CN113004219A

CN113004219A - Thiazole ring-containing amide compound and preparation method and application thereof

Info

Publication number: CN113004219A
Application number: CN202110265219.4A
Authority: CN
Inventors: 周霞; 王磊; 金林红; 路辉
Original assignee: Guizhou University
Current assignee: Guizhou University
Priority date: 2021-03-11
Filing date: 2021-03-11
Publication date: 2021-06-22

Abstract

The invention discloses a thiazole ring-containing amide compound and a preparation method and application thereof, belonging to the field of chemical technology and pesticides. The invention synthesizes a series of compounds containing thiazole ring amides by taking p-phenylenediamine as a raw material, and the synthesized compounds containing thiazole ring amides have good inhibition effect on Xanthomonas oryzae pv. Oryza (Xoo), Xanthomonas oryzae pv. Oryza (Xoc) and Xanthomonas anopolis pv. citri (Xac) in agricultural pests and diseases, and can be used for preparing plant bacteria resistant medicaments.

Description

Thiazole ring-containing amide compound and preparation method and application thereof

Technical Field

The invention relates to the field of chemical technology and pesticides, in particular to a thiazole ring-containing amide compound and a preparation method and application thereof.

Background

Amide is an important nitrogen-containing organic functional group, and is widely applied to the pesticide chemical fields of insect killing, sterilization, weeding, virus resistance and the like due to broad-spectrum biological activity. In recent years, amide-based compounds have attracted much attention. According to the reports of documents, the compounds have the activities of resisting tumors, fatigue, bacteria, insects and mites, and the like. A series of commercial drugs with good biological activity are successfully developed, such as chlorantraniliprole, cyantraniliprole and the like.

The heterocyclic compound has wide biological activities of insect killing, sterilization, weeding and the like, has low toxicity to human bodies, and is introduced into compounds with different structures. Through structural modification and optimization, a compound with good biological activity can be obtained.

In 2011, Liu et al (Liu, H.D.; Fan, J.X.; et al synthetic Commun, 2011,41,3197-3206) designed and synthesized a series of thiazole-2-ammonia compounds, and the results of biological activity tests show that: most of target compounds show inhibitory activities to different degrees on eight fungi, namely apple ring rot, wheat scab, cucumber scab, tomato early blight, asparagus blight, peanut brown spot, rape sclerotinia rot and rice blast.

In 2012, cinnabar and the like (cinnabar, Wangdianyang, Yuanyan, and the like. organic chemistry, 2012,32(11):2115-2121.) introduce phenoxy acetate groups with good biological activity into the 2-position of 1, 3-thiazole ring by the active group splicing principle, and a series of 1, 3-thiazole derivatives containing phenoxy acetate group structures are designed and synthesized. The fungistatic activity of the target compound is determined by a growth rate method by taking cucumber fusarium oxysporum, apple ring spot pathogen, tomato early blight pathogen, peanut brown spot pathogen and wheat scab pathogen as test objects. Part of the targets show good bacteriostatic activity on wheat scab germs.

In 2017, a series of 2-substituted phenoxy-N- (4-substituted phenyl-5- (1H-1,2, 4-triazol-1-yl) thiazol-2-yl) acetamide derivatives were designed and synthesized by Liao (Liao, G.P.; Zhou, X.; Xiao, W.; et al. heterocyclic Chem.,2017.54,1506-1513.) and the like. The biological activity test result shows that: most of the compounds show moderate to excellent inhibitory activity on two bacteria of rice bacterial blight and citrus canker.

In summary, in order to find a novel compound with high efficiency, low toxicity and low residue, a thiazole ring with good biological activity is introduced into an amide structure compound, and the compound with higher biological activity is obtained through structure modification, optimization and biological activity screening. Amide compounds containing thiazole rings have good biological activity, but no report about the application of amide structures containing thiazole rings in the activity of resisting plant germs is found.

Disclosure of Invention

The invention aims to provide a thiazole ring amide compound, a preparation method and application thereof, which are used for solving the problems in the prior art and ensuring that the thiazole ring amide compound has obvious activity of resisting plant bacteria.

In order to achieve the purpose, the invention provides the following scheme:

the invention provides a thiazole ring-containing amide compound which has a structure shown in a general formula A:

wherein R' is a halogen atom, methyl, hydrogen or CF₃Any one of (a);

r is any one of methyl, ethyl or isopropyl.

Further, the halogen atom is F, Cl or Br.

Another object of the present invention is to provide a preparation method of the above thiazole ring-containing amide compound, comprising the following steps:

the specific route for key intermediates is as follows:

(1) synthesis of key intermediate N-Boc p-phenylenediamine 1

(2) Synthesis of key intermediate N-Boc-4-amino substituted phenylamide 2

(3) Synthesis of key intermediate 4-aminophenyl substituted amide 3

(4) Synthesis of key intermediate N- (4-isothiocyanatophenyl) substituted amide 4

(5) Synthesis of key intermediate N- (4-thioureidophenyl) substituted amide 5

(6) Synthesis of key intermediate alpha-bromoacetophenone 6

(7) Object Compound A₁-A₃₆Synthesis of (2)

The invention also provides a composition containing the thiazole ring-containing amide compound.

The invention also provides the application of the thiazole ring-containing amide compound or the composition in preventing and controlling agricultural pests.

Further, the agricultural diseases and insect pests are rice bacterial blight, rice bacterial streak or citrus canker.

The fifth object of the present invention is to provide a method for controlling agricultural pests, which comprises allowing the above-mentioned compound or composition to act on the pests of agricultural pests or their living environment.

The invention discloses the following technical effects:

the invention synthesizes a series of compounds containing thiazole ring amides by taking p-phenylenediamine as a raw material, and the synthesized compounds containing thiazole ring amides have good inhibition effect on rice bacterial blight, rice bacterial streak and citrus canker in agricultural diseases and insect pests, and can be used for preparing anti-plant bacteria medicaments.

Detailed Description

Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The description and examples are intended to be illustrative only.

As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.

Example 1

Synthesis of N- (4- ((4- (4-fluorophenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₁) The method comprises the following steps:

(1) and (3) synthesizing an intermediate N-Boc p-phenylenediamine 1: in a 150mL Schlenk reaction flask, p-phenylenediamine (13.87mmol,1.0eq) was accurately weighed, argon gas was charged into the system, methylene chloride (40mL) was injected into the reaction flask using a disposable syringe, the mixture was cooled under ice bath conditions for 15min to 0 ℃ and di-tert-butyldicarbonate (6.94mmol,0.50eq) CH was added dropwise using a disposable syringe₂Cl₂After the solution is added, the reaction is carried out for 10 hours at room temperature. TLC monitored the progress of the reaction. Removing CH by desolventizing under reduced pressure₂Cl₂. Dry loading, column chromatography purification [ V (EA): V (PE)]After desolventizing under reduced pressure, 1.97g of a white solid was obtained with a yield of 87.5%.

(2) Synthesis of intermediate N-Boc-4-aminophenylacetamide 2: in a 50mL round-bottom flask, N-Boc-p-phenylenediamine (2.40mmol, 1.0eq) was dissolved in CH₂Cl₂(20mL) was stirred for 10min in an ice bath, and acetyl chloride (2.64mmol,1.10eq) was slowly added dropwise using a disposable syringe, after which the reaction was carried out at room temperature for 30 min. Decompression desolventizing, recrystallization with absolute ethyl alcohol (5mL), suction filtration to obtain the intermediate N-Boc-4-aminophenylacetamide, with the yield close to 100%.

(3) Synthesis of intermediate 4-aminophenylacetamide 3: in a 50mL round-bottom flask, N-Boc-4-aminophenylacetamide (13.87mmol,1.0eq) was dissolved in CH₂Cl₂In the middle, the mixture is cooled for 15min in an ice bath. Excess HCl (138.7mmol, 10.0eq) was slowly added dropwise, after which addition was complete. The reaction was stirred for 20min under ice-bath. TLC followed the progress of the reaction. After the reaction is finished, adding excessive saturation into the reaction systemPotassium carbonate solution, and adjusting the pH value of the system to 7.2-7.5. CH (CH)₂Cl₂Extraction (30 mL. times.3) and combining the organic phases. Anhydrous Na₂SO₄Drying the organic phase, filtering, and removing CH by desolventizing under reduced pressure₂Cl₂A white solid was obtained. The yield thereof was found to be 65%.

(4) Synthesis of intermediate N- (4-isothiocyanatophenyl) acetamide 4: 4-Aminophenylacetamide (5.61mmol,1.0eq), carbon disulfide (56.10mmol,10.0eq) and triethylamine (5.50mmol,0.9eq) were dissolved in absolute ethanol, and after the addition, the reaction was carried out at room temperature for 40min, and the degree of progress of the reaction was monitored by TLC. N, N-lutidine (0.168mmol,0.30eq) was added under ice-bath conditions, stirred for 10min, and di-tert-butyl dicarbonate (5.55mmol,0.99eq) was slowly added dropwise using a one-off dropper. After the addition, the reaction was carried out at room temperature for 5 hours. TLC monitored the progress of the reaction. Vacuum desolventizing, column chromatography purifying [ V (CH)₂Cl₂):V(MeOH)＝30:1]After desolventization, a white solid was obtained in 75% yield.

(5) Synthesis of intermediate N- (4-thioureidophenyl) acetamide 5: n- (4-isothiocyanatophenyl) acetamide (3.63mmol,1.00eq) was dissolved in anhydrous ethanol, excess ammonia (36.30mmol,10.00eq) was added, and after the addition, the reaction was carried out at room temperature for 2 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, filtration was performed, and recrystallization was performed using a mixed solvent of [ v (meoh): v (etoh) ═ 1:10], to obtain 0.791g of a white solid through filtration, with a yield of 87%.

(6) Synthesizing alpha-bromo-4-fluoroacetophenone: adding Br₂(2.20mmol, 1.10eq) was added dropwise to 4-fluoroacetophenone (2.00mmol,1.0eq) in CH₂Cl₂In the solution of (1). The reaction was stirred at room temperature for 5 hours. After the reaction is finished, pouring the reaction solution into distilled water, and obtaining CH₂Cl₂Extracted three times (50 mL. times.3). And combining organic phases, and removing the solvent under reduced pressure to obtain the alpha-bromo-4-fluoroacetophenone with the yield of 75%.

(7) Synthesis of N- (4- ((4- (4-fluorophenyl) thiazol-2-yl) amino) phenyl) acetamide: alpha-bromo-4-fluoroacetophenone (2.05mmol, 1.00eq) and intermediate N- (4-thioureidophenyl) acetamide (2.25mmol, 1.10eq) were dissolved in anhydrous ethanol and then heated under reflux for 5 h. TLC monitored the progress of the reaction. After the reaction is completed. Filtering, dissolving the solid in CH₂Cl₂Washing with saturated potassium carbonate solution, extracting, drying organic phase with anhydrous sodium sulfate, vacuum filtering, purifying with column chromatography to obtain crude product, and removing solvent under reduced pressure to obtain solid target compound.

Example 2

Synthesis of N- (4- ((4- (3-fluorophenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₂) The method comprises the following steps:

synthesis of (1) (2) (3) (4) (5) intermediate 5: the procedure was as in (1) (2) (3) (4) (5) of example 1.

2. Synthesizing alpha-bromo-3-fluoroacetophenone: the procedure is as in (6) of example 1, except that 3-fluoroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3-fluorophenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo 3-fluoroacetophenone is used.

Example 3

N- (4- (4- (3, 4-difluorophenyl) thiazol-2-ylamino) phenyl) acetamide (compound No. A)₃) The method comprises the following steps:

2. Synthesizing alpha-bromo-3, 4-difluoroacetophenone: the procedure is as in step (6) of example 1, except that 3, 4-difluoroethanone is used as the starting material for the reaction.

Synthesis of N- (4- ((4- (3, 4-difluorophenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo 3, 4-difluoroacetophenone is used.

Example 4

Synthesis of N- (4- (4- (4-chlorophenyl) thiazol-2-ylamino) phenyl) acetamide (Compound No. A)₄) The method comprises the following steps:

2. Synthesizing alpha-bromo-4-chloroacetophenone: the procedure is as in (6) of example 1, except that 4-chloroacetophenone is used as the starting material.

Synthesis of N- (4- (4- (4-chlorophenyl) thiazol-2-ylamino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo 4-chloroacetophenone is used.

Example 5

Synthesis of N- (4- (4- (3-chlorophenyl) thiazol-2-ylamino) phenyl) acetamide (Compound No. A)₅) The method comprises the following steps:

2. Synthesizing alpha-bromo-3-chloroacetophenone: the procedure is as in (6) of example 1, except that 3-fluoroacetophenone is used as the starting material.

Synthesis of N- (4- (4- (3-chlorophenyl) thiazol-2-ylamino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo 3-chloroacetophenone.

Example 6

Synthesis of N- (4- ((4- (3, 4-dichlorophenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₆) The method comprises the following steps:

2. Synthesizing alpha-bromo-3, 4-dichloroethanone: the procedure is as in step (6) of example 1, except that 3, 4-dichloroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3, 4-dichlorophenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo 3, 4-dichloroacetophenone is used.

Example 7

Synthesis of N- (4- ((4- (4-bromophenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₇) The method comprises the following steps:

2. Synthesis of alpha-bromo-4-bromoacetophenone: the process is carried out as in (6) of example 1, except that 4-bromoacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (4-bromophenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo 4-bromoacetophenone is used.

Example 8

Synthesis of N-4((4- (3-bromophenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₈) The method comprises the following steps:

2. Synthesis of alpha-bromo-3-bromoacetophenone: the procedure is as in (6) of example 1, except that 3-bromoacetophenone is used as the starting material.

Synthesis of N-4((4- (3-bromophenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo-3-bromoacetophenone is used.

Example 9

Synthesis of N- (4- ((4- (trifluoromethyl) phenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₉) The method comprises the following steps:

2. Synthesis of α -bromo 4-trifluoromethylacetophenone: the procedure was as in (6) in example 1, except that 4-trifluoromethylacetophenone was used as the starting material.

Synthesis of N- (4- ((4- (trifluoromethyl) phenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in step (7) of example 1, except that α -bromo 4-trifluoromethylacetophenone is used.

Example 10

Synthesis of N- (4- ((3- (trifluoromethyl) phenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₉) The method comprises the following steps:

2. Synthesis of α -bromo 3-trifluoromethylacetophenone: the procedure was as in (6) in example 1, except that 3-trifluoromethylacetophenone was used as the starting material.

Synthesis of N- (4- ((4- (trifluoromethyl) phenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromo 3-trifluoromethylacetophenone is used.

Example 11

N- (4- ((4- (4-methylphenyl) thiazol-2-yl)) Synthesis of amino) phenyl) acetamide (Compound No. A)₁₁) The method comprises the following steps:

synthesis of (1) (2) (3) (4) (1) (5) intermediate 5: the procedure was as in example 1 (2), (3), (4), (1) and (5).

2. Synthesis of α -bromo 4-methylacetophenone: the procedure was as in (6) in example 1, except that 4-methylacetophenone was used as the starting material for the reaction.

Synthesis of N- (4- ((4- (4-methylphenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in step (7) of example 1, except that α -bromo 4-methylacetophenone is used.

Example 12

Synthesis of N- (4- ((4-phenyl) thiazol-2-yl) amino) phenyl) acetamide (Compound No. A)₁₂) The method comprises the following steps:

2. And (3) synthesizing alpha-bromoacetophenone: the procedure is as in step (6) of example 1, except that acetophenone is used as the starting material.

Synthesis of N- (4- ((4-phenyl) thiazol-2-yl) amino) phenyl) acetamide: the procedure is as in (7) of example 1, except that α -bromoacetophenone is used.

Example 13

Synthesis of N- (4- ((4- (4-fluorophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₁₃) The method comprises the following steps:

1.(1) (2) Synthesis of intermediate 2: the procedure was as in (1) and (2) of example 1.

2. Synthesis of intermediate 3: the procedure is as in example 1, step 3, except that propionyl chloride is used as the starting material for the reaction.

3. Synthesis of intermediate 4: the procedure is as in example 1, step 4, except that 4-aminophenylpropionamide is used as the starting material.

4. Synthesizing alpha-bromo-4-fluoroacetophenone: as in step (6) of example 1.

Synthesis of N- (4- ((4- (4-fluorophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 4-fluoroacetophenone is used.

Example 14

Synthesis of N- (4- ((4- (3-fluorophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₁₄) The method comprises the following steps:

4. Synthesizing alpha-bromo-3-fluoroacetophenone: the procedure is as in (6) of example 1, except that 3-fluoroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3-fluorophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 3-fluoroacetophenone is used.

Example 15

Synthesis of N- (4- ((4- (3, 4-difluorophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₁₅) The method comprises the following steps:

4. Synthesizing alpha-bromo-3, 4-difluoroacetophenone: the procedure is as in step (6) of example 1, except that 3, 4-difluoroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3, 4-difluorophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 3, 4-difluoroacetophenone is used.

Example 16

Synthesis of N- (4- ((4- (4-chlorophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₁₆) The method comprises the following steps:

4. Synthesizing alpha-bromo-4-chloroacetophenone: the procedure is as in (6) of example 1, except that 4-chloroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (4-chlorophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 4-chloroacetophenone is used.

Example 17

Synthesis of N- (4- ((4- (3-chlorophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₁₇) The method comprises the following steps:

4. Synthesizing alpha-bromo-3-chloroacetophenone: the procedure is as in (6) of example 1, except that 3-chloroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3-chlorophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 3-chloroacetophenone is used.

Example 18

Synthesis of N- (4- ((4- (3, 4-dichlorophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₁₈) The method comprises the following steps:

4. Synthesis of α -bromo-3, 4-dichloroacetophenone: the procedure is as in step (6) of example 1, except that 3, 4-dichloroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3, 4-dichlorophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 3, 4-dichloroacetophenone is used.

Example 19

Synthesis of N- (4- ((4- (4-bromophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₁₉) The method comprises the following steps:

4. Synthesis of alpha-bromo-4-bromoacetophenone: the process is carried out as in (6) of example 1, except that 4-bromoacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (4-bromophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 4-bromoacetophenone is used.

Example 20

Synthesis of N- (4- ((4- (3-bromophenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₂₀) The method comprises the following steps:

4. Synthesis of alpha-bromo-3-bromoacetophenone: the procedure is as in (6) of example 1, except that 3-bromoacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3-bromophenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo-3-bromoacetophenone is used.

Example 21

Synthesis of N- (4- ((4- (4-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₂₁) The method comprises the following steps:

4. Synthesis of α -bromo 4-trifluoromethylacetophenone: the procedure was as in (6) in example 1, except that 4-trifluoromethylacetophenone was used as the starting material.

Synthesis of N- (4- ((4- (4-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in step (7) of example 1, except that α -bromo 4-trifluoromethylacetophenone is used.

Example 22

Synthesis of N- (4- ((4- (3-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₂₂) The method comprises the following steps:

4. Synthesis of α -bromo 3-trifluoromethylacetophenone: the procedure was as in (6) in example 1, except that 3-trifluoromethylacetophenone was used as the starting material.

Synthesis of N- (4- ((4- (3-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in (7) of example 1, except that α -bromo 3-trifluoromethylacetophenone is used.

Example 23

Synthesis of N- (4- ((4- (4-methylphenyl) thiazol-2-yl) amino) phenyl) propanamide (Compound No. A)₂₃) The method comprises the following steps:

4. Synthesis of α -bromo 4-methylacetophenone: the procedure was as in (6) in example 1, except that 4-methylacetophenone was used as the starting material for the reaction.

Synthesis of N- (4- ((4- (4-methylphenyl) thiazol-2-yl) amino) phenyl) propanamide: the procedure is as in step (7) of example 1, except that α -bromo 4-methylacetophenone is used.

Example 24

Synthesis of N- (4- (4-phenyl) thiazol-2-yl) amino) phenyl) propionamide (Compound No. A₂₄) The method comprises the following steps:

4. And (3) synthesizing alpha-bromoacetophenone: the procedure is as in step (6) of example 1, except that acetophenone is used as the starting material.

Synthesis of N- (4- (4-phenyl) thiazol-2-yl) amino) phenyl) propionamide: the procedure is as in step (7) of example 1, except that a-bromo 4-methylacetophenone

Example 25

Synthesis of N- (4- ((4- (4-fluorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₂₅) The method comprises the following steps:

2. Synthesis of intermediate 3: the procedure is as in example 1, step 3, except that isobutyryl chloride is used as the starting material.

3. Synthesis of intermediate 4: the procedure is as in example 1, step 4, except that 4-aminophenylisobutyramide is used as the starting material.

4. Synthesizing alpha-bromo-4-fluoroacetophenone: as in step (6) of example 1.

Synthesis of N- (4- ((4- (4-fluorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 4-fluoroacetophenone is used.

Example 26

Synthesis of N- (4- ((4- (3-fluorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₂₆) The method comprises the following steps:

4. Synthesizing alpha-bromo-4-fluoroacetophenone: the procedure is as in (6) of example 1, except that 3-fluoroacetophenone is used as the starting material.

Synthesis of N- (4- ((4- (3-fluorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 3-fluoroacetophenone is used.

Example 27

Synthesis of N- (4- ((4- (3, 4-difluorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₂₇) The method comprises the following steps:

Synthesis of N- (4- ((4- (3, 4-difluorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 3, 4-difluoroacetophenone is used.

Example 28

Synthesis of N- (4- ((4- (4-chlorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₂₈) The method comprises the following steps:

Synthesis of N- (4- ((4- (4-chlorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 4-chloroacetophenone is used.

Example 29

Synthesis of N- (4- ((4- (3-chlorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₂₉) The method comprises the following steps:

Synthesis of N- (4- ((4- (3-chlorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 3-chloroacetophenone is used.

Example 30

N- (4- ((4- (3, 4-dichlorophenyl) thiazol-2-yl) amino) phenyl)) Synthesis of isobutyramide (Compound No. A)₃₀) The method comprises the following steps:

Synthesis of N- (4- ((4- (3, 4-dichlorophenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 3, 4-dichloroacetophenone is used.

Example 31

Synthesis of N- (4- ((4- (4-bromophenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₃₁) The method comprises the following steps:

Synthesis of N- (4- ((4- (4-bromophenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 4-bromoacetophenone is used.

Example 32

Synthesis of N- (4- ((4- (3-bromophenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₃₂) The method comprises the following steps:

Example 33

Synthesis of N- (4- ((4- (4-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₃₃) The method comprises the following steps:

Synthesis of N- (4- ((4- (4-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in step (7) of example 1, except that α -bromo 4-trifluoromethylacetophenone is used.

Example 34

Synthesis of N- (4- ((4- (3-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₃₄) The method comprises the following steps:

Synthesis of N- (4- ((4- (3-trifluoromethylphenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromo 3-trifluoromethylacetophenone is used.

Example 35

Synthesis of N- (4- ((4- (4-methylphenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A)₃₅) The method comprises the following steps:

Example 36

Synthesis of N- (4- (4-phenyl) thiazol-2-yl) amino) phenyl) isobutyramide (Compound No. A₃₆) The method comprises the following steps:

Synthesis of N- (4- (4-phenyl) thiazol-2-yl) amino) phenyl) isobutyramide: the procedure is as in (7) of example 1, except that α -bromoacetophenone is used.

The physicochemical properties and mass spectrum data of the synthesized amide derivatives containing thiazole ring are shown in Table 1, and the nuclear magnetic resonance hydrogen spectrum: (¹H NMR) and carbon Spectroscopy (¹³C NMR) data are shown in table 2.

TABLE 1 Targeted rationalization properties and their mass spectrometry data

TABLE 2 NMR and C spectra data for target compounds

Activity test example 1: and (3) testing the biological activity of the plant bacteria:

test method

A turbidity method (Paw D., et al.,1994) is adopted for the target compound A₁-A₃₆And (5) carrying out in-vitro bacteriostatic activity test.

Preparation of NB medium.

Weighing 10g of peptone, 30g of glucose, 2g of yeast powder and 6g of beef extract one by one according to the formula of NB medium, sequentially pouring the weighed medicines into a 4000mL beaker, adding 2000mL of secondary distilled water, stirring until the mixture is completely dissolved, and adjusting the pH to 7.0-7.2 by using 5.0mol/L NaOH solution.

B. Dispensing

According to the requirements of the test, 4mL NB medium solution was accurately pipetted using a 5mL pipette and dispensed into 15 x 150mm tubes. And after the culture medium is subpackaged, a rubber plug is plugged at the opening of the test tube. Then, two layers of newspaper are used for wrapping the rubber plug, two rubber bands are used for binding the newspaper, and a black marker pen is used for marking the name, the group and the preparation date of the culture medium.

C. Sterilization

Placing the packaged NB culture medium in a sterilization basket, placing in a high pressure steam sterilization pot, and continuously sterilizing at 121 deg.C for 30 min. And then opening the air release valve to release air, taking out after the pressure in the sterilization pot is recovered to normal pressure, and placing the sterilization pot in a dry and ventilated place for later use.

D. Preparation of the medicinal solution

7.50mg of the compound to be tested was accurately weighed using a ten-thousandth analytical balance, placed in a 1.50mL centrifuge tube, dissolved by adding 150. mu.L DMSO, and shaken for 30 seconds using a vortex mixer to completely dissolve the solid substance. 80. mu.L, 40. mu.L of the prepared drug solution was accurately pipetted into a 15mL centrifuge tube using a 100. mu.L pipette. 40. mu.L of DMSO was added to the centrifuge tube containing 40. mu.L of the drug solution. 4mL of a solution containing 0.1% Tween-20 (100. mu.L Tween-20 was added to 100mL of sterilized secondary water and shaken to be uniform) was added to the above centrifuge tube containing the liquid medicine, and a blank control containing 80. mu.L DMSO was diluted with 4mL of a 0.1% Tween-20 solution and shaken to be uniform. Bismerthiazol and copper thielavone are used as positive control drugs, and DMSO is used as a blank control. Each treatment was repeated three times. And placing the prepared liquid medicine to be tested under aseptic conditions for later use.

E. Determination of blank value

The 96-well plate was placed in a microplate reader at a wavelength of 595nm (OD)₅₉₅) To measure the light source, the absorbance of the empty plate was measured.

F. Preparation of drug-containing NB Medium

In a sterile operation box, 1mL of the liquid medicine is accurately transferred by using a 1mL liquid transfer gun and added into a test tube of the NB culture medium which is subpackaged, and the liquid medicine is fully shaken up.

E. Determination of background values

Accurately transferring 200 μ L of the above solution to 96-well plate with 200 μ L pipette, repeating each tube for three times, recording and numbering, placing in microplate reader, and measuring wavelength at 595nm (OD)₅₉₅) For the measurement of the light source, the absorbance thereof was measured.

G. Inoculating bacteria

Under aseptic conditions, 40 μ L of the solution was pipetted into NB medium containing fresh pathogenic bacteria (OD ═ 0.6-0.8) using a 100 μ L pipette, added to the previously prepared toxin-containing NB medium, and the test tube mouth was sterilized by burning with an alcohol burner. Repackaging the test tube, placing the test tube in a shaking table, and culturing the test tube for 36 to 48 hours at the conditions of 180rpm and 30 +/-1 ℃.

H. Bactericidal bioactivity test

Following the above experimental procedures, blank control OD was measured using a microplate reader₅₉₅Value, until it grows to OD₅₉₅When the value is 0.6 to 0.8, the measurement is started. Each treatment was repeated three times and the average was taken. And the inhibitory activity of the agent against bacteria was calculated by the following formula:

I(％)＝(CK-T)/CK×100％

wherein I is inhibition ratio (%), CK is blank control OD₅₉₅Value, T is the treatment group OD₅₉₅The value is obtained.

The results of the target compound biological activity test against plant bacteria are shown in table 3:

TABLE 3 target Compound A₁-A₃₆The inhibition activity (inhibition rate%) against bacterial blight of rice (Xoo), bacterial canker of rice (Xoc) and bacterial canker of citrus (Xac)^a

^aThe average of three replicates;^bthe commercial medicaments of bismerthiazol and thiabendazole serve as positive control medicaments;

testing the target compound A by a turbidity method under the condition of 200 and 100 mu g/mL medicament concentration₁-A₃₆The inhibition activity to three plant bacteria (Xoo, Xoc, xca) was repeated three times with commercial fungicides bismerthiazol and copper thielavia as positive control agents and chemical reagent dimethylsulfoxide as blank control agent, and the test results are shown in table 3 above. The test results show that: as can be seen from Table 3, the inhibition ratio of the target compound against rice bacterial blight disease (Xoo) ranges from 14% to 98% at 200. mu.g/mL, and the target compound A is at a concentration of 200. mu.g/mL₁、A₆Has the best inhibiting effect on rice bacterial blight (Xoo). The inhibition rates are respectively 98% and 87%, and are superior to those of positive control medicaments of bismerthiazol and thiabendazole. Under the concentration of 200 mug/mL, the inhibition rate of the target compound on the rice bacterial streak (Xoc) is within the range of 17% -78%, the inhibition effect of the target compound on the rice bacterial streak (Xoc) is relatively poor, but the compound A is₁The antibacterial effect of the composition is more prominent, the inhibition rate is 78% under the concentration of 200 mu g/mL, and the inhibition rate is 51% under the concentration of 100 mu g/mL, which is better than or equal to that of a positive control. The inhibition rate of the target compound on the citrus canker pathogen (Xac) ranges from 19% to 85%, wherein the compound A₁、A₄The antibacterial effect is optimal, and the inhibition rates are 87% and 81% respectively at the concentration of 200 mug/mL; the inhibition rates at 100. mu.g/mL were 55% and 62%, respectively, which were comparable to the positive control.

Activity test example 2: part of compound target compound anti-plant bacterial activity toxicological linear regression curve

Adopting a turbidity method, and carrying out the concentration measurement on five strips with different concentrations of 200, 100, 50, 25 and 12.5 mu g/mLUnder the test, the half inhibition concentration (EC) of partial compound with better initial activity performance on three plant bacteria Xoo, Xac and Xoc is tested₅₀) This was repeated three times. And calculating and analyzing by using SPSS 17.0 software. The results are shown in Table 4.

TABLE 4 part toxicological linear regression curves of the target compounds against plant bacteria

in order to further determine and analyze the bacteriostatic activity of the target compound on Xoo, Xac and Xoc three bacteria. Measuring the amount of target Compound EC₅₀The results are shown in Table 4. Compound A₁，A₄，A₆EC against Xao of rice leaf blight bacterium₅₀156.7, 179.2 and 144.7 mu M respectively, which is superior to that of a control medicament, namely bismerthiazol (EC)₅₀230.5 μ M) and thiediazole copper (EC)₅₀545.2 μ M). Furthermore, the method is simple. Compound A₁Has optimal inhibiting effect on Xac of citrus canker pathogen, and has EC₅₀The value is 152.0 μ M, which is superior to commercial Thiodiazole copper (EC)₅₀476.5 μ M), with the control drug bismertizol (EC)₅₀162.7 μ M) activity was comparable. Compound A₄Has good bacteriostatic activity on citrus canker pathogenic bacterium Xac, and the EC thereof₅₀194.9 mu M, which is superior to the control drug bismerthiazol (EC)₅₀254.9 μ M) and copper thielavone (EC)₅₀607.5 μ M). In addition, the compounds tested in Table 4 (except for A)₂₅) Has better or equivalent inhibiting effect on rice streak germ (Xoc) than the control medicament.

As shown in tables 3 and 4, the structure-activity relationship (SAR) of the target compound can be preliminarily discussed. The type and position of the substituent R on the phenyl ring has a significant effect on the bactericidal activity of the target compound. First, F, Cl, Br and CF at the 4-position of the benzene ring₃The electrons can be absorbed equallyTo significantly increase the bactericidal activity of the target compound, whereas the 3-position is not conducive to an increase in bactericidal activity. For example, the order of the inhibitory activity of the target compound against rice bacterial blight disease (Xoo) is A₁>A₂，A₄>A₅The results confirm the above conclusion. In addition, the sequence of the inhibitory activity of the target compound on rice bacterial blight (Xoo) and citrus canker pathogen (Xac) is A₁(4-F)>A₄(4-Cl)>A₇(4-Br) and the 4-F substituted benzene ring can obviously improve the bacteriostatic effect of the target compound. Finally, compared with different groups at the same position on a benzene ring, the target compound with an electron-withdrawing substituent at the 4-position on the benzene ring has higher inhibitory activity on the three bacteria than the electron-donating substituent at the same position, for example, the antibacterial activity sequence of the target compound is A₁(4-F)>A₄(4-Cl)>A₁₁(4-CH₃). The length and type of the alkyl chain connected with the amide have great influence on the antibacterial activity of the target compound, and the longer the alkyl chain connected with the amide is, the more adverse effect is on improving the antibacterial activity of the target compound.

The experimental activity data show that the compounds containing thiazole ring amides have certain inhibiting effect on plant pathogenic bacteria such as rice bacterial blight, rice stripe disease, citrus canker and the like, wherein part of target compounds show excellent activity for resisting the plant pathogenic bacteria, can be used as potential plant bacterium resisting medicines, and have better application prospect.

The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.

Claims

1. A thiazole ring-containing amide compound is characterized by having a structure shown as a general formula A:

wherein R' is a halogen atom, methyl, hydrogen or CF₃Any one of (a);

r is any one of methyl, ethyl or isopropyl.

2. The thiazole-containing cyclic amide compound of claim 1, wherein said halogen atom is F, Cl or Br.

3. A process for preparing thiazole ring-containing amides according to any of claims 1-2, which comprises the steps of:

(1) p-phenylenediamine and di-tert-butyl carbonic diester react at room temperature to prepare a compound 1;

(2) reacting the compound 1 with RCOCl at room temperature to obtain a compound 2;

(3) compound 2 generates compound 3 under the ice bath condition in the presence of hydrochloric acid;

(4) reacting the compound 3 with carbon disulfide and di-tert-butyl carbonic diester in the presence of triethylamine and N, N-dimethylpyridine to prepare a compound 4;

(5) transformingCompound 4 with NH₃Reacting to generate a compound 5;

(6) to be provided with

As a raw material, with Br₂Reacting to obtain a compound 6;

(7) heating and refluxing the compound 5 and the compound 6 in the presence of ethanol to prepare a compound shown in a formula A;

wherein R' is a halogen atom, methyl, hydrogen or CF₃Any one of (a);

r is any one of methyl, ethyl or isopropyl.

4. A composition comprising the thiazole ring-containing amide compound according to any one of claims 1 to 2.

5. Use of the thiazole ring-containing amide compound according to any one of claims 1 to 2 or the composition according to claim 4 for controlling agricultural pests.

6. The use according to claim 5, wherein the agricultural pest is rice bacterial blight, rice leptospora oryzae or citrus canker.

7. A method for controlling an agricultural pest, characterized in that a compound according to any one of claims 1 to 2 or a composition according to claim 4 is allowed to act on the pest of the agricultural pest or its living environment.

8. A method of controlling an agricultural pest according to claim 7 wherein the agricultural pest is rice bacterial blight, rice streak germ or citrus canker germ.