CN116947679A - Bisamide compound containing sevoflurane isopropyl, and preparation method and application thereof - Google Patents

Bisamide compound containing sevoflurane isopropyl, and preparation method and application thereof Download PDF

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CN116947679A
CN116947679A CN202310914372.4A CN202310914372A CN116947679A CN 116947679 A CN116947679 A CN 116947679A CN 202310914372 A CN202310914372 A CN 202310914372A CN 116947679 A CN116947679 A CN 116947679A
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沈新良
吴华龙
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Zhejiang Yulong Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Environmental Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Insects & Arthropods (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a general formula (I-V) compound, which is used for preparing a bisamide compound containing sevoflurane isopropyl, and the sevoflurane isopropyl bisamide compound has excellent insecticidal activity, particularly has excellent high insecticidal activity on resistant populations, has no interactive resistance with the conventional insecticide chlorantraniliprole, and has good insecticidal effect and good quick-acting performance at low dosage; in addition, the heptafluoroisopropyl bisamide compoundThe preparation method is simple, efficient and easy for industrialized production, and has wide application prospect in the fields of agriculture, forestry and gardening for pest control.

Description

Bisamide compound containing sevoflurane isopropyl, and preparation method and application thereof
The divisional application is a divisional application of Chinese patent application with application date 2022-12-07, application number CN 2022115602361 and the invention name of "a bisamide compound containing sevoflurane isopropyl and a preparation method and application thereof".
The invention requests two homeland priorities, namely a diamide compound with a priority of 2021, 12 and 22 months, a priority number of CN 2021115835066, a preparation method and application of the diamide compound, a diamide compound with sevoflurane isopropyl, a diamide compound with a priority of 2022, 09 and 23 months, a priority number of CN 2022111613460, and a preparation method and application of the diamide compound with sevoflurane isopropyl.
Technical Field
The invention belongs to the field of pesticides, and relates to a bisamide compound containing sevoflurane isopropyl, and a preparation method and application thereof.
Technical Field
Neonicotinoid insecticides, represented by imidacloprid, are a class of ultra-efficient insecticides, currently the global market is stabilized at over 20 billion dollars, but are used frequently in large numbers, resulting in serious resistance; the chlorantraniliprole (structural formula: CK 01) serving as the 'king pesticide' in the androstane pesticide market for more than ten years also has serious resistance problems in most regions of the world at present, and the dosage of the chlorantraniliprole needs to be increased to achieve the original effect, so that certain problems are caused for agricultural production, environment and ecology.
The damage caused by pests and the like is still very remarkable, and the pests have resistance to the existing pesticides and are not friendly to the environment, so that new pesticides with better activity, lower dosage and more friendly environment are always required to be developed. The investment for pesticide creation is continuously increased by domestic and overseas scientific research institutions and enterprises, and a plurality of novel pesticides with high activity, low dosage and environmental friendliness are also produced.
The metadiamide pesticide Broflanilide (structural formula: CK 02) developed by the joint cooperation of Sanjing chemical company and Pasteur company in Japan is marketed, and the Chinese name is bromofluorobenzene bisamide which is mainly used for fruits and vegetables, beans, cotton, corn, grains, flowers and non-crops, has very good effect on preventing and controlling pests such as lepidoptera, coleoptera, termite, ant, cockroach, fly and the like, and is shown in Chinese patent CN102119173B in detail, an amide derivative, a pest control agent containing the amide derivative and a use method thereof. However, the research of a plurality of domestic enterprises and research institutions shows that the Broflanilide has poor quick-acting property and poor insecticidal effect under low dosage, and structure optimization and improvement are carried out on the basis, and a series of novel pesticides with high activity, low dosage and environmental friendliness are also found. See Chinese patent CN 109497062B for details, which is a kind of m-diamide compound, a preparation method and application thereof, and is representative (structural formula: CK 03); chinese patent CN 110194726B is a benzamide compound and application thereof, and is representative (structural formula: CK 04). So that more medication choices are provided in the production of crops such as agriculture, gardening and the like.
We have found that the formula: CK02, formula: CK03 and formula: the CK04 structural compounds, at low doses, still have improved insecticidal efficacy against certain resistant pests and have the formula: CK03 and formula: the CK04 compound has the advantages of improved quick-acting property, low total yield of the compound preparation, high process cost and adverse industrial production and large-scale application. There is still a need in the art to actively develop new pesticides with high insecticidal activity, no cross resistance and industrialization prospect at low dosage to meet the demands of agriculture and forest industry.
[ invention ]
Aiming at the defects of the prior art, the invention aims to provide a bisamide compound containing heptafluoroisopropyl as well as a preparation method and application thereof, and a novel pesticide compound with no cross resistance with the existing pesticide, which has higher insecticidal activity and good quick-acting performance at low dosage, is favorable for ecological and environmental protection, and meets the demands of agriculture, forest industry and gardening fields.
To achieve the purpose, the invention adopts the following technical scheme.
Firstly, the invention provides a bisamide compound containing sevoflurane isopropyl, which has a structure shown in the following structural general formula (I):
Wherein m is independently represented as an integer of 1 to 3; n is independently an integer of 0 to 5;
R 1 the substituents may be located at any substitutable position on the phenyl ring, R 1 Independently selected from H, fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, trifluoromethoxy, methyl, ethyl, methanesulfonyl, cyano, or nitro;
when m is 2 or 3, R 1 The substituents may be the same or different;
R 2 independently selected from C1-C5 alkyl or benzyl with optional substituents.
Preferably, n is independently represented as 1 or 2.
The insecticidal composition has the structure shown in the general formula (I), has very good insecticidal activity at low dosage, even reaches 90% -100% of insecticidal activity, has no interactive resistance with chlorantraniliprole, reduces the dosage of medicaments in practical application, reduces medicament residues in application, and is more beneficial to ecology and environmental protection.
In the present invention, as a preferable embodiment, in the general formula (i), when m=1; the heptafluoroisopropyl-containing bisamide compound has a structure shown in the following general formula (II):
wherein R is 1 Independently selected from H, fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, trifluoromethoxy, methyl, ethyl, methanesulfonyl, cyano, or nitro;
R 2 Independently selected from C1-C5 alkyl or benzyl optionally substituted;
n is independently 1 or 2.
In the present invention, as another preferable embodiment, in the general formula (II), R 1 When the position of the substituent is determined, the heptafluoroisopropyl-containing bisamide compound has a structure shown in the following general formula (III):
wherein R is 1 Independently selected from H, fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, trifluoromethoxy, methyl, ethyl, methanesulfonyl, cyano, or nitro;
R 2 independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
n is independently 1 or 2.
The invention is thatIn a particularly preferred embodiment, in the structure of the formula III, R 1 Independently selected from H, fluoro, trifluoromethyl, trifluoromethoxy, cyano or nitro;
R 2 independently selected from methyl, ethyl or n-propyl;
n is independently 1 or 2.
Wherein, when m=1, representative compounds and CK02 materialization indexes are shown in the following table:
list one
The specific chemical structural formula and chemical name are represented as follows:
2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- [ (phenylcarbonyl) (2-ethoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-fluorophenyl) carbonyl ] (2-methoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-fluorophenyl) carbonyl ] (2-ethoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-trifluoromethylphenyl) carbonyl ] (2-methoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-trifluoromethylphenyl) carbonyl ] (2-ethoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-cyanophenyl) carbonyl ] (2-methoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-cyanophenyl) carbonyl ] (2-ethoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-trifluoromethoxyphenyl) carbonyl ] (2-methoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-trifluoromethoxyphenyl) carbonyl ] (2-ethoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- [ (phenylcarbonyl) (3-methoxypropyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- [ (phenylcarbonyl) (3-ethoxypropyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- [ (4-fluorophenylcarbonyl) (3-methoxypropyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- [ (4-fluorophenylcarbonyl) (3-ethoxypropyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-trifluoromethylphenyl) carbonyl ] (3-methoxypropyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
2-fluoro-3- { [ (4-trifluoromethylphenyl) carbonyl ] (3-ethoxypropyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide
The compounds of the general formula (I) according to the invention can be prepared by the following processes, where the radicals in the formulae are as defined above, unless otherwise indicated. The raw materials and reagents used in the present invention are generally commercially available in the form of industrial products unless otherwise specified. In order to realize the preparation method of the compound of the general formula (I), a synthetic route is designed, and the preparation method of the compound of the general formula (I) is realized through the following preparation method processes of the first step and the second step.
Step one: an intermediate compound of the following general formula (I-V) is synthesized:
the preparation method is realized by the following two preparation methods:
preparation method I-A: the intermediate compound of the general formula (I-V) is synthesized from the benzoic acid general formula (I-I) series raw materials through the steps of acyl chlorination reaction, amidation reaction, N-alkylation reaction, hydrolysis reaction and the like. The preparation method has the following reaction formula:
preparation method I-A
The preparation method I-B can also be adopted: the intermediate compound of the general formula (I-V) is synthesized by the steps of carrying out N-alkylation reaction on a methyl 3-amino-2-fluorobenzoate raw material, carrying out amidation reaction with a benzoyl chloride general formula (I-II) raw material, carrying out hydrolysis reaction and the like. The preparation method has the following reaction formula:
preparation method I-B
The benzoic acid general formula (I-I) series raw materials and the 3-amino-2-fluorobenzoic acid methyl ester raw materials related in the preparation methods I-A and I-B are known compounds, are medical and pesticide intermediates, and can be directly purchased in the market. Chinese patent CN111320548A also discloses another method for the synthetic preparation of methyl 3-amino-2-fluorobenzoate. Other esters of methyl 3-amino-2-fluorobenzoate such as: ethyl 3-amino-2-fluorobenzoate, n-butyl 3-amino-2-fluorobenzoate, isobutyl 3-amino-2-fluorobenzoate and the like are generally suitable for the preparation method of the present invention, and a raw material of methyl 3-amino-2-fluorobenzoate is preferably used.
The acylating agents which are usually used for the acyl chlorination reaction involved in the preparation methods I-A, I-B are: thionyl chloride, sulfuryl chloride, oxalyl chloride, methanesulfonyl chloride, benzoyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene, and the like are preferably adopted, the molar dosage of the thionyl chloride is 1.0-10.0 times that of the benzoic acid general formula (I-I) series raw material, the preferred economic dosage is 1.0-3.0 times, the solvent adopted in the acyl chlorination reaction is dichloromethane, chloroform, dichloroethane, toluene, xylene, and the like, and the preferred solvent is dichloroethane, toluene, and the like; the acid chloride reaction temperature is generally 20-150 ℃, preferably 40-100 ℃; the acid chloride reaction time is generally 1 to 5 hours, preferably 2 to 3 hours.
The Friedel-crafts used in amidation reaction in the preparation method I-A and I-B are triethylamine, pyridine, N-diisopropylethylamine, N-dimethylaniline, tetramethyl ethylenediamine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide or potassium tert-butoxide and the like, preferably triethylamine or pyridine is adopted, the molar dosage is 1.0-5.0 times of that of the benzoyl chloride general formula (I-II) series raw materials, and the preferred economic dosage is 1.0-2.0 times; the amidation reaction adopts dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or 1, 3-dimethyl-2-imidazolidinone and the like, and preferably adopts dichloroethane, toluene, acetonitrile, N-dimethylformamide or 1, 3-dimethyl-2-imidazolidinone and the like, the dosage is 1-20 times of the weight of the raw materials of the benzoyl chloride general formula (I-II), and the preferred economic dosage is 2-5 times; the amidation reaction temperature is generally-5 to 150 ℃, preferably 0 to 50 ℃; the reaction time is generally 1 to 4 hours, preferably 2 to 3 hours.
The general formula of the alkylating reagent used for the N-alkylation reaction involved in the preparation methods I-A and I-B is as follows:
wherein X is halogen, preferably bromine or iodine;
n is independently an integer of 0 to 5; preferably 1 or 2.
R 2 Independently represent a C1-C5 alkyl group or a benzyl group which may have an optional substituent; preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl, p-chlorobenzyl, p-bromobenzyl, p-fluorobenzyl and the like.
The N-alkylating reagent adopted by the invention is generally a known compound, is an intermediate of medicines and pesticides, and is conventionally as follows: bromomethyl ether, bromomethyl ethyl ether, 1-bromo-2-methoxyethane, 1-bromo-2-ethoxyethane, 1-bromo-3-methoxypropane, 1-bromo-3-ethoxypropane, 1-bromo-2-n-propoxyethane and the like, and can be directly purchased in the market or realized by synthesis. The synthesis of N-alkylating agents is described in detail in reference, wang Yan et al, 1-bromo-1-ethoxypropane, journal of the Chinese medical industry, 2004,35 (4), 203-204; chen Fener, et al, J.pharmaceutical industries, 1995,26 (2), 88-89; U.S. patent US5264150 relates to examples. The molar amount of the N-alkylating agent is 1.0 to 5.0 times, preferably 1.0 to 2.0 times, the amount of the raw material of the general formula (I-III) or the methyl 3-amino-2-fluorobenzoate; the N-alkylating reagent is added into the reaction system generally in a dropwise manner or in a one-time or multi-time manner, preferably in a dropwise manner; the solvent used in the N-alkylation reaction is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile, toluene, xylene, tetrahydrofuran, dioxane or acetone, etc., preferably N, N-dimethylformamide, N-dimethylacetamide or acetonitrile, etc., and the amount is 1.0 to 20.0 times, preferably 2 to 10 times, that of the raw material of the general formula (I-III) or the raw material of 3-amino-2-fluorobenzoic acid methyl ester; the alkali used in the N-alkylation reaction is pyridine, N-diisopropylethylamine, N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium amide or lithium diisopropylamide and the like, preferably sodium carbonate, potassium carbonate or sodium hydride is used, the molar amount of the alkali is 1.0-5.0 times that of the raw material of the general formula (I-III) or the raw material of the 3-amino-2-fluorobenzoic acid methyl ester, and the preferable amount is 2.0-5.0 times; the N-alkylation reaction temperature is 20-200 ℃, preferably 20-100 ℃; the N-alkylation reaction time is generally 2 to 12 hours, preferably 2 to 10 hours.
In the first step, the total yield of the preparation methods I-A and I-B is obviously higher than that of the preparation method I-B, and the preparation method I-A is preferred.
Step two: the synthesis of the compounds of the general formula (I) can also be carried out by the following two preparation methods.
The preparation method is that the intermediate compound of the general formula (I-V) is subjected to an acyl chlorination reaction and then is subjected to an amidation reaction and a bromination reaction with a raw material of 4- (1, 2, 3-heptafluoropropane-2-yl) -2- (trifluoromethyl) aniline to synthesize the compound of the general formula (I). The preparation method comprises the following steps:
preparation method II-A
Another preparation method can also be adopted:
the intermediate compound of the general formula (I-V) is directly amidated with 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) aniline raw material to directly synthesize the compound of the general formula (I) after acyl chlorination reaction. The preparation method comprises the following steps:
process for the preparation II-B
The acylating agent commonly used in the acyl chlorination reaction involved in the preparation method of the step is: thionyl chloride, sulfuryl chloride, oxalyl chloride, methanesulfonyl chloride, benzoyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphosgene, or the like is preferably adopted, and the molar amount of the thionyl chloride is 1.0-10.0 times, preferably 1.0-3.0 times of that of the raw material of the general formula (I-V); the solvent used for the acyl chlorination is dichloromethane, chloroform, dichloroethane, acetonitrile, toluene or xylene, etc., preferably the solvent is dichloroethane, toluene, etc.; the acid chloride reaction temperature is generally 20-150 ℃, preferably 40-100 ℃; the acid chloride reaction time is generally 1 to 5 hours, preferably 2 to 3 hours.
This procedure gives the starting material 4- (1, 2, 3-heptafluoropropane-2-yl) -2- (trifluoromethyl) aniline and this fraction involved in process II-A a preparation method of raw material 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) aniline in preparation method II-B, the preparation process is detailed in examples 1,1-2 of Chinese patent CN102119143B, and a great deal of report is also made in foreign journals, and the present application is not described in detail. They are generally used in molar amounts of from 1.0 to 2.0 times, preferably from 1.0 to 1.5 times, the starting materials of the general formula (I-VII).
The amidation reaction solvent involved in the production method II-A and the production method II-B in this step is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile, dichloroethane, toluene, xylene, tetrahydrofuran, dioxane or acetone, etc., preferably N, N-dimethylformamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, acetonitrile or toluene, etc. The use amount is 1.0-20.0 times of the weight of the raw materials of the general formula (I-VII), preferably 2-10 times; the alkali used in the amidation reaction involved in the preparation method II-B in this step is tetramethyl ethylenediamine, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide and the like, preferably tetramethyl ethylenediamine, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide or sodium hydride and the like, and the molar amount of the alkali is 1.0 to 5.0 times, preferably 1.0 to 1.5 times, the molar amount of the raw material of the general formula (I-VII);
The amidation reaction temperature involved in the preparation method II-A and the preparation method II-B in the step is-20-200 ℃, preferably 20-150 ℃; the reaction time is 2 to 20 hours, preferably 5 to 10 hours.
The bromination reaction involved in the preparation method II-A in the step is a bromination reagent such as N-bromosuccinimide, dibromohydantoin, phosphorus tribromide, phosphorus pentabromide, phosphorus tribromide or liquid bromine, and the like, and the N-bromosuccinimide, the dibromohydantoin and the like are preferably used. The molar amount of the brominating reagent is 1.0 to 5.0 times, preferably 1.0 to 1.5 times that of the raw materials of the general formula (I-VIII); the alkali for bromination reaction is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, sodium amide, lithium diisopropylamide and the like, preferably sodium carbonate, potassium carbonate or sodium hydride, and the molar amount of the alkali is 1.0-5.0 times, preferably 1.0-1.5 times, of the molar amount of the raw materials in the general formula (I-VIII); the solvent for bromination reaction is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile, dichloroethane, toluene, xylene, tetrahydrofuran, dioxane or acetone, etc., preferably N, N-dimethylformamide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, acetonitrile or toluene, etc., and the use amount is 1.0-20.0 times, preferably 2-10 times, the weight of the raw material of the general formula (I-VIII); the reaction temperature of the bromination reaction is 0-100 ℃, preferably 20-100 ℃; the reaction time is 2 to 20 hours, preferably 5 to 10 hours.
In the second step, the total yield of the preparation method II-A and the preparation method II-B is obviously higher than that of the preparation method II-B, and the preparation method II-A is preferably selected.
In the present invention, the operations of distillation, reduced pressure distillation, filtration, drying, extraction, delamination, etc., involved in the operation of the production process are conventional operations, and basic operations of general chemical professionals are not described in detail herein, and synthetic examples are described in detail.
In the invention, on one hand, the bisamide compound containing the heptafluoroisopropyl, which is obtained through molecular structure optimization, has excellent insecticidal activity, particularly has excellent high insecticidal activity on resistant populations, has no cross resistance with the existing pesticide chlorantraniliprole, and has good insecticidal effect and quick-acting property at low dosage; on the other hand, the preparation method of the compound shown in the general formula (I) is simple, efficient and easy for industrial production, and has wide application prospect in the fields of agriculture, forestry and gardening for pest control.
In the present invention, the pests include lepidoptera, coleoptera, hemiptera, thysanoptera, diptera, orthoptera, homoptera, isoptera, hymenoptera, tetranychus pests and nematodes, mosquitoes, flies, ants, and the like.
The compound of the invention has wide application range, and the applied plants or ranges mainly comprise the following categories: vegetables such as cucumber, luffa, watermelon, melon, pumpkin, melon, spinach, celery, cabbage, chinese cabbage, cucurbit, capsicum, eggplant, tomato, onion, ginger, garlic, leek, lettuce, kidney bean, tonka bean, broad bean, radish, carrot, potato, yam; cereal grains such as wheat, barley, maize, rice, sorghum; fruit trees such as apples, pears, bananas, oranges, grapes, litchis, mangoes; flowers, peony, rose and crane; oil crops such as peanut, soybean, canola, sunflower, sesame; sugar crops, such as sugar beet, sugar cane; other crops such as strawberry, potato, sweet potato, tobacco and tea. It can also be used in gardening, forestry, household sanitation, public sanitation area, etc. The above-listed plants or ranges have no limitation on the range of use of the sevoflurane-isopropyl-containing bisamides of the present invention.
In one aspect, the compounds of the invention may be used in formulations comprising an agropharmaceutically acceptable carrier, including a solid carrier or a liquid carrier. The compound of the formula (I) containing heptafluoroisopropyl as an active component is dissolved or dispersed in a carrier or prepared into a preparation. The preparation can be made into powder, wettable powder, soluble powder, granule, water dispersible granule, suspension, microemulsion, emulsion, water emulsion or emulsion, etc.
In another aspect, the use of the present invention also provides an insecticide composition. The compound of the general formula (I) containing the sevoflurane isopropyl has no cross resistance with the existing pesticide chlorantraniliprole, can be mixed with the existing pesticide, can improve the use effect of the existing pesticide due to the resistance problem, expands the insecticidal spectrum, and other mixed active ingredients can be one or more of common varieties such as chlorantraniliprole, abamectin, imidacloprid, pymetrozine, fipronil, dinotefuran, molluscacide amine, cartap, thiamethoxam and the like, preferably amide pesticide varieties are used, the pesticide composition comprises an active ingredient and a carrier acceptable in agropharmacy, the active ingredient is at least one active ingredient in the compound of the general formula (I) containing the sevoflurane isopropyl, and the mixing percentage ratio of other active ingredients is 0.1-99.9%.
[ detailed description ] of the invention
The technical solution of the present invention will be further described by the following specific embodiments, and it should be apparent to those skilled in the art that the examples are only for aiding in understanding the present invention and should not be construed as limiting the present invention in any way.
The raw materials described in the synthetic examples of the present invention are not specifically described, but are generally obtained by market purchase, and generally have a content specification of 95% or more, the content is not precisely corrected, the percentage concentration described in the synthetic examples is not specifically described, but generally refer to the weight percentage concentration, the HPLC content data is the area normalization content, the yield is the molar yield, and the yield data is also not precisely corrected.
Synthesis example 1 (preparation method of I-A and II-A)
Synthetic preparation of 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide (structural formula SYN 001).
Step one:
into a 250ml four-port glass reaction bottle, 100g of dichloroethane, 25g (0.20 mol) of benzoic acid, 72g (0.60 mol) of thionyl chloride, heating and refluxing for 3-5 hours, cooling to room temperature, transferring the reaction solution to a 500ml rotary evaporator, decompressing and desolventizing to 80 ℃ to obtain benzoyl chloride oily liquid, cooling to about 25 ℃, and adding 25g of new dichloroethane for dissolving for standby.
In another 250ml four-port glass reaction flask, 100g of dichloroethane, 35g (0.20 mol) of methyl 3-amino-2-fluorobenzoate, 24g (0.30 mol) of pyridine, cooling to 5-25 ℃ in an ice bath, dropwise adding the benzoyl chloride standby liquid into the flask within 1 hour, reacting for 1-2 hours at 5-25 ℃, adding 50ml of water, stirring for 0.5 hour, layering to obtain a solvent layer, transferring the solvent layer into a 500ml rotary evaporator, decompressing and desolventizing to 80 ℃ to obtain 53g of methyl 2-fluoro-3- [ (phenylcarbonyl) amino ] benzoate as a white solid, and using the white solid with 94 percent of normalized HPLC (yield 91.2%) for the next reaction without further treatment. The reaction formula is as follows:
In another 250ml four-port glass reaction bottle, 200g of N, N-dimethylformamide, 15g (0.10 mol) of potassium carbonate are put into the four-port glass reaction bottle, 25g (0.086 mol) of 2-fluoro-3- [ (phenylcarbonyl) amino ] methyl benzoate material synthesized above is put into the four-port glass reaction bottle, the temperature is raised to 45-55 ℃, 15.8g (0.11 mol) of 1-bromo-2-methoxyethane is dripped in 1 hour, the temperature is kept for 5 hours, water is cooled to room temperature, the reaction solution is poured into 500ml ice water for precipitation, 150g of dichloromethane is extracted and layered, the dichloromethane layer is obtained, the obtained dichloromethane layer is transferred into a rotary evaporator for decompression and desolventization to 80 ℃ to obtain oily liquid, 50g of methanol, 60g (0.15 mol) of 10% liquid alkali is added, the temperature is raised to 25-35 ℃, the temperature is kept for 2 hours, 50g of water is added to adjust the pH to 1-2, 150g of dichloromethane is added for layering, the obtained dichloromethane layer is transferred into the rotary evaporator for decompression and desolventization to 80 ℃ to obtain light brown oily liquid, the dichloromethane layer is cooled and crystallized, the obtained after one-step of the water is decompressed to 90% (the two-2.82% of phenylcarbonyl) is subjected to direct treatment (2.82-2 mol) of phenylcarbonyl). The reaction formula is as follows:
step two: synthesis of SYN001 Compounds
Into a 250ml four-port glass reaction flask, 200g of dichloroethane, 25g (0.071 mol) of 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid synthesized above, 24g (0.20 mol) of thionyl chloride, heating and refluxing for 3-5 hours, cooling to room temperature, transferring the reaction solution to a 500ml rotary evaporator, decompressing and desolventizing to 80 ℃ to obtain an oily liquid of acyl chloride, cooling to about 25 ℃, adding 150g of acetonitrile for dissolution, transferring to the reaction flask, and adding 27.8g (0.08 mol) of raw material of 4- (1, 2, 3-heptafluoropropane-2-yl) -2- (trifluoromethyl) aniline, heating and refluxing for 5-10 hours. Cooling to room temperature, pouring into 300ml ice water to precipitate, extracting 200g dichloroethane, washing with 50ml water for layering to obtain a dichloroethane layer, drying and filtering with anhydrous magnesium sulfate, decompressing and desolventizing to 80 ℃ to obtain oily 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide intermediate, adding 250g of N, N-dimethylformamide for dissolution, transferring the reaction solution into a 500ml reaction bottle, cooling to 0-25 ℃, adding 18g (0.1 mol) of N-bromosuccinimide, and carrying out heat preservation reaction for 5-10 hours. Pouring into 500ml ice water to separate out, extracting with 200g of dichloromethane, washing with 50ml of water to separate the dichloromethane layer, and removing the dichloromethane layer under reduced pressure until the temperature reaches 80 ℃ to obtain 54g of crude product of oily 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide (namely structural formula SYN 001), wherein the HPLC (high performance liquid chromatography) has 85 percent, and the three-step reaction yield is 91.4 percent calculated by 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid. The reaction formula is as follows:
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54g of crude compound is recrystallized by using 150g of normal hexane and 50g of ethyl acetate mixed solvent at 0-5 ℃ to obtain 40g of white crystal dry product, wherein the normalized content of HPLC is 96%, and the melting point is: 179.5-180.5, crystallization yield 83.6%, total yield 76.5% after crystallization in step two.
The nuclear magnetism and mass spectrum data are as follows:
nuclear magnetic hydrogen spectroscopy was performed using Bruker AV-400spectrometer (400 MHz), TMS as an internal standard, and DMSO-d6 (same below) as a solvent; high resolution mass spectra were determined using a UHR-TOF maXis (ESI) mass spectrometer (the same applies hereinafter).
1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.57(s,1H,CONH),8.39(s,1H),7.92(s,1H),7.61-7.51(m,3H),7.34-7.24(m,5H),4.32-3.70(m,2H),3.68-3.45(m,2H),3.19(s,3H)。HRMS(ESI)calcd.for C 27 H 18 BrF 11 N 2 NaO 3 [(M+Na) + ]:729.0223[(M+Na) + ],731.0202[(M+2+Na) + ]；Found:729.0213[(M+Na) + ],731.0196[(M+2+Na) + ]。
Synthesis example 2 (preparation method of I-A and II-B)
Synthetic preparation of 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide (structural formula SYN 001).
Step one: 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid (0.071 mol), the same procedure as in Synthesis example 1 was followed.
Step two: synthesis of SYN001 Compounds
Into a 250ml four-port glass reaction flask, 200g of dichloroethane, 25g (0.071 mol) of 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid obtained by the synthesis in the step one of example 1 above, 24g (0.20 mol) of thionyl chloride, heating and refluxing for 3-5 hours, cooling to room temperature, transferring the reaction solution to a 500ml rotary evaporator, desolventizing under reduced pressure to 80℃to obtain an acid chloride oily liquid, cooling to about 25℃and adding 150g of N, N-dimethylformamide for dissolution, transferring to the reaction flask, and adding 35g (0.08 mol) of 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) aniline raw material, adding 5.8g (0.08 mol) of potassium methoxide, heating to 55-65 ℃ for reaction for 5-10 hours, cooling to room temperature, pouring into 500ml ice water for precipitation, extracting 200g of dichloromethane, washing and layering with 50ml of water to obtain a dichloromethane layer, decompressing and desolventizing to 80 ℃ to obtain 55g of crude product of oily 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide (namely structural formula SYN 001) compound with the average content of 56 percent by HPLC, this step had a total of 61.3% yield of 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid. The reaction formula is as follows:
55g of crude compound is recrystallized by using 150g of normal hexane and 50g of ethyl acetate as a mixed solvent at 0-5 ℃ to obtain 15g of beige crystal dry product, wherein the content of HPLC normalized is 92%, the crystallization yield is 44.8%, and the total yield after the second crystallization is 27.5%.
Synthesis example 3 (preparation method of I-B and II-A)
Synthetic preparation of 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide (structural formula SYN 001).
Step one:
into a 250ml four-port glass reaction bottle, 100g of dichloroethane, 25g (0.20 mol) of benzoic acid, 72g (0.6 mol) of thionyl chloride, heating and refluxing for 3-5 hours, cooling to room temperature, transferring the reaction solution to a 500ml rotary evaporator, decompressing and desolventizing to 80 ℃ to obtain benzoyl chloride oily liquid, cooling to about 25 ℃, and adding 25g of new dichloroethane for dissolving for standby.
Into another 250ml four-port glass reaction flask, 200g of N, N-dimethylformamide is added, 35g (0.20 mol) of 3-amino-2-fluorobenzoic acid methyl ester is added, the temperature is reduced to 10-25 ℃, 8g (0.2 mol) of 60% sodium hydride is added in portions under the protection of nitrogen, the temperature is controlled to 15-25 ℃,30 g (0.21 mol) of 1-bromo-2-methoxyethane is dripped in for 1 hour, and the temperature is raised to 45-55 ℃ for reaction for about 5 hours. Cooling water to room temperature, pouring the reaction solution into 500ml ice water to separate out 150g dichloroethane, extracting, layering to obtain a dichloroethane layer, drying with anhydrous magnesium sulfate, filtering to obtain a dichloroethane layer, transferring to a 500ml four-port glass reaction bottle, adding 24g (0.30 mol) of pyridine, cooling to 5-25 ℃ in an ice bath, dripping the benzoyl chloride standby liquid in the previous step within 1 hour, reacting for 1-2 hours at 5-25 ℃, completing the reaction, adding 50ml of water, stirring for 0.5 hour, layering to obtain a solvent layer, transferring to a 500ml rotary evaporator, decompressing and desolventizing to 80 ℃ to obtain an oily liquid, adding 100g of methanol, 12g (0.30 mol) of 10% caustic soda liquid, heating to 25-35 ℃, preserving and reacting for 2 hours, adding 100g of water, adjusting pH to 1-2 with 30% hydrochloric acid, adding 300g of dichloromethane, extracting, layering to obtain a dichloromethane layer, transferring to the rotary evaporator, decompressing and desolventizing to 80 ℃ to obtain an oily liquid 44g, cooling, and obtaining an oily liquid with 80% (the four steps of 55.4% benzoic acid and 2-3% fluorine-2- [ (2-methoxyethyl) phenyl ] after cooling, and directly treating for the following amino-carbonyl reaction. The reaction formula is as follows:
Step two: synthesis of SYN001 Compounds
Into a 250ml four-port glass reaction flask, 200g of dichloroethane, 28g (0.071 mol) of 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid synthesized above, 24g (0.20 mol) of thionyl chloride, heating and refluxing for 3-5 hours, cooling to room temperature, transferring the reaction solution to a 500ml rotary evaporator, decompressing and desolventizing to 80 ℃ to obtain an oily liquid of acyl chloride, cooling to about 25 ℃, adding 150g of acetonitrile for dissolution, transferring to the reaction flask, and adding 27.8g (0.08 mol) of raw material of 4- (1, 2, 3-heptafluoropropane-2-yl) -2- (trifluoromethyl) aniline, heating and refluxing for 5-10 hours. Cooling to room temperature, pouring into 300ml ice water to precipitate, extracting 200g dichloroethane, washing with 50ml water for layering to obtain a dichloroethane layer, drying and filtering with anhydrous magnesium sulfate, decompressing and desolventizing to 80 ℃ to obtain oily 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide intermediate, adding 250g of N, N-dimethylformamide for dissolution, transferring the reaction solution into a 500ml reaction bottle, cooling to 0-25 ℃, adding 18g (0.10 mol) of N-bromosuccinimide, and carrying out heat preservation reaction for 5-10 hours. Pouring into 500ml ice water to separate out, extracting with 200g of dichloromethane, washing with 50ml of water to separate the dichloromethane layer, and removing the dichloromethane layer under reduced pressure until the temperature reaches 80 ℃ to obtain 58g of crude product of oily 2-fluoro-3- [ (phenylcarbonyl) (2-methoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide (namely structural formula SYN 001) with the HPLC normalized content of 78%, wherein the three-step reaction yield is 90.0 percent calculated by 2-fluoro-3- [ (2-methoxyethyl) (phenylcarbonyl) amino ] benzoic acid. The reaction formula is as follows:
58g of a crude compound with 78% of HPLC normalization content is recrystallized by using 150g of normal hexane and 50g of ethyl acetate mixed solvent at 0-5 ℃ to obtain 35g of white crystal dry product, wherein the HPLC normalization content is 96%, melting point: 179.5-180.5, single-step crystallization yield 77.4%, step two crystallization yield 69.7%. The total yield after crystallization in the step one and the step two is 38.6 percent.
Synthesis example 4 (preparation method of I-A and II-A)
Preparation of 2-fluoro-3- [ (phenylcarbonyl) (2-ethoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide. (structural formula SYN002 as follows)
Step one:
a similar procedure and feed ratio were followed in step one of Synthesis example 1, wherein 15.8g (0.11 mol) of 1-bromo-2-methoxyethane for N-alkylation was replaced with 17.5g (0.11 mol) of 1-bromo-2-ethoxyethane, with no change in the other conditions.
26g of cold-cured light brown crystals were obtained, the HPLC normalized content being 90%, as 2-fluoro-3- [ (2-ethoxyethyl) (phenylcarbonyl) amino ] benzoic acid (0.070 mol) for use without treatment, directly in the next reaction. The reaction formula is as follows:
step two: synthesis of SYN002 Compounds
The material obtained in step one, (0.070 mol) was used for the synthesis in step two, and the procedure was the same as in step two of synthesis example 1.
Finally, 54.3g of crude 2-fluoro-3- [ (phenylcarbonyl) (2-ethoxyethyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide (i.e. of formula SYN 002) are obtained as an oily crude product, HPLC-normalized content 86%, the three-step reaction yield of this step being 92.4% in terms of 2-fluoro-3- [ (2-ethoxyethyl) (phenylcarbonyl) amino ] benzoic acid. The reaction formula is as follows:
54.3g of crude compound are recrystallized from 150g of normal hexane and 50g of ethyl acetate mixed solvent at 0-5 ℃ to obtain 41g of white crystal dry product, the HPLC normalization content is 96%, melting point: 157.1-157.9, crystallization yield 84.2%, total yield 77.8% after step two crystallization.
The nuclear magnetism and mass spectrum data are as follows:
1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.54(s,1H,CONH),8.39(s,1H),7.92(s,1H),7.63-7.30(m,3H),7.29-7.10(m,5H),4.08-3.45(m,4H),3.44-3.32(m,2H),1.01(t,J＝6.8Hz,3H)。HRMS(ESI)calcd.for C 28 H 20 BrF 11 N 2 NaO 3 [(M+Na) + ]:743.0379[(M+Na) + ],745.0359[(M+2+Na) + ]；Found:743.0370[(M+Na) + ],745.0355[(M+2+Na) + ]。
synthesis example 5
The procedure is analogous to procedure one of synthetic example 4.
The resulting cold-postcured light brown crystals 26g, HPLC normalized to 90%, were 2-fluoro-3- [ (2-ethoxyethyl) (phenylcarbonyl) amino ] benzoic acid (0.070 mol).
Then, 100g of normal hexane plus 20g of ethyl acetate are used for recrystallization at about 0-25 ℃ to obtain 20g of white crystal dry product. HPLC content 98%. Melting point: 129.5-130.2 ℃ and has the following structural formula:
the nuclear magnetism and mass spectrum data are as follows:
1 H-NMR(400MHz,DMSO-d6)δ(ppm):13.27(s,1H,CO2H),7.72-7.55(m,2H),7.35-7.05(m,6H),4.20-3.80(m,2H),3.65-3.45(m,2H),3.32-3.27(m,2H),0.94(t,J＝6.8Hz,3H,CH3)。
HRMS(ESI)calcd.for C 18 H 18 FNNaO 4 [(M+Na) + ]:354.1118；Found:354.1115。
synthesis example 6
Synthesis of 2-fluoro-3- [ (phenylcarbonyl) (3-methoxypropyl) amino ] -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide, has the following structural formula: formula SYN011.
Step one: a similar procedure and feed ratio were followed in step one of Synthesis example 1, wherein 15.8g (0.11 mol) of N-alkylated 1-bromo-2-methoxyethane was replaced with 17.5g (0.11 mol) of 1-bromo-3-methoxypropane, with no change in the other conditions. The yield and content data of the obtained 2-fluoro-3- [ (3-methoxypropyl) (phenylcarbonyl) amino ] benzoic acid are similar.
Step two: according to the similar operation and feeding proportion of the step two of the synthesis example 1, the structure is to obtain a white crystal dry product of the target compound SYN011, wherein the content of HPLC normalized is 96%, and the melting point is as follows: the obtained yield data are similar at 143.1-144.5 ℃.
The nuclear magnetism and mass spectrum data are as follows:
1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.62(s,1H,CONH),8.39(s,1H),7.93(s,1H),7.63-7.30(m,3H),7.27-7.10(m,5H),3.88-3.45(m,2H),3.42-3.32(m,2H),3.16(s,3H,CH3O),1.90-1.60(m,2H)。HRMS(ESI)calcd.for C 28 H 20 BrF 11 N 2 NaO 3 [(M+Na) + ]:743.0379[(M+Na) + ],745.0359[(M+2+Na) + ]；Found:743.0359[(M+Na) + ],745.0343[(M+2+Na) + ]。
synthesis example 7
Synthesis of 2-fluoro-3- { [ (4-fluorophenyl) carbonyl ] (2-ethoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide has the following structural formula: formula SYN004.
Step one, step two: the procedure and the feed ratio were similar in step one and step two of Synthesis example 1, in which 25g (0.20 mol) of benzoic acid was replaced with 28.6g (0.20 mol) of p-fluorobenzoic acid.
N-alkylation 15.8g (0.11 mol) of 1-bromo-2-methoxyethane were replaced by 17.5g (0.11 mol) of 1-bromo-2-ethoxyethane, all other conditions being unchanged. The yield and content data of the obtained target compound are similar.
Melting point: the nuclear magnetism and mass spectrum data at 168.2-169.2 ℃ are as follows:
1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.52(s,1H,CONH),8.38(s,1H),7.92(s,1H),7.67(dd,J＝7.6Hz,and 6.8Hz,1H),7.60-7.50(m,1H),7.48-7.20(m,3H),7.18-6.95(m,2H),4.20-3.72(m,2H),3.68-3.45(m,2H),3.42-3.32(m,2H),1.01(t,J＝6.8Hz,3H,CH3)。
HRMS(ESI)calcd.For C 28 H 19 BrF 12 N 2 NaO 3 [(M+Na) + ]:761.0285[(M+Na) + ],763.0265[(M+2+Na) + ]；Found:761.0263[(M+Na) + ],763.0248[(M+2+Na) + ]。
synthesis example 8
Synthesis of 2-fluoro-3- { [ (3, 5-dichloro-4-methylphenyl) carbonyl ] (2-ethoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide. The structural formula is as follows: SYN021.
Step one, step two: the procedure and proportions of the procedure were analogous to those of step one and step two of synthesis example 1, wherein benzoyl chloride was replaced with 3, 5-dichloro-4-methylbenzoyl chloride, to give the title compound. The yield and content data of the obtained target compound are similar. The total yield calculated on 3, 5-dichloro-4-methylbenzoyl chloride was 63%, melting point: the nuclear magnetism and mass spectrum data at 92.2-93.5 ℃ are as follows:
1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.52(s,1H,CONH),8.36(s,1H),7.92(s,1H),7.74(s,1H),7.61(s,1H),7.50-7.00(m,3H),4.10-3.75(m,2H),3.72-3.50(m,2H),3.40-3.35(m,2H),2.47(s,3H),1.10-0.95(m,3H)。
HRMS(ESI)calcd.for C 29 H 20 BrCl 2 F 11 N 2 NaO 3 [(M+Na) + ]:824.9756[(M+Na) + ],826.9736[(M+2+Na) + ]；Found:824.9444[(M+Na) + ],826.9424[(M+2+Na) + ]。
synthesis example 9
Synthesis of 2-fluoro-3- { [ (4-fluorophenyl) carbonyl ] (2-N-propoxyethyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide has the following structural formula: SYN024.
Step one, step two: the procedure and the feed ratio were similar in step one and step two of Synthesis example 1, in which 25g (0.20 mol) of benzoic acid was replaced with 28.6g (0.20 mol) of p-fluorobenzoic acid.
N-alkylation 1-bromo-2-methoxyethane 15.8g (0.11 mol) of the starting material was replaced with 18.7g (0.11 mol) of 1-bromo-2-N-propoxyethane, with the other conditions and operations being similar. The yield and content data of the obtained target compound are similar. Melting point: 156.5-156.8 ℃.
Synthesis of comparative example 1
Synthesis of 2-fluoro-3- { [ (3, 5-dichloro-4-methylphenyl) carbonyl ] (methyl) amino } -N- [ 2-bromo-4- (1, 2, 3-heptafluoropropane-2-yl) -6- (trifluoromethyl) phenyl ] benzamide.
Following a procedure analogous to that of examples 1,1-3 to 1-7 of chinese CN 102119143B, wherein 1-7 steps, benzoyl chloride was replaced with the same molar amount of 3, 5-dichloro-4-methylbenzoyl chloride, the title compound was obtained in a total yield of 3.8% based on 3, 5-dichloro-4-methylbenzoyl chloride starting material, melting point: the nuclear magnetism and mass spectrum data at the temperature of 124.1-125.3 ℃ are as follows:
1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.65(s,1H,CONH),8.32(s,1H),7.88(s,1H),7.70(s,1H),7.60(s,1H),7.38-7.30(m,3H),3.32(s,3H),2.47(s,3H)。
HRMS(ESI)calcd.for C 26 H 14 BrCl 2 F 11 N 2 NaO 2 [(M+Na) + ]:766.9338[(M+Na) + ],768.9317[(M+2+Na) + ]；Found:766.9321[(M+Na) + ],768.9299[(M+2+Na) + ]。
the structural formula and the reaction formula are as follows:
the compounds in Table II were prepared or preparable by a similar method to those in step I and step II of Synthesis example 1, except for the compounds described above, and the nuclear magnetism and mass spectrum data of a part of the compounds synthesized by reference to Synthesis example 1 are shown in Table II below.
Watch II
Other compounds of formula (I) according to the invention can be synthesized by the methods described above.
Formulation example 1
And (3) preparing a suspending agent sample, namely mixing active ingredients, auxiliary agents, water and the like according to the formula proportion (weight) of the raw materials in the following table III, performing high shearing, performing sand milling for three times by a sand mill, and detecting to be qualified to obtain the suspending agent sample, wherein the active ingredients can be selected from any one of the compounds in the general formula (I) or mixed with the existing pesticide varieties in the market.
Watch III
Formulation example 2
And (3) preparing an emulsifiable concentrate sample, namely heating and stirring auxiliary agents such as active ingredients, solvents, emulsifying agents and the like to be clear and transparent according to the formula proportion (weight) of raw materials in the fourth table, and detecting to be qualified to obtain the emulsifiable concentrate sample, wherein the active ingredients can be selected from one compound suitable for preparing emulsifiable concentrates in the compound shown in the general formula (I) or mixed with the existing pesticide varieties in the market.
Table four
Biological Activity test examples
The test of various pests with partial compounds of the general formula (I) of the compounds obtained according to the invention
Compound preparation: weighing a certain mass of crude drug by using a balance (0.001 g), preparing a 1% mother solution by using DMF, and diluting the mother solution into a test concentration by using distilled water containing 0.1% Tween-80 for later use; if the preparation is prepared, a preparation sample with a certain mass is weighed by a balance (0.001 g) according to the content of the active ingredients of the preparation, and the preparation sample is diluted into a test concentration by distilled water for standby.
Test example 1 Compounds for indoor biological Activity assay on Plutella xylostella
A plutella xylostella (Plutella xylostella) sensitive population and a chlorantraniliprole resistant population, and breeding with radish seedlings indoors;
the test method comprises the following steps: and (3) determining the activity of plutella xylostella: soaking appropriate amount of folium Raphani in the solution for 30s, naturally drying in shade in plastic culture dish filled with filter paper, collecting 10 heads of 2-year-old Plutella xylostella, and placing in a 22 deg.C observation room under illumination (16/8 hr). After 2 days, the insects are touched by a writing brush, no reaction is regarded as dead insects, the process is repeated for 3 times, and a blank control without adding a medicament is additionally arranged.
The results of the measurement of the activity of SYN001 and the like on plutella xylostella are shown in Table five: at the test concentration of 0.2mg/L, the activities of the compounds SYN001, SYN003, SYN004, SYN006, SYN008, SYN011, SYN013 and SYN024 on the sensitive population of the plutella xylostella and the activity of the plutella xylostella against the chlorantraniliprole population reach 100 percent, which is equivalent to that of the comparison sample CK02 bromofluorobenzene bisamide. When the test concentration is 0.1mg/L, the activities of SYN001, SYN003, SYN004, SYN006, SYN008, SYN011, SYN013, SYN021 and SYN024 on the sensitive population of the plutella xylostella are all more than or equal to 90 percent, which is equivalent to that of a comparison sample CK02 bromofluorobenzamide, and the activities of SYN003, SYN004, SYN006, SYN008, SYN011, SYN013 and SYN024 on the population of the plutella xylostella anti-chlorantraniliprole are all 100 percent, which is equivalent to that of a comparison sample CK02 bromofluorobenzamide. At a low concentration of 0.05mg/L, SYN003, SYN004, SYN006, SYN008, SYN011, SYN013 and SYN024 have higher activity on the chlorantraniliprole population of plutella xylostella than the activity of the chlorantraniliprole of the comparison sample CK 02. Unexpectedly, the comparative sample CK05 was inactive against the diamondback moth anti-chlorantraniliprole population at the tested concentrations, indicating that the CK05 compound has cross-resistance to chlorantraniliprole.
The compounds SYN001, SYN003, SYN004, SYN006, SYN008, SYN011, SYN013, SYN021 and SYN024 have no cross resistance with chlorantraniliprole.
Table five results of determination of the Activity of the Compound of general formula (I) on Plutella xylostella
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Test example 2 test of insecticidal quick-acting Properties of Compounds
According to the method of test example 1, compounds SYN001, SYN003, SYN006, SYN008, SYN0011 and CK02 are selected to conduct parallel measurement of insecticidal activity of the plutella xylostella sensitive population, dead numbers are investigated after 12 hours, 24 hours and 48 hours of the drug administration, mortality is calculated, and insecticidal quick-acting effects are compared, and test results are shown in a table six:
the test results show that: compounds SYN001, SYN003, SYN006, SYN008, SYN0011 all showed different degrees of death after 12 hours of administration, and were more effective than the comparative CK02 bromofluorobenzene bisamide.
The results of measuring the quick-acting activity of the compound of general formula (I) on plutella xylostella
Test example 3 Compounds for indoor biological Activity assay on Chilo suppressalis
Chilo suppressalis activity assay: soaking caulis Zizaniae Caduciflorae slice in the water for 30s, naturally drying in shade in plastic culture dish filled with filter paper, inoculating 10 heads of 3-year old Chilo suppressalis, and observing at 26deg.C under illumination (16/8 hr). After 4 days, the insects are touched by a writing brush, no reaction is regarded as dead insects, the process is repeated for 3 times, and a blank control without adding a medicament is additionally arranged.
The test results are shown in Table seven:
the results show that: SYN001, SYN003, SYN004, SYN006, SYN008, SYN011, SYN013 and SYN024 have better activity under the tested concentration, and are equivalent to the comparative sample CK 02. The comparative sample CK05 was not active against chilo suppressalis at the tested concentration.
Table seven part results of determination of Activity of Compounds of general formula (I) on Chilo suppressalis
Test example 4 indoor biological Activity assay of Compounds against Spodoptera frugiperda
Determination of spodoptera frugiperda activity: soaking appropriate amount of corn leaf for 30s, naturally drying in shade in plastic culture dish filled with filter paper, collecting 10 heads of spodoptera frugiperda of 2 years old, and placing in 26 deg.C and illumination (16/8 hr) observation room. After 2 days, the insects are touched by a writing brush, no reaction is regarded as dead insects, the process is repeated for 3 times, and a blank control without adding a medicament is additionally arranged.
The test results are shown in Table eight:
the results show that: SYN001, SYN003, SYN004, SYN006, SYN008, SYN011, SYN013 and SYN024 have better activity under the tested concentration, and are equivalent to the comparative sample CK 02. The control CK05 was not active against spodoptera frugiperda at the concentrations tested.
Table eight part determination of the Activity of the Compounds of formula (I) on Spodoptera frugiperda
In organic molecules, due to the electronegativity, volume size or spatial configuration of substituents, the conductivity or receptor binding variability of the whole molecule in organisms such as insects and plants can be large, the displayed biological activity can also be large, the conductivity and receptor binding suitability of the molecule are unpredictable, and a great deal of creative labor is required for knowing.
In the application, on one hand, the bisamide compound containing the heptafluoroisopropyl is obtained through molecular structure optimization, and experiments show that the bisamide compound has excellent insecticidal activity, particularly has excellent high insecticidal activity on resistant populations, has no interactive resistance with the existing insecticidal chlorantraniliprole, and has good insecticidal effect and good quick-acting performance at low dose; on the other hand, the preparation method of the compound shown in the general formula (I) is simple, efficient and easy for industrial production, and has wide application prospect in the fields of agriculture, forestry and gardening for pest control.
The inventors state that the present application describes a bisamide compound containing a heptafluoroisopropyl group, and a preparation method and application thereof by the above-described representative examples, but the present application is not limited to the above-described examples, and does not mean that the present application can be realized by depending on the above-described examples. It should be apparent to those skilled in the art that any modification of the present application, equivalent substitution of raw materials for the product of the present application, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present application and the scope of disclosure.

Claims (2)

1. A compound of formula (i-v):
wherein R is 1 Independently selected from H, fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, trifluoromethoxy, methyl, ethyl, methanesulfonyl, cyano, or nitro;
R 2 independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
n is independently 1 or 2.
2. The compounds of the general formula (I-V) according to claim 1, characterized in that they are used in the field of synthetic pesticides.
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