4-bromobenzaldehyde, and the rest is the same as in Example 1.

[0107] 1 H NMR(600MHz,DMSO-d6)δ:9.77(s,1H),9.55(s,1H),9.01(s,1H),7.99(d,J=8.5Hz,2H),7.80 (d,J=8.5Hz,2H),7.40(d,J=2.2Hz,1H),7.25(dd,J=8.2,2.2Hz,1H),6.89(d,J=8.2Hz,1H); 13C NMR(151MHz,DMSO-d6)δ:172.50,168.34,167.16,149.53,146.41,134.16,132.79,13 2.10,131.73,127.86,121.59,120.28,116.75,114.42,113.65;ESI-HRMS(m / z),calcd for C 15 H 11 BrN3O2S[M+H] + :377.97168,found:377.97294.

[0108] Embodiment 18

[0109] Preparation of 4-{5-[(4-methylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A18):

[0110] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0111] (2) Synthesis of 4-{5-[(4-methylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A18), wherein the substituted benzaldehyde is 4-methylbenzaldehyde, and the rest is the same as in Example 1.

[0112] 1 H NMR(600MHz,DMSO-d6)δ:9.96(s,2H),8.97(s,1H),7.96(d,J=8.1Hz,2H),7.45–7.36 (m,2H),7.25(dd,J=8.2,2.2Hz,1H),7.19(s,1H),6.89(d,J=8.2Hz,1H),2.51(s,3H); 13 C NMR(151MHz,DMSO-d6)δ:172.94,169.11,166.71,146.40(2C),144.69,132.47,130.5 (2C),130.32(2C),121.67,120.21,116.71,114.34,21.88;ESI-HRMS(m / z),calcdfor C 16 H 14 N3O2S[M+H] + :312.07883,found:312.08012.

[0113] Embodiment 19

[0114] Preparation of 4-{5-[(4-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A19):

[0115] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0116] (2) Synthesis of 4-{5-[(4-methoxybenzylene)amino]-1,3,4-thiadiazol-2-yl}catechol (A19), wherein the substituted benzaldehyde is 4-methoxybenzaldehyde, and the rest is the same as in Example 1.

[0117] 1 H NMR(600MHz, DMSO-d6)δ:9.73(d,J=175.8Hz,2H),8.92(s,1H),8.05–8.00(m,2H),7.40(d,J=2 .2Hz,1H),7.24(dd,J=8.2,2.2Hz,1H),7.17–7.13(m,2H),6.89(d,J=8.2Hz,1H),3.88(s,3H); 13 C NMR(151MHz,DMSO-d6)δ:173.20,168.39,166.29,164.16,149.33,146.38,132.67,132.2 9,127.79,121.79,120.12,116.71,115.24,114.99,114.35,56.15;ESI-HRMS(m / z),calcd for C 16 H 14 N3O3S[M+H] + :328.07422,found:328.07504.

[0118] Embodiment 20

[0119] Preparation of 4-{5-[(4-nitrobenzylethylene)amino]-1,3,4-thiadiazole-2-yl}catechol (A20):

[0120] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0121] (2) Synthesis of 4-{5-[(4-nitrobenzylethylene)amino]-1,3,4-thiadiazol-2-yl}catechol (A20), wherein the substituted benzaldehyde is 4-nitrobenzaldehyde, and the rest is the same as in Example 1, and finally a reddish brown solid is obtained.

[0122] 1H NMR(600MHz,DMSO-d6)δ:9.70(s,2H),9.18(s,1H),8.43–8.40(m,2H),8.33–8.29 (m,2H),7.43(d,J=2.2Hz,1H),7.29(dd,J=8.1,2.2Hz,1H),6.91(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:172.03,167.79,167.57,150.31,149.73,146.46,140.37,131. 38,131.12,124.76,124.68,121.44,120.41,116.79,114.49;ESI-HRMS(m / z),calcdfor C 15 H 11 N4O4S[M+H] + :343.04880,found:343.04955.

[0123] Embodiment 21

[0124] Preparation of 4-{5-[(4-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A21):

[0125] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0126] (2) Synthesis of 4-{5-[(4-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A21), wherein the substituted benzaldehyde is 4-hydroxybenzaldehyde, and the rest is the same as in Example 1.

[0127] 1 H NMR (600MHz, DMSO-d6) δ: 9.78 (s, 3H), 8.83 (s, 1H), 7.92–7.89 (m, 2H), 7.38 (d, J = 2.2Hz, 1H), 7.23 (dd, J = 8.2, 2.2Hz, 1H), 6.94 (d, J = 5.3Hz, 3H); 13 C NMR(151MHz,DMSO-d6)δ:191.37,168.34,165.93,164.11,149.39,146.43,133.04,13 2.58,128.72,121.79,120.05,116.77,116.67,116.38,114.28;ESI-HRMS(m / z),calcd for C 15 H12 N3O3S[M+H] + :314.05881,found:314.05939.

[0128] Embodiment 22

[0129] Preparation of 4-{5-[(2,4-difluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A22):

[0130] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0131] (2) Synthesis of 4-{5-[(2,4-difluorobenzylidine)amino]-1,3,4-thiadiazol-2-yl}catechol (A22), wherein the substituted benzaldehyde is 2,4-difluorobenzaldehyde, and the rest is the same as in Example 1.

[0132] 1 H NMR(600MHz,DMSO-d6)δ:9.67(d,J=117.4Hz,2H),9.02(s,1H),8.23(td,J=8.5,6.6Hz,1H),7.51(ddt,J=11.9 ,9.2,4.6Hz,1H),7.42(d,J=2.2Hz,1H),7.32(dd,J=8.5,2.5Hz,1H),7.30–7.23(m,1H),6.89(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:172.43,167.37,161.03,149.56,146.41,131.36,131.30,12 1.54,120.33,116.72,114.41,113.70,113.58,105.59,105.42;ESI-HRMS(m / z),calcd for C 15 H 10 F2N3O2S[M+H] + :334.04489,found:334.04563.

[0133] Embodiment 23

[0134] Preparation of 4-{5-[(2,4-dichlorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A23):

[0135] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0136] (2) Synthesis of 4-{5-[(2,4-dichlorobenzylidine)amino]-1,3,4-thiadiazol-2-yl}catechol (A23), wherein the substituted benzaldehyde is 2,4-dichlorobenzaldehyde, and the rest is the same as in Example 1.

[0137] 1 H NMR (600MHz, DMSO-d6) δ: 9.60 (s, 2H), 9.15 (s, 1H), 8.24 (d, J = 8.5Hz, 1H), 7.90–7.83 (m, 1H), 7. 64(ddt,J=8.3,1.8,0.9Hz,1H),7.28(dd,J=8.2,2.2Hz,1H),7.19(s,1H),6.89(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:172.10,167.77,163.24,149.66,146.43,139.22,137.56,13 0.86,130.81,130.51,128.92,121.46,120.46,116.74,114.42;ESI-HRMS(m / z),calcd for C 15 H 10 Cl2N3O2S[M+H] + :365.98508,found:365.98653.

[0138] Embodiment 24

[0139] Preparation of 4-{5-[(2,4-dimethylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A24):

[0140] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0141] (2) Synthesis of 4-{5-[(2,4-dimethylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A24), wherein the substituted benzaldehyde is 2,4-dimethylbenzaldehyde, and the rest is the same as in Example 1.

[0142] 1H NMR(600MHz, DMSO-d6)δ:10.17(s,1H),9.63(d,J=125.1Hz,1H),9.09(s,1H),7.72(d,J= 7.8Hz,1H),7.27–7.15(m,4H),6.89(d,J=8.2Hz,1H),3.34(s,3H),2.51(p,J=1.8Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ:193.26,167.42,149.37,146.39,144.77,141.20,132.77,132.55,1 32.17,129.57,127.83,127.54,120.19,116.70,114.33,21.66,19.40;ESI-HRMS(m / z),calcd for C 17 H 16 N3O2S[M+H] + :326.09491,found:326.09577.

[0143] Embodiment 25

[0144] Preparation of 4-{5-[(3,4-difluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A25):

[0145] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0146] (2) Synthesis of 4-{5-[(3,4-difluorobenzylidine)amino]-1,3,4-thiadiazol-2-yl}catechol (A25), wherein the substituted benzaldehyde is 3,4-difluorobenzaldehyde, and the rest is the same as in Example 1.

[0147] 1 H NMR(600MHz,DMSO-d6)δ:9.96(s,1H),9.02(d,J=1.0Hz,2H),7.70–7.65(m,2H), 7.41(d,J=2.2Hz,1H),7.26(d,J=2.2Hz,1H),6.98(s,1H),6.89(d,J=8.2Hz,1H); 13CNMR(151MHz,DMSO-d6)δ:167.89,167.32,157.39,149.61,147.66,146.44,146.08,12 2.85,121.50,120.29,118.83,116.76,116.42,114.45,113.67;ESI-HRMS(m / z),calcd forC 15 H 10 F2N3O2S[M+H] + :334.04437,found:334.04563.

[0148] Embodiment 26

[0149] Preparation of 4-{5-[(3,4-dibromobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A26):

[0150] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0151] (2) Synthesis of 4-{5-[(3,4-dibromobenzylidine)amino]-1,3,4-thiadiazol-2-yl}catechol (A26), wherein the substituted benzaldehyde is 3,4-dibromobenzaldehyde, and the rest is the same as in Example 1.

[0152] 1 H NMR(600MHz,DMSO-d6)δ:9.96(s,1H),9.00(s,1H),8.37(d,J=1.8Hz,1H),8.03–7.9 3(m,3H),7.41(d,J=2.2Hz,1H),7.26(dd,J=8.2,2.2Hz,1H),6.90(d,J=8.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ:191.88,172.10,167.47,167.07,149.66,146.45,136.00,135. 12,134.99,134.95,130.09,125.30,120.33,116.76,114.46;ESI-HRMS(m / z),calcdfor C 15 H 10 Br2N3O2S[M+H] + :455.88065,found:455.88345.

[0153] Embodiment 27

[0154] Preparation of 4-{5-[(3,4-dimethylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A27):

[0155] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0156] (2) Synthesis of 4-{5-[(3,4-dimethylbenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A27), wherein the substituted benzaldehyde is 3,4-dimethylbenzaldehyde, and the rest is the same as in Example 1.

[0157] 1 H NMR(600MHz, DMSO-d6)δ:9.91(s,2H),8.91(s,1H),7.84(d,J=1.8Hz,1H),7.76(dd,J=7.8,1.8Hz,1H),7.40(d, J=2.2Hz,1H),7.35(d,J=7.9Hz,1H),7.24(dd,J=8.2,2.2Hz,1H),6.89(d,J=8.2Hz,1H),2.32(d,J=4.1Hz,6H); 13 C NMR(151MHz,DMSO-d6)δ:172.99,169.14,166.64,149.41,146.39,143.62,137.84,132.79,1 30.91,130.77,128.56,121.71,120.18,116.72,114.39,20.28,19.76;ESI-HRMS(m / z),calcd for C 17 H 16 N3O2S[M+H] + :326.09457,found:326.09577.

[0158] Embodiment 28

[0159] Preparation of 4-{5-[(3,4-dimethoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A28):

[0160] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0161] (2) Synthesis of 4-{5-[(3,4-dimethoxybenzylene)amino]-1,3,4-thiadiazol-2-yl}catechol (A28), wherein the substituted benzaldehyde is 3,4-dimethoxybenzaldehyde, and the rest is the same as in Example 1.

[0162] 1 H NMR (600MHz, DMSO-d6) δ: 9.84 (s, 2H), 8.89 (s, 1H), 7.56 (dd, J = 8.2, 1.9Hz, 1H), 7.39 (d, J = 2.2Hz, 2H),7.24(dd,J=8.2,2.2Hz,1H),6.98(dd,J=8.2,2.2Hz,1H),6.88(d,J=8.1Hz,1H),3.86(s,6H); 13 C NMR(151MHz,DMSO-d6)δ:191.88,168.54,149.67,149.32,147.64,120.15,118.86,116.70,1 16.39,114.32,113.62,112.00,111.75,110.39,109.89,56.35,56.02;ESI-HRMS(m / z),calcd for C 17 H 16 N3O4S[M+H] + :358.08414,found:358.08560.

[0163] Embodiment 29

[0164] Preparation of 4-{5-[(3,4-dihydroxybenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A29):

[0165] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0166] (2) Synthesis of 4-{5-[(3,4-dihydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A29), wherein the substituted benzaldehyde is 3,4-dihydroxybenzaldehyde, and the rest is the same as in Example 1.

[0167] 1 H NMR(600MHz,DMSO-d6)δ:9.70(s,2H),8.74(s,1H),7.49(d,J=2.0Hz,1H),7.41–7.3 4(m,2H),7.27(dd,J=8.0,2.0Hz,2H),6.92(d,J=8.1Hz,2H),6.88(d,J=8.2Hz,1H); 13C NMR(151MHz,DMSO-d6)δ:191.56,168.62,152.63,149.23,146.48,146.36,129.31,126. 77,124.95,120.08,116.69,116.30,116.01,114.85,114.30;ESI-HRMS(m / z),calcdfor C 15 H 12 N3O4S[M+H] + :330.05341,found:330.05430.

[0168] Embodiment 30

[0169] Preparation of 4-{5-[(3,5-dimethoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A30):

[0170] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0171] (2) Synthesis of 4-{5-[(3,5-dimethoxybenzylene)amino]-1,3,4-thiadiazol-2-yl}catechol (A30), wherein the substituted benzaldehyde is 3,5-dimethoxybenzaldehyde, and the rest is the same as in Example 1.

[0172] 1 H NMR(600MHz,DMSO-d6)δ:9.68(s,2H),8.95(s,1H),7.41(d,J=2.2Hz,1H),7.29–7 .21(m,3H),6.90(d,J=8.2Hz,1H),6.78(t,J=2.3Hz,1H),3.83(d,J=11.7Hz,6H); 13 CNMR(151MHz,DMSO-d6)δ:193.26,172.55,169.19,167.03,161.25,149.53,146.43,136.94,1 21.59,120.22,116.76,114.47,107.86,107.39,106.35,56.07,56.03;ESI-HRMS(m / z),calcd for C 17 H 16 N3O4S[M+H] + :358.08405,found:358.08560.

[0173] Embodiment 31

[0174] Preparation of 4-{5-[(3-methoxy-4-hydroxybenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol (A31):

[0175] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0176] (2) Synthesis of 4-{5-[(3-methoxy-4-hydroxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A31), wherein the substituted benzaldehyde is 3-methoxy-4-hydroxybenzaldehyde, and the rest is the same as in Example 1.

[0177] 1 H NMR(600MHz,DMSO-d6)δ:10.27(s,1H),9.77(s,1H),9.37(d,J=61.8Hz,2H),7.42(dd,J=8.1,1.9Hz,1H ),7.39(d,J=1.8Hz,1H),7.19(d,J=2.2Hz,1H),7.02–6.95(m,2H),6.79(d,J=8.2Hz,1H),3.84(s,3H); 13 C NMR(151MHz,DMSO-d6)δ:196.23,172.74,162.06,158.27,153.39,152.58,150.86,133.9 3,131.28,127.36,123.67,121.17,120.62,118.41,115.95,60.81;ESI-HRMS(m / z),calcd for C 16 H 14 N3O4S[M+H] + :344.06876,found:344.06995.

[0178] Embodiment 32

[0179] Preparation of 4-{5-[(2-hydroxy-3-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A32):

[0180] (1) Synthesis of 4-(5-amino-1,3,4-thiadiazol-2-yl)-o-diphenol, same as in Example 1.

[0181] (2) Synthesis of 4-{5-[(2-hydroxy-3-methoxybenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol (A32), wherein the substituted benzaldehyde is 2-hydroxy-3-methoxybenzaldehyde, and the rest is the same as in Example 1.

[0182] 1 H NMR (600MHz, DMSO-d6) δ: 10.99 (s, 1H), 9.64 (s, 2H), 9.22 (s, 1H), 7.48 (dd, J=8.0, 1.4Hz, 1H), 7.41 (d, J= 2.2Hz,1H),7.25(ddd,J=16.5,8.1,1.8Hz,2H),6.95(t,J=7.9Hz,1H),6.88(d,J=8.2Hz,1H),3.87(s,3H); 13 C NMR(151MHz,DMSO-d6)δ:172.17,167.34,166.79,150.80,149.48,148.69,146.40,122.0 0,121.63,120.44,120.33,119.90,117.32,116.70,114.33,56.47;ESI-HRMS(m / z),calcd for C 16 H 14 N3O4S[M+H] + :344.06952,found:344.06995.

[0183] Embodiment 33

[0184] The derivatives of Example 1-32 and the positive agent zinc thiazole were prepared into a solution with a concentration of 200 μg / mL using 1.5% DMSO, and a 1.5% DMSO solution was used as a negative control. The liquid was sprayed evenly on the cabbage slices. After the liquid was absorbed, a wound 20 mm long and 4 mm deep was made in the center of each treated cabbage slice, and 10 μL of cabbage soft rot bacteria was inoculated, and observation was carried out on the 3rd day. The preventive effect of protocatechuic acid derivatives on cabbage soft rot bacteria was calculated according to the following public statement (Table 1). There were 6 derivatives with a live preventive effect of more than 40% on cabbage soft rot bacteria, 4 with 40-20%, and 22 with less than 20%. Among them, the preventive effect of derivatives A6, A8, A9, and A10 on cabbage soft rot bacteria was significantly higher than the preventive effect of the positive control agent zinc thiazole. The preventive effects of derivatives A6, A8, A9, A10 and zinc thiazole were 73.58%, 89.44%, 84.51%, 74.62% and 72.82%, respectively.

[0185]

[0186] Table 1 Preventive effects of 32 protocatechuic acid derivatives on Chinese cabbage soft rot pathogens

[0187]

[0188] Embodiment 34

[0189] A wound 20 mm long and 4 mm deep was made in the center of the cabbage slice, and 10 μL of cabbage soft rot bacteria was inoculated. The derivatives and zinc thiazole solution were prepared according to Example 33. After the wound was dried, the solution was evenly sprayed on the cabbage slices and observed on the 3rd day. The therapeutic effect of protocatechuic acid derivatives on cabbage soft rot bacteria was calculated according to the following public statement (Table 2). There were 6 derivatives with a living body therapeutic effect of more than 40% on cabbage soft rot bacteria, 4 with 40-20%, and 22 with less than 20%. Among them, the therapeutic effect of derivatives A6, A8, A9, and A10 on cabbage soft rot bacteria was significantly higher than the therapeutic effect of the positive control agent zinc thiazole. The therapeutic effects of derivatives A6, A8, A9, A10 and zinc thiazole were 69.21%, 83.95%, 82.54%, 69.85% and 68.24%, respectively.

[0190]

[0191] Table 2 The therapeutic effects of 32 protocatechuic acid derivatives on Chinese cabbage soft rot pathogens

[0192]

[0193]

[0194] Embodiment 35

[0195] Take methyl thiophanate as the positive agent and prepare the liquid according to Example 33. Spray the liquid evenly on the cut surface of the potato pieces. After the liquid is absorbed, place the cut surface in a sterile culture dish containing the bacterial solution of potato ring rot bacteria and soak for 15 minutes. Observe on the 3rd day and calculate the preventive effect according to the following formula (Table 3). There are 10 derivatives with a live preventive effect of more than 40% on potato ring rot bacteria, 4 with 40-20%, and 18 with less than 20%. Among them, the preventive effects of derivatives A1, A2, and A6 on potato ring rot bacteria are 69.61%, 67.31%, and 85.44%, which are significantly higher than the preventive effect of the positive control agent methyl thiophanate (66.21%).

[0196]

[0197] Table 3 Preventive effects of 32 protocatechuic acid derivatives on potato ring rot pathogens

[0198]

[0199]

[0200] Embodiment 36

[0201] Place the cut surface of potato pieces in a sterile culture dish containing a bacterial solution of potato ring rot pathogen and soak for 15 minutes. Take methyl thiophanate as the positive agent, and prepare the remaining solutions according to Example 33. After the bacterial solution is absorbed, spray the solution evenly on the cut surface of the potato pieces. Observe on the 3rd day. And calculate the therapeutic effect according to the following formula (Table 4). There are 6 derivatives with a living therapeutic effect of more than 40% on potato ring rot pathogen, 5 with 40-20%, and 21 with less than 20%. Among them, the therapeutic effects of derivatives A1, A2, and A6 on potato ring rot pathogen are 64.06%, 62.73%, and 77.67%, which are significantly higher than the therapeutic effect of the positive control agent methyl thiophanate (60.44%).

[0202]

[0203] Table 4 The therapeutic effects of 32 protocatechuic acid derivatives on potato ring rot pathogens

[0204]

[0205]

[0206] Embodiment 37

[0207] According to Example 33, the derivative 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazole-2-yl} catechol in Example 8 and the positive control thiazol zinc were prepared into a liquid medicine. After a wound was made on the stem at the base of the cabbage seedling using a sterile needle, the sample liquid medicine was sprayed. After standing for 24 hours, 100 μL of the suspension of cabbage soft rot bacteria was injected into the wound. Observation was carried out on the 7th day, and the infection status of the cabbage seedling leaves was recorded to determine its disease index, and the preventive effect was calculated according to the following formula. Without drug control, the disease index of cabbage seedlings in the prevention experiment can reach 91.93%. After the derivative 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazole-2-yl} catechol acted, the incidence of cabbage seedlings was significantly improved, and the disease index was reduced to 10.17%, which was lower than the positive control thiazol zinc (disease index 21.97%). The preventive effect of the derivative 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol was 88.94%, which was greater than the preventive effect of the positive control zinc thiazole (77.10%).

[0208]

[0209] Embodiment 38

[0210] After a wound was made on the stem at the base of the cabbage seedling using a sterile needle, 100 μL of the suspension of the cabbage soft rot pathogen was injected into the wound and left to stand for 24 hours. According to Example 33, the derivative 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol in Example 8 and the positive control thiazole zinc were prepared into a liquid. The liquid was evenly sprayed on the cabbage seedlings. Observation was performed on the 7th day, and the infection status of the cabbage seedling leaves was recorded to determine its disease index, and the treatment effect was calculated according to the following formula. In the case of no drug control, the disease index of the cabbage seedlings in the treatment experiment can reach 92.40%. After the derivative 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazole-2-yl}catechol acted, the incidence of the cabbage seedlings was significantly improved, and the disease index was reduced to 15.47%, which was lower than the disease index of the positive control thiazole zinc treatment group of 27.97%. The therapeutic effect of the derivative 4-{5-[(3-fluorobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol was 83.27%, which was greater than the therapeutic effect of the positive control zinc thiazole (69.72%).

[0211]

[0212] Embodiment 39

[0213] According to Example 33, the derivative 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazole-2-yl}catechol in Example 6 and the positive control methyl thiophanate were prepared into a liquid medicine. The liquid medicine was evenly sprayed on the surface of potato seedlings. After 24 hours, the potato seedlings were infected with bacteria by injection, and each seedling was injected with 100 μL of potato ring rot fungus suspension. Observation was carried out on the 7th day, and the disease index of the potted plants in the prevention experiment was calculated. Without drug control, the disease index of potato seedlings in the prevention experiment can reach 97.00%. After the derivative 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazole-2-yl}catechol acted, the disease situation of potato seedlings was significantly improved, and the disease index was reduced to 13.73%, which was lower than the disease index of 22.10% of the positive control methyl thiophanate treatment group. The preventive effect of the derivative 4-{5-[(2-nitrobenzylidene)amino]-1,3,4-thiadiazol-2-yl}catechol was 85.84%, which was greater than the preventive effect of the positive control methylthiophanate 77.22%.

[0214]

[0215] Embodiment 40

[0216] The potato seedlings were infected with bacteria by injection, and each seedling was injected with 100 μL of potato ring rot fungus suspension and left to stand for 24 hours. According to Example 33, the derivative 4-{5-[(2-nitrobenzylmethyl)amino]-1,3,4-thiadiazole-2-yl}catechol in Example 6 and the positive control methyl thiophanate were prepared into a liquid medicine. The liquid medicine was evenly sprayed on the surface of the potato seedlings. Observation was carried out on the 7th day, and the disease index of the potted plants in the treatment experiment was calculated. Without drug control, the disease index of the potato seedlings in the treatment experiment could reach 97.67%. After the positive drug methyl thiophanate and its derivative 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazol-2-yl}catechol were used, the disease situation of potato seedlings was significantly improved. The disease index of 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazol-2-yl}catechol was reduced to 22.83%, which was lower than the disease index of 27.43% in the methyl thiophanate treatment group. The therapeutic effect of 4-{5-[(2-nitrobenzyl)amino]-1,3,4-thiadiazol-2-yl}catechol was 76.62%, which was stronger than the methyl thiophanate treatment effect of 71.91%.

[0217]

Claims

1. A protocatechuic acid derivative, characterized in that: The structural formula is: R=2-F; 2-Cl; 2-Br; 2-CH3; 2-OCH3; 2-NO2; 2-OH; 3-F; 3-Cl; 3-Br; 3-CH3; 3-OCH3; 3-NO2; 3-OH; 4-F; 4-Cl; 4-Br; 4-CH3; 4-OCH3; 4-NO2; 4-OH; 2,4-difluoro; 2,4-dichloro; 2,4-dimethyl; 3,4-difluoro; 3,4-dibromo; 3,4-dimethyl; 3,4-dimethoxy; 3,4-dihydroxy; 3,5-dimethoxy; 3-OCH3-4-OH; 2-OH-3-OCH3.

2. The protocatechuic acid derivative according to claim 1, characterized in that The R=2-F, 2-Cl, 2-NO2, 3-F, 3-Cl or 3-Br.

3. The method for preparing a protocatechuic acid derivative according to claim 1, characterized in that: The steps include: (1) Weigh protocatechuic acid and thiosemicarbazide, add 20-50 mL of phosphorus oxychloride, stir thoroughly and heat to 60-100° C., and continue stirring for 4-8 hours; the molar ratio of protocatechuic acid to thiosemicarbazide is 1:1-3, and the reaction is monitored by thin layer spot plate until the reaction is complete; after cooling to room temperature, slowly add 40-80 mL of distilled water in an ice water bath, react at 80-120° C. for 3-6 hours, and monitor by thin layer spot plate until the reaction is complete; after the reaction solution is cooled, pour it into ice water, adjust the pH with NaOH solution, and stir to produce precipitation; after filtering, the filter cake is recrystallized with a mixture of DMF:H2O in a volume ratio of 1:1-3 to obtain a light pink powder 4-(5-amino-1,3,4-thiadiazole-2-yl)-o-diphenol; (2) taking the light pink powder obtained in step (1) and substituted benzaldehyde in a molar ratio of 1:1-2, dissolving them in anhydrous ethanol, dropping a small amount of acetic acid, stirring and reflux for reaction for 3-6 hours, and monitoring by thin layer spot plate until the reaction is complete; evaporating most of the ethanol, cooling and filtering, washing the filter cake with distilled water and filtering, and then recrystallizing with ethanol to obtain the yellow or reddish brown protocatechuic acid derivative solid; The substituted benzaldehydes are 2-fluorobenzaldehyde, 2-chlorobenzaldehyde, 2-bromobenzaldehyde, 2-methylbenzaldehyde, 2-methoxybenzaldehyde, 2-nitrobenzaldehyde, 2-hydroxybenzaldehyde, 3-fluorobenzaldehyde, 3-chlorobenzaldehyde, 3-bromobenzaldehyde, 3-methylbenzaldehyde, 3-methoxybenzaldehyde, 3-nitrobenzaldehyde, 3-hydroxybenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-methylbenzaldehyde, 4- Anisaldehyde, 4-nitrobenzaldehyde, 4-hydroxybenzaldehyde, 2,4-difluorobenzaldehyde, 2,4-dichlorobenzaldehyde, 2,4-dimethylbenzaldehyde, 3,4-difluorobenzaldehyde, 3,4-dibromobenzaldehyde, 3,4-dimethylbenzaldehyde, 3,4-dimethoxybenzaldehyde, 3,4-dihydroxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 3-methoxy-4-hydroxybenzaldehyde or 2-hydroxy-3-methoxybenzaldehyde.

4. The method for preparing a protocatechuic acid derivative according to claim 3, wherein the molar ratio of protocatechuic acid to thiosemicarbazide in step (1) is 1:

1.

5. The method for preparing a protocatechuic acid derivative according to claim 3, wherein the molar ratio of the light pink solid to the substituted benzaldehyde in step (2) is 1:1.

25.

6. Use of the protocatechuic acid derivative according to claim 1 or 2 in killing cabbage soft rot bacteria or potato ring rot bacteria.

7. Use of the protocatechuic acid derivative according to claim 1 or 2 for preventing and treating cabbage soft rot or potato ring rot.

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