CN113788790B - Aromatic heterocyclic amide derivative and its application - Google Patents
Aromatic heterocyclic amide derivative and its application Download PDFInfo
- Publication number
- CN113788790B CN113788790B CN202111211881.8A CN202111211881A CN113788790B CN 113788790 B CN113788790 B CN 113788790B CN 202111211881 A CN202111211881 A CN 202111211881A CN 113788790 B CN113788790 B CN 113788790B
- Authority
- CN
- China
- Prior art keywords
- substitution
- substituted
- group
- pathogenic bacteria
- plant pathogenic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
- A01N43/10—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with sulfur as the ring hetero atom
-
- 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
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
-
- 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
-
- 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
- A01N43/82—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 three ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to an aromatic heterocyclic amide derivative, a preparation method and application thereof, wherein the structure of the derivative is shown in a general formula I, and the definition of each substituent is shown in the specification and the claims. The derivative disclosed by the invention is based on the structure of a succinic dehydrogenase inhibitor bactericide, remains a heterocyclic amide part, prolongs an amine connecting bridge part, and has obvious activity of inhibiting plant pathogenic bacteria. A-CONH-Ph-K-Y-M (I)
Description
Technical Field
The invention relates to an aromatic heterocyclic amide derivative and application thereof.
Background
The succinic acid dehydrogenase inhibitor (SDHI) bactericide is an agricultural bactericide which is developed after a methoxy acrylic acid ester bactericide and has a novel action mechanism, and the action mechanism is mainly to inhibit the activity of pathogenic bacteria succinic acid dehydrogenase so as to interfere the respiration of the bacteria succinic acid dehydrogenase, so that the bacteria succinic acid dehydrogenase has the advantages of specific action, strong and durable drug effect and obvious yield increasing effect.
However, succinate dehydrogenase inhibitors have a medium-high risk of resistance and are harmful to aquatic organisms, and various researches are required to alleviate or solve the problems of the resistance and aquatic organism toxicity.
Disclosure of Invention
The invention aims to provide a novel aromatic heterocyclic amide derivative with a novel structure and remarkable plant pathogenic bacteria inhibition activity.
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:
A-CONH-Ph-K-Y-M (I)
wherein A is a substituted or unsubstituted 5-6 membered heteroaryl;
K is a substituted or unsubstituted phenyl, a substituted or unsubstituted 5-6 membered heterocyclyl or a substituted or unsubstituted 5-6 membered heteroaryl;
y is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heterocyclic group, a substituted or unsubstituted 5-6 membered heteroaryl group or a substituted or unsubstituted nitrogen-, oxygen-or/and sulfur-containing fatty chain,
M is a substituted or unsubstituted phenyl, a substituted or unsubstituted 5-6 membered heterocyclyl or a substituted or unsubstituted 5-6 membered heteroaryl;
wherein each of the above substitutions independently refers to a substitution with one or more groups selected from the group consisting of halogen, hydroxy, C 1～C6 alkyl, C 1～C6 alkoxy, C 1～C6 halogenated alkyl, C 1～C6 halogenated alkoxy;
Each heteroaryl, each heterocyclyl described above independently contains 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N, S.
In another preferred embodiment, A is a substituted 5-6 membered heteroaryl selected from the group consisting of pyrazolyl, pyridinyl, thienyl, pyridazinyl, thiazolyl, furanyl, pyrazinyl, and 1, 4-thiahexacyclic ring, wherein said substitution is by 1,2, or 3 groups selected from the group consisting of halogen, C 1～C4 alkyl, C 1～C4 alkoxy, C 1～C4 halogenated alkyl, and C 1～C4 halogenated alkoxy.
In another preferred embodiment, a is a substituted pyrazolyl, pyridinyl, thiophenyl. In another preferred embodiment, said substitution is by 1 or 2 groups selected from the group consisting of halogen, C 1～C3 alkyl, C 1～C3 halogenated alkyl, preferably fluoroalkyl. In another preferred embodiment, the substitution is by 1 or 2 groups selected from F, cl, br, methyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl.
In another preferred embodiment, K is a substituted or unsubstituted phenyl, pyrazolyl, pyridinyl, thiazolyl, furanyl, pyrazinyl or thiophenyl group, said substitution being by 1,2 or 3 groups selected from the group consisting of halogen, C 1～C4 alkyl, C 1～C4 alkoxy, C 1～C4 halogenated alkyl, C 1～C4 halogenated alkoxy.
In another preferred embodiment, K is substituted or unsubstituted phenyl, pyrazolyl, pyridinyl, thiazolyl, furanyl, pyrazinyl, or thiophenyl. More preferably, K is substituted or unsubstituted phenyl, pyridyl, furyl, thienyl. In another preferred embodiment, the substitution means mono-or poly-substitution by halogen. In another preferred embodiment, the substitution is by 1 or 2 groups selected from F, cl, br.
In another preferred embodiment Y is a substituted or unsubstituted phenyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, pyrazinyl, thienyl, oxadiazolyl, thiadiazolyl, said substitution being by 1, 2 or 3 groups selected from the group consisting of halogen, C 1～C4 alkyl, C 1～C4 alkoxy, C 1～C4 halogenated alkyl, C 1～C4 halogenated alkoxy, or
Y is a group selected from the group consisting of: Wherein R, R ', R' are each independently H, halogen, C 1～C4 alkyl, C 1～C4 alkoxy, C 1～C4 halogenated alkyl, C 1～C4 halogenated alkoxy.
In another preferred embodiment, Y is a substituted or unsubstituted phenyl, pyrazolyl, thiazolyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, or a group selected from the group consisting of: Wherein the substitution is 1 or 2 groups selected from halogen, hydroxy, nitro, cyano, methyl, methoxy, halomethyl and halomethoxy, and R, R' are independently H, halogen, methyl, methoxy, halomethyl and halomethoxy.
In another preferred embodiment, Y is a substituted or unsubstituted phenyl, pyrazolyl, thiazolyl, furanyl, thienyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 5-thiadiazolyl,R, R' are each independently H, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy.
In another preferred embodiment, M is a substituted or unsubstituted phenyl, pyrazolyl, pyridinyl, thiazolyl, furanyl, pyrazinyl or thiophenyl group, said substitution being by 1,2 or 3 groups selected from the group consisting of halogen, C 1～C4 alkyl, C 1～C4 alkoxy, C 1～C4 halogenated alkyl, C 1～C4 halogenated alkoxy.
In another preferred embodiment, M is a substituted or unsubstituted phenyl, pyrazolyl, pyridinyl, thiazolyl, furanyl, pyrazinyl, or thiophenyl. More preferably, M is substituted or unsubstituted phenyl, pyridyl, furyl, thienyl. In another preferred embodiment, the substitution means mono-or poly-substitution by halogen. In another preferred embodiment, the substitution is by 1 or 2 groups selected from F, cl, br.
In another preferred embodiment, the compound is any one of I-1 to I-220.
In a second aspect of the present invention there is provided an agricultural composition comprising:
(a) 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, the agricultural composition comprises 0.001 wt% to 99.99 wt% of the compound of the first aspect, an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof, or a combination thereof, based on 100% of the total weight of the composition.
In a third aspect of the invention, there is provided the use of a compound according to the first aspect, an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof, or an agricultural composition according to the second aspect, for controlling agricultural plant diseases, or for the preparation of a fungicide for controlling agricultural plant diseases.
In another preferred example, the plant disease is a plant disease caused by a plant pathogen of ascomycota, basidiomycota, deuteromycota, or oomycota.
In another preferred example, the ascomycota includes sclerotium (Sclerotinia) such as Sclerotinia sclerotiorum and the like, sphaerotheca (Sphaerotheca) such as cucumber powdery mildew and the like, gibberella (Gibberella) such as wheat scab and the like.
In another preferred embodiment, the basidiomycota includes Puccinia (Puccinia) such as wheat stripe rust, leaf rust, stem rust, and the like.
In another preferred example, the phylum of the half-known fungus includes Rhizoctonia (Rhizoctonia) such as Rhizoctonia solani, etc., botrytis (Botrytis) such as Botrytis cinerea, etc., phoma (Macrophoma) such as Rhizoctonia cerealis, etc.
In another preferred example, the oomycete phylum includes Phytophthora (Phytophthora) such as Phytophthora potato and the like, and Peronospora (ronophthora) such as Peronospora sojae and the like.
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. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.
Detailed Description
Through extensive and intensive studies, the inventor of the application combines the chemical structure of succinic dehydrogenase inhibitor bactericides to synthesize a novel aromatic heterocyclic amide derivative with a novel structure in a mode of prolonging an amine connecting bridge, and has remarkable activity of inhibiting plant pathogenic bacteria, so that the aromatic heterocyclic amide derivative is applied to the research of bactericide creation. On this basis, the present application has been completed.
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-C6" means having 1,2,3, 4, 5 or 6 carbon atoms, "C 1-C4" means having 1,2,3 or 4 carbon atoms, and so on. "5-6 membered" means having 5 or 6 ring atoms, and so on.
The term "alkyl" refers to a straight or branched chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
The term "alkenyl" refers to a straight or branched hydrocarbon group containing at least one double bond, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
The term "alkynyl" refers to a straight or branched chain alkynyl group containing one triple bond, such as ethynyl, propynyl, or the like.
The term "alkoxy" refers to a straight or branched chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or the like.
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, same or different, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl or the like.
The term "heterocyclyl" means a saturated or unsaturated, non-aromatic cyclic group containing at least one (e.g., 1,2, 3 or 4) ring heteroatom (e.g., N, O or S), such as tetrahydropyridinyl, pyrrolinyl, dihydropyridinyl, dihydrofuranyl, dihydrothiophenyl, morpholinyl.
The term "heteroaryl" means an aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) ring heteroatom (e.g., N, O, or S), such as pyrazolyl, furanyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, pyrimidinyl, pyranyl, oxadiazolyl, thiadiazolyl, and the like.
In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The disubstitution means having two substituents and so on.
The term "active substance of the present invention" or "active compound of the present invention" refers to a compound of the structure represented by the general formula (I) or an optical isomer, a cis-trans isomer, or an agropharmaceutically acceptable salt thereof.
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, for example acetate, benzoate and the like.
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, cabbage downy mildew, spinach downy mildew, radish downy mildew, grape downy mildew, onion downy mildew), white rust (rape white rust, cabbage white rust), damping off (rape damping off, tobacco damping off, tomato damping off, chili damping off, eggplant damping off, cucumber damping off, cotton seedling damping off), cotton rot (chili cotton rot, luffa cotton rot, white gourd cotton rot), epidemic disease (broad bean damping off, grape downy mildew), Cucumber epidemic disease, white gourd epidemic disease, watermelon epidemic disease, melon epidemic disease, pepper 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 (pepper root rot, eggplant root rot, bean root rot, cucumber root rot, balsam pear root rot, cotton root rot, broad bean root rot), seedling blight (cotton seedling blight, sesame seedling blight, pepper seedling blight, cucumber seedling blight, cabbage seedling blight), verticillium wilt (cotton verticillium wilt, sunflower verticillium wilt, tomato verticillium wilt, pepper verticillium wilt, verticillium wilt), black star (zucchini black star, melon black star), gray mold (cotton boll black gray), The plant growth regulator comprises red-hemp gray mold, tomato gray mold, pepper gray mold, bean gray mold, order gray mold, fatigue gray mold, kiwi gray mold, grass gray mold), 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, castor black spot, tomato black spot, pepper black spot, eggplant black spot, kidney bean black spot, cucumber black spot, celery black spot, carrot black spot, apple black spot), Peanut black spot), spot blight (tomato spot blight, pepper spot blight, celery spot blight), early blight (tomato early blight, pepper early blight, eggplant early blight, potato early blight, celery early blight), 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 cup-based rot, bean stem-based rot), and others (maize round spot, kenaf waist folding, rice blast, chestnut black sheath disease, sugarcane eye spot, cotton boll Qu Ran disease, crown rot, soybean stem rot, soybean black spot, melon soybean spot, peanut net spot disease), Brown leaf spot of tea, white spot of capsicum, white spot of white gourd, black rot of bean, heart rot of fatigue, leaf mold of kenaf, black spot of kenaf, stem spot of jute, purple spot of soybean, leaf spot of sesame, gray spot of castor bean, brown leaf spot of tea, brown round spot of eggplant, red spot of bean, white spot of balsam pear, spot of watermelon, yellow spot of black spot of jute, root and stem rot of sunflower, carbon rot of bean, leaf spot of eggplant, target spot of cucumber, leaf mold of tomato, leaf mold of eggplant, leaf mold of broad bean, red spot of broad bean) and the like, basidiomycetes 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 (maize head smut, maize smut, sorghum head smut, sorghum diffuse black ear, sorghum hard smut, gao Liangzhu smut, chestnut black ear, sugarcane black ear, bean rust) and others (such as wheat sheath blight, rice sheath blight, etc.), ascomycete diseases such as powdery mildew (wheat powdery mildew, white rice powdery mildew, sesame powdery mildew, sunflower powdery mildew, beet powdery mildew, pea powdery mildew, loofah powdery mildew, pumpkin powdery mildew, white gourd powdery mildew, grape powdery mildew, broad bean powdery mildew), powdery mildew (flax powdery mildew), sclerotinia rot of colza, 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), cladosporium cucumerinum (apple cladosporium cucumerinum, pear cladosporium), clubroot (cabbage clubroot, cauliflower clubroot, root-skimming club disease, 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 liquid solvents are used as diluents or carriers, essentially suitable are, for example, aromatic hydrocarbons, such as xylene, toluene or alkylnaphthalene, chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, vinyl chloride or dichloromethane, aliphatic hydrocarbons, such as cyclohexane or paraffins, 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 frequently polar solvents, such as dimethylformamide, dimethyl sulfoxide 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., ferric oxide, british oxide, and Prussian blue, organic dyes, e.g., azo dyes or metal phthalocyanine dyes, trace nutrients, e.g., salts of iron, manganese, boron, copper, cobalt, aluminum, and zinc, and the like, may be used.
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 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 pharmaceutically acceptable salt thereof has better control effect on gray mold of cucumber, sclerotinia rot of colza and banded sclerotial blight of rice.
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 procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts 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.
Example 1
(E) The preparation scheme for the preparation of the-3- (difluoromethyl) -1-methyl-N- (3 '- (phenoxymethyl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide is shown below:
reagents and conditions of (a) dichloromethane, N, N-dimethylformamide, at room temperature for 0.5 hours, (b) dichloromethane, pyridine, at 0 ℃ to room temperature for 1 hour, (C) 1, 4-dioxane, potassium carbonate, water, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, at 100 ℃, reflux, argon protection, (d) potassium carbonate, potassium iodide, acetonitrile, at 4 hours, at 60 ℃;
Specifically, the method comprises the following steps:
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, 20mL of methylene chloride 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 at room temperature were conducted, so that the reaction solution was seen to be clear from cloudy gradually, TLC was followed, and the reaction was terminated after 1 hour. Spin-drying the solvent gave intermediate 1, which was redissolved using 10mL of dichloromethane for further use.
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, 20mL of methylene chloride was added to dissolve, pyridine (1.277 g,16.06 mmol) was added, intermediate 1 obtained by one-step reaction was added dropwise with stirring at 0℃for 5min, the reaction was continued at room temperature after 15min, 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).
Intermediate 3[N- (3 '- (bromomethyl) - [1,1' -biphenyl ] -2-yl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide ]
A50 mL eggplant-shaped bottle was charged with the intermediate 2 (0.798 g,2.42 mmol) obtained in the previous reaction, 3- (bromomethyl) phenyl) boric acid (0.604 g,2.81 mmol) was charged, 10mL of 1, 4-dioxane was added, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.111 g,0.15 mmol) was charged, 10mL of an aqueous potassium carbonate solution (2M) was added, argon was used for protection, evacuation was performed for 30min, reflux reaction was stirred at 100℃and the reaction was followed by TLC, and after 1.5 hours, the reaction was completed. 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 on a dry method, column chromatographed 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) ,0.894g,87.99％).1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.70(s,1H),8.26(s,1H),7.91(s,1H),7.50(d,J＝10.0Hz,2H),7.48(s,1H),7.42(s,1H),7.32(s,1H),7.21(d,J＝29.0Hz,2H),4.98(s,2H),3.81(s,3H).
Compound I-217[ (E) -3- (difluoromethyl) -1-methyl-N- (3 '- (phenoxymethyl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ]
Into a 100mL eggplant-shaped bottle, intermediate 3 (0.882 g,2.1 mmol) was charged, 15mL of acetonitrile was added to dissolve, calcium carbonate (0.308 g,3.08 mmol) and potassium iodide (0.863 g,4.21 mmol) were added, and then an excess of phenol (0.3995 g,4.2 mmol) was slowly added to the reaction solution at 0℃under argon protection, vacuum was applied for 30min, the mixture was transferred to 60℃under stirring reflux, and the reaction was completed after 4 hours by TLC tracking. 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, gradient eluting petroleum ether-ethyl acetate=2:1 (V: V) →petroleum ether-ethyl acetate=2:1 (V: V), and spin-drying the solvent to obtain a compound I-217 (yellow solid) ,0.354g,38.93％).1H NMR(400MHz,DMSO-d6)δ8.83(s,4H),8.72(s,4H),8.23(s,4H),7.91(s,4H),7.57–7.51(m,11H),7.48(s,5H),7.33(s,9H),7.21(d,J＝18.5Hz,6H),7.10(s,8H),6.91(s,2H),5.14(s,8H),3.81(s,12H).
HRMS (ESI) M/z [ M+H ] +C25H21F2N3O2, calculated 433.1602, found 434.1601.
Example 2
[ 2-Chloro-N- (3 '- (phenoxymethyl) - [1,1' -biphenyl ] -2-yl) nicotinamide ] was prepared using a synthetic method similar to example 18, except that:
The 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylic acid starting material described in step (a) was 2-chloronicotinic acid.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.61(s,1H),8.48(s,1H),8.22(s,1H),7.90(d,J＝10.0Hz,2H),7.55(t,J＝12.5Hz,3H),7.48(s,1H),7.31(s,3H),7.22(s,1H),7.10(s,2H),6.92(s,1H),5.14(s,2H);HRMS(ESI)m/z[M+H]+C25H19ClN2O2,: 414.1135, found 415.1137.
Example 3
(E) -3- (difluoromethyl) -1-methyl-N- (4 '- (5-phenyl-1, 3, 4-oxadiazol-2-yl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] was prepared using a similar synthetic method to example 18, except that:
(3- (bromomethyl) phenyl) boronic acid in the step (c) is adopted as a raw material of (3-formylphenyl) boronic acid.
The phenol raw material in the step (d) adopts benzoyl hydrazine.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ8.94(s,4H),8.70(s,4H),8.22(s,4H),7.98(d,J＝10.0Hz,16H),7.61(s,11H),7.51(s,3H),7.32(s,5H),7.27–7.09(m,14H),3.82(s,12H);HRMS(ESI)m/z[M+H]+C26H19F2N5O2,: 471.1507, found 472.1509.
Example 4
[ 2-Chloro-N- (4 '- (5-phenyl-1, 3, 4-oxadiazol-2-yl) - [1,1' -biphenyl ] -2-yl) nicotinamide ] was prepared using a synthesis similar to example 18, except that:
The 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylic acid starting material described in step (a) was 2-chloronicotinic acid.
(3- (Bromomethyl) phenyl) boronic acid in the step (c) is adopted as a raw material of (3-formylphenyl) boronic acid.
The phenol raw material in the step (d) adopts benzoyl hydrazine.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.62(s,4H),8.57(d,J＝70.0Hz,8H),8.22(s,4H),7.97(d,J＝10.0Hz,17H),7.86(s,2H),7.62(s,11H),7.51(s,3H),7.31(s,4H),7.21(d,J＝15.0Hz,12H);HRMS(ESI)m/z[M+H]+C26H17ClN4O2,: 452.1040, found 453.1039.
Example 5
(E) -3- (difluoromethyl) -1-methyl-N- (4 '- (3-phenyl-1, 2, 4-thiadiazol-5-yl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] was prepared using a similar synthetic method to example 18, except:
(4-cyanophenyl) boronic acid was used as the starting material in the step (c) (3- (bromomethyl) phenyl) boronic acid.
The phenol raw material in the step (d) adopts thiobenzamide.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.70(s,1H),8.24(d,J＝20.0Hz,3H),7.93(s,2H),7.52(d,J＝10.0Hz,4H),7.33(s,1H),7.29–7.15(m,4H),3.81(s,3H).;HRMS(ESI)m/z[M+H]+C26H19F2N5OS,: 487.1278, found 488.1280.
Example 6
[ 2-Chloro-N- (4 '- (3-phenyl-1, 2, 4-thiadiazol-5-yl) - [1,1' -biphenyl ] -2-yl) nicotinamide ] was prepared using a synthetic method similar to example 18, except that:
The 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylic acid starting material described in step (a) was 2-chloronicotinic acid.
(4-Cyanophenyl) boronic acid was used as the starting material in the step (c) (3- (bromomethyl) phenyl) boronic acid.
The phenol raw material in the step (d) adopts thiobenzamide.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.37(s,27H),8.54(d,J＝70.0Hz,55H),8.31(s,1H),8.26(d,J＝20.0Hz,78H),7.95(s,52H),7.88(s,14H),7.50(d,J＝10.0Hz,99H),7.33(s,25H),7.21(d,J＝15.0Hz,80H);HRMS(ESI)m/z[M+H]+C26H17ClN4OS,: 468.0812, found 469.0811.
Example 7
(E) -3- (difluoromethyl) -1-methyl-N- (4 '- (3-phenyl-1, 2, 4-oxadiazol-5-yl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] was prepared using a similar synthetic method to example 18, except that:
The (3- (bromomethyl) phenyl) boronic acid material in the step (c) is 4-aminomethylphenylboronic acid.
The phenol raw material in the step (d) adopts benzaldehyde.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.01(s,4H),8.73(s,4H),8.22(s,4H),7.95(s,8H),7.85(s,7H),7.55–7.47(m,15H),7.32(s,5H),7.24(d,J＝15.0Hz,12H),7.11(s,2H),3.81(s,12H);HRMS(ESI)m/z[M+H]+C26H19F2N5O2,: 471.1507, found 472.1508.
Example 8
[ 2-Chloro-N- (4 '- (3-phenyl-1, 2, 4-oxadiazol-5-yl) - [1,1' -biphenyl ] -2-yl) nicotinamide ] was prepared using a synthesis similar to example 18, except that:
The 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylic acid starting material described in step (a) was 2-chloronicotinic acid.
The (3- (bromomethyl) phenyl) boronic acid material in the step (c) is 4-aminomethylphenylboronic acid.
The phenol raw material in the step (d) adopts benzaldehyde.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.43(s,2H),8.54(d,J＝70.0Hz,4H),8.24(s,2H),7.94(s,4H),7.86(d,J＝5.0Hz,5H),7.55–7.47(m,8H),7.32(s,2H),7.21(d,J＝15.0Hz,6H);HRMS(ESI)m/z[M+H]+C26H17ClN4O2,: 452.1040, found 453.1039.
Example 9
(E) -3- (difluoromethyl) -1-methyl-N- (3 '- ((phenoxyimino) methyl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide
The preparation was carried out in a similar manner to example 18, except that:
the aminophenylboronic acid material in step (c) is (3-formylphenyl) boronic acid.
The phenol raw material in the step (d) adopts o-phenylhydroxylamine (phenol and potassium tert-butoxide can be used for reacting for 0.5h in methanol solution, and DMF is used as solvent to react with 2,4, 6-trimethylbenzenesulfonyl hydroxylamine for 1h under the ice bath condition to obtain the o-phenylhydroxylamine)
In the final reaction step, intermediate 3 (0.817 g,2.3 mmol) was put into a 100mL eggplant-shaped bottle, a certain amount of water, 15mL of acetic acid and 15mlDMSO mmol were added into the bottle, then o-phenylenediamine (0.501 g,4.6 mmol) was slowly added into the reaction solution at 0 ℃, the reaction was stirred at room temperature and refluxed, TLC was followed, and the reaction was completed after 24 hours. The reaction solution was dried by spin, an appropriate amount of ethyl acetate was added, 3g of silica gel was added, and after mixing uniformly, dried by spin-drying, loading by dry method, silica gel column chromatography, petroleum ether→petroleum ether: ethyl acetate=2:1 (V: V) →petroleum ether: ethyl acetate=2:1 (V: V) gradient elution, and solvent was dried by spin-drying to give compound I-219 (white solid, 0.254 g, 28.66%).
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.01(s,5H),8.72(s,5H),8.30(s,5H),8.24(s,5H),7.85(d,J＝5.0Hz,10H),7.54(t,J＝12.5Hz,15H),7.32(s,6H),7.30–7.17(m,18H),6.81(d,J＝15.0Hz,15H),3.80(s,15H);HRMS(ESI)m/z[M+H]+C25H20F2N4O2,: 446.1554, found 447.1553.
Example 10
(E) -2-chloro-N- (3 '- ((phenoxyimino) methyl) - [1,1' -biphenyl ] -2-yl) nicotinamide ] was prepared using a synthesis similar to example 18, except that:
3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylic acid as described in step (a) using 2-chloronicotinic acid
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.61(s,1H),8.50(s,1H),8.29(s,1H),8.22(s,1H),7.92–7.80(m,3H),7.55(s,1H),7.51(d,J＝4.5Hz,2H),7.31(s,1H),7.22(d,J＝15.0Hz,3H),6.81(d,J＝15.0Hz,3H);HRMS(ESI)m/z[M+H]+C25H18ClN3O2,: 427.1088, found 428.1090.
Example 11
(E) -3- (difluoromethyl) -1-methyl-N- (4 '- (5-phenylthiophen-2-yl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide the preparation scheme is shown below:
Reagents and conditions of (a) dichloromethane, N, N-dimethylformamide, room temperature, 0.5 hours, (b) dichloromethane, pyridine, 0 ℃ to room temperature, 1 hour, (C) 1, 4-dioxane, potassium carbonate, water, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, 100 ℃, reflux, argon protection, (d) 1, 4-dioxane, potassium carbonate, water, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, 100 ℃, reflux, argon protection, (e) 1, 4-dioxane, potassium carbonate, water, [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride, 100 ℃, reflux, argon protection;
Specifically, the method comprises the following steps:
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, 20mL of methylene chloride 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 at room temperature were conducted, so that the reaction solution was seen to be clear from cloudy gradually, TLC was followed, and the reaction was terminated after 1 hour. Spin-drying the solvent gave intermediate 1, which was redissolved using 10mL of dichloromethane for further use.
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, 20mL of methylene chloride was added to dissolve, pyridine (1.277 g,16.06 mmol) was added, intermediate 1 obtained by one-step reaction was added dropwise with stirring at 0℃for 5min, the reaction was continued at room temperature after 15min, 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).
Intermediate 3[N- (4 '-bromo- [1,1' -biphenyl ] -2-yl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide ]
A50 mL eggplant-shaped bottle was charged with the intermediate 2 (0.798 g,2.42 mmol) obtained in the previous reaction, 4-bromophenyl) boric acid (0.607 g,3.02 mmol) was charged, 10mL of 1, 4-dioxane was added, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.111 g,0.15 mmol) was charged, 10mL of an aqueous potassium carbonate solution (2M) was added, argon was used for protection, evacuation was performed for 30min, reflux reaction was stirred at 100℃and the reaction was followed by TLC, and after 1.5 hours, the reaction was completed. 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 on a dry method, column chromatographed 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 (brown solid) ,0.765g,77.82％).1H NMR(400MHz,DMSO-d6)δ8.81(s,2H),8.72(s,2H),8.22(s,2H),7.56–7.48(m,9H),7.31(s,2H),7.15(d,J＝49.7Hz,3H),3.83(s,6H).
Intermediate 4[ (5-phenylthiophen-2-yl) boronic acid ]
A50 mL eggplant-shaped bottle was charged with (5-bromothiophen-2-yl) boric acid (0.621 g,3.00 mmol), bromobenzene (0.565 g,3.60 mmol) was further charged, 10mL of 1, 4-dioxane was added, and [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride (0.111 g,0.15 mmol) was charged, 10mL of an aqueous potassium carbonate solution (2M) was added, argon was used for protection, and the reaction was stirred and refluxed at 100℃for 30min under vacuum, followed by TLC and ended 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 on a dry method, column chromatographed on silica gel, gradient elution of petroleum ether→petroleum ether: ethyl acetate=1:1 (V: V) →petroleum ether: ethyl acetate=1:2 (V: V), dried with solvent to give intermediate 4 (white solid, 0.496g, 81.05%). 1H NMR(400MHz,DMSO-d6 ) Delta 7.80 (s, 5H), 7.45 (s, 8H), 7.32 (s, 3H), 1.73 (s, 6H).
Compound I-55[ (E) -3- (difluoromethyl) -1-methyl-N- (4 '- (5-phenylthiophen-2-yl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ]
Into a 100mL eggplant-shaped bottle, intermediate 3 (0.765 g,1.9 mmol) was charged, intermediate 4 (0.496 g,2.43 mmol) was further charged, 10mL of 1, 4-dioxane was added, and [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride (0.111 g,0.15 mmol) was charged, 10mL of an aqueous potassium carbonate solution (2M) was added, argon was used for protection, oxygen was removed by evacuation for 30min, reflux reaction was stirred at 100 ℃, TLC was followed, and the reaction was completed after 1.5 hours. The reaction solution is filtered by diatomite, washed by ethyl acetate, dried by spin-drying the solvent, adding proper amount of ethyl acetate, adding 3g of silica gel, uniformly mixing, then drying by spin-drying, loading by dry method, silica gel column chromatography, gradient elution of petroleum ether to petroleum ether ethyl acetate=1:1 (V: V) to petroleum ether ethyl acetate=1:2 (V: V), and drying the solvent by spin-drying to obtain the compound I-55 (white solid) ,0.526g,56.99％).1H NMR(400MHz,DMSO-d6)δ8.81(s,19H),8.72(s,19H),8.21(s,20H),7.86(d,J＝69.9Hz,73H),7.79–7.79(m,2H),7.47(d,J＝20.1Hz,73H),7.32(d,J＝10.0Hz,58H),7.26–7.16(m,66H),3.81(s,57H).
HRMS (ESI) M/z [ M+H ] +C28H21F2N3 OS calculated 485.1373, found 486.1371.
Example 12
[ 2-Chloro-N- (4 '- (4-phenylthiophen-2-yl) - [1,1' -biphenyl ] -2-yl) nicotinamide ] was prepared using a synthetic method similar to example 28, except that:
The 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylic acid starting material described in step (a) was 2-chloronicotinic acid.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.45(s,19H),8.55(d,J＝70.0Hz,39H),8.31(s,1H),8.22(s,20H),7.96(s,37H),7.86(s,10H),7.55(s,22H),7.51(d,J＝15.0Hz,54H),7.38(s,58H),7.31(d,J＝5.0Hz,31H),7.21(d,J＝15.0Hz,57H);HRMS(ESI)m/z[M+H]+C28H19ClN2OS,: 466.0907, found 467.0908.
Example 13
Preparation of [ (E) -3- (difluoromethyl) -1-methyl-N- (4 '- (5-phenyl-1, 3, 4-thiadiazol-2-yl) - [1,1' -biphenyl ] -2-yl) -1H-pyrazole-4-carboxamide ] using a similar synthetic method to example 28, except:
The reaction of (5-bromothiophen-2-yl) boronic acid with bromobenzene described in step (d) is replaced by the reaction of 4- (N, N-dimethylcarbamoyl) phenylboronic acid with phenylthioacid, hydrazide.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ8.79(s,2H),8.72(s,2H),8.25(s,2H),8.02(d,J＝4.2Hz,1H),7.97(d,J＝35.0Hz,7H),7.53(d,J＝5.0Hz,8H),7.33(s,2H),7.27–7.11(m,7H),3.81(s,6H);HRMS(ESI)m/z[M+H]+C26H19F2N5OS,: 487.1278, found 488.1276.
Example 14
[ 2-Chloro-N- (4 '- (5-phenyl-1, 3, 4-thiadiazol-2-yl) - [1,1' -biphenyl ] -2-yl) nicotinamide ] was prepared using a synthetic method similar to example 28, except that:
The 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylic acid starting material described in step (a) was 2-chloronicotinic acid.
The reaction of (5-bromothiophen-2-yl) boronic acid with bromobenzene described in step (d) is replaced by the reaction of 4- (N, N-dimethylcarbamoyl) phenylboronic acid with phenylthioacid, hydrazide.
The final test results were calculated as ：1H NMR(400MHz,DMSO-d6)δ9.73(s,10H),8.61(s,10H),8.47(s,10H),8.22(s,10H),8.17–8.05(m,2H),7.97(d,J＝35.0Hz,39H),7.87(s,5H),7.55(d,J＝5.0Hz,37H),7.31(s,9H),7.20(d,J＝15.0Hz,29H).;HRMS(ESI)m/z[M+H]+C26H17ClN4OS,: 468.0812, found 469.0813.
EXAMPLE 15 biological Activity assay
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) DEG C 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 a constant temperature cabinet at the temperature of (25+/-1) DEG C for 2 days.
The slant culture of Rhizoctonia solani is inoculated into potato dextrose agar solid medium (PDA) plate for activation, and the culture is carried out in an incubator at (25+ -1) °C for 2 days.
Determination of antibacterial Activity by hypha growth Rate method
Placing a sterile triangular flask containing 49mL of PDA culture medium in a microwave oven to melt the PDA, placing the flask in a constant-temperature oven to keep the temperature of the culture medium at 55-60 ℃, rapidly pouring 1mL of prepared drug-containing solution in a sterile workbench, fully and uniformly mixing, and respectively pouring the solution into 3 sterile culture dishes with the diameter of 9cm to prepare drug-containing plates, and cooling and solidifying.
The 1mL of the pre-formulated drug-containing solution included 0.5mL of drug-containing Dimethylsulfoxide (DMSO) solution and 0.5mL of 0.1% Tween 80 aqueous solution, wherein 0.5mL DMSO+0.5mL 0.1% Tween 80 aqueous solution was used as the blank.
Selecting plant pathogenic fungi with equivalent growth vigor (growth diameter is within 1 cm), perforating along the outer edge of colony growth to obtain plant pathogenic fungi cake (diameter is 5 mm), transferring the cake to circle center position of PDA plate prepared before by inoculating needle, sticking mycelium surface of the cake on PDA culture medium surface, and culturing the plates inoculated with different plant pathogenic fungi at 25+ -1deg.C or 21+ -1deg.C for 48-96 hr.
Colony growth diameter was measured by the crisscross method and inhibition was calculated using the following formula:
The results of preparing a list of compounds of formula (I) and their bacteriostatic activity (hypha growth inhibition rate for Sclerotinia sclerotiorum at 1ppm concentration, for Botrytis cinerea at 10ppm concentration and for Rhizoctonia solani at 1ppm concentration) are shown in the following tables 1 to 4:
S.S. represents Sclerotinia sclerotiorum (Sclerotinia sclerotiorum);
B.C. represents Botrytis cinerea;
R.S. represents Rhizoctonia solani (Rhizoctonia solani).
TABLE 1
The inhibition rate of the fluxapyroxad (1 mug/mL) to the sclerotinia sclerotiorum is 70-90%, the inhibition rate of the fluxapyroxad (10 mug/mL) to the cucumber botrytis cinerea is 50-60%, and the inhibition rate of the fluxapyroxad (1 mug/mL) to the rice sheath blight is 70-90%.
From the table data, it can be seen that the compounds of the present invention have an inhibitory effect on Rhizoctonia solani, sclerotinia sclerotiorum and Botrytis cinerea. Wherein, for the botrytis cinerea, most of the compounds have the biological activity basically equivalent to that of the fluxapyroxad, and the biological activity of part of the compounds is even better than that of the fluxapyroxad. For example, the inhibition rate of the compounds I-109 to I-125 in Table 1 against Botrytis cinerea is >70%.
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 (17)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111211881.8A CN113788790B (en) | 2021-10-18 | 2021-10-18 | Aromatic heterocyclic amide derivative and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111211881.8A CN113788790B (en) | 2021-10-18 | 2021-10-18 | Aromatic heterocyclic amide derivative and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113788790A CN113788790A (en) | 2021-12-14 |
| CN113788790B true CN113788790B (en) | 2025-02-18 |
Family
ID=78878128
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111211881.8A Active CN113788790B (en) | 2021-10-18 | 2021-10-18 | Aromatic heterocyclic amide derivative and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113788790B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397422A (en) * | 2016-08-29 | 2017-02-15 | 南京农业大学 | Nicotinamide compound containing chiral oxazoline and application of same as agricultural bactericide |
| CN109232469A (en) * | 2018-11-26 | 2019-01-18 | 南开大学 | A kind of three substituted thiazole amide derivatives and its preparation method and application |
| CN110372686A (en) * | 2018-04-13 | 2019-10-25 | 南京农业大学 | Adjacent (2- oxazoline group) aniline heterocyclic amides and the purposes as disinfectant use in agriculture |
| CN111087345A (en) * | 2019-12-27 | 2020-05-01 | 华东理工大学 | Azobenzene heterocyclic amide derivatives and preparation method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR086992A1 (en) * | 2011-06-20 | 2014-02-05 | Bayer Ip Gmbh | TIENILPIRI (MI) DINILPIRAZOLES |
| CN109422704A (en) * | 2018-11-26 | 2019-03-05 | 南开大学 | A kind of 4 substituted thiazole amide derivatives and its preparation method and application |
| CN110128346A (en) * | 2019-05-17 | 2019-08-16 | 南开大学 | A kind of biarylamide pyrazole derivatives and preparation method and use thereof |
| CN111393429A (en) * | 2020-04-21 | 2020-07-10 | 南开大学 | A class of isothiazole bioxadiazole biphenyl amide derivatives and their preparation method and use |
-
2021
- 2021-10-18 CN CN202111211881.8A patent/CN113788790B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397422A (en) * | 2016-08-29 | 2017-02-15 | 南京农业大学 | Nicotinamide compound containing chiral oxazoline and application of same as agricultural bactericide |
| CN110372686A (en) * | 2018-04-13 | 2019-10-25 | 南京农业大学 | Adjacent (2- oxazoline group) aniline heterocyclic amides and the purposes as disinfectant use in agriculture |
| CN109232469A (en) * | 2018-11-26 | 2019-01-18 | 南开大学 | A kind of three substituted thiazole amide derivatives and its preparation method and application |
| CN111087345A (en) * | 2019-12-27 | 2020-05-01 | 华东理工大学 | Azobenzene heterocyclic amide derivatives and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113788790A (en) | 2021-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100855652B1 (en) | Tetrazoyl oxime derivatives and pesticides containing the same as active ingredients | |
| KR101380139B1 (en) | Novel microbiocides | |
| JP5529044B2 (en) | Bactericidal heterocyclic compounds | |
| JP4936623B2 (en) | Fungicide | |
| KR100369753B1 (en) | Oxime derivatives and agricultural chemicals containing the same | |
| WO1996019442A1 (en) | Benzamidoxime derivative, process for production thereof, and agrohorticultural bactericide | |
| EA024512B1 (en) | Herbicidally and fungicidally active 3-phenylisoxazoline-5-carboxamides and 3-phenylisoxazoline-5-thioamides | |
| BRPI0709030B1 (en) | n-2- (hetero) arylethylcarboxamide derivative, pest controlling agent comprising the same, and method for controlling pests | |
| CN108069984B (en) | Substituted five-membered heterocyclic compound containing pyrimido ring and preparation method and application thereof | |
| CN111087345B (en) | Azobenzene heterocyclic amide derivative, and preparation method and application thereof | |
| JP2020531534A (en) | Microbial quinoline (thio) carboxamide derivative | |
| CN113788790B (en) | Aromatic heterocyclic amide derivative and its application | |
| CN115197131B (en) | Azo 2-aminonicotinic acid benzyl ester derivatives and preparation method and use thereof | |
| EP0889033A1 (en) | Alpha-substituted benzyl heterocyclic derivatives, intermediates for producing the same, and pesticides containing the same as active ingredient | |
| TW202317524A (en) | Formamide derivative and plant disease control agent for agriculture and horticulture | |
| TW568909B (en) | Cyanomethylene compound, process of producing the compound and agricultural or horticultural bactericide | |
| CN110396083B (en) | Pyridazinonyl-contained butenolide compound and application thereof | |
| CN111057024A (en) | Sydney ketone and Sydney ketone imine compound and preparation method and use thereof | |
| CN105777640B (en) | A kind of pyrazole cyclohexanediol ether compound and its application | |
| CN115232083B (en) | Substituted isoxazole ethylamine compounds and preparation method and use thereof | |
| WO2015040352A1 (en) | Agricultural chemicals | |
| JP2001172217A (en) | Ethylene derivative having acaricidal activity and germicidal activity | |
| US11440900B2 (en) | Agricultural chemicals | |
| JP3023607B2 (en) | Thiadiazole carboxamide derivatives, plant disease controlling agents and methods of using the same | |
| JP3593355B2 (en) | Antibacterial and antifungal agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |