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CN-121974849-A - Quinoline derivative containing piperazine structure and preparation method and application thereof

CN121974849ACN 121974849 ACN121974849 ACN 121974849ACN-121974849-A

Abstract

The invention belongs to the technical field of pesticide chemistry, and relates to quinoline derivatives containing piperazine structures, and a preparation method and application thereof. The quinoline derivative containing the piperazine structure has broad-spectrum inhibition activity on plant pathogenic bacteria such as plant pathogenic fungi, particularly has excellent inhibition activity on apple rot pathogen, rape sclerotinia rot pathogen, botrytis cinerea, wheat take-all pathogen and rice blast pathogen, and is expected to be developed into a novel efficient, safe, economic and environment-friendly green bactericide.

Inventors

  • XU GONG
  • LIN GUOTAI
  • ZHU JIAYI
  • YIN MINGHUI
  • XU DAN

Assignees

  • 西北农林科技大学深圳研究院

Dates

Publication Date
20260505
Application Date
20260409

Claims (8)

  1. 1. A quinoline derivative containing a piperazine structure is characterized by having a structure shown in a formula (I) or stereoisomers, tautomers, isotopic derivatives and pesticide acceptable salts thereof; R 1 is selected from amino, hydroxy, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, substituted benzene ring or aromatic heterocycle; The substituent substituted in R 1 is selected from any one or more of halogen, alkyl, alkoxy, amino, amido, hydroxyl, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl and aryl; The aromatic heterocycle in R 1 is C1-C10 nitrogen-containing heterocycle, C1-C10 oxygen-containing heterocycle or C1-C10 sulfur-containing heterocycle; The halogen in R 1 is fluorine, chlorine, bromine or iodine; R 2 is selected from hydrogen, halogen, amino, amido, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkylthio or C1-C8 alkylamino; The halogen in R 2 is fluorine, chlorine, bromine or iodine; R 3 is selected from hydrogen, C1-C8 alkyl, substituted benzene ring or aromatic heterocycle; The substituent substituted in R 3 is selected from any one or more of halogen, alkyl, alkoxy, amino, amido, hydroxyl, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl and aryl; the aromatic heterocycle in R 3 is C1-C10 nitrogen-containing heterocycle, C1-C10 oxygen-containing heterocycle or C1-C10 sulfur-containing heterocycle; The halogen in R 3 is fluorine, chlorine, bromine or iodine; R 4 is selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 haloalkyl, substituted benzene ring or aromatic heterocycle; The substituent substituted in R 4 is selected from any one or more of halogen, alkyl, alkoxy, amino, amido, hydroxyl, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl and aryl; the aromatic heterocycle in R 4 is C1-C10 nitrogen-containing heterocycle, C1-C10 oxygen-containing heterocycle or C1-C10 sulfur-containing heterocycle; the halogen in R 4 is fluorine, chlorine, bromine or iodine; n is an integer of 0 to 4; x is nitrogen or oxygen.
  2. 2. The quinoline derivative according to claim 1, wherein the quinoline derivative is selected from the group consisting of: 。
  3. 3. a process for the preparation of quinoline derivatives according to any one of claims 1-2, comprising: Route 1: ; Route 2: ; Route 3: 。
  4. 4. a process according to claim 3, wherein, The route 1 includes: 2-aminobenzophenone C is synthesized by nucleophilic addition reaction of Grignard reagent B on cyano by taking differently substituted 2-aminobenzonitrile A as raw material, and then 2-aminobenzoketone C and 4-chloroacetoacetate D are taken as raw materials, and a compound E containing quinoline core skeleton is constructed by a one-pot method through [4+2] cyclization-aromatization reaction catalyzed by Lewis acid; Reacting a compound E containing a quinoline core skeleton with piperazine-1-carboxylic acid tert-butyl ester F to obtain an intermediate G, removing Boc protection from the intermediate G under an acidic condition to obtain an intermediate H, and carrying out nucleophilic substitution on the intermediate H by SN 2 to obtain a target quinoline derivative; The route 2 includes: 2-aminobenzophenone C is synthesized by nucleophilic addition reaction of Grignard reagent B on cyano by taking differently substituted 2-aminobenzonitrile A as raw material, and then 2-aminobenzoketone C and 4-chloroacetoacetate D are taken as raw materials, and a compound E containing quinoline core skeleton is constructed by a one-pot method through [4+2] cyclization-aromatization reaction catalyzed by Lewis acid; Reacting piperazine-1-carboxylic acid tert-butyl ester K with acyl chloride J with different substitution to obtain an intermediate L, and removing Boc under an acidic condition to obtain an intermediate M; the route 3 includes: Hydrolyzing the carboxylic ester compound under alkaline condition to obtain intermediate acid N, and then carrying out condensation reaction with amine, phenol or alcohol reagent to obtain the target quinoline derivative.
  5. 5. A bactericidal composition characterized in that the active ingredient of the bactericidal composition comprises the quinoline derivative according to any one of claims 1 to 2.
  6. 6. Use of the quinoline derivatives according to any one of claims 1 to 2 or the fungicidal composition according to claim 5 for controlling plant diseases caused by phytopathogens.
  7. 7. The use according to claim 6, wherein the phytopathogen is a phytopathogenic fungus selected from one or more of the group consisting of phylum plasmodiophoromycota, oomycota, phylum chytrium, phylum zygomycota, phylum ascomycota, phylum basidiomycota and phylum half-known.
  8. 8. The use according to claim 6, wherein the plant diseases include rot, take-all, ring rot, sclerotinia, gray mold, banded sclerotial blight, scab, rice blast, late blight, pepper blight, powdery mildew, downy mildew, wilt and brown spot.

Description

Quinoline derivative containing piperazine structure and preparation method and application thereof Technical Field The invention belongs to the technical field of pesticide chemistry, and relates to quinoline derivatives containing piperazine structures, and a preparation method and application thereof. Background Fungal diseases account for more than 70% of the total plant diseases, and crop yield loss caused by the fungal diseases constitutes a serious threat to grain safety. At present, chemical control is still the most economical, efficient and widely applied strategy for controlling plant fungal diseases. However, long-term, single use of bactericides for specific targets tends to create directional selection pressure on pathogenic bacterial populations, accelerating the formation and spread of drug resistant populations. Therefore, the development of a novel bactericide with a novel target or a novel action mechanism has become an urgent need for coping with fungal drug resistance challenges and realizing sustainable treatment of diseases. Quinoline alkaloid and its derivatives widely exist in nature, and show abundant and excellent biological activities such as bacteriostasis, disinsection, anti-inflammatory and anti-tumor. In the field of pharmaceutical chemistry, quinolines are of great interest because of their diverse biological activities. However, the application of the compound in the pesticide field is still limited, and only few varieties such as iprovalicarb quinoline, fluorogenic quinoline, phenoxyquinoline and the like are commercialized at present, so that the compound has wide research and development space. With the wide application and unreasonable use of various bactericides in the market, the problem of drug resistance of fungi to the bactericides is increasingly serious. Therefore, the development of a novel efficient bactericide to cope with the drug resistance of fungi has important significance for guaranteeing the sustainable development of agriculture. Disclosure of Invention In order to solve the technical problems in the prior art, the invention provides a quinoline derivative containing a piperazine structure, a preparation method and application thereof, and the quinoline derivative has high-efficiency broad-spectrum inhibition effect on plant pathogenic bacteria, especially plant pathogenic fungi. Aiming at the actual problems that plant pathogenic fungi cause great harm to agricultural production in China and the drug resistance is becoming serious day by day, the invention utilizes the design of computer-aided drugs, screens out the Miao-nationality compound with certain antibacterial activity through the cyclic feedback of virtual screening, organic synthesis, active primary screening, structural modification and biological activity comprehensive evaluation, and carries out structural derivation on the Miao-nationality compound to synthesize a series of quinoline derivatives containing piperazine structures, thereby laying a foundation for the creation of novel bactericides and the treatment of fungal drug resistance. In one aspect, the invention provides a quinoline derivative containing a piperazine structure, which has a structure shown in a formula (I) or stereoisomers, tautomers, isotopic derivatives and pesticide acceptable salts thereof; R 1 is selected from amino, hydroxy, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, substituted benzene ring or aromatic heterocycle; The substituent substituted in R 1 is selected from any one or more of halogen, alkyl, alkoxy, amino, amido, hydroxyl, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl and aryl; The aromatic heterocycle in R 1 is C1-C10 nitrogen-containing heterocycle, C1-C10 oxygen-containing heterocycle or C1-C10 sulfur-containing heterocycle; The halogen in R 1 is fluorine, chlorine, bromine or iodine; R 2 is selected from hydrogen, halogen, amino, amido, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkylthio or C1-C8 alkylamino; The halogen in R 2 is fluorine, chlorine, bromine or iodine; R 3 is selected from hydrogen, C1-C8 alkyl, substituted benzene ring or aromatic heterocycle; The substituent substituted in R 3 is selected from any one or more of halogen, alkyl, alkoxy, amino, amido, hydroxyl, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl and aryl; the aromatic heterocycle in R 3 is C1-C10 nitrogen-containing heterocycle, C1-C10 oxygen-containing heterocycle or C1-C10 sulfur-containing heterocycle; The halogen in R 3 is fluorine, chlorine, bromine or iodine; R 4 is selected from hydrogen, hydroxy, C1-C8 alkyl, C1-C8 haloalkyl, substituted benzene ring or aromatic heterocycle; The substituent substituted in R 4 is selected from any one or more of halogen, alkyl, alkoxy, amino, amido, hydroxyl, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoac