WO2021259224A1 - 三嗪苯甲酸酯类化合物及其应用 - Google Patents

三嗪苯甲酸酯类化合物及其应用 Download PDF

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WO2021259224A1
WO2021259224A1 PCT/CN2021/101396 CN2021101396W WO2021259224A1 WO 2021259224 A1 WO2021259224 A1 WO 2021259224A1 CN 2021101396 W CN2021101396 W CN 2021101396W WO 2021259224 A1 WO2021259224 A1 WO 2021259224A1
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compound
clch
alkyl
methyl
chch
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PCT/CN2021/101396
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English (en)
French (fr)
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陈霖
杨辉斌
马宏娟
王刚
崔东亮
李斌
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沈阳中化农药化工研发有限公司
江苏扬农化工股份有限公司
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Priority claimed from CN202010582185.7A external-priority patent/CN113831299B/zh
Priority claimed from CN202010582153.7A external-priority patent/CN113831298B/zh
Application filed by 沈阳中化农药化工研发有限公司, 江苏扬农化工股份有限公司 filed Critical 沈阳中化农药化工研发有限公司
Priority to EP21828024.6A priority Critical patent/EP4169910A1/en
Priority to AU2021297861A priority patent/AU2021297861B2/en
Priority to US18/002,421 priority patent/US20230227415A1/en
Priority to CN202180014764.4A priority patent/CN115103837B/zh
Priority to BR112022026400A priority patent/BR112022026400A2/pt
Priority to CA3183861A priority patent/CA3183861A1/en
Publication of WO2021259224A1 publication Critical patent/WO2021259224A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/30—Only oxygen atoms
    • C07D251/32—Cyanuric acid; Isocyanuric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/38—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/66—1,3,5-Triazines, not hydrogenated and not substituted at the ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P13/00—Herbicides; Algicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/30—Only oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of herbicides, and specifically relates to a triazine benzoate compound and an application thereof.
  • CN1341105A discloses that the compounds of the following general formula have herbicidal activity:
  • R 5 may be the carboxylate substituent COOR 20 .
  • R 20 can be selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, and can be (C 1 -C 6 -Alkoxy)carbonyl, (C 3 -C 6 -alkenyloxy)carbonyl, (C 3 -C 6 -alkynyloxy)carbonyl or C 1 -C 6 -alkoxy-(C 1 -C 6 -Alkoxy)carbonyl is further substituted.
  • CN1341105A discloses that the compound KC 1 (the compound No. 30 in Table 3 in the patent specification) can effectively control Amaranthus retroflexus, Chenopodium chinense, rice bagweed and Setaria macrophylla at doses of 7.81 and 3.91g/ha through post-emergence application methods; At the same time , the preparation of the photoactive compound KC 2 (R body, compound No. 12 in Table 3 in the patent specification) is disclosed, but its herbicidal activity is not reported.
  • the purpose of the present invention is to provide a triazine benzoate compound with novel structure and good herbicidal activity and a herbicidal composition using the compound as an active component to meet the needs of rapid development of production.
  • the present invention provides a novel triazine benzoate compound having a structure as shown in general formula (I):
  • W is selected from O or S
  • X 1 is selected from H or F
  • X 2 is selected from halogen, CN, CONH 2 or CSNH 2 ;
  • R 1 is selected from methyl or ethyl
  • R 2 is selected from methyl or ethyl
  • R 3 is selected from H or methyl
  • R 4 is selected from H or C 1 -C 3 alkyl
  • a further preferred compound of the present invention is, in the general formula I:
  • W is selected from O or S
  • X 1 is selected from H or F
  • X 2 is selected from Cl, Br or CN;
  • R 1 is selected from methyl
  • R 2 is selected from methyl
  • R 3 is selected from H or methyl
  • R 4 is selected from H, methyl, ethyl or isopropyl
  • R 5 is selected from CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, (CH 3 ) 2 CHCH 2 -, CH 3 CH 2 CH (CH 3 )-, (CH 3 ) 3 C-, CH 3 CH 2 CH 2 CH 2 CH 2 -, (CH 3 ) 2 CHCH 2 CH 2 -, (CH 3 ) 3 CCH 2 -, CH 3 CH 2 CH(CH 3 )CH 2 -, CH 3 CH 2 CH 2 CH(CH 3 )-, CH 3 CH 2 C(CH 3 ) 2 -, ClCH 2 CH 2 -, ClCH 2 CH 2 CH 2 -, CH 3 ClCHCH 2 -, CH 2 Cl(CH 3 )CH-, ClCH 2 CH 2 CH 2 CH 2 -, CH 3 ClCHCH 2 -, CH 2 Cl(CH 3 )CH-, ClCH 2 CH 2 CH 2 CH 2 -, CH 3 ClCHCHCH 2 -, CH 2 Cl(CH 3
  • a further preferred compound of the present invention is, in the general formula I:
  • W is selected from S
  • X 1 is selected from F
  • X 2 is selected from Cl
  • R 1 is selected from methyl
  • R 2 is selected from methyl
  • R 3 is selected from H or methyl
  • R 4 is selected from H or methyl
  • R 5 is selected from CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, (CH 3 ) 2 CHCH 2 -, CH 3 CH 2 CH (CH 3 )-, (CH 3 ) 3 C-, CH 3 CH 2 CH 2 CH 2 CH 2 -, (CH 3 ) 2 CHCH 2 CH 2 -, (CH 3 ) 3 CCH 2 -, CH 3 CH 2 CH(CH 3 )CH 2 -, CH 3 CH 2 CH 2 CH(CH 3 )-, CH 3 CH 2 C(CH 3 ) 2 -, ClCH 2 CH 2 -, ClCH 2 CH 2 CH 2 -, CH 3 ClCHCH 2 -, CH 2 Cl(CH 3 )CH-, ClCH 2 CH 2 CH 2 CH 2 -, CH 3 ClCHCH 2 -, CH 2 Cl(CH 3 )CH-, ClCH 2 CH 2 CH 2 CH 2 -, CH 3 ClCHCHCH 2 -, CH 2 Cl(CH 3
  • the optical isomer of the compound represented by formula I is in the S configuration or the content of the S configuration is greater than 60%.
  • Halogen refers to fluorine, chlorine, bromine, and iodine.
  • Alkyl refers to straight or branched chain forms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, N-hexyl and other groups.
  • Haloalkyl refers to a group in which an alkyl group is substituted by one or more halogen atoms, such as chloroethyl, trifluoromethyl, and the like.
  • Cycloalkyl refers to including cyclic chain forms, such as cyclopropyl, methylcyclopropyl, cyclopropylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkenyl refers to straight-chain or branched alkenyl, such as 1-propenyl, 2-propenyl, butenyl, pentenyl and hexenyl groups. When the compound substituent is an alkenyl group, it also includes Z-form or E-form configuration isomers formed when different atoms are connected on both sides of the carbon-carbon double bond.
  • Alkynyl refers to straight-chain or branched alkynyl groups, such as 1-propynyl, 2-propynyl, butynyl, pentynyl, and hexynyl.
  • Alkoxy refers to a group with an oxygen atom attached to the end of the alkyl group, such as methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy and the like.
  • Alkylthio refers to a group with a sulfur atom attached to the end of an alkyl group, such as methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio and the like.
  • Alkylsulfinyl refers to a group with a sulfinyl group attached to the end of an alkyl group, such as methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, tert-butylsulfinyl and the like.
  • Alkylsulfonyl refers to a group with a sulfonyl group attached to the end of an alkyl group, such as methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl and the like.
  • a 5-7 membered aliphatic heterocyclic ring containing 1-4 heteroatoms refers to a 5-7 membered heterocyclic compound containing 1-4 heteroatoms without aromatic characteristics, such as ethylene oxide, tetrahydrofuran, imidazolinone, caprolactam Wait.
  • a 5-7 membered aromatic heterocyclic ring containing 1-4 heteroatoms refers to a 5-7 membered aromatic heterocyclic compound containing 1-4 heteroatoms, such as furan, thiophene, pyridine and the like.
  • the compound of general formula (I) of the present invention can be prepared by the following method.
  • the definitions of other groups are the same as before:
  • the intermediate aminobenzoate (II) reacts with the carbonylation reagent to form isocyanate (III), which is then reacted with 1,3-disubstituted urea or 1,3-disubstituted thiourea in an organic solvent at a temperature of -10°C to Under the boiling point of the organic solvent, react for 0.5 to 48 hours to obtain compound (I) of general formula.
  • the organic solvent can be selected from chloroform, dichloromethane, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, DMF, THF, or dioxane.
  • alkali substances such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, is beneficial to the reaction.
  • the carbonylation reagent is selected from triphosgene, carbonyl diimidazole (DCI), phosgene, diphosgene, chloroformate and the like.
  • the intermediate nitrobenzoate (IV) is reacted with a suitable reducing agent at a temperature of -10°C to the boiling point of the solvent for 0.5 to 48 hours to prepare the intermediate aminobenzoate (II).
  • the solvent can be selected from alcohols, such as methanol, ethanol, isopropanol, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., and esters, such as ethyl acetate, methyl acetate, and the like.
  • the reducing agent is selected from hydrogen, a catalytic amount of transition metal or a catalytic amount of transition metal compound; among them, the transition metal is especially selected from group VIII compounds, preferably Ni, Pd, Pt, etc. (used directly or via activated carbon, aluminum oxide , Silica and other media load); hydrogen can be provided by hydrogen storage cylinders, or can be generated in situ from active metals (such as reduced iron powder, reduced zinc powder, stannous chloride, etc.) under acidic conditions (such as hydrochloric acid, sulfuric acid) And participate in the reduction reaction.
  • group VIII compounds preferably Ni, Pd, Pt, etc. (used directly or via activated carbon, aluminum oxide , Silica and other media load)
  • hydrogen can be provided by hydrogen storage cylinders, or can be generated in situ from active metals (such as reduced iron powder, reduced zinc powder, stannous chloride, etc.) under acidic conditions (such as hydrochloric acid, sulfuric acid) And participate in the reduction reaction.
  • Suitable reducing agents also include metal hydrides, semi-metal hydrides and their derivatives, such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride, borane and the like.
  • Intermediate nitrobenzoic acid (V, commercially available) and substituted hydroxycarboxylic acid ester (VI, commercially available) are dissolved in a suitable solvent, and reacted at a temperature of -10°C to the boiling point of the solvent for 0.5 to 48 hours.
  • the intermediate nitrobenzoate (IV) is prepared under the action of the dehydrating agent.
  • the solvent can be selected from chloroform, dichloromethane, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, DMF, THF, or dioxane.
  • Dehydrating agent can choose dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC ⁇ HCl) and so on.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC ⁇ HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • alkali substances such as triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), etc.
  • the intermediate nitrobenzoate (IV) can also be prepared from the intermediate nitrobenzoic acid (V) and the corresponding substituted carboxylic acid ester (VII, commercially available) with easy leaving groups in a suitable solvent, It is prepared by reacting at a temperature of -10°C to the boiling point of the solvent for 0.5 to 48 hours.
  • the solvent can be selected from chloroform, dichloromethane, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, DMF, THF, or dioxane.
  • alkali substances such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, is beneficial to the reaction.
  • L is a leaving group, such as chlorine, bromine, iodine, methanesulfonate group, and p-toluenesulfonate group.
  • the intermediate nitrobenzoate (IV) can also be prepared from the intermediate nitrobenzoic acid (V) and oxalyl chloride, thionyl chloride, phosphorus trichloride or phosphorus pentachloride in a suitable solvent at a temperature of -10
  • the acid chloride (VIII) is prepared by reacting at °C to the boiling point of the solvent for 0.5 to 48 hours, which is then obtained by alcoholysis reaction with the substituted hydroxycarboxylic acid ester (VI).
  • Suitable solvents for preparing acid chlorides are selected from dichloromethane, chloroform, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, acetonitrile, THF, dioxane or dimethyl sulfoxide and the like.
  • Suitable solvents for the alcoholysis reaction are selected from chloroform, dichloromethane, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, DMF, THF, or dioxane.
  • the addition of a suitable base material is beneficial to the reaction, and the suitable base is selected from organic bases such as DMF, triethylamine, N,N-dimethylaniline or pyridine.
  • the compound of general formula (I) of the present invention can also be prepared by the following method.
  • the definitions of other groups are the same as before:
  • Dehydrating agent can choose dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC ⁇ HCl) and so on.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC ⁇ HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • alkali substances such as triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), etc.
  • the compound of general formula (I) of the present invention can also be prepared by the following method.
  • the definitions of other groups are the same as before:
  • the intermediate triazine benzoic acid (IX) and the corresponding substituted carboxylic acid ester (VII, commercially available) with easy leaving groups are reacted in a suitable solvent at a temperature of -10°C to the boiling point of the solvent for 0.5 ⁇
  • the compound (I) of general formula was prepared in 48 hours.
  • the solvent can be selected from chloroform, dichloromethane, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, DMF, THF, or dioxane.
  • alkali substances such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, is beneficial to the reaction.
  • L is a leaving group, such as chlorine, bromine, iodine, methanesulfonate group, and p-toluenesulfonate group.
  • the compound of general formula (I) of the present invention can also be prepared by the following method.
  • the definitions of other groups are the same as before:
  • Suitable solvents for preparing acid chlorides are selected from dichloromethane, chloroform, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, acetonitrile, THF, dioxane or dimethyl sulfoxide and the like.
  • Suitable solvents for the alcoholysis reaction are selected from chloroform, dichloromethane, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, DMF, THF, or dioxane.
  • the addition of a suitable base material is beneficial to the reaction, and the suitable base is selected from organic bases such as DMF, triethylamine, N,N-dimethylaniline or pyridine.
  • the intermediate triazine benzoic acid (IX) can be dissolved in a suitable solvent from the intermediate triazine benzoate (XI, R is methyl, ethyl, n-propyl, isopropyl, benzyl, etc.).
  • acidic aqueous solution such as sulfuric acid, hydrochloric acid, phosphoric acid, etc.
  • alkaline aqueous solution such as sodium hydroxide, potassium hydroxide, etc.
  • Lewis acid such as boron tribromide
  • organosilicon reagents such as trimethylsilyl iodide, trimethylchlorosilane, etc.
  • the solvent can be selected from acetonitrile, chloroform, dichloromethane, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, DMF, THF, or dioxane and the like.
  • a carboxylate group is further introduced.
  • the electronegativity and spatial structure of the entire molecule will be greatly different, so that the entire molecule can be transported in organisms such as plants.
  • the conductivity varies greatly.
  • the appropriate transport properties of biologically active molecules play an important role in the effectiveness of the drug.
  • the suitability of the transport properties of biologically active molecules is unpredictable and requires a lot of creative work to know.
  • the compound containing two carboxylic acid ester structures of the present invention has unexpectedly high herbicidal activity. It can effectively control dicotyledonous weeds when used after emergence at a lower dose, especially for Broadleaf weeds have unexpectedly satisfactory results.
  • the photoactive carboxylic acid ester compound mainly of the S configuration of the present invention has unexpectedly high herbicidal activity and can effectively control weeds at a certain dose.
  • the technical solution of the present invention also includes the use of the compound of general formula (I) for controlling weeds.
  • the present invention also includes herbicidal compositions using the compound of general formula (I) as the active ingredient.
  • the weight percentage of the active component in the herbicidal composition is 5-90%.
  • the herbicidal composition also includes an agriculturally acceptable carrier.
  • the herbicidal composition of the present invention can be applied in the form of various formulations.
  • the compound of the present invention is dissolved or dispersed in a carrier to prepare a formulation so as to be easier to disperse when used as a herbicide.
  • these chemical agents can be made into wettable powders or emulsifiable concentrates. Therefore, in these compositions, at least one liquid or solid carrier is added, and it is usually necessary to add a suitable surfactant.
  • Another embodiment of the present invention is a method for controlling weeds, which comprises applying a herbicidal effective amount of the herbicidal composition of the present invention to the weed or the place where the weed grows or the surface of its growth medium.
  • a herbicidal effective amount of the herbicidal composition of the present invention is selected from 1 g to 500 g per hectare, and the effective amount is preferably 2 g to 250 g per hectare.
  • one or more other herbicides can be added to the herbicidal composition of the present invention, which can produce additional advantages and effects.
  • the compound of the present invention can be used alone or mixed with other known insecticides, fungicides, plant growth regulators or fertilizers.
  • Example 1 Compound 1 2-chloro-4-fluoro-5-(3,5-dimethyl-2,4,6-trioxo-1,3,5-triazin-1-yl)benzoic acid Synthesis of (1-ethoxycarbonyl) ethyl ester
  • 2-chloro-4-fluoro-5-nitrobenzoic acid isopropyl ester 14.40g, 55mmol
  • 30mL ethanol and 60mL tetrahydrofuran to form a solution
  • reduced iron powder 11.00g 197mmol
  • concentrated hydrochloric acid 40mL, about 480mmol
  • the solvent was distilled off under reduced pressure, and the residue was added with 100 mL of water, and extracted with ethyl acetate (50 mL ⁇ 3).
  • the reaction solution was poured into 60 mL of ice-water mixture, the precipitated gray solid was obtained by filtration, rinsed twice with 30 mL of water, and dried to obtain the intermediate 2-chloro-4-fluoro-5-(3 ,5-Dimethyl-2,4,6-trioxo-1,3,5-triazin-1-yl)benzoic acid 3.90g, the yield is 98%.
  • Example 2 Compound 33 2-chloro-4-fluoro-5-(3,5-dimethyl-2,4,6-trioxo-1,3,5-triazin-1-yl)benzoic acid Synthesis of (1-(2-Butynyloxycarbonyl)) ethyl ester
  • reaction solution was poured into 50 mL of water, extracted with dichloromethane (25 mL ⁇ 2), and the combined organic layer was washed with 25 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.85 g of a pale yellow liquid with a yield of 75%. It can be used directly in the next reaction without further purification.
  • Step b) Compound 33 2-chloro-4-fluoro-5-(3,5-dimethyl-2,4,6-trioxo-1,3,5-triazin-1-yl)benzoic acid ( Synthesis of 1-(2-Butynyloxycarbonyl)) ethyl ester
  • reaction solution was poured into 50 mL of water, extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic layer was washed with 25 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow viscous liquid.
  • Example 4 Compound 154 2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl)benzoic acid ( Synthesis of 1-(3,3-dichloroallyloxycarbonyl)) ethyl ester
  • the 2-chloro-5-nitrobenzoic acid benzyl ester (30.00g, 100mmol) prepared in the previous step was mixed with a mixed solvent consisting of 50mL ethanol and 50mL tetrahydrofuran to form a solution, and reduced iron powder (19.50 g, 350mmol), concentrated hydrochloric acid (66mL, about 800mmol) was added dropwise to it under an ice-water bath, and after the addition, it was returned to room temperature and reacted for 1h.
  • the solvent was distilled off under reduced pressure, and the residue was added with 100 mL of water and extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 25.80 g of yellow liquid. Cooled A dark yellow solid can be obtained later with a crude yield of 99%.
  • the obtained 5-amino-2-chlorobenzoic acid benzyl ester can be directly used in the next step of synthesis without further purification.
  • ethanol can be used for recrystallization to obtain a pale yellow solid.
  • Example 5 Compound 166 2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl)benzoic acid ( Synthesis of 1-(acetone glycidyl carbonyl)) ethyl ester
  • reaction solution was poured into 50 mL of water, extracted with dichloromethane (50 mL ⁇ 2), and the combined organic layer was washed with 25 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 10.10 g of a pale yellow liquid with a yield of 76%. It can be used directly in the next reaction without further purification.
  • Step b) Compound 166 2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl)benzoic acid (1 -(Acetone glycidyl carbonyl)) ethyl ester synthesis
  • the 2-chloro-4-fluoro-5-nitrobenzoic acid benzyl ester (7.75g, 25mmol) prepared in the previous step was formed into a solution with 25mL ethyl acetate, and stannous chloride dihydrate was added (22.00g, 98mmol), react under heating and reflux for 2h.
  • the reaction solution was poured into 100 mL of ice-water mixture, and the pH of the system was adjusted to 9-10 with dilute NaOH solution.
  • the deposited precipitate was filtered and rinsed with ethyl acetate several times.
  • reaction solution was poured into 20 mL of water, extracted with ethyl acetate (10 mL ⁇ 3), the combined organic layer was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow viscous liquid.
  • Example 7 Compound 241 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl ) Synthesis of (cyclopropylmethoxycarbonyl) methyl benzoate
  • reaction solution was poured into 50 mL of water, extracted with dichloromethane (30 mL ⁇ 2), and the combined organic layer was washed with 25 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.60 g of a colorless liquid with a yield of 62%. It can be used directly in the next reaction without further purification.
  • Example 8 Compound 248 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl )(1-Ethoxycarbonyl)ethyl benzoate
  • Example 9 Compound 266(R)-2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazine Synthesis of 1-(1-yl)benzoic acid (1-(2-chloroethoxycarbonyl) ethyl ester
  • reaction solution was poured into 50 mL of water, extracted with dichloromethane (50 mL ⁇ 2), and the combined organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 8.50 g of yellow liquid with a yield of 79%. It can be used directly in the next reaction without further purification.
  • Step b) Compound 266(R)-2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazine- Synthesis of 1-(yl)benzoic acid (1-(2-chloroethoxycarbonyl) ethyl ester
  • Example 10 Compound 267(S)-2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazine Synthesis of 1-(1-yl)benzoic acid (1-(2-chloroethoxycarbonyl) ethyl ester
  • reaction solution was poured into 50 mL of water, extracted with dichloromethane (50 mL ⁇ 2), and the combined organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 8.50 g of yellow liquid with a yield of 79%. It can be used directly in the next reaction without further purification.
  • Step b) Compound 267(S)-2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazine- Synthesis of (1-(2-chloroethoxycarbonyl)ethyl 1-yl)benzoic acid
  • Example 11 Compound 281(E)-2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazine Synthesis of 1-(1-yl)benzoic acid (1-(3-chloroallyloxycarbonyl)) ethyl ester
  • Example 12 Compound 298 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl ) Synthesis of (1-(Isoxazolin-2-ylmethoxycarbonyl)) ethyl benzoate
  • Step c) Compound 298 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl) Synthesis of (1-(Isoxazolin-2-ylmethoxycarbonyl)) ethyl benzoate
  • Example 13 Compound 300 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl ) Synthesis of (1-(2-fluoroethoxycarbonyl)) propyl benzoate
  • reaction solution was poured into 50 mL of water and extracted with dichloromethane (50 mL ⁇ 2). The combined organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.60 g of yellow liquid with a yield of 68%. It can be used directly in the next reaction without further purification.
  • Step b) Compound 300 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl) Synthesis of (1-(2-Fluoroethoxycarbonyl)) Propyl Benzoate
  • reaction solution was poured into 20 mL of water, extracted with ethyl acetate (10 mL ⁇ 3), the combined organic layer was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow viscous liquid.
  • Example 14 Compound 306 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl )(1-Methyl-1-ethoxycarbonyl)ethyl benzoate
  • reaction solution was poured into 50 mL of water and extracted with 50 mL of dichloromethane.
  • the combined organic layer was washed with 30 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.70 g of yellow liquid with a crude yield of 33%.
  • the obtained intermediate 2-chloro-4-fluoro-5-nitrobenzoic acid (1-methyl-1-ethoxycarbonyl) ethyl ester was directly used in the next step of synthesis without further purification.
  • Step c) Compound 306 2-chloro-4-fluoro-5-(3,5-dimethyl-2,6-dioxo-4-thio-1,3,5-triazin-1-yl) Synthesis of (1-methyl-1-ethoxycarbonyl) ethyl benzoate
  • test design dose spray treatment (spray pressure 1.95kg/cm 2 , spray volume 500L/hm 2 , crawler speed 1.48km/h) on a crawler crop sprayer (designed and produced by British Engineer Research Ltd.).
  • the test is set to be repeated 3 times. After treatment, the test materials are placed in the operation hall. After the liquid is naturally dried, it is placed in the greenhouse for management according to conventional methods. Observe and record the response of weeds to the drugs. After treatment, regularly visually observe the control effect of the test drugs on weeds. It is represented by 0-100%, with "0" representing no preventive effect and "100%" representing complete kill.
  • test results show that the compound of general formula I generally has a relatively high control effect on a variety of weeds.
  • Some of the tested compounds such as compounds 221, 222, 225, 241, 245, 246, 247, 248, 249, 250, 264, 265, 266, 267, 268, 269, 270, 273, 281, 283, 287 , 289, 290, 291, 293, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305 at an application dose of 150g ai/hm 2 have a good control effect on Zinnia. The prevention effect is 100%.
  • test results show that the compound of general formula I generally has a relatively high control effect on a variety of weeds.
  • Some of the tested compounds such as compounds 138, 160, 221, 222, 225, 241, 245, 246, 247, 248, 249, 250, 264, 265, 266, 267, 268, 269, 270, 273, 281 , 283, 287, 289, 290, 291, 293, 295, 296, 297, 298, 300, 301, 302, 303, 304, 305, 306 at an application dose of 150g ai/hm 2 has a better The prevention effect is 100%.
  • the test results show that the compound of general formula I generally has a relatively high control effect on a variety of weeds.
  • Some of the tested compounds such as compounds 117, 221, 222, 225, 241, 245, 246, 247, 248, 250, 264, 268, 273, 281, 283, 287, 291, 295, 296, 297, 298
  • the application dose of 150g ai/hm 2 has a good control effect on Setaria viridis, and the control effect is not less than 80%.
  • test results show that the compound of general formula I generally has a relatively high control effect on a variety of weeds.
  • Some of the tested compounds such as compounds 221, 222, 225, 241, 245, 246, 247, 248, 249, 250, 264, 265, 266, 267, 268, 269, 270, 273, 281, 283, 287 , 291, 293, 295, 296, 297, 298, 301, 306 at the application dose of 150g ai/hm 2 has a good control effect on barnyardgrass, the control effect is not less than 90%.
  • Table 2 The herbicidal activity of some compounds of general formula (I) (post-emergence, control effect %)
  • Table 3 Parallel comparison of herbicidal activity of some compounds of general formula (I) on Zinnia (post-emergence, control effect %)
  • Table 4 Parallel comparison of herbicidal activity of some compounds of general formula (I) on Abutilon (post-emergence, control effect %)
  • Table 5 Parallel comparison of the herbicidal activity of some compounds of general formula (I) on Setaria viridis (post-emergence, control effect %)

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Abstract

本发明公开了一种三嗪苯甲酸酯类化合物，具有如通式(I)所示的结构或其立体异构体：通式I中各取代基定义见说明书。本发明通式I化合物具有优良的除草活性，可用于防治杂草。

Description

三嗪苯甲酸酯类化合物及其应用 技术领域
本发明属于除草剂领域，具体涉及一种三嗪苯甲酸酯类化合物及其应用。
背景技术
由于杂草种群的演替、变迁以及对化学农药抗药性的产生和迅速发展，人们对生态环境保护意识的不断加强，对化学农药污染、农药对非靶标生物影响的认识以及在农药生态环境中归宿问题的重视不断提高。随着世界耕地面积的逐渐减少、人口的不断增长及对粮食需求量的增加，迫使人们迅速发展农业生产技术、改进完善耕作制度，并需要不断发明新型的和改进的除草化合物和组合物。
CN1341105A公开了下列通式化合物具有除草活性：
Figure PCTCN2021101396-appb-000001
其中，R 5可为羧酸酯取代基COOR 20。R 20可选自C 1-C 6-烷基、C 1-C 6-卤代烷基、C 2-C 6-链烯基或C 2-C 6-炔基，并可由(C 1-C 6-烷氧基)羰基、(C 3-C 6-链烯氧基)羰基、(C 3-C 6-炔氧基)羰基或C 1-C 6-烷氧基-(C 1-C 6-烷氧基)羰基进一步取代。
CN1341105A公开了化合物KC 1(专利说明书中表3第30号化合物)在7.81和3.91g/ha剂量下，通过苗后施用方法，可以有效地控制反枝苋、藜、饭包草和大狗尾草；同时公开了具有光活性的化合物KC 2(R体，专利说明书中表3第12号化合物)的制备，但未报道其除草活性。
Figure PCTCN2021101396-appb-000002
在现有技术中，如本发明所示的三嗪苯甲酸酯类化合物及其除草活性未见公开。
发明内容
本发明的目的是提供一种结构新颖、具有很好除草活性的三嗪苯甲酸酯类化合物及以该类化合物为活性组分的除草组合物，以满足生产迅速发展的需要。
本发明的技术方案如下：
本发明提供了一种新颖的三嗪苯甲酸酯类化合物，具有如通式(I)所示的结构：
Figure PCTCN2021101396-appb-000003
其中：
W选自O或S；
X 1选自H或F；
X 2选自卤素、CN、CONH 2或CSNH 2；
R 1选自甲基或乙基；
R 2选自甲基或乙基；
R 3选自H或甲基；
R 4选自H或C 1-C 3烷基；
R 5选自CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、(CH 3) 2CHCH 2-、CH 3CH 2CH(CH 3)-、(CH 3) 3C-、CH 3CH 2CH 2CH 2CH 2-、(CH 3) 2CHCH 2CH 2-、(CH 3) 3CCH 2-、CH 3CH 2CH(CH 3)CH 2-、CH 3CH 2CH 2CH(CH 3)-、CH 3CH 2C(CH 3) 2-、CH 3CH＝CHCH 2-、CH 3C≡CCH 2-、C 1-C 10卤代烷基、C 1-C 6烷硫基C 1-C 6烷基、C 1-C 6烷基亚磺酰基C 1-C 6烷基、C 1-C 6烷基磺酰基C 1-C 6烷基、(C 1-C 6烷基) 2氨基C 1-C 6烷基、C 3-C 10环烷基、C 3-C 6环烷基C 1-C 6烷基、C 3-C 10卤代环烷基、C 3-C 6卤代环烷基C 1-C 6烷基、C 2-C 10卤代烯基、C 1-C 6烷氧基C 2-C 6烯基、C 1-C 6烷硫基C 2-C 6烯基、C 1-C 6烷基亚磺酰基C 2-C 6烯基、C 1-C 6烷基磺酰基C 2-C 6烯基、(C 1-C 6烷基) 2氨基C 2-C 6烯基、C 3-C 10环烯基、C 3-C 6环烷基C 2-C 6烯基、C 3-C 6卤代环烷基C 2-C 6烯基、C 2-C 10卤代炔基、C 1-C 6烷氧基C 2-C 6炔基、C 1-C 6烷硫基C 2-C 6炔基、C 1-C 6烷基亚磺酰基C 2-C 6炔基、C 1-C 6烷基磺酰基C 2-C 6炔基、(C 1-C 6烷基) 2氨基C 2-C 6炔基、C 3-C 10环炔基、C 3-C 6环烷基C 2-C 6炔基、C 3-C 6卤代环烷基C 2-C 6炔基、苯基、苯基C 1-C 6烷基、含有1-4个杂原子的5-7元脂杂环、含有1-4个杂原子的5-7元芳杂环、含有1-4个杂原子的5-7元脂杂环C 1-C 6烷基或含有1-4个杂原子的5-7元芳杂环C 1-C 6烷基，前述苯基、脂杂环、芳杂环上的氢可被一个或多个下述取代基取代，取代基选自硝基、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基、C 2-C 6烯基、C 2-C 6炔基、苯基或被一个或多个卤素取代的苯基；
或，R 3选自H同时R 4不选自H时，式I所示化合物的光学异构体。
本发明进一步优选的化合物为，通式I中：
W选自O或S；
X 1选自H或F；
X 2选自Cl、Br或CN；
R 1选自甲基；
R 2选自甲基；
R 3选自H或甲基；
R 4选自H、甲基、乙基或异丙基；
R 5选自CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、(CH 3) 2CHCH 2-、CH 3CH 2CH(CH 3)-、(CH 3) 3C-、CH 3CH 2CH 2CH 2CH 2-、(CH 3) 2CHCH 2CH 2-、(CH 3) 3CCH 2-、CH 3CH 2CH(CH 3)CH 2-、CH 3CH 2CH 2CH(CH 3)-、CH 3CH 2C(CH 3) 2-、ClCH 2CH 2-、ClCH 2CH 2CH 2-、CH 3ClCHCH 2-、CH 2Cl(CH 3)CH-、ClCH 2CH 2CH 2CH 2-、CH 3ClCHCH 2CH 2-、CH 3CH 2ClCHCH 2-、CH 3CH 2CH 2ClCH-、ClCH 2CH 2CH(CH 3)-、ClCH 2(CH 3) 2C-、ClCH 2CH 2CH 2CH 2CH 2-、CH 3CH＝CHCH 2-、ClCH＝CHCH 2-、Cl 2C＝CHCH 2-、ClCH＝CClCH 2-、CH 3C≡CCH 2-、ClC≡CCH 2-、或如下取代基：
Figure PCTCN2021101396-appb-000004
或，R 3选自H同时R 4不选自H时，式I所示化合物的光学异构体。
本发明更进一步优选的化合物为，通式I中：
W选自S；
X 1选自F；
X 2选自Cl；
R 1选自甲基；
R 2选自甲基；
R 3选自H或甲基；
R 4选自H或甲基；
R 5选自CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、(CH 3) 2CHCH 2-、CH 3CH 2CH(CH 3)-、(CH 3) 3C-、CH 3CH 2CH 2CH 2CH 2-、(CH 3) 2CHCH 2CH 2-、(CH 3) 3CCH 2-、CH 3CH 2CH(CH 3)CH 2-、CH 3CH 2CH 2CH(CH 3)-、CH 3CH 2C(CH 3) 2-、ClCH 2CH 2-、ClCH 2CH 2CH 2-、CH 3ClCHCH 2-、CH 2Cl(CH 3)CH-、ClCH 2CH 2CH 2CH 2-、CH 3ClCHCH 2CH 2-、CH 3CH 2ClCHCH 2-、CH 3CH 2CH 2ClCH-、ClCH 2CH 2CH(CH 3)-、ClCH 2(CH 3) 2C-、ClCH 2CH 2CH 2CH 2CH 2-、CH 3CH＝CHCH 2-、ClCH＝CHCH 2-、Cl 2C＝CHCH 2-、ClCH＝CClCH 2-、CH 3C≡CCH 2-、ClC≡CCH 2-或如下取代基：
Figure PCTCN2021101396-appb-000005
或，R 3选自H同时R 4选自甲基时，式I所示化合物的光学异构体为S构型或者S构型含量大于60％。
上面给出的通式I化合物的定义中，汇集所用术语定义如下：
卤素是指氟、氯、溴、碘。烷基是指直链或支链形式，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、特丁基、正戊基、异戊基、正己基等基团。卤代烷基是指烷基被一个或多个卤原子取代的基团，如氯乙基、三氟甲基等。环烷基是指包括环状链形式，例如环丙基、甲基环丙基、环丙基环丙基、环丁基、环戊基、环己基等基团。烯基是指直链或支链烯基，如1-丙烯基、2-丙烯基、丁烯基、戊烯基和已烯基等基团。化合物取代基为烯基时，还包括当碳碳双键两侧连接不同原子时形成的Z式或E式的构型异构体。炔基是指直链或支链炔基，如1-丙炔基、2-丙炔基、丁炔基、戊炔基和己炔基等基团。烷氧基是指烷基末端连有氧原子的基团，例如甲氧基、乙氧基、正丙氧基、异丙氧基、特丁氧基等。烷硫基是指烷基末端连有硫原子的基团，例如甲硫基、乙硫基、正丙硫基、异丙硫基、特丁硫基等。烷基亚磺酰基是指烷基末端连有亚磺酰基的基团，例如甲亚磺酰基、乙基亚磺酰基、异丙基亚磺酰基、特丁基亚磺酰基等。烷基磺酰基是指烷基末端连有磺酰基的基团，例如甲磺酰基、乙基磺酰基、异丙基磺酰基、特丁基磺酰基等。含有1-4个杂原子的5-7元脂杂环是指含有1-4个杂原子的5-7元没有芳香特征的杂环化合物，如环氧乙烷、四氢呋喃、咪唑啉酮、己内酰胺等。含有1-4个杂原子的5-7元芳杂环是指含有1-4个杂原子的5-7元具有芳香特征的杂环化合物，如呋喃、噻吩、吡啶等。
本发明的通式(I)化合物可由如下方法制备，反应式中除另有注明的外，其他各基团的定义同前：
Figure PCTCN2021101396-appb-000006
中间体氨基苯甲酸酯(II)与羰基化试剂反应形成异氰酸酯(III)，再与1,3-二取代脲或1,3-二取代硫脲在有机溶剂中、温度为-10℃到有机溶剂沸点下，反应0.5～48小时制得通式化合物(I)。有机溶剂可选自氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。加入碱类物质，如三乙胺、吡啶、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸氢钠等对反应有利。
羰基化试剂选自三光气、羰基二咪唑(DCI)、光气、双光气、氯甲酸酯等。
Figure PCTCN2021101396-appb-000007
中间体硝基苯甲酸酯(IV)与合适的还原剂，在温度为-10℃到溶剂沸点下反应0.5～48小时制得中间体氨基苯甲酸酯(II)。溶剂可选自醇类，如甲醇、乙醇、异丙醇等，醚类如乙醚、四氢呋喃、二氧六环等，酯类，如乙酸乙酯、乙酸甲酯等。
还原剂选自氢气、在催化量的过渡金属或催化量的过渡金属化合物；其中，过渡金属尤其可选第VIII族化合物，优选Ni、Pd、Pt等(直接使用或经由活性炭、三氧化二铝、二氧化硅等介质负载)；氢气可由储氢钢瓶提供，也可以由活泼金属(如还原铁粉、还原锌粉、氯化亚锡等)在酸性条件(如盐酸、硫酸)下原位发生并参与还原反应。
合适的还原剂还包括金属氢化物、半金属氢化物及其衍生物，如氢化铝锂、二异丁基氢化铝、硼氢化钠、硼烷等。
中间体IV可由如下三条路线制备：
路线一：
Figure PCTCN2021101396-appb-000008
中间体硝基苯甲酸(V，有市售)与取代羟基羧酸酯(VI，有市售)溶于适宜的溶剂中，在温度为-10℃到溶剂沸点下反应0.5～48小时，在脱水剂作用下制得中间体硝基苯甲酸酯(IV)。溶剂可选自氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。脱水剂可选择二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl)等。加入碱类物质，如三乙胺、吡啶、4-二甲氨基吡啶(DMAP)等对反应有利。
路线二：
Figure PCTCN2021101396-appb-000009
中间体硝基苯甲酸酯(IV)还可由中间体硝基苯甲酸(V)与相应的带有易离去基团的取代羧酸酯(VII，有市售)在适宜的溶剂中，在温度为-10℃到溶剂沸点下反应0.5～48小时制得。溶剂可选自氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。加入碱类物质，如三乙胺、吡啶、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸氢钠等对反应有利。
取代羧酸酯(VII)中，L为离去基团，例如氯、溴、碘、甲基磺酸酯基、对甲基苯磺酸酯基等。
路线三：
Figure PCTCN2021101396-appb-000010
中间体硝基苯甲酸酯(IV)还可由中间体硝基苯甲酸(V)与草酰氯、二氯亚砜、三氯化磷或五氯化磷在适宜的溶剂中、温度为-10℃到溶剂沸点下反应0.5～48小时制得酰氯(VIII)，再与取代羟基羧酸酯(VI)发生醇解反应得到。制备酰氯的适宜溶剂选自二氯甲烷、氯仿、四氯化碳、己烷、苯、甲苯、乙酸乙酯、乙腈、THF、二氧六环或二甲基亚砜等。醇解反应适宜的溶剂选自氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。加入适宜的碱类物质对反应有利，适宜的碱选自有机碱如DMF、三乙胺、N,N-二甲基苯胺或吡啶等。
本发明的通式(I)化合物还可由如下方法制备，反应式中除另有注明的外，其他各基团的定义同前：
Figure PCTCN2021101396-appb-000011
中间体三嗪苯甲酸(IX)与取代羟基羧酸酯(VI，有市售)溶于适宜的溶剂中，在温度为-10℃到溶剂沸点下反应0.5～48小时，在脱水剂作用下制得通式化合物(I)。溶剂可选自氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。脱水剂可选择二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl)等。加入碱类物质，如三乙胺、吡啶、4-二甲氨基吡啶(DMAP)等对反应有利。
本发明的通式(I)化合物也可由如下方法制备，反应式中除另有注明的外，其他各基团的定义同前：
Figure PCTCN2021101396-appb-000012
中间体三嗪苯甲酸(IX)与相应的带有易离去基团的取代羧酸酯(VII，有市售)在适宜的溶剂中，在温度为-10℃到溶剂沸点下反应0.5～48小时制得通式化合物(I)。溶剂可选自氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。加入碱类物质，如三乙胺、吡啶、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸氢钠等对反应有利。
取代羧酸酯(VII)中，L为离去基团，例如氯、溴、碘、甲基磺酸酯基、对甲基苯磺酸酯基等。
本发明的通式(I)化合物也可由如下方法制备，反应式中除另有注明的外，其他各基团的定义同前：
Figure PCTCN2021101396-appb-000013
中间体三嗪苯甲酸(IX)与草酰氯、二氯亚砜、三氯化磷或五氯化磷在适宜的溶剂中、温度为-10℃到溶剂沸点下反应0.5～48小时制得酰氯(X)，再与取代羟基羧酸酯(VI)发生醇解反应得到通式化合物(I)。制备酰氯的适宜溶剂选自二氯甲烷、氯仿、四氯化碳、己烷、苯、甲苯、乙酸乙酯、乙腈、THF、二氧六环或二甲基亚砜等。醇解反应适宜的溶剂选自氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。加入适宜的碱类物质对反应有利，适宜的碱选自有机碱如DMF、三乙胺、N,N-二甲基苯胺或吡啶等。
Figure PCTCN2021101396-appb-000014
中间体三嗪苯甲酸(IX)可由中间体三嗪苯甲酸酯(XI，R为甲基、乙基、正丙基、异丙基、苄基等)溶于适宜的溶剂中，在温度为-10℃到溶剂沸点下反应0.5～48小时，在酸性水溶液(如硫酸、盐酸、磷酸等)、碱性水溶液(如氢氧化钠、氢氧化钾等)或Lewis酸(如三溴化硼、三氯化硼、三氟化硼、三氯化铝等)、有机硅试剂(如三甲基碘硅烷、三甲基氯硅烷等)作用下制得。溶剂可选自乙腈、氯仿、二氯甲烷、四氯化碳、己烷、苯、甲苯、乙酸乙酯、DMF、THF或二氧六环等。
在有机分子中，由于其手性结构的不同，会使整个分子与作用靶标的结合度有较大的差异。生物活性分子合适的空间结构对药效的发挥起着重要的作用。生物活性分子空间结构的合适性是不可预知的，需要大量的创造性劳动才能获知。
在本发明化合物中，进一步引入了羧酸酯基团，引入基团后，会使整个分子在电负性、空间结构等方面有较大的差异，从而使整个分子在植物等生物体内的输导性差异很大。生物活性分子合适的输导性能对药效的发挥起着重要的作用。生物活性分子输导性能的合适性是不可预知的，需要大量的创造性劳动才能获知。
同已知的苯甲酸酯类化合物相比，本发明同时含两个羧酸酯结构的化合物具有意想不到的高除草活性，在较低剂量下苗后使用可有效控制双子叶杂草，尤其对阔叶杂草具有令人出乎意料的满意效果。
同R构型的羧酸酯化合物相比，本发明以S构型为主的光活性羧酸酯化合物具有意想不到的高除草活性，在一定剂量下可有效控制杂草。
因此本发明的技术方案还包括通式(I)化合物用于控制杂草的用途。
本发明还包括以通式(I)化合物作为活性组分的除草组合物。该除草组合物中活性组分的重量百分含量为5-90％。该除草组合物中还包括农业上可接受的载体。
本发明的除草组合物可以多种制剂的形式施用。通常将本发明的化合物溶解或分散于载体中配制成制剂以便作为除草剂使用时更易于分散。例如：这些化学制剂可被制成可湿性粉剂或乳油。因此，在这些组合物中，至少加入一种液体或固体载体，并且通常需要加入适当的表面活性剂。
本发明另外的实施方案为防治杂草的方法，该方法包括将除草有效量的本发明的除草组合物施于所述杂草或所述杂草生长的场所或其生长介质的表面上。通常选择的较为适 宜有效量为每公顷1克到500克，优选有效量为每公顷2克到250克。对于某些应用，可在本发明的除草组合物中加入一种或多种其它的除草剂，由此可产生附加的优点和效果。
本发明的化合物既可以单独使用也可以和其它已知的杀虫剂、杀菌剂、植物生长调节剂或肥料等一起混合使用。
应明确的是，在本发明的权利要求所限定的范围内，可进行各种变换和改动。
具体实施方法
下列合成实施例、生测试验结果可用来进一步说明本发明，但不意味着限制本发明。
合成实施例
实施例1：化合物1 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000015
步骤a)中间体2-氯-4-氟-5-硝基苯甲酸异丙酯的合成
Figure PCTCN2021101396-appb-000016
在250mL的反应瓶中加入2-氯-4-氟-5-硝基苯甲酸(13.20g,60mmol)、甲苯(60mL)、二氯亚砜(7.5mL,103mmol)，回流反应3h。反应体系由悬浊液变为澄清溶液。减压蒸出溶剂和过量的二氯亚砜，残余物用20mL二氯甲烷稀释后备用。
在另一250mL的反应瓶中依次加入二氯甲烷(60mL)、异丙醇(4.00g,67mmol)和三乙胺(9.0mL,65mmol)，室温下向其中滴加上述制备的酰氯二氯甲烷溶液，滴加完毕后继续在室温下搅拌2h。反应液倾入100mL水中，用50mL二氯甲烷萃取，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得14.40g黄色液体，粗收率92％。得到的2-氯-4-氟-5-硝基苯甲酸异丙酯，不经进一步纯化，直接应用于下一步合成中。
步骤b)中间体5-氨基-2-氯-4-氟苯甲酸异丙酯的合成
Figure PCTCN2021101396-appb-000017
在250mL的反应瓶中，2-氯-4-氟-5-硝基苯甲酸异丙酯(14.40g,55mmol)与30mL乙醇和60mL四氢呋喃组成的混合溶剂形成溶液，加入还原铁粉(11.00g,197mmol)，冰水浴下向其中滴加浓盐酸(40mL,约480mmol)，滴加完毕后恢复至室温下反应1h。减压蒸出溶剂，残余物加入100mL水，用乙酸乙酯萃取(50mL×3)，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得13.00g棕色液体，冷却后可得到棕褐色固体，粗收率102％。得到的5-氨基-2-氯-4-氟苯甲酸异丙酯，可不经进一步纯化，直接应用于下一步合成中。若要纯化，可用乙醇进行重结晶，得到黄色固体。
步骤c)中间体2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸异丙酯的合成
Figure PCTCN2021101396-appb-000018
在250mL的反应瓶中加入50mL乙酸乙酯，再依次加入5-氨基-2-氯-4-氟苯甲酸异丙酯(13.00g,56mmol)、三乙胺(9.0mL,65mmol)和羰基二咪唑(DCI,22.50g,140mmol)形成溶液，加热升温至50℃，反应30min。再向其中加入1,3-二甲基脲(5.90g,67mmol)，随后升温至回流，反应2h。反应完成后，向其中加入100mL乙酸乙酯，经饱和食盐水洗涤(50mL×2)，无水硫酸镁干燥，减压浓缩得褐色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:9,then 1:4)，得到15.35g黄色液体，收率73％。
步骤d)中间体2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸的合成
Figure PCTCN2021101396-appb-000019
在100mL的反应瓶中加入2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸异丙酯(4.46g,12mmol)和浓硫酸(12.0mL,220mmol)形成溶液，加热升温至80℃，反应4h。反应完成后，将反应液倒入60mL冰水混合物中，析出的灰色固体通过过滤得到，用30mL水润洗两次，晾干即可得到中间体2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸3.90g，收率98％。
步骤e)化合物1 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000020
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(0.50g,1.5mmol)、乳酸乙酯(0.20g,1.7mmol)、4-(N,N-二甲氨基)吡啶(DMAP,0.05g,0.4mmol)混合溶于50mL二氯甲烷中形成灰白色悬浊液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,0.60g,3.1mmol)，反应体系由悬浊液变为澄清溶液。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(15mL×2)，合并的有机层经15mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得褐色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物1 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(1-乙氧羰基)乙酯0.27g，黄色液体，收率41％。
实施例2：化合物33 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(1-(2-丁炔氧羰基))乙酯的合成
Figure PCTCN2021101396-appb-000021
步骤a)中间体2-溴丙酸(2-丁炔-1-醇)酯的合成
Figure PCTCN2021101396-appb-000022
在250mL的反应瓶中将2-溴丙酸(3.82g,25.0mmol)、2-丁炔-1-醇(1.80g,25.7mmol)、4-(N,N-二甲氨基)吡啶(DMAP,0.60g,5.0mmol)混合于50mL二氯甲烷中形成溶液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,9.60g,50.0mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(25mL×2)，合并的有机层经25mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得到淡黄色液体3.85g，收率75％。可不经过进一步提纯，直接用于下一步反应中。
步骤b)化合物33 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(1-(2-丁炔氧羰基))乙酯的合成
Figure PCTCN2021101396-appb-000023
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(0.50g,1.5mmol)和碳酸钾(0.22g,1.6mmol)混合溶于7.5mL N,N-二甲基甲酰胺(DMF)中形成灰白色悬浊液，室温下向其中加入2-溴丙酸(2-丁炔-1-醇)酯(0.33g,1.6mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入30mL水中，用乙酸乙酯萃取(15mL×3)，合并的有机层经15mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物33 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(1-(2-丁炔氧羰基))乙酯0.45g，黄色液体，收率66％。
实施例3：化合物42 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(2-甲基-1-乙氧羰基)丙酯的合成
Figure PCTCN2021101396-appb-000024
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(0.66g,2.0mmol)和碳酸钾(0.29g,2.1mmol)混合溶于10mL N,N-二甲基甲酰胺(DMF)中形成灰白色悬浊液，室温下向其中加入2-溴-3-甲基丁酸乙酯(0.42g,2.0mmol,有市售)。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用乙酸乙酯萃取(20mL×3)，合并的有机层经25mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物42 2-氯-4-氟-5-(3,5-二甲基-2,4,6-三氧代-1,3,5-三嗪-1-基)苯甲酸(2-甲基-1-乙氧羰基)丙酯0.37g，橙色液体，收率40％。
实施例4：化合物154 2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(3,3-二氯烯丙氧羰基))乙酯的合成
Figure PCTCN2021101396-appb-000025
步骤a)中间体2-氯-5-硝基苯甲酸苄酯的合成
Figure PCTCN2021101396-appb-000026
在250mL的反应瓶中加入2-氯-5-硝基苯甲酸(20.16g,100mmol)、甲苯(100mL)、二氯亚砜(12.5mL,170mmol)，回流反应3h。反应体系由悬浊液变为澄清溶液。减压蒸出溶剂和过量的二氯亚砜，残余物用50mL二氯甲烷稀释后备用。
在另一250mL的反应瓶中依次加入二氯甲烷(100mL)、苯甲醇(12.50g,116mmol)和三乙胺(15.0mL,108mmol)，室温下向其中滴加上述制备的酰氯二氯甲烷溶液，滴加完毕后继续在室温下搅拌2h。反应液倾入100mL水中，用50mL二氯甲烷萃取，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得30.00g黄色液体，粗收率103％。得到的2-氯-5-硝基苯甲酸苄酯，不经进一步纯化，直接应用于下一步合成中。
步骤b)中间体5-氨基-2-氯苯甲酸苄酯的合成
Figure PCTCN2021101396-appb-000027
在250mL的反应瓶中，将上步制得的2-氯-5-硝基苯甲酸苄酯(30.00g,100mmol)与50mL乙醇和50mL四氢呋喃组成的混合溶剂形成溶液，加入还原铁粉(19.50g,350mmol)，冰水浴下向其中滴加浓盐酸(66mL,约800mmol)，滴加完毕后恢复至室温下反应1h。减压蒸出溶剂，残余物加入100mL水，用乙酸乙酯萃取(50mL×3)，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得25.80g黄色液体，冷却后可得到深黄色固体，粗收率99％。得到的5-氨基-2-氯苯甲酸苄酯，可不经进一步纯化，直接应用于下一步合成中。若要纯化，可用乙醇进行重结晶，得到淡黄色固体。
步骤c)中间体2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸苄酯的合成
Figure PCTCN2021101396-appb-000028
在250mL的反应瓶中加入100mL乙酸乙酯，再依次加入5-氨基-2-氯苯甲酸苄酯(25.80g,99mmol)、三乙胺(15.0mL,108mmol)和羰基二咪唑(DCI,40.00g,247mmol)形成溶液，加热升温至50℃，反应30min。再向其中加入1,3-二甲基硫脲(11.00g,106mmol)，随后升温至回流，反应2h。反应完成后，向其中加入100mL乙酸乙酯，经饱和食盐水洗涤(50mL×2)，无水硫酸镁干燥，减压浓缩得褐色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:9,then 1:4)，得到27.50g黄色液体，收率66％。得到的2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸苄酯，可不经进一步纯化，直接应用于下一步合成中。若要纯化，可用乙酸乙酯/乙醇混合溶剂进行重结晶，得到白色固体。
步骤d)中间体2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸的合成
Figure PCTCN2021101396-appb-000029
在250mL的反应瓶中将2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸苄酯(18.68g,44.7mmol)溶于50mL乙腈中，室温下向其中加入三甲基碘硅烷(25.00g,125.0mmol)，保持反应在室温下过夜。反应完成后，将反应液倒入60mL饱和碳酸氢钠水溶液中，用甲基叔丁基醚洗涤(50mL×3)，水层再用浓盐酸调节pH＝2～3后有固体析出，过滤晾干即可得到中间体2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸13.60g，淡黄色固体，收率93％。
步骤e)化合物154 2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(3,3-二氯烯丙氧羰基))乙酯的合成
Figure PCTCN2021101396-appb-000030
在100mL的反应瓶中将2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.50g,1.5mmol)、乳酸(3,3-二氯烯丙)酯(0.35g,1.7mmol)、4-(N,N-二甲氨基)吡啶(DMAP,0.05g,0.4mmol)混合溶于15mL二氯甲烷中形成悬浊液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,0.60g,3.1mmol)，反应体系由悬浊液变为澄清溶液。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(15mL×2)，合并的有机层经15mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:6)，得到化合物154 2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(3,3-二氯烯丙氧羰基))乙酯0.49g，淡黄色液体，收率63％。
实施例5：化合物166 2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(丙酮缩甘油羰基))乙酯的合成
Figure PCTCN2021101396-appb-000031
步骤a)中间体2-溴丙酸(丙酮缩甘油)酯的合成
Figure PCTCN2021101396-appb-000032
在250mL的反应瓶中将2-溴丙酸(7.65g,50.0mmol)、丙酮缩甘油(7.00g,53.0mmol)、4-(N,N-二甲氨基)吡啶(DMAP,1.22g,10.0mmol)混合于50mL二氯甲烷中形成溶液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,14.40g,75.0mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(50mL×2)，合并的有机层经25mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得到淡黄色液体10.10g，收率76％。可不经过进一步提纯，直接用于下一步反应中。
步骤b)化合物166 2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(丙酮缩甘油羰基))乙酯的合成
Figure PCTCN2021101396-appb-000033
在100mL的反应瓶中将2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.33g,1.0mmol)和碳酸钾(0.18g,1.3mmol)混合溶于5mL N,N-二甲基甲酰胺(DMF)中形成悬浊液，室温下向其中加入2-溴丙酸(丙酮缩甘油)酯(0.30g,1.1mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入20mL水中，用乙酸乙酯萃取(10mL×3)，合并的有机层经10mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物166 2-氯-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(丙酮缩甘油羰基))乙酯0.40g，无色泡沫状物质，收率77％。
实施例6：化合物222 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(3-氯丙氧羰基)甲酯的合成
Figure PCTCN2021101396-appb-000034
步骤a)中间体2-氯-4-氟-5-硝基苯甲酸苄酯的合成
Figure PCTCN2021101396-appb-000035
在250mL的反应瓶中加入2-氯-5-硝基苯甲酸(8.80g,40mmol)、甲苯(40mL)、二氯亚砜(5.0mL,68mmol)，回流反应3h。反应体系由悬浊液变为澄清溶液。减压蒸出溶剂和过量的二氯亚砜，残余物用20mL二氯甲烷稀释后备用。
在另一250mL的反应瓶中依次加入二氯甲烷(40mL)、苯甲醇(5.00g,46mmol)和三乙胺(6.0mL,43mmol)，室温下向其中滴加上述制备的酰氯二氯甲烷溶液，滴加完毕后继续在室温下搅拌2h。反应液倾入100mL水中，用50mL二氯甲烷萃取，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得13.00g黄色液体，粗收率105％。得到的2-氯-4-氟-5-硝基苯甲酸苄酯，不经进一步纯化，直接应用于下一步合成中。
步骤b)中间体5-氨基-2-氯-4-氟苯甲酸苄酯的合成
Figure PCTCN2021101396-appb-000036
在250mL的反应瓶中，将上步制得的2-氯-4-氟-5-硝基苯甲酸苄酯(7.75g,25mmol)与25mL乙酸乙酯形成溶液，加入二水合氯化亚锡(22.00g,98mmol)，加热回流下反应2h。将反应液倒入100mL冰水混合物中，用稀NaOH溶液调节体系pH＝9～10。析出的沉淀过滤并用乙酸乙酯润洗几次。合并的有机层经25mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得6.10g黄色液体，冷却后可得到褐色固体，粗收率87％。得到的5-氨基-2-氯-4-氟苯甲酸苄酯，可不经进一步纯化，直接应用于下一步合成中。若要纯化，可用乙醇进行重结晶，得到黄色固体。
步骤c)中间体2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸苄酯的合成
Figure PCTCN2021101396-appb-000037
在250mL的反应瓶中加入40mL乙酸乙酯，再依次加入5-氨基-2-氯-4-氟苯甲酸苄酯(5.60g,20.0mmol)、三乙胺(3.5mL,25.0mmol)和羰基二咪唑(DCI,8.50g,52.4mmol)形成溶液，加热升温至50℃，反应30min。再向其中加入1,3-二甲基硫脲(2.60g,25.0mmol)，随后升温至回流，反应2h。反应完成后，向其中加入40mL乙酸乙酯，经饱和食盐水洗涤(25mL×2)，无水硫酸镁干燥，减压浓缩得褐色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:9,then 1:4)，得到7.40g黄色液体，收率85％。得到的2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸苄酯，可不经进一步纯化，直接应用于下一步合成中。若要纯化，可用乙酸乙酯/乙醇混合溶剂进行重结晶，得到白色固体。
步骤d)中间体2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸的合成
Figure PCTCN2021101396-appb-000038
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸苄酯(4.36g,10.0mmol)溶于50mL甲醇中，室温下向其中加入10％钯炭催化剂(0.20g,0.2mmol)，50℃下向其中通入氢气流，反应4h。反应完成后，过滤除去不溶物，将反应液倒入60mL饱和碳酸氢钠水溶液中，用甲基叔丁基醚洗涤(50mL×3)，水层再用浓盐酸调节pH＝2～3后有固体析出，过滤晾干即可得到中间体2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸2.88g，淡黄色固体，收率83％。
步骤e)化合物222 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(3-氯丙氧羰基)甲酯的合成
Figure PCTCN2021101396-appb-000039
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.42g,1.2mmol)、碳酸钾(0.20g,1.4mmol)混合溶于溶于5mL N,N-二甲基甲酰胺(DMF)中形成悬浊液，室温下向其中加入2-溴乙酸(3-氯丙醇)酯(0.28g,1.3mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入20mL水中，用乙酸乙酯萃取(10mL×3)，合并的有机层经10mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物222 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(3-氯丙氧羰基)甲酯0.55g，无色泡沫状物质，收率94％。
实施例7：化合物241 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(环丙甲氧羰基)甲酯的合成
Figure PCTCN2021101396-appb-000040
步骤a)中间体2-溴乙酸(环丙甲醇)酯的合成
Figure PCTCN2021101396-appb-000041
在250mL的反应瓶中将2-溴乙酸(4.16g,30.0mmol)、环丙甲醇(2.38g,33.0mmol)、4-(N,N-二甲氨基)吡啶(DMAP,0.75g,6.0mmol)混合于30mL二氯甲烷中形成溶液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,8.60g,45.0mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(30mL×2)，合并的有机层经25mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得到无色液体3.60g，收率62％。可不经过进一步提纯，直接用于下一步反应中。
步骤b)化合物241 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(环丙甲氧羰基)甲酯的合成
Figure PCTCN2021101396-appb-000042
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.42g,1.2mmol)和碳酸钾(0.20g,1.4mmol)混合溶于5mL N,N-二甲基甲酰胺(DMF)中形成悬浊液，室温下向其中加入2-溴乙酸(环丙甲醇)酯(0.25g,1.3mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入20mL水中，用乙酸乙酯萃取(10mL×3)，合并的有机层经10mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物241 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(环丙甲氧羰基)甲酯0.52g，无色泡沫状物质，收率93％。
实施例8：化合物248 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-乙氧羰基)乙酯
Figure PCTCN2021101396-appb-000043
步骤a)中间体2-氯-4-氟-5-硝基苯甲酸(1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000044
在250mL的反应瓶中加入2-氯-4-氟-5-硝基苯甲酸(4.40g,20.0mmol)、甲苯(20mL)、二氯亚砜(3.0mL,41.1mmol)，回流反应3h。反应体系由悬浊液变为澄清溶液。减压蒸出溶剂和过量的二氯亚砜，残余物用10mL二氯甲烷稀释后备用。
在另一250mL的反应瓶中依次加入二氯甲烷(20mL)、乳酸乙酯(2.65g,22.4mmol)和三乙胺(3.0mL,21.5mmol)，室温下向其中滴加上述制备的酰氯二氯甲烷溶液，滴加完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用50mL二氯甲烷萃取，合并的有机层经30mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得6.16g黄色液体，粗收率96％。得到的2-氯-4-氟-5-硝基苯甲酸苯甲酸(1-乙氧羰基)乙酯，不经进一步纯化，直接应用于下一步合成中。
步骤b)中间体5-氨基-2-氯-4-氟苯甲酸(1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000045
在250mL的反应瓶中，2-氯-4-氟-5-硝基苯甲酸(1-乙氧基-1-氧代-2-丙醇)酯(6.16g,19.3mmol)与20mL乙醇和20mL四氢呋喃组成的混合溶剂形成溶液，加入还原铁粉(4.00g,71.6mmol)，冰水浴下向其中滴加浓盐酸(15.0mL,约180mmol)，滴加完毕后恢复至室温下反应1h。减压蒸出溶剂，残余物加入50mL水，用乙酸乙酯萃取(30mL×3)，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得4.00g黄色液体，粗收率72％。得到的5-氨基-2-氯-4-氟苯甲酸(1-乙氧羰基)乙酯，不经进一步纯化，直接应用于下一步合成中。
步骤c)化合物248 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000046
在250mL的反应瓶中加入30mL乙酸乙酯，再依次加入5-氨基-2-氯-4-氟苯甲酸(1-乙氧羰基)乙酯(4.00g,13.8mmol)、三乙胺(2.5mL,18.0mmol)和羰基二咪唑(DCI,5.60g,34.5mmol)形成溶液，加热升温至50℃，反应30min。再向其中加入1,3-二甲基硫脲(1.75g,16.8mmol)，随后升温至回流，反应2h。反应完成后，向其中加入60mL乙酸乙酯，经饱和食盐水洗涤(30mL×2)，无水硫酸镁干燥，减压浓缩得褐色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:9,then 1:4)，得到化合物248 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-乙氧羰基)乙酯4.20g，黄色液体，收率68％。纯度：95.3％。(HPLC：17.574min(50.8％)；19.589min(44.5％)；色谱条件：DAICEL Chemical Industries,Ltd.ChiralPak AD-H型手性柱，异丙醇:正己烷＝10:90，流速1.0mL/s，检测波长254nm。)
实施例9：化合物266(R)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氯乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000047
步骤a)中间体(S)-2-溴丙酸(2-氯乙醇)酯的合成
Figure PCTCN2021101396-appb-000048
在250mL的反应瓶中将(S)-2-溴丙酸(7.65g,50.0mmol)、2-氯乙醇(4.10g,50.9mmol)、4-(N,N-二甲氨基)吡啶(DMAP,1.22g,10.0mmol)混合于50mL二氯甲烷中形成溶液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,19.20g,100.0mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(50mL×2)，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得到黄色液体8.50g，收率79％。可不经过进一步提纯，直接用于下一步反应中。
步骤b)化合物266(R)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1- 基)苯甲酸(1-(2-氯乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000049
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.24g,0.7mmol)和碳酸钾(0.10g,0.7mmol)混合溶于5mL N,N-二甲基甲酰胺(DMF)中形成悬浊液，室温下向其中加入(S)-2-溴丙酸(2-氯乙醇)酯(0.15g,0.7mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入20mL水中，用乙酸乙酯萃取(10mL×3)，合并的有机层经10mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物266(R)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氯乙氧羰基)乙酯0.12g，无色泡沫状物质，收率36％。纯度：96.7％。(HPLC：18.167min；色谱条件：DAICEL Chemical Industries,Ltd.ChiralPak AD-H型手性柱，异丙醇:正己烷＝10:90，流速1.0mL/s，检测波长254nm。)
实施例10：化合物267(S)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氯乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000050
步骤a)中间体(R)-2-溴丙酸(2-氯乙醇)酯的合成
Figure PCTCN2021101396-appb-000051
在250mL的反应瓶中将(R)-2-溴丙酸(7.65g,50.0mmol)、2-氯乙醇(4.10g,50.9mmol)、4-(N,N-二甲氨基)吡啶(DMAP,1.22g,10.0mmol)混合于50mL二氯甲烷中形成溶液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,19.20g,100.0mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(50mL×2)，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得到黄色液体8.50g，收率79％。可不经过进一步提纯，直接用于下一步反应中。
步骤b)化合物267(S)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氯乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000052
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.24g,0.7mmol)和碳酸钾(0.10g,0.7mmol)混合溶于5mL N,N-二甲基甲酰胺(DMF)中形成悬浊液，室温下向其中加入(R)-2-溴丙酸(2-氯乙醇)酯(0.15g,0.7mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入20mL水中，用乙酸乙酯萃取(10mL×3)，合并的有机层经10mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物267(S)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氯乙氧羰基)乙酯0.12g，无色泡 沫状物质，收率36％。纯度：95.8％(HPLC：20.650min；色谱条件：DAICEL Chemical Industries,Ltd.ChiralPak AD-H型手性柱，异丙醇:正己烷＝10:90，流速1.0mL/s，检测波长254nm。)
实施例11：化合物281(E)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(3-氯烯丙氧羰基))乙酯的合成
Figure PCTCN2021101396-appb-000053
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.42g,1.2mmol)、乳酸(3-氯烯丙醇)酯(0.25g,1.5mmol,有市售)、4-(N,N-二甲氨基)吡啶(DMAP,0.03g,0.2mmol)混合溶于15mL二氯甲烷中形成悬浊液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,0.35g,1.8mmol)，反应体系由悬浊液变为澄清溶液。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(15mL×2)，合并的有机层经15mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:6)，得到化合物281(E)-2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(3-氯烯丙氧羰基))乙酯0.15g，无色液体，收率25％。
实施例12：化合物298 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(异恶唑啉-2-基甲氧羰基))乙酯的合成
Figure PCTCN2021101396-appb-000054
步骤a)中间体2-溴丙酰氯的合成
Figure PCTCN2021101396-appb-000055
在100mL的反应瓶中将2-溴丙酸(0.50g,3.27mmol)溶于20mL二氯甲烷中，加入草酰氯(1.66g,13.07mmol)，室温下滴加2滴N,N-二甲基甲酰胺。加料完毕后继续在室温下搅拌2h。旋除溶剂及多余的草酰氯，溶于10mL二氯甲烷中备用。
步骤b)中间体2-溴-1-(异恶唑烷-2-基)丙烷-1-酮的合成
Figure PCTCN2021101396-appb-000056
在100mL的反应瓶中将4-氢异恶唑盐酸盐(0.36g,3.27mmol)溶于20mL二氯甲烷中，加入上步制得的2-溴丙酰氯，加入三乙胺(0.66g,6.54mmol)。加料完毕后继续在室温下搅拌2h。旋除溶剂，无需提纯，直接用于下一步反应中。
步骤c)化合物298 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(异恶唑啉-2-基甲氧羰基))乙酯的合成
Figure PCTCN2021101396-appb-000057
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1.00g,2.89mmol)和碳酸钾(0.72g,3.47mmol)混合溶于5mL N,N-二甲基甲酰胺(DMF)中形成悬浊液，室温下向其中加入上步制得的2-溴-1-(异恶唑烷-2-基)丙烷-1-酮。加料完毕后升温至80摄氏度，搅拌2h。2h后反应完毕，将反应液倾入20mL水中，用乙酸乙酯萃取(10mL×3)，合并的有机层经10mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到目标化合物298 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(异恶唑啉-2-基甲氧羰基))乙酯，淡黄色油状液体120mg，收率9％。
实施例13：化合物300 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氟乙氧羰基))丙酯的合成
Figure PCTCN2021101396-appb-000058
步骤a)中间体2-溴丁酸(2-氟乙醇)酯的合成
Figure PCTCN2021101396-appb-000059
在250mL的反应瓶中将2-溴丁酸(4.18g,25.0mmol)、2-氟乙醇(1.63g,25.5mmol)、4-(N,N-二甲氨基)吡啶(DMAP,0.61g,5.0mmol)混合于25mL二氯甲烷中形成溶液。室温下向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,9.60g,50.0mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用二氯甲烷萃取(50mL×2)，合并的有机层经50mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得到黄色液体3.60g，收率68％。可不经过进一步提纯，直接用于下一步反应中。
步骤b)化合物300 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氟乙氧羰基))丙酯的合成
Figure PCTCN2021101396-appb-000060
在100mL的反应瓶中将2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(0.52g,1.5mmol)和碳酸钾(0.22g,1.6mmol)混合溶于5mL N,N-二甲基甲酰胺(DMF)中形成悬浊液，室温下向其中加入2-溴丁酸(2-氟乙醇)酯(0.32g,1.5mmol)。加料完毕后继续在室温下搅拌2h。反应液倾入20mL水中，用乙酸乙酯萃取(10mL×3)，合并的有机层经10mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得黄色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:4)，得到化合物300 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-(2-氟乙氧羰基))丙酯0.50g，无色泡沫状物质，收率70％。
实施例14：化合物306 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-甲基-1-乙氧羰基)乙酯
Figure PCTCN2021101396-appb-000061
步骤a)中间体2-氯-4-氟-5-硝基苯甲酸(1-甲基-1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000062
在250mL的反应瓶中加入2-氯-4-氟-5-硝基苯甲酸(5.49g,25.0mmol)、α-羟基异丁酸乙酯(4.00g,30.0mmol)、4-(N,N-二甲氨基)吡啶(DMAP,0.30g,2.5mmol)和二氯甲烷(50mL)，室温搅拌下，向其中分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,9.60g,50.0mmol),反应体系由悬浊液变为澄清溶液。加料完毕后继续在室温下搅拌2h。反应液倾入50mL水中，用50mL二氯甲烷萃取，合并的有机层经30mL饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩得2.70g黄色液体，粗收率33％。得到的中间体2-氯-4-氟-5-硝基苯甲酸(1-甲基-1-乙氧羰基)乙酯，不经进一步纯化，直接应用于下一步合成中。
步骤b)中间体5-氨基-2-氯-4-氟苯甲酸(1-甲基-1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000063
在100mL的反应瓶中，2-氯-4-氟-5-硝基苯甲酸(1-甲基-1-乙氧羰基)乙酯(2.70g,8.10mmol)与20mL甲醇混合形成溶液，加入10％钯/炭催化剂(0.25g)，室温下反应向其中通入氢气流2h。TLC监测反应完全后，过滤除去催化剂。滤液经减压蒸出溶剂，得到1.80g黄色液体，粗收率73％。得到的5-氨基-2-氯-4-氟苯甲酸(1-甲基-1-乙氧羰基)乙酯，不经进一步纯化，直接应用于下一步合成中。
步骤c)化合物306 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-甲基-1-乙氧羰基)乙酯的合成
Figure PCTCN2021101396-appb-000064
在100mL的反应瓶中加入15mL甲苯，再依次加入5-氨基-2-氯-4-氟苯甲酸(1-甲基-1-乙氧羰基)乙酯(1.80g,6.0mmol)和三光气(0.90g,3.0mmol)，加热升温至回流并保持反应在回流条件下进行2h。恢复至室温后得到异氰酸酯的甲苯溶液备用。
在另一100mL反应瓶中依次加入15mL甲苯、1,3-二甲基硫脲(1.75g,16.8mmol)和三乙胺(1.0mL,7.2mmol)，室温下向其中滴入上述制备的异氰酸酯甲苯溶液，滴加完毕后，再加入羰基二咪唑(DCI,1.45g,9.0mmol)，加热升温至回流并保持反应在回流条件下进行2h。反应完成后，向其中加入30mL甲苯，经饱和食盐水洗涤(15mL×2)，无水硫酸镁干燥，减压浓缩得褐色粘稠液体。柱色谱分离(SiO 2，EtOAc:P.E.＝1:9,then1:4)，得到化合物306 2-氯-4-氟-5-(3,5-二甲基-2,6-二氧代-4-硫代-1,3,5-三嗪-1-基)苯甲酸(1-甲基-1-乙氧羰基)乙酯1.80g，白色固体(m.p.98～100℃)，收率66％。
按照上述记载的方法替换起始物质即可获得通式I所示的其它化合物，通式I的部分化合物的结构和物理性质见表1。
Figure PCTCN2021101396-appb-000065
表1
Figure PCTCN2021101396-appb-000066
Figure PCTCN2021101396-appb-000067
Figure PCTCN2021101396-appb-000068
Figure PCTCN2021101396-appb-000069
Figure PCTCN2021101396-appb-000070
Figure PCTCN2021101396-appb-000071
Figure PCTCN2021101396-appb-000072
Figure PCTCN2021101396-appb-000073
Figure PCTCN2021101396-appb-000074
Figure PCTCN2021101396-appb-000075
Figure PCTCN2021101396-appb-000076
Figure PCTCN2021101396-appb-000077
Figure PCTCN2021101396-appb-000078
Figure PCTCN2021101396-appb-000079
Figure PCTCN2021101396-appb-000080
Figure PCTCN2021101396-appb-000081
Figure PCTCN2021101396-appb-000082
Figure PCTCN2021101396-appb-000083
Figure PCTCN2021101396-appb-000084
Figure PCTCN2021101396-appb-000085
Figure PCTCN2021101396-appb-000086
Figure PCTCN2021101396-appb-000087
部分化合物的 1H NMR(CDCl 3,600MHz)δ(ppm)数据如下：
化合物1 8.00(d,1H,J＝7.2Hz),7.39(d,1H,J＝8.4Hz),5.32(q,1H,J＝7.2Hz),4.23(q,2H,J＝7.2Hz),3.42(s,6H),1.60(d,3H,J＝7.2Hz),1.29(t,3H,J＝7.2Hz).
化合物15 8.02(d,1H,J＝7.8Hz),7.40(d,1H,J＝9.0Hz),5.37(q,1H,J＝7.2Hz),4.40-4.46(m,2H),3.70(t,2H,J＝6.0Hz),3.42(2s,6H),1.65(d,3H,J＝6.6Hz).
化合物16 8.00(d,1H,J＝7.2Hz),7.41(d,1H,J＝9.0Hz),5.33(q,1H,J＝7.2Hz),4.35(t,2H,J＝6.0Hz),3.60(t,2H,J＝6.6Hz),3.43(2s,6H),2.09-2.17(m,2H),1.62(d,3H,J＝6.6Hz).
化合物19 8.01(d,1H,J＝7.2Hz),7.40(d,1H,J＝9.0Hz),5.32(q,1H,J＝6.6Hz),4.22(t,2H,J＝6.0Hz),3.56(t,2H,J＝6.0Hz),3.42(2s,6H),1.83-1.85(m,4H),1.62(d,3H,J＝6.0Hz).
化合物33 8.01(d,1H,J＝7.8Hz),7.40(d,1H,J＝9.6Hz),5.36(q,1H,J＝7.2Hz),4.74(dq,2H,J＝15.0Hz,J＝2.4Hz),3.43(2s,6H),1.86(t,3H,J＝2.4Hz),1.63(d,3H,J＝7.2Hz).
化合物35 8.02(d,1H,J＝7.2Hz),7.40(d,1H,J＝9.6Hz),5.34(q,1H,J＝6.6Hz),4.01(m,2H),3.43(2s,6H),1.62(d,3H,J＝6.6Hz),1.11-1.18(m,1H),0.55-0.59(m,2H),0.27-0.30(m,2H).
化合物37 8.01(d,1H,J＝7.2Hz),7.40(d,1H,J＝9.0Hz),5.33(q,1H,J＝6.6Hz),4.03-4.10(m,2H),3.42(2s,6H),2.18-2.26(m,1H),1.71-1.77(m,2H),1.61(d,3H,J＝6.6Hz),1.50-1.61(m,4H),1.20-1.25(m,2H).
化合物41 7.99(d,1H,J＝8.4Hz),7.40(d,1H,J＝9.0Hz),5.19(dd,1H,J＝4.8Hz,J＝7.2Hz),4.20-4.28(m,2H),3.43(2s,6H),1.96-2.07(m,2H),1.29(t,3H,J＝7.2Hz),1.06(t,3H,J＝7.2Hz).
化合物42 7.97(d,1H,J＝7.8Hz),7.40(d,1H,J＝9.0Hz),5.09(d,1H,J＝4.2Hz),4.20-4.28(m,2H),3.43(2s,6H),2.34-2.39(m,1H),1.29(t,3H,J＝7.2Hz),1.08(d,3H,J＝6.6Hz),1.06(d,3H,J＝6.6Hz).
化合物97 7.95(d,1H,J＝3.0Hz),7.63(d,1H,J＝8.4Hz),7.39(dd,1H,J＝2.4Hz,J＝8.4Hz),4.91(s,2H),4.45(t,2H,J＝6.0Hz),3.78(s,6H),3.71(t,2H,J＝6.0Hz).
化合物117 7.94(d,1H,J＝2.4Hz),7.62(d,1H,J＝8.4Hz),7.38(dd,1H,J＝3.0Hz,J＝8.4Hz),4.87(s,2H),4.03(d,2H,J＝7.2Hz),3.78(s,6H),1.15(m,1H),0.58(m,2H),0.30(m,2H).
化合物121 7.94(d,1H,J＝3.0Hz),7.62(d,1H,J＝7.8Hz),7.39(dd,1H,J＝3.0Hz,J＝7.8Hz),4.91(s,2H),4.53(dd,1H,J＝2.4Hz,J＝12.6Hz),4.05(dd,J＝6.6Hz,J＝12.0Hz),3.78(s,6H),3.23(ddd,1H,J＝3.0Hz,J＝4.2Hz,J＝9.6Hz),2.86(t,1H,J＝4.2Hz),2.66(dd,1H,J＝2.4Hz,J＝4.8Hz).
化合物123 7.96(d,1H,J＝3.0Hz),7.62(d,1H,J＝7.8Hz),7.39(dd,1H,J＝2.4Hz,J＝8.4Hz),4.89(2d,2H,J＝15.6Hz),4.31-4.36(m,2H),4.17-4.20(m,1H),4.06-4.08(m,1H),3.78(s,6H),3.76-3.78(m,1H),1.42(s,3H),1.35(s,3H).
化合物138 7.91(d,1H,J＝2.4Hz),7.61(d,1H,J＝7.8Hz),7.37(dd,1H,J＝3.0Hz,J＝8.4Hz),5.38(q,1H,J＝7.2Hz),4.38-4.47(m,2H),3.78(s,6H),3.71(t,2H,J＝6.0Hz),1.65(d,3H,J＝7.2Hz).
化合物139 7.91(d,1H,J＝2.4Hz),7.61(d,1H,J＝7.8Hz),7.37(dd,1H,J＝3.0Hz,J＝8.4Hz),5.38(q,1H,J＝7.2Hz),4.38-4.47(m,2H),3.78(s,6H),3.70(t,2H,J＝6.0Hz),1.65(d,3H,J＝7.2Hz).
化合物140 7.91(d,1H,J＝2.4Hz),7.61(d,1H,J＝7.8Hz),7.37(dd,1H,J＝3.0Hz,J＝8.4Hz),5.38(q,1H,J＝7.2Hz),4.38-4.47(m,2H),3.78(s,6H),3.70(t,2H,J＝6.0Hz),1.65(d,3H,J＝7.2Hz).
化合物152 7.88(d,1H,J＝3.0Hz),7.62(d,1H,J＝8.4Hz),7.37(dd,1H,J＝3.0Hz,J＝8.4Hz),6.37(ddt,1H,J＝6.6Hz,J＝14.4Hz,J＝1.2Hz),6.05(dq,1H,J＝13.8Hz,J＝6.6Hz),5.34(q,1H,J＝6.6Hz),4.65(ddd,2H,J＝13.2Hz,J＝6.6Hz,1.2Hz),3.79(s,6H),1.62(d,3H,J＝6.6Hz)..
化合物154 7.88(d,1H,J＝2.4Hz),7.62(d,1H,J＝8.4Hz),7.37(dd,1H,J＝3.0Hz,J＝8.4Hz),6.07(t,1H,J＝7.2Hz),5.35(q,1H,J＝7.2Hz),4.77(d,2H,J＝7.2Hz),3.78(s,6H),1.63(d,3H,J＝7.2Hz).
化合物160 7.90(d,1H,J＝2.4Hz),7.61(d,1H,J＝8.4Hz),7.36(dd,1H,J＝2.4Hz,J＝8.4Hz),5.36(q,1H,J＝7.2Hz),4.01(ddd,2H,J＝7.8Hz,J＝11.4Hz,J＝19.2Hz),3.78(s,6H),1.63(d,3H,J＝7.8Hz),1.11-1.18(m,1H),0.55-0.59(m,2H),0.27-0.30(m,2H).
化合物164 7.91(dd,1H,J＝1.2Hz,J＝2.4Hz),7.61(d,1H,J＝8.4Hz),7.36(dd,1H,J＝2.4Hz,J＝7.8Hz),5.36(dq,1H,J＝1.2Hz,J＝7.2Hz),4.50(ddd,J＝3.0Hz,J＝4.8Hz,J＝12.0Hz),4.04(ddd,1H,J＝5.4Hz,J＝12.0Hz,J＝27.0Hz),3.78(s,6H),3.74-3.78(m,1H),3.19-3.25(m,1H),2.84(dt,J＝7.2Hz,J＝4.2Hz),2.65(ddd,J＝3.0Hz,J＝4.8Hz,J＝22.2Hz),1.65(d,3H,J＝6.6Hz).
化合物166 7.92(dd,1H,J＝3.0Hz,J＝22.8Hz),7.61(d,1H,J＝9.0Hz),7.37(dd,1H,J＝2.4Hz,J＝8.4Hz),5.35-5.41(m,1H),4.31-4.35(m,1H),4.19-4.27(m,1H),4.14-4.35(m,1H),4.02-4.07(m,1H),3.78(s,6H),3.75-3.79(m,1H),1.64(d,3H,J＝7.2Hz),1.41(d,3H,J＝6.0Hz),1.33(d,3H,J＝10.2Hz).
化合物221 8.07(d,1H,J＝7.8Hz),7.43(d,1H,J＝9.0Hz),4.90(s,2H),4.46(t,2H,J＝6.0Hz),3.78(s,6H),3.71(t,2H,J＝6.0Hz).
化合物222 8.05(d,1H,J＝7.8Hz),7.43(d,1H,J＝9.0Hz),4.85(s,2H),4.37(t,2H,J＝6.0Hz),3.78(s,6H),3.61(t,2H,J＝6.0Hz),2.14(pent,2H,J＝6.0Hz).
化合物225 8.05(d,1H,J＝7.8Hz),7.43(d,1H,J＝8.4Hz),4.85(s,2H),4.23-4.26(m,2H),3.78(s,6H),3.55-3.59(m,2H),1.82-1.87(m,4H).
化合物241 8.06(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.0Hz),4.86(s,2H),4.03(d,2H,J＝6.6Hz),3.78(s,6H),1.16-1.18(m,1H),0.58-0.61(m,2H),0.29-0.31(m,2H).
化合物245 8.07(d,1H,J＝7.8Hz),7.43(d,1H,J＝9.6Hz),4.90(s,2H),4.55(dd,1H,J＝2.4Hz,J＝12.0Hz),4.04(dd,1H,J＝6.0Hz,J＝12.0Hz),3.78(s,6H),3.23-3.25(m,1H),2.86-2.88(m,1H),2.66-2.68(m,1H).
化合物246 8.07(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.0Hz),4.89(s,2H),4.25-4.30(m,1H),4.10-4.16(m,2H),3.85-3.90(m,1H),3.78(s,6H),3.77-3.81(m,1H),1.99-2.04(m,1H),1.86-1.95(m,2H),1.57-1.64(m,1H).
化合物247 8.09(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.0Hz),4.89(2d,2H,J＝16.2Hz),4.32-4.37(m,2H),4.16-4.20(m,1H),3.78(s,6H),3.76-3.78(m,1H),1.42(s,3H),1.35(s,3H).
化合物248 8.01(d,1H,J＝7.2Hz),7.41(d,1H,J＝9.0Hz),5.32(q,1H,J＝7.2Hz),4.24(q,2H,J＝7.2Hz),3.78(s,6H),1.61(d,3H,J＝7.2Hz),1.26(t,3H,J＝7.2Hz).
化合物249 8.02(d,1H,J＝8.4Hz),7.41(d,1H,J＝9.0Hz),5.32(q,1H,J＝7.2Hz),4.30(q,2H,J＝7.2Hz),3.78(s,6H),1.61(d,3H,J＝6.6Hz),1.29(t,3H,J＝7.2Hz).
化合物250 8.02(d,1H,J＝7.8Hz),7.41(d,1H,J＝9.0Hz),5.32(q,1H,J＝7.2Hz),4.23(q,2H,J＝7.2Hz),3.78(s,6H),1.61(d,3H,J＝6.6Hz),1.29(t,3H,J＝7.2Hz).
化合物264 8.02(d,1H,J＝7.8Hz),7.42(d,1H,J＝9.0Hz),5.38(q,1H,J＝7.2Hz),4.63-4.69(m,1H),4.55-4.61(m,1H),4.36-4.49(m,2H),3.78(2s,6H),1.65(d,3H,J＝7.2Hz).
化合物265 8.04(d,1H,J＝7.8Hz),7.42(d,1H,J＝9.0Hz),5.37(q,1H,J＝7.2Hz),4.39-4.48(m,2H),3.78(2s,6H),3.71(t,2H,J＝6.0Hz),1.65(d,3H,J＝7.2Hz).
化合物266 8.03(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.0Hz),5.37(q,1H,J＝7.2Hz),4.39-4.48(m,2H),3.78(2s,6H),3.70(t,2H,J＝6.0Hz),1.65(d,3H,J＝7.8Hz).
化合物267 8.03(d,1H,J＝7.8Hz),7.42(d,1H,J＝9.6Hz),5.37(q,1H,J＝7.2Hz),4.40-4.47(m,2H),3.78(2s,6H),3.70(t,2H,J＝5.4Hz),1.65(d,3H,J＝7.2Hz).
化合物268 8.02(d,1H,J＝7.8Hz),7.42(d,1H,J＝8.4Hz),5.33(q,1H,J＝7.2Hz),4.35(t,2H,J＝6.0Hz),3.78(2s,6H),3.60(t,2H,J＝6.0Hz),2.09-2.17(m,2H),1.62(d,3H,J＝6.6Hz).
化合物269 8.01(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.0Hz),5.33(q,1H,J＝7.2Hz),4.35(t,2H,J＝6.0Hz),3.78(2s,6H),3.60(t,2H,J＝6.0Hz),2.09-2.17(m,2H),1.62(d,3H,J＝6.6Hz).
化合物270 8.01(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.0Hz),5.33(q,1H,J＝7.2Hz),4.35(t,2H,J＝6.0Hz),3.78(2s,6H),3.60(t,2H,J＝6.0Hz),2.09-2.17(m,2H),1.62(d,3H,J＝6.6Hz).
化合物273 8.02(d,1H,J＝7.8Hz),7.42(d,1H,J＝9.0Hz),5.32(q,1H,J＝7.2Hz),4.22(t,2H,J＝6.0Hz),3.78(2s,6H),3.56(t,2H,J＝6.0Hz),1.83-1.85(m,4H),1.62(d,3H,J＝6.0Hz).
化合物281 8.01(d,1H,J＝7.8Hz),7.42(d,1H,J＝9.0Hz),6.36(dt,1H,J＝13.2Hz,J＝1.2Hz),6.05(q,1H,J＝6.6Hz),5.33(q,1H,J＝7.2Hz),4.65(dt,2H,J＝13.2Hz,1.2Hz),3.79(s,6H),1.62(d,3H,J＝7.2Hz).
化合物283 8.01(d,1H,J＝7.2Hz),7.42(d,1H,J＝8.4Hz),6.06(t,1H,J＝6.6Hz),5.34(q,1H,J＝7.2Hz),4.77(dd,2H,J＝6.6Hz,1.2Hz),3.78(s,6H),1.62(d,3H,J＝7.2Hz).
化合物287 8.03(d,1H,J＝7.2Hz),7.41(d,1H,J＝9.0Hz),5.37(q,1H,J＝7.2Hz),4.74(dq,2H,J＝15.0Hz,J＝2.4Hz),3.78(2s,6H),1.86(t,3H,J＝2.4Hz),1.63(d,3H,J＝7.2Hz).
化合物289 7.97(d,1H,J＝8.4Hz),7.40(d,1H,J＝9.0Hz),7.31-7.37(m,5H),5.39(q,2H,J＝7.2Hz),5.21(2d,2H,J＝12.6Hz),3.78(s,6H),1.62(d,3H,J＝7.2Hz).
化合物290 8.02(d,1H,J＝7.8Hz),7.38-7.41(m,3H),7.31-7.34(m,2H),7.26-7.28(m,1H),6.67(d,1H,J＝15.6Hz),6.27(dt,1H,J＝15.6Hz,J＝6.6Hz),5.37(q,1H,J＝7.2Hz),4.83(ddq,2H,J＝1.2Hz,J＝12.0Hz,J＝6.6Hz),3.77(s,3H),3.76(s,3H),1.64(d,3H,J＝6.6Hz).
化合物291 8.03(d,1H,J＝7.2Hz),7.41(d,1H,J＝10.2Hz),5.34(q,1H,J＝7.2Hz),4.01(m,2H),3.78(2s,6H),1.63(d,3H,J＝7.2Hz),1.11-1.18(m,1H),0.56-0.58(m,2H),0.28-0.30(m,2H).
化合物293 8.02(d,1H,J＝7.8Hz),7.41(d,1H,J＝9.0Hz),5.34(q,1H,J＝7.2Hz),4.03-4.10(m,2H),3.78(2s,6H),2.18-2.26(m,1H),1.71-1.76(m,2H),1.62(d,3H,J＝7.2Hz),1.50-1.61(m,4H),1.20-1.25(m,2H).
化合物295 8.03(d,1H,J＝7.2Hz),7.41(d,1H,J＝9.6Hz),5.38(q,1H,J＝7.2Hz),4.51(ddd,1H,J＝3.6Hz,J＝6.0Hz,J＝12.6Hz),4.03(ddd,1H,J＝6.0Hz,J＝12.6Hz,J＝29.4Hz),3.78(2s,6H),3.19-3.25(m,1H),2.85(dt,1H,J＝7.8Hz,J＝4.2Hz),2.66(ddd,1H,J＝3.0Hz,J＝4.8Hz,J＝22.2Hz),1.64(dd,3H,J＝1.2Hz,J＝7.2Hz),1.11-1.18(m,1H),0.56-0.58(m,2H),0.28-0.30(m,2H).
化合物296 8.04(d,1H,J＝7.2Hz),7.41(d,1H,J＝9.0Hz),5.37(dq,1H,J＝9.6Hz,J＝7.2Hz),4.24(q,1H,J＝6.6Hz),4.10-4.16(m,3H),3.83-3.87(m,1H),3.78(2s,6H),3.75-3.79(m,1H),1.96-2.03(m,1H),1.86-1.94(m,2H),1.63(dd,3H,J＝2.4Hz,J＝7.2Hz).
化合物297 8.05(d,1H,J＝7.2Hz),7.41(d,1H,J＝9.0Hz),5.37(dq,1H,J＝6.6Hz,J＝13.8Hz),4.31-4.36(m,1H),4.18-4.28(m,1H),4.10-4.36(m,1H),4.02-4.07(m,1H),3.78(s,6H),3.74-3.79(m,1H),1.63(d,3H,J＝6.6Hz),1.41(d,3H,J＝6.0Hz),1.33(d,3H,J＝12.6Hz).
化合物298 8.05(d,J＝7.8Hz,1H),7.36(d,J＝9.1Hz,1H),5.66(q,J＝6.9Hz,1H),4.13–4.07(m,2H),4.02(q,J＝7.7Hz,1H),3.98-3.92(m,1H),3.76(s,3H),3.75(s,3H),1.58(d,J＝6.9Hz,3H),1.25-1.22(m,2H).
化合物299 8.00(d,1H,J＝7.8Hz),7.41(d,1H,J＝9.0Hz),5.20(dd,1H,J＝4.8Hz,J＝7.2Hz),4.21-4.27(m,2H),3.78(2s,6H),1.96-2.03(m,2H),1.29(t,3H,J＝7.2Hz),1.07(t,3H,J＝7.2Hz).
化合物300 8.00(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.6Hz),5.25(dd,1H,J＝4.8Hz,J＝7.8Hz),4.63-4.68(m,1H),4.55-4.61(m,1H),4.35-4.50(m,2H),3.78(2s,6H),2.00-2.08(m,2H),1.08(t,3H,J＝7.8Hz).
化合物301 8.01(d,1H,J＝7.8Hz),7.42(d,1H,J＝9.0Hz),5.25(dd,1H,J＝4.8Hz,J＝7.8Hz),4.44-4.48(m,1H),4.38-4.42(m,1H),3.78(2s,6H),3.70(t,2H,J＝5.4Hz),1.99-2.08(m,2H),1.09(t,3H,J＝7.2Hz).
化合物302 8.00(d,1H,J＝7.8Hz),7.42(d,1H,J＝9.0Hz),5.20(dd,1H,J＝4.8Hz,J＝7.2Hz),4.35(t,2H,J＝6.0Hz),3.78(2s,6H),3.60(t,2H,J＝6.0Hz),2.08-2.17(m,2H),1.97-2.03(m,2H),1.07(t,3H,J＝7.2Hz).
化合物303 8.00(d,1H,J＝8.4Hz),7.42(d,1H,J＝9.0Hz),5.19(dd,1H,J＝4.8Hz,J＝6.6Hz),4.22(t,2H,J＝6.0Hz),3.78(2s,6H),3.56(t,2H,J＝6.0Hz),1.97-2.04(m,2H),1.82-1.85(m,4H),1.07(t,3H,J＝7.2Hz).
化合物304 8.01(d,1H,J＝8.4Hz),7.41(d,1H,J＝9.0Hz),5.22(dd,1H,J＝6.0Hz,J＝7.2Hz),4.22(dq,2H,J＝7.8Hz,J＝10.8Hz),3.78(2s,6H),1.97-2.07(m,2H),1.11-1.17(m,1H),1.08(t,3H,J＝7.2Hz),0.55-0.59(m,2H),0.26-0.31(m,2H).
化合物305 7.99(d,1H,J＝7.2Hz),7.42(d,1H,J＝9.6Hz),5.09(d,1H,J＝4.2Hz),4.20-4.28(m,2H),3.78(2s,6H),2.34-2.39(m,1H),1.29(t,3H,J＝7.2Hz),1.08(d,3H,J＝6.6Hz),1.06(d,3H,J＝6.6Hz).
化合物306 7.91(d,1H,J＝7.8Hz),7.39(d,1H,J＝9.0Hz),4.22(q,2H,J＝7.2Hz),3.78(s,6H),1.68(s,6H),1.06(t,3H,J＝7.2Hz).
生测实施例
实施例15：除草活性的测定
将阔叶杂草(百日草、苘麻)或禾本科杂草(狗尾草、稗草)种子分别播于直径为7cm的装有营养土的纸杯中，播后覆土1cm，镇压、淋水后在温室按常规方法培养，待杂草2-3叶期后茎叶喷雾处理。
原药用丙酮溶解后，按试验要求用1‰的吐温80静置自来水配制所需浓度的待测液。按试验设计剂量，在履带式作物喷雾机(英国Engineer Research Ltd.设计生产)上进行喷雾处理(喷雾压力1.95kg/cm 2，喷液量500L/hm 2，履带速度1.48km/h)。试验设3次重复。试材处理后置于操作大厅，待药液自然阴干后，放于温室内按常规方法管理，观察并记录杂草对药剂的反应情况，处理后定期目测供试药剂对杂草的防除效果，用0～100％来表示，以“0”代表无防效和“100％”代表完全杀死。
试验结果表明，通式I化合物对多种杂草普遍具有较高防效。部分供试的化合物中，如化合物221、222、225、241、245、246、247、248、249、250、264、265、266、267、268、269、270、273、281、283、287、289、290、291、293、295、296、297、298、299、300、301、302、303、304、305在施用剂量为150g a.i./hm 2对百日草具有较好的防效，防效为100％。
试验结果表明，通式I化合物对多种杂草普遍具有较高防效。部分供试的化合物中，如化合物138、160、221、222、225、241、245、246、247、248、249、250、264、265、266、267、268、269、270、273、281、283、287、289、290、291、293、295、296、297、298、300、301、302、303、304、305、306在施用剂量为150g a.i./hm 2对苘麻具有较好的防效，防效为100％。
试验结果表明，通式I化合物对多种杂草普遍具有较高防效。部分供试的化合物中，如化合物117、221、222、225、241、245、246、247、248、250、264、268、273、281、283、287、291、295、296、297、298在施用剂量为150g a.i./hm 2对狗尾草具有较好的防效，防效不低于80％。
试验结果表明，通式I化合物对多种杂草普遍具有较高防效。部分供试的化合物中，如化合物221、222、225、241、245、246、247、248、249、250、264、265、266、267、268、269、270、273、281、283、287、291、293、295、296、297、298、301、306在施用剂量为150g a.i./hm 2对稗草具有较好的防效，防效不低于90％。
Figure PCTCN2021101396-appb-000088
按照以上测试方法，选取部分通式I化合物与专利CN1341105A具体公开的如下化合物KC 1(专利说明书中表3第30号化合物)进行除草活性的平行试验，施用剂量为37.5g a.i./hm 2和9.375g a.i./hm 2。结果见表2。
表2：部分通式(I)化合物的除草活性(苗后，防效％)
Figure PCTCN2021101396-appb-000089
按照以上测试方法，选取部分通式I化合物与专利CN1341105A具体公开的如下化合物KC 1(专利说明书中表3第30号化合物)、KC 2(R体，专利说明书中表3第12号化合物)对百日草、苘麻、狗尾草和稗草分别进行除草活性的平行试验，结果见表3～表6。
表3：部分通式(I)化合物对百日草的除草活性平行比较(苗后，防效％)
Figure PCTCN2021101396-appb-000090
注：“/”表示未测
表4：部分通式(I)化合物对苘麻的除草活性平行比较(苗后，防效％)
Figure PCTCN2021101396-appb-000091
注：“/”表示未测
表5：部分通式(I)化合物对狗尾草的除草活性平行比较(苗后，防效％)
Figure PCTCN2021101396-appb-000092
表6：部分通式(I)化合物对稗草的除草活性平行比较(苗后，防效％)
Figure PCTCN2021101396-appb-000093

Claims (6)

  1. 一种三嗪苯甲酸酯类化合物，其特征在于，化合物如通式I所示：
    Figure PCTCN2021101396-appb-100001
    其中：
    W选自O或S；
    X 1选自H或F；
    X 2选自卤素、CN、CONH 2或CSNH 2；
    R 1选自甲基或乙基；
    R 2选自甲基或乙基；
    R 3选自H或甲基；
    R 4选自H或C 1-C 3烷基；
    R 5选自CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、(CH 3) 2CHCH 2-、CH 3CH 2CH(CH 3)-、(CH 3) 3C-、CH 3CH 2CH 2CH 2CH 2-、(CH 3) 2CHCH 2CH 2-、(CH 3) 3CCH 2-、CH 3CH 2CH(CH 3)CH 2-、CH 3CH 2CH 2CH(CH 3)-、CH 3CH 2C(CH 3) 2-、CH 3CH＝CHCH 2-、CH 3C≡CCH 2-、C 1-C 10卤代烷基、C 1-C 6烷硫基C 1-C 6烷基、C 1-C 6烷基亚磺酰基C 1-C 6烷基、C 1-C 6烷基磺酰基C 1-C 6烷基、(C 1-C 6烷基) 2氨基C 1-C 6烷基、C 3-C 10环烷基、C 3-C 6环烷基C 1-C 6烷基、C 3-C 10卤代环烷基、C 3-C 6卤代环烷基C 1-C 6烷基、C 2-C 10卤代烯基、C 1-C 6烷氧基C 2-C 6烯基、C 1-C 6烷硫基C 2-C 6烯基、C 1-C 6烷基亚磺酰基C 2-C 6烯基、C 1-C 6烷基磺酰基C 2-C 6烯基、(C 1-C 6烷基) 2氨基C 2-C 6烯基、C 3-C 10环烯基、C 3-C 6环烷基C 2-C 6烯基、C 3-C 6卤代环烷基C 2-C 6烯基、C 2-C 10卤代炔基、C 1-C 6烷氧基C 2-C 6炔基、C 1-C 6烷硫基C 2-C 6炔基、C 1-C 6烷基亚磺酰基C 2-C 6炔基、C 1-C 6烷基磺酰基C 2-C 6炔基、(C 1-C 6烷基) 2氨基C 2-C 6炔基、C 3-C 10环炔基、C 3-C 6环烷基C 2-C 6炔基、C 3-C 6卤代环烷基C 2-C 6炔基、苯基、苯基C 1-C 6烷基、含有1-4个杂原子的5-7元脂杂环、含有1-4个杂原子的5-7元芳杂环、含有1-4个杂原子的5-7元脂杂环C 1-C 6烷基或含有1-4个杂原子的5-7元芳杂环C 1-C 6烷基，前述苯基、脂杂环、芳杂环上的氢可被一个或多个下述取代基取代，取代基选自硝基、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基、C 2-C 6烯基、C 2-C 6炔基、苯基或被一个或多个卤素取代的苯基；
    或，R 3选自H同时R 4不选自H时，式I所示化合物的光学异构体。
  2. 按照权利要求1所述的化合物，其特征在于，通式I中：
    W选自O或S；
    X 1选自H或F；
    X 2选自Cl、Br或CN；
    R 1选自甲基；
    R 2选自甲基；
    R 3选自H或甲基；
    R 4选自H、甲基、乙基或异丙基；
    R 5选自CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、(CH 3) 2CHCH 2-、CH 3CH 2CH(CH 3)-、(CH 3) 3C-、CH 3CH 2CH 2CH 2CH 2-、(CH 3) 2CHCH 2CH 2-、(CH 3) 3CCH 2-、CH 3CH 2CH(CH 3)CH 2-、CH 3CH 2CH 2CH(CH 3)-、CH 3CH 2C(CH 3) 2-、ClCH 2CH 2-、ClCH 2CH 2CH 2-、CH 3ClCHCH 2-、CH 2Cl(CH 3)CH-、ClCH 2CH 2CH 2CH 2-、CH 3ClCHCH 2CH 2-、CH 3CH 2ClCHCH 2-、CH 3CH 2CH 2ClCH-、ClCH 2CH 2CH(CH 3)-、ClCH 2(CH 3) 2C-、ClCH 2CH 2CH 2CH 2CH 2-、CH 3CH＝CHCH 2-、ClCH＝CHCH 2-、Cl 2C＝CHCH 2-、ClCH＝CClCH 2-、CH 3C≡CCH 2-、ClC≡CCH 2-、或如下取代基：
    Figure PCTCN2021101396-appb-100002
    或，R 3选自H同时R 4不选自H时，式I所示化合物的光学异构体。
  3. 按照权利要求2所述的化合物，其特征在于，通式I中：
    W选自S；
    X 1选自F；
    X 2选自Cl；
    R 1选自甲基；
    R 2选自甲基；
    R 3选自H或甲基；
    R 4选自H或甲基；
    R 5选自CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、(CH 3) 2CHCH 2-、CH 3CH 2CH(CH 3)-、(CH 3) 3C-、CH 3CH 2CH 2CH 2CH 2-、(CH 3) 2CHCH 2CH 2-、(CH 3) 3CCH 2-、CH 3CH 2CH(CH 3)CH 2-、CH 3CH 2CH 2CH(CH 3)-、CH 3CH 2C(CH 3) 2-、ClCH 2CH 2-、ClCH 2CH 2CH 2-、CH 3ClCHCH 2-、CH 2Cl(CH 3)CH-、ClCH 2CH 2CH 2CH 2-、CH 3ClCHCH 2CH 2-、CH 3CH 2ClCHCH 2-、CH 3CH 2CH 2ClCH-、ClCH 2CH 2CH(CH 3)-、ClCH 2(CH 3) 2C-、ClCH 2CH 2CH 2CH 2CH 2-、CH 3CH＝CHCH 2-、ClCH＝CHCH 2-、Cl 2C＝CHCH 2-、ClCH＝CClCH 2-、CH 3C≡CCH 2-、ClC≡CCH 2-或如下取代基：
    Figure PCTCN2021101396-appb-100003
    或，R 3选自H同时R 4选自甲基时，式I所示化合物的光学异构体为S构型或者S构型含量大于60％。
  4. 一种权利要求1所述的通式I化合物在用于控制杂草中的应用。
  5. 一种除草组合物，其特征在于：除草组合物为活性物质和可接受的载体，活性组分为权利要求1所述的通式I化合物，组合物中活性组分的重量百分含量为1-99％。
  6. 一种如权利要求5所述的除草组合物的控制杂草的方法，其特征在于：向杂草或杂草的生长介质或地点上施用除草有效剂量的如权利要求5所述的除草组合物。
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023117670A1 (en) 2021-12-22 2023-06-29 Syngenta Crop Protection Ag Triazine herbicidal compounds
WO2023144004A1 (en) 2022-01-26 2023-08-03 Syngenta Crop Protection Ag Herbicidal compounds
EP4230621A1 (de) 2022-02-22 2023-08-23 Bayer AG Substituierte n-benzoesäureuracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
EP4230620A1 (de) 2022-02-22 2023-08-23 Bayer Aktiengesellschaft Substituierte n-amino-n´-benzoesäureuracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2023161172A1 (de) 2022-02-22 2023-08-31 Bayer Aktiengesellschaft Substituierte n-benzoesäureuracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2024104954A1 (de) 2022-11-16 2024-05-23 Bayer Aktiengesellschaft Substituierte cycloalkyloxyphenyluracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2024104956A1 (de) 2022-11-16 2024-05-23 Bayer Aktiengesellschaft Substituierte cycloalkylsulfanylphenyluracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2024104952A1 (de) 2022-11-16 2024-05-23 Bayer Aktiengesellschaft Substituierte cyclopropyloxyphenyluracile sowie deren salze und ihre verwendung als herbizide wirkstoffe

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5447904A (en) * 1992-08-24 1995-09-05 Bayer Aktiengesellschaft 3-aryl-triazine-2,4-diones
CN1341105A (zh) 1999-02-23 2002-03-20 巴斯福股份公司 1－芳基－1,3,5－三嗪－4－硫酮－2,6－二酮,其制备和作为除草剂的用途
WO2019162702A1 (en) * 2018-02-26 2019-08-29 AlzeCure Pharma AB Triazine derivatives for treating diseases relating to neurotrophins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5447904A (en) * 1992-08-24 1995-09-05 Bayer Aktiengesellschaft 3-aryl-triazine-2,4-diones
CN1341105A (zh) 1999-02-23 2002-03-20 巴斯福股份公司 1－芳基－1,3,5－三嗪－4－硫酮－2,6－二酮,其制备和作为除草剂的用途
WO2019162702A1 (en) * 2018-02-26 2019-08-29 AlzeCure Pharma AB Triazine derivatives for treating diseases relating to neurotrophins

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023117670A1 (en) 2021-12-22 2023-06-29 Syngenta Crop Protection Ag Triazine herbicidal compounds
WO2023144004A1 (en) 2022-01-26 2023-08-03 Syngenta Crop Protection Ag Herbicidal compounds
EP4230621A1 (de) 2022-02-22 2023-08-23 Bayer AG Substituierte n-benzoesäureuracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
EP4230620A1 (de) 2022-02-22 2023-08-23 Bayer Aktiengesellschaft Substituierte n-amino-n´-benzoesäureuracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2023161172A1 (de) 2022-02-22 2023-08-31 Bayer Aktiengesellschaft Substituierte n-benzoesäureuracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2024104954A1 (de) 2022-11-16 2024-05-23 Bayer Aktiengesellschaft Substituierte cycloalkyloxyphenyluracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2024104956A1 (de) 2022-11-16 2024-05-23 Bayer Aktiengesellschaft Substituierte cycloalkylsulfanylphenyluracile sowie deren salze und ihre verwendung als herbizide wirkstoffe
WO2024104952A1 (de) 2022-11-16 2024-05-23 Bayer Aktiengesellschaft Substituierte cyclopropyloxyphenyluracile sowie deren salze und ihre verwendung als herbizide wirkstoffe

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