CN113149927B - Vanillin isoxazole compound and preparation method and application thereof - Google Patents
Vanillin isoxazole compound and preparation method and application thereof Download PDFInfo
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- CN113149927B CN113149927B CN202110494154.0A CN202110494154A CN113149927B CN 113149927 B CN113149927 B CN 113149927B CN 202110494154 A CN202110494154 A CN 202110494154A CN 113149927 B CN113149927 B CN 113149927B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
Abstract
The invention relates to the technical field of bactericides, in particular toRelates to a vanillin isoxazole compound and a preparation method and application thereof. The vanillin isoxazole compound has a structural general formula shown in a formula A:
wherein R is 1 Any one selected from H, acetyl, propargyl and benzyl; r is 2 Any one selected from substituted or unsubstituted aromatic groups. According to the invention, an isoxazole structure is introduced into a vanillin structure, a series of vanillin isoxazole compounds are designed and synthesized, the biological activity is researched, the structure-activity relationship is investigated, the compounds with excellent bactericidal activity are obtained, the foundation is laid for screening better bactericides, the speed and efficiency of creating new pesticides are favorably improved, the pesticide development cost is reduced, and the success rate of finding the novel pesticides with high efficiency, low toxicity, biological safety and environmental friendliness is improved.
Description
Technical Field
The invention relates to the technical field of bactericides, in particular to a vanillin isoxazole compound and a preparation method and application thereof.
Background
Plant pathogenic bacteria are closely related to most plant diseases, and the plant pathogenic bacteria can cause various diseases of plants, directly influence the plant yield and the product quality, and have great influence on agricultural production and national economy. At present, the prevention and treatment measures for plant diseases are mainly chemical bactericides. However, the long-term administration or frequent use of a single agent leads to an increase in the resistance of phytopathogens to fungicides. In addition, the problem of residue in agricultural products or environment due to medication is also becoming a focus of attention.
Therefore, the development of a lead compound with high efficiency, low toxicity, biosafety and environmental friendliness is of great significance.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first purpose of the present invention is to provide vanillin isoxazole compounds which have excellent fungicidal activity, low toxicity, biosafety and environmental friendliness.
The second object of the present invention is to provide a method for preparing vanillin isoxazole compounds.
The third purpose of the invention is to provide the application of the vanillin isoxazole compound in the preparation of the bactericidal pesticide.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the vanillin isoxazole compound has a structural general formula shown as a formula A:
wherein R is 1 Any one selected from H, acetyl, propargyl and benzyl; r 2 Any one selected from substituted or unsubstituted aromatic groups.
According to the invention, an isoxazole structure is introduced into a vanillin structure, a series of vanillin isoxazole compounds are designed and synthesized, the biological activity is researched, the structure-activity relationship is investigated, the compounds with excellent bactericidal activity are obtained, the foundation is laid for screening better bactericides, the speed and efficiency of creating new pesticides are favorably improved, the pesticide development cost is reduced, and the success rate of finding the novel pesticides with high efficiency, low toxicity, biological safety and environmental friendliness is improved.
In a particular embodiment of the invention, the aromatic group is phenyl or naphthyl.
In a particular embodiment of the invention, R 2 Is phenyl; or R 2 Is composed of
R 3 The number of (A) is 1 to 5，R 3 Selected from any one of halogen group, alkyl group and alkoxy group. Further, the halogen group includes F and Cl; the alkyl group includes C1 to C6 alkyl groups such as methyl, ethyl, n-propyl and isopropyl; the alkoxy group includes C1 to C6 alkoxy groups such as methoxy, ethoxy and propoxy.
In a particular embodiment of the invention, R 3 At least one selected from F, cl, methoxy, methyl, ethyl and n-propyl.
In a particular embodiment of the invention, R 2 Is composed of
In a particular embodiment of the invention, R 1 Is acetyl or H, R 2 Is phenyl, p-fluorine substituted phenyl, p-chlorine substituted phenyl, p-methyl substituted phenyl, p-methoxy substituted phenyl or p-ethyl substituted phenyl.
The invention also provides a preparation method of the vanillin isoxazole compound, which comprises the following steps:
when R is 1 When the number of the aldehyde oxime is H, reacting the aldehyde oxime with the compound B in a solvent under the action of a catalyst and an oxidant to obtain a compound IV; wherein, the structural formulas of the compound B and the compound IV are respectively as follows:
when R is 1 When the compound is acetyl, reacting the compound IV with an acetylation reagent under the action of organic base to obtain a compound V; wherein the structural formula of the compound V is as follows:
when R is 1 When the compound is propargyl, reacting the compound IV with a propargylation reagent under the action of sodium hydride to obtain a compound VI; wherein, the structural formula of the compound VI is as follows：
When R is 1 When the compound is benzyl, reacting the compound IV with a benzylation reagent under the action of sodium hydride to obtain a compound VII; wherein the structural formula of the compound VII is as follows:
in a specific embodiment of the invention, the catalyst is potassium chloride and the oxidant is oxone complex salt. Further, the solvent is water, preferably deionized water.
In a particular embodiment of the invention, when R is 1 And when the H is H, reacting for 12 to 24 hours at normal temperature.
In a particular embodiment of the invention, the molar ratio of vanillin aldoxime to compound B is 1: 1 to 1.5, preferably 1: 1.2 to 1.3.
In a specific embodiment of the present invention, the compound B includes any one of phenylacetylene, p-chlorophenylacetylene, p-fluorophenylacetylene, p-methoxyphenylacetylene, p-methylphenylacetylene, p-ethylphenylacetylene and p-propylphenylacetylene.
In a particular embodiment of the invention, the post-treatment of the compound iv comprises: and (3) extracting and separating the reacted materials by using ethyl acetate until no product remains in the water phase, collecting an organic phase, drying, removing the ethyl acetate, and performing column chromatography separation and purification.
In a particular embodiment of the invention, the organic base is pyridine and the acetylating agent is acetic anhydride.
In a particular embodiment of the invention, when R is 1 And when the acetyl is acetyl, reacting for 12 to 24 hours at normal temperature.
In a particular embodiment of the invention, the molar ratio of compound IV to the acetylating reagent is 1: 1 to 3, preferably 1: 1.5 to 2.
In a particular embodiment of the invention, the work-up of compound v comprises: concentrating the reacted materials, extracting the concentrated materials by using ethyl acetate, then washing by using deionized water, combining and collecting organic phases, drying, removing solvent, and then performing column chromatography separation and purification.
In a specific embodiment of the invention, the propargylating agent is 3-bromopropyne.
In a particular embodiment of the invention, when R is 1 And in the case of propargyl, reacting for 8-16 h at normal temperature.
In a particular embodiment of the invention, the molar ratio of compound IV to propargylating reagent is 1: 1 to 3, preferably 1: 1.5 to 2.
In a particular embodiment of the invention, the work-up of the compound VI comprises: adding a large amount of deionized water into the reacted materials to quench the reaction, then spin-drying, extracting by using ethyl acetate and deionized water, collecting an organic phase, drying, removing the solvent, and then performing column chromatography separation and purification.
In a particular embodiment of the invention, the benzylating agent is benzyl bromide.
In a particular embodiment of the invention, when R is 1 And when the benzyl is adopted, the reaction is carried out for 8 to 16 hours at normal temperature.
In a particular embodiment of the invention, the molar ratio of compound IV to benzylation reagent is 1: 1 to 3, preferably 1: 2 to 2.5.
In a particular embodiment of the invention, said post-treatment of the compound vii comprises: adding a large amount of deionized water into the reacted materials to quench the reaction, then spin-drying, extracting by adopting ethyl acetate and deionized water, collecting an organic phase, drying, removing the solvent, and recrystallizing.
The reaction time of each step can be adjusted adaptively by monitoring the reaction degree by TLC.
In a specific embodiment of the present invention, the preparation of vanillin oxime comprises: vanillin and hydroxylamine hydrochloride are put into an alcohol solvent, and stirred and reacted for 12-24 hours at normal temperature under the action of an acid-binding agent.
In a particular embodiment of the invention, the post-treatment of vanillin oxime comprises: and (4) carrying out solid-liquid separation to collect liquid, and concentrating the liquid.
The invention also provides application of any one of the vanillin isoxazole compounds in preparation of a bactericidal pesticide.
In a specific embodiment of the present invention, the bactericidal pesticide is a bactericidal pesticide that inhibits a plant pathogenic fungus.
In a specific embodiment of the invention, the plant pathogenic fungi comprise at least one of tobacco gray mold, fusarium layered, fusarium equiseti, corn round spot, colletotrichum gloeosporioides and phoma nikoides.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the invention, an isoxazole structure is introduced into a vanillin structure, a series of vanillin isoxazole compounds are designed and synthesized, the biological activity is researched, the structure-activity relationship is investigated, and the compound with excellent bactericidal activity is obtained;
(2) The vanillin isoxazole compound has certain inhibition effect on the growth of plant pathogenic fungi hyphae such as tobacco gray mold, fusarium stratified, fusarium equiseti, corn round spot, colletotrichum gloeosporioides, phoma graminearum and the like, is safe and easy to degrade, lays a foundation for screening better bactericides, is beneficial to improving the speed and efficiency of creating new pesticides, reduces the development cost of the pesticides, and improves the success rate of finding the novel pesticides which are efficient, low-toxicity, biologically safe and environment-friendly.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following detailed description, but those skilled in the art will understand that the following described examples are some, not all, of the examples of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The vanillin isoxazole compound has a structural general formula shown in a formula A:
wherein R is 1 Any one selected from H, acetyl, propargyl and benzyl; r 2 Any one selected from substituted or unsubstituted aromatic groups.
According to the invention, an isoxazole structure is introduced into a vanillin structure, a series of vanillin isoxazole compounds are designed and synthesized, the biological activity is researched, the structure-activity relationship is investigated, and the compound with excellent bactericidal activity is obtained.
In a particular embodiment of the invention, the aromatic group is phenyl or naphthyl.
In a particular embodiment of the invention, R 2 Is phenyl; or R 2 Is composed of
R 3 The number of (A) is 1 to 5, R 3 Selected from any one of a halogen group, an alkyl group and an alkoxy group. Further, the halogen group includes F and Cl; the alkyl group comprises C1-C6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl and the like; the alkoxy group includes C1-C6 alkoxy groups such as methoxy, ethoxy, propoxy and the like. Where "C1 to C6" refers to carbon atoms in the group having any integer value in the range of 1 to 6, such as 1, 2, 3, 4, 5, 6 carbon atoms.
In a particular embodiment of the invention, R 3 At least one selected from F, cl, methoxy, methyl, ethyl and n-propyl.
In a particular embodiment of the invention, R 2 Is composed of
The wavy line referred to in the present invention represents R 2 To the rest of the compound.
In a particular embodiment of the invention, R 1 Is acetyl or H, R 2 Is phenyl, p-fluorine substituted phenyl, p-chlorine substituted phenyl, p-methyl substituted phenyl, p-methoxy substituted phenyl or p-ethyl substituted phenyl.
As in various embodiments, the structural formulas of the vanillin isoxazole compounds can each be as follows:
the invention also provides a preparation method of the vanillin isoxazole compound, which comprises the following steps:
when R is 1 When the molecular weight is H, reacting vanillin oxime with the compound B in a solvent under the action of a catalyst and an oxidant to obtain a compound IV;
when R is 1 When the compound is acetyl, reacting the compound IV with an acetylation reagent under the action of organic base to obtain a compound V;
when R is 1 When the compound is propargyl, reacting the compound IV with a propargylation reagent under the action of sodium hydride to obtain a compound VI;
when R is 1 When the compound is benzyl, reacting the compound IV with a benzylation reagent under the action of sodium hydride to obtain a compound VII;
wherein, the compound B isThe structural formulas of the compound IV, the compound V, the compound VI and the compound VII are respectively as follows:
the synthetic route of the steps is as follows:
in a specific embodiment of the invention, the catalyst is potassium chloride and the oxidant is oxone complex salt. Further, the solvent is water, preferably deionized water.
In a particular embodiment of the invention, when R is 1 And when the H is H, reacting for 12 to 24 hours at normal temperature.
In a particular embodiment of the invention, the molar ratio of vanillin aldoxime to compound B is 1: 1 to 1.5, preferably 1: 1.2 to 1.3.
In a specific embodiment of the present invention, the compound B includes any one of phenylacetylene, p-chlorophenylacetylene, p-fluorophenylacetylene, p-methoxyphenylacetylene, p-methylphenylacetylene, p-ethylphenylacetylene and p-propylphenylacetylene.
In a particular embodiment of the invention, the post-treatment of the compound iv comprises: and (3) extracting and separating the reacted materials by using ethyl acetate until no product remains in the water phase, collecting an organic phase, drying, removing the ethyl acetate, and performing column chromatography separation and purification.
In practical practice, the preparation of the compound IV comprises: and adding deionized water serving as a reaction solvent into vanillin oxime, adding a catalyst, an oxidant and the compound B, and stirring at room temperature for reaction. The reaction progress was monitored by TLC [ V (petroleum ether) = V (ethyl acetate) = 3: 1], and when the reaction was completed, the reaction was stopped and post-treatment was performed.
In a particular embodiment of the invention, the organic base is pyridine and the acetylating agent is acetic anhydride.
In a particular embodiment of the invention, when R 1 And when the acetyl is acetyl, reacting for 12 to 24 hours at normal temperature.
In a particular embodiment of the invention, the molar ratio of compound IV to the acetylating reagent is 1: 1 to 3, preferably 1: 1.5 to 2.
In a particular embodiment of the invention, the work-up of compound v comprises: concentrating the reacted material, extracting the concentrated material by ethyl acetate, washing by deionized water, combining and collecting organic phases, drying, removing solvent, and performing column chromatography separation and purification.
In practice, the preparation of compound v comprises: and taking the compound IV, adding dry pyridine to fully dissolve the raw materials, slowly dropwise adding an acetylation reagent into the reaction system in an ice water bath, and then stirring at normal temperature for reaction. The reaction progress was monitored by TLC [ V (petroleum ether) = 2.5: 1], and when the reaction was completed, the reaction was stopped and worked up.
In a specific embodiment of the invention, the propargylating agent is 3-bromopropyne.
In a particular embodiment of the invention, when R is 1 And in the case of propargyl, reacting for 8-16 h at normal temperature.
In a particular embodiment of the invention, the molar ratio of compound IV to propargylating reagent is 1: 1 to 3, preferably 1: 1.5 to 2.
In a particular embodiment of the invention, the work-up of the compound VI comprises: adding a large amount of deionized water into the reacted materials to quench the reaction, then spin-drying, extracting by adopting ethyl acetate and deionized water, collecting an organic phase, drying, removing the solvent, and then carrying out column chromatography separation and purification.
In practice, the preparation of said compound VI comprises: taking a compound IV, adopting anhydrous DMF as a reaction solvent, fixing a reaction container in a low-temperature cooling liquid circulating pump, setting the temperature to be lower than 0 ℃, such as-30 ℃, then adding sodium hydride, stirring at low temperature for 5min, slowly dropwise adding a propargylation reagent after confirming that the solution does not generate gas, and then moving a reaction system to room temperature for reaction. The reaction progress was monitored by TLC [ V (petroleum ether) = 2.5: 1], and when the reaction was completed, the reaction was stopped and worked up.
In a particular embodiment of the invention, the benzylating agent is benzyl bromide.
In a particular embodiment of the invention, when R 1 And when the benzyl is adopted, the reaction is carried out for 8 to 16 hours at normal temperature.
In a particular embodiment of the invention, the molar ratio of compound IV to benzylation reagent is 1: 1 to 3, preferably 1: 2 to 2.5.
In a particular embodiment of the invention, said post-treatment of the compound vii comprises: adding a large amount of deionized water into the reacted materials to quench the reaction, then spin-drying, extracting by adopting ethyl acetate and deionized water, collecting an organic phase, drying, removing the solvent, and then carrying out recrystallization treatment.
In practical practice, the preparation of said compound VII comprises: taking a compound IV, adopting anhydrous DMF as a reaction solvent, fixing a reaction container in a low-temperature cooling liquid circulating pump, setting the temperature to be lower than 0 ℃, such as minus 30 ℃, then adding sodium hydride, stirring at low temperature for 5min, slowly dropwise adding a benzylation reagent after confirming that the solution does not generate gas, and then moving a reaction system to room temperature for reaction. The reaction progress was monitored by TLC [ V (petroleum ether) = V (ethyl acetate) = 4: 1], and when the reaction was completed, the reaction was stopped for post-treatment.
The reaction time of each step can be adjusted adaptively by monitoring the reaction degree by TLC.
In a specific embodiment of the present invention, the preparation of vanillin oxime comprises: vanillin and hydroxylamine hydrochloride are put into an alcohol solvent, and stirred and reacted for 12-24 hours at normal temperature under the action of an acid-binding agent.
In a specific embodiment of the present invention, the alcoholic solvent is methanol; the acid-binding agent is inorganic base such as potassium carbonate.
In a particular embodiment of the invention, the post-treatment of vanillin oxime comprises: and (4) carrying out solid-liquid separation to collect liquid, and concentrating the liquid.
The invention also provides application of any one of the vanillin isoxazole compounds in preparation of a bactericidal pesticide.
In a specific embodiment of the present invention, the bactericidal pesticide is a bactericidal pesticide that inhibits a plant pathogenic fungus.
In a specific embodiment of the invention, the plant pathogenic fungi comprise at least one of tobacco gray mold, fusarium layered, fusarium equiseti, corn round spot, colletotrichum gloeosporioides and phoma nikoides.
Example 1
This example provides vanillin isoxazoles compound IV 2 And process for their preparation, compounds IV 2 The synthetic route of (2) is as follows:
the specific synthesis steps are as follows:
step (i): weighing 30g of vanillin in a 1000mL round bottom flask, adding anhydrous methanol for dissolving, then adding 16.44g of hydroxylamine hydrochloride and 32.76g of anhydrous potassium carbonate, stirring at room temperature, and completely detecting the reaction by TLC [ V (petroleum ether) = V (ethyl acetate) = 2: 1 ]. And after the reaction is stopped, carrying out suction filtration on the reacted materials, collecting filtrate, and then concentrating the filtrate under reduced pressure to obtain the vanillin oxime pure product.
Step (ii): 4g of vanillin oxime was placed in a 250mL round bottom flask, 50mL of deionized water was added as the reaction solvent, and then 9.15g of Oxone (2 KHSO) complex salt was added 5 ·KHSO 4 ·K 2 SO 4 ) 1.78g of potassium chloride and 3.24mL of phenylacetylene, and stirred at room temperature for 18h, TLC [ V (petroleum ether) = V (ethyl acetate) = 3: 1]]The reaction was stopped by monitoring until the reaction was complete. After the reaction is stopped, adding 300mL of ethyl acetate into the reacted materials, extracting for 2 times, separating, detecting by TLC that no product remains in the water phase, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, then spin-drying the ethyl acetate, and separating by column chromatography to obtain the vanillin isoxazole compound IV 2 The yield was 60%.
Example 2
This example provides vanillin isoxazoles IV 1 And a process for its preparation, with reference to the synthetic route of example 1, with the only difference that: (iii) replacing phenylacetylene in step (ii) with equimolar p-methoxyphenylacetylene.
Example 3
This example provides vanillin isoxazoles IV 3 And a process for its preparation, with reference to the synthetic route of example 1, with the only difference that: (iii) replacing phenylacetylene in step (ii) with equimolar amounts of p-chlorophenylacetylene.
Example 4
This example provides vanillin isoxazoles IV 4 And a process for its preparation, with reference to the synthetic route of example 1, with the only difference that: (iii) replacing phenylacetylene in step (ii) with equimolar amounts of p-fluoroacetylene.
Example 5
This example provides vanillin isoxazoles compound IV 5 And a process for its preparation, reference being made to the synthetic route of example 1, with the only differences being: (iii) replacing phenylacetylene in step (ii) with equimolar amounts of p-methylphenylacetylene.
Example 6
This example provides vanillin isoxazoles IV 6 And a process for its preparation, with reference to the synthetic route of example 1, with the only difference that: (iii) replacing the phenylacetylene in step (ii) with an equimolar amount of p-ethylphenylacetylene.
Example 7
This example provides vanillin isoxazoles IV 7 And a process for its preparation, with reference to the synthetic route of example 1, with the only difference that: (iii) replacing phenylacetylene in step (ii) with equimolar amounts of p-propylphenylacetylene.
Example 8
This example provides vanillin isoxazole compound V 2 And process for their preparation, compound V 2 The synthetic route of (2) is as follows:
the specific synthesis steps are as follows:
synthesis of Compound IV with reference to the synthetic route of example 1 2 ；
Step (iii): 0.4g of compound IV are weighed 2 Adding into a 50mL round bottom flask, pumping 10mL dry pyridine under pressure to dissolve the raw material, slowly adding 0.25mL acetic anhydride dropwise into the reaction system in an ice-water bath, and stirring at room temperature for reaction of 18h, TLC [ V (petroleum ether) = V (ethyl acetate) = 2.5: 1]The reaction was stopped by monitoring until the reaction was complete. Then concentrating the reacted materials under reduced pressure, extracting the concentrated product with ethyl acetate (2 times, 50mL each time), washing with deionized water (1 time, 25 mL), combining organic phases, adding anhydrous sodium sulfate, drying, filtering, spin-drying the filtrate, and purifying by column chromatography to obtain compound V 2 The yield was 84%.
Example 9
This example provides vanillin isoxazole Compound V 1 And a process for its preparation, by reference to the synthetic route of example 8, except that: (iv) reacting the compound IV in step (iii) 2 Substitution to equimolar IV 1 。
Example 10
This example provides vanillin isoxazole compound V 3 And a process for its preparation, reference being made to the synthetic route of example 8, with the only differences being: (iv) reacting the compound IV of step (iii) 2 Substitution to equimolar IV 3 。
Example 11
This example provides vanillin isoxazole compound V 4 And a process for its preparation, reference being made to the synthetic route of example 8, with the only differences being: (iv) reacting the compound IV of step (iii) 2 Substitution to equimolar IV 4 。
Example 12
This example provides vanillin isoxazole compound V 5 And a process for its preparation, by reference to the synthetic route of example 8, except that: (iv) reacting the compound IV in step (iii) 2 Replacement is made toMolar IV 5 。
Example 13
This example provides vanillin isoxazole compound V 6 And a process for its preparation, reference being made to the synthetic route of example 8, with the only differences being: (iv) reacting the compound IV of step (iii) 2 Substitution to equimolar IV 6 。
Example 14
This example provides vanillin isoxazole compound V 7 And a process for its preparation, by reference to the synthetic route of example 8, except that: (iv) reacting the compound IV in step (iii) 2 Substitution to equimolar IV 7 。
Example 15
This example provides vanillin isoxazoles compound VI 2 Process for their preparation, compound VI 2 The synthetic route of (2) is as follows:
the specific synthesis steps are as follows:
synthesis of Compound IV by the synthetic route of reference example 1 2 ；
Step (iv): 0.5g of compound IV are weighed 2 A50 mL round-bottom flask was charged, and 10mL of anhydrous DMF was pumped under pressure as a reaction solvent. Fixing the round bottom flask in a low temperature cooling liquid circulating pump, setting the temperature at-30 deg.C, adding 0.15g sodium hydride, stirring at low temperature for 5min to ensure no gas generation, slowly adding 0.25mL 3-bromopropyne dropwise, transferring the reaction system to room temperature, and reacting for 12h, TLC [ V (petroleum ether) = V (ethyl acetate) = 2.5: 1]]The reaction was stopped by monitoring until the reaction was complete. Transferring the reacted materials into a 2000mL round bottom flask, adding a large amount of deionized water to quench the reaction, then spin-drying at 70 ℃, adding ethyl acetate (2 times of 100mL each time) and deionized water (2 times of 40mL each time) for extraction, merging organic phases, adding anhydrous sodium sulfate for drying, filtering, spin-drying filtrate, and performing column chromatography to obtain a compound VI 2 。
Example 16
This example provides vanillin isoxazoles compound VI 1 And a process for its preparation, by reference to the synthetic route of example 15, except that: (iii) reacting the compound IV in step (iv) 2 Substitution to equimolar IV 1 。
Example 17
This example provides vanillin isoxazoles compound VI 3 And a process for its preparation, by reference to the synthetic route of example 15, except that: (iii) reacting the compound IV in step (iv) 2 Substitution to equimolar IV 3 。
Example 18
This example provides vanillin isoxazoles compound VI 4 And a process for its preparation, by reference to the synthetic route of example 15, except that: (iii) reacting the compound IV in step (iv) 2 Substitution to equimolar IV 4 。
Example 19
This example provides vanillin isoxazoles compound VI 5 And a process for its preparation, by reference to the synthetic route of example 15, except that: (iii) reacting the compound IV in step (iv) 2 Substitution to equimolar IV 5 。
Example 20
This example provides vanillin isoxazoles compound VI 6 And a process for its preparation, by reference to the synthetic route of example 15, except that: (iii) reacting the compound IV in step (iv) 2 Substitution to equimolar IV 6 。
Example 21
This example provides vanillin isoxazoles compound VI 7 And a process for its preparation, by reference to the synthetic route of example 15, except that: (iii) reacting the compound IV in step (iv) 2 Substitution to equimolar IV 7 。
Example 22
This example provides vanilloid isoxazole compound VII 2 And process for their preparation, compounds VII 2 The synthetic route of (2) is as follows:
the specific synthesis steps are as follows:
synthesis of Compound IV with reference to the synthetic route of example 1 2 ；
Step (v): 0.5g of compound IV are weighed 2 A50 mL round-bottom flask was charged, and 10mL of anhydrous DMF was pumped under pressure as a reaction solvent to dissolve it sufficiently. Fixing the round bottom flask in a cooling liquid circulating pump with cooling liquid at-30 deg.C, adding 0.15g sodium hydride into the reaction system, stirring at low temperature for 5min, slowly adding 0.55mL benzyl bromide dropwise after the reaction system generates no gas, transferring the reaction system to room temperature, reacting for 14h, and reacting at room temperature for 14h, wherein the reaction system comprises petroleum ether, V (ethyl acetate) = 4: 1, and reacting with sodium bromide]The reaction was stopped by monitoring until the reaction was complete. Transferring the reacted materials into a 2000mL round-bottom flask, adding a large amount of deionized water to quench the reaction, then spin-drying at 70 ℃, adding ethyl acetate (50 mL each time for 2 times) and deionized water (20 mL each time for 2 times) for extraction, combining organic phases, adding anhydrous sodium sulfate for drying, filtering, spin-drying filtrate, and recrystallizing by adopting petroleum ether-ethyl acetate to obtain a compound VII 2 。
Example 23
This example provides vanilloid isoxazole compound VII 1 And a process for its preparation, by reference to the synthetic route of example 22, except that: (iv) reacting the compound IV of step (v) 2 Substitution to equimolar IV 1 。
Example 24
This example provides vanillin isoxazoles compound VII 3 And a process for its preparation, reference being made to the scheme of example 22, with the only differences being: (iv) reacting the compound IV of step (v) 2 Substitution to equimolar IV 3 。
Example 25
This example provides vanilloid isoxazole compound VII 4 And a process for its preparation, reference being made to the scheme of example 22, with the only differences being: (iv) reacting the compound IV of step (v) 2 Substitution to equimolar IV 4 。
Example 26
This example provides vanilloid isoxazole compound VII 5 And a process for its preparation, by reference to the synthetic route of example 22, except that: (iv) reacting the compound IV of step (v) 2 Substitution to equimolar IV 5 。
Example 27
This example provides vanilloid isoxazole compound VII 6 And a process for its preparation, by reference to the synthetic route of example 22, except that: (iv) reacting the compound IV of step (v) 2 Substitution to equimolar IV 6 。
Example 28
This example provides vanillin isoxazoles compound VII 7 And a process for its preparation, by reference to the synthetic route of example 22, except that: (iv) reacting the compound IV of step (v) 2 Substitution to equimolar IV 7 。
The physicochemical data of the 28 compounds prepared in the above examples are shown in Table 1 below, and the NMR spectra are given in the following Table 1 H NMR、 13 The C NMR data are shown in Table 2.
The structural general formula of the 28 compounds is as follows:
TABLE 1 physicochemical data for the respective compounds
TABLE 2 preparation of the respective compounds 1 H NMR、 13 C NMR characterization data
Experimental example 1
Measurement of fungicidal Activity
(1) The experimental materials were as follows:
the strain source is as follows: the plant protection research institute of the Chinese academy of agricultural sciences, and the Peking academy of agricultural sciences plant protection laboratory Pestcide team laboratory.
Test strains: tobacco gray mold, fusarium graminearum, fusarium equiseti, corn round spot, colletotrichum gloeosporioides and phoma herbarum.
PDA culture medium: 200g/L of potato, 15g/L of agar and 20g/L of glucose, and adding deionized water to the mixture until the volume is 1L.
The instrument comprises the following steps: SPX-250B-Z biochemical incubator, pipette gun (Eppendorf Co., germany), SW-CJ-1FD single-person single-side purification workbench, and LDZX-50KBS vertical pressure steam sterilizer.
Reagent: acetone, ethanol (analytical grade, beijing chemical reagents Co.), diyne amide (Xiongdatong crop protection Co., ltd.).
Reagent to be tested: comprises 28 vanillin isoxazole compounds in the table 1 and a reference medicament, namely diacetylenimide.
(2) The experimental method comprises the following steps:
preparing a drug-containing culture medium: the medicaments are respectively dissolved in acetone to prepare test liquid medicine with the concentration of 5000 mug/mL, and the test liquid medicine is stored in a refrigerator at 4 ℃ for standby. 1.0mL of the liquid medicine is respectively sucked from 5000 mug/mL of the liquid medicine and is added to 100mL of PDA culture medium, and the medicine-containing culture medium with the mass concentration of 50 mug/mL is prepared. The drug-containing medium was poured into 9 petri dishes with a diameter of 9cm to make 11 mL/dish of drug-containing medium plate.
(3) And (3) bactericidal activity determination: the inhibition rate I of the drug-containing culture medium with the mass concentration of 50 mug/mL to the growth of the plant pathogenic fungi hyphae is detected by adopting a hyphae growth rate measuring method.
Activating the strain on a PDA culture medium plate for 5 days, and then punching bacterium blocks with the diameter of 6mm on the edges of the bacterium colonies to respectively inoculate the bacterium blocks on different drug-containing culture medium plates. Using 50 microgram/mL culture medium containing diyne bacteria amide as reagent control, 1% culture medium containing acetone as reagent control, and setting blank control, and repeating for 3 times. Culturing in 25 deg.C incubator in dark place. When the colonies of the blank control grew to 6-7 cm, the diameter of each colony was measured by the cross method, and the average value was taken.
Calculating the inhibition rate according to the average diameter of the bacterial colony in the corrected blank control and each culture medium plate containing the medicine, wherein the formula is as follows:
D 1 : blank control colony diameter;
processing the diameter of the bacterial colony; i: the inhibition rate.
The bacteriostatic activity data of the vanillin isoxazole compound at the mass concentration of 50 mu g/mL are shown in a table 3.
TABLE 3 Primary screening results (50. Mu.g/mL) for inhibitory Activity of different Compounds against six pathogenic bacteria
From the above table, it can be known that, at a mass concentration of 50 μ g/mL, 28 vanillin isoxazole compounds have a certain inhibition effect on the growth of 6 plant pathogenic fungi hyphae. Different pathogenic bacteria have certain differences in sensitivity to 28 vanillin isoxazole compounds, and the inhibition rate of most of the vanillin isoxazole compounds to different pathogenic bacteria is higher than that of diyne bacteria amide. Wherein, the sensitivity of the botrytis cinerea to vanillin isoxazole compounds is the highest, and 21 compounds with the hypha growth inhibition rate higher than 78 percent are available; 19 compounds with the growth inhibition rate of fusarium disease hyphae higher than 16% are layered; 16 compounds with the fusarium equiseti hypha growth inhibition rate higher than 24 percent; 26 compounds with the hypha growth inhibition rate of the corn round spot higher than 18%; 21 compounds with the growth inhibition rate of colletotrichum gloeosporioides hypha higher than 28%; 13 compounds with the hypha growth inhibition rate of the corn northern leaf blight higher than 23 percent.
Vanillin isoxazole compound V 2 (R 1 ＝Ac；R 2 ＝C 6 H 5 -) has the strongest bacteriostatic activity, and has over 57 percent of inhibition rate on 5 strains, and has over 79 percent of inhibition rate on 4 strains of tobacco botrytis cinerea, corn leaf spot pathogen, colletotrichum gloeosporioides and grass stem spot mildew. Vanillin isoxazoles compound IV 2 (R 1 ＝H；R 2 ＝C 6 H 5 -) next time, the inhibitor has an inhibition rate of more than 69% on 4 pathogenic bacteria. Vanillin isoxazole compound V 4 (R 1 ＝Ac；R 2 ＝4-F-C 6 H 4 -) has an inhibitory effect of 50% or more on 4 pathogenic bacteria. IV 3 (R 1 ＝H；R 2 ＝4-Cl-C 6 H 4 -)、Ⅳ 5 (R 1 ＝H；R 2 ＝4-CH 3 -C 6 H 4 -)、Ⅴ 1 (R 1 ＝Ac；R 2 ＝4-OCH 3 -C 6 H 4 -)、Ⅴ 6 (R 1 ＝Ac；R 2 ＝4-C 2 H 5 -C 6 H 4 -) had an inhibitory effect on all 3 strains of greater than 50%. IV 6 (R 1 ＝H；R 2 ＝4-C 2 H 5 -C 6 H 4 -) has 93 percent of bacteriostatic effect on the tobacco botrytis cinerea.
Comparison of R 1 The influence of the substituent species on the antibacterial activity is based on the number of compounds with the antibacterial rate of more than or equal to 60 percent for 6 test strains as reference, R 1 The compounds with acetyl Ac have the best inhibitory activity, R 1 Inhibitory Activity of Compounds of H, R 1 Is benzyl Bn, propargyl-C 3 H 3 The inhibitory activity of the compound of (a) is relatively low. Comparison of R 2 The influence of the substituent species on the antibacterial activity is based on the number of compounds with the antibacterial rate of more than or equal to 60 percent for 6 test strains as reference, R 2 Is C 6 H 5 The inhibitory activity of the compound of (A) is best, R 2 Is 4-C 3 H 7 -C 6 H 4 The inhibitory activity of the compound of (a) - (b) is relatively low.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (18)
1. The vanillin isoxazole compound is characterized by having a general structural formula shown as a formula A:
wherein R is 1 Any one selected from H, acetyl, propargyl and benzyl;
R 2 is phenyl;or R 2 Is composed of
，R 3 The number of (2) is 1~5, R 3 Any one selected from a halogen group, an alkyl group and an alkoxy group;
the alkyl is selected from C1-C6 alkyl;
the alkoxy is selected from C1-C6 alkoxy.
2. The vanillin isoxazole compound according to claim 1, wherein the halogen group is selected from F and Cl.
3. The vanillin isoxazole compound according to claim 2, wherein R is 3 At least one selected from F, cl, methoxy, methyl, ethyl, and propyl.
4. The vanillin isoxazole compound according to claim 2, wherein R is 2 Is composed of
。
5. The vanillin isoxazole compound according to claim 1, wherein R is 1 Is acetyl or H, R 2 Is phenyl, p-fluorine substituted phenyl, p-chlorine substituted phenyl, p-methyl substituted phenyl, p-methoxy substituted phenyl or p-ethyl substituted phenyl.
6. The process for the preparation of vanillin isoxazole compounds according to any of claims 1 to 5, characterized by comprising the following steps:
when R is 1 When the molecular weight is H, reacting vanillin oxime with the compound B in a solvent under the action of a catalyst and an oxidant to obtain a compound IV; wherein, the structural formulas of the compound B and the compound IV are respectively as follows:
when R is 1 When the compound is acetyl, reacting the compound IV with an acetylation reagent under the action of organic base to obtain a compound V; wherein the structural formula of the compound V is as follows:
when R is 1 When the compound is propargyl, reacting the compound IV with a propargylation reagent under the action of sodium hydride to obtain a compound VI; wherein the structural formula of the compound VI is as follows:
when R is 1 When the compound is benzyl, reacting the compound IV with a benzylation reagent under the action of sodium hydride to obtain a compound VII; wherein the structural formula of the compound VII is as follows:
7. the method for producing vanillin isoxazole according to claim 6, wherein the catalyst is potassium chloride and the oxidizing agent is oxone complex salt.
8. The method for producing vanillin isoxazole compounds according to claim 6, characterized in that the molar ratio of vanillin oxime to compound B is 1: 1 (1 to 1.5).
9. The method for preparing vanillin isoxazole compounds according to claim 6, wherein the compound B is any one selected from phenylacetylene, p-chlorophenylacetylene, p-fluorophenylacetylene, p-methoxyphenylacetylene, p-methylphenylacetylene, p-ethylphenylacetylene and p-propylphenylacetylene.
10. The method for producing vanillin isoxazole according to claim 6, characterized in that the organic base is pyridine and the acetylating agent is acetic anhydride.
11. The process for the preparation of vanillin isoxazoles according to claim 6, characterized in that the molar ratio of compound IV to the acetylating agent is 1: (1~3).
12. The method for producing a vanillin isoxazole compound according to claim 6, wherein the propargylating agent is 3-bromopropyne.
13. The process for the preparation of vanillin isoxazoles according to claim 6, characterized in that the molar ratio of compound IV to propargylating agent is 1: 1~3.
14. The method for preparing vanillin isoxazole according to claim 6, wherein the benzylating agent is benzyl bromide.
15. The process for the preparation of vanillin isoxazoles according to claim 6, characterized in that the molar ratio of compound IV to benzylation agent is 1: 1~3.
16. Use of the vanillin isoxazole compound according to any one of claims 1 to 5 for the preparation of a bactericidal pesticide.
17. Use according to claim 16, wherein the bactericidal pesticide is a plant pathogenic fungi-inhibiting bactericidal pesticide.
18. Use according to claim 17, wherein the phytopathogen fungus is selected from at least one of fusarium laminarinum, fusarium equiseti, colletotrichum gloeosporioides and phoma nivale.
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