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CN-121991054-A - Isoazole-containing formononetin derivative and preparation method and application thereof

CN121991054ACN 121991054 ACN121991054 ACN 121991054ACN-121991054-A

Abstract

The invention discloses an isoxazole-containing formononetin derivative and a preparation method and application thereof, and belongs to the technical field of pesticide synthesis. According to the invention, an isoxazole group with excellent activity is introduced into the structure of formononetin, a series of formononetin derivatives containing isoxazole are synthesized, and the test of the activity of the synthesized formononetin derivatives containing isoxazole for inhibiting plant pathogenic fungi shows that the synthesized formononetin derivatives containing isoxazole can effectively inhibit plant pathogenic fungi, in particular to kiwi fruit phomopsis (Ps).

Inventors

  • XUE WEI
  • GENG XIAOTING
  • Pan Sizhu
  • TIAN FANG
  • SHEN DAN
  • YANG HAN
  • YANG YING
  • Sun Mingman
  • HAO GEFEI

Assignees

  • 贵州大学

Dates

Publication Date
20260508
Application Date
20260203

Claims (10)

  1. 1. An isoxazole-containing formononetin derivative, which is characterized by having the following structural formula: ; wherein R is independently selected from H, one or more halogens, one or more alkyl groups, one or more substituted alkyl groups, and one or more alkoxy groups.
  2. 2. The isoxazole-containing formononetin derivative according to claim 1, wherein the halogen is R=2-Cl, 3-Cl, 4-Cl, 2,3-di-Cl, 2,4-di-Cl, 2-Br, 3-Br, 2-F, 3-F, 4-F, 2,3-di-F, 2,4-di-F, 3,4-di-F, wherein the alkyl group is R=2-CH 3 、3-CH 3 , 4-Et, 4-i-Pr, wherein the substituted alkyl group is R=4-CF 3 , 4-CN, and wherein the alkoxy group is R=3-OCH 3 、4-OCH 3 .
  3. 3. A process for the preparation of an isoxazole containing formononetin derivative according to claim 1 or 2, characterized in that the steps comprise: (1) Taking formononetin and epibromohydrin as raw materials, reacting in a solvent under an alkaline condition at normal temperature, adding ice water after the reaction is finished to separate out a product, and filtering to obtain a filter cake, namely an intermediate a; the structural formula of the intermediate a is as follows: ; (2) Taking the intermediate a and 4-Boc-aminopiperidine as raw materials, taking anhydrous potassium carbonate as a catalyst, and heating in a solvent for reaction to prepare an intermediate b; The structural formula of the intermediate b is as follows: ; (3) Taking the intermediate b as a raw material, removing boc protection to obtain an intermediate c; the structural formula of the intermediate c is as follows: ; (4) Various substituted aldehydes are used as raw materials and react with hydroxylamine hydrochloride at normal temperature under neutral conditions to obtain an intermediate d; The structural formula of the intermediate d is as follows: Wherein R is independently selected from H, one or more halogens, one or more alkyl groups, one or more substituted alkyl groups, one or more alkoxy groups; (5) Taking the intermediate d as a raw material, and reacting with N-chlorosuccinimide at normal temperature to obtain an intermediate e; The structural formula of the intermediate e is as follows: Wherein R is independently selected from H, one or more halogens, one or more alkyl groups, one or more substituted alkyl groups, one or more alkoxy groups; (6) Taking the intermediate e as a raw material, and reacting with 3-bromopropyne at normal temperature under alkaline conditions to obtain an intermediate f; the structural formula of the intermediate f is as follows: wherein R is independently selected from H, one or more halogens, one or more alkyl groups, one or more substituted alkyl groups, one or more alkoxy groups; (7) The formononetin derivative containing the isoxazole is prepared by taking the intermediate c and the intermediate f as raw materials and anhydrous potassium carbonate as a catalyst under the condition of heating reflux.
  4. 4. The method according to claim 3, wherein the alkaline condition in the step (1) is provided by anhydrous potassium carbonate, the molar ratio of formononetin, epibromohydrin and anhydrous potassium carbonate is 3.73:11.18:11.18, and the reaction time is 24 hours at normal temperature.
  5. 5. The preparation method according to claim 3, wherein in the step (2), the molar ratio of the intermediate a, the 4-Boc-aminopiperidine and the anhydrous potassium carbonate is 3.08:6.17:9.25, and the heating reaction is performed at 80 ℃ for 6-10 hours.
  6. 6. The process according to claim 3, wherein the step of removing the boc protection in the step (3) comprises dissolving the intermediate b in methanol, heating to 70 ℃, adding a certain amount of 10% HCl solution by mass dropwise, reacting 3-4 h, and removing the boc protection.
  7. 7. The preparation method of the epoxy resin composition according to claim 3, wherein in the step (4), the molar ratio of the various substituted aldehydes to the hydroxylamine hydrochloride is (5.40-9.42), the reaction time at the normal temperature is 2-3 hours, the molar ratio of the intermediate d to the N-chlorosuccinimide in the step (5) is (5.50-9.08), the molar ratio of the intermediate d to the N-chlorosuccinimide in the step (5) is (6.05-9.99), and the reaction time at the normal temperature is 3-4 hours.
  8. 8. The preparation method of claim 3, wherein the molar ratio of the intermediate e to the 3-bromopropyne in the step (6) is (5.89-8.87): 14.71-22.17), the alkaline condition is provided by sodium bicarbonate, the normal temperature reaction time is 20-24 hours, the molar ratio of the intermediate c, the intermediate f and the anhydrous potassium carbonate in the step (7) is 2.36:3.53:7.07, and the heating reflux time is 6-10 hours.
  9. 9. Use of an isoxazole-containing formononetin derivative according to claim 1 or 2 in the preparation of a medicament for inhibiting phytopathogenic fungi.
  10. 10. The use according to claim 9, wherein the plant pathogenic fungi comprise rhizoctonia solani, rs, phytophthora capsici, pc, sclerotium rot of colza, ss, gibberella wheat, fg, phomopsis actinidiae, ps, colletotrichum gloeosporioides, cg, plasmopara viticola, bd, black spot of chinese cabbage, ab, black rot of apple, vm, fusarium capsici, fo and fusarium oxysporum cucumber, foc.

Description

Isoazole-containing formononetin derivative and preparation method and application thereof Technical Field The invention belongs to the technical field of pesticide synthesis, and particularly relates to an isoxazole-containing formononetin derivative, and a preparation method and application thereof. Background Plant fungal diseases seriously threaten the growth and development of crops and cause a certain harm to the yield and quality of agricultural products, which causes great loss of farmer economy. In recent years, green pesticides have been rapidly developed in the global scope due to their high activity, low dosage, no residue, etc. Therefore, developing a green pesticide which is friendly to the environment and has good biological activity is a big hot spot today. Isoflavone is a flavonoid compound having various biological activities. Whereas formononetin (7-hydroxy-4' -methoxyisoflavone) is one of the isoflavones, it is mainly extracted from red clover, astragalus and soybean, and its biological activities such as antioxidation, anticancer and anti-inflammatory are of great concern and application is also much, but application in agricultural chemicals is relatively little. Therefore, the formononetin as a natural product has certain research significance and application value in the aspect of plant antibacterial and antiviral drugs. In 2015, wang et al found that the natural compound formononetin was effective in inhibiting enterovirus 71 (EV 71) replication. In 2017, lin et al synthesized formononetin derivatives, the optimal compounds were very potent in proliferation inhibition of triple negative breast cancer cells (IC 50 = 5.44 ± 1.28 μm). 2023, mahmoudvand et al have shown that IC 50 was 9.3 μm for formononetin to kill 50% of the promastigotes from in vitro experiments to mechanism exploration. In 2024, musa et al verified that formononetin significantly inhibited β -hexosaminidase release in both rat and human basophilic leukemia cells by computer modeling and cell experiments. In 2024, qian et al combined with metabonomics and network pharmacology demonstrated that formononetin regulated cardiomyocytes and improved isoprenaline-induced cardiac fibrosis. A great deal of literature is consulted to find that research on formononetin and its derivatives is mainly focused on the medical field, but few applications and reports on formononetin and its derivatives are made in the pesticide field. The unique structure of isoxazole heterocycle makes it a dominant framework for developing bioactive molecules. The isoxazole ring-containing compounds exhibit various pharmacological and pesticidal activities such as anti-inflammatory, bacteriostatic, antiviral and herbicidal effects. As such, the structure has been successfully applied to a number of commercial products such as the anti-inflammatory agents isoxicam, the herbicides clomazone and clomazone, and the bactericides hymexazol and imazalil, and the like. In view of the above, there is no synthesis of an isoxazole-containing formononetin derivative by introducing an isoxazole group into the formononetin structure, nor is there any use of an isoxazole-containing formononetin derivative for agricultural activity studies. Disclosure of Invention The invention aims to provide an isoxazole-containing formononetin derivative, and a preparation method and application thereof. The provided formononetin derivative containing isoxazole can be used for inhibiting plant pathogenic fungi, in particular to phomopsis of kiwi fruits. In order to achieve the purpose, the invention provides one of the following technical schemes, namely, an isoxazole-containing formononetin derivative is provided, and the structure of the formononetin derivative is shown as the following formula: wherein R is independently selected from H, one or more halogens, one or more alkyl groups, one or more substituted alkyl groups, and one or more alkoxy groups; preferably, the halogen is F, cl or Br. The halogen is R=2-Cl, 3-Cl, 4-Cl, 2,3-di-Cl, 2,4-di-Cl, 2-Br, 3-Br, 2-F, 3-F, 4-F, 2,3-di-F, 2,4-di-F, 3,4-di-F, wherein the alkyl is R=2-CH 3、3-CH3, 4-Et, 4-i-Pr, the substituted alkyl is R=4-CF 3, 4-CN, and the alkoxy is R=3-OCH 3、4-OCH3. The second technical scheme of the invention provides a preparation method of the formononetin derivative containing isoxazole, which comprises the following steps: (1) Taking formononetin and epibromohydrin as raw materials, reacting in a solvent under an alkaline condition at normal temperature, adding ice water after the reaction is finished to separate out a product, and filtering to obtain a filter cake, namely an intermediate a; the structural formula of the intermediate a is as follows: ; (2) Taking the intermediate a and 4-Boc-aminopiperidine as raw materials, taking anhydrous potassium carbonate as a catalyst, and heating in a solvent for reaction to prepare an intermediate b; The structural formula of the intermediate b is as follows: ; (3)