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CN118221639A - N-substituted phenylpyrazole derivative and preparation and application thereof - Google Patents

N-substituted phenylpyrazole derivative and preparation and application thereof Download PDF

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Publication number
CN118221639A
CN118221639A CN202211646968.2A CN202211646968A CN118221639A CN 118221639 A CN118221639 A CN 118221639A CN 202211646968 A CN202211646968 A CN 202211646968A CN 118221639 A CN118221639 A CN 118221639A
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Prior art keywords
alkyl
alkoxy
halogenated
hydrogen
compound
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CN202211646968.2A
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Inventor
王传伟
张军
包如胜
陈伟健
陈健
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Shunyi Co ltd
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Shunyi Co ltd
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Priority to CN202211646968.2A priority Critical patent/CN118221639A/en
Priority to PCT/CN2023/138021 priority patent/WO2024131588A1/en
Publication of CN118221639A publication Critical patent/CN118221639A/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/34—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the groups, e.g. biuret; Thio analogues thereof; Urea-aldehyde condensation products
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/04—Insecticides

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  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Environmental Sciences (AREA)
  • Zoology (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Insects & Arthropods (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to an N-substituted phenylpyrazole derivative and application thereof. In particular, the present invention relates to compounds of formula (I) or isotopically-labelled compounds thereof, or optical isomers, geometric isomers, tautomers or mixtures of isomers thereof, or agropharmaceutically acceptable salts thereof, as N-substituted phenylpyrazole derivatives, and to the use of said compounds for the preparation of pesticides for pest control. The compound can achieve better pest control effect with lower dosage, and especially aims at pests of lepidoptera, coleoptera, homoptera, hemiptera, thysanoptera, isoptera, diptera, hymenoptera, phagostimula, lupulus, orthoptera, blattaria, flea, acarina, nematoda and the like.

Description

N-substituted phenylpyrazole derivative and preparation and application thereof
Technical Field
The invention belongs to the field of pesticides, and particularly relates to an N-substituted phenylpyrazole derivative and application thereof.
Background
The pesticide is important agricultural production data, is widely used for preventing and controlling plant diseases and insect pests in the fields of agriculture, forestry, sanitation and the like, and plays an important role in guaranteeing the safety of grains, the quality safety of agricultural products and the safety of ecological environment. Although many pesticides exist in the market, due to the continuous expansion of the market and the long-term use of some pesticides, serious environmental safety, pest resistance and other problems are brought, in addition, the economical efficiency of pesticide use and the environment-friendly requirement of pesticides require that research personnel continuously develop novel pesticides with high efficiency, safety, economy, environment protection and different action modes. The existing pesticide on the market has few varieties and gradually shows different degrees of resistance, so the characteristics of developing new pesticides and having no mutual resistance with other pesticides are at great expense, and the development of compounds with new action sites and the selection of pesticides with different action mechanisms are the best ways for solving the problems.
As researchers continue to develop and research, polyfluoro atom substituted compounds gradually enter the field of view of researchers, and patent application CN106103414A, CN105873908A, CN111050559a discloses the study of polyfluoro compounds, but the above-mentioned results of the study are still not satisfactory in terms of efficacy, durability, toxicity, etc.
Disclosure of Invention
The invention aims to provide a novel N-substituted phenylpyrazole compound, which can achieve better pest control effect with lower dosage, and particularly aims at pests such as lepidoptera, hemiptera, diptera or homoptera.
In a first aspect, the present invention provides a compound of formula (I) or an isotopically-labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or an agropharmaceutically acceptable salt thereof, as an N-substituted phenylpyrazole derivative,
Wherein,
W is-O-R 1 or-N-R 1(R2);
R 1、R2 is each independently hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-12 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl C 1-3 alkyl, C 3-8 heterocyclyl C 1-3 alkyl, aryl C 1-3 alkyl, haloaryl C 1-3 alkyl or haloc 3-8 heteroaryl C 1-3 alkyl; Or (b)
R 1、R2 and N connected with the R 1、R2 form ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered heterocyclic alkane containing C, N, O or S;
R 3 is hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxy, C 1-6 alkyl, halogenated C 1-C6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl, halogenated C 2-C6 alkenyl, C 2-6 alkynyl, halogenated C 2-C6 alkynyl, C 6-12 aryl or halogenated aryl;
r 4 is hydrogen, C 1-6 alkyl, -C (=O) -C 1-6 alkyl, -C 1-6 alkylene-C (=O) -C 1-6 alkyl, -C (=O) -OC 1-6 alkyl, -C 1-6 alkylene-C (=O) -O-C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-12 aryl, aryl-C 1-3 alkyl, or C 3-8 cycloalkyl C 1-3 alkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl;
n=0, 1, 2, 3, 4 or 5.
In one embodiment of the invention, wherein,
W is-O-R 1 or-N-R 1(R2);
r 1、R2 is each independently hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, Halogenated C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl, C 3-6 heteroaryl, C 3-8 cycloalkyl C 1-3 alkyl, C 3-6 heterocyclyl C 1-3 alkyl, aryl C 1-3 alkyl, haloaryl C 1-3 alkyl or haloc 3-6 heteroaryl C 1-3 alkyl; Or (b)
R 1、R2 and N connected with the R 1、R2 form quaternary, five-membered, six-membered or seven-membered heterocyclic alkane containing C, N, O or S;
R 3 is hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxy, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl;
R 4 is hydrogen, C 1-3 alkyl, -C (=O) -C 1-3 alkyl, -C 1-3 alkylene-C (=O) -C 1-3 alkyl, -C (=O) -OC 1-3 alkyl, -C 1-3 alkylene-C (=O) -O-C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl;
n＝0、1、2、3。
in another embodiment of the present invention, wherein,
W is-O-R 1 or-N-R 1(R2);
R 1、R2 is each independently hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 2-4 alkenyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 heterocyclyl, C 6-8 aryl; or (b)
R 1、R2 and N connected with the R 1、R2 form five-membered, six-membered or seven-membered heterocyclic alkane containing C, N, O;
R 3 is hydrogen, halogen, C 1-3 alkyl;
R 4 is hydrogen, C 1-3 alkyl, C 3-8 cycloalkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl;
n＝0、1、2。
In another preferred embodiment of the present invention, wherein,
W is-O-R 1 or-N-R 1(R2);
R 1、R2 is each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, monochloroethyl, dichloroethyl, monofluoromethyl, difluoromethyl, methoxy, ethoxy, ethylene, propylene, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, methylphenyl, ethylphenyl; or (b)
R 1、R2 and the N connected with the R 1、R2 form six-membered heterocyclic alkane containing C, N, O;
R 3 is hydrogen, C 1-3 alkyl;
R 4 is hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl;
n＝0、1、2。
For the sake of brevity, the "N-substituted phenylpyrazole derivative", "compound of formula (I)" or "compound of the invention" described hereinafter may also encompass any isotopically-labelled compound of formula (I), or an optical isomer, geometrical isomer, tautomer or mixture of isomers thereof, or an agropharmaceutically acceptable salt thereof.
The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may exist in either the R configuration or the S configuration, and thus the various isomers constituted are optical isomers. Optical isomers include all diastereoisomers, enantiomers, meso, racemates or mixtures thereof. For example, the optical isomers may be separated by chiral chromatography columns or by chiral synthesis.
The term "geometric isomer" means that when a double bond is present in a compound, the compound may exist as cis, trans, E and Z isomers. Geometric isomers include cis, trans, E, Z, or mixtures thereof.
The term "tautomer" refers to an isomer that results from the rapid movement of an atom in a molecule at two positions. Those skilled in the art will appreciate that: tautomers can be transformed into each other, and in a certain state, an equilibrium state may be reached and coexist.
Unless otherwise indicated, references herein to "N-substituted phenylpyrazole derivatives", "compounds of formula (I)" or "compounds of the invention" also encompass isotopically-labelled compounds in which any one of the atoms of the compound is replaced by an isotopic atom thereof. The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic number as, but a different atomic mass or mass number than, an atom typically found in nature.
Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, such as 2 H (D) and 3 H (T), isotopes of carbon, such as 11C、13 C and 14 C, isotopes of chlorine, such as 37 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15O、17 O and 18 O, and isotopes of sulfur, such as 35 S.
Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously used in a manner analogous to those described in the examples and preparations attached herein.
The compounds of formula (I) may exist in the form of pharmaceutically acceptable salts, for example, acid addition salts and/or base addition salts of the compounds of formula (I). As used herein, unless otherwise indicated, "pharmaceutically acceptable salts" include acid addition salts or base addition salts that may occur within the compounds of formula (I).
The agropharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexylamine sulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2- (4-hydroxybenzyl) benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, napthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts. Semi-salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts:Properties, selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing agropharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
To avoid ambiguity, definitions are given below for terms used herein. Unless otherwise indicated, the terms used herein have the following meanings.
The term "hydroxy" refers to-OH; the term "amino" refers to-NH 2; the term "nitro" refers to-NO 2; the term "cyano" refers to —cn; the term "phenoxy" refers to-O-Phe; and the term "benzyloxy" refers to-O-CH 2 -Phe.
As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.
As used herein, the term "each independently" means that when the number of substituents exceeds one, the substituents may be the same or different.
As used herein, the term "alkyl" refers to saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, the alkyl group has 1 to 8, or 1 to 6, or 1 to 3 carbon atoms. For example, the term "C 1-8 alkyl" refers to a straight or branched chain radical having 1 to 8 carbon atoms. The term "C 1-8 alkyl" includes the terms "C 1-6 alkyl", "C 1-C3 alkyl" and "C 1-C4 alkyl" in its definition. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R) -2-methylbutyl, (S) -2-methylbutyl, 3-methylbutyl, 2, 3-dimethylpropyl, 2, 3-dimethylbutyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.
As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). For example, the term "C 1-C6 haloalkyl" refers to a C 1-C6 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). As another example, the term "C 1-C4 haloalkyl" refers to a C 1-C4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom); the term "C 1-C3 haloalkyl" refers to a C 1-C3 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom); and the term "C 1-C2 haloalkyl" refers to a C 1-C2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). As yet another example, the term "C 1 haloalkyl" refers to a methyl group having 1, 2, or 3 halo substituents. Examples of haloalkyl groups include: CF 3、C2F5、CHF2、CH2F、CH2CF3、CH2 Cl, and the like.
As used herein, the term "N-membered heterocycloalkyl" refers to a heterocycloalkyl having m ring-forming carbon atoms and (N-m) ring-forming heteroatoms selected from O, S and N. For example, 4-7 membered heterocycloalkyl groups include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine, oxetane, thietane, azepane. Furthermore, heterocycloalkyl groups can be optionally substituted with one or more suitable substituents.
In this context, a range of numbers relating to the number of substituents, the number of carbon atoms, and the number of ring atoms represents a list of all integers within the range, and the range is merely a simplified representation. For example: "1-4 substituents" means 1, 2, 3 or 4 substituents; "3-8 ring atoms" means 3, 4, 5, 6, 7 or 8 ring atoms. Accordingly, a range of numbers relating to the number of substituents, the number of carbon atoms, the number of ring atoms also encompasses any one of its subranges, and each subrange is also considered disclosed herein.
The compounds of the present invention may be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those skilled in the art can refer to the synthetic routes of the specific compounds of the specific examples of the present invention, and appropriately adjust the reaction raw materials and reaction conditions to obtain synthetic methods of other compounds.
The present invention provides a process for the preparation of compounds of formula (I) as N-substituted phenylpyrazole derivatives:
The synthesis scheme I is as follows:
The target compound I can be prepared by a synthesis scheme I. The compound M and the compound N react under alkaline conditions to obtain the target compound I. Wherein Y is fluorine, chlorine, bromine or iodine.
The synthesis scheme II is as follows:
The target compound I' can be prepared by a second synthesis scheme. The compound A 1 reacts with C to obtain A 2;A2, and substitution reaction is carried out to obtain A 3; a3 is subjected to diazotization, reduction and ring closure to obtain A 4;A4, and the A 4;A4 reacts with a halogenating reagent to obtain T 1; the compound B 1 reacts with the compound D to obtain B 2;B2, and the B 2;B2 is subjected to a Suzuki coupling reaction with T1 through a one-pot method without further treatment to obtain T 2; then reacts with the compound N under alkaline condition to obtain the target compound I'. Wherein Y is fluorine, chlorine, bromine or iodine, and Z is bromine or iodine.
Wherein T 1 can also be prepared by the following route:
the compound E reacts with F to obtain A 3;A3, and the A 4;A4 reacts with a halogenating reagent to obtain T 1 through diazotization, reduction and ring closure; wherein Z is bromine or iodine.
In addition, the present invention also lists a number of exemplary compounds that have been synthesized, the specific group selections of which are shown in Table 1 below. It is to be understood that the scope of the present invention is not limited to the exemplary compounds listed in the following table, and that the selection of each group of the compounds in the following table 1 may be arbitrarily combined without particular limitation.
Table 1 in general formula I-1, w=or 1,n＝0,X1、X2、X3、X4、R1、R3、R4 is specifically shown in the following table.
In table 2 of formula I, w=or 1,n＝1,X1、X2、X3、X4、R1、R3、R4 is specifically shown in table 1.
In table 3 of formula I, w=or 1,n＝2,X1、X2、X3、X4、R1、R3、R4 is specifically shown in table 1.
In table 4 of formula I, w=or 1,n＝3,X1、X2、X3、X4、R1、R3、R4 is specifically shown in table 1.
Table 5 is shown in Table I-2 below as ,W＝NR1R2,n＝0,X1、X2、X3、X4、R1、R2、R3、R4.
,W＝NR1R2,n＝1,X1、X2、X3、X4、R1、R2、R3、R4 In Table 6 of the general formula I is shown in particular in Table 5.
,W＝NR1R2,n＝2,X1、X2、X3、X4、R1、R2、R3、R4 In Table 7 of the general formula I is shown in particular in Table 5.
,W＝NR1R2,n＝3,X1、X2、X3、X4、R1、R2、R3、R4 In Table 8 of the general formula I is shown in particular in Table 5.
In a second aspect, the present invention provides an insecticidal composition comprising a compound of formula (I) or an isotopically-labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or an agropharmaceutically acceptable salt thereof, and an agropharmaceutically acceptable carrier.
The agropharmaceutically acceptable carrier may be an organic or inorganic inert carrier material, for example, suitable carriers include water, gelatin, gum arabic, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, mannitol, cellulose derivatives, sodium saccharin, magnesium carbonate, saline, glycerol, ethanol and the like. In addition, the pesticide composition may contain other additives such as preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, lubricants, glidants and the like.
The dosage form of the pesticide composition of the present invention may be a liquid dosage form, a solid dosage form or a semisolid dosage form, without particular limitation. In some embodiments, the formulation of the pesticide composition is selected from the group consisting of powders, granules, liquids, suspensions or sprays, preferably wettable powders, wettable liquids, soluble powders, dispersible liquids, aqueous solutions, microemulsions, emulsifiable concentrates, aqueous emulsions, sprayable solutions, dispersible oil suspensions, microcapsule suspensions, water dispersible granules, water soluble granules, large granules, granules for broadcasting and soil application, aerosols, ultra low volume formulations and wax formulations.
The content of the compound of the present invention in the pesticidal composition thereof may be adjusted according to actual needs (e.g., dosage form, mode of administration, administration subject, etc.), including but not limited to, 0.001mg/L to 10mg/L, for example, 0.001mg/L, 0.01mg/L, 0.1mg/L, 0.5mg/L, 1mg/L, 2.5mg/L, 5mg/L, or 10mg/L.
The specific frequency of administration may be determined by one of skill in the relevant art, for example, 1 day 1,2 days 1, 3 days 1,4 days 1, 5 days 1, 6 days 1, 1 day 2, 1 day 3, etc.
In a third aspect, the present invention provides the use of a compound of formula (I) or an isotopically-labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or an agropharmaceutically acceptable salt thereof, in the manufacture of a pesticide for pest control.
The compounds according to the invention are suitable for controlling pests or mites, i.e. for controlling pests or mites, which are harmful or unwanted insects or mites, especially those encountered in agriculture, forestry, storage protection and material protection and in the hygiene sector, are active against generally sensitive and resistant species and are effective at all stages of pest or mite development.
The invention also relates to a method for controlling pests or mites, which comprises applying to the locus of the insect, to the locus of the pest, to the area to be protected, or directly onto the insect to be controlled a prophylactically effective amount of a compound of formula (I). The compounds of the invention may also be used to control other invertebrate pests or organisms.
In particular, the insect habitat, pest habitat or pest mite habitat refers to an environment in which insects, pests or pest mites live or their eggs are present, including air around them, food consumed, or objects contacted. For example, protection of plants against diseases caused by viruses, fungi or bacteria can be achieved by controlling insects or mites which eat, destroy or contact edible agricultural products, ornamental plants, turf, pasture plants or other plants of economic value by applying the active compounds to the seeds of the plants (before planting), to the seedlings, or to the cuttings, leaves, stems, fruits, grains and/or roots of the plants, or to the soil or other growing medium (before or after planting of the crops), or by controlling sap-feeding pests such as whiteflies, planthoppers, aphids and the like or mites such as tetranychus urticae, tetranychus cinnabarinus and the like; the plants include plants propagated by conventional methods, as well as plants having insect or pest resistance, herbicide resistance, high yield, and/or other beneficial traits by modern biotechnology altering genes. It is contemplated that these compounds can be used to protect fabrics, paper, stored grains, seeds and other food, house, building and other items and/or sites by applying the compounds of the present invention to or near these objects.
The inventors of the present invention have found that even when the compounds of the present invention are applied in lower doses, they are equally capable of controlling animal pests, in particular insects, arachnids, worms, nematodes and molluscs, encountered in the field of agriculture, horticulture, livestock rearing, aquaculture, forestry, gardening and leisure facilities, the protection of stored products and materials and hygiene. These compounds are preferably used as pesticides. They are effective against normally sensitive and resistant species, and against all or part of the developmental stage. The above pests include:
Pests from the phylum arthropoda (Arthropoda), in particular from the arachnidae class (ARACHNIDA), for example the genus pinus (Acarus siro), the genus matrimony goiter (Aceria kuko), the genus citrus goiter (Aceriasheldoni)), the genus acanthopodium (Aculops spp.), the genus acanthopodium (Aculus spp.) (for example the genus fagoiter (Aculus fockeui), the genus apple goiter (Aculus schlechtendali)), the genus huperzia (amblyroma spp.)), the genus hawkthorn spider (Amphitetranychus viennensis), the genus sharp-edged ticks (Argas spp.), the genus boophulusspp.), the genus shorthand mites (Brevipalpus p.) (for example the genus rhodobryodes (Brevipalpus phoenicis)), the genus aphis (Bryobia graminum), the genus alfalfa spp.) (Bryobia praetiosa), the genus spiny (Centruroides spp.), the genus football (Chorioptes spp.)), the genus chicken mites (Dermanyssus gallinae), the genus house mites (Dermatophagoides pteronyssinus), the genus dust (Dermatophagoides farinae), the genus of the genus tetranychus (62 spp.);
Pests from Coleoptera (Coleoptera), e.g., striped beetle (), phaseolus, coralloides (spp.), leaf beetle (), click beetle (spp.) (e.g., straight click beetle (), black beetle (), june beetle (), furniture beetle (), star beetle (spp.)), flower beetle (Anthonius spp.) (e.g., cotton boll-shaped beetle (), pinus (spp.)), pear beetle (spp.)), sugarcane beetle (spp.)), saphenous (spp.) (e.g., beet saphenous, fur beetle (spp.), oxa bean (Bruchus spp.) (e.g., pea beetle (), silkworm beetle (), beetle (spp.)), sweet potato beetle (e.g., sph.)), sweet potato beetle (spp.)), sweet potato beetle (e.g., sph.)), beetle (spp.)), sweet potato beetle (e.g., beetle (spp.)), beetle (c.)), beetle (p.)), beetle (e., root neck elephant (Cosmopolites spp.) (e.g., banana black elephant (Cosmopolitessordidus));
Pests from Diptera (Diptera), such as Aedes (Aedes spp.) (e.g., aedes aegypti (AEDESAEGYPTI), aedes albopictus (Aedes albopictus), aedes albopictus (Aedes sticticus), aedes aegypti (Aedesvexans)), liriomyza (Agromyza spp.) (e.g., liriomyza sativae (Agromyza frontella), liriomyza sativae (Agromyza parvicornis)), bactrocera (Agromyza parvicornis spp.)), anopheles (Anopheles spp.) (e.g., anopheles tetranychus (Agromyza parvicornis), anopheles gambiae (Agromyza parvicornis spp.)), fruit fly (Agromyza parvicornis spp.) (e.g., melon fly (Agromyza parvicornis), fruit fly (Agromyza parvicornis), olive fruit (Agromyza parvicornis)), garden 2 (Agromyza parvicornis), colored fly (Agromyza parvicornis), red head fly (Agromyza parvicornis), tsetse (Agromyza parvicornis), midrange (Agromyza parvicornis), midlet (Agromyza parvicornis spp.), tsetse (Agromyza parvicornis), agromyza parvicornis spp (Agromyza parvicornis, and brassica (Agromyza parvicornis spp.) (Agromyza parvicornis, and brassica spp. (Agromyza parvicornis).
Pests from heteroptera (Heteroptera), for example, cucurbita moschata (ANASA TRISTIS), lygus (Antestiopsis spp.), boisea spp, lygus (Blissus spp.), lygus (calocorisspp.), lygus (Campylomma livida), lygus (Cavelerius spp.), bed bugs (cimex spp.) (e.g., cimex adjunctus, tropical bugs (Cimex hemipterus), temperature zone bugs (Cimexlectularius), hepials (Cimex pilosellus)), white-leaf mais (Collaria spp.)), creontiades dilutus, piper (Dasynus piperis), dichelops furcatus, lygus thickii (Diconocoris hewetti), lygus (Dysdercus spp.), stinkbugs (eucyslus spp.);
Pests from homoptera (Homoptera), such as Acizzia acaciaebaileyanae, acizziadodonaeae, psyllid (Acizzia uncatoides), locusta longhead (Acrida turrita), eustachys (Acyrthosipon spp.) (such as pisum sativum (Acyrthosiphon pisum)), acrogonia spp, aeneolamia spp., long Maimu lupin (Agonoscena spp.), cerzus verniciosa (Aleyrodesproletella), kefir point whitefly (Aleurolobus barodensis), bemisia gossypii (Aleurothrixusfloccosus), plant-on-fimbriae (Allocaridara malayensis), mangifer leaf hopper (Amrasca spp.) (such as leafhopper (Amrasca bigutulla), leafhopper (AMRASCA DEVASTANS)), myzus persicae (Anuraphiscardui), pymetrozine (Aonidiella spp.) (such as red green aphid (Aonidiella aurantii), huang Shen pygee (Aonidiella citrina), su Tieshen pygee (Aonidiella inornata)), piroma (Aphanostigma piri), aphid (Aphis) (such as black bean aphid (Aphis craccivora), beet aphid (Aphisfabae), strawberry root (Aphis forbesi), cotton plant-on (AMRASCA DEVASTANS), green plant-on-seed aphid (APHIS GLYCINES), and green pepper (APHIS GLYCINES, APHIS GLYCINES;
Pests from Hymenoptera (Hymenoptera), for example, genus phyllotreta (Acromyrmex spp.), genus cercospora (Athalia spp.) (for example, cercospora flavescens (Athalia rosae)), genus phyllotreta (Atta spp.)), genus pinus (Diprion spp.) (for example, legendria pinnatifida (Diprion similis)), genus phyllotreta (Hoplocampa spp.) (for example, hoplocampa cookei, melissa (Hoplocampa testudinea)), genus Mao Yi (Lasius spp.);
Pests from the order of isoptera (Isoptera), such as, for example, coptermes spp (e.g., taiwan termites Coptotermes formosanus), termite horn (Cornitermes cumulans), termite sand (Cryptotermes spp), termite jacaragonium (incosittermes spp), termite oryzates Microtermesobesi, termite terra Odontotermes spp, termite bulk (reticlermes spp), termite Huang Zhisan (Reticulitermes flavipes), termite us (Reticulitermes hesperus);
Pests from Lepidoptera (Lepidoptera), such as, for example, cercospora spinosa (Achroia grisella), sang Jianwen noctuid (Acronicta major), brown stripe moth (Adoxophyes spp.) (such as, for example, cotton brown stripe moth (Adoxophyesorana)), spodoptera exigua (Aedia leucomelas), agrotis (Agrotis sp.) (such as, for example, yellow land tiger (Agrotissegetum), agrotis ypsilon)), helicoverpa (alabaca spp.) (such as, for example, cotton leaf helicoverpa (Alabama argillacea)), navel orange moth (Amyelois transitella), leaf moth (Anarsia spp.), dry land noctuid (Anticarsia spp.) (such as, for example, soybean noctuid (ANTICARSIA GEMMATALIS)), leaf roller (Argyroploce spp)), cabbage looper (2), indica (Barathra brassicae), pine moth (2), brown moth (Barathra brassicae), brown moth (bustep)), cotton leaf roller (Barathra brassicae), apple moth (Barathra brassicae), fruit moth (Barathra brassicae), and other such as, for example, cotton leaf moth (Barathra brassicae ) and other such as, for example, cotton moth (Barathra brassicae ) are described above;
Pests from the order orthoptera (Orthoptera) or the order hopped (Saltatoria), for example, house cricket (Achetadomesticus), dichroplus spp., mole cricket (Gryllotalpa spp.) (e.g., mole cricket (Gryllotalpagryllotalpa)), sugarcane locust (Hieroglyphus spp.)), migratory locust (Locusta spp.) (e.g., migratory locust (Locustamigratoria)), black locust (Melanoplus spp.) (e.g., melanoplus devastator), desert locust (Schistocerca gregaria);
Pests from the order of the lice (PHTHIRAPTERA), for example, pediculus (DAMALINIA spp.), pediculus (Haematopinus spp.), pediculus (Linognathus spp.), pediculus (Pediculus spp.), rhizobium japonicum (Phylloxera vastatrix), pediculus pubescens (Ptirus pubis), pediculus (Trichodectes spp.);
Pests from the order Thysanoptera (Thysanoptera), for example, maize Thrips flavus (Anaphothripsobscurus), rice Thrips (Baliothrips biformis), fusarium vitis (Drepanothris reuteri), enneothrips flavens, frankliniella spp.) (for example, tabaci (Frankliniellafusca), frankliniella occidentalis (FRANKLINIELLA OCCIDENTALIS), thresh Thrips (Frankliniellaschultzei), frankliniella occidentalis (FRANKLINIELLA TRITICI), bilberry Thrips (FRANKLINIELLAVACCINII), frankliniella occidentalis (FRANKLINIELLA WILLIAMSI)), male Thrips (Heliothrips spp.), greenhouse Thrips (Hercinothrips femoralis), grape Thrips (Rhipiphorothrips cruentatus), hard Thrips (Scirtothrips spp.), small bean Thrips (Taeniothrips cardamoni), thrips (threps spp.) (for example, palmi Thrips (THRIPS PALMI), tabaci (threps tabaci)));
Plant pests from the phylum nematophaga (Nematoda), i.e. plant parasitic nematodes, in particular field aphelenchus (Aglenchus spp.) (e.g. caenorhabditis elegans (Aglenchus agricola)), granuliform (anguinaspp.) (e.g. wheat kernel nematodes (Anguina triciti)), aphelenchus (Aphelenchoides spp.) (e.g. peanut aphelenchus (Aphelenchoides arachidis), strawberry aphelenchus (Aphelenchoides fragariae)), echinococcus (Belonolaimus spp.) (e.g. spinosa (Belonolaimus gracilis), spinetoceros (Belonolaimus longicaudatus), norgestis (Belonolaimus nortoni)), caenorhabditis (Bursaphelenchus spp.) (e.g. caenorhabditis elenchus (Bursaphelenchus cocophilus), caenorhabditis (Bursaphelenchus eremus), pine wood nematodes (Bursaphelenchus xylophilus));
In another preferred embodiment of the present invention, the pest may be selected from the group consisting of plutella xylostella, armyworm, spodoptera frugiperda, asian corn borer.
Those skilled in the art will appreciate that the definitions and preferences described in one aspect of the invention apply equally to other aspects. It will be apparent to those skilled in the art that embodiments of the various aspects of the invention may be combined in various ways without departing from the subject matter and concepts of the invention, and such combinations are included within the scope of the invention.
Detailed Description
The compounds of formula (I) according to the invention can be synthesized by a number of methods familiar to those skilled in the art of organic synthesis. Some exemplary synthetic methods for compounds of formula (I) are given in the following specific examples, which are well known in the art of synthetic chemistry. Obviously, referring to the exemplary schemes in this patent, one skilled in the art can readily design synthetic routes for other compounds of formula (I) by appropriate adjustments of reactants, reaction conditions, and protecting groups.
The invention is further illustrated by the following examples; but these examples do not limit the scope of the invention. All reactants used in each example were obtained commercially unless otherwise stated; the instruments and equipment used in the synthesis experiments and the product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.
Specifically, the test conditions for the nuclear magnetic resonance hydrogen spectrum used in the examples are: at room temperature, a Bruker (Bruker) 400MHz or 600MHz nuclear magnetic resonance apparatus was used with CDCl 3,d6-DMSO,CD3 OD or d 6 -acetone as solvents (reported in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks occur, the following abbreviations will be used: s (singlet ), d (doublet, doublet), t (triplet ), q (quartet, quartet), m (multiplet ), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constant J, in units of hertz (Hz).
The mass spectrometry methods used in the examples were: agilent 1260HPLC was used; agilent 6120ESI.
Phase A: acetonitrile (0.1% formic acid); and B phase: water (0.1% formic acid).
Gradient elution: 0-2min,80-5% B;2-6min,5% B.
Flow rate: 0.6ml/min.
Detection wavelength: 254nm.
MS parameters: ESI is scanning, collision induced ionization: 70V.
And (3) drying nitrogen: 12L/min, atomization gas pressure: 40psi, gas temperature: 350 ℃.
And (3) taking a proper amount of sample, dissolving the sample in 0.5mL of methanol, and sampling, and performing primary MS full scanning under a positive ESI mode to obtain the reading of the excimer ion peak [ M+1] +.
The following abbreviations are used throughout the present invention:
i-PrOH: isopropyl alcohol
DIPEA: n, N-diisopropylethylamine
DMSO: dimethyl sulfoxide;
DMF: n, N-dimethylformamide
THF: tetrahydrofuran (THF)
NBS: n-bromosuccinimide
NIS: n-iodosuccinimide
NaHCO3: sodium bicarbonate
K2CO3: potassium carbonate
H2O water
NaH: sodium hydride
NaOH: sodium hydroxide
NaSO4: sodium sulfate
CataCXium A-Pd-G2-chloro [ (n-butylbis (1-adamantyl) phosphine) -2- (2-aminobiphenyl) ] palladium (II)
Pd (Ph 3P) 4-tetrakis (triphenylphosphine) palladium
G: g; mg: milligrams; mol: moles; mmol: millimoles; m: mol/L, mol/L; mL: milliliters; h: hours; min: and (3) minutes.
"RT", "room temperature" means a temperature of about 0deg.C to about 40deg.C or about 20deg.C to about 30deg.C or about 23deg.C to about 28deg.C or about 25deg.C. In the context of the present invention, all numbers disclosed herein are approximate, whether or not the word "about" or "about" is used.
The following synthetic schemes describe the steps for preparing the disclosed compounds. Wherein R 1、R2、R3、R4、X1、X2、X3、X4 and n have the meanings described in the present invention.
Intermediate T 1: synthesis of 1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -4-iodo-1H-pyrazole
Step 1: synthesis of 2, 6-dichloro-4- (perfluoropropan-2-yl) aniline
2, 6-Dichloroaniline (64.8 g,0.4 mol) and 500ml of ethyl acetate+500 ml of water were placed in a 2L reaction flask, tetrabutylammonium bisulfate (13.6 g,40 mmol), sodium dithionite (69.6 g,0.4 mol) were added in this order while stirring, then a mixture of heptafluoroisopropyl iodide (130.24 g,0.44 mol) and 100ml of ethyl acetate was slowly added dropwise over 60min while maintaining the pH between 6 and 7 by dropwise addition of a 40% K 2CO3 solution, and after completion, the reaction was stirred at RT. After 6h, the reaction was completed, left to stand for delamination, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, washed with saturated NaCl solution and 2.5% HCl solution, dried over sodium sulfate, and suction-filtered and rotary-distilled to obtain the product. 63.2g of red liquid was obtained in yield: 48%. LC-MS (M+1) M/z= 331.0.
Step 2: synthesis of 1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazole
2, 6-Dichloro-4- (perfluoropropan-2-yl) aniline (22.4 g,68 mmol) and 150ml glacial acetic acid, 75ml 50% strength by mass sulfuric acid are placed in a 1000ml four-necked flask, and a solution of sodium nitrite (5.4 g,78.2 mmol) in 10ml water is slowly added over 30min at 0-5 ℃. After the addition was complete, the reaction mixture was stirred at this temperature for 15min, then ascorbic acid (14.0 g,78.2 mmol) was added in one portion. The reaction mixture was warmed to room temperature over 2h, then heated to 65℃and 1, 3-tetramethoxypropane (11.3 g,68 mmol) was added at this temperature. The reaction was stirred at this temperature for a further 5h. After the reaction was completed, cooled to room temperature, diluted with 250ml of water, the mixture was extracted 2 times with 200ml of ethyl acetate, the combined organic phases were washed with 150ml of 10% by mass aqueous NaOH, the organic phases were dried over NaSO 4, filtered off with suction, and the solvent was removed by rotary evaporation under reduced pressure to give 21.5g of a red oil, yield: 83%. LC-MS (M+1) M/z= 381.1.
Step 3: synthesis of 1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -4-iodo-1H-pyrazole
1- (2, 6-Dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazole (38.1 g,0.1 mol) and 200ml of acetonitrile were placed in a 500ml reaction flask, NIS (24.8 g,0.11 mol) was added in portions with stirring, and the mixture was stirred at RT for 30 minutes, and then heated to 90℃with reflux and stirring for 6 hours. After the reaction is completed, cooling to room temperature, adding water for quenching, extracting 200ml by ethyl acetate for 3 times, combining organic phases, washing with water, saturated saline water, drying by sodium sulfate, and carrying out suction filtration and rotary evaporation to obtain a product. Repeatedly washing with n-hexane and purifying by passing through the sand core funnel paved with silica gel. 45.0g of red liquid was obtained, yield: 89%. LC-MS (M+1) M/z= 507.2.
Intermediate T 2: synthesis of 2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide
Step 1: synthesis of 5-bromo-2-chloro-N-cyclopropylnicotinamide
5-Bromo-2-chloronicotinic acid (118 g,0.5 mol) and 300ml toluene were placed in a 1000ml reaction flask, and thionyl chloride (59.5 g,5 mol) was slowly added with stirring, followed by 2ml DMF for catalysis. After the completion, the temperature is raised to 80 ℃ for reflux reaction for 2 hours. After the reaction is finished, cooling to room temperature, and removing the solvent and unreacted substances by rotary evaporation under reduced pressure to obtain the acyl chloride for standby.
Cyclopropylamine (34.2 g,0.6 mol) and 800ml of methylene chloride were placed in a 2000ml reaction flask, triethylamine (60.6 g,0.6 mol) was added under stirring under ice-bath conditions, then the acid chloride obtained in the above step was slowly added dropwise, and after completion, the reaction was stirred at RT overnight. After 12h, the reaction was completed, 500ml of water was added, and stirred, and the mixture was allowed to stand for delamination, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, and the solvent was removed by rotary evaporation to obtain 128g of a white solid, yield: 93%.
LC-MS:(M+1)m/z＝275.1。
Step 2: 2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl)
Synthesis of nicotinamide
5-Bromo-2-chloro-N-cyclopropylnicotinamide (1.65G, 6 mmol) and 30ml i-PrOH were placed in a 100ml reaction flask, tetrahydroxydiborane (1.1G, 12 mmol), DIPEA (2.33G, 18 mmol), cataCXium A-Pd-G2 (10% mmol) were added in sequence, the nitrogen was evacuated for 3 times, reacted for 6h at 65℃after which the TLC monitored the reaction to completion, and cooled to room temperature.
1- (2, 6-Dichloro-4- (perfluoropropan-2-yl) phenyl) -4-iodo-1H-pyrazole (3.04 g,6 mmol), potassium carbonate (2.49 g,18 mmol), H2O (8 mL), pd (Ph 3P) 4 (10% mmol), evacuated for 3 times, reacted overnight at 80℃after completion of the TLC monitoring reaction, dichloromethane extraction 3 times, anhydrous sodium sulfate drying, filtration, concentration under reduced pressure, flash column chromatography purification gave 2.07g of pale yellow solid, yield: 60%.
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.28(s,1H),8.16(s,1H),7.96(s,1H),7.75(s,2H),6.75(s,1H),3.01–2.90(m,1H),0.91–0.78(m,2H),0.75–0.58(m,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝575.1。
EXAMPLE 1 Synthesis of methyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compound 1-1 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, methyl chloroformate (0.14 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.37g, yield: 85%).
1H NMR(400MHz,Chloroform-d)δ8.54(s,1H),8.06(s,1H),7.85(s,1H),7.75(s,1H),7.66(s,2H),4.10(s,3H),2.75(s,1H),1.11(d,J＝7.7Hz,2H),0.80(d,J＝6.1Hz,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝633.1。
Example 22 Synthesis of isopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-6 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, isopropyl chloroformate (0.17 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.33g, yield: 71%).
1H NMR(400MHz,Chloroform-d)δ8.83(d,J＝2.5Hz,1H),8.64(d,J＝2.4Hz,1H),8.53(s,1H),8.22(d,J＝2.4Hz,1H),8.11(s,2H),4.77(td,J＝6.3,1.4Hz,1H),2.78(ddt,J＝13.5,7.3,3.5Hz,1H),1.04(dd,J＝6.2,2.3Hz,6H),0.76(dt,J＝7.5,2.6Hz,4H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝661.0。
Example 3 Synthesis of butyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-7 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, butyl chloroformate (0.19 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.38g, yield: 81%).
1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),8.13(s,1H),7.92(s,1H),7.83(s,1H),7.75(s,2H),4.11(d,J＝6.3Hz,2H),2.83(dt,J＝7.1,3.6Hz,1H),1.41(s,2H),1.30(d,J＝8.0Hz,2H),1.14(d,J＝7.0Hz,3H),0.94(d,J＝10.5Hz,2H),0.89(t,J＝7.5Hz,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝675.1。
Example 42 Synthesis of chloroethyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-14 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, and after 30min 2-chloroethyl chloroformate (0.20 g,1.4 mmol) was slowly added and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.25g, yield: 52%).
1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.62(d,J＝2.4Hz,1H),8.52(s,1H),8.21(d,J＝2.4Hz,1H),8.11(s,2H),3.96–3.80(m,2H),3.75(dd,J＝6.0,3.9Hz,2H),2.84(dd,J＝7.1,3.4Hz,1H),1.12–0.95(m,2H),0.90–0.64(m,2H).
19F NMR(376MHz,DMSO-d6)δ-75.02,-180.69.
LC-MS:(M+1)m/z＝681.0。
EXAMPLE 5 Synthesis of allyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-23 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, allyl chloroformate (0.17 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.34g, yield: 73%).
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.15(s,1H),7.94(s,1H),7.88(d,J＝2.5Hz,1H),7.76(s,2H),6.10–5.74(m,1H),5.39(d,J＝17.1Hz,1H),5.31(dd,J＝10.4,1.4Hz,1H),4.71(dt,J＝5.9,1.5Hz,2H),3.05–2.86(m,1H),1.04–0.73(m,4H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝659.2。
Example 62 Synthesis of methoxyethyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-29 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 30ml DMF were placed in a 100ml reaction flask, potassium carbonate (0.29 g,2.1 mmol) was then added, ethyl 2-methoxychloroformate (0.19 g,1.4 mmol) was then slowly added and the reaction was stirred at 80℃overnight after completion. After 12h the reaction was completed, cooled to room temperature, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x3 times), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.36g, yield: 73%).
1H NMR(400MHz,CDCl3)δ8.61(d,J＝2.4Hz,1H),7.98(s,1H),7.77(d,J＝2.4Hz,1H),7.29(t,J＝7.9Hz,1H),7.11(s,2H),4.26–4.21(m,2H),3.68–3.59(m,2H),3.45(s,3H),2.84–2.82(m,1H),1.01–0.84(m,1H),0.61–0.49(m,3H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝677.0。
EXAMPLE 7 Synthesis of cyclopentyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-39 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 30ml DMF were placed in a 100ml reaction flask, potassium carbonate (0.29 g,2.1 mmol) was then added, and then cyclopentyl chloroformate (0.21 g,1.4 mmol) was slowly added, and the reaction was stirred at 80℃overnight after completion. After 12h the reaction was completed, cooled to room temperature, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.36g, yield: 60%).
1H NMR(400MHz,CDCl3)δ8.75(d,J＝2.4Hz,1H),7.86(s,1H),7.75(d,J＝2.4Hz,1H),7.21(s,1H),6.98(d,J＝8.6Hz,2H),4.65–4.63(m,1H),2.95–2.80(m,1H),2.84–2.82(m,4H),2.01–1.95(m,4H),0.92–0.84(m,2H),0.60–0.49(m,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝687.1。
EXAMPLE 8 Synthesis of phenyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-41 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 30ml DMF were placed in a 100ml reaction flask, potassium carbonate (0.29 g,2.1 mmol) was then added, phenyl chloroformate (0.20 g,1.4 mmol) was then slowly added and the reaction was stirred at 80℃overnight. After 12h the reaction was completed, cooled to room temperature, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.42g, yield: 86%).
1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.69(s,1H),8.52(s,1H),8.23(d,J＝2.4Hz,1H),8.11(s,2H),7.39–7.32(m,2H),7.18(dt,J＝6.7,1.3Hz,2H),6.99–6.86(m,1H),2.94–2.90(m,1H),1.14–0.93(m,2H),0.88–0.72(m,2H).
19F NMR(376MHz,DMSO-d6)δ-75.02,-180.69.
LC-MS:(M+1)m/z＝695.2。
EXAMPLE 9 Synthesis of benzyl (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) (cyclopropyl) carbamate (corresponding to Compounds 1-42 of Table 1)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 30ml DMF were placed in a 100ml reaction flask, potassium carbonate (0.29 g,2.1 mmol) was then added, benzyl chloroformate (0.24 g,1.4 mmol) was then slowly added and the reaction was stirred at 80℃overnight. After 12h the reaction was completed, cooled to room temperature, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.36g, yield: 73%).
1H NMR(400MHz,DMSO-d6)δ8.61(d,J＝2.4Hz,1H),8.16(s,1H),7.98(s,1H),7.80–7.70(m,1H),7.68(d,J＝9.0Hz,2H),7.32(d,J＝8.9Hz,2H),7.10(d,J＝9.0Hz,2H),6.98(d,J＝8.9Hz,1H),5.15(s,2H),2.86–2.80(m,1H),1.03–0.82(m,2H),0.62–0.46(m,2H).
19F NMR(376MHz,DMSO-d6)δ-75.02,-180.69.
LC-MS:(M+1)m/z＝709.1。
Example 10 Synthesis of methyl N- (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) -N-cyclopropylglycine (corresponding to Compound 2-1 of Table 2)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, methyl chloroacetate (0.15 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.22g, yield: 49%).
1H NMR(400MHz,Chloroform-d)δ8.66(s,1H),8.16(s,1H),7.95(s,1H),7.89(s,1H),7.76(s,2H),3.82(s,3H),3.80–3.62(m,2H),3.04–2.74(m,1H),1.36–1.19(m,2H),0.84(d,J＝6.9Hz,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝647.1。
EXAMPLE 11 Synthesis of isopropyl N- (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) -N-cyclopropylglycine (corresponding to Compounds 2-6 of Table 2)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, isopropyl chloroacetate (0.19 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.22g, yield: 44%).
1H NMR(400MHz,Chloroform-d)δ8.66(s,1H),8.16(s,1H),7.95(s,1H),7.89(s,1H),7.76(s,2H),5.12(td,J＝6.3,3.9Hz,2H),4.16–4.05(m,1H),2.95(s,1H),1.31(dd,J＝6.2,3.9Hz,6H),1.05–0.76(m,4H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝676.1。
EXAMPLE 12 Synthesis of allyl N- (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) -N-cyclopropylglycine (corresponding to Compounds 2-23 of Table 2)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, propylene chloroacetate (0.18 g,1.4 mmol) was slowly added after 30min, and the reaction was stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.18g, yield: 38%).
1H NMR(400MHz,DMSO-d6)δ8.88(d,J＝4.7Hz,1H),8.69(s,1H),8.56(d,J＝3.9Hz,1H),8.22(d,J＝3.8Hz,1H),8.12(t,J＝2.7Hz,2H),5.96(ddt,J＝16.3,10.5,4.7Hz,1H),5.38(d,J＝17.5Hz,1H),5.26(d,J＝11.3Hz,1H),4.67(d,J＝5.2Hz,2H),4.49–4.19(m,2H),2.91(s,1H),0.63(d,J＝15.5Hz,2H),0.53(d,J＝6.9Hz,2H).
19F NMR(376MHz,DMSO-d6)δ-74.61,-181.18.
LC-MS:(M+1)m/z＝673.1
EXAMPLE 13 Synthesis of benzyl N- (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) -N-cyclopropylglycine (corresponding to Compounds 2-42 of Table 2)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, benzyl chloroacetate (0.20 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.20g, yield: 40%).
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.10(d,J＝4.9Hz,1H),7.88(d,J＝4.7Hz,1H),7.81(q,J＝2.5Hz,1H),7.77(d,J＝4.4Hz,2H),7.41-7.38(m,4H),7.28(s,1H),5.25(d,J＝4.3Hz,2H),4.65(d,J＝46.2Hz,2H),2.94(q,J＝5.4Hz,1H),0.87–0.83(m,4H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝723.2。
EXAMPLE 14 Synthesis of methyl 3- (2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide) propanoate (corresponding to Compound 3-1 of Table 3)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, methyl chloropropionate (0.17 g,1.4 mmol) was slowly added after 30min, and the reaction was stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.23g, yield: 50%).
1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.82(d,J＝2.4Hz,1H),8.55(s,1H),8.20(d,J＝2.4Hz,1H),8.12(s,2H),3.52(s,3H),2.99–2.67(m,2H),1.24(s,1H),0.84(dd,J＝6.8,2.1Hz,2H),0.72(td,J＝7.5,2.4Hz,2H),0.65–0.30(m,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝661.2。
Example 15 Synthesis of 2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) -N- (dimethylcarbamoyl) nicotinamide (corresponding to Compound 5-1 of Table 5)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, N-dimethylcarbamoyl chloride (0.15 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.34g, yield: 75%).
1H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.22(s,1H),8.09(s,1H),7.88(s,1H),7.68(s,2H),3.11–2.61(m,1H),1.18(d,J＝2.2Hz,6H),0.87(d,J＝6.7Hz,2H),0.69–0.48(m,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝646.1。
EXAMPLE 16 Synthesis of 2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) -N- (ethyl (methyl) carbamoyl) nicotinamide (corresponding to Compounds 5-6 of Table 5)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, N-methyl-N-ethylcarbamoyl chloride (0.17 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.33g, yield: 72%).
1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.83(d,J＝2.5Hz,1H),8.55(s,1H),8.20(d,J＝2.5Hz,1H),8.12(s,2H),3.07(s,1H),2.82(s,2H),1.20(t,J＝7.1Hz,3H),1.08–0.93(m,3H),0.89–0.61(m,4H).
19F NMR(376MHz,DMSO-d6)δ-74.61,-181.18,
LC-MS:(M+1)m/z＝660.1。
EXAMPLE 17 Synthesis of 2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) -N- (methoxy (methyl) carbamoyl) nicotinamide (corresponding to Compounds 5-7 of Table 5)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, N-methyl-N-methoxycarbamoyl chloride (0.18 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.19g, yield: 41%).
1H NMR(400MHz,Chloroform-d)δ8.62(d,J＝2.5Hz,1H),8.14(s,1H),7.93(s,1H),7.83(d,J＝2.4Hz,1H),7.75(s,2H),3.93(s,3H),2.75(s,3H),2.83(dt,J＝7.0,3.3Hz,1H),1.32–1.18(m,2H),0.88(dq,J＝5.1,1.9Hz,2H).
19F NMR(377MHz,CDCl3)δ-75.24,-181.57.
LC-MS:(M+1)m/z＝662.3。
EXAMPLE 18 Synthesis of 2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) -N- (diisopropylcarbamoyl) nicotinamide (corresponding to Compounds 5-11 of Table 5)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, N-diisopropylcarbamoyl chloride (0.23 g,1.4 mmol) was slowly added after 30min, and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.28g, yield: 58%).
1H NMR(400MHz,DMSO-d6)δ8.89(d,J＝7.4Hz,1H),8.64(d,J＝2.5Hz,1H),8.54(s,1H),8.18(d,J＝2.5Hz,1H),8.13(d,J＝6.7Hz,2H),3.81(dtd,J＝24.1,12.3,11.2,5.8Hz,2H),3.32(dt,J＝6.8,3.5Hz,1H),1.26–1.10(m,12H),0.98(dd,J＝7.0,2.6Hz,2H),0.84(t,J＝3.3Hz,2H).
19F NMR(376MHz,DMSO-d6)δ-74.61,-181.18,
LC-MS:(M+1)m/z＝702.0。
EXAMPLE 19 Synthesis of N- (bis (2-chloroethyl) carbamoyl) -2-chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (corresponding to Compounds 5-17 of Table 5)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, N-bis (2-chloroethyl) carbamoyl chloride (0.31 g,1.4 mmol) was slowly added after 30min and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.34g, yield: 66%).
1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.71(d,J＝4.4Hz,1H),8.56(s,1H),8.20(d,J＝2.4Hz,1H),8.12(s,2H),4.03–3.80(m,4H),3.81–3.57(m,4H),3.38(d,J＝4.3Hz,1H),1.11–0.63(m,4H).
19F NMR(376MHz,DMSO-d6)δ-74.61,-181.18.
LC-MS:(M+1)m/z＝742.0。
Example 20 Synthesis of N- (2-chloro-5- (1- (2, 6-dichloro-4- (perfluoropropane-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinoyl) -N-cyclopropylmorpholine-4-carboxamide (corresponding to Compounds 5-38 of Table 5)
2-Chloro-N-cyclopropyl-5- (1- (2, 6-dichloro-4- (perfluoropropan-2-yl) phenyl) -1H-pyrazol-4-yl) nicotinamide (0.4 g,0.7 mmol) and 15ml THF were placed in a 50ml reaction flask, 60% NaH (0.06 g,1.4 mmol) was added portionwise under ice bath, after 30min 4-morpholinocarbonyl chloride (0.21 g,1.4 mmol) was slowly added and the reaction stirred at room temperature overnight. After 12h the reaction was completed, quenched with water (30 ml), the aqueous phase extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =10/1 ] to give the title compound (white solid, 0.15g, yield: 31%).
1H NMR(400MHz,DMSO-d6)δ8.88(d,J＝11.4Hz,1H),8.72(d,J＝7.4Hz,1H),8.59(s,1H),8.46(s,1H),8.13(s,2H),3.61–3.51(m,4H),3.13(t,J＝4.4Hz,4H),2.82(d,J＝10.5Hz,1H),0.83–0.34(m,4H).
19F NMR(376MHz,DMSO-d6)δ-74.61,-181.18,
LC-MS:(M+1)m/z＝688.1。
Test example: biological Activity test
1) Compound preparation: the raw medicine with a certain mass is weighed by an analytical balance (0.0001 g), dissolved by N, N dimethylformamide containing 1 per mill of Tween-80 emulsifier to prepare a mother solution with the concentration of 1 percent, and then diluted by distilled water for standby.
2) Test method
Leaf dipping method: putting proper amount of radish/cabbage/corn leaves into a plastic culture dish filled with filter paper after being fully soaked in the prepared liquid medicine for 30s, naturally drying in the shade, putting 8 heads of 2-3-year-old plutella xylostella/armyworm/spodoptera frugiperda into a 22 ℃ illumination (16/8 h) observation room in each dish. After 48 hours, the insects are touched by a writing brush, and no reaction is considered as dead insects. Each treatment was repeated 3 times and solvent controls were set. The test concentrations were 100mg/L, 10mg/L, 1mg/L, 0.25mg/L, and 0.0625mg/L, respectively.
Film method for artificial feed: the prepared Asiatic corn borer artificial feed is poured into a 12-hole plate while the feed is hot, 3ml of artificial feed is added into each hole, and the feed is fully cooled for standby. 1 12-well plate is made for each concentration gradient of each medicament, 1 repetition is made for each 12-well plate, 3 repetitions are added for each well, 50 mu L of the medicament corresponding to the concentration gradient is added, and the mixture is dried. Each hole is connected with 1 head 3-year corn borer larvae. Control 3 12 well plates, 1 replicate per 12 well plate, 3 replicates total, and 50 μl of fresh water per well. Placing into an insect-breeding room with temperature of 26+ -2deg.C and illumination of 16 h:8 h (L:D) and humidity of 50=70%, breeding, investigating death condition of test insects at 48h after test, and counting death number of test insects. The test concentrations were 100mg/L, 50mg/L, 25mg/L, 12.5mg/L, respectively.
Test results show that the compound has higher mortality rate on plutella xylostella, armyworm and spodoptera frugiperda corn borer under different doses;
the specific test results are shown in tables 6 to 9.
TABLE 6 mortality of the inventive Compounds to Plutella xylostella at different doses
TABLE 7 mortality of the compounds of the invention against myxoplasma at various doses
TABLE 8 lethality of the inventive compounds to Spodoptera frugiperda at various doses
Comparison test:
CN111050559a discloses insecticidal compounds MC having a similar substituted structure 1 A part of the compounds of the general formula I of the invention are selected to participate in the experiment, and the comparison result with MC 1 is as follows:
TABLE 9 mortality of the inventive Compounds to Asian corn borers at different doses
The above effects show that the compound of the general formula I has obvious difference in molecular structure compared with MC compounds by introducing carbonyl structure at N-substituted position, the difference leads to the change of interaction and combination opportunity of molecules and receptors, and unexpected effects are obtained, namely, the compound of the general formula I has excellent killing activity on various pests and mites, especially lepidoptera pests such as diamond back moth, armyworm, spodoptera frugiperda, asian corn borer and the like which are recognized in the world and difficult to prevent, and can be expected to have outstanding prevention and control effects even if the compound consumption is further reduced.
In addition to pest control properties, the compounds according to the invention surprisingly also show improved degradation properties compared to the compounds of the prior art. In addition, the compounds according to the invention also surprisingly show a lower toxicity to bees (or aquatic animals) than the compounds of the prior art.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.

Claims (10)

1. A compound of formula (I) as an N-substituted phenylpyrazole derivative or an isotopically labelled compound thereof, or an optical isomer, a geometrical isomer, a tautomer or a mixture of isomers thereof, or an agropharmaceutically acceptable salt thereof,
Wherein,
W is-O-R 1 or-N-R 1(R2);
R 1、R2 is each independently hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-12 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl C 1-3 alkyl, C 3-8 heterocyclyl C 1-3 alkyl, aryl C 1-3 alkyl, haloaryl C 1-3 alkyl or haloc 3-8 heteroaryl C 1-3 alkyl; Or (b)
R 1、R2 and N connected with the R 1、R2 form ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered heterocyclic alkane containing C, N, O or S;
R 3 is hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxy, C 1-6 alkyl, halogenated C 1-C6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl, halogenated C 2-C6 alkenyl, C 2-6 alkynyl, halogenated C 2-C6 alkynyl, C 6-12 aryl or halogenated aryl;
r 4 is hydrogen, C 1-6 alkyl, -C (=O) -C 1-6 alkyl, -C 1-6 alkylene-C (=O) -C 1-6 alkyl, -C (=O) -OC 1-6 alkyl, -C 1-6 alkylene-C (=O) -O-C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-12 aryl, aryl-C 1-3 alkyl, or C 3-8 cycloalkyl C 1-3 alkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl;
n=0, 1, 2, 3, 4 or 5.
2. The compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or an agropharmaceutically acceptable salt thereof, according to claim 1,
W is-O-R 1 or-N-R 1(R2);
r 1、R2 is each independently hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, Halogenated C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl, C 3-6 heteroaryl, C 3-8 cycloalkyl C 1-3 alkyl, C 3-6 heterocyclyl C 1-3 alkyl, aryl C 1-3 alkyl, haloaryl C 1-3 alkyl or haloc 3-6 heteroaryl C 1-3 alkyl; Or (b)
R 1、R2 and N connected with the R 1、R2 form quaternary, five-membered, six-membered or seven-membered heterocyclic alkane containing C, N, O or S;
R 3 is hydrogen, halogen, hydroxy, cyano, nitro, amino, carboxy, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl;
R 4 is hydrogen, C 1-3 alkyl, -C (=O) -C 1-3 alkyl, -C 1-3 alkylene-C (=O) -C 1-3 alkyl, -C (=O) -OC 1-3 alkyl, -C 1-3 alkylene-C (=O) -O-C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl;
n＝0、1、2、3。
3. The compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or an agropharmaceutically acceptable salt thereof, according to claim 1,
W is-O-R 1 or-N-R 1(R2);
R 1、R2 is each independently hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 2-4 alkenyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 heterocyclyl, C 6-8 aryl; or (b)
R 1、R2 and N connected with the R 1、R2 form five-membered, six-membered or seven-membered heterocyclic alkane containing C, N, O;
R 3 is hydrogen, halogen, C 1-3 alkyl;
R 4 is hydrogen, C 1-3 alkyl, C 3-8 cycloalkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl;
n＝0、1、2。
4. the compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or an agropharmaceutically acceptable salt thereof, according to claim 1,
W is-O-R 1 or-N-R 1(R2);
R 1、R2 is each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, monochloroethyl, dichloroethyl, monofluoromethyl, difluoromethyl, methoxy, ethoxy, ethylene, propylene, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, cyclopropane, cyclobutane, cyclopentane, phenyl, methylphenyl, ethylphenyl; or (b)
R 1、R2 and the N connected with the R 1、R2 form six-membered heterocyclic alkane containing C, N, O;
R 3 is hydrogen, C 1-3 alkyl;
R 4 is hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl;
X 1、X2、X3 and X 4 are each independently selected from hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl;
n＝0、1、2。
5. A compound of formula (I) or an isotopically-labelled compound thereof as claimed in claim 1, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or an agropharmaceutically acceptable salt thereof, having the formula:
6. A pesticidal composition comprising a compound of formula (I) or an isotopically-labelled compound thereof as defined in any one of claims 1 to 5, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or an agropharmaceutically acceptable salt thereof, and an agropharmaceutically acceptable carrier.
7. The pesticide composition of claim 6 in a dosage form selected from the group consisting of powders, granules, liquids, suspensions or sprays, preferably wettable powders, wettable liquids, soluble powders, dispersible liquids, aqueous solutions, microemulsions, emulsifiable concentrates, aqueous emulsions, sprayable solutions, dispersible oil suspensions, microcapsule suspensions, water dispersible granules, water soluble granules, macrogranules, granules for broadcasting and soil application, aerosols, ultra low volume formulations and wax formulations.
8. Use of a compound of formula (I) according to any one of claims 1 to 5 or an isotopically labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or an agropharmaceutically acceptable salt thereof, for the preparation of a pesticide for pest control.
9. The use according to claim 8, wherein the pest is selected from the group consisting of pests belonging to the phylum arthropoda, coleoptera, diptera, heteroptera, homoptera, hymenoptera, isoptera, lepidoptera, orthoptera, lice, thysanoptera, nematophaga.
10. The use according to claim 9, wherein the pest is selected from the group consisting of plutella xylostella, armyworm, spodoptera frugiperda, corn borer.
CN202211646968.2A 2022-12-21 2022-12-21 N-substituted phenylpyrazole derivative and preparation and application thereof Pending CN118221639A (en)

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