WO2021169606A1 - 阿维菌素B2a衍生物及其制备方法与应用 - Google Patents

阿维菌素B2a衍生物及其制备方法与应用 Download PDF

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WO2021169606A1
WO2021169606A1 PCT/CN2021/070074 CN2021070074W WO2021169606A1 WO 2021169606 A1 WO2021169606 A1 WO 2021169606A1 CN 2021070074 W CN2021070074 W CN 2021070074W WO 2021169606 A1 WO2021169606 A1 WO 2021169606A1
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formula
compound represented
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moles
dichloromethane
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French (fr)
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张建军
许庆博
李金明
张江波
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中国农业大学
内蒙古嘉宝仕生物科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of agricultural organic chemistry, and specifically relates to a novel type of abamectin B2a structure where 2,3-position and 23,24-position are ethylenic bonds, and 4"-substituted derivatives (abbreviated as "abamectin”) B2a homoene derivatives”), their preparation methods and their application as insecticides.
  • abamectin B2a structure where 2,3-position and 23,24-position are ethylenic bonds
  • 4"-substituted derivatives abamectin B2a structure where 2,3-position and 23,24-position are ethylenic bonds
  • 4"-substituted derivatives abamectin B2a structure where 2,3-position and 23,24-position are ethylenic bonds
  • 4"-substituted derivatives abamectin B2a structure where 2,3-position and 23,24-position are ethylenic bonds
  • Abamectin is a widely used agricultural or veterinary antiseptic, insecticide, and acaricide, also known as Amethin.
  • Abamectin is a type of sixteen-membered macrolide compound with bactericidal, insecticidal, acaricidal and nematicidal activities first developed by Omura Tomo from Kitasato University in Japan and Merck in the United States. The mold Streptomyces Avermitilis is produced by fermentation.
  • Abamectin contains 8 structurally similar components A1a, A2a, A1b, A2b, B1a, B2a, B1b and B2b, among which the biological activity of the B component is far superior to that of the A component.
  • the commercial abamectin pesticide technical is based on abamectin B1a as the main active ingredient (B1a is not less than 90%, and Bla/Blb>20), which is calibrated by the mass fraction of B1a.
  • B1a is not less than 90%, and Bla/Blb>20
  • the component B2a with low control effect on target pests is separated and discarded as a by-product.
  • the chemical structures of B1a and B2a As follows (J. Am. Chem. Soc. 1981, 103, 4216-4221):
  • the chemical structure difference between B1a and B2a is in the following two aspects (specially marked by the dashed box in the figure above): First, the 22 and 23-positions of B1a are ethylenic bonds, while the 22, 23 of B2a The-position is a saturated single bond; secondly, the 23 position of B1a does not contain a hydroxyl group (OH), while the 23 position of B2a contains a hydroxyl group (OH).
  • B1a Because of its high-efficiency and broad-spectrum insecticidal activity, it has become a widely used insecticide in the market, and B2a has become a fermentation by-product with extremely low commercial value. Therefore, the structural modification of the natural fermentation by-product B2a and the search for compounds with higher biological activity than B2a are of great significance for the efficient use of B2a and the creation of new drugs.
  • One aspect of the present invention relates to a novel abamectin B2a with an ethylenic bond between the 2,3-position and 23,24-position, and a 4"-substituted derivative as shown in formula I (abbreviated as "Avitin” B2a homoene derivatives”), their preparation methods and insecticidal compositions comprising at least one of them as an active ingredient.
  • the present invention also relates to the preparation methods of the compositions and the control of these new compounds and compositions Harmful pests, especially for controlling crop beet armyworm, diamondback moth, root knot nematode and other insecticidal activities.
  • R is selected from any one of the following groups: hydroxyl (Ia), amino (Ib), NHR 1 (Ic), NHCOR 2 (Id);
  • R 1 and R 2 in the NHR 1 and NHCOR 2 groups are as follows:
  • R1 and R2 are the same or different, and each independently represents: C1-C6 alkyl substituted or unsubstituted by halogen or C1-C3 alkyl, C3-C6 alkenyl substituted or unsubstituted by halogen or C1-C3 alkyl , C3-C6 alkynyl substituted or unsubstituted by halogen or C1-C3 alkyl.
  • alkyl group itself or as part of another substituent will be the following groups: for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. and their isomers Such as isopropyl, isobutyl, tert-butyl, isopentyl and so on.
  • halogen refers to fluorine, chlorine, bromine, and iodine, and fluorine, chlorine and bromine are preferred.
  • C3-C6 alkynyl groups refer to unsaturated aliphatic groups containing up to 6 carbon atoms, such as propargyl, 2-butynyl, 3-butynyl and the like.
  • the compounds represented by the general formula (I) are stable white solids. They have high-value insecticidal activity and can be used for pest control in agriculture and other related fields.
  • the compounds of formula (I) are It has good insecticidal activity in a wide concentration range.
  • avermectin B2a homoene derivative pesticides acceptable salt also belongs to the protection scope of the present invention, and the salt can be an organic acid salt or an inorganic acid salt, such as benzoate, substituted benzoate, Citrate, lactate, aldonic acid, hydrochloride or sulfate.
  • the present invention also provides a method for synthesizing the compound represented by the above formula (I):
  • the method includes:
  • the compound represented by the formula (Ia) is the compound defined when R in the formula (I) is a hydroxyl group.
  • the compound represented by the formula (Ic) is the compound defined when R is NHR 1 in the formula (I).
  • the compound (Ib) is the compound defined when R in the formula (I) is an amino group.
  • the compound represented by the formula (Id) is the compound defined when R is NHCOR 2 in the formula (I).
  • R in the compound of formula (I) is amino (compound Ib) or alkylamino (compound Ic)
  • the present invention also provides a method for preparing compounds Ib and Ic to form salts.
  • the method for preparing compounds Ib and Ic to form a salt includes the following steps: dissolving compound Ib or Ic in an organic solvent, adding a salt-forming reagent and concentrating and drying to obtain the salt-forming product of the corresponding target derivative.
  • the organic solvent is selected from at least one of common organic solvents such as dichloromethane, dichloroethane, trichloromethane, tetrahydrofuran and ethyl acetate;
  • the salt-forming reagents are benzoic acid, substituted benzoic acid, citric acid, Organic or inorganic acids such as lactic acid, aldonic acid, hydrochloric acid, or sulfuric acid.
  • the organic solvent is selected from dichloromethane, 1,2-dichloroethane, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, trichloromethane, tetrachloromethane, At least one of petroleum ether, chlorobenzene, dioxane and tetrahydrofuran, further may be selected from at least one of dichloromethane, 1,2-dichloroethane and isopropyl acetate, and further may be two Methyl chloride; relative to 1 mole of abamectin B2a, the amount of organic solvent can be 1-100L, further 2-10L, still further 3-5L, specifically 4L.
  • the alkaline medium is selected from at least one of pyridine, triethylamine, ethylenediamine, tetramethylethylenediamine, triethylenediamine, and N-methylmorpholine; it can be further selected from pyridine and triethylamine , At least one of tetramethylethylenediamine, and further can be tetramethylethylenediamine; relative to 1 mole of abamectin B2a (the same amount is mentioned below), the amount of alkaline medium is 1 -50 moles, further 1.05-20 moles, still further 1.2-10 moles, specifically 2.3 moles.
  • the amount of the protective agent allyl chloroformate can be 2-12 moles, further 2-6 moles, still further 2-3 moles, for example 2.4 moles.
  • Suitable reaction conditions include: the temperature may be -30°C to 30°C, further -30°C to 10°C, and the time may be 1-10 hours, and further 1-2 hours.
  • the organic solvent is selected from at least one of dichloromethane, n-hexane, benzene, toluene, chloroform, tetrachloromethane, petroleum ether, chlorobenzene, dioxane, methanol and tetrahydrofuran Species, further selected from at least one of dichloromethane, trichloromethane and tetrahydrofuran, and furthermore dichloromethane; relative to 1 mole of the compound represented by formula (II), the amount of organic solvent can be 1-100L, and further It is 2-10L, and further is 3-5L, such as 3.2L.
  • the elimination reagent is selected from at least one of acetic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride, and benzenesulfonyl chloride; further selected from trifluoromethanesulfonic anhydride or methanesulfonyl chloride;
  • the sulfonyl chloride is further trifluoromethanesulfonic anhydride; relative to 1 mol of the compound represented by formula (II), the amount of the elimination reagent can be 0.5-20 mol, further 1-10 mol, and still further 1-5 mol, For example, 1.2 moles.
  • the organic base is selected from pyridine, triethylamine, ethylenediamine, tetramethylethylenediamine, triethylenediamine, N-methylmorpholine, tetramethylammonium hydroxide, potassium tert-butoxide, monoethanolamine , At least one of triethanolamine; further selected from at least one of pyridine, triethylamine, tetramethylethylenediamine, and still further pyridine.
  • the amount of organic base used is 1-50 mol, further 1.05-20 mol, still further 1.2-10 mol, specifically 3.9 mol.
  • the elimination catalyst is at least one of DBU (1,8-diazabicycloundec-7-ene), DMAP (4-dimethylaminopyridine), sodium sulfate, potassium sulfate, 4-picoline Species, further selected from DBU and/or DMAP.
  • the amount of the catalyst used is 0.1-5 mol, further 0.1-2 mol, and still further 0.1-1.5 mol, relative to 1 mol of the compound represented by formula (II).
  • Suitable reaction conditions include: the temperature can be -50°C to 40°C, further -30°C to 20°C, and further -5°C to -0°C; time can be 1-10 hours, further 2-3 hours.
  • the reaction is further carried out in an inert atmosphere, such as a nitrogen atmosphere.
  • the organic solvent is selected from at least one of dichloromethane, n-hexane, benzene, toluene, chloroform, tetrachloromethane, petroleum ether, chlorobenzene, dioxane, methanol and tetrahydrofuran
  • One is further selected from at least one of dichloromethane, trichloromethane and tetrahydrofuran, and further is dichloromethane; relative to 1 mole of the compound represented by formula (III), the amount of organic solvent can be 1-100L, Further it is 2-10L, still further it is 3-5L, for example 3.1L.
  • the amount of the catalyst tetrakistriphenylphosphine palladium can be 0.001-0.1 parts by mass, further 0.005-0.03 parts by mass, and still further 0.01-0.02 parts by mass.
  • the amount of sodium borohydride used is 0.001-0.1 parts by mass relative to 1 part by mass of the compound represented by formula (III), further 0.01-0.04 parts by mass, and still further 0.02-0.03 parts by mass.
  • Suitable deprotection reaction conditions include: the temperature can be from -10°C to 20°C, and further from 0°C to 5°C; the time can be from 0.5 to 4 hours, and further to 1-2 hours.
  • the organic solvent is selected from dichloromethane, 1,2-dichloroethane, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, trichloromethane, tetrachloromethane, At least one of petroleum ether, chlorobenzene, dioxane and tetrahydrofuran, further selected from at least one of dichloromethane, 1,2-dichloroethane and isopropyl acetate, and furthermore dichloromethane Relative to 1 mole of the compound represented by the formula (Ia), the amount of the organic solvent can be 1-100L, further 2-10L, still further 3-5L, specifically 3.1L.
  • the alkaline medium is selected from at least one of pyridine, triethylamine, ethylenediamine, tetramethylethylenediamine, triethylenediamine, and N-methylmorpholine; Methyl ethylene diamine, most further is tetramethyl ethylene diamine; relative to 1 mole of the compound represented by formula (Ia), the amount of alkaline medium used is 1-10 moles, further 1.05-5 moles, and still further 1.2-3 moles, specifically 2.3 moles.
  • the amount of the protective agent allyl chloroformate is 1-8 mol, further 1-3 mol, still further 1-1.2 mol, specifically 1.17 mol.
  • Suitable reaction conditions include: the temperature can be between -30°C and 30°C, and the time is between 0.5-24 hours.
  • the organic solvent is selected from at least one of dichloromethane, n-hexane, benzene, toluene, chloroform, tetrachloromethane, petroleum ether, chlorobenzene, dioxane and tetrahydrofuran, and further At least one selected from dichloromethane, trichloromethane and tetrahydrofuran, further dichloromethane; relative to 1 mole of the compound represented by formula (IV), the amount of organic solvent can be 1-100L, further 2- 10L, furthermore 3-5L, specifically 3.1L.
  • the base is selected from at least one of pyridine, triethylamine, ethylenediamine, tetramethylethylenediamine, triethylenediamine, and N-methylmorpholine; further selected from pyridine, triethylamine, tetramethyl Ethylenediamine is further tetramethylethylenediamine; relative to 1 mol of the compound represented by formula (IV), the amount of base used is 1-10 mol, further 1.05-5 mol, and still further 1.2-3 mol , Such as 2.3 moles.
  • the amount of oxidizing agent dimethyl sulfoxide is 1-8 moles, further 2-5 moles, and still further 2.8-3 moles; benzene dichloride phosphoric acid
  • the amount of fat used is 0.5-6 moles, further 0.8-5 moles, and still further 1-2 moles.
  • Suitable oxidation reaction conditions include: the temperature may be -30°C to 0°C, further -20°C to -10°C, the time may be 0.5-2 hours, and further 0.6-1 hour.
  • the organic solvent is selected from dichloromethane, 1,2-dichloroethane, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, trichloromethane, tetrachloromethane, At least one of petroleum ether, chlorobenzene, dioxane and tetrahydrofuran, further selected from at least one of dichloromethane, 1,2-dichloroethane, and isopropyl acetate, and most further is dichloromethane Relative to 1 mole of the compound represented by the formula (V), the amount of the organic solvent can be 1-100L, further 1-10L, still further 1-5L, specifically 2.2L.
  • the Lewis acid is selected from at least one of acetic acid, propionic acid, zinc trifluoroacetate, zinc chloride, zinc p-toluenesulfonate, boron trifluoride, aluminum chloride, iron chloride, and antimony pentafluoride, and At least one selected from the group consisting of acetic acid, zinc chloride, and zinc trifluoroacetate, the most further being acetic acid and/or zinc trifluoroacetate; the amount of Lewis acid used is 0.01 to 1 mole of the compound represented by formula (V) 10 mol, further 0.05-5 mol, still further 0.10-4 mol; the amount of alkyl ammonia (R 1 NH 2 ) can be 1.5-50 mol, further 3-20 mol, still further 5-10 mol
  • the amount of the reducing agent sodium borohydride is 0.001-0.5 parts by weight, further 0.005-0.3 parts by weight, and still more 0.01- 0.02 parts by weight.
  • Suitable conditions for amination and reduction reactions include: the temperature can be from -30°C to 50°C, further from 5°C to 25°C, and further from 10°C to 15°C, and the time can be 0.5-8 hours, and further 0.5-2 hours. .
  • the organic solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, methanol, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, chloroform, and tetrachloroethane.
  • At least one of methane, petroleum ether, chlorobenzene, dioxane, and tetrahydrofuran further selected from at least one of dichloromethane, 1,2-dichloroethane, methanol, and isopropyl acetate, the most further It is a mixed solvent of dichloromethane and methanol, the volume ratio of the two can be 10:1 to 1:1, specifically 3:1; relative to 1 mole of the compound represented by formula (VI), the amount of organic solvent can be It is 1-100L, further 2-10L, still further 3-5L, specifically 3.6L.
  • the amount of palladium tetrakis-triphenylphosphorus catalyst may be 0.001-0.1 parts by mass, further 0.005-0.03 parts by mass, and still further 0.01-0.02 parts by mass;
  • the amount of sodium borohydride used is 0.001-0.1 parts by mass, further 0.01-0.04 parts by mass, and still further 0.02-0.03 parts by mass.
  • Suitable deprotection reaction conditions include: temperature can be -10°C-20°C, further 0°C-5°C; time can be 0.5-4 hours, further 1-2 hours.
  • the organic solvent is selected from dichloromethane, 1,2-dichloroethane, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, chloroform, tetrachloromethane, petroleum ether At least one of chlorobenzene, dioxane and tetrahydrofuran, further selected from at least one of dichloromethane, 1,2-dichloroethane, and isopropyl acetate, and furthermore is dichloromethane;
  • the amount of the organic solvent can be 1-100L, further 2-10L, still further 3-5L, specifically 3.1L.
  • the Lewis acid is selected from at least one of zinc trifluoroacetate, zinc chloride, zinc p-toluenesulfonate, boron trifluoride, aluminum chloride, iron chloride, and antimony pentafluoride, and is further selected from zinc chloride , At least one of zinc p-toluenesulfonate and zinc trifluoroacetate, and further is zinc trifluoroacetate; relative to 1 mole of the compound represented by formula (V), the amount of Lewis acid used is 0.01-10 moles, which is selected as 0.05-5 moles, further 0.10-3 moles; the amount of hexamethyldisilazane can be 1.5-50 moles, further 3-20 moles, further 4.5-10 moles, specifically 4.7 moles; Relative to 1 part by mass of the compound represented by formula (V), the amount of the reducing agent sodium borohydride can be 0.001-0.5 parts by mass, further 0.005-0.4 parts by mass, and still further 0.01-0.
  • Suitable conditions for the amination and reduction reaction include: the temperature can be 0°C-80°C, further 5°C-70°C; the time can be 1-8 hours, further 1-2 hours.
  • the organic solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, methanol, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, chloroform, and tetrachloroethane.
  • At least one of methane, petroleum ether, chlorobenzene, dioxane and tetrahydrofuran further selected from at least one of methylene chloride, 1,2-dichloroethane, methanol and isopropyl acetate, and further It is a mixed solvent of dichloromethane and methanol.
  • the volume ratio of the two can be 10:1 to 1:1, specifically 3:1.
  • the amount of organic solvent can be 1-100L, further 2-10L, still further 3-5L.
  • the amount of the catalyst tetrakistriphenylphosphine palladium can be 0.001-0.1 parts by mass, further 0.005-0.03 parts by mass, and still further 0.01-0.02 parts by mass; boron
  • the amount of sodium hydride used is 0.001-0.1 parts by mass, further 0.01-0.04 parts by mass, and still further 0.02-0.03 parts by mass.
  • Suitable deprotection reaction conditions include: temperature can be -10°C-20°C, further 0°C-5°C; time can be 0.5-4 hours, further 1-2 hours.
  • the organic solvent is selected from dichloromethane, 1,2-dichloroethane, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, trichloromethane, tetrachloromethane, At least one of petroleum ether, chlorobenzene, dioxane and tetrahydrofuran, further selected from at least one of dichloromethane, 1,2-dichloroethane and isopropyl acetate, and furthermore dichloromethane Relative to 1 mole of the compound represented by formula (VII), the amount of organic solvent can be 1-100L, further 1-10L, still further 1-5L, specifically 1.8L.
  • the alkaline medium is selected from at least one of pyridine, triethylamine, ethylenediamine, tetramethylethylenediamine, triethylenediamine, and N-methylmorpholine; further selected from pyridine, triethylamine, Tetramethylethylenediamine is further pyridine; relative to 1 mol of the compound represented by formula (VII), the amount of alkaline medium used is 0.1-10 mol, further 0.1-5 mol, and still further 0.1-3 mol .
  • the amount of the acylating agent anhydride or acid chloride is 0.1-8 mol, further 0.1-3 mol, and still further 0.1-1.2 mol.
  • Suitable acylation reaction conditions include: temperature can be -30°C-50°C, further 0°C-30°C; time can be 1-30 hours, further 1-24 hours.
  • the organic solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, methanol, isopropyl acetate, ethyl acetate, n-hexane, benzene, toluene, chloroform, and tetrachloroethane.
  • At least one of methane, petroleum ether, chlorobenzene, dioxane and tetrahydrofuran further selected from at least one of methylene chloride, 1,2-dichloroethane, methanol and isopropyl acetate, and further It is a mixed solvent of dichloromethane and methanol, the volume ratio of the two can be (10-1):1, specifically 3:1; relative to 1 mole of the compound represented by formula (VIII), the amount of organic solvent can be It is 1-100L, further 2-10L, still further 3-5L, specifically 3.6L.
  • the amount of the catalyst tetrakistriphenylphosphine palladium can be 0.001-0.1 parts by mass, further 0.005-0.03 parts by mass, and still further 0.01-0.02 parts by mass; boron
  • the amount of sodium hydride used is 0.001-0.1 parts by mass, further 0.01-0.04 parts by mass, and still further 0.03-0.04 parts by mass.
  • Suitable deprotection reaction conditions include: temperature can be -10°C-20°C, further 0°C-5°C; time can be 0.5-4 hours, further 1-2 hours.
  • the amount of the salt-forming reagent may be 1-8 moles, further 1-3 moles, and further 1-1.2 moles relative to 1 mole of the compound represented by formula (Ib) or formula (Ic) .
  • the compound Ia of the present invention is an important intermediate for preparing insecticidal, acaricidal and nematicidal compounds. As a novel compound, it becomes one of the objectives of the present invention.
  • the salt-formed products of compounds Ia, Ib, Ic, Id and Ib, Ic show very good active ingredients, and show high prevention or treatment in insecticide, acaricide, nematode control, etc. It has the characteristics of high activity, wide insecticidal spectrum, no resistance, safety, and long residual effect.
  • the compounds of the present invention can be used to successfully control, in particular, Lepidoptera, Coleoptera, Orthoptera, Isoptera, Rodents, Anoptera, Trichophagus, Thysanoptera, etc. Harmful organisms such as Pteroptera, Hemiptera (such as aphids), Hymenoptera, Diptera, Siphonaptera, Thysanura and Acarina, especially Acarina, Diptera, Thysanoptera, Lepidoptera And Coleoptera and other harmful organisms.
  • Harmful organisms such as Pteroptera, Hemiptera (such as aphids), Hymenoptera, Diptera, Siphonaptera, Thysanura and Acarina, especially Acarina, Diptera, Thysanoptera, Lepidoptera And Coleoptera and other harmful organisms.
  • Venus genus Acaroid (such as Acaroid mites), Tumor mites (such as Citrus Tumor mites), Long-winged Moth, Woodmoth, Bee-spotted Moth, Peeled Moth, Neighbors Plutella, Leafminer, Sword Spodoptera, Spodoptera, Spodoptera, Acupuncture Gall Mite (such as Acupuncture Gall Mite) ), Aedes genus, Pterodactylus genus, Diptera genus, Lithocarpus genus, Click beetle genus, Spodoptera spp (such as beet armyworm), Spodoptera litura, Spodoptera cotton leaf, Spodoptera , Quercus sylvestris, Cervus sylvestris, Saccharomyces spp, Oligodactylus spp, Whitefly spp, Trialeurodes vaporariorum, Whitefly spp, Cabbage white
  • sphaeroides spp. Golden Spotted Spodoptera Genus, Spodoptera, Chrysosphaeria, Brown Buckler, Orange-brown Buckler stage, Black-brown Buckler stage, Goldgrass Borer, Chiroptera, Colin, Drosophila, Grapefruit Codling moth, Double Propionis, Cnaphalocrocis spp, Cnaphalus spp, Soft clams, Wide-eating brown soft scales, Slugs moths, Coleus spp., Jiabei spruce moths Moth genus, Noctuidae genus, Lychee genus, Rice borer genus, Ringworm genus, Noctuidae genus, Rhizocephala genus, Heterodactylus genus, Cossid genus, Pyrocephalus genus, Gray lamp moth, Pyrola sylvestris, Pan-African Pyrola sy
  • Noctura genus Noctura genus, Noctura genus, Pyrola sylvestris, Pyrocera sylvestris genus, Sphaerotheca genus, Moth genus, Pitfly genus, Spodoptera genus, Noctuid genus, Flower thrips Genus, Juglans spp., Stomachida, S. sylvestris, S. sylvestris, Spruce S. sylvestris, Tsetus spp., S. sylvestris, S.
  • Berry Ruler Moth Yellow Spodoptera, Micronocida, Pterodactylus, Spodoptera, Spinymoth, Small House Ant, Small House Ant, Pigumoth, Housefly Genus, Pseudomonas spp., Spodoptera spp., Aphid spp., Noctuidae spp., Longhorn moth spp., Neopine leaf wasp spp., Spodoptera spp., Black-tailed leafhopper spp., Green bug spp., Brown planthopper , Nebo genus, Noctura genus, Tubule genus, Small worm genus, Shipmoth genus, Silk moth genus, Spodoptera genus, Pine nest moth genus, Madfly genus, New small worm genus, Heye Moth genus, Clawworm genus, Pseudocystis genus, Noctura
  • Geometridus Sphingidae, Pyrocephalidae, Geometridus, Ultralittle Moth, Brown Sphagnum, Spodoptera, Spodoptera, Panonychus, Variety , Berry Moth, Quasi-transpterous Moth, Noctuidae, Ring-winged Moth, Micrograss Borer, Red Bollworm, Red Bell Wheat Moth, Louse, Spring Fly, Bok Spring Fly, Pterocephalus spp., Pterocephalus spp., Gallus spp., Spodoptera spp., Periplaneta spp., Zhougemoth spp., S. spp., Protoxella spp., S.
  • spp. Spodoptera spp., Spodoptera spp., Black and white sphincter spp. , Narrow-striped moths, Small-footed moths, Sting fly genus, Squishys genus, Brown nest moth genus, Noctuidae genus, Pterodactylus genus, Chironomus spp.
  • the compounds of the present invention can also be used to control pests of mites.
  • the mites include: spider mites (for example, Tetranychus cinnabarinus), gall mites, acaroid mites, tarsal mites, tarsal mites, dwarf mites, Tetranychus mites, port mites, root mites, oriole mites, phytosei mites, long hair mites Mites, mesei mites, cancer mites, semi-mange mites, giant whiskers, sucking mites, carnivorous mites, velvet mites and big red mites, etc.,
  • the compounds of the present invention can also be used to control harmful organisms in the class of nematodes.
  • the pests include: for example, Meloidogyne, Cyst Nematode, Ditylenchus, Leaf Nematode, etc.;
  • cyst nematode genera such as Heterodera glycines; Heteroderm genus, such as Solanum tuberosum; Root-knot nematodes such as Meloidogyne incognita, Meloidogyne javanica, and Heteroderm, such as Heterodera soy; perforation Nematodes, such as similar perforated nematodes; Pratylenchus neglectans, such as Pratylenchus neglectans and Paratylenchus puncture nematodes; Dalmatian nematodes, such as semi-perforated nematodes; Long needle nematodes, Trichodonta spp., Sword nematodes Genus, Ditylenchus, Apheenchoides and Anguilla.
  • the compounds of the present invention can be used to control, ie inhibit and/or eliminate harmful organisms that appear on plants, especially harmful organisms on useful plants and ornamental plants in agriculture, horticulture and forestry, or appear in various parts of said plants. Fruits, flowers, leaves, stems, tubers or roots of the above-mentioned types of pests. After using the compound of the present invention, sometimes the plant parts that grow later can also be protected from harmful organisms.
  • Target crops especially include grains such as wheat, barley, rye, oats, rice, corn and sorghum; sugar beets such as sugar beets and fodder beets; fruits such as pome, stone fruit, soft nuts and citrus fruits, Such as apples, pears, plums, peaches, apricots, oranges, lemons, grapefruit and mandarin oranges, cherries and berries such as strawberries, raspberries and blackberries; legumes such as kidney beans, lentils, peas and soybeans; oil plants , Such as rape, mustard, poppy, olive, sunflower, coconut, sesame oil, cocoa, and groundnut; Cucurbitaceae, such as gourd, cucumber, and melon; fibrous plants, such as cotton, flax, hemp, and jute; vegetables, such as spinach, kudzu , Asparagus, cabbage, carrots, onions, tomatoes, potatoes and peppers; Lauraceae, such as avocado, cinnamon and camphor; and tobacco, nuts, coffee
  • the present invention also relates to a pesticide composition containing at least one compound of the present invention.
  • the pesticide composition includes an avermectin B2a homoene derivative (the compound represented by formula I) and an agriculturally acceptable carrier.
  • the avermectin B2a homoene derivative can be a single compound of the present invention or a mixture of several compounds of the present invention.
  • the pesticide composition can be prepared into any dosage form that is acceptable in pesticide science, such as emulsifiable concentrates, colloidal suspensions, directly sprayable or dilutable solutions, coatable pastes, thin emulsions, wettable powders, soluble powders, and soluble powders. Dispersible powder, wettable powder, powder, granule and polymer encapsulation, the specific dosage form can be selected according to the expected target and environment.
  • Active ingredients are calculated in pure form, such as solid active ingredients of a specific particle size, or further used in those compositions together with at least one conventional adjuvant in formulation technology, such as fillers such as solvents or solid carriers , Or surface active compounds (surfactants), in the field of parasite control for humans, domestic animals, productive livestock and pets, only physiologically acceptable additives can be used.
  • Suitable solvents are: aromatic hydrocarbons, preferably hydrocarbons containing 8 to 12 carbon atoms, such as mixed xylene or substituted naphthalene; aliphatic or cycloaliphatic hydrocarbons, such as paraffin or cyclohexane; ketones, such as cyclohexane Hexanone, isophorone or diacetone alcohol; alcohols, such as ethanol, propanol or butanol; glycols and their acyls and esters, such as propylene glycol, dipropylene glycol, ethylene glycol or ethylene glycol monomethyl Acyl or monoethyl ether; strong polar solvents such as N-methylpyrrolidin-2-one, dimethyl sulfoxide or N,N-dimethylformamide, water, unepoxidized or epoxidized vegetable oil , Such as unepoxidized or epoxidized rapeseed oil, castor oil, coconut oil or soybean oil, and silicone oil.
  • the solid carriers used for eg powders and dispersible powders are usually calcite, talc, kaolin, montmorillonite, attapulgite, silicic acid, pumice, broken brick, sepiolite, bentonite, dolomite, plant residue powder.
  • the surface active compound is a nonionic, cationic and/or anionic surfactant or a mixture of surfactants with good emulsifying, dispersing and wetting properties.
  • the following surfactants are to be regarded as examples only; many other surfactants that are conventional in formulation technology and suitable according to the present invention are described in the relevant literature.
  • Nonionic surfactants are especially tallow nonylphenol-polyethoxyethanol, castor oil polyglycol ether, polyoxypropylene-polyoxyethylene adduct, tributylphenoxypolyethoxyethanol, poly Ethylene glycol, octylphenoxypolyethoxyethanol, polyoxyethylene sorbitan trioleate.
  • the cationic surfactant is especially a quaternary ammonium salt containing at least one alkyl group having 8-22 carbon atoms as a substituent and a lower non-halogenated or halogenated alkyl group, a benzyl group or a lower hydroxyalkyl group as the other Substituents.
  • the salt is further in the form of halide, methyl sulfate or ethyl sulfate. Examples are stearoyl-trimethyl-ammonium chloride and benzyl-bis-(2-chloroethyl)-ethyl-ammonium bromide.
  • Suitable anionic surfactants can be water-soluble soaps and water-soluble synthetic surface-active compounds.
  • Suitable soaps are the sodium or potassium salts of oleic acid or stearic acid, or the sodium or potassium salts of naturally occurring fatty acid mixtures that can be obtained, for example, from coconut oil or tall oil; in addition to the fatty acid methyl-taurine Acid salt.
  • synthetic surfactants are more often used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.
  • Fatty acid sulfonates and sulfates are usually in the form of alkali metal salts, alkaline earth metal salts, or substituted or unsubstituted ammonium salts, usually having an alkyl group of 8-22 carbon atoms, and the alkyl group also includes the alkyl group of the acyl group.
  • alkali metal salts usually having an alkyl group of 8-22 carbon atoms
  • the alkyl group also includes the alkyl group of the acyl group.
  • Examples are the sodium or calcium salt of lignin sulfonic acid, the sodium or calcium salt of dodecyl sulfonate, or the sodium or calcium salt of a mixture of fatty alcohol sulfates made from natural fatty acids.
  • sulfate ester and sulfonate salts of fatty alcohol-ethylene oxide adducts are also included.
  • the sulfonated benzimidazole derivative further contains 2 sulfonic acid groups and a fatty acid group having 8-22 carbon atoms.
  • the alkyl aryl sulfonate is, for example, the sodium, calcium or triethanolammonium salt of dodecylbenzene sulfonic acid, the sodium, calcium or triethanolammonium salt of dibutyl tea sulfonic acid, or naphthalene sulfonic acid -Sodium, calcium or triethanolammonium salt of formaldehyde condensate.
  • Agrochemical preparations usually have an active compound content of 0.1-99%, further 0.1-95%; solid or liquid additives (excluding surfactants) content of 1-99.9%, further 5-99.9%; surface activity
  • the content of the agent is 0-25%, and further 0.1-20%; although the concentrated composition is a further step as a commercial product, the end user usually uses a diluted composition containing a relatively low concentration of the active compound.
  • Emulsifiable concentrate is a liquid crystal
  • Active ingredient 1-90%, preferably 5-20%;
  • Surfactant 1-30%, preferably 10-20%;
  • Solvent 5-98%, preferably 70-85%.
  • Active ingredient 1-99%, preferably 5-65%;
  • Surfactant 0-80%, preferably 0.1-65%;
  • Solvent 5-98%, preferably 70-85%.
  • Stabilizer 0-3%, preferably 0.1-3%;
  • Active ingredient 0.1-10%, preferably 0.1-1%;
  • Solid carrier 99.9-90%, preferably 99.9-99%.
  • Active ingredient 5-75%, preferably 10-50%;
  • Surfactant 1-40%, preferably 2-30%.
  • Active ingredient 0.5-90%, preferably 25-80%;
  • Surfactant 0.5-20%, preferably 1-15%;
  • Solid carrier 5-99%, preferably 15-98%.
  • Active ingredient 0.5-30%, preferably 5-20%;
  • Solid carrier 99.5-70%, preferably 95-80%.
  • composition of the present invention may also contain other solid or liquid additives, such as stabilizers, such as vegetable oils or epoxidized vegetable oils (such as epoxidized coconut oil, rapeseed oil or soybean oil), antifoaming agents, such as silicone oil, preservatives , Viscosity modifiers, adhesives and/or tackifiers, as well as fertilizers or other active ingredients used to obtain special effects, such as acaricides, bactericides, fungicides, nematicides, molluscicides or Selective herbicide.
  • stabilizers such as vegetable oils or epoxidized vegetable oils (such as epoxidized coconut oil, rapeseed oil or soybean oil)
  • antifoaming agents such as silicone oil, preservatives , Viscosity modifiers, adhesives and/or tackifiers, as well as fertilizers or other active ingredients used to obtain special effects, such as acaricides, bactericides, fungicides, nematicides
  • the pesticide composition of the present invention is prepared in a known manner, in the absence of auxiliary agents, for example, by grinding, sieving and/or squeezing a solid active ingredient or a mixture of active ingredients to, for example, a certain particle size, and at least In the presence of an adjuvant, for example, by first mixing/or grinding the active ingredient or a mixture of active cinnamon ingredients and the adjuvant.
  • auxiliary agents for example, by grinding, sieving and/or squeezing a solid active ingredient or a mixture of active ingredients to, for example, a certain particle size, and at least In the presence of an adjuvant, for example, by first mixing/or grinding the active ingredient or a mixture of active cinnamon ingredients and the adjuvant.
  • an adjuvant for example, by first mixing/or grinding the active ingredient or a mixture of active cinnamon ingredients and the adjuvant.
  • the invention also relates to methods for preparing the compositions of the invention and the use of compounds of formula (I) in preparing these compositions.
  • the present invention also relates to a method of using the above-mentioned pesticide composition, that is, a method for controlling the above-mentioned types of harmful organisms, such as spraying, misting, dusting, coating, seed dressing, broadcasting or pouring, and the method is based on the expected target.
  • the typical concentration and dosage is 0.1-1000ppm, preferably 0.1-500ppm active ingredient.
  • the dosage per hectare is usually 1-2000 g active ingredient/ha, especially 10-1000 g/ha, preferably 20-600 g/ha; more preferably 20-100 g/ha.
  • a further application method is to apply the pesticide to the leaves of the plant (foliar application), and the frequency and amount of application depend on the risk of infestation by the pest.
  • foliar application a further application method
  • the site of the plant is impregnated with a liquid formulation or when the active ingredient is incorporated into the site of the plant such as the soil in solid form, for example in granular form (soil application)
  • the active ingredient can also enter the plant through the roots (systemic action) .
  • the particles can be applied to the irrigated rice field in a metered amount.
  • the crop protection products of the present invention are also suitable for protecting plant propagation materials, such as seeds, fruit seeds, tubers or grains, or plant cuttings from animal pests.
  • the propagation material can be treated with the composition before planting; for example, the seeds can be dressed before sowing.
  • the active ingredient of the present invention can also be applied to grains (coating) by dipping seeds in a liquid formulation or coating them with a solid formulation.
  • the composition can also be applied to the planting site when the propagation material is planted, for example to the seed border during the sowing process.
  • the present invention also relates to a method for processing the plant propagation material and the plant propagation material thus treated, thereby imparting insect resistance to this material.
  • the present invention focuses on the synthesis and activity screening of B2a derivative compounds, carries out research work on the comprehensive utilization of abamectin B2, successively designs and synthesizes multiple series of B2a derivatives with brand-new structures, and conducts extensive insecticidal activity determination on target compounds.
  • the patent of the present invention discloses a class of compounds derived from B2 with a novel structure. The 2,3-position and 23,24-position are olefinic bonds, and the 4"-position is amino or methylamino. These compounds have multiple targets Efficient insecticidal activity.
  • Figure 1 is a reaction flow chart of step A in the method for synthesizing the compound of formula (I).
  • Figure 2 is a reaction flow chart of step B in the method for synthesizing the compound of formula (I).
  • Figure 3 is a reaction flow chart of step C in the method for synthesizing the compound of formula (I).
  • Figure 4 is a reaction flow chart of step D in the method for synthesizing the compound of formula (I).
  • Figure 5 is a reaction flow chart of step E in the method for synthesizing the compound of formula (I).
  • Fig. 6 is a reaction flow chart of step F in the method for synthesizing the compound of formula (I).
  • Fig. 7 is a reaction flow chart of step G in the method for synthesizing the compound of formula (I).
  • Fig. 8 is a reaction flow chart of step H in the method for synthesizing the compound of formula (I).
  • Figure 9 is a reaction flow chart of step I in the method for synthesizing the compound of formula (I).
  • Fig. 10 is a reaction flow chart of step J in the method for synthesizing the compound of formula (I).
  • Figure 11 is a reaction flow chart of step K in the method for synthesizing the compound of formula (I).
  • Figure 12 is a hydrogen nuclear magnetic resonance spectrum of the compound represented by formula V prepared in Example 1.5 of the present invention.
  • Figure 13 is a carbon nuclear magnetic resonance spectrum of the compound represented by formula V prepared in Example 1.5 of the present invention.
  • Figure 14 is a hydrogen nuclear magnetic resonance spectrum of the compound represented by formula Ia prepared in Example 1.3 of the present invention.
  • Figure 15 is a carbon nuclear magnetic resonance spectrum of the compound represented by formula Ia prepared in Example 1.3 of the present invention.
  • Figure 16 is a proton nuclear magnetic resonance spectrum of the compound represented by formula Ic (R 1 is CH 3 ) prepared in Example 1.7 of the present invention.
  • Figure 17 is a carbon nuclear magnetic resonance spectrum of the compound represented by formula Ic (R 1 is CH 3 ) prepared in Example 1.7 of the present invention.
  • Figure 18 is a hydrogen nuclear magnetic resonance spectrum of the Ic benzoate prepared in Example 1.12 of the present invention.
  • Figure 19 is a carbon nuclear magnetic resonance spectrum of the Ic benzoate prepared in Example 1.12 of the present invention.
  • Figure 20 is a single crystal structure diagram of the Ic benzoate prepared in Example 1.12 of the present invention (determining the position of the 2,3-ethylenic bond).
  • Figure 21 is a single crystal structure diagram of the Ic benzoate prepared in Example 1.12 of the present invention (determining the position of the 23,24-ethylenic bond).
  • R 1 is CH 3 .
  • R 1 in formula (VI) is CH 3 ;
  • R 1 represents CH 3 .
  • R 2 in formula (VII) is CH 3
  • R 2 in formula (VIII) is CH 3 ;
  • R 2 represents CH 3 .
  • R is hydroxyl (Ia), R is amino (Ib), R is NHR 1 (Ic) or R is NHCOR 2 (Id);
  • R1 and R2 in the groups of compounds (Ic) and (Id) are defined as specified above.
  • the active ingredient described in the following examples may be at least one of the compounds represented by formula I.
  • Example 2.1 Emulsifiable concentrate
  • Example 1 Emulsifiable concentrate a b c Active ingredient 5% 15% 20% Calcium dodecylbenzene sulfonate 5% 8% 6% Castor oil polyglycol ether 5% - - (36mol ethylene oxide, solvent) - - - Tributylphenol Polyethylene Glycol Ether - 12% 4% (30mol ethylene oxide, solvent) - - - Cyclohexanone - 15% 20% Xylene mixture 75% 50% 50% 50%
  • the finely ground active ingredients and additives are mixed to produce a solution suitable for use in droplet form.
  • Example 3 Granules a b c Active ingredient 5% 15% 20% Kaolin 93% - 55% Highly dispersed silicic acid 2% - 7% Attapulgite - 85% 8%
  • the active ingredient was dissolved in dichloromethane, the solution was sprayed onto the carrier mixture, and the solvent was evaporated under reduced pressure.
  • the active ingredients and additives are mixed together, and the mixture is ground in a suitable mill to produce a wettable powder, which can be diluted with water to form a suspension of the desired concentration.
  • the active ingredients are mixed with the additives, the mixture is ground, wetted with water, extruded, granulated, and the granules are dried in a stream of air.
  • the finely ground active ingredient is uniformly applied to kaolin moistened with polyethylene glycol to produce dust-free coated granules.
  • the finely ground active ingredients and additives are mixed to obtain a suspension, and the suspension is diluted with water to produce a suspension of the desired concentration.
  • Example 9 Powder a b Active ingredient 5% 10% talc 95% - Kaolin - 90%
  • the temperature, humidity, and light can be adjusted as needed.
  • the original drug is first completely dissolved in a solvent, and the required concentration of mother liquid is prepared with 0.1% Tween 80 water as required, and then diluted according to the test design dose into a series with a certain concentration gradient Liquid medicine.
  • the 24-well plate method is used. Take 0.5ml of the prepared bacterial suspension (more than 200 second-instar root-knot nematodes) and add it to the 24-well plate, and add 0.5ml of the liquid medicine in the order of the experimental design from low to high, repeat 4 times, and set a blank Contrast.
  • the present invention focuses on the synthesis and activity screening of B2a derivative compounds, carries out research work on the comprehensive utilization of abamectin B2, designs and synthesizes multiple series of B2a derivatives with new structures, and conducts extensive insecticidal activity determination on target compounds.
  • the patent of the present invention discloses a class of compounds derived from B2 with a novel structure. The 2,3-position and 23,24-position are olefinic bonds, and the 4"-position is amino or methylamino. These compounds have multiple targets Efficient insecticidal activity.

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Abstract

本发明公开了一种阿维菌素B2a高烯衍生物及其制备方法与应用。该阿维菌素B2a高烯衍生物的结构式如式I所示。该化合物对多个靶标具有高效的杀虫活性，特别是防治农作物甜菜夜蛾、小菜蛾、根结线虫等杀虫活性用途。

Description

阿维菌素B2a衍生物及其制备方法与应用 技术领域
本发明属于农业有机化学领域，具体涉及一类新颖的阿维菌素B2a结构中2,3-位与23,24-位为烯键,4”-取代的衍生物(简称“阿维菌素B2a高烯衍生物”)，以及它们的制备方法与作为杀虫剂的应用。
背景技术
阿维菌素是一种被广泛使用的农用或兽用杀菌、杀虫、杀螨剂，也称阿灭丁。阿维菌素是由日本北里大学大村智等和美国Merck公司首先开发的一类具有杀菌、杀虫、杀螨、杀线虫活性的十六元大环内酯化合物，由链霉菌中阿维链霉菌Streptomyces Avermitilis发酵产生。阿维菌素含有8个结构相似的组分A1a、A2a、A1b、A2b、B1a、B2a、B1b和B2b，其中B组分的生物活性远远优于A组分。目前以商品化销售的阿维菌素农药原药是以阿维菌素B1a为主要有效成分(其中B1a不低于90％、Bla/Blb>20),以B1a的质量分数来标定。而在阿维菌素B1a的生产过程中，为了获得高纯度的阿维菌素B1a,对目标害虫防治效果低的组分B2a则是作为副产物被分离出来而废弃，B1a和B2a的化学结构如下(J.Am.Chem.Soc.1981,103,4216-4221)：
Figure PCTCN2021070074-appb-000001
从分子结构可以看出，B1a与B2a的化学结构差异在以下两个方面(上图中虚线框特别标出)：其一，B1a的22,23-位为烯键，而B2a的22,23-位为饱和单键；其二，B1a的23位不含有羟基(OH)，而B2a的23位含有一个羟基(OH)，这些化学结构的细微差异造成了二者生物活性的巨大不同，B1a因其高效广谱的杀虫活性而成为市场上广泛使用的杀虫剂，而B2a成为商业价值极低的发酵副产品。因此，针对天然发酵副产物B2a开展结构修饰，寻找比B2a具有更高生物活性的化合物，对B2a的高效利用及新药创制具有重要的意义。
发明公开
本发明一方面涉及一种新颖的阿维菌素B2a的2,3-位与23,24-位之间为烯键,4”-取代的如式I所示的衍生物(简称“阿维菌素B2a高烯衍生物”)，它们的制备方法以及包括它们中的至少一个化合物作为活性成分的杀虫组合物。本发明还涉及所述组合物的制备方法和这些新化合物和组合物防治有害病虫，特别是防治农作物甜菜夜蛾、小菜蛾、根结线虫等杀虫活性用途。
本发明所述阿维菌素B2a高烯衍生物的结构通式如式(Ⅰ)所示：
Figure PCTCN2021070074-appb-000002
所述式(Ⅰ)中，R选自下述任意一种基团：羟基(Ⅰa)、氨基(Ⅰb)、NHR 1(Ⅰc)、NHCOR 2(Ⅰd)；
其中：NHR 1和NHCOR 2基团中R 1、R 2的定义如下：
R1、R2相同或不同，各自独立的表示为：被卤素或C1～C3烷基取代或者未取代的C1～C6烷基，被卤素或C1～C3烷基取代或者未取代的C3～C6烯烃基，被卤素或C1～C3烷基取代或者未取代的C3～C6炔烃基。
根据所表明的碳原子数目，烷基本身或者作为另一个取代基的一部分将是下述基团：例如甲基、乙基、丙基、丁基、戊基、己基等和它们的异构体如异丙基、异丁基、叔丁基、异戊基等。整个说明书中，卤素是指氟、氯、溴、碘，最好选择氟、氯和溴。C3～C6烯烃基是指包括1个或者多个双键的不饱和脂肪基，如：1-丙烯基、烯丙基、1-丁烯基、2-丁烯基、3-丁烯基、CH3CH＝CHCH＝CH-等。C3～C6炔烃基是指最多包含6个碳原子的不饱和脂肪基，如：炔丙基、2-丁炔基、3-丁炔基等。
在通常状况下，通式为式(Ⅰ)所示的化合物是稳定的白色固体，它们具有 很高价值的杀虫活性，能够用于农业和其它相关领域内防治虫害，式(Ⅰ)化合物在较宽的浓度范围下都具有很好的杀虫活性。
在带有上述所定义的R取代基团的式(Ⅰ)的化合物中，下列化合物是非常重要的，因为它们具有特别卓越的杀虫性能：
4”-羟基阿维菌素B2a高烯衍生化合物(化合物Ⅰa，式I中R为羟基的化合物)；
4”-氨基阿维菌素B2a高烯衍生化合物(化合物Ⅰb，式I中R为氨基的化合物)；
4”-甲氨基阿维菌素B2a高烯衍生化合物(化合物Ⅰc1，式I中R为NHR 1，且R 1为甲基的化合物)；
4”-乙基氨基阿维菌素B2a高烯衍生化合物(化合物Ⅰc2，式I中R为NHR 1，且R 1为乙基的化合物)；
4”-乙酰氨基阿维菌素B2a高烯衍生化合物(化合物Id1，式I中R为NHCOR 2，且R 2为甲基的化合物)；
4”-丙酰氨基阿维菌素B2a高烯衍生化合物(化合物Id2，式I中R为NHCOR 2，且R 2为乙基的化合物)。
上述阿维菌素B2a高烯衍生物农药学上可接受的盐也属于本发明的保护范围，所述盐可为有机酸盐或无机酸盐，如苯甲酸盐、取代苯甲酸盐、柠檬酸盐、乳酸盐、醛糖酸盐、盐酸盐或硫酸盐。
另外，上面指出的第一个化合物(化合物Ⅰa)作为进一步合成具有杀虫物质的中间体，具有特别的意义。
另一方面，本发明还提供了如上式(Ⅰ)所示化合物的合成方法：
其中，该方法包括：
A)有机溶剂中，在碱性介质存在下，将阿维菌素B2a和保护试剂氯甲酸稀丙酯在-30℃～30℃之间反应，使得阿维菌素B2a中的C5-OH和4”-OH中的氢替换为烯丙氧羰基得式(Ⅱ)所示化合物；(反应流程图见图1)
Figure PCTCN2021070074-appb-000003
B)将式(Ⅱ)所示化合物在有机碱、消除试剂以及消除催化剂存在下，使得式(Ⅱ)中的C23-OH与C24-H发生脱水消除形成烯键，同时C3＝C4之间的烯键异构为C2＝C3烯键，得到式(Ⅲ)所示化合物；(反应流程图见图2)
Figure PCTCN2021070074-appb-000004
C)在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式(Ⅲ)所示化合物与硼氢化钠反应，得到式(Ⅰa)所示化合物；(反应流程图见图3)
Figure PCTCN2021070074-appb-000005
该式(Ⅰa)所示化合物即为所述式(Ⅰ)中R为羟基时定义的化合物。
进一步的，可以以式(Ⅰa)所示化合物为中间体，制备式(Ⅰc)和式(Ⅰb)所示化合物。
D)有机溶剂中，在碱性介质存在下，将式(Ⅰa)化合物和保护试剂氯甲酸烯丙酯进行反应，使得式(Ⅰa)中的C5-OH中的氢替换为烯丙氧羰基得式 (Ⅳ)所示化合物；(反应流程图见图4)
Figure PCTCN2021070074-appb-000006
E)在有机溶剂中，碱存在下，将式(Ⅳ)与氧化试剂二甲基亚砜、酰氯反应，使得式(Ⅳ)中的C4”-羟基氧化成羰基，得到式(Ⅴ)所示化合物；(反应流程图见图5)
Figure PCTCN2021070074-appb-000007
F)在有机溶剂中，在路易斯酸催化下，将式(Ⅴ)与烷基氨(R 1NH 2)反应，使得式(Ⅴ)中的C4”-羰基氨化为C4”-亚烷氨基后，再加入还原剂硼氢化钠，使得C4”-亚烷氨基还原成C4”-烷氨基，得到式(Ⅵ)所示化合物；(反应流程图见图6)
Figure PCTCN2021070074-appb-000008
其中，R 1NH 2与式(Ⅵ)中R 1的定义同式I；
G)式(Ⅵ)化合物在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式 (Ⅵ)化合物与硼氢化钠反应，脱去C5-OH的保护基团Alloc，得到式(Ⅰc)所示化合物；(反应流程图见图7)
Figure PCTCN2021070074-appb-000009
该式(Ⅰc)所示化合物即为所述式(Ⅰ)中R为NHR 1时定义的化合物。
或者：
H)在有机溶剂中，在路易斯酸催化下，将式(Ⅴ)化合物与六甲基二硅氮烷反应，使得式(Ⅴ)中的C4”-羰基氨化为C4”-亚氨基后，再加入甲醇和还原剂硼氢化钠，使得C4”-亚氨基还原成C4”-氨基，得到式(Ⅶ)所示化合物；(反应流程图见图8)
Figure PCTCN2021070074-appb-000010
I)在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式(Ⅶ)所示化合物与硼氢化钠反应，脱去C5-OH的保护基团Alloc，得到式(Ⅰb)所示物质；(反应流程图见图9)
Figure PCTCN2021070074-appb-000011
该化合物(Ⅰb)即为所述式(Ⅰ)中R为氨基时定义的化合物。
或者：
J)在有机溶剂中，在碱性介质存在下，将式(Ⅶ)与酰化试剂酸酐或酰氯 反应，使得式(Ⅶ)中的C4”-氨基发生酰化反应，得到式(Ⅷ)所示化合物；(反应流程图见图10)
Figure PCTCN2021070074-appb-000012
其中，式(Ⅷ)中R 2的定义同式I；
K)在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式(Ⅷ)所示化合物与硼氢化钠反应，脱去C5-OH的保护基团Alloc，得到式(Ⅰd)所示物质：
Figure PCTCN2021070074-appb-000013
该式(Ⅰd)所示化合物即为所述式(Ⅰ)中R为NHCOR 2时定义的化合物。
当式(Ⅰ)化合物中R为氨基(化合物Ⅰb)或烷氨基(化合物Ⅰc)时，本发明还提供了一种制备化合物Ⅰb、Ⅰc成盐的方法。
所述制备化合物Ⅰb、Ⅰc成盐的方法，包括下述步骤：将化合物Ⅰb或者Ⅰc溶于有机溶剂中，加入成盐试剂浓缩干燥，即得到相应目标衍生物的成盐产物。
其中，所述有机溶剂选自二氯甲烷、二氯乙烷、三氯甲烷、四氢呋喃和乙酸乙酯等常用有机溶剂中的至少一种；成盐试剂为苯甲酸、取代苯甲酸、柠檬酸、乳酸、醛糖酸、盐酸或硫酸等有机酸或者无机酸。
上述方法步骤A)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步可选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，更进一步可为二氯甲烷；相对于1摩尔的阿维菌素B2a， 有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体如4L。
其中，碱性介质选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中的至少一种；进一步可选自吡啶、三乙胺、四甲基乙二胺中的至少一种，更进一步可为四甲基乙二胺；相对于1摩尔的阿维菌素B2a(以下提到用量时候相同)，碱性介质的用量为1-50摩尔，进一步为1.05-20摩尔，更进一步为1.2-10摩尔，具体如2.3摩尔。
其中，相对于1摩尔的阿维菌素B2a，保护试剂氯甲酸烯丙酯的用量可以为2-12摩尔，进一步为2-6摩尔，更进一步为2-3摩尔，具体如2.4摩尔。
合适反应条件包括：温度可以为-30℃至30℃，进一步为-30℃至10℃，时间可以为1-10小时，进一步为1-2小时。
上述方法步骤B)中，所述有机溶剂选自二氯甲烷、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环、甲醇和四氢呋喃中的至少一种，进一步选自二氯甲烷、三氯甲烷和四氢呋喃中的至少一种，更进一步为二氯甲烷；相对于1摩尔式(Ⅱ)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体如3.2L。
其中，消除试剂选自乙酸酐、三氟乙酸酐、三氟甲磺酸酐、甲磺酰氯、对甲基苯磺酰氯、苯磺酰氯中的至少一种；进一步选自三氟甲磺酸酐或甲磺酰氯，更进一步为三氟甲磺酸酐；相对于1摩尔的式(Ⅱ)所示化合物，消除试剂用量可以为0.5-20摩尔，进一步为1-10摩尔，更进一步为1-5摩尔，具体如1.2摩尔。
所述有机碱选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中、四甲基氢氧化铵、叔丁醇钾、一乙醇胺、三乙醇胺中的至少一种；进一步选自吡啶、三乙胺、四甲基乙二胺中的至少一种，更进一步为吡啶。相对于1摩尔的式(Ⅱ)所示化合物，有机碱的用量为1-50摩尔，进一步为1.05-20摩尔，更进一步为1.2-10摩尔，具体如3.9摩尔。
所述消除催化剂为DBU(1,8-二氮杂二环十一碳-7-烯)、DMAP(4-二甲氨基吡啶)、硫酸钠、硫酸钾、4-甲基吡啶中的至少一种，进一步选自DBU和/或DMAP。相对于1摩尔的式(Ⅱ)所示化合物，催化剂的用量为0.1-5摩尔，进一步为0.1-2摩尔，更进一步为0.1-1.5摩尔。
合适反应条件包括：温度可以为-50℃至40℃，进一步为-30℃至20℃，更进一步为-5℃至-0℃；时间可以为1-10小时，进一步为2-3小时。所述反应进一步在惰性气氛中进行，如氮气气氛。
上述方法步骤C)中，所述有机溶剂选自二氯甲烷、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环、甲醇和四氢呋喃中的至少一种，进一步选自二氯甲烷、三氯甲烷和四氢呋喃中的至少一种，更进一步为二氯甲烷；相对于1摩尔的式(Ⅲ)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体如3.1L。
其中，相对于1质量份的式(Ⅲ)所示化合物，催化剂四三苯基膦钯的用量可以为0.001-0.1质量份，进一步为0.005-0.03质量份，更进一步为0.01-0.02质量份。相对于1质量份的式(Ⅲ)所示化合物，硼氢化钠的用量为0.001-0.1质量份，进一步为0.01-0.04质量份，更进一步为0.02-0.03质量份。
合适脱保护反应条件包括：温度可以为-10℃至20℃，进一步为0℃至5℃；时间可以为0.5-4小时，进一步为1-2小时。
上述方法步骤D)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，更进一步为二氯甲烷；相对于1摩尔的式(Ⅰa)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体如3.1L。
其中，碱性介质选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中的至少一种；进一步自吡啶、三乙胺、四甲基乙二胺，最进一步为四甲基乙二胺；相对于1摩尔的式(Ⅰa)所示化合物，碱性介质的用量为1-10摩尔，进一步为1.05-5摩尔，更进一步为1.2-3摩尔，具体如2.3摩尔。
其中，相对于1摩尔的式(Ⅰa)所示化合物，保护试剂氯甲酸稀丙酯的用量为1-8摩尔，进一步为1-3摩尔，更进一步为1-1.2摩尔，具体如1.17摩尔。
合适的反应条件包括：温度可以为-30℃～30℃之间，时间为0.5-24小时。
上述方法步骤E中，所述有机溶剂选自二氯甲烷、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、三氯甲烷和四氢呋喃中的至少一种，进一步为二氯甲烷；相对于1摩尔的式(Ⅳ)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体如3.1L。
其中，碱选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉的至少一种；进一步选自吡啶、三乙胺、四甲基乙二胺，更进一步为四甲基乙二胺；相对于1摩尔的式(Ⅳ)所示化合物，碱的用量为1-10摩尔，进一步 为1.05-5摩尔，更进一步为1.2-3摩尔，具体如2.3摩尔。
其中，相对于1摩尔的式(Ⅳ)所示化合物，氧化试剂二甲基亚砜的用量为1-8摩尔，进一步为2-5摩尔，更进一步为2.8-3摩尔；二氯化磷酸苯脂的用量为0.5-6摩尔，进一步为0.8-5摩尔，更进一步为1-2摩尔。
合适氧化反应条件包括：温度可以为-30℃至0℃，进一步为-20℃至-10℃，时间可以为0.5-2小时，进一步为0.6-1小时。
上述方法步骤F)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，最进一步为二氯甲烷；相对于1摩尔的式(V)所示化合物，有机溶剂的用量可以为1-100L，进一步为1-10L，更进一步为1-5L，具体可为2.2L。
其中，路易斯酸选自乙酸、丙酸、三氟乙酸锌、氯化锌、对甲苯磺酸锌、三氟化硼、氯化铝、氯化铁、五氟化锑中的至少一种，进一步选自乙酸、氯化锌、三氟乙酸锌中的至少一种，最进一步为乙酸和/或三氟乙酸锌；相对于1摩尔的式(V)所示化合物，路易斯酸的用量为0.01-10尔，进一步为0.05-5摩尔，更进一步为0.10-4摩尔；烷基氨(R 1NH 2)的用量可以为1.5-50摩尔，进一步为3-20摩尔，更进一步为5-10摩尔，具体可为9.2摩尔；相对于1质量份的式(V)所示化合物，所述还原剂硼氢化钠的用量为0.001-0.5重量份，进一步为0.005-0.3重量份，更进一步为0.01-0.02重量份。
合适氨化、还原反应条件包括：温度可以为-30℃至50℃，进一步为5℃-25℃，更进一步为10℃-15℃，时间可以为0.5-8小时，进一步为0.5-2小时。
上述方法步骤G)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、甲醇、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、1,2-二氯乙烷、甲醇和乙酸异丙酯中的至少一种，最进一步为二氯甲烷和甲醇的混合溶剂，两者的体积比可为10：1-1：1，具体可为3：1；相对于1摩尔的式(Ⅵ)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体可为3.6L。
其中，相对于1质量份的式(Ⅵ)所示化合物，催化剂四-三苯基磷钯用量可以为0.001-0.1质量份，进一步为0.005-0.03质量份，更进一步为0.01-0.02质量份；硼氢化钠的用量为0.001-0.1质量份，进一步为0.01-0.04质量份，更进一 步为0.02-0.03质量份。
合适脱保护反应条件包括：温度可以为-10℃-20℃，进一步为0℃-5℃；时间可以为0.5-4小时，进一步可为1-2小时。
上述方法步骤H)中，有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，更进一步为二氯甲烷；相对于1摩尔的式(V)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体可为3.1L。
其中，路易斯酸选自三氟乙酸锌、氯化锌、对甲苯磺酸锌、三氟化硼、氯化铝、氯化铁、五氟化锑中的至少一种，进一步选自氯化锌、对甲苯磺酸锌和三氟乙酸锌中的至少一种，更进一步为三氟乙酸锌；相对于1摩尔的式(V)所示化合物，路易斯酸的用量为0.01-10摩尔，选为0.05-5摩尔，更进一步为0.10-3摩尔；六甲基二硅氮烷的用量可以为1.5-50摩尔，进一步为3-20摩尔，更进一步为4.5-10摩尔，具体可为4.7摩尔；相对于1质量份的式(V)所示化合物，还原剂硼氢化钠的用量可为0.001-0.5质量份，进一步为0.005-0.4质量份，更进一步为0.01-0.02质量份；所述甲醇的用量为0.5-5质量份，进一步为1-3质量份，更进一步为1.5-2质量份。
合适氨化、还原反应条件包括：温度可以为0℃-80℃，进一步为5℃-70℃；时间可以为1-8小时，进一步为1-2小时。
上述方法步骤I)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、甲醇、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、1,2-二氯乙烷、甲醇和乙酸异丙酯中的至少一种，更进一步为二氯甲烷和甲醇的混合溶剂，两者的体积比可为10：1-1：1，具体可为3：1，对于1摩尔的式(Ⅶ)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L。
其中，相对于1质量份的式(Ⅶ)所示化合物，催化剂四三苯基膦钯用量可以为0.001-0.1质量份，进一步为0.005-0.03质量份，更进一步为0.01-0.02质量份；硼氢化钠的用量为0.001-0.1质量份，进一步为0.01-0.04质量份，更进一步为0.02-0.03质量份。
合适脱保护反应条件包括：温度可以为-10℃-20℃，进一步为0℃-5℃；时间可以为0.5-4小时，进一步为1-2小时。
上述方法步骤J)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异 丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，更进一步为二氯甲烷；相对于1摩尔的式(Ⅶ)所示化合物，有机溶剂的用量可以为1-100L，进一步为1-10L，更进一步为1-5L，具体可为1.8L。
其中，碱性介质选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中的至少一种；进一步选自吡啶、三乙胺、四甲基乙二胺，更进一步为吡啶；相对于1摩尔的式(Ⅶ)所示化合物，碱性介质的用量为0.1-10摩尔，进一步为0.1-5摩尔，更进一步为0.1-3摩尔。
其中，相对于1摩尔的式(Ⅶ)所示化合物，酰化试剂酸酐或酰氯的用量为0.1-8摩尔，进一步为0.1-3摩尔，更进一步为0.1-1.2摩尔。
合适酰化反应条件包括：温度可以为-30℃-50℃，进一步为0℃-30℃；时间可以为1-30小时，进一步为1-24小时。
上述方法步骤K)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、甲醇、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，进一步选自二氯甲烷、1,2-二氯乙烷、甲醇和乙酸异丙酯中的至少一种，更进一步为二氯甲烷和甲醇的混合溶剂，两者的体积比可为(10-1)：1，具体可为3：1；相对于1摩尔的式(Ⅷ)所示化合物，有机溶剂的用量可以为1-100L，进一步为2-10L，更进一步为3-5L，具体可为3.6L。
其中，相对于1质量份的式(Ⅷ)所示化合物，催化剂四三苯基膦钯用量可以为0.001-0.1质量份，进一步为0.005-0.03质量份，更进一步为0.01-0.02质量份；硼氢化钠的用量为0.001-0.1质量份，进一步为0.01-0.04质量份，更进一步为0.03-0.04质量份。
合适脱保护反应条件包括：温度可以为-10℃-20℃，进一步为0℃-5℃；时间可以为0.5-4小时，进一步为1-2小时。
上述成盐方法中，相对于1摩尔的式(Ⅰb)或式(Ⅰc)所示化合物，成盐试剂的用量可以为1-8摩尔，进一步为1-3摩尔，更进一步为1-1.2摩尔。
再一方面，本发明中化合物Ⅰa是制备杀虫、杀螨、杀线虫化合物的重要中间体，它作为一个新颖的化合物而成为本发明的目的之一。
在有害生物防治领域，化合物Ⅰa、Ⅰb、Ⅰc、Ⅰd及Ⅰb、Ⅰc的成盐产物体现出很好的活性成分，在杀虫、杀螨、杀线虫等中体现出了很高的预防或治疗活性，具有活性高、杀虫谱广、无抗药性、安全、残效期长等特点。
在本发明主题的范围内可以使用本发明的化合物可能成功地防治特别是鳞翅目、鞘翅目、直翅目、等翅目、啮虫目、虱目、食毛目、缨翅目、异翅亚目、半翅目(如蚜虫)、膜翅目、双翅目、蚤目、缨尾目和蜱螨目等有害生物，尤其是蜱螨目、双翅目、缨翅目、鳞翅目和鞘翅目等有害生物。
可以特别良好地防治下列有害生物：
金星尺蛾属、粉螨属(如粗脚粉螨)、瘤瘿螨属(如柑桔瘤瘿螨)、长翅卷蛾属、木蛾属、蜂斑螟属、皮细蛾属、邻菜蛾属、潜叶蛾属、剑纹夜蛾属、卷蛾属、狼夜蛾属、针刺瘿螨属(如斯氏针刺瘿螨)褐带卷蛾属(如棉揭带卷蛾)、伊蚊属、透翅属、双纹蛾属、石蛾属、叩甲属、灰翅夜蛾属(如甜菜夜蛾)、波纹夜蛾属、棉叶波纹夜蛾、地夜蛾属、栎钩翅蛾属、鹿尺蛾属、标叶卷蛾属、寡夜蛾属、粉虱属、软毛粉虱、粉虱属、甘蓝粉虱、背巨冬夜蛾属、林尺蛾属、鹿蛾属、鲁夜蛾属、花蜱属、盾缘椿属、西卷蛾属、奂夜蛾属、杂夜蛾属、尺蛾属、芹莱夜蛾属、条麦蛾属、镰翅小卷蛾属、柞蚕属、花象属、棉铃象、干煞夜蛾属、大豆夜蛾、肾圆盾蚧属、秀夜蛾属、光卷蛾属、蚜科、蚜属、斜纹小卷蛾属、潜叶麦蛾属、类黄卷蛾属、黄卷蛾属、灯蛾属、锐缘蜱属、银蛾属、银纹夜蛾属、条小卷蛾属、带卷蛾属、造桥虫属、圆盾蚧属、委夜蛾属、隐食甲属、甜菜隐食甲、切叶蚁属、地蛛属、丫纹夜蛾属、朽木夜蛾属、尖翅小卷蛾属、松果小卷蛾属、枣尖蛾属、松芽果麦蛾属、纹透翅蛾属、粉虱属、甘薯粉虱、毛蚊属、黑.毛蚊、蜚蠊属、小蠊属、睫冬夜蛾属、尖须夜蛾属、霜尺蛾属、家蚕蛾属、卜夜蛾属、牛蜱属、甘薯麦蛾属、暗水螟属、短须螨属、苔螨属、粉蝶尺蛾属、干夜蛾属、玉米干蛾属、白沙尺蛾属、石竹卷蛾属、果斑螟属、干果斑螟、尺蛾属、冶冬夜蛾属、丽蝇属、红头丽蝇、标冬夜蛾属、花细蛾属、烟卷蛾属、委夜峨属、灰尺蛾属、蛀果蛾属、桃蛀果蛾、迁粉蝶属、蛮夜蛾属、金钱松草小卷蛾属、美加锻卷蛾属、茎蜂属、斑条夜峨属、翎夜蛾属、小条实蝇属、角叶蚤属、蜡蚧属、凹胫跳甲属、蚤凹胫跳甲、大戟透翅蛾属、洽夜蛾属、榆织蛾属、卡夜蛾属、奇尺蛾属、禾草螟属、痒满属、色卷蛾属、金斑夜蛾属、锞纹夜蛾属、金蝇属、褐圆盾蜂属、橙褐圆盾阶、黑褐圆盾阶、金草螟属、绮钩蛾属、臭虫属、果蠢蛾属、葡萄果蠹蛾、双斜卷蛾属、纵卷叶野螟属、云卷蛾属、软蛤属、广食褐软蚧、细卷蛾属、鞘蛾属、焦尺蛾属、加布云杉细卷蛾属、峦冬夜蛾属、荔枝尖细蛾属、米螟属、环斑夜蛾属、兜夜蛾属、根颈象属、禾尖蛾属、木蠹蛾属、草螟属、灰灯蛾属、绒毛螟属、泛非绒毛螟、弧翅卷蛾属、透明缓夜蛾属、蚱蝉属、隐斑螟属、异形小卷蛾属、桃异形小卷蛾、隐卷蛾属、斜栉柄卷蛾属、栉首蚤属、冬夜蛾属、象虫属、库蚊属、疽蝇属、小卷蛾属、苹果 皮小卷蛾、寡鬃实蝇属、线夜蛾属、茸毒蛾属、白腰天蛾属、松毛虫属、织蛾属、皮蠹属、皮刺螨属、鸡皮刺螨、金弧夜蛾属、绢野螟属、歹夜蛾属、杆草螟属、棕麦蛾属、梢斑螟属、棉铃虫属、苏丹棉铃虫、松叶蜂属、松叶蜂科、幽夜蛾属、盲蝽属、可可狄盲蝽、月织蛾属、叉蚤属、镰钩蛾属、果蝇属、黑尾果蝇、透点阴鹿蛾属、棉红蝽属、涤尺蛾属、山卷蛾属、金刚钻属、槐小卷蛾属、刺槐英螟属、尺蛾属、栖夜蛾属、斑螟属、谐夜蛾属、小绿叶蝉属、清夜蛾属、皮小卷蛾属、黑小卷蛾属、歧角螟属、始叶螨属、鹅耳栃始叶螨、粉斑螟属、白斑小卷蛾属、叶小卷蛾属、淡褐卷蛾属、蛛蛾属、洲尺蛾属、癞象属、尺蛾属、小绮夜蛾属、芽谷虻属、瘿螨属、棉蚜属、苹果棉蚜、斑叶蝉属、枝灯蛾属、紫草蛾属、英斑螟属、花小卷蛾属、长翅蝶属、显松伏弗尺蛾属、棕卷蛾属、纹尺蛾属、小花尺蛾属、锦夜蛾属、黄毒蛾属、犹冬夜蛾属、网斑螟属、东风夜蛾属、扁盾蝽属、广颜寄蝇属、文夜蛾属、切夜蛾属、暗斑螟属、薄翅野螟属、树麦蛾属、桑小卷蛾属、厕蝇属、麦穗夜蛾属、夜蛾属、花蓟马属、胡桃麦蛾属、胃蝇属、麦蛾属、吉松叶蜂属、云杉吉松叶蜂、舌蝇属、雕蛾属、绢野螟属、黑麦蛾属、尺蟻蛾属、健角敛夜蛾属、细蛾属、松苗夜蛾属、小食心虫属、松球果小卷蛾属、核桃小卷蛾属、云杉尖小卷蛾属、蝼蛄属、草毒蛾属、柳小卷蛾属、血虱属、哈灯蛾属、巢蛾属、烟翅斑蛾属、广翅小卷蛾属、实夜蛾属、网夜蛾属、实夜蛾属、菜心野螟属、蛀茎夜蛾属、篱蓟马属、双纹螟属、狭翅夜蛾属、刺蛾属、灯蛾属、雕蛾属、同斑螟属、长卷蛾属、卷蛾属、实叶峰属、委夜蛾属、卷蛾属、璃眼蜱属、角剑夜蛾属、涅尺蛾属、天蛾属、松天蛾属、麦蛾属、白蛾属、美国白蛾、鹰夜蛾属、皮蝇属、虱蝇属、斑蝶属、艺夜蛾属、条细卷蛾属、姬尺蛾属、极夜蛾属、逸色夜蛾属、污灯蛾属、硬蜱属、尺蛾属、亮冬夜蛾属、突尾尺蛾属、茄茎麦蛾属、番茄茎麦蛾、唇尖蛾属、硬毛夜蛾属、美皮夜蛾属、灰飞虱属、毛蚁属、皮小卷蛾属、瘦跗叶甲属、马铃薯叶甲、稻缘蝽属、球蚧属、欧果坚球蚧、蛎盾蚧属、衣鱼属、台湾衣鱼、粘夜蛾属、白翅野螟属、蜚蠊属、马德拉蜚蠊、纹潜蛾属、旋纹潜蛾、颚虱属、粉啮虫属、稻水象属、俚夜蛾属、潜叶细蛾属、珂冬夜蛾属、果冬夜蛾属、花翅小卷蛾属、花翅小卷蛾、叶尺蛾属、飞蝗属、褶尺蛾属、夜蛾属、锥额野螟属、绿蝇属、毒蛾属、潜蛾属、银锭夜蛾属、大窗钩蛾属、蛀心夜蛾属、长管蚜属、天幕毛虫属、稻粗角螟属、甘蓝夜蛾属、甘蓝夜蛾、烟草天蛾、刷须野螟属、豆小卷蛾属、潜蝇属、、小卷蛾属、准蜂属、鳃金龟属、莹叶甲属、辐射松洁卷蛾属、麦点半途夜蛾属、贯夜蛾属、莓尺蛾属、黄尖翅麦蛾属、微夜蛾属、翅须刺蛾属、毛胫夜蛾属、刺蛾属、小家蚁属、小家蚁、皮谷蛾属、家蝇属、髓斑螟属、光腹 夜蛾属、瘤蚜属、螟蛉夜蛾属、长角蛾属、新松叶蜂属、切夜蛾属、黑尾叶蝉属、绿蝽属、褐飞虱属、尼波羽蛾属、模夜蛾属、瘤蛾属、小卷蛾属、舟蛾属、蚕蛾属、狼夜蛾属、松巢蛾属、狂蝇属、新小卷蛾属、禾夜蛾属、爪冬夜蛾属、秋尺蛾属、夜蛾属、扁蛾属、嘴壶夜蛾属、钝缘蜱属、古毒蛾属、麦杆夜蛾属、稻瘿蚊属、切根属、胖夜蛾属、梦尼夜蛾属、锯谷盗属、麦杆蝇属、瑞典麦杆蝇、壁蜂属、秆野螟属、亚洲玉米螟、欧洲玉米螟、耳象属、尾尺蛾属、大天蛾属、尖须野螟属、尺蛾属、超小卷蛾属、褐卷蛾属、小眼夜蛾属、小眼夜蛾、全爪螨属、变丽蝇属、浆果小卷蛾属、准透翅蛾属、夜蛾属、环翅卷蛾属、微草螟属、红铃虫属、红铃麦蛾、虱属、泉蝇属、波菜泉蝇、刺小卷蛾属、透翅蛾属、瘿绵蜡属、疆夜蛾属、大蠊属、周尺蛾属、实小卷蛾属、原细卷蛾属、细卷蛾属、黑野螟属、庭园斑象属、草种蝇属、麻篱灯蛾属、麦蛾属、马铃薯麦蛾、叶潜蛾属、皱叶刺瘿蟠属、柑桔皱叶刺瘿螨、小潜细蛾属、姬夜蛾属、根瘤蚜属、粉蝶属、菜粉蝶、皮蝽属、臀纹粉蚧属、茎麦蛾属、石竹小卷蛾属、大羽蛾属、谷斑螟属、弧翅夜蛾属、菜蛾属(如小菜蛾)、透翅蛾属、灰夜蛾属、弧丽金龟属、展冬夜蛾属、多食跗线蟠属、侧多食跗线螨、巢蛾属、木蠹蛾属、条草螟属、尺卷蛾属、波翅天蛾属、傲天蛾属、木蛾属、日足饰羽蛾属、粘虫属、果象属、白盾蚧属、弱蚀卷蛾属、粉蚧属、翅小卷蛾属、瘙螨属、木虱属、蚤跳甲属、羽蛾属、铅卷蛾属、綿蚧属、械叶绵蚧、螟蛾属、野螟属、新西兰按松卷蛾属、莹叶甲属、笠圆盾蚧属、莽夜蛾属、散白蚁属、实小卷蛾属、绕实蝇属、苹绕实蝇、扁头蜱属、根螨属、谷蠹属、红猎蝽属、缢管蚜属、黑痣小卷蛾属、沁夜蛾属、梢小卷蛾属、象虫属、涓夜蛾属、桑蝗属、淡剑夜蛾属、杂食尺蛾属、褐盲蝽属、可可褐盲蝽、黑盔蚧属、樗蚕蛾属、带叶蝉属、疥螨属、尖翅蛾属、金龟科、黑卵蜂属、沙漠蝗属、二叉蚜属、山背舟蛾属、举肢蛾属、眼蕈蚊属、白禾螟属、橘硬蓟马属、苔螟属、岩尺蛾属、黑蝽属、幽夜蛾属、庶尺蛾属、蛀茎夜蛾属、透翅蛾属、寡夜蛾属、刀夜蛾属、扇夜蛾属、长管蚜属、米象属、麦蛾属、火蚁属、目天蛾属、矛夜蛾属、长须卷蛾属、彩翅卷蛾属、蜂形透翅蛾属、红节天蛾属、白小卷蛾属、贪夜蛾属、棉贪夜蛾、黑白尖蛾属、举肢蛾属、窄纹蛾属、小尺蛾属、螫蝇属、曲小卷蛾属、褐巢蛾属、集冬夜蛾属、兴透翅蛾属、同环足摇蚊属、纹卷蛾属、锌纹夜蛾属、夹竹桃鹿蛾属、虻属、带蓟马属、塘蜩属、跗线螨属、特夜蛾属、粉甲属、灰尺蛾属、曲翼冬夜蛾属、叶蟠属、异舟蛾属、豆小卷蛾属、蓟马属(如棕榈蓟马、烟蓟马)、顿袋蛾属、尖尾网蛾属、幕谷蛾属、大蚊属、卷蛾科属、卷蛾属、陌夜蛾属、粉虱属、温室粉虱、椎猎蝽属、拟谷盗属、嚼虱属、粉夜蛾属、粉纹夜蛾、个木虱 属、柑个木虱、彩毛夜蛾属、光尺蛾属、斑皮蠹属、红棒球灯蛾属、缨突野螟属、尖盾蚧属、柑桔尖盾蚧、拟三色星灯蛾属、胡蜂属、小透翅蛾属、美冬夜蛾属、潢尺蛾属、客蚤属、印鼠客蚤、鲁夜蛾属、木冬夜蛾属、木虻属、喜巢蛾属、巢蛾属、斑克松夜蛾属、镰须夜蛾属、线小卷蛾属、透翅蛾属、豹蠹蛾属、斑蛾属。
在本发明主题的范围内还可以使用本发明的化合物防治螨虫类的有害生物。所述螨虫包括：叶螨(例如朱砂叶螨)、瘿螨、粉螨、跄线螨、蒲螨、矮蒲螨、叶爪螨、浦口螨、根螨、甲螨、植绥螨、长须螨、美绥螨、巨蟹螨、半疥螨、巨须螨、吸螨、肉食螨、绒螨及大赤螨等，
在本发明主题的范围内还可以使用本发明的化合物防治线虫纲的有害生物。所述害虫包括：例如根结线虫属，胞囊线虫、茎线虫以及叶线虫等；
特别是胞囊线虫属，例如甜菜包囊线虫；球异皮线虫属，例如马铃薯金线虫；根结线虫属如南方根结线虫、爪哇根结线虫和异皮线虫属例如大豆异皮线虫；穿孔线虫属，如相似穿孔线虫；短体线虫属，如落选短体线虫(Pratylenchus neglectans)和穿刺短体线虫；小垫刃线虫属，如半穿刺线虫；长针线虫属、毛刺线虫属、剑线虫属、茎线虫属、滑刃线虫属(Apheenchoides)和鳗线虫属。
本发明的化合物可用于防治即抑制和/或消灭出现在植物上的有害生物，特别是在农业、园艺和林业中的有用植物和观赏植物上的有害生物，或出现在所述植物的各部分如果实、花、叶、茎、块茎或根上的上述类型的有害生物。使用本发明所述的化合物后，有时之后生长的植物部分也能受到保护免于那些有害生物的侵袭。
靶标作物特别包括谷物，如小麦、大麦、黑麦、燕麦、稻、玉米和高粱；甜菜，如糖用甜菜和饲用甜菜；水果，例如梨果、核果、无核小果和柑橘类水果，如苹果、梨、李子、桃、杏、橙、柠檬、葡萄柚和中国柑桔、樱桃和浆果，例如草莓、覆盆子和黑莓；豆科植物，如菜豆、小扁豆、豌豆和大豆；油料植物，如油菜、芥末、罂粟、橄榄、向日葵、椰子、蒐麻油、可可和落花生；葫芦科，如葫芦、黄瓜和甜瓜；纤维植物，例如棉花、亚麻、大麻和黄麻；蔬菜，例如菠菜、葛苣、芦笋、卷心菜、胡萝卜、洋葱、番茄、马铃薯和辣椒；樟科，例如鳄梨、肉桂和樟脑；和烟草，坚果，咖啡，茄子，糖用甘蔗，茶，胡椒，葡萄，蛇麻子，香蕉，天然橡胶植物和观赏植物。
本发明还涉及含至少一种本发明所述化合物的农药组合物。
该农药组合物包括阿维菌素B2a高烯衍生物(式I所示的化合物)和农业上可接受的载体。
所述阿维菌素B2a高烯衍生物既可为本发明的单一化合物，也可为本发明几种化合物的混合物。
所述农药组合物可制备成为农药学上可接受的任意剂型，如乳油、胶悬剂、可直接喷雾或可稀释溶液、可涂敷的糊剂、稀乳剂、可湿性粉剂、可溶性粉剂、可分散性粉剂、可湿性粉剂、粉剂、颗粒剂和聚合物的包囊，具体剂型可根据预期的目标和环境进行选择。
活性成分以纯的形式计算，例如特定粒径的固体活性成分，或进一步与至少一种制剂技术中的常规助剂一起，用于那些组合物，所述常规助剂如填充剂例如溶剂或固体载体，或表面活性化合物(表面活性剂)，在人、家养动物、生产性牲畜和宠物的寄生虫防治领域，只能使用生理学上可容许的添加剂。
合适的溶剂有：芳香烃，最好选择含有8到12个碳原子的烃，如混合的二甲苯或取代萘；脂族或环脂族烃，如石蜡或环己烷；酮类，如环己酮、异佛尔酮或双丙酮醇；醇类，如乙醇、丙醇或丁醇；二元醇及其酰类和酯类，如丙二醇、二丙二醇、乙二醇或乙二醇单甲酰或单乙醚；强极性溶剂如N-甲基吡咯烷-2-酮，二甲基亚砜或N,N-二甲基甲酰胺，水，未环氧化的或环氧化的植物油，如未环氧化的或环氧化的菜籽油、蓖麻油、椰子油或豆油，和硅油。
用于例如粉剂和可分散性粉剂的固体载体通常是方解石、滑石、高岭土、蒙脱土、硅镁土、硅酸、浮石、碎砖、海泡石、膨润土、白云石、植物残渣粉末。
根据欲配制的活性化合物的性质，表面活性化合物是具有良好的乳化、分散和润湿性能的非离子、阳离子和/或阴离子表面活性剂或表面活性剂混合物。下列表面活性剂仅视为实例；在制剂技术中常规的并且按照本发明适宜的许多其他表面活性剂描述于相关文献中。
非离子表面活性剂尤其是脂壬基酚-聚乙氧基乙醇、蓖麻油聚乙二醇醚、聚氧丙烯-聚氧乙烯加合物、三丁基苯氧基聚乙氧基乙醇、聚乙二醇、辛基苯氧基聚乙氧基乙醇、聚氧乙烯脱水山梨糖醇三油酸酯。
阳离子表面活性剂尤其是季胺盐，所述季铵盐含有至少一个具有8-22个碳原子的烷基作为取代基和低级非卤代或卤代烷基、苯甲基或低级羟基烷基作为其他取代基。盐进一步是卤化物、甲基硫酸盐或乙基硫酸盐的形式。实例是硬脂酰-三甲基-氯化胺和苯甲基-二-(2-氯乙基)-乙基-溴化铵。
适宜的阴离子表面活性剂可以是水溶性皂和水溶性合成的表面活性化合物。适宜的皂是油酸或硬脂酸的钠盐或钾盐，或可由例如椰子油或妥尔油中获得的天然存在的脂肪酸混合物的钠盐或钾盐；此外还有脂肪酸甲基-牛磺酸盐。然而，更经常使用的是合成的表面活性剂，特别是脂肪磺酸盐、脂肪硫酸盐、磺化苯并 咪唑衍生物或烷基芳基磺酸盐。脂肪酸磺酸盐和硫酸盐通常是碱金属盐、碱土金属盐或取代的或未取代的铵盐的形式，通常具有8-22个碳原子的烷基，所述烷基也包括酰基的烷基部分；实例是木质素磺酸的钠盐或钙盐，十二烷基磺酸酯的钠盐或钙盐，或由天然的脂肪酸制得的脂肪醇硫酸盐混合物的钠盐或钙盐。还包括脂肪醇-环氧乙烷加合物的硫酸酯盐和磺酸盐。磺化苯并咪唑衍生物进一步含2个磺酸基和具有8-22个碳原子的脂肪酸基。烷基芳基磺酸盐是例如十二烷基苯磺酸的钠盐、钙盐或三乙醇铵盐，二丁基茶磺酸的钠盐、钙盐或三乙醇铵盐，或萘磺酸-甲醛缩合物的钠盐、钙盐或三乙醇铵盐。
农用化学制剂通常活性化合物的含量为0.1-99％，进一步为0.1-95％；固体或液体助剂(不包括表面活性剂)的含量为1-99.9％，进一步为5-99.9％；表面活性剂的含量为0-25％,进一步为0.1-20％；尽管浓缩的组合物作为商品是更进一步的，但最终用户通常使用含有相对较低浓度的活性化合物的稀释的组合物。进一步的组合物尤其具有如下的组成(％＝重量百分率)：
乳油：
活性成分：    1-90％,   优选5-20％；
表面活性剂：  1-30％，  优选10-20％；
溶剂：        5-98％,   优选70-85％。
溶液剂：
活性成分：    1-99％,   优选5-65％；
表面活性剂：  0-80％，  优选0.1-65％；
溶剂：        5-98％,   优选70-85％。
稳定剂：      0-3％，   优选0.1-3％；
粉剂：
活性成分：    0.1-10％,   优选0.1-1％；
固体载体：    99.9-90％， 优选99.9-99％。
胶悬剂：
活性成分：    5-75％,   优选10-50％；
水：          94-24％,  优选88-30％；
表面活性剂：  1-40％,   优选2-30％。
可湿性粉剂：
活性成分：     0.5-90％,  优选25-80％；
表面活性剂：    0.5-20％,  优选1-15％；
固体载体：       5-99％,    优选15-98％。
颗粒剂：
活性成分：     0.5-30％,   优选5-20％；
固体载体：     99.5-70％,  优选95-80％。
本发明的组合物还可含其他固体或液体助剂，如稳定剂，例如植物油或环氧化植物油(例如环氧化椰子油、菜籽油或豆油)、消泡剂，例如硅油，防腐剂，粘度调节剂，粘合剂和/或增粘剂，以及肥料或用于获得特殊效果的其他活性成分，例如杀螨剂、杀细菌剂、杀真菌剂、杀线虫剂、杀软体动物剂或选择性除草剂。
本发明的农药组合物是以已知方式制备的，在无助剂存在下，例如通过研磨、筛分和/或挤压固体活性成分或活性成分的混合物至例如某一粒径，和在至少一种助剂的存在下，例如通过先混合/或研磨活性成分或活桂成分的混合物与助剂。本发明也涉及制备本发明组合物的方法和式(I)化合物在制备这些组合物中的用途。
本发明还涉及上述农药组合物的使用方法，即防治上述类型的有害生物的方法，如喷雾、弥雾、喷粉、包衣、拌种、撒施或浇泼，所述方法根据预期的目标和主要的环境进行选择，典型的浓度用量是0.l-1000ppm，优选0.1-500ppm活性成分。每公顷的用量通常是l-2000g活性成分/公顷，特别是10-1000g/公顷，优选20-600g/公顷；更优选是20-100g/公顷。
在作物保护领域，进一步的施药方法是施药至植物的叶片(叶面施用)，施药的次数和用量取决于被所述有害生物侵扰的危险性。然而，当用液体制剂浸渍植物的位点或当将活性成分以固体形式例如以颗粒形式掺入植物位点例如土壤中(土壤施用)时，活性成分还可通过根(内吸作用)进入植物。在水稻作物的情况下，所述颗粒可以计量的用量施用到灌水的稻田中。
本发明的作物保护产品还适用于保护植物繁殖材料，例如种子，如果实、块茎或谷物，或植物插枝免于动物有害生物的侵袭。繁殖材料可在种植前用组合物处理；例如种子可在播种前拌种。还可通过将种子浸漬于液体制剂或用固体制剂将其包衣将本发明的活性成分施用到谷物上(包衣)。组合物还可在种植繁殖材料时施用到种植位点，例如播种过程中施用到种畦。本发明还涉及所述植物繁殖材料的处理方法和如此处理的植物繁殖材料，由此赋予这种材料的抗虫害性。
此外，本发明所提供的式I所示化合物以及含该式I所示化合物的组合物在防治上述类型的有害生物的用途也属于本发明的保护范围。
本发明聚焦B2a的衍生化合物的合成与活性筛选，开展阿维菌素B2综合利用研究工作，先后设计合成多个系列全新结构的B2a衍生物，并对目标化合物进行了广 泛的杀虫活性测定。本发明专利揭示由B2衍生合成得到的一类结构全新，2,3-位与23,24-位之间为烯键，4”-位为氨基或甲氨基的化合物，这些化合物对多个靶标高效的杀虫活性。
附图说明
图1为式(Ⅰ)所述化合物的合成方法中步骤A的反应流程图。
图2为式(Ⅰ)所述化合物的合成方法中步骤B的反应流程图。
图3为式(Ⅰ)所述化合物的合成方法中步骤C的反应流程图。
图4为式(Ⅰ)所述化合物的合成方法中步骤D的反应流程图。
图5为式(Ⅰ)所述化合物的合成方法中步骤E的反应流程图。
图6为式(Ⅰ)所述化合物的合成方法中步骤F的反应流程图。
图7为式(Ⅰ)所述化合物的合成方法中步骤G的反应流程图。
图8为式(Ⅰ)所述化合物的合成方法中步骤H的反应流程图。
图9为式(Ⅰ)所述化合物的合成方法中步骤I的反应流程图。
图10为式(Ⅰ)所述化合物的合成方法中步骤J的反应流程图。
图11为式(Ⅰ)所述化合物的合成方法中步骤K的反应流程图。
图12为本发明实施例1.5所制备的式V所示化合物的核磁共振氢谱图。
图13为本发明实施例1.5所制备的式V所示化合物的核磁共振碳谱图。
图14为本发明实施例1.3所制备的式Ⅰa所示化合物的核磁共振氢谱图。
图15为本发明实施例1.3所制备的式Ⅰa所示化合物的核磁共振碳谱图。
图16为本发明实施例1.7所制备的式Ⅰc(R 1为CH 3)所示化合物的核磁共振氢谱图。
图17为本发明实施例1.7所制备的式Ⅰc(R 1为CH 3)所示化合物的核磁共振碳谱图。
图18为本发明实施例1.12所制备的Ic苯甲酸盐的核磁共振氢谱图。
图19为本发明实施例1.12所制备的Ic苯甲酸盐的核磁共振碳谱图。
图20为本发明实施例1.12所制备的Ic苯甲酸盐的单晶结构图(确定2,3-烯键位置)。
图21为本发明实施例1.12所制备的Ic苯甲酸盐的单晶结构图(确定23,24-烯键位置)。
实施发明的最佳方式
下面通过具体实施例对本发明进行说明，但本发明并不局限于此，凡在本发明的精神和原则之内所做的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中的定量试验，均设置三次重复实验，结果取平均值。
1，式(Ⅰ)所述化合物的合成具体实施方式：
实施例1.1 4”,5-烯丙基阿维菌素B2a(式Ⅱ)的制备
Figure PCTCN2021070074-appb-000014
向1000mL三口瓶中加入100g(0.112摩尔)的阿维菌素B2a和400mL无水二氯甲烷，溶解充分后，降温到-15℃，加入四甲基乙二胺30g(0.258摩尔)，降温到-20℃，缓慢滴加氯甲酸稀丙酯32g(0.265摩尔)溶无水二氯甲烷50ml的混合溶液，1小时滴完，在-20℃下反应1小时，反应完成后用稀盐酸洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩，过柱得到116g产物Ⅱ，收率98％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)；δ5.68～6.06(m,5H,H9,H10,H11,CH 2＝CH-CH 2O),5.53～5.65(m,1H,H3),5.24～5.46(m,7H,H5,H1″,H19,CH 2＝CH-CH 2O),4.91～5.06(m,1H,H15),4.57～4.86(m,7H,H1′,H8ax2,CH 2＝CH-CH 2O),4.14(d,J＝6.1Hz,1H,H13),3.71～4.03(m,6H,7-OH,H23,23-OH,H5″,H5′,H6),3.41～3.71(m,10H,H25,H17,H3″,H3′,3″-OCH 3,3′-OCH 3),3.36～3.42(m,1H,H2),3.26(m,2H,H4′,H4”),2.48～2.79(m,2H,H12,H24),2.18～2.43(m,6H,H16x2,H2′,H2″),1.76～2.10(m,7H,H18,Me4a,H20),1.45～1.69(m,8H,Me14a,H26,H27x2,H22x2),1.24～1.35(m,6H,Me6′,Me6″),1.19(d,J＝6.9Hz,3H,Me12a),0.86～1.03(m,9H,H28,Me24a,Me26a)； 13C NMR(75 MHz,CDCl 3)δ172.89,154.47,154.35,139.03,137.61,135.30,132.78,131.17,124.43,121.15,120.07,118.41,118.35,117.23,99.30,97.81,94.47,81.33,80.56,80.30,80.15,78.94,76.93,76.30,75.23,73.18,70.47,69.51,68.38,68.21,68.08,67.41,66.79,65.85,56.69,56.11,45.38,40.85,40.41,39.39,36.07,35.38,34.79,34.70,34.15,33.79,29.32,26.93,19.86,19.29,18.01,16.97,14.80,13.43,12.09,11.46.HRMS:calcd for C 56H 82O 19(M+H) +:1059.5529；found,1059.5534.
实施例1.2 4”,5-烯丙氧羰基阿维菌素B2a高烯衍生化合物(式Ⅲ)的制 备
Figure PCTCN2021070074-appb-000015
将式(Ⅱ)所示物质118g(0.112摩尔)溶于350mL无水二氯甲烷，加入吡啶35克(0.442摩尔)，溶解充分后，氮气保护，降温到-5℃，加入三氟甲磺酸酐36.6g(0.130摩尔)，0.5小时滴完，在-5℃下反应2小时，加入消除催化剂DBU 7.61g(1,8-二氮杂二环十一碳-7-烯，0.05摩尔)，并将温度逐渐升至室温下继续反应3小时，液相色谱监测反应完全。反应完成后用稀盐酸洗涤有机相，二氯甲烷萃取，无水硫酸钠干燥后蒸除二氯甲烷，柱层析纯化得到式(Ⅲ)所示的产物105g，收率90％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ5.96–5.72(m,6H,H3,H9,H10,H11,CH 2＝CH-CH 2O),5.51–5.37(m,9H,H1”,H23,H4’,H 4”,H19,CH 2＝CH-CH 2O),5.01(s,1H,H15),4.86–4.66(m,7H,H1’,7-OH,H6,CH 2＝CH-CH 2O),4.33(d,J＝6.4Hz,1H,H13),4.11–3.53(m,11H,H4,20-CH 2,H3’,H3”,H5’,H5”,8-CH 2,22-CH 2),3.50–3.38(m,8H,H17,H25,3’-OCH 3,3”-OCH 3),3.35–3.21(m,2H,18-CH 2),2.19(m,J＝9.7Hz,6H,16-CH 2,2’-CH 2,2”-CH 2),1.77–1.44(m,14H,H12,Me24a,Me14a,Me4a,H26,27-CH 2),1.28(d,J＝6.4Hz,6H,6’-Me,6”-Me),1.19(d,J＝7.0Hz,3H,28-Me),1.00(t,J＝7.4Hz,3H,Me12a),0.80(d,J＝6.7Hz,3H,Me26a). 13C NMR(75MHz,CDCl 3)δ173.20,154.44,154.25,138.94,137.74,134.73,132.94,131.17,124.41,121.19,120.10,118.42,117.86,117.09,99.35,97.83,94.28,81.18,80.69,80.30,80.05,79.01,76.88,76.30,75.25,73.22,70.51,69.53,68.40,68.21,68.09,67.52,66.75,65.86,56.72,56.20,45.43,40.90,40.42,39.39,36.21,35.80,34.80,34.72,34.11,33.84,29.35,26.36,19.95,19.31,18.04,16.99,14.87,13.42,12.21,11.65.HRMS:calcd for C 56H 80O 18(M+H)+:1041.5417；found,1041.5415.
实施例1.3 4”-羟基阿维菌素B2a高烯衍生化合物(式Ia)的制备
Figure PCTCN2021070074-appb-000016
将式(Ⅲ)所示物质116g(0.112摩尔)溶于350mL无水二氯甲烷，溶解充分后，降温到0℃，加入四-三苯基磷钯1.16g(0.01重量份)，加入硼氢化钠2.32g(0.02重量份)，在0℃下反应1小时，反应完成后用稀盐酸洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩,过柱得到94g产物Ⅰa，最终产率为96％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ5.74(dd,3H,H9,H10,H11),5.49–5.35(m,4H,H15,H23,4”-OH,H19),5.04–4.92(m,1H,5-OH),4.79(d,1H,7-OH),4.68(m,2H,H1’,H1”),4.34–4.25(m,1H,H5),4.19–4.07(m,1H,H3),3.96(t,3H,H4,20-CH 2),3.87–3.45(m,7H,H3’,H3”,H13,H5’,H5”CH 2),3.43(d,6H,3’-OCH 3,3”-OCH 3),3.31–3.09(m,3H,H4”,18-CH 2),2.61–2.45(m,2H,H17,H4’),2.31(dd,3H,H25,16-CH 2),2.05(m,4H,2’-CH 2,2”CH 2),1.88–1.46(m,16H,H6,H12,Me24a,Me14a,Me4a,H26,22-CH 2,27-CH 2),1.27(t,6H,6’-Me,6”-Me),1.16(d,3H,28-Me),0.96(t,3H,Me12a),0.77(d,3H,Me26a)； 13C NMR(75MHz,CDCl 3)；δ173.50,139.28,137.79,137.68,134.74,133.07,124.38,120.11,117.86,117.69,117.08,98.17,96.35,94.31,81.22,80.12,80.06,79.05,78.77,77.86,76.88,75.77,73.19,68.14,68.06,67.98,67.78,67.39,66.89,56.21,56.05,45.41,40.23,39.41,36.50,35.80,35.21,34.30,33.86,26.36,19.93,19.63,18.79,18.08,17.34,14.86,12.21,11.65.HRMS:calcd for C 48H 72O 14(M+H) +:873.4995；found,873.4997.
实施例1.4 5-烯丙氧羰基阿维菌素B2a高烯衍生化合物(式Ⅳ)的制备
Figure PCTCN2021070074-appb-000017
将式(Ⅰa)所示物质98g(0.112摩尔)溶于350mL无水二氯甲烷，溶解充 分后，溶解充分后，降温到-15℃，加入四甲基乙二胺30g(0.258摩尔)，降温到-20℃，缓慢滴加氯甲酸稀丙酯16g(0.132摩尔)溶无水二氯甲烷50ml的混合溶液，0.5小时滴完，在-20℃下反应1小时，反应完成后用稀盐酸洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩,过柱得到104g产物Ⅳ，最终产率为97％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ6.03–5.90(m,1H,CH 2＝CH-CH 2-O),5.88–5.68(m,3H,H9,H10,H11),5.67–5.16(m,8H,H15,H23,4”-OH,H19,H5,CH 2＝CH-CH 2-O,H1’),4.98(d,1H,H1”),4.79(d,1H,7-OH),4.65(dt,4H,H5’,H5”,CH 2＝CH-CH 2-O),4.18–4.01(m,2H,H3,H4),3.99–3.52(m,7H,H3’,H3”,H13,20-CH 2,CH 2),3.42(d,6H,3’-OCH 3,3”-OCH 3),3.39–3.35(m,1H,H4”),3.31–3.11(m,2H,18-CH 2),2.54(dd,2H,H17,H4’),2.37–2.01(m,7H,H25,16-CH 2,2’-CH 2,2”CH 2),1.60(dd,16H,H6,H12,Me24a,Me14a,Me4a,H26,,22-CH 2,27-CH 2),1.26(t,6H,6’-Me,6”-Me),1.16(d,3H,28-Me),0.96(t,3H,Me12a),0.76(d,3H,Me26a)； 13C NMR(75MHz,CDCl 3)δ173.15,154.50,138.92,137.77,134.76,133.04,132.78,131.17,124.39,121.22,120.12,118.36,117.85,117.10,98.17,96.35,94.29,81.18,80.56,80.11,79.06,77.87,76.90,76.27,75.77,73.23,73.18,68.39,68.23,68.13,67.99,67.78,66.88,56.20,56.06,45.43,40.22,39.38,36.43,35.80,35.20,34.29,33.88,26.35,19.94,19.30,18.78,18.07,17.34,14.86,12.20,11.65.HRMS:calcd for C 52H 76O 16(M+H) +:957.5206；found,957.5222.
实施例1.5 5-烯丙氧羰基-4”-羰基阿维菌素B2a高烯衍生化合物(Ⅴ)的制备
Figure PCTCN2021070074-appb-000018
将式(Ⅳ)所示物质107g(0.112摩尔)溶于350mL无水二氯甲烷，溶解充分后，降温到-20℃，加入四甲基乙二胺30g(0.258摩尔)，再加入二甲基亚砜25g(0.320摩尔)，滴加二氯化磷酸苯酯25g(0.118摩尔)的50ml二氯甲烷溶液，大约1小时滴完后，在-20℃下继续反应1小时，反应完成后用稀盐酸洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩过柱得到99g产物Ⅴ，产率 93％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ5.93(s,1H,CH 2＝CH-CH 2-O),5.73(dd,3H,H9,H10,H11),5.55(d,2H,H15,H23),5.38(ddd,4H,H19,H5,CH 2＝CH-CH 2-O),5.26(dd,1H,H1’),4.99(d,1H,H1”),4.81(d,1H,7-OH),4.65(dt,4H,H5’,H5”,CH 2＝CH-CH 2-O),4.41(d,1H,H5),4.19(d,2H,H3,H4),4.06(dd,7H,H3’,H3”,H13,20-CH 2,CH 2),3.47(d,6H,3’-OCH 3,3”-OCH 3),3.35(dd,2H,18-CH 2),2.63–2.40(m,2H,H17,H4’),2.30(d,3H,H25,16-CH 2),2.08(d,4H,2’-CH2,2”CH 2),1.85–1.40(m,16H,H6,H12,Me24a,Me14a,Me4a,H26,,22-CH 2,27-CH 2),1.27(dd,6H,6’-Me,6”-Me),1.16(d,3H,28-Me),0.96(t,3H,Me12a),0.76(d,3H,Me26a)； 13C NMR(75MHz,CDCl 3)δ205.59,173.17,154.49,139.02,137.59,134.69,133.04,132.81,131.16,124.48,121.19,120.07,118.37,117.91,117.10,97.72,96.35,94.34,81.31,80.89,80.55,78.87,77.72,76.91,76.28,73.21,70.43,68.20,68.13,68.40,67.97,66.63,57.97,56.18,45.41,40.20,39.36,39.09,36.44,35.80,35.19,34.31,33.85,26.36,19.99,19.31,18.80,18.03,14.88,13.57,12.21,11.65.HRMS:calcd for C 52H 76O 16(M+H) +:955.5050；found,957.5052.
实施例1.6 5-烯丙氧羰基-4”-甲氨基阿维菌素B2a高烯衍生化合物(Ⅵ)的制备
Figure PCTCN2021070074-appb-000019
式(Ⅵ)中R 1为CH 3。
将式(Ⅴ)所示物质107g(0.112摩尔)溶于250mL无水二氯甲烷，溶解充分后，降温到10℃，加入醋酸24g(0.40摩尔)，再加入质量分数40％甲胺的甲醇溶液80g(1.030摩尔)在10℃下反应2小时后，加入硼氢化钠2.14g(0.02重量份)，在15℃下反应1小时，反应完成后依次用稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩过柱得到85g产物Ⅵ，产率78％。
结构确证数据：1H NMR(300MHz,CDCl 3)δ5.8-5.85(m,5H,H-9,H-10,H-11,H-1″,CH 2＝CH-CH 2-O),5.56(m,3H,H-23,CH 2＝CH-CH 2-O),5.35-5.44(m,5H,H-15,H-19,H-3,CH 2＝CH-CH 2-O),5.08(s,1H,NH),4.92(d,1H,H-1′),4.8(s,2H, CH2-8a),4.39-4.50(m,1H,H-5),4.25-4.29(m,1H,H-5″),3.85-4.10(m,7H,H-3′,H-17,H-13,H-5′,H-4″,H-6,7-OH),3.58-3.79(m,1H,H-3″),3.31-3.49(m,11H,3″-OMe,H4,H-25,3′-OMe,N-Me),2.56(m,1H,H-4′),2.01-2.40(m,3H,H-12,H-2′),1.9(s,3H,4-Me),1.10-1.53(m,14H,H-18,H-20,H-26,H-27,14-Me,H-2″,22-CH 2),0.9-1.08(m,20H,27-Me,24-Me,26-Me,H-16,6′-Me,6″-Me,12-Me)； 13C NMR(75MHz,CDCl 3)δ173.32,155.59,139.07,138.88,137.80,134.73,133.57,132.82,131.72,131.52,124.82,121.49,120.54,118.89,118.04,117.17,98.72,96.44,94.55,81.35,80.66,80.16,79.04,76.89,75.24,73.26,73.20,68.63,68.26,68.15,68.09,67.07,66.95,60.04,56.85,55.41,45.59,38.41,36.42,36.11,35.27,34.58,30.96,26.53,20.34,19.42,18.96,18.04,17.80,15.20,14.84,12.32,11.67.HRMS:calcd for C 53H 79NO 15(M+H) +:970.5522；found,970.5517.
实施例1.7 5-羟基-4”-甲氨基阿维菌素B2a高烯衍生化合物(Ⅰc)的制备
Figure PCTCN2021070074-appb-000020
式(Ⅵ)中R 1代表的意义为CH 3；
式(Ⅰc)中R 1代表的意义为CH 3。
将式(Ⅵ)所示物质108g(0.112摩尔)溶于300mL无水二氯甲烷与100mL甲醇的混合溶剂中，溶解充分后，降温到0℃，加入四-三苯基磷钯1.08g(0.01重量份)，加入硼氢化钠2.16g(0.02重量份)，在0℃下反应1小时，反应完成后，依次用稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩过柱得到97g产物Ⅰc，产率98％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ5.74(d,3H,H9,H10,4”-NH),5.39(d,4H,H3,H11,H15,H23),4.98(d,1H,5-OH),4.78(d,1H,H19),4.67(s,2H,H1’,H1”),4.30(d,1H,H5),4.11(s,1H,7-OH),4.04–3.88(m,4H,H5’,H5”,CH 2),3.86–3.51(m,4H,H3’,H3”,H13,H25),3.40(d,6H,3’-OCH 3,3”-OCH 3),3.34–3.15(m,2H,H17,H4’),2.66(s,1H,H4),2.57(s,3H,NHMe),2.54–2.45(m,1H,H4”),2.38–1.97(m,7H,H6,20-CH 2,2’-CH 2,2”CH 2),1.87(s,6H,16-CH 2,18-CH 2,22-CH 2),1.51(dd,13H,H12,Me24a,Me14a,Me4a,H26,27-CH 2), 1.24(t,6H,6’-Me,6”-Me),1.16(d,3H,28-Me),0.96(t,3H,Me12a),0.76(d,3H,Me26a)； 13C NMR(75MHz,CDCl 3)δ173.44,155.59,139.27,137.79,137.63,134.73,133.10,124.36,120.11,117.91,117.70,117.06,98.31,96.34,94.43,81.28,80.15,80.05,78.95,78.86,76.26,75.14,73.18,67.98,67.39,67.09,66.95,59.75,56.39,55.13,45.40,40.23,39.44,38.15,36.50,35.80,35.21,34.33,33.86,30.67,26.35,19.88,19.62,18.79,19.90,17.78,14.84,12.20,11.65；HRMS:calcd for C 49H 75NO 13(M+H) +:886.5311；found,886.5305。
实施例1.8.5-烯丙氧羰基-4”-氨基阿维菌素B2a高烯衍生化合物(Ⅶ)的制备
Figure PCTCN2021070074-appb-000021
将式(Ⅴ)所示物质107g(0.112摩尔)溶于350mL无水二氯甲烷，溶解充分后，再加入六甲基二硅氮烷85g(0.526摩尔)，三氟乙酸锌33g(0.112摩尔)，在50℃下反应2小时，降温到5℃后，加入甲醇150g(1.5重量份)，分批加入硼氢化钠8g(0.08重量份)，在15℃下反应1小时。反应完成后，依次用稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩过柱得到91g产物Ⅶ，产率85％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ5.72-5.78(m,5H,H-10,H-11,H-23,CH 2＝CH-CH 2-O),5.35-5.44(m,5H,H-15,H-19,H-3,H-9,CH 2＝CH-CH 2-O),5.11(s,2H,NH 2),4.78(m,4H,H-1″,H-1′,CH 2＝CH-CH 2-O),4.69(s,2H,CH2-8a),4.40-4.42(m,1H,H-5),4.30-4.31(m,1H,H-5″),3.83-4.08(m,7H,H-3′,H-17,H-13,H-5′,H-4″,H-6,7-OH),3.52-3.71(m,1H,H-3″),3.29-3.49(m,8H,3″-OMe,H-25,3′-OMe,H4),2.52(m,1H,H-4′),2.00-2.38(m,5H,H-12,H-22,H-2′),1.88(s,3H,4-Me),1.07-1.50(m,12H,H-18,H-20,H-26,H-27,14-Me,H-2″),0.86-1.07(m,20H,27-Me,24-Me,26-Me,H-16,5′-Me,5″-Me,12-Me)； 13C NMR(75MHz,CDCl 3)δ172.86,154.44,138.97,137.58,134.71,132.98,131.97,131.17,130.47,128.44,124.65,121.35,120.14,118.24,117.91,117.10,98.27,96.31,81.28,80.53, 80.34,78.96,76.97,74.37,73.28,73.09,68.29,68.18,67.98,66.80,65.21,56.22,54.98,50.24,45.42,39.36,35.76,31.52,30.20,29.34,28.95,26.31,22.28,19.55,18.76,17.90,16.84,14.79,13.71,13.32,12.15,11.65.HRMS:calcd for C 52H 77NO 15(M+H) +:956.5366；found,956.5358
实施例1.9.5-羟基-4”-氨基阿维菌素B2a高烯衍生化合物(Ⅰb)的制备
Figure PCTCN2021070074-appb-000022
将式(Ⅶ)所示物质107g(0.112摩尔)溶于300mL无水二氯甲烷与100mL甲醇的混合溶剂中，溶解充分后，降温到0℃，加入四-三苯基磷钯1.07g(0.01重量份)，加入硼氢化钠2.14g(0.02重量份)，在0℃下反应1小时，反应完成后，依次用稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩过柱得到93g产物Ⅰb，产率95％。
结构确证数据如下：1H NMR(300MHz,CDCl 3)δ5.72-5.78(m,4H,H-10,H-11,H-1″,H3),5.56(d,1H,H-23),5.35-5.44(m,3H,H-15,H-19,H-9),5.11(s,2H,NH2),4.78(m,2H,H-1′,5-OH),4.69(s,2H,CH2-8a),4.40-4.42(m,1H,H-5),4.30-4.31(m,1H,H-5″),3.83-4.08(m,7H,H-3′,H-17,H-13,H-5′,H-4″,H-6,7-OH),3.52-3.71(m,1H,H-3″),3.29-3.49(m,8H,3″-OMe,H-4,H-25,3′-OMe),2.52(m,3H,H-4′,22-CH 2),2.00-2.38(m,3H,H-12,H-2′),1.88(s,3H,4-Me),1.07-1.50(m,12H,H-18,H-20,H-26,H-27,14-Me,H-2″),0.86-1.07(m,20H,27-Me,24-Me,26-Me,H-16,5′-Me,5″-Me,12-Me)； 13C NMR(75MHz,CDCl 3)δ173.56,139.30,137.78,137.70,134.73,133.09,124.38,120.2,117.92,117.70,117.06,98.38,96.36,94.42,81.28,80.19,80.06,79.03,78.75,76.86,75.01,73.20,68.14,68.06,68.00,67.40,66.90,65.89,56.35,54.94,50.55,45.41,39.44,36.62,35.81,35.22,34.35,33.85,29.33,26.36,19.91,19.63,18.79,17.95,16.96,14.85,12.21,11.65.HRMS:calcd for C 48H 73NO 13(M+H) +:872.5155；found,872.5145.
实施例1.10.5-烯丙氧羰基-4”-乙酰氨基阿维菌素B2a高烯衍生化合物(Ⅷ)的制备
Figure PCTCN2021070074-appb-000023
式(Ⅶ)中R 2代表的意义为CH 3
将式(Ⅶ)所示物质107g(0.112摩尔)，加入200mL无水二氯甲烷，吡啶53g(0.67摩尔)，充分溶解。20℃下滴加乙酸酐61g(0.6摩尔)，20℃下反应过夜。反应完成后，依次用稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩过柱得到107g产物Ⅷ，产率96％。
结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ5.68～6.05(m,4H,H9,H10,H11,CH 2＝ CH-CH 2O),5.52～5.63(m,2H,H3,H23),5.22～5.43(m,5H,H5,H1″,H19, CH 2 ＝CH-CH 2O),5.11(s,1H,NH),4.92～5.06(m,1H,H15),4.59～4.86(m,5H,H1′,H8ax2,CH 2＝CH- CH 2 O),4.09-4.16(m,2H,H13,7-OH),3.94(m,1H,H4),3.71～4.03(m,6H,H5″,H5′,H6,H17,H3″,H3′),3.30～3.48(m,10H,H25,3″-OCH 3,3′-OCH 3,R2-CH 3),3.22(m,1H,H4′),3.14(t,1H,H4″),2.45～2.60(m,1H,H12),1.77～2.39(m,13H,H16x2,H2′,H2″,H18,Me4a,H20),1.45～1.69(m,8H,Me14a,H26,H27x2,H22x2),1.13～1.32(m,9H,Me6′,Me6″,Me12a),0.84～1.01(m,9H,Me28,Me24a,Me26a)； 13C NMR(75MHz,CDCl 3)δ173.15,170.31,154.50,138.97,137.65,134.72,133.04,132.80,131.17,124.44,121.21,120.10,118.36,117.89,117.11,98.31,96.35,94.30,81.25,80.72,80.56,78.99,76.89,73.23,73.18,72.97,68.40,68.20,68.13,67.98,66.69,65.16,56.30,55.73,48.11,45.43,40.22,39.39,36.44,35.80,35.20,34.32,33.85,31.55,26.35,23.13,19.96,19.31,18.79,17.96,16.72,14.86,12.20,11.65.HRMS:calcd for C 54H 79NO 16(M+H) +:998.5472；found,998.5461.
实施例1.11.5-羟基-4”-乙酰氨基阿维菌素B2a高烯衍生化合物(Ⅰd)的制备
Figure PCTCN2021070074-appb-000024
式(Ⅷ)中R 2代表的意义为CH 3；
式(Ⅰd)中R 2代表的意义为CH 3。
将式(Ⅷ)所示物质112g(0.112摩尔)溶于300mL无水二氯甲烷与100mL甲醇的混合溶剂中，溶解充分后，降温到0℃，加入四-三苯基磷钯1.1g(0.01重量份)，加入硼氢化钠4.4g(0.04重量份)，在0℃下反应1小时，反应完成后，依次用稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗有机相，二氯甲烷萃取，无水硫酸钠干燥，浓缩过柱得到98g产物Ⅰd1，产率96％。 1H NMR(300MHz,CDCl 3)δ5.69～5.87(m,5H,H3,H9,H10,H11,H23),5.35～5.48(m,2H,H1″,H19),5.11(s,1H,NH),4.91～5.08(m,1H,H15),4.67-4.84(m,3H,H8ax2,H1′),3.95-4.06(m,4H,5-OH,7-OH,H5,H6),3.74～3.89(m,3H,H13,H5″,H5′),3.41～3.68(m,11H,H17,H25,H4,H3″,H3′,3″-OCH 3,3′-OCH 3),3.27-3.18(m,2H,H4′,H4″),2.51～2.62(m,1H,H12),2.21～2.41(m,6H,H16x2,H2′,H2″),1.84～2.05(m,7H,H18,Me4a,H20),1.40～1.65(m,8H,Me14a,H26,H27x2,H22x2),1.15～1.36(m,12H,Me6′,Me6″,Me12a,R 2-CH 3),0.84～1.03(m,9H,H28,Me24a,Me26a)； 13C NMR(75MHz,CDCl 3)δ173.32,170.37,137.61,134.67,133.00,131.99,124.67,124.43,120.06,117.95,117.11,98.30,96.33,94.32,81.29,80.72,80.05,78.98,76.91,73.13,72.97,68.01,67.36,66.69,65.15,56.24,55.67,48.11,45.39,39.41,35.80,31.54,30.22,29.65,29.31,28.97,27.05,26.33,23.02,22.30,19.55,18.81,18.75 17.93,16.68,14.82,13.72,13.33,12.17,11.66.HRMS:calcd for C 50H 75NO 14(M+H) +:914.5260；found,914.5251
实施例1.12.化合物Ⅰc苯甲酸盐的制备
将式(Ⅰc)(R1代表的意义为CH 3)所示物质100g(0.112摩尔)，溶于300mL无水二氯甲烷，加入苯甲酸14g(0.114摩尔)，浓缩干燥，即得到式(Ⅰc)(R1代表的意义为CH 3)所示物质的成盐产物。化合物Ic成盐产物的单晶结构及数据 见图18、图19、图20、图21及表1、表2、表3)。结构确证数据如下： 1H NMR(300MHz,CDCl 3)δ8.15–8.03(m,2H,ph-H),7.49(s,1H,ph-H),7.44–7.34(m,2H,ph-H),5.86(d,1H,H9),5.75–5.62(m,4H,H10,H11,4”-NH 2),5.39(d,3H,H3,H15,H23),4.98(d,1H,5-OH),4.77(d,1H,H19),4.67(s,2H,H1’,H1”),4.30(d,1H,H5),4.03(d,1H,7-OH),3.98–3.47(m,8H,H5’,H5”,H3’,H3”,H13,H25,CH 2),3.40(d,6H,3’-OCH 3,3”-OCH 3),3.28(dd,1H,H4’),3.21(t,1H,H17),2.92(d,1H,H4),2.69(s,3H,NHMe),2.58–2.46(m,1H,H4”),2.42–1.37(m,26H,H6,20-CH 2,2’-CH 2,2”CH 2,16-CH 2,18-CH2,22-CH 2,13H,H12,Me24a,Me14a,Me4a,H26,27-CH 2),1.34(d,3H,6”-Me),1.21(d,3H,6’-Me),1.15(d,3H,28-Me),0.95(t,3H,Me12a),0.76(d,3H,Me26a)； 13C NMR(75MHz,CDCl 3)δ173.43,170.70,139.29,137.70,137.60,134.72,133.08,131.6,129.50(2C),127.66(2C),124.39,120.10,117.91,117.70,117.06,98.13,96.35,94.42,81.30,80.49,80.05,78.84,76.29,74.41,73.17,68.09,67.99,67.39,66.85,66.15,59.54,56.32,55.36,45.42,40.25,39.41,36.49,35.79,35.20,34.29,33.85,30.53,26.35,23.50,19.90,19.60,18.79,17.87,17.45,14.84,13.70,13.28,12.20,11.66.HRMS:calcd for C 56H 81NO 15(M+H) +:1008.5679；found,1008.5681。
表1单晶衍射具体测试条件及相关参数
Figure PCTCN2021070074-appb-000025
Figure PCTCN2021070074-appb-000026
表2单晶中部分键长
Figure PCTCN2021070074-appb-000027
表3键角名称及数值
Figure PCTCN2021070074-appb-000028
下列所示本发明的化合物通式为(Ⅰ)所示：
Figure PCTCN2021070074-appb-000029
式(Ⅰ)中R代表的意义为：
R为羟基(Ⅰa)、R为氨基(Ⅰb)、R为NHR 1(Ⅰc)或者R为NHCOR 2(Ⅰd)；
其中：化合物(Ⅰc)和(Ⅰd)基团中R1、R2定义为前面所特别说明。
2，典型的制剂组合物和他们的制备如下所述：
用于作物保护的制剂实施例(％＝重量百分率)
下述实施例中所述的活性成分可为式I所示的化合物中的至少一种。
实施例2.1：乳油
实施例1：乳油 a b c
活性成分 5％ 15％ 20％
十二烷基苯磺酸钙 5％ 8％ 6％
蓖麻油聚乙二醇醚 5％ - -
(36mol环氧乙烷，溶剂) - - -
三丁基酚聚乙二醇醚 - 12％ 4％
(30mol环氧乙烷，溶剂) - - -
环己酮 - 15％ 20％
二甲苯混合物 75％ 50％ 50％
混合磨细的活性成分和添加剂，产生乳油，用水稀释可产生希望浓度的乳剂。
实施例2.2：溶液
Figure PCTCN2021070074-appb-000030
混合磨细的活性成分和添加剂，产生适用于以微滴形式使用的溶液。
实施例2.3：颗粒剂
实施例3：颗粒剂 a b c
活性成分 5％ 15％ 20％
高岭土 93％ - 55％
高度分散的硅酸 2％ - 7％
硅镁土 - 85％ 8％
将活性成分溶解于二氯甲烷中，将溶液喷到载体混合物上，减压蒸去溶剂。
实施例2.4：可湿性粉剂
Figure PCTCN2021070074-appb-000031
将活性成分和添加剂混合到一起，将混合物在适宜的磨中研磨，产生可湿性粉剂，用水稀释可形成希望浓度的悬浮剂。
实施例2.5：乳油
活性成分 10％
辛基酚聚乙二醇醚(4-5摩尔环氧乙烷) 3％
十二烷基苯磺酸钙 3％
蓖麻油聚乙二醇醚(36摩尔环氧乙烷) 4％
环己酮 35％
二甲苯混合物 55％
混合磨细的活性成分和添加剂，产生乳油，用水稀释可产生希望浓度的乳剂。
实施例2.6：颗粒剂
活性成分 10％
木质素磺酸钠 3％
羧甲基纤维素 2％
高岭土 85％
将活性成分与添加剂混合到一起，将混合物研磨，用水润湿，挤出，造粒，在空气流中干燥颗粒。
实施例2.7：涂敷颗粒剂
活性成分 4％
聚乙二醇(分子量200) 4％
高岭土 82％
在混合器中，将磨细的活性成分均匀地涂敷到用聚乙二醇润湿的高岭土上， 产生无尘涂敷颗粒剂。
实施例2.8：胶悬剂
Figure PCTCN2021070074-appb-000032
混合磨细的活性成分与添加剂，得到胶悬剂，用水稀释该胶悬剂，可产生希望浓度的悬浮剂。
实施例2.9：粉剂
实施例9：粉剂 a b
活性成分 5％ 10％
滑石 95％ -
高岭土 - 90％
将活性成分和段体棍合并在合适的磨子里粉碎后得到可供使用的粉剂。
3，生物活性测定：
3.1，试验方法
3.2，试验条件
杀虫剂实验室，正常室温。
杀虫剂观察室，温度、湿度、光照按需可调节。
温室，全天候日光温室。
3.3，药液配制
用电子分析天平准确称取供试药剂，原药先以溶剂完全溶解，用质量分数0.1％吐温80水根据需要配制成所需浓度母液，再按试验设计剂量稀释成具一定浓度梯度的系列药液。
3.4，生物活性测定实施例
实施例3.4.1，对南方根结线虫活性测定
采用24孔板法。取配制好的菌悬液(二龄根结线虫200头以上)0.5ml加入到24孔板中，并按试验设计从低到高的顺序，加入0.5ml药液，4次重复，另设空白对照。
实施例3.4.2，对蚕豆蚜活性测定
采用喷雾法。取带有2日龄若蚜的蚕豆苗，按试验设计从低到高的顺序，用airbrush手动喷雾器将配制好的药液均匀喷于虫、苗，以液体不滴落为宜，自然阴干后置于观察室培养，3次重复，另设空白对照。
实施例3.4.3，对粘虫活性测定
采用喷雾法。将温室栽培的新鲜玉米中部叶片剪成3cm小段，按试验设计从低到高的顺序，用airbrush手动喷雾器将配制好的药液均匀喷于叶片正反面，置于放有滤纸的直径为6cm的培养皿中，自然阴干后接入整齐的健康试虫，每处理10头，3次重复，另设空白对照。
实施例3.4.4，对小菜蛾活性测定
采用喷雾法。将温室培养的甘蓝叶片，除去表面腊质层，用打孔器打成直径为3cm的圆形叶碟，按试验设计浓度从低到高的顺序，用airbrush手动喷雾器将配制好的药液均匀喷于叶片正反面，置于放有滤纸的直径为6cm的培养皿中，自然阴干后接入整齐的健康试虫，每处理10头，3次重复，另设空白对照。
实施例3.4.5，甜菜夜蛾活性测定
采用喷雾法。将温室培养的甘蓝叶片，除去表面腊质层，用打孔器打成直径为3cm的圆形叶碟，按试验设计从低到高的顺序，用airbrush手动喷雾器将配制好的药液均匀喷于叶片正反面，置于放有滤纸的直径为6cm的培养皿中，自然阴干后接入整齐的健康试虫，每处理10头，3次重复，另设空白对照。
实施例3.4.6，亚洲玉米螟活性测定
采用喷雾法。将温室栽培新鲜玉米秸秆剪成4cm小段，按试验设计从低到高的顺序，用airbrush手动喷雾器将配制好的药液均匀喷于玉米秸秆，置于放有滤纸的直径为6cm的培养皿中，自然阴干后接入整齐的健康试虫，每处理10头，3次重复，另设空白对照。
实施例3.4.7，棕榈蓟马活性测定
采用喷雾法。取含有新鲜的茄子叶片，用打孔器打成直径为30.cm的圆形叶碟，按试验设计从低到高的顺序，用airbrush手动喷雾器将配制好的药液进行喷雾处理，待叶片自然阴干后，接入蓟马3龄若虫，每处理15头，用封口膜密封，试验设3次重复，另设空白对照。
实施例3.4.8，朱砂叶螨活性测定
采用喷雾法。选择具有两片真叶的菜豆苗，移栽于培养纸杯中，每杯一株。待移栽苗恢复正常生长后，于处理前三小时剪去心叶及一片真叶，在上面接上适量的雌成螨，并记录基数，3次重复，另设空白对照。
下表为生物活性测定结果见下表：
Figure PCTCN2021070074-appb-000033
工业应用
本发明聚焦B2a衍生化合物合成与活性筛选，开展阿维菌素B2综合利用研究工作，先后设计合成多个系列全新结构B2a衍生物，并对目标化合物进行了广 泛的杀虫活性测定。本发明专利揭示由B2衍生合成得到的一类结构全新，2,3-位与23,24-位之间为烯键，4”-位为氨基或甲氨基的化合物，这些化合物对多个靶标高效的杀虫活性。

Claims (25)

  1. 式(Ⅰ)所示化合物或农药学上可接受的盐：
    Figure PCTCN2021070074-appb-100001
    所述式(Ⅰ)中，R选自下述任意一种基团：羟基、氨基、NHR 1和NHCOR 2；
    其中：NHR 1和NHCOR 2基团中R 1、R 2的定义如下：
    R 1、R 2相同或不同，各自独立的表示为：被卤素或C1～C3烷基取代或者未取代的C1～C6烷基，被卤素或C1～C3烷基取代或者未取代的C3～C6烯烃基，被卤素或C1～C3烷基取代或者未取代的C3～C6炔烃基。
  2. 根据权利要求1所述的化合物或农药学上可接受的盐，其特征在于：所述式(Ⅰ)所示化合物选自下述任意化合物：
    1)所述式(Ⅰ)中R为羟基的化合物；
    2)所述式(Ⅰ)中R为氨基的化合物；
    3)所述式(Ⅰ)中R为NHR 1，且R 1为甲基的化合物；
    4)所述式(Ⅰ)中R为NHR 1，且R 1为乙基的化合物；
    5)所述式(Ⅰ)中R为NHCOR 2，且R 2为甲基的化合物；
    6)所述式(Ⅰ)中R为NHCOR 2，且R 2为乙基的化合物。
  3. 根据权利要求1或2所述化合物或农药学上可接受的盐，其特征在于：所述盐为有机酸盐或无机酸盐，包括苯甲酸盐、取代苯甲酸盐、柠檬酸盐、乳酸盐、醛糖酸盐、盐酸盐或硫酸盐。
  4. 权利要求1所述式(Ⅰ)中R为羟基的化合物的制备方法，包括下述步骤：
    A)有机溶剂中，在碱性介质存在下，将阿维菌素B2a和保护试剂氯甲酸稀 丙酯进行反应，得到式(Ⅱ)所示化合物；
    Figure PCTCN2021070074-appb-100002
    B)将式(Ⅱ)所示化合物在有机碱、消除试剂以及消除催化剂存在下，使得式(Ⅱ)中的C23-OH与C24-H发生脱水消除形成烯键，同时C3＝C4之间的烯键异构为C2＝C3烯键，得到式(Ⅲ)所示化合物；
    Figure PCTCN2021070074-appb-100003
    C)在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式(Ⅲ)所示化合物与硼氢化钠进行脱保护反应，得到式(Ⅰa)所示化合物，即所述式(Ⅰ)中R为羟基的化合物；
    Figure PCTCN2021070074-appb-100004
  5. 根据权利要求4所述的制备方法，其特征在于：
    所述步骤A)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙 酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，最优选为二氯甲烷；相对于1摩尔的阿维菌素B2a，有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤A)中，所述碱性介质选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中的至少一种；优选自吡啶、三乙胺、四甲基乙二胺中的至少一种，最优选为四甲基乙二胺；相对于1摩尔的阿维菌素B2a，所述碱性介质的用量为1-50摩尔，优选为1.05-20摩尔，更优选为1.2-10摩尔；
    相对于1摩尔的阿维菌素B2a，所述保护试剂氯甲酸稀丙酯的用量为可以为2-12摩尔，优选为2-6摩尔，更优选为2-3摩尔；
    所述反应的反应条件包括：温度为-30℃至30℃，优选为-30℃至10℃，时间为1-10小时，优选为1-2小时；
    所述步骤B)中，所述有机溶剂选自二氯甲烷、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环、甲醇和四氢呋喃中的至少一种，优选自二氯甲烷、三氯甲烷和四氢呋喃中的至少一种，最优选为二氯甲烷；相对于1摩尔式(Ⅱ)所示化合物，有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤B)中，所述消除试剂选自乙酸酐、三氟乙酸酐、三氟甲磺酸酐、甲磺酰氯、对甲基苯磺酰氯、苯磺酰氯中的至少一种；优选三氟甲磺酸酐、甲磺酰氯，最优选为三氟甲磺酸酐；相对于1摩尔的式(Ⅱ)所示化合物，消除试剂用量为0.5-20摩尔，优选为1-10摩尔，更优选为1-5摩尔；
    所述步骤B)中，所述有机碱选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中、四甲基氢氧化铵、叔丁醇钾、一乙醇胺、三乙醇胺中的至少一种；优选自吡啶、三乙胺、四甲基乙二胺中的至少一种，最优选为吡啶。相对于1摩尔的式(Ⅱ)所示化合物，有机碱的用量为1-50摩尔，优选为1.05-20摩尔，更优选为1.2-10摩尔；
    所述步骤B)中，所述消除催化剂为DBU、DMAP、硫酸钠、硫酸钾、4-甲基吡啶中的至少一种，优选自DBU和/或DMAP；相对于1摩尔的式(Ⅱ)所示化合物，催化剂的用量为0.1-5摩尔，优选为0.1-2摩尔，更优选为0.1-1.5摩尔；
    所述步骤B)中，所述反应条件包括：温度为-50℃至40℃，优选为-30℃至20℃，更优选为-5℃至-0℃；时间为1-10小时，优选为2-3小时；所述反应优选 在惰性气氛中进行，如氮气气氛。
    所述步骤C)中，所述有机溶剂选自二氯甲烷、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环、甲醇和四氢呋喃中的至少一种，优选自二氯甲烷、三氯甲烷和四氢呋喃中的至少一种，最优选为二氯甲烷；相对于1摩尔的式(Ⅲ)所示化合物，有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤C)中，相对于1质量份的式(Ⅲ)所示化合物，催化剂四三苯基膦钯的用量为0.001-0.1质量份，优选为0.005-0.03质量份，更优选为0.01-0.02质量份；相对于1质量份的式(Ⅲ)所示化合物，硼氢化钠的用量为0.001-0.1质量份，优选为0.01-0.04质量份，更优选为0.02-0.03质量份。
    所述脱保护反应的反应条件包括：温度为-10℃至20℃，优选为0℃至5℃；时间为0.5-4小时，优选为1-2小时。
  6. 权利要求1所述式(Ⅰ)中R为NHR 1的化合物的制备方法，包括下述步骤：
    D)有机溶剂中，在碱性介质存在下，将式(Ⅰa)化合物和保护试剂氯甲酸稀丙酯进行反应，得到式(Ⅳ)所示化合物；
    Figure PCTCN2021070074-appb-100005
    E)在有机溶剂中，碱存在下，将式(Ⅳ)与氧化试剂二甲基亚砜、酰氯反应，得到式(Ⅴ)所示化合物；
    Figure PCTCN2021070074-appb-100006
    F)在有机溶剂中，在路易斯酸催化下，将式(Ⅴ)与烷基氨R 1NH 2反应，使得式(Ⅴ)中的C4”-羰基氨化为C4”-亚烷氨基后，再加入还原剂硼氢化钠，使得C4”-亚烷氨基还原成C4”-烷氨基，得到式(Ⅵ)所示化合物；
    Figure PCTCN2021070074-appb-100007
    其中，R 1NH 2与式(Ⅵ)中R 1的定义同式I；
    G)式(Ⅵ)化合物在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式(Ⅵ)化合物与硼氢化钠反应，脱去C5-OH的保护基团Alloc，得到式(Ⅰc)所示化合物，即为所述式(Ⅰ)中R为NHR 1时定义的化合物；
    Figure PCTCN2021070074-appb-100008
  7. 根据权利要求6所述的制备方法，其特征在于：
    所述步骤D)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，最优选为二氯甲烷；相对于1摩尔的式(Ⅰa)所示化合物，所述有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤D)中，碱性介质选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中的至少一种；优选自吡啶、三乙胺、四甲基乙二胺，最优选为四甲基乙二胺；相对于1摩尔的式(Ⅰa)所示化合物，碱性介质的用量为1-10摩尔，优选为1.05-5摩尔，更优选为1.2-3摩尔；
    其中，相对于1摩尔的式(Ⅰa)所示化合物，保护试剂氯甲酸稀丙酯的用量为1-8摩尔，优选为1-3摩尔，更优选为1-1.2摩尔；
    合适的反应条件包括：温度为-30℃～30℃之间，时间为0.5-24小时；
    所述步骤E)中，所述有机溶剂选自二氯甲烷、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选选自二氯甲烷、三氯甲烷和四氢呋喃中的至少一种，最优选为二氯甲烷；相对于1摩尔的式(Ⅳ)所示化合物，有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤E中，碱选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉的至少一种；优选自吡啶、三乙胺、四甲基乙二胺，最优选为四甲基乙二胺；相对于1摩尔的式(Ⅳ)所示化合物，碱的用量为1-10摩尔，优选为1.05-5摩尔，更优选为1.2-3摩尔；
    其中，相对于1摩尔的式(Ⅳ)所示化合物，氧化试剂二甲基亚砜的用量为1-8摩尔，优选为2-5摩尔，更优选为2.8-3摩尔；二氯化磷酸苯脂的用量为0.5-6摩尔，优选为0.8-5摩尔，更优选为1-2摩尔；
    合适的反应条件包括：温度为-30℃至0℃，优选为-20℃至-10℃，时间为0.5-2小时，优选为0.6-1小时；
    所述步骤F)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，最优选为二氯甲烷；相对于1摩尔的式(V)所示化合物，有机溶剂的用量为1-100L，优选为1-10L，更优选为1-5L；
    其中，路易斯酸选自乙酸、丙酸、三氟乙酸锌、氯化锌、对甲苯磺酸锌、三氟化硼、氯化铝、氯化铁、五氟化锑中的至少一种，优选乙酸、氯化锌、三氟乙酸锌中的至少一种，最优选为乙酸和/或三氟乙酸锌；相对于1摩尔的式(V)所示化合物，路易斯酸的用量为0.01-10尔，优选为0.05-5摩尔，更优选为0.10-4摩尔；烷基氨(R 1NH 2)的用量为1.5-50摩尔，优选为3-20摩尔，更优选为5-10摩尔；相对于1质量份的式(V)所示化合物，所述还原剂硼氢化钠的用量为0.001-0.5质量份，优选为0.005-0.3质量份，更优选为0.01-0.02质量份；
    合适氨化、还原反应条件包括：温度为-30℃至50℃，优选为5℃-25℃，更优选为10℃-15℃，时间为0.5-8小时，优选为0.5-2小时；
    所述步骤G)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、甲醇、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、 二氧六环和四氢呋喃中的至少一种，优选自二氯甲烷、1,2-二氯乙烷、甲醇和乙酸异丙酯中的至少一种，最优选为二氯甲烷和甲醇的混合溶剂，两者的体积比为10：1-1：1；相对于1摩尔的式(Ⅵ)所示化合物，有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    其中，相对于1质量份的式(Ⅵ)所示化合物，催化剂四-三苯基磷钯用量为0.001-0.1质量份，优选为0.005-0.03质量份，更优选为0.01-0.02质量份；硼氢化钠的用量为0.001-0.1质量份，优选为0.01-0.04质量份，更优选为0.02-0.03质量份；
    合适脱保护反应条件包括：温度可以为-10℃-20℃，优选为0℃-5℃，时间可以为0.5-4小时，优选为1-2小时。
  8. 权利要求1所述式(Ⅰ)中R为氨基的化合物的制备方法，包括下述步骤：
    H)在有机溶剂中，在路易斯酸催化下，将式(Ⅴ)化合物与六甲基二硅氮烷反应，使得式(Ⅴ)中的C4”-羰基氨化为C4”-亚氨基后，再加入甲醇和还原剂硼氢化钠，使得C4”-亚氨基还原成C4”-氨基，得到式(Ⅶ)所示化合物；
    Figure PCTCN2021070074-appb-100009
    I)在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式(Ⅶ)所示化合物与硼氢化钠反应，脱去C5-OH的保护基团Alloc，得到式(Ⅰb)所示化合物，即为所述式(Ⅰ)中R为氨基时定义的化合物；
    Figure PCTCN2021070074-appb-100010
  9. 根据权利要求8所述的方法，其特征在于：
    所述步骤H)中，有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，最优选为二氯甲烷；相对于1摩尔的式(V)所示化合物，有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤H)中，路易斯酸选自三氟乙酸锌、氯化锌、对甲苯磺酸锌、三氟化硼、氯化铝、氯化铁、五氟化锑中的至少一种，优选氯化锌、对甲苯磺酸锌和三氟乙酸锌中的至少一种，最优选为三氟乙酸锌；相对于1摩尔的式(V)所示化合物，路易斯酸的用量为0.01-10摩尔，选为0.05-5摩尔，更优选为0.10-3摩尔；六甲基二硅氮烷的用量为1.5-50摩尔，优选为3-20摩尔，更优选为4.5-10摩尔；相对于1质量份的式(V)所示化合物，还原剂硼氢化钠的用量为0.001-0.5质量份，优选为0.005-0.4质量份，更优选为0.01-0.02质量份；所述甲醇的用量为0.5-5质量份，优选为1-3质量份，更优选为1.5-2质量份；
    合适氨化、还原反应条件包括：温度为0℃-80℃，优选为5℃-70℃，时间为1-8小时，优选为1-2小时；
    所述步骤I)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、甲醇、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选自二氯甲烷、1,2-二氯乙烷、甲醇和乙酸异丙酯中的至少一种，最优选为二氯甲烷和甲醇的混合溶剂，两者的体积比可为10：1-1：1，对于1摩尔的式(Ⅶ)所示化合物，有机溶剂的用量为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤I)中，相对于1质量份的式(Ⅶ)所示化合物，催化剂四三苯基膦钯用量可以为0.001-0.1质量份，优选为0.005-0.03质量份，更优选为0.01-0.02质量份；硼氢化钠的用量为0.001-0.1质量份，优选为0.01-0.04质量份，更优选为0.02-0.03质量份；
    合适脱保护反应条件包括：温度为-10℃-20℃，优选为0℃-5℃，时间为0.5-4小时，优选为1-2小时。
  10. 权利要求1所述式(Ⅰ)中R为NHCOR 2的化合物的制备方法，包括下述步骤：
    J)在有机溶剂中，在碱存在下，将式(Ⅶ)与酰化试剂酸酐或酰氯反应，使得式(Ⅶ)中的C4”-氨基发生酰化反应，得到式(Ⅷ)所示化合物；
    Figure PCTCN2021070074-appb-100011
    其中，式(Ⅷ)中R 2的定义同式I；
    K)在有机溶剂中，在催化剂四三苯基膦钯的存在下，使式(Ⅷ)所示化合物与硼氢化钠反应，脱去C5-OH的保护基团Alloc，得到式(Ⅰd)所示化合物，即为所述式(Ⅰ)中R为NHCOR 2时定义的化合物；
    Figure PCTCN2021070074-appb-100012
  11. 根据权利要求10所述的方法，其特征在于：
    所述步骤J)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选自二氯甲烷、1,2-二氯乙烷和乙酸异丙酯中的至少一种，最优选为二氯甲烷；相对于1摩尔的式(Ⅶ)所示化合物，有机溶剂的用量可以为1-100L，优选为1-10L，更优选为1-5L；
    所述步骤J)中，所述碱性介质选自吡啶、三乙胺、乙二胺、四甲基乙二胺、三乙烯二胺、N-甲基吗啉中的至少一种；优选自吡啶、三乙胺、四甲基乙二胺，最优选为吡啶；相对于1摩尔的式(Ⅶ)所示化合物，碱性介质的用量为0.1-10摩尔，优选为0.1-5摩尔，更优选为0.1-3摩尔；
    相对于1摩尔的式(Ⅶ)所示化合物，酰化试剂酸酐或酰氯的用量为0.1-8摩尔，优选为0.1-3摩尔，更优选为0.1-1.2摩尔；
    合适酰化反应条件包括：温度为-30℃-50℃，优选为0℃-30℃，时间为1- 30小时，优选为1-24小时；
    所述步骤K)中，所述有机溶剂选自二氯甲烷、1,2-二氯乙烷、甲醇、乙酸异丙酯、乙酸乙酯、正己烷、苯、甲苯、三氯甲烷、四氯甲烷、石油醚、氯苯、二氧六环和四氢呋喃中的至少一种，优选自二氯甲烷、1,2-二氯乙烷、甲醇和乙酸异丙酯中的至少一种，最优选为二氯甲烷和甲醇的混合溶剂，两者的体积比为(10-1)：1；相对于1摩尔的式(Ⅷ)所示化合物，有机溶剂的用量可以为1-100L，优选为2-10L，更优选为3-5L；
    所述步骤K)中，相对于1质量份的式(Ⅷ)所示化合物，催化剂四三苯基膦钯用量可以为0.001-0.1质量份，优选为0.005-0.03质量份，更优选为0.01-0.02质量份；硼氢化钠的用量为0.001-0.1质量份，优选为0.01-0.04质量份，更优选为0.03-0.04质量份；
    合适脱保护反应条件包括：温度为-10℃-20℃，优选为0℃-5℃，时间为0.5-4小时，优选为1-2小时。
  12. 权利要求1所述的式(Ⅰ)所示化合物或农药学上可接受的盐在防治有害生物中的应用或在制备防治有害生物制剂中的应用。
  13. 根据权利要求12所述的应用，其特征在于：所述有害生物包括下述害虫：鳞翅目、鞘翅目、直翅目、等翅目、啮虫目、虱目、食毛目、缨翅目、异翅亚目、半翅目、膜翅目、双翅目、蚤目、缨尾目和蜱螨，尤其是蜱螨目、双翅目、缨翅目、鳞翅目和鞘翅目有害生物；
    或，所述有害生物包括螨虫，所述所述螨虫包括：叶螨、瘿螨、粉螨、跄线螨、蒲螨、矮蒲螨、叶爪螨、浦口螨、根螨、甲螨、植绥螨、长须螨、美绥螨、巨蟹螨、半疥螨、巨须螨、吸螨、肉食螨、绒螨及大赤螨；
    或，所述有害生物包括线虫，所述线虫包括下述属的线虫：胞囊线虫属、球异皮线虫属、根结线虫属、穿孔线虫属、短体线虫属、小垫刃线虫属、长针线虫属、毛刺线虫属、剑线虫属、茎线虫属、滑刃线虫属和鳗线虫属。
  14. 根据权利要求13所述的应用，其特征在于：所述有害生物为出现在植物上的有害生物，特别是在农业、园艺和林业中的有用植物和观赏植物上的有害生物，或出现在所述植物的各部分上的有害生物；
    所述植物包括谷物、甜菜、水果，豆科植物，油料植物，葫芦科植物，纤维植物，蔬菜，樟科植物，烟草，坚果，咖啡，糖用甘蔗，茶，胡椒，蛇麻子，天然橡胶植物和观赏植物。
  15. 一种农药组合物，其活性成分包括权利要求1中式(Ⅰ)所示化合物中的至少一种。
  16. 根据权利要求15所述的农药组合物，其特征在于：所述农药组合物还包括农业上可接受的载体。
  17. 根据权利要求15或16所述的组合物，其特征在于：所述农药组合物制备成农药学上可接受的任意剂型，包括乳油、胶悬剂、可直接喷雾或可稀释溶液、可涂敷的糊剂、稀乳剂、可湿性粉剂、可溶性粉剂、可分散性粉剂、可湿性粉剂、粉剂、颗粒剂和聚合物的包囊。
  18. 一种乳油，包括下述质量百分含量的物质：
    活性成分：1-90％,优选5-20％；
    表面活性剂：1-30％，优选10-20％；
    溶剂：5-98％,优选70-85％；
    所述活性成分为权利要求1中式(Ⅰ)所示化合物或权利要求15所述的农药组合物。
  19. 一种溶液剂，包括下述质量百分含量的物质：
    活性成分：1-99％,优选5-65％；
    表面活性剂：0-80％，优选0.1-65％；
    溶剂：5-98％,优选70-85％。
    稳定剂：0-3％，优选0.1-3％；
    所述活性成分为权利要求1中式(Ⅰ)所示化合物或权利要求15所述的农药组合物。
  20. 一种粉剂，包括下述质量百分含量的物质：
    活性成分：0.1-10％,优选0.1-1％；
    固体载体：99.9-90％，优选99.9-99％；
    所述活性成分为权利要求1中式(Ⅰ)所示化合物或权利要求15所述的农药组合物。
  21. 一种胶悬剂，包括下述质量百分含量的物质：
    活性成分：5-75％,优选10-50％；
    水：94-24％,优选88-30％；
    表面活性剂：1-40％,优选2-30％；
    所述活性成分为权利要求1中式(Ⅰ)所示化合物或权利要求15所述的农药组合物。
  22. 一种可湿性粉剂，包括下述质量百分含量的物质：
    活性成分：0.5-90％,优选25-80％；
    表面活性剂：0.5-20％,优选1-15％；
    固体载体：5-99％,优选15-98％；
    所述活性成分为权利要求1中式(Ⅰ)所示化合物或权利要求15所述的农药组合物。
  23. 一种颗粒剂，包括下述质量百分含量的物质：
    活性成分：0.5-30％,优选5-20％；
    固体载体：99.5-70％,优选95-80％；
    所述活性成分为权利要求1中式(Ⅰ)所示化合物或权利要求15所述的农药组合物。
  24. 权利要求15-17任一项所述的组合物的使用方法，包括喷雾、弥雾、喷粉、包衣、拌种、撒施或浇泼。
  25. 根据权利要求24所述的使用方法，其特征在：所述组合物使用时，活性成分典型的浓度用量是0.l-1000ppm，优选0.1-500ppm；每公顷的用量通常是l-2000g活性成分/公顷，特别是10-1000g/公顷，优选20-600g/公顷；更优选为20-100g/公顷。
PCT/CN2021/070074 2020-02-27 2021-01-04 阿维菌素B2a衍生物及其制备方法与应用 WO2021169606A1 (zh)

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Publication number Priority date Publication date Assignee Title
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015135467A1 (zh) * 2014-03-10 2015-09-17 浙江海正药业股份有限公司 十六元大环内酯类化合物及其应用
CN107513088A (zh) * 2016-06-17 2017-12-26 浙江海正药业股份有限公司 天维菌素衍生物及其抗寄生虫的用途
CN111269281A (zh) * 2020-02-27 2020-06-12 中国农业大学 阿维菌素B2a衍生物及其制备方法与应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4831016A (en) * 1986-10-31 1989-05-16 Merck & Co., Inc. Reduced avermectin derivatives
CN101528761A (zh) * 2006-08-17 2009-09-09 拜尔农作物科学股份公司 阿维菌素衍生物
CN103833811A (zh) * 2014-03-25 2014-06-04 武汉大学 一种阿维菌素衍生物及其制备方法
CN104497080A (zh) * 2014-11-28 2015-04-08 大庆志飞生物化工有限公司 阿维菌素酯类化合物及其制备方法和用途
CN107344954B (zh) * 2017-08-07 2020-08-11 河北蓝泰化工科技有限公司 增效型甲氨基阿维菌素b1或b2的盐及制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015135467A1 (zh) * 2014-03-10 2015-09-17 浙江海正药业股份有限公司 十六元大环内酯类化合物及其应用
CN107513088A (zh) * 2016-06-17 2017-12-26 浙江海正药业股份有限公司 天维菌素衍生物及其抗寄生虫的用途
CN111269281A (zh) * 2020-02-27 2020-06-12 中国农业大学 阿维菌素B2a衍生物及其制备方法与应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
XIANG HUAPING: "Research Progress of Abamectin B 2 Derivatives in Organic Synthesis", MODERN CHEMICAL RESEARCH, 1 July 2018 (2018-07-01), pages 169 - 170, XP055841409 *
ZHEN CHEN: "Thesis", 1 June 2016, ZHEJIANG AGRICULTURE AND FORESTRY UNIVERSITY, CN, article ZHEN CHEN: "Design, Synthesis and Bioactivity Studies of Novel Avermectin B1a Derivatives", pages: 1 - 130, XP055841597 *

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