CN111087345B - Azobenzene heterocyclic amide derivative, and preparation method and application thereof - Google Patents

Azobenzene heterocyclic amide derivative, and preparation method and application thereof Download PDF

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CN111087345B
CN111087345B CN201911382960.8A CN201911382960A CN111087345B CN 111087345 B CN111087345 B CN 111087345B CN 201911382960 A CN201911382960 A CN 201911382960A CN 111087345 B CN111087345 B CN 111087345B
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alkyl
halogen
cyano
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CN111087345A (en
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邵旭升
李忠
付稳
程家高
徐晓勇
须志平
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East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
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  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to an azobenzene heterocyclic amide derivative, a preparation method and application thereof, wherein the azobenzene heterocyclic amide derivative has the following general formula:

Description

Azobenzene heterocyclic amide derivative, and preparation method and application thereof
Technical Field
The invention relates to an azobenzene heterocyclic amide derivative, a preparation method and application thereof.
Background
Pyrazole amide bactericides inhibit the activity of fungal pathogens by acting on succinate dehydrogenase in the mitochondrial respiratory chain complex (II), thereby inhibiting the germination of fungal pathogen spores, growth of shoot tubes and mycelium. It is reported by FRAC et al that this class of bactericides has a medium to high risk of resistance and is detrimental to raw water organisms.
Therefore, the problems of resistance, aquatic toxicity and the like of the pyrazole amide succinate dehydrogenase inhibitor bactericide are solved, and the application of the pyrazole amide succinate dehydrogenase inhibitor bactericide to the bactericide is the technical problem to be solved by the invention.
Disclosure of Invention
The invention aims to obtain the azobenzene heterocyclic amide derivative with high efficiency, low toxicity, good environmental compatibility and novel structure by introducing azobenzene into a pyrazole amide structure and carrying out reasonable molecular design. Through tests, the derivatives have remarkable activity of inhibiting plant pathogenic bacteria.
In a first aspect of the present invention, there is provided a compound of formula (I), an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof:
In the method, in the process of the invention,
Ring a is selected from the group consisting of substituted or unsubstituted: a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano, C 1-C6 alkyl, C 1-C6 haloalkyl;
Ring Q is a substituted or unsubstituted group of: phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy;
Ring W is a substituted or unsubstituted group of: phenyl or 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C8 cycloalkyl, C 5-C7 cycloalkenyl, 3-8 membered heterocyclyl, C 6-C10 aryl, 5-14 membered heteroaryl;
Wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C8 cycloalkyl, C 5-C7 cycloalkenyl, 3-8 membered heterocyclyl, C 6-C10 aryl, 5-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano;
wherein the heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O or S.
In another preferred embodiment, ring a is selected from the group consisting of substituted or unsubstituted: a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, C 1-C3 alkyl, C 1-C3 haloalkyl.
In another preferred embodiment, ring W is a substituted or unsubstituted group of: phenyl or 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, 8-14 membered heteroaryl.
In another preferred embodiment, ring a is selected from the group consisting of substituted or unsubstituted: pyrazolyl, pyridinyl, thiazolyl, furanyl, pyrazinyl or 1, 4-oxathiolanyl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, C 1-C3 alkyl, C 1-C3 haloalkyl.
In another preferred embodiment, ring Q is selected from the group consisting of substituted or unsubstituted: phenyl, pyrazolyl, pyridinyl, thiazolyl, furanyl, pyrazinyl or thienyl; wherein the substitution refers to substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy.
In another preferred embodiment, ring W is selected from the group consisting of substituted or unsubstituted: phenyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, pyrazinyl or thiophenyl, wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl; Wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C6 cycloalkyl, the C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano.
In another preferred embodiment, the compound, optical isomer, cis-trans isomer, or agropharmaceutically acceptable salt thereof has the structure of formula I:
In the method, in the process of the invention,
Ring W is phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl,
Each R A is independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy;
Each R B is independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl;
wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano;
m is an integer of 1, 2, 3 or 4;
n is an integer of 1, 2, 3, 4 or 5.
In another preferred embodiment, each R B is independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C2 alkyl, C 1-C2 alkoxy, C 1-C2 haloalkyl, C 1-C2 haloalkoxy. In a further preferred embodiment of the present invention,At the meta or para position of the benzene ring W, R B, n are as defined above.
In another preferred embodiment, the compound, optical isomer, cis-trans isomer, or agropharmaceutically acceptable salt thereof has a structure represented by formula (vii), formula (viii), or formula (IX):
In the method, in the process of the invention,
Ring W is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl,
R 1、R2、R3、R4、R5 are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy;
R 6、R7、R8、R9、R10 are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl or 8-14 membered heteroaryl;
Wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano.
In another preferred embodiment, each R 1、R2、R3、R4、R5 is independently hydrogen or halogen.
In another preferred embodiment, each R 6、R7、R8、R9、R10 is independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C2 alkyl, C 1-C2 alkoxy, C 1-C2 haloalkyl, C 1-C2 haloalkoxy.
In another preferred embodiment, halogen is fluorine or chlorine.
In another preferred embodiment, ring A, Q, W is selected from the groups shown in tables 1-4.
In another preferred embodiment, the compound, optical isomer, cis-trans isomer, or agropharmaceutically acceptable salt thereof is selected from the compounds shown in table 1, table 2, table 3 or table 4.
In another preferred embodiment, the compound is selected from the compounds shown in table 2, table 3 or table 4.
In another preferred embodiment, the compound is selected from the group consisting of the compounds in table 2, table 3 or table 4 having s.s. and/or b.c. bacteriostasis (%) of 50 or more.
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (i) according to the first aspect, comprising the steps of:
Method one
(I) In the presence of an inert solvent, the solvent,Reacting with oxalyl chloride, and then reacting with 2-bromoaniline to obtain a compound II;
(ii) In an inert solvent, under the action of a catalyst, reacting a compound II with a compound III to obtain a compound IV;
(iii) Reacting the compound IV with the compound VI in an inert solvent to obtain a compound I;
Method II
(I') reacting a compound III with a compound VI in an inert solvent to obtain a compound E;
(ii') reacting the compound E with 2-bromoaniline in an inert solvent under the action of a catalyst to obtain a compound F;
(iii') Compounds F and F in an inert solvent Reacting to obtain a compound I;
In the method, in the process of the invention,
A. q, W are defined above.
In another preferred embodiment, step (i) comprises two stages, (i-1)With oxalyl chloride to obtainAnd reacting with 2-bromoaniline to obtain a compound II.
In another preferred embodiment, in step (i) or (iii'), the inert solvent is selected from: dichloromethane, 1, 4-dioxane, tetrahydrofuran.
In another preferred embodiment, in step (i-1), N-dimethylformamide is also added.
In another preferred embodiment, in step (i-2), a base is further added, the base being selected from the group consisting of: pyridine, potassium carbonate, sodium carbonate, triethylamine, N-diisopropylethylamine.
In another preferred embodiment, in step (ii) or (ii'), the catalyst is a palladium catalyst.
In another preferred embodiment, in step (ii) or (ii'), the inert solvent is selected from: 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide.
In another preferred embodiment, in step (II) or (II '), the catalyst is [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, tetrakis (triphenylphosphine) palladium, bis-triphenylphosphine palladium dichloride.
In another preferred embodiment, in step (ii) or (ii'), the reaction is carried out under alkaline conditions, the base being selected from: potassium carbonate, sodium carbonate.
In another preferred embodiment, in step (ii) or (ii'), the reaction temperature is 60 to 120 ℃; preferably 90-110 deg.c.
In another preferred embodiment, in step (iii) or (i'), the inert solvent is toluene.
In another preferred embodiment, the process for the preparation of the compound of formula (I) further comprises the preparation of compound VI:
(i ") in an inert solvent, Reaction with an oxidizing agent gives the compound VI, wherein W is as defined above.
In another preferred embodiment, in step (i'), the oxidizing agent is selected from the group consisting of: potassium hydrogen persulfate.
In another preferred embodiment, in step (i'), the inert solvent is selected from: dichloromethane.
In a third aspect of the present invention there is provided an agricultural composition comprising:
(a) 0.001% to 99.99% by weight of a compound of the first aspect, an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof, or a combination thereof; and
(B) Pharmaceutically acceptable carriers and/or excipients.
In another preferred embodiment, component (a) comprises from 0.01 to 99.9 wt%, preferably from 0.05 to 90 wt% of the agricultural composition.
In another preferred embodiment, the agricultural composition further comprises other active substances selected from the group consisting of: insecticide, bait, bactericide, acaricide, nematicide, fungicide or insect growth regulator.
In another preferred embodiment, there is provided a method of preparing an agricultural composition comprising the steps of: combining the compound of the first aspect of (a), an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof, or a combination thereof; and (b) an agropharmaceutically acceptable carrier and/or excipient, thereby forming an agricultural composition.
In a fourth aspect, the present invention provides a compound according to the first aspect, an optical isomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, or an agricultural composition according to the third aspect, for use in controlling agricultural plant diseases, or for use in preparing a bactericide for controlling agricultural plant diseases.
In another preferred embodiment, the pathogen is selected from the group consisting of: ascomycota, basidiomycota, deuteromycota, oomycota, or a combination thereof.
In another preferred embodiment, the pathogen is selected from the group consisting of: sclerotinia, monofilament shell gibberella genus Puccinia, rhizoctonia, and Botrytis, phoma, and its preparation method Phytophthora and Peronospora.
In another preferred embodiment, the pathogen is selected from the group consisting of: sclerotinia sclerotiorum, cucumber powdery mildew, wheat scab, wheat stripe rust, stem rust, rice sheath blight, potato late blight, and soybean downy mildew.
In another preferred embodiment, there is provided a method of sterilization comprising applying the above compound, an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt or an agricultural composition thereof to a plant body, an animal body, soil around it or an environment which is or may be subjected to a pathogen.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor of the present invention has studied extensively for a long time, and has found that by introducing azobenzene into pyrazole amide, an azobenzene heterocyclic amide derivative with high efficiency, low toxicity, good environmental compatibility and novel structure is obtained, and the biological activity result shows that the azobenzene heterocyclic amide derivative has remarkable activity of inhibiting plant pathogenic bacteria.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
In the present invention, the term "C 1-C8 alkyl" refers to a straight or branched chain alkyl group having 1, 2,3, 4, 5, 6, 7, or 8 carbon atoms, preferably C 1-C6 alkyl, examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like. In the present invention, alkyl also includes substituted alkyl groups, and the substituents may be halo, hydroxy, cyano, nitro, etc.
In the present invention, the term "C 2-C6 alkenyl" refers to straight or branched alkenyl groups having 2, 3,4, 5, or 6 carbon atoms, including but not limited to vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like. In the present invention, alkenyl also includes substituted alkenyl groups, and the substituents may be halo, hydroxy, cyano, nitro, and the like.
In the present invention, the term "C 2-C6 alkynyl" refers to straight or branched chain alkynyl groups having 2,3, 4, 5 or 6 carbon atoms, including but not limited to ethynyl, propynyl or the like. In the present invention, alkynyl also includes substituted alkynyl groups, and substituents may be halo, hydroxy, cyano, nitro, and the like.
In the present invention, the term "C 3-C8 cycloalkyl" refers to a cyclic alkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like, preferably C 3-C6 cycloalkyl. In the present invention, cycloalkyl also includes substituted cycloalkyl groups, and the substituents may be halo, hydroxy, cyano, nitro, etc.
In the present invention, the term "C 5-C7 cycloalkenyl" refers to cyclic alkenyl groups having 5, 6, or 7 carbon atoms, having one or more double bonds, including, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 3-cyclohexanedienyl, 1, 4-cyclohexanedienyl, or the like. In the present invention, cycloalkenyl further includes substituted cycloalkenyl, and the substituent may be halo, hydroxy, cyano, nitro, etc.
In the present invention, the term "C 1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1,2, 3, 4,5 or 6 carbon atoms, for example: examples of C 1-C6 alkyl-O-or C 1-C5 alkyl-O-C 1-C5 alkyl, alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like. In the present invention, alkoxy also includes substituted alkoxy groups, and the substituents may be halo, hydroxy, cyano, nitro, and the like.
In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "halogenated" refers to groups substituted with one or more of the above halogen atoms, which may be the same or different.
The term "C 1-C8 haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, including, but not limited to: trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl or the like.
In the present invention, the term "ring" or "ring system" refers to a carbocyclic or heterocyclic ring.
In the present invention, the term "ring system" refers to a fused ring in which two or more rings are joined together.
The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, e.g., 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring systems) in which at least one heteroatom is present in a ring having at least one carbon atom. Each heteroatom-containing heterocycle may bear 1,2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, where the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of a ring or ring system molecule. In the present invention, the heterocyclic group is preferably a 3-8 membered heterocyclic group, more preferably a 5-7 membered heterocyclic group. Typical monocyclic heterocycles include, but are not limited to, tetrahydrofuranyl, 4, 5-dihydrothiazol-2-yl, 2-cyanoimino-4-oxo-1, 3-thiazolidin-3-yl, 2-cyanoimino-4-oxo-1, 3-thiazinan-3-yl, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. In the present invention, the heterocyclic group includes a substituted heterocyclic group, and the substituent may be a halogen, a hydroxyl group, a cyano group, a nitro group or the like.
The term "heteroaromatic ring system" refers to a ring system in which at least one ring in the ring system is an aromatic ring.
As used herein, the term "heteroaryl" refers to a heteroaromatic system of 1-4 heteroatoms, 5-14 ring atoms, comprising a single ring (e.g., "5, 6, or 7 membered heteroaryl") and multiple rings (e.g., "8-14 membered heterobicyclic or tricyclic ring system" or "8-12 membered heterobicyclic ring system"), wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, including but not limited to: pyridyl, thiazolyl, isothiazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, 1H-tetrazolyl, 1H-1,2, 3-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, tetrazolyl, benzofuran, benzo [ b ] thiophene, indole, quinoline, isoquinoline, 1H-indazole, 1H-benzo [ d ] imidazole, benzo [ d ] thiazole, benzo [ d ] oxazole, benzo [ d ] isoxazole benzo [ d ] [1,2,3] thiadiazole, 2, 3-dihydroimidazo [1,2-a ] pyridine, quinazoline, quinoxaline, cinnoline, phthalazine, 1, 8-naphthyridine, 4,5,6, 7-tetrahydrobenzo [ b ] thiophene, benzo [ b ] thiophene-1, 1-dioxane, 8H-indeno [2,1-b ] thiophene, 7, 8-dihydro-6H-cyclopenta [4,5] thieno [2,3-d ] pyrimidine, 3,5,6, 7-tetrahydro-4H-cyclopenta [4,5] thieno [2,3-d ] pyrimidin-4-one, spiro [ indoline-3, 2'- [1,3] dioxolane ] -2-one, spiro [ indoline-3, 2' - [1,3] dioxane ] -2-one, or indoline-2, 3-dione, and the like. In the present invention, heteroaryl includes substituted heteroaryl, and the substituent may be halo, hydroxy, cyano, nitro, etc.
Unless otherwise indicated, it is assumed that any heteroatom in an underfilling state has sufficient hydrogen atoms to complement its valence.
When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, e.g., alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds.
As described herein, compounds of the present invention may be substituted with any number of substituents or functional groups to extend their scope of inclusion.
The term "inert solvent" refers to various solvents that do not react with the starting materials, including various straight, branched or cyclic alcohols, ethers or ketones, haloalkanes, 1, 4-dioxane, acetonitrile, tetrahydrofuran, N-Dimethylformamide (DMF), dimethylsulfoxide (DMSO), and the like.
The term "agropharmaceutically acceptable salt" means that the anion of the salt is known and acceptable in forming the fungicide pharmaceutically acceptable salt. Preferably, the salt is water soluble. Suitably, the acid addition salts formed with compounds of formula (I) include salts formed with inorganic acids, for example hydrochloride, phosphate, sulphate, nitrate; and salts formed with organic acids such as acetates, benzoates, and the like. Salts which may be formed with the compounds of the present invention are also within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to salts formed with inorganic or organic acids and bases in the acid or base form.
Specific functional groups and chemical term definitions are described in detail below. For the purposes of the present invention, chemical elements are in accordance with those defined in Periodic Table of THE ELEMENTS, CAS version, handbook of CHEMISTRY AND PHYSICS,75 th Ed.. The definition of specific functional groups is also described herein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, which is incorporated by reference in its entirety.
Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures thereof. In addition, an asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and mixtures thereof are encompassed by the present invention.
According to the invention, the mixture of isomers may contain various isomer ratios. For example, in a mixture of only two isomers, there may be a combination of: all ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are within the scope of the present invention, as would be readily understood by one of ordinary skill in the art.
The present invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and 36 Cl, respectively. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, for example, the radioisotopes of 3 H and 14 C, are also useful in drug and substrate tissue distribution experiments. Tritium, 3 H and carbon-14, 14 C, are relatively easy to prepare and detect. Is the first choice in isotopes. In addition, heavier isotopic substitutions such as deuterium, 2 H, may be preferred in certain situations because of their good metabolic stability which may be advantageous in certain therapies, such as increasing half-life or reducing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by using readily available isotopically-labeled reagents in place of non-isotopically-labeled reagents using the protocols disclosed in the examples.
If one is to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary, separating the resulting diastereomeric mixture and removing the chiral auxiliary to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith using an appropriate optically active acid or base, and then the resulting mixture can be separated by conventional means such as fractional crystallization or chromatography to give the pure enantiomer.
The active substance and the bactericide of the invention
The "compound of the present invention", "active substance of the present invention" or "active compound of the present invention" refer to a compound of the structure shown in the general formula (I) or an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof, which has a remarkable activity of inhibiting plant pathogenic bacteria.
Specifically, the compound of the present invention refers to a compound represented by the formula (I), an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof:
A particularly preferred class of compounds has the structure of formula (VII), (VIII) or (IX)
Examples of controlling diseases include, but are not limited to: downy mildew (cucumber downy mildew, rape downy mildew, soybean downy mildew, beet downy mildew, sugarcane downy mildew, tobacco downy mildew, pea downy mildew, luffa downy mildew, white gourd downy mildew, melon downy mildew, cabbage downy mildew, spinach downy mildew, radish downy mildew, grape downy mildew, onion downy mildew), white rust (white rust of rape, white rust of cabbage), damping off (rape damping off, tobacco damping off, tomato damping off, pepper damping off, eggplant damping off, cucumber damping off, cotton seedling damping off), cotton rot (chilli soft rot, luffa soft rot, white gourd soft rot), epidemic disease (broad bean epidemic disease, Cucumber epidemic disease, white gourd epidemic disease, watermelon epidemic disease, melon epidemic disease, capsicum epidemic disease, leek epidemic disease, garlic epidemic disease, cotton epidemic disease), late blight (Ma Lingpan late blight, tomato late blight) and the like; root rot (capsicum root rot, eggplant root rot, bean root rot, cucumber root rot, balsam pear root rot, cotton root rot, broad bean root rot), damping off (cotton seedling damping off, sesame damping off, capsicum damping off, cucumber damping off, cabbage damping off), verticillium wilt (cotton verticillium wilt, tomato verticillium wilt, capsicum verticillium wilt, eggplant verticillium wilt), scab (cucurbita pepo scab, wax gourd scab, melon scab), gray mold (gray mold of cotton boll, gray mold of kenaf, gray mold of tomato, gray mold of capsicum) gray mold of kidney bean, gray mold of cucumber, gray mold of soybean, gray mold of kiwi fruit, gray mold of grass duck, gray mold of, Gray mold of leek, gray mold of spinach), brown spot (cotton brown spot, jute brown spot, beet brown spot, peanut brown spot, pepper brown spot, white gourd brown spot, soybean brown spot, sunflower brown spot, pea brown spot, broad bean brown spot), black spot (flax false black spot, rape black spot, sesame black spot, sunflower black spot, castor black spot, tomato black spot, pepper black spot, eggplant black spot, bean black spot, cucumber black spot, celery black spot, carrot black spot, apple black spot, peanut black spot), spot blight (tomato black spot, pepper black spot, celery black spot), early blight (tomato early blight, early blight), Early blight of pepper, early blight of eggplant, early blight of potato, early blight of celery), ring rot (soybean ring rot, sesame ring rot, bean ring rot), leaf blight (sesame leaf blight, sunflower leaf blight, watermelon leaf blight, melon leaf blight), stem rot (tomato stem rot, bean stem rot), and others (maize round spot disease, kenaf waist folding accident, rice blast, black chestnut sheath disease, sugarcane eye spot disease, peanut crown rot, soybean stem rot, soybean black spot disease melon and leaf spot, peanut net spot, brown spot, white pepper leaf spot, black rot of bean sprouts, heart rot of spinach, leaf mold of kenaf and leaf spot of kenaf, Yellow tinge, purple spot of beans, leaf spot of sesame, gray spot of castor, brown leaf spot of tea, brown starfish of eggplant, red spot of beans, white spot of balsam pear, spot of watermelon, yellow spot of jute, dry rot of sunflower rhizome, carbon rot of beans, leaf spot of eggplant, target spot of cucumber, leaf mold of tomato, leaf mold of eggplant, red spot of broad bean) and the like: basidiomycete diseases such as rust (wheat stripe rust, wheat stalk rust, wheat leaf rust, peanut rust, sunflower rust, deer rust, leek rust, onion rust, chestnut rust, soybean rust), smut (head smut, smut of maize, head smut of sorghum, scattered smut of sorghum), Sorghum smut, gao Liangzhu smut, black ear of chestnut grain, black ear of sugarcane, bean rust) and others (such as banded sclerotial blight of wheat, sheath blight of rice, etc.); Ascomycete diseases such as powdery mildew (wheat powdery mildew, shanzi powdery mildew, sesame powdery mildew, sunflower powdery mildew, beet powdery mildew, eggplant powdery mildew, pea powdery mildew, luffa powdery mildew, pumpkin powdery mildew, white gourd powdery mildew, melon powdery mildew, grape powdery mildew, broad bean powdery mildew), sclerotinia (flax sclerotium disease, rape sclerotinia, soybean sclerotinia, peanut sclerotinia, tobacco sclerotinia, capsicum sclerotinia, eggplant sclerotinia, kidney bean sclerotinia, pea sclerotinia, cucumber sclerotinia, balsam pear sclerotinia, white gourd sclerotinia, watermelon sclerotinia, celery sclerotinia), cladospori (apple cladospori, pear cladospori), Clubroot (cabbage clubroot, cauliflower clubroot, radix Isatidis, mustard clubroot, radish clubroot, turnip clubroot, rape clubroot).
Bactericide composition containing "active substance of the present invention
The "active substances according to the invention" can be prepared in a conventional manner as fungicide compositions. These active compounds can be formulated as conventional formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, natural and synthetic materials impregnated with the active substance, microcapsules in polymers, coated compounds for seeds, and formulations for use with combustion devices, such as fumigating cartridges, fumigating cans and fumigating trays, and ULV Cold and hot mist (Cold mist) formulations.
These formulations can be produced by known methods, for example by mixing the active compound with extenders, which are liquid or liquefied gas or solid diluents or carriers, and optionally surfactants, i.e. emulsifiers and/or dispersants and/or foam formers. For example, when water is used as the extender, organic solvents may also be used as adjuvants.
When a liquid solvent is used as a diluent or carrier, it is basically suitable, for example: aromatic hydrocarbons such as xylene, toluene or alkyl naphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, vinyl chloride or dichloromethane; aliphatic hydrocarbons, such as cyclohexane or paraffin waxes, such as mineral oil fractions; alcohols, such as ethanol or ethylene glycol, and their ethers and lipids; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; or less commonly polar solvents such as dimethylformamide, dimethylsulfoxide, and water.
The diluent or carrier for the liquefied gas refers to a liquid that will become a gas at normal temperature and pressure, such as an aerosol propellant, e.g., halogenated hydrocarbons, as well as butane, propane, nitrogen, and carbon dioxide.
The solid carrier may be ground natural minerals such as kaolin, clay, talc, quartz, activated clay, montmorillonite, or diatomaceous earth; and ground synthetic minerals such as highly dispersed silicic acid, alumina, and silicate. Solid carriers for the particles are crushed and graded natural zircon, such as calcite, marble, pumice, sepiolite, dolomite, particles synthesized from inorganic and organic grits, and particles of organic materials such as sawdust, coconut shells, corn cobs and tobacco stalks, and the like.
Nonionic and anionic emulsifying trains can be used as emulsifiers and/or foam formers. Such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates, and albumin hydrolysates. The dispersing agent comprises lignin sulfite waste liquid and methyl cellulose.
Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions, for example gum arabic, polyvinyl alcohol and polyvinyl acetate, can be used in the formulation.
Colorants such as inorganic dyes, e.g., iron oxide, cobalt oxide, and Prussian blue; organic dyes such as azo dyes or metal phthalocyanine dyes; trace nutrients such as salts of iron, manganese, boron, copper, cobalt, aluminum, and zinc, and the like.
The "active compounds according to the invention" can be present in their commercial preparations or in the dosage forms used prepared from these preparations in a mixture with other active compounds, such as pesticides, bactericides, fungicides, herbicides, growth control agents and the like. Pesticides include, for example, phosphates, carbamates, chlorinated hydrocarbons, and substances produced by microorganisms, such as avermectin, and the like, and fungicides include methoxy acrylates, amides, triazoles, and the like.
Furthermore, the "active compounds according to the invention" can also be present in their commercial preparations or in the dosage forms used prepared from these preparations in a mixture with synergists, which are compounds which increase the action of the active compounds, since the active compounds themselves are active, it being possible for the synergists not to be necessary.
These formulations generally contain from 0.001 to 99.99% by weight, preferably from 0.01 to 99.9% by weight, more preferably from 0.05 to 90% by weight of the "active compound of the invention", based on the total weight of the fungicide composition. The concentration of the active compound in the commercial preparation or use dosage form may vary widely. The concentration of the active compound in the dosage form used may be from 0.0000001 to 100% (g/v), preferably between 0.0001 and 1% (g/v).
The test shows that the compound shown in the formula (I), the optical isomer, the cis-trans isomer or the salt thereof acceptable in agronomic science has better control effect on gray mold and sclerotinia rot of cucumber.
Stereoisomers of all compounds (e.g., those having asymmetric carbon atoms which may be present as a result of various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated as falling within the scope of the present invention. The individual stereoisomers of the compounds of the invention may not be present simultaneously with the other isomers (e.g., having particular activity as one pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S or R, defined by the International Association of theory and application chemistry (IUPAC) 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of crystals by derivatization into diastereomers, or by chiral column chromatography. Individual optical isomers may be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.
The compounds of the present invention are prepared, isolated and purified in sequence to give the compounds in an amount of 90% by weight or more, for example 95% or more and 99% or more ("very pure" compounds), as listed in the text description. Such "very pure" compounds of the invention are also included herein as part of the invention.
All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both the cis (Z) and the trans (E) olefin isomers, as well as the cis and trans isomers of carbocycles and heterocycles.
Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
Preparation method
The compounds represented by the general formula of the present invention can be produced by a method, however, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. Reagents may be purchased commercially if available.
The preparation method of the compound comprises the following steps:
Method one
(1) Reacting five-membered or six-membered heterocyclic carboxylic acid with oxalyl chloride to obtain heterocyclic acyl chloride, and reacting with 2-bromoaniline without purification to obtain a compound shown in the following formula (II);
(2) Reacting a compound of formula (II) with a compound of formula (III) below in the presence of a catalyst in a suitable solvent at 60-120 ℃ under the protection of argon to form a compound of formula (IV);
(3) Dissolving a compound of the formula (V) and potassium hydrogen persulfate composite salt in a proper solvent, mixing and stirring until the reaction is finished to obtain a compound of the formula (VI), and directly reacting the compound of the formula (VI) with the compound of the formula (IV) in the proper solvent under the protection of argon at 20-100 ℃ to form the compound of the formula (I);
when the corresponding compound cannot be synthesized according to the above steps, the azo synthesis reaction in step (3), the coupling reaction in step (2) and finally the heterocyclic acid chloride may be sequentially carried out to obtain the objective compound.
Method II
Wherein ring A, ring Q, ring W and substituents thereof are as defined above.
The synthesis reaction parameters may be used, for example, to prepare the compounds of the present invention from readily available starting materials using the following general methods and procedures. It will be appreciated that other process conditions may be used given typical or optimized process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, catalysts, pressures, etc.), unless otherwise indicated. The optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art by routine optimization procedures.
The starting materials for the following reactions are generally known compounds or may be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers, others may be prepared by steps described in the text of standard references or obvious modifications, for example, the process described in CN 104530037 a.
In the preparation process of the present invention, each reaction is usually carried out in an inert solvent at a reaction temperature of-20 to 120 ℃ (preferably-10 to 0 ℃ or 20 to 30 ℃ or 80 to 100 ℃). The reaction time is usually 2 to 24 hours, preferably 4 to 18 hours, and the reaction time can be appropriately prolonged according to the reaction requirement, and the specific reaction time is determined according to the reaction degree.
The bases used in the reaction include (but are not limited to): triethylamine, diisopropylethylamine, diethylamine, piperidine, piperazine, morpholine, N-methylmorpholine, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or a combination thereof.
The invention has the following main advantages:
(1) The azobenzene heterocyclic amide derivative provided by the invention has the advantages of high efficiency, low toxicity, good environmental compatibility and novel structure;
(2) The compound is particularly suitable for inhibiting sclerotinia rot, botrytis cinerea, powdery mildew of cucumber, gibberella wheat, stripe rust of wheat, leaf rust of wheat, stem rust of rice, sheath blight of rice, late blight of potato and downy mildew of soybean.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to literature reported in the art.
Except for the special descriptions, all reactions of the invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is in degrees centigrade.
Examples
Example 1 preparation of (E) -3-difluoromethyl-1-methyl-N- (2 '-phenylazo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide
The flow is as follows:
reagents and conditions: (a) Dichloromethane, N-dimethylformamide, room temperature, 0.5 hours; (b) dichloromethane, pyridine, 0 ℃ to room temperature for 1 hour; (c) 1, 4-dioxane, potassium carbonate, water, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, 100 ℃, reflux and argon protection; (d) dichloromethane, water, room temperature, 1 hour; (e) toluene, acetic acid, 60 ℃, reflux and argon protection;
Synthesis of intermediate 1[ 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxamide ]
Into a 50mL eggplant-shaped bottle, 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid (0.707 g,4.01 mmol) was charged, methylene chloride (20 mL) was added, oxalyl chloride (1.29 g,9.96 mmol) was added, 1 drop of N, N-dimethylformamide was added dropwise, and stirring and refluxing were carried out at room temperature, so that it was apparent that the reaction solution gradually became clear from cloudiness, TLC was followed, and the reaction was terminated after 1 hour. The solvent was dried to give intermediate 1, which was redissolved in dichloromethane (10 mL) for further use.
Synthesis of intermediate 2[ N-2-bromo-3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxamide ]
Into a 100mL eggplant-shaped bottle, 2-bromoaniline (1.860 g,10.49 mmol) was put into the bottle, methylene chloride (20 mL) was added to dissolve the compound, pyridine (1.277 g,16.06 mmol) was added, and intermediate 1 (dropwise added for 5 min) obtained by one-step reaction was added dropwise with stirring at 0℃to react for 15min, then the reaction was continued at room temperature, TLC followed by reaction, and after 1 hr the reaction was completed. Washing and purifying the reaction solution with water, saturated sodium chloride aqueous solution, 0.5% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively, collecting dichloromethane, and spin-drying the solvent to obtain intermediate 2 (off-white solid ,3.042g,87.84％).1H NMR(400MHz,DMSO)δ9.78(s,1H),8.51(s,1H),7.71(dd,J＝8.0,1.2Hz,1H),7.54(dd,J＝7.9,1.4Hz,1H),7.42(td,J＝7.9,1.3Hz,1H),7.31(t,J＝54.0Hz,3H),7.21(td,J＝7.8,1.5Hz,1H),3.97(s,3H).
Synthesis of intermediate 3[N- (2 '-amino- [1,1' -diphenyl ] -2-yl) -3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxamide ]
A50 mL eggplant-shaped bottle was charged with intermediate 2 (0.798 g,2.42 mmol) obtained in the previous reaction, 2-aminophenylboronic acid (0.397 g,2.81 mmol) was charged, 1, 4-dioxane (10 mL) was added, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride (0.111 g,0.15 mmol) was charged, an aqueous potassium carbonate solution (10 mL, 2M) was added, argon was used for protection, oxygen was removed by evacuation for 30min, stirring and refluxing were performed at 100℃and TLC was followed to complete the reaction after 1.5 hours. The reaction solution was filtered with celite, washed with ethyl acetate, dried with solvent, added with an appropriate amount of ethyl acetate, added with 3g of silica gel, dried after mixing uniformly, loaded with sample by dry method, column chromatography on silica gel, gradient elution of petroleum ether to petroleum ether ethyl acetate=1:1 (V: V) →petroleum ether ethyl acetate=1:2 (V: V), dried with solvent to give intermediate 3 (pale yellow solid) ,0.778g,93.96％).1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.10(s,1H),7.71(d,J＝7.8Hz,1H),7.43–7.37(m,1H),7.33–7.27(m,2H),7.20(t,J＝54.1Hz,1H),7.14–7.08(m,1H),6.99(dd,J＝7.6,1.5Hz,1H),6.85(dd,J＝8.0,0.8Hz,1H),6.70(td,J＝7.5,1.0Hz,1H),4.89(s,2H),3.91(s,3H).
Synthesis of intermediate 4[ nitrobenzene ]
Into a 250mL eggplant-shaped bottle was charged aniline (2.043 g,21.84 mmol), methylene chloride (50 mL) was added to dissolve, and a potassium hydrogen persulfate complex salt (27.378 g,44.48 mmol) was dissolved in water (100 mL) and slowly added to the methylene chloride reaction solution, and the reaction was stirred at room temperature to give a gradual green reaction, followed by TLC and completion of the reaction after 1 hour. The reaction solution was extracted with dichloromethane and the dichloromethane phase was collected, and the solvent was dried to give intermediate 4 (green solid). The nitrosobenzene is unstable and is directly put into the next step without further separation and purification.
Compound I-1[ (E) -3-difluoromethyl-1-methyl-N- (2 '-phenylazo- [1,1' -diphenyl ] -2-yl) -1-hydro-pyrazole-4-carboxamide ]
Into a 100mL eggplant-shaped bottle, intermediate 3 (0.75 g,2.21 mmol) was put, toluene (15 mL) was added to dissolve, acetic acid (1.514 g,26.08 mmol) was added, intermediate 4 obtained in the previous step was dissolved with toluene (5 mL), and was slowly added to the reaction solution at 0℃under argon protection, vacuum was applied for 30min, the reaction was transferred to 60℃under stirring and reflux, TLC was followed, and after 48 hours the reaction was completed. Spin-drying the reaction solution, adding a proper amount of dichloromethane, adding 3g of silica gel, uniformly mixing, spin-drying, loading by a dry method, performing silica gel column chromatography, and performing gradient elution on petroleum ether, ethyl acetate=2:1 (V: V), and spin-drying the solvent to obtain the compound I-1 (orange solid ,0.228g,23.90％).1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.04(s,1H),7.69–7.64(m,1H),7.64–7.47(m,9H),7.47–7.41(m,1H),7.37–7.29(m,2H),6.92(t,J＝54.1Hz,1H),3.83(s,3H);HRMS(ESI)m/z[M+H]+C24H19F2N5O, calculated value: 431.1558, actual measurement value: 432.1559).
Example 2 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '-phenylazo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-151)
Compound I-151 was synthesized in a similar manner to example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.21(s,1H),7.88(s,1H),7.87–7.79(m,3H),7.66–7.53(m,5H),7.52–7.38(m,4H),7.20(t,J＝54.1Hz,1H),3.85(s,3H);HRMS(ESI)m/z[M+H]+C24H19F2N5O, below: 431.1558, found 432.1559.
Example 3 preparation of (E) -3-difluoromethyl-1-methyl-N- (4 '-phenylazo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-301)
Compound i-301 was synthesized using a synthesis method similar to that of example 1, except that:
The aminophenylboronic acid raw material in the step (c) adopts 4-aminophenylboronic acid.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.25(s,1H),7.92–7.86(m,4H),7.68–7.55(m,5H),7.51–7.35(m,4H),7.25(t,J＝54.1Hz,1H),3.90(s,3H);HRMS(ESI)m/z[M+H]+C24H19F2N5O, below: 431.1558, found 432.1559.
Example 4 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (2-fluorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-166)
Compound i-166 was synthesized using a synthesis method similar to that of example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 2-fluoroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.18(s,1H),7.93(s,1H),7.91–7.83(m,1H),7.70(t,J＝7.8Hz,1H),7.66–7.58(m,3H),7.55–7.38(m,5H),7.35(t,J＝7.7Hz,1H),7.18(t,J＝54.1Hz,1H),3.84(s,3H);HRMS(ESI)m/z[M+H]+C24H18F3N5O, below: 449.1463, found 432.1462.
Example 5 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (2-chlorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-171)
Compound I-171 was synthesized using a synthesis method similar to that of example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 2-chloroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.19(s,1H),7.94(s,1H),7.92–7.86(m,1H),7.71(d,J＝8.0Hz,1H),7.64(d,J＝4.7Hz,3H),7.61–7.55(m,1H),7.46(dddd,J＝18.1,8.6,5.3,2.1Hz,5H),7.19(t,J＝54.2Hz,1H),3.84(s,3H);HRMS(ESI)m/z[M+H]+C24H18ClF2N5O, below: 465.1168, found 465.1166.
Example 6 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (3-chlorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-201)
Compound i-201 was synthesized using a synthesis method similar to that of example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 3-chloroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.20(s,1H),7.94(s,1H),7.92–7.86(m,1H),7.86–7.79(m,2H),7.69–7.56(m,4H),7.56–7.37(m,4H),7.19(t,J＝54.1Hz,1H),3.84(s,3H);HRMS(ESI)m/z[M+H]+C24H18ClF2N5O, below: 465.1168, found 465.1166.
Example 7 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (3-fluorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-196)
Compound I-196 was synthesized using a synthesis similar to that described in example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 3-fluoroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.19(s,1H),7.94(s,1H),7.91–7.84(m,1H),7.74(d,J＝7.9Hz,1H),7.70–7.56(m,4H),7.55–7.38(m,5H),7.19(t,J＝54.1Hz,1H),3.84(s,3H);HRMS(ESI)m/z[M+H]+C24H18F3N5O, below: 449.1463, found 432.1462.
Example 8 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (4-fluorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-226)
Compound I-226 was synthesized using a synthesis method similar to that of example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 4-fluoroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.19(s,1H),7.96–7.89(m,3H),7.88–7.82(m,1H),7.66–7.57(m,2H),7.54–7.38(m,6H),7.19(t,J＝54.1Hz,1H),3.84(s,3H);HRMS(ESI)m/z[M+H]+C24H18F3N5O, below: 449.1463, found 432.1462.
Example 9 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (4-chlorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-231)
Compound I-231 was synthesized using a synthesis method similar to that of example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 4-chloroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.19(s,1H),7.93(s,1H),7.86(d,J＝8.4Hz,3H),7.66(d,J＝8.6Hz,2H),7.61(d,J＝4.7Hz,2H),7.55–7.37(m,4H),7.19(t,J＝54.1Hz,1H),3.84(s,3H);HRMS(ESI)m/z[M+H]+C24H18ClF2N5O, below: 465.1168, found 465.1166.
Example 10 preparation of (E) -3-difluoromethyl-1-methyl-N- (4 '- (2-fluorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-316)
Compound i-316 was synthesized using a synthesis method similar to that of example 1, except that:
The aminophenylboronic acid raw material in the step (c) adopts 4-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 2-fluoroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.26(s,1H),7.92(d,J＝8.3Hz,2H),7.73(t,J＝7.7Hz,1H),7.68–7.58(m,3H),7.56–7.39(m,5H),7.36(t,J＝6.4Hz,1H),7.21(t,J＝52.9Hz,1H),3.91(s,3H);HRMS(ESI)m/z[M+H]+C24H18F3N5O, below: 449.1463, found 432.1462.
Example 11 preparation of (E) -3-difluoromethyl-1-methyl-N- (4 '- (2, 6-difluorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-406)
Compound (I-406) was synthesized using a synthesis method similar to that of example 1, except that:
The aminophenylboronic acid raw material in the step (c) adopts 4-aminophenylboronic acid.
The aniline material in step (d) is 2, 6-difluoroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.28(s,1H),7.91(d,J＝8.3Hz,2H),7.72(t,J＝7.7Hz,1H),7.66–7.54(m,3H),7.52–7.41(m,4H),7.38(t,J＝6.4Hz,1H),7.24(t,J＝52.9Hz,1H),3.95(s,3H);HRMS(ESI)m/z[M+H]+C24H17F4N5O, below: 467.1369, found 467.1371.
Example 12 preparation of [ (E) -3-difluoromethyl-1-methyl-N- (4 '- (2, 6-difluorophenylazo) -3',5 '-difluoro- [1,1' -diphenyl ] -2-yl) -1-hydro-pyrazole-4-carboxamide ] (I-409)
The flow is as follows:
Reagents and conditions: (f) dichloromethane, water, room temperature, 1 hour; (g) toluene, acetic acid, 60 ℃, reflux and argon protection; (h) 1, 4-dioxane, potassium carbonate, water, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, 100 ℃, reflux and argon protection; (i) Dichloromethane, N-dimethylformamide, room temperature, 0.5 hours; (j) dichloromethane, pyridine, 0 ℃ to room temperature for 1 hour;
Intermediate 5[1, 3-difluoro-2-nitrosobenzene ]
Into a 250mL eggplant-shaped bottle, 2, 6-difluoroaniline (2 mL,18.02 mmol) was charged, methylene chloride (20 mL) was added for dissolution, and potassium hydrogen persulfate complex salt (23.993 g,38.98 mmol) was dissolved with water (100 mL) and slowly added to the methylene chloride reaction solution, the reaction was stirred at room temperature, followed by TLC for 5 hours, and the reaction was terminated. The reaction solution was extracted with dichloromethane and the dichloromethane phase was collected, and the solvent was dried to give intermediate 5 (pale yellow solid). Intermediate 10 may be unstable and is therefore directly fed to the next step without further isolation and purification.
Intermediate 6[1- (4-bromo-2, 6-difluorophenyl) -2- (2, 6-difluorophenyl) azo ]
Into a 100mL eggplant-shaped bottle, 4-bromo-2, 6-difluoroaniline (0.642 g,3.02 mmol) and intermediate 5 (1.2 g,8.39 mmol) obtained in the above reaction were charged, toluene (15 mL) and acetic acid (15 mL) were added respectively, trifluoroacetic acid (2.5 mL) was added under argon protection, reflux reaction was stirred at 60℃and the reaction was followed by TLC and ended after 24 hours. The reaction solution is dried by spinning, a proper amount of DCM is added, 3g of silica gel is added, and the mixture is dried by spinning; dry loading, silica gel column chromatography, petroleum ether-ethyl acetate=40:1 (V: V) -petroleum ether-ethyl acetate=20:1 (V: V) gradient elution; spin-drying the solvent to afford intermediate 6 (red solid) ,0.603g,59.94％).1H NMR(400MHz,DMSO)δ7.77(d,J＝8.8Hz,2H),7.65(tt,J＝8.3,6.1Hz,1H),7.42–7.31(m,2H).
Intermediate 7[4'-2, 6-difluorophenylazo-3', 5 '-difluoro- [1,1' -diphenyl ] -2-amine ]
A50 mL eggplant-shaped bottle was charged with intermediate 6 (0.298 g,1 mmol) obtained in the previous reaction, 2-aminophenylboronic acid (0.178 g,1.27 mmol) was charged, 1, 4-dioxane (6 mL) was added, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride (0.053 g,0.07 mmol) was charged, an aqueous potassium carbonate solution (6 mL, 2M) was added, argon was used for protection, oxygen was removed by evacuation for 30min, stirring and reflux reaction was performed at 100℃and TLC was followed for 2 hours to complete the reaction. The reaction solution was filtered with celite, washed with ethyl acetate, dried with solvent, added with an appropriate amount of ethyl acetate, added with 3g of silica gel, dried after mixing uniformly, loaded with sample by dry method, column chromatography on silica gel, gradient elution of petroleum ether to ethyl acetate=20:1 (V: V) →petroleum ether to ethyl acetate=10:1 (V: V), dried with solvent to give intermediate 7 (red solid) ,0.129g,30.71％).1H NMR(400MHz,DMSO-d6)δ7.63(tt,J＝8.4,6.1Hz,1H),7.38(dd,J＝19.5,9.8Hz,4H),7.11(dd,J＝12.0,4.5Hz,2H),6.80(d,J＝7.7Hz,1H),6.67(td,J＝7.5,1.0Hz,1H),5.22(s,2H).
[ (E) -3-difluoromethyl-1-methyl-N- (4 '- (2, 6-difluorophenylazo) -3',5 '-difluoro- [1,1' -diphenyl ] -2-yl) -1-hydro-pyrazole-4-carboxamide ] (I-409)
An intermediate 7 (0.110 g,0.32 mmol) was charged into a 25mL eggplant-shaped bottle, methylene chloride (4 mL) was added to dissolve the intermediate, pyridine (0.1 mL,1.24 mmol) was added, a methylene chloride solution of intermediate 1 (about 0.9 mmol) was slowly added to the reaction solution at 0℃and after the completion of the dropwise addition, the mixture was transferred to room temperature and stirred for reflux reaction, and the reaction was completed after 0.5 hours by TLC tracing. The reaction solution was washed with water, saturated NaHCO 3, saturated NaCl, and then the organic phase was collected, 3g of silica gel was added, spin-dried, dry column chromatography was performed, and gradient elution was performed from petroleum ether to petroleum ether: ethyl acetate=2:1 (V: V) →petroleum ether: ethyl acetate=1:1 (V: V), and the solvent was spin-dried to give compound I-409 (calculated as red solid ,0.142g,88.20％).1H NMR(400MHz,CDCl3)δ8.12(d,J＝8.1Hz,1H),8.04–7.83(m,2H),7.50–7.42(m,1H),7.38(tt,J＝8.5,5.8Hz,1H),7.33–7.24(m,2H),7.15–7.02(m,4H),6.73(t,J＝54.2Hz,1H),3.91(s,3H);HRMS(ESI)m/z[M+H]+C24H15F6N5O,: 50.3.1181, measured: 503.1182).
Example 13 preparation of (E) -3-difluoromethyl-1-methyl-N- (4 '- (2-chlorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-321)
Compound (I-321) was synthesized by a similar synthetic method to example 1, except that:
The aminophenylboronic acid raw material in the step (c) adopts 4-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 2-chloroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.22(s,1H),7.91(d,J＝8.3Hz,2H),7.70(t,J＝7.7Hz,1H),7.65–7.52(m,3H),7.50–7.36(m,5H),7.34(t,J＝6.4Hz,1H),7.22(t,J＝52.9Hz,1H),3.88(s,3H);HRMS(ESI)m/z[M+H]+C24H18ClF2N5O, below: 465.1168, found 465.1167.
Example 14 preparation of (E) -3-difluoromethyl-1-methyl-N- (4 '- (2-methylphenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-331)
Compound i-331 was synthesized using a synthesis method similar to that of example 1, except that:
The aminophenylboronic acid raw material in the step (c) adopts 4-aminophenylboronic acid.
The aniline material in step (d) is 2-methylaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.21(s,1H),7.95(d,J＝8.3Hz,2H),7.73(t,J＝7.7Hz,1H),7.67–7.55(m,3H),7.54–7.39(m,5H),7.36(t,J＝6.4Hz,1H),7.25(t,J＝52.9Hz,1H),3.93(s,3H),2.45(s,3H);HRMS(ESI)m/z[M+H]+C25H21F2N5O, below: 445.1714, found 445.1713.
Example 15 preparation of (E) -3-difluoromethyl-1-methyl-N- (4 '- (2, 6-dichlorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-441)
Compound I-441 was synthesized by a similar synthetic method to example 1, except that:
The aminophenylboronic acid raw material in the step (c) adopts 4-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 2, 6-dichloroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.21(s,1H),7.90(d,J＝8.3Hz,2H),7.72(t,J＝7.7Hz,1H),7.65–7.51(m,3H),7.50–7.42(m,4H),7.35(t,J＝6.4Hz,1H),7.23(t,J＝52.9Hz,1H),3.89(s,3H);HRMS(ESI)m/z[M+H]+C24H17Cl2F2N5O, below: 499.0778, found 499.0778.
Example 16 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (2, 6-dichlorophenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-261)
Compounds I-261 were synthesized using a similar synthetic method to that of example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline raw material in the step (d) adopts 2, 6-dichloroaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.19(s,1H),7.95(s,1H),7.93–7.87(m,1H),7.74(d,J＝8.0Hz,1H),7.65(d,J＝4.7Hz,2H),7.63–7.58(m,1H),7.44(dddd,J＝18.1,8.6,5.3,2.1Hz,5H),7.20(t,J＝54.2Hz,1H),3.86(s,3H);HRMS(ESI)m/z[M+H]+C24H17Cl2F2N5O, below: 499.0778, found 499.0778.
Example 17 preparation of (E) -3-difluoromethyl-1-methyl-N- (3 '- (2-methylphenyl) azo- [1,1' -diphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] (I-181)
Compound i-181 was synthesized by a synthesis method similar to that of example 1, except that:
the aminophenylboronic acid raw material in the step (c) adopts 3-aminophenylboronic acid.
The aniline material in step (d) is 2-methylaniline.
Characterization results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.22(s,1H),7.974(s,1H),7.95–7.87(m,1H),7.71(d,J＝8.0Hz,1H),7.63(d,J＝4.7Hz,3H),7.62–7.53(m,1H),7.49(dddd,J＝18.1,8.6,5.3,2.1Hz,5H),7.23(t,J＝54.2Hz,1H),3.89(s,3H),2.44(s,3H);HRMS(ESI)m/z[M+H]+C25H21F2N5O, below: 445.1714, found 445.1713.
Example 18: preparation of other Compounds from tables 1-4
The procedure of example 1-example 12 was repeated except that different starting materials were used, thereby producing the other compounds shown in Table 1.
EXAMPLE 19 biological Activity assay
(1) Activated culture of test plant pathogenic fungi
And inoculating the slant culture of the cucumber botrytis cinerea to a potato dextrose agar solid culture medium plate for activation, and performing activation culture in a constant temperature box at the temperature of (21+/-1) ℃ for 4 days.
The slant culture of Sclerotinia sclerotiorum is picked by an inoculating needle, inoculated into a potato dextrose agar solid culture medium (PDA) plate for activation, and subjected to activation culture in an incubator at the temperature of (25+/-1) ℃ for 2 days.
(2) Determination of antibacterial Activity by hypha growth Rate method
The sterile triangular flask containing PDA culture medium (49 mL) is placed in a microwave oven to melt the PDA, the PDA is placed in a constant temperature oven to keep the temperature of the culture medium at 55-60 ℃, the prepared drug-containing solution (1 mL) is rapidly poured into a sterile workbench, and after the drug-containing solution and the drug-containing solution are fully and uniformly mixed, the drug-containing solution and the sterile workbench are respectively poured into 3 sterile culture dishes with the diameter of 9cm to prepare drug-containing plates, and the drug-containing plates are cooled and solidified.
The above pre-formulated drug-containing solutions (1 mL) included drug-containing Dimethylsulfoxide (DMSO) solution (0.5 mL) and 0.1% Tween 80 aqueous solution (0.5 mL), wherein the blank used DMSO (0.5 mL) +0.1% Tween 80 aqueous solution (0.5 mL).
Selecting plant pathogenic fungi with equivalent growth vigor (the growth diameter is within 1 cm) from activated plant pathogenic fungi to be tested, and punching the plant pathogenic fungi along the growth outer edge of the colony by a puncher to obtain a plant pathogenic fungi cake to be tested (the diameter is 5 mm); transferring the bacterial cake to the circle center of the prepared PDA plate by using an inoculating needle, enabling the mycelium surface of the bacterial cake to be attached to the surface of a PDA culture medium, and respectively placing the plates inoculated with different plant pathogenic fungi at 25+/-1 ℃ or 21+/-1 ℃ for culturing for 48-96 hours.
Colony growth diameter was measured by the crisscross method and inhibition was calculated using the following formula:
The results of the preparation of a list of compounds of formula (I) and their bacteriostatic activity (rate of inhibition of hyphal growth of Sclerotinia sclerotiorum at a concentration of 1ppm and of Sclerotinia cucumeris at a concentration of 10 ppm) are shown in tables 1 to 4 below:
In the table: S.S. represents Sclerotinia sclerotiorum (Sclerotinia sclerotiorum);
B.C. represents Botrytis cinerea.
TABLE 1
TABLE 2
TABLE 3 Table 3
TABLE 4 Table 4
The inhibition rate of the fluxapyroxad (1 mug/mL) to the sclerotinia sclerotiorum is 85-95%, and the inhibition rate of the fluxapyroxad (10 mug/mL) to the cucumber botrytis cinerea is 50-60%.
Thus, it can be seen that the compounds of the present invention have a biological activity substantially equivalent to or even superior to that of fluxapyroxad. For example, the inhibition rate of most of the compounds (I-151-300) in Table 2 to Sclerotinia sclerotiorum is > 70%, the inhibition rate of most of the compounds (I-301-450) in Table 3 to Sclerotinia cucumber is > 50%, and the inhibition rate of the compounds (e.g., I-460, I-462, I-470, I-471, I-475, I-476, I-485, I-486, I-491, I-492, I-494) in Table 4 to Sclerotinia cucumber is > 60%.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. A compound of formula (I) or an agropharmaceutically acceptable salt thereof:
In the method, in the process of the invention,
Ring a is selected from a substituted or unsubstituted pyrazole ring, wherein the substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano, C 1-C6 alkyl, C 1-C6 haloalkyl;
Ring Q is a substituted or unsubstituted group of: phenyl, wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy;
Ring W is a substituted or unsubstituted group of: phenyl or 5-6 membered heteroaryl, wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C8 cycloalkyl, C 5-C7 cycloalkenyl, 3-8 membered heterocyclyl, C 6-C10 aryl, 5-14 membered heteroaryl;
Wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C8 cycloalkyl, C 5-C7 cycloalkenyl, 3-8 membered heterocyclyl, C 6-C10 aryl, 5-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano;
wherein the heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O or S.
2. The compound of claim 1, or an agropharmaceutically acceptable salt thereof, wherein ring a is selected from substituted or unsubstituted pyrazolyl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, C 1-C3 alkyl, C 1-C3 haloalkyl.
3. The compound of claim 1, or an agropharmaceutically acceptable salt thereof, wherein ring Q is selected from substituted or unsubstituted phenyl; wherein the substitution refers to substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy.
4. The compound of claim 1, or an agropharmaceutically acceptable salt thereof, wherein ring W is selected from the group consisting of substituted or unsubstituted: phenyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, pyrazinyl or thiophenyl, wherein said substitution means substitution with one or more groups selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-to 7-membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl; Wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C6 cycloalkyl, the C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano.
5. The compound of claim 1, or an agropharmaceutically acceptable salt thereof, having the structure of formula I':
In the method, in the process of the invention,
Ring W is phenyl or 5-6 membered heteroaryl,
Each R A is independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy;
Each R B is independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl;
wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano;
m is an integer of 1, 2, 3 or 4;
n is an integer of 1, 2, 3, 4 or 5.
6. The compound of claim 1, an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof, having a structure represented by formula (vii), formula (viii), or formula (IX):
In the method, in the process of the invention,
Ring W is a 5-6 membered heteroaryl,
R 1、R2、R3、R4、R5 are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 1-C6 haloalkoxy;
R 6、R7、R8、R9、R10 are each independently selected from the group consisting of: hydrogen, halogen, hydroxy, nitro, cyano, C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C8 haloalkyl, C 2-C6 haloalkenyl, C 2-C6 haloalkynyl, C 1-C6 haloalkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl or 8-14 membered heteroaryl;
Wherein the C 1-C8 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 3-C6 cycloalkyl, C 5-C7 cycloalkenyl, 5-7 membered heterocyclyl, C 6-C10 aryl, 8-14 membered heteroaryl may be further optionally substituted with one or more groups selected from the group consisting of: halogen, hydroxy, nitro, cyano.
7. A compound according to claim 1, or an agropharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
8. A process for the preparation of a compound of formula (i) according to claim 1, comprising the steps of:
Method one
(I) In the presence of an inert solvent, the solvent,Reacting with oxalyl chloride, and then reacting with 2-bromoaniline to obtain a compound II;
(ii) In an inert solvent, under the action of a catalyst, reacting a compound II with a compound III to obtain a compound IV;
(iii) Reacting the compound IV with the compound VI in an inert solvent to obtain a compound I;
Method II
(I') reacting a compound III with a compound VI in an inert solvent to obtain a compound E;
(ii') reacting the compound E with 2-bromoaniline in an inert solvent under the action of a catalyst to obtain a compound F;
(iii') Compounds F and F in an inert solvent Reacting to obtain a compound I;
In the method, in the process of the invention,
A. q, W is defined in claim 1.
9. An agricultural composition, wherein the composition comprises:
(a) 0.001% to 99.99% by weight of the compound of any one of claims 1-7, or an agropharmaceutically acceptable salt, or a combination thereof; and
(B) Pharmaceutically acceptable carriers and/or excipients.
10. Use of a compound according to any one of claims 1 to 7, or a agropharmaceutically acceptable salt or an agricultural composition according to claim 9, for controlling agricultural plant diseases, or for the preparation of a fungicide for controlling agricultural plant diseases.
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