Butenolide compounds containing thiazolidinone structure, and preparation method and application thereof

Abstract

The present application relates to the field of agrochemical technology, and particularly relates to a butenolide compound containing a thiazolidine ketone structure and a preparation method and application thereof. The butenolide compound containing the thiazolidine ketone structure has the following general structure: the compound has excellent bactericidal activity on various pathogenic bacteria in agriculture or other fields, and can advantageously protect important crops and livestock in agriculture and horticulture, and the environment for human survival from pathogenic bacteria.

Description

Technical Field

[0001] This invention relates to the field of agricultural chemistry, and in particular to a butenolactone compound containing a thiazolidinone structure, its preparation method, and its application. Background Technology

[0002] Spirocyclobutene lactones are widely found in nature, such as spirofragilid, lambertellol A, crossalactone D, and pyrenolide D. These natural products possess a variety of excellent biological activities, including insecticidal, fungicidal, spore germination inhibitory, anti-inflammatory, and antitumor effects. Commercially available spirocyclobutene lactone pesticides include spirodiclofen, spirodiclofen, spirotetramat, and methoxypiperidine ethyl ester, making them a class of excellent agricultural insecticides and acaricides. Therefore, spirocyclobutene lactones are a highly valuable pharmacodynamic group worthy of in-depth research and development.

[0003] For example, patent CN111574507A discloses a compound containing a natural butenolactone skeleton, its preparation, and its application, showing good control effects against various pests and plant pathogenic fungi. Patent CN110396083A discloses a compound containing pyridazinone-butenolactones, exhibiting excellent control effects against common diseases of various important agricultural and horticultural crops. These prior art demonstrates the excellent effects of butenolactone compounds in controlling plant diseases; however, these patents suffer from drawbacks such as insufficient compound stability, long synthetic routes, and high costs. Furthermore, patent CN104370891 discloses 5-(butenolactone-3-ethylene)-2-aminoimidazolinone compounds with good fungicidal effects against various plant pathogens, including rice sheath blight, rapeseed sclerotinia rot, and pepper blight pathogens; however, toxicity tests show that these compounds have relatively low toxicity, indicating a gap from commercial application, and significant room for improvement in their antibacterial activity.

[0004] It is evident that there is still room for improvement in the application of butenolactone compounds in the field of agricultural chemistry for the prevention and control of pests and diseases. Summary of the Invention

[0005] The purpose of this invention is to provide a butenolactone compound containing a thiazolidinone structure that can prevent and control various plant pathogens, as well as its preparation method and application.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] This invention first provides a butenolactone compound containing a thiazolidinone structure, which has the following general structural formula:

[0008]

[0009] In the formula:

[0010] R1 and R2 are each independently selected from hydrogen and C1-C. 12 Alkyl group; or, R1, R2 and the attached carbon atom form a C3-C group. 12 cycloalkyl or C3-C 12 Cyclic heteroalkyl groups, wherein the heteroatom in the heteroalkyl group is N, O, or S, wherein the C3-C 12 cycloalkyl or C3-C 12 The hydrogen atom on the cyclic heteroalkyl group can be monosubstituted or polysubstituted by R5;

[0011] R3 is selected from hydrogen, hydroxyl group, C1-C 12 Alkyl, C5-C7 cycloalkyl, unsubstituted or containing 1-3 R6-substituted aryl or heteroaryl groups;

[0012] R4 is selected from C1-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy, halogenated C1-C 12 Alkoxy, C3-C 12 Cycloalkyl, aryl or heteroaryl groups substituted with 1-3 R6 groups, or biphenyl or diphenyl ethers substituted with one or more R6 groups;

[0013] R5 is selected from hydroxyl, carbonyl, methoxy, methoxyoxime, formyl, halogen, C1-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy or halogenated C1-C 12 Alkoxy;

[0014] R6 is selected from halogen, hydroxyl, amino, cyano, nitro, C1-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy, halogenated C1-C 12 Alkoxy, C3-C 12 cycloalkyl, C1-C 12 Alkylthio, Halogenated C1-C 12 Alkylthio, C1-C 12 Alkylamino, halogenated C1-C 12 Alkylamino, di(C1-C) 12 Alkyl)amino, halodi(C1-C) 12 Alkyl)amino, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkenyl groups, halogenated C2-C 12 Alkenyl group, C2-C 12Acryloxy group, halogenated C2-C 12 Acryloxy group, C1-C 12 Alkyl sulfonyl, halogenated C1-C 12 Alkyl sulfonyl, C1-C 12 Alkyl carbonyl, halogenated C1-C 12 Alkyl carbonyl, C1-C 12 Alkoxy carbonyl, halogenated C1-C 12 Alkoxycarbonyl, C1-C 12 Alkoxy C1-C 12 Alkyl, halogenated C1-C 12 Alkoxy C1-C 12 Alkyl, C1-C 12 Alkylthio C1-C 12 Alkyl, halogenated C1-C 12 Alkylthio C1-C 12 Alkyl, C1-C 12 Alkoxycarbonyl C1-C 12 Alkyl, halogenated C1-C 12 Alkoxycarbonyl C1-C 12 Alkyl, C1-C 12 Alkylthiocarbonyl C1-C 12 Alkyl, halogenated C1-C 12 Alkylthiocarbonyl C1-C 12 Alkyl, C1-C 12 Alkyl carbonyloxy group, halogenated C1-C 12 Alkyl carbonyloxy group, C1-C 12 Alkoxycarbonyloxy, halogenated C1-C 12 Alkoxycarbonyloxy, C1-C 12 Alkylsulfonyloxy, halogenated C1-C 12 Alkylsulfonyloxy, C1-C 12 Alkoxy C1-C 12 Alkoxy or halogenated C1-C 12 Alkoxy C1-C 12 Alkyl group.

[0015] This invention discovers that introducing thiazolidinones into butenolactone compounds can significantly improve the antibacterial activity of butenolactone compounds and greatly enhance their toxicity, resulting in a significantly enhanced antibacterial effect.

[0016] The terms used in the definitions of compounds of general formula I given above are generally defined as follows:

[0017] Halogens: refer to fluorine, chlorine, bromine or iodine.

[0018] Alkyl: Straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.

[0019] Cycloalkyl: substituted or unsubstituted cyclic alkyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl, or substituted cyclopropyl, cyclopentyl, cyclohexyl, etc. Substituents include alkyl groups, halogens, etc.

[0020] Halogenated alkyl groups: straight-chain or branched alkyl groups in which hydrogen atoms may be partially or completely replaced by halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.

[0021] Alkyl sulfonyl group: A straight or branched alkyl group is attached to the structure via a sulfinyl group (-SO2), such as a methyl sulfonyl group.

[0022] Halogenated alkyl sulfonyl groups: straight-chain or branched alkyl sulfonyl groups, in which the hydrogen atoms on the alkyl group may be partially or completely replaced by halogen atoms.

[0023] Alkylaminothio groups: such as CH3NHS-, C2H5NHS-, etc.

[0024] Dialkylaminothio groups: such as (CH3)2NS-, (C2H5)2NS-, etc.

[0025] Alkylaminosulfonyl: such as alkyl-NH-SO2-, etc.

[0026] Dialkylaminosulfonyl: such as (alkyl)2-N-SO2- etc.

[0027] Alkylsulfonylaminocarbonyl: such as alkyl-SO2-NH-CO-, etc.

[0028] Alkyl carbonyl aminosulfonyl: such as alkyl-CO-NH-SO2-, etc.

[0029] Alkyl carbonyl alkyl: such as alkyl-CO-alkyl- etc.

[0030] Alkylsulfonyloxy groups: such as alkyl-S(O)2-O-, etc.

[0031] Halogenated alkyl sulfonyloxy groups: The hydrogen atoms on the alkyl group of an alkyl sulfonyloxy group may be partially or completely replaced by halogen atoms, such as CF3-SO2-O, etc.

[0032] Cycloalkyloxycarbonyl groups: such as cyclopropoxycarbonyl, cyclohexyl, oxycarbonyl, etc.

[0033] Alkoxy: A straight-chain or branched alkyl group that is attached to the structure via an oxygen atom bond.

[0034] Halogenated alkoxy groups: Straight-chain or branched alkoxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. Examples include chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, and trifluoroethoxy.

[0035] Halogenated alkoxycarbonyl: The hydrogen atoms on the alkyl group of the alkoxycarbonyl group can be partially or completely replaced by halogen atoms, such as ClCH2CH2OCO-, CF3CH2OCO-, etc.

[0036] Alkoxyalkyl: alkyl-O-alkyl-, such as CH3OCH2-, etc.

[0037] Halogenated alkoxyalkyl groups: The hydrogen atoms on the alkyl group of an alkoxyalkyl group may be partially or completely replaced by halogen atoms, such as ClCH2CH2OCH2-, CF3CH2OCH2-, etc.

[0038] Alkoxycarbonyl alkyl: Alkoxycarbonyl-alkyl-, such as CH3OCOCH2-, etc.

[0039] Halogenated alkoxycarbonyl alkyl groups: The alkyl group of an alkoxycarbonyl alkyl group is partially or completely replaced by a halogen atom, such as CF3CH2OCOCH2-.

[0040] Alkyl carbonyloxy groups: such as CH3COO-, etc.

[0041] Halogenated alkyl carbonyloxy groups: The hydrogen atoms of alkyl carbonyloxy groups can be partially or completely replaced by halogen atoms, such as CF3COO-.

[0042] Alkoxycarbonyloxy group: Alkoxycarbonyl-oxy-, such as CH3OCOO-, etc.

[0043] Halogenated alkoxycarbonyloxy: The hydrogen atoms on the alkyl group of alkoxycarbonyloxy can be partially or completely replaced by halogen atoms, such as CF3OCOO-.

[0044] Alkylthiocarbonylalkyl: Alkylthiocarbonyl-alkyl-, such as CH3SCOCH2-, etc.

[0045] Haloalkylthiocarbonylalkyl: The hydrogen atoms on the alkyl group of alkylthiocarbonylalkyl group may be partially or completely replaced by halogen atoms, such as CF3CH2SCOCH2-, etc.

[0046] Alkoxy groups: such as CH3OCH2O-, etc.

[0047] Halogenated alkoxy groups: The hydrogen atom on the alkoxy group can be partially or completely replaced by a halogen atom, for example, CF3OCH2O-.

[0048] Alkoxycarbonyl: such as CH3OCH2CH2OCO-, etc.

[0049] Alkylthio group: a straight-chain or branched alkyl group that is attached to the structure via a sulfur atom bond.

[0050] Haloalkylthio groups: Straight-chain or branched alkylthio groups in which hydrogen atoms on these alkyl groups may be partially or completely replaced by halogen atoms. Examples include chloromethylthio, dichloromethylthio, trichloromethylthio, trifluoromethylthio, and chlorofluoromethylthio.

[0051] Alkylthioalkyl: alkyl-S-alkyl-, such as CH3SCH2-, etc.

[0052] Haloalkylthioalkyl: The hydrogen atoms on the alkyl group of alkylthioalkyl can be partially or completely replaced by halogen atoms, such as ClCH2CH2SCH2-, CF3CH2SCH2-, etc.

[0053] Alkylamino: Straight-chain or branched alkyl groups, linked to the structure by nitrogen atoms.

[0054] Halogenated alkylamino: Straight-chain or branched alkylamino, in which hydrogen atoms on the alkyl group may be partially or completely replaced by halogen atoms.

[0055] Dialkylamino compounds: such as (CH3)2N-, (CH3CH2)2N-, etc.

[0056] Halogenated dialkylamino: The hydrogen atoms on the alkyl group can be partially or completely replaced by halogen atoms, such as (CF3)2N-, (CF3CH2)2N-.

[0057] Alkenyl groups: straight-chain or branched alkenes, such as vinyl, 1-propenyl, 2-propenyl, and various butenyl, pentenyl, and hexenyl isomers. Alkenyl groups also include polyenes, such as 1,2-propadienyl and 2,4-hexadienyl.

[0058] Halogenated alkenyl groups: straight-chain or branched alkenes in which hydrogen atoms may be partially or completely replaced by hydrogen atoms.

[0059] Alkenyl group: Straight-chain or branched alkenes, which are attached to the structure by oxygen atoms.

[0060] Halogenated olefins: Straight-chain or branched olefins in which hydrogen atoms may be partially or completely replaced by olefin atoms.

[0061] Alkynyl group: Straight-chain or branched alkynes, such as ethynyl, 1-propynyl, 2-propynyl and various butynyl, pentyynyl and hexynyl isomers. Alkynyl groups also include groups composed of multiple triple bonds, such as 2,5-hexadiynyl.

[0062] Halogenated alkynyl groups: straight-chain or branched alkynyl groups in which hydrogen atoms may be partially or completely replaced by hydrogen atoms.

[0063] Alkyl carbonyl: An alkyl group is attached to a structure via a carbonyl group, such as CH3CO-, CH3CH2CO-, etc.

[0064] Halogenated alkyl carbonyl: The hydrogen atoms on the alkyl group can be partially or completely replaced by hydrogen atoms, such as CF3CO-.

[0065] Alkoxycarbonyl group: An alkoxy group is attached to the structure via a carbonyl group. Examples include CH3OCO- and CH3CH2OCO-.

[0066] Amino carbonyl groups: such as NH2CO-, etc.

[0067] Alkylaminocarbonyl: alkyl-NH-CO-, such as CH3NHCO-, etc.

[0068] Dialkylaminocarbonyl: such as (CH3)2NCO-, (CH3CH2)2NCO-. The aryl moiety in (hetero)aryl, (hetero)arylalkyl, (hetero)arylcarbonyl, (hetero)arylmethylcarbonyl, (hetero)arylcarbonylalkyl, (hetero)aryloxycarbonyl, (hetero)arylalkyloxycarbonyl includes phenyl or naphthyl, etc.

[0069] Heteroaryl groups are five- or six-membered rings containing one or more N, O, or S heteroatoms. Examples include furanyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and quinolinyl.

[0070] (Miscellaneous) aryl groups: such as phenyl groups.

[0071] (Miscellaneous) arylalkyl: such as benzyl, phenethyl, p-fluorobenzyl, etc.

[0072] (Miscellaneous) aryl carbonyl groups: such as benzoyl, 4-chlorobenzoyl, etc.

[0073] (Hetero)arylmethyl carbonyl: such as PhCH2CO-. (Hetero)arylcarbonyl alkyl: such as PhCOCH2-, etc.

[0074] (Miscellaneous) aryloxycarbonyl groups: such as phenoxycarbonyl, 4-fluorophenoxycarbonyl, 4-chlorophenoxycarbonyl, naphthoxycarbonyl, etc.

[0075] Arylalkyloxycarbonyl: such as benzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-trifluoromethylbenzyloxycarbonyl, etc.

[0076] (Hetero)Aromatic alkyloxycarbonyl: such as PhCH2OCO-, 4-ClPhCH2OCO, etc.

[0077] Preferably, in the compound represented by general formula I:

[0078] R1 and R2 are each independently selected from hydrogen or C1-C4 alkyl; or, R1 and R2 can form C5-C6 cycloalkyl or C5-C6 cycloheteroalkyl with the attached carbon atom, wherein the heteroatom in the heteroalkyl is N, O or S, wherein the C3-C 12 cycloalkyl or C3-C12 The hydrogen atom on the cyclic heteroalkyl group can be monosubstituted by R5;

[0079] R3 is selected from hydrogen, C1-C4 alkyl, C1-C4 cycloalkyl, unsubstituted or containing 1-3 R6-substituted aryl or heteroaryl groups;

[0080] R4 is selected from aryl or heteroaryl groups substituted with 1-3 R6 groups, biphenyl or diphenyl ethers substituted with one or two R6 groups;

[0081] R5 is selected from hydroxyl, carbonyl, methoxy, methoxyoxime, formyl, halogen, C1-C4 alkyl, and halo-C1-C4 alkyl;

[0082] R6 is selected from halogen, hydroxyl, amino, cyano, nitro, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C4 cycloalkyl, C1-C4 alkylthio, halo-C1-C4 alkylthio, C1-C4 alkylamino, halo-C1-C4 alkylamino, C1-C4 alkylsulfonyl, halo-C1-C4 alkylsulfonyl, C1-C4 alkylcarbonyl, and halo-C1-C4 alkylcarbonyl.

[0083] Preferably, in the compound represented by general formula I:

[0084] R1 and R2 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl; or, R1 and R2 can form a five- or six-membered carbon ring with the attached carbon atom, and the hydrogen on the carbon ring can be monosubstituted by R5.

[0085] R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, substituted or substituted with 1-3 R6 groups, aryl or heteroaryl groups;

[0086] R4 is selected from aryl or heteroaryl groups substituted with 1-3 R6 groups, biphenyl or diphenyl ethers substituted with one or two R6 groups;

[0087] R5 is selected from hydroxyl, carbonyl, methoxy, methoxyoxime or halogen;

[0088] R6 is selected from halogen, hydroxyl, amino, cyano, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C1-C4 alkylthio or halogenated C1-C4 alkylthio.

[0089] Preferably, in the compound represented by general formula I:

[0090] R1 and R2 are selected from methyl groups;

[0091] R1 and R2 can form saturated five- or six-membered carbon rings with the attached carbon atoms, and the hydrogen on the carbon ring can be monosubstituted by R5.

[0092] R3 is selected from methyl or phenyl substituted with R6;

[0093] R4 is selected from phenyl groups substituted with R6, biphenyl groups substituted with one or two R6 groups, or diphenyl ethers.

[0094] R5 is selected from methoxy or methoxyoxime;

[0095] R6 is selected from methyl, tert-butyl, halogen, nitro, methylthio, methoxy, or trifluoromethyl.

[0096] The preferred compounds represented by general formula I of this invention include the following compounds:

[0097] When R1=R2=-(CH2)5-, R3=CH3, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-1-1-I-1-21 in sequence.

[0098] When R1=R2=CH3, R3=CH3, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-2-1—I-2-21 in sequence.

[0099] When R1 = R2 = CH3, R3 = Ph, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-3-1 to I-3-21 in sequence.

[0100] When R1=R2=-(CH2)5-, R3=Ph, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-4-1—I-4-21 in sequence.

[0101] When R1=R2=-(CH2)5-, R3=4-FPh, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-5-1—I-5-21 in sequence.

[0102] When R1=R2=-(CH2)5-, R3=4-ClPh, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-6-1—I-6-21 in sequence.

[0103] When R1=R2=-(CH2)5-, R3=4-BrPh, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-7-1—I-7-21 in sequence.

[0104] When R1=R2=-(CH2)5-, R3=4-C4H9Ph, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-8-1—I-8-21 in sequence.

[0105] When R1=R2=-(CH2)5-, R3=4-OCH3Ph, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-9-1—I-9-21 in sequence.

[0106] When R1=R2=-(CH2)5-, R3=4-SCH3Ph, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-10-1—I-10-21 in sequence.

[0107] When R1=R2=-(CH2)5-, R3=4-SO2Ph, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-11-1—I-11-21 in sequence.

[0108] When R1=R2=-(CH2)5-, R3=4-CF3Ph, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-12-1—I-12-21 in sequence.

[0109] When R1=R2=-(CH2)5-, R3=3-BrPh, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-13-1—I-13-21 in sequence.

[0110] When R1=R2=-(CH2)5-, R3=3-ClPh, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-14-1-I-14-21 in sequence.

[0111] When R1=R2=-(CH2)5-, R3=3-FPh, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compound numbers I-15-1-I-15-21 in sequence.

[0112] When R1=R2=-(CH2)5-, R3=3-CF3Ph, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-16-1—I-16-21 in sequence.

[0113] When R1=R2=-(CH2)5-, R3=3-NO2Ph, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-17-1—I-17-21 in sequence.

[0114] When R1=R2=-(CH2)5-, R3=3-OCH3Ph, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compounds numbered I-18-1—I-18-21 in sequence.

[0115] When R1=R2=-(CH2)5-, R3=2-BrPh, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-19-1—I-19-21 in sequence.

[0116] When R1=R2=-(CH2)5-, R3=2-ClPh, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-20-1—I-20-21 in sequence.

[0117] When R1=R2=-(CH2)5-, R3=2-FPh, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-21-1—I-21-21 in sequence.

[0118] When R1=R2=-CH2CH2CHOCH3CH2CH2-, R3=CH3, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-22-1-I-22-21 in sequence.

[0119] When R1=R2=-CH2CH2CHOCH3CH2CH2-, R3=Ph, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-23-1-I-23-21 in sequence.

[0120] When R1=R2=-CH2CH2CNOCH3CH2CH2-, R3=CH3, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-24-1-I-24-21 in sequence.

[0121] When R1=R2=-CH2CH2CNOCH3CH2CH2-, R3=Ph, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-25-1-I-25-21 in sequence.

[0122] When R1=R2=-CH2CH2CHOHCH2CH2-, R3=CH3, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-26-1-I-26-21 in sequence.

[0123] When R1=R2=-CH2CH2CHOHCH2CH2-, R3=Ph, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-27-1-I-27-21 in sequence.

[0124] When R1=R2=-CH2CH2COCH2CH2-, R3=CH3, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-28-1-I-28-21 in sequence.

[0125] When R1=R2=-CH2CH2COCH2CH2-, R3=Ph, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-29-1-I-29-21 in sequence.

[0126] When R1=R2=-CH2CH2CHFCH2CH2-, R3=CH3, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-30-1-I-30-21 in sequence.

[0127] When R1=R2=-CH2CH2CHFCH2CH2-, R3=Ph, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-31-1-I-31-21 in sequence.

[0128] When R1=R2=-CH2CH2CHClCH2CH2-, R3=CH3, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-32-1-I-32-21 in sequence.

[0129] When R1=R2=-CH2CH2CHClCH2CH2-, R3=Ph, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-33-1-I-33-21 in sequence.

[0130] When R1=R2=-CH2CH2CHBrCH2CH2-, R3=CH3, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-34-1-I-34-21 in sequence.

[0131] When R1=R2=-CH2CH2CHBrCH2CH2-, R3=Ph, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-35-1-I-35-21 in sequence.

[0132] When R1 = R2 = CH3, R3 = CH3NH, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-36-1-I-36-21 in sequence.

[0133] When R1=R2=-(CH2)5-, R3=CH3NH, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, and the compound numbers are I-37-1-I-37-21 in sequence.

[0134] When R1=R2=CH3, R3=(CH3)2N, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, and the compound numbers are I-38-1-I-38-21 in sequence.

[0135] When R1=R2=-(CH2)5-, R3=(CH3)2N, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compound numbers I-39-1-I-39-21 in sequence.

[0136] When R1 = R2 = CH3, R3 = Cl, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-40-1 to I-40-21 in sequence.

[0137] When R1=R2=-(CH2)5-, R3=Cl, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-41-1—I-41-21 in sequence.

[0138] When R1 = R2 = CH3, R3 = F, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-42-1 to I-42-21 in sequence.

[0139] When R1=R2=-(CH2)5-, R3=F, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-43-1—I-43-21 in sequence.

[0140] When R1 = R2 = CH3, R3 = Br, and the substituent R4 is as shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-44-1-I-44-21 in sequence.

[0141] When R1=R2=-(CH2)5-, R3=Br, and the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, the compound numbers are I-45-1-I-45-21 in sequence.

[0142] When R1=R2=-(CH2)5-, R3=C5H4N, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compound numbers I-46-1-I-46-21 in sequence.

[0143] When R1 = R2 = CH3, R3 = C5H4N, the substituent R4 is shown in Table 1, corresponding to 1-21 in Table 1, representing compound numbers I-47-1-I-47-21 in sequence.

[0144] In the above n-R3Ph, n represents the substitution position of R3 on the benzene ring, such as 4-FPh refers to 4-fluorophenyl, and 3-OCH3Ph refers to 3-methoxyphenyl.

[0145] Table 1

[0146]

[0147] The present invention also provides a butenolactone intermediate containing a thiazolidinone structure, having a structure as shown in general formula 3:

[0148]

[0149] R is selected from NH and S;

[0150] R1 and R2 are each independently selected from hydrogen or C1-C. 12 Alkyl group; or, R1, R2 and the attached carbon atom form a C3-C group. 12 cycloalkyl or C3-C 12 Cyclic heteroalkyl groups, wherein the heteroatom in the heteroalkyl group is N, O, or S, wherein the C3-C 12 cycloalkyl or C3-C 12 The hydrogen atom on the cyclic heteroalkyl group can be monosubstituted or polysubstituted by R5;

[0151] R3 is selected from hydrogen, hydroxyl group, C1-C 12 Alkyl, C5-C7 cycloalkyl, unsubstituted or containing 1-3 R6-substituted aryl or heteroaryl groups;

[0152] R5 is selected from hydroxyl, carbonyl, methoxy, methoxyoxime, formyl, halogen, C1-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy or halogenated C1-C 12 Alkoxy;

[0153] R6 is selected from halogen, hydroxyl, amino, cyano, nitro, C1-C 12 Alkyl, halogenated C1-C 12 Alkyl, C1-C 12 Alkoxy, halogenated C1-C12 Alkoxy, C3-C 12 cycloalkyl, C1-C 12 Alkylthio, Halogenated C1-C 12 Alkylthio, C1-C 12 Alkylamino, halogenated C1-C 12 Alkylamino, di(C1-C) 12 Alkyl)amino, halodi(C1-C) 12 Alkyl)amino, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkenyl groups, halogenated C2-C 12 Alkenyl group, C2-C 12 Acryloxy group, halogenated C2-C 12 Acryloxy group, C1-C 12 Alkyl sulfonyl, halogenated C1-C 12 Alkyl sulfonyl, C1-C 12 Alkyl carbonyl, halogenated C1-C 12 Alkyl carbonyl, C1-C 12 Alkoxy carbonyl, halogenated C1-C 12 Alkoxycarbonyl, C1-C 12 Alkoxy C1-C 12 Alkyl, halogenated C1-C 12 Alkoxy C1-C 12 Alkyl, C1-C 12 Alkylthio C1-C 12 Alkyl, halogenated C1-C 12 Alkylthio C1-C 12 Alkyl, C1-C 12 Alkoxycarbonyl C1-C 12 Alkyl, halogenated C1-C 12 Alkoxycarbonyl C1-C 12 Alkyl, C1-C 12 Alkylthiocarbonyl C1-C 12 Alkyl, halogenated C1-C 12 Alkylthiocarbonyl C1-C 12 Alkyl, C1-C 12 Alkyl carbonyloxy group, halogenated C1-C 12 Alkyl carbonyloxy group, C1-C 12 Alkoxycarbonyloxy, halogenated C1-C 12 Alkoxycarbonyloxy, C1-C 12 Alkylsulfonyloxy, halogenated C1-C 12 Alkylsulfonyloxy, C1-C 12 Alkoxy C1-C 12 Alkoxy or halogenated C1-C 12Alkoxy C1-C 12 Alkyl group.

[0154] During the optimization of intermediates, this invention unexpectedly discovered that, in the intermediate compounds with the structure shown in general formula 3, when R is selected from either NH or S, they exhibit good antibacterial activity, similar to the compounds shown in general formula I, with a particularly outstanding antibacterial effect. However, when R is other common groups such as ketones, the antibacterial effect is poor.

[0155] The preferred intermediate compounds represented by general formula 3 of this invention include:

[0156]

[0157] This invention further provides a method for preparing the above-mentioned butenolactone compounds containing a thiazolidinone structure, wherein the compound of general formula I is synthesized via the following route:

[0158]

[0159] In the formula, R, R1, R2, R3, and R4 are defined as described above.

[0160] Preferably, the method for preparing the butenolactone compound containing a thiazolidinone structure includes the following steps:

[0161] (1) In a first solvent, the intermediate compound represented by general formula 3 is methylated under the action of a base to obtain compound 4; the base is selected from one or more of potassium carbonate, cesium carbonate, sodium hydride, sodium ethoxide and sodium hydroxide, the first solvent is selected from acetonitrile and / or acetone, and the reaction temperature is heated from room temperature to reflux temperature;

[0162] (2) In a second solvent, compound 4 reacts with NH2-R4 under reflux conditions with acid catalysis to obtain the compound shown in general formula I; the second solvent is selected from toluene and / or xylene, and the acid is selected from one or more of oxalic acid, acetic acid and propionic acid.

[0163] Preferably, the base in step (1) is potassium carbonate and / or cesium carbonate; more preferably, the molar ratio of the base to the intermediate compound shown in formula 3 is 1.5:1-2:1; the molar ratio of iodomethane to the intermediate compound shown in formula 3 is 1.2:1-1.5:1; and the volume molar ratio of the first solvent to the intermediate compound shown in formula 3 is (190-210) mL:20 mmol.

[0164] Preferably, the first solvent in step (1) is acetonitrile.

[0165] Preferably, the methylation reaction temperature in step (1) is the reflux temperature.

[0166] Preferably, the acid in step (2) is oxalic acid and / or acetic acid; more preferably, the molar ratio of the acid to compound 4 is 1.2:1-1.5:1;

[0167] Preferably, the second solvent in step (2) is toluene.

[0168] Preferably, the reflux temperature in step (2) is 110-120°C.

[0169] This invention also provides a method for preparing the butenolactone intermediate containing the thiazolidinone structure, the synthetic route of which is as follows:

[0170]

[0171] In the formula, R, R1, R2, and R3 are defined as described above.

[0172] Preferably, compound 2 is prepared from compound 1, and the synthetic route of the butenolactone intermediate containing the thiazolidinone structure is as follows:

[0173]

[0174] Preferably, the method for preparing the butenolactone intermediate containing a thiazolidinone structure includes:

[0175] 1) Compound 1 reacts with diketene in the presence of a catalyst to give 3-acetylbutenolactone compound 2, wherein the catalyst is selected from triethylamine and / or diisopropylethylamine;

[0176] 2) In the third solvent, compound 2 and The intermediate compound of general formula 3 is obtained by reflux reaction under the action of an organic base; wherein R is selected from NH and S; the organic base is selected from one or more of ethanolamine, piperidine, pyridine, sodium acetate and ammonium acetate; and the third solvent is selected from toluene and / or xylene.

[0177] Preferably, the catalyst in step 1) is triethylamine.

[0178] Preferably, the organic base in step 2) is ethanolamine and / or ammonium acetate; more preferably, the molar ratio of the organic base to compound 2 is 3:1-5:1.

[0179] Preferably, the third solvent in step 2) is toluene; more preferably, the volume molar ratio of toluene to compound 2 is (190-210) mL: 20 mmol.

[0180] Preferably, the reflux temperature in step 2) is 110-120°C.

[0181] The present invention also provides the use of the butenolactone compounds containing the thiazolidinone structure and the butenolactone intermediates containing the thiazolidinone structure in the preparation of bactericides.

[0182] Preferably, the formulation of the fungicide includes at least one of emulsifiable concentrate, wettable powder, suspension concentrate, powder, soluble powder, aqueous solution, water-dispersible granules, fumigant, granules, and seed coating agent.

[0183] The examples of diseases described below are only used to illustrate the present invention, but are by no means limiting the present invention.

[0184] The compound represented by general formula I and the intermediate compound represented by general formula 3 can be used to control the following diseases: Oomycete diseases, such as downy mildew (downy mildew of cucumber, rapeseed, soybean, beet, sugarcane, tobacco, pea, loofah, winter melon, cantaloupe, Chinese cabbage, spinach, radish, grape, and onion), and white rust (white rust of rapeseed, Chinese cabbage, etc.). White rust, damping-off (rapeseed damping-off, tobacco damping-off, tomato damping-off, pepper damping-off, eggplant damping-off, cucumber damping-off, cotton seedling damping-off), cottony rot (pepper cottony rot, loofah cottony rot, winter melon cottony rot), blight (broad bean blight, cucumber blight, pumpkin blight, winter melon blight, watermelon blight, cantaloupe blight, pepper blight, leek blight, garlic blight, cotton blight), late blight (potato late blight, tomato late blight), etc.Deuteromycete diseases, such as wilt (sweet potato wilt, cotton wilt, sesame wilt, castor bean wilt, tomato wilt, bean wilt, cucumber wilt, loofah wilt, pumpkin wilt, winter melon wilt, watermelon wilt, cantaloupe wilt, pepper wilt, broad bean wilt, rapeseed wilt, soybean wilt), root rot (pepper root rot, eggplant root rot, bean root rot, cucumber root rot, bitter gourd root rot, cotton black root rot, broad bean root rot), damping-off (cotton seedling damping-off, sesame damping-off, pepper damping-off, cucumber damping-off, cabbage damping-off), anthracnose (sorghum anthracnose, cotton anthracnose, kenaf anthracnose, yellow horse anthracnose, flax anthracnose, tobacco anthracnose, mulberry anthracnose, pepper anthracnose, etc.). Anthracnose in various vegetables including peppers, eggplants, broad beans, cucumbers, bitter melons, zucchini, winter melons, watermelons, cantaloupes, and lychees; Verticillium wilt in various vegetables including cotton, sunflowers, tomatoes, peppers, and eggplants; black spot in various vegetables including zucchini, winter melons, and cantaloupes; gray mold in various vegetables including cotton bolls, kenaf, tomatoes, peppers, beans, celery, spinach, and kiwifruit; and brown spot in various vegetables including cotton, jute, beets, peanuts, peppers, winter melons, soybeans, sunflowers, peas, and broad beans. Spot diseases, black spot (flax false black spot, rapeseed black spot, sesame black spot, sunflower black spot, castor bean black spot, tomato black spot, pepper black spot, eggplant black spot, green bean black spot, cucumber black spot, celery black spot, carrot black rot, carrot black spot, apple black spot, peanut black spot), leaf spot (tomato leaf spot, pepper leaf spot, celery leaf spot), early blight (tomato early blight, pepper early blight, eggplant early blight, potato early blight, celery early blight), ring spot (soybean ring spot, sesame ring spot, green bean ring spot), leaf blight (sesame leaf blight, sunflower leaf blight, watermelon leaf blight, melon leaf blight), stem base rot (tomato stem base rot, green bean stem base rot), and others. (It includes diseases such as wheat scab, rice bakanae disease, corn circular spot, kenaf waist break, rice blast, chestnut black sheath disease, sugarcane eye spot, cotton boll aspergillosis, peanut crown rot, soybean stem blight, soybean black spot, melon large leaf spot, peanut net spot, tea red leaf spot, pepper white star disease, winter melon leaf spot, celery black rot, spinach heart rot, kenaf leaf mold, kenaf spot, jute stem spot, soybean purple spot, sesame leaf spot, castor bean gray spot, tea brown leaf spot, eggplant brown round star disease, common bean red spot, bitter gourd white spot, watermelon spot, jute blight, sunflower root and stem rot, common bean anthracnose, soybean target spot, eggplant scab leaf spot, cucumber target spot, tomato leaf mold, eggplant leaf mold, broad bean red spot, etc.)Basidiomycete diseases, such as rust (wheat stripe rust, wheat stem rust, wheat leaf rust, flower rust, sunflower rust, sugarcane rust, leek rust, onion rust, chestnut rust, soybean rust, and common bean rust), smut (corn silk smut, corn smut, sorghum silk smut, sorghum loose smut, sorghum sturdy smut, sorghum stalk smut, chestnut smut, and sugarcane smut) and others (such as wheat sheath blight and rice sheath blight); ascomycete diseases, such as powdery mildew (wheat powdery mildew, rapeseed powdery mildew, and sesame powdery mildew). Powdery mildew in sunflowers, beets, eggplants, peas, loofahs, pumpkins, zucchini, winter melons, cantaloupes, grapes, and broad beans; sclerotinia stem rot in flax, rapeseed, soybeans, peanuts, tobacco, peppers, eggplants, beans, peas, cucumbers, bitter melons, winter melons, watermelons, and celery; and black spot in apples and pears.

[0185] Based on the above technical solution, the beneficial effects of the present invention are as follows:

[0186] This invention significantly improves the bactericidal activity and efficacy of compounds by introducing a thiazolidinone structure into the butenolactone skeleton structure, effectively protecting important crops and livestock in agriculture and horticulture, as well as the environment on which humans depend for survival, from pathogens. Attached Figure Description

[0187] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0188] Figure 1 The compounds 3-1 (Figure A) and 3-14 (Figure B) provided by this invention exhibit EC50 activity against the wheat scab pathogen. 50 The images show the concentrations of compound 3-1 on the plates. In Figure A, from left to right in the first row, the concentrations of compound 3-1 are 1.0 mg / L, 0.25 mg / L, and 0.063 mg / L, respectively; in the second row, from left to right, the concentrations of compound 3-1 are 0.016 mg / L and 0.0040 mg / L, respectively. The last plate is the control group (CK). In Figure B, from left to right in the first row, the first plate is the control group (CK), and the concentrations of compound 3-14 in the remaining plates are 50 mg / L and 12.5 mg / L, respectively; in the second row, from left to right, the concentrations of compound 3-14 are 3.13 mg / L, 0.78 mg / L, and 0.20 mg / L, respectively.

[0189] Figure 2 The EC50 of cyazofamid (Figure A) and compounds 3-5 (Figure B) provided by this invention against the pathogenic fungus Fusarium graminearum of wheat is shown. 50 The images show the concentrations of cyazofamid on the test plates. In Figure A, from left to right in the first row, the first plate is the control group (CK), and the concentrations of cyazofamid in the remaining plates are 10 mg / L and 2.5 mg / L, respectively. In the second row, from left to right, the concentrations of cyazofamid are 0.63 mg / L, 0.16 mg / L, and 0.039 mg / L, respectively. In Figure B, from left to right in the first row, the first plate is the control group (CK), and the concentrations of compounds 3-5 in the remaining plates are 5.0 mg / L and 1.3 mg / L, respectively. In the second row, from left to right, the concentrations of compounds 3-5 are 0.31 mg / L, 0.075 mg / L, and 0.019 mg / L, respectively.

[0190] Figure 3 The EC50 of cyazofamid (Figure A) and compound 3-1 (Figure B) provided by this invention against the pathogenic fungus *Bakanaeda bakanae* of rice is shown. 50 The plate images show the concentrations of cyazofamid in the following images: In Image A, from left to right in the first row, the concentrations of cyazofamid were 5.0 mg / L, 0.31 mg / L, and 0.075 mg / L; in the second row, from left to right, the first plate was the control group (CK), and the concentrations of cyazofamid in the remaining plates were 1.3 mg / L and 0.019 mg / L. In Image B, from left to right in the first row, the concentrations of compound 3-1 were 1.0 mg / L, 0.25 mg / L, and 0.063 mg / L; in the second row, from left to right, the concentrations of compound 3-1 were 0.016 mg / L and 0.0040 mg / L, and the last plate was the control group (CK).

[0191] Figure 4 Compounds 3-5 (Figure A) and 3-22 (Figure B) exhibit EC50 activity against the rice bakanae disease pathogen. 50 The images show the concentrations of compounds 3-5 in the first row (from left to right): 4.0 mg / L, 1.0 mg / L, and 0.25 mg / L, respectively. In the second row (from left to right), the first plate is the control group (CK), and the remaining plates show concentrations of compounds 3-5 of 2.0 mg / L and 0.5 mg / L, respectively. In image B, the concentrations of compounds 3-22 in the first row (from left to right): 4.0 mg / L, 1.0 mg / L, and 0.25 mg / L, respectively. In the second row (from left to right), the concentrations of compounds 3-22 are 0.063 mg / L and 0.016 mg / L, respectively. The last plate is the control group (CK).

[0192] Figure 5 These are test plate photos of 50 mg / L cyazofamid and compound 3-1 against resistant strains T2-5, T10, and T32.

[0193] Figure 6 These are test plate photos of 50 mg / L cyazofamid and compound 3-1 against resistant strains T18, T48, and T79.

[0194] Figure 7 These are test plate photos of low concentrations (0.5 mg / L and 1 mg / L) of compound 3-1 against standard strain 2021, resistant strain T10, and resistant strain T2-5.

[0195] Figure 8 These are photographs of test plates containing low concentrations (0.5 mg / L and 1 mg / L) of compound 3-1 against resistant strains T32, T13, and T12. Detailed Implementation

[0196] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0197] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0198] Unless otherwise noted, all raw materials used below are commercially available.

[0199] Example 1: Preparation of the intermediate compound shown in Formula 3

[0200] This embodiment provides an intermediate—5–(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-2-thio-4-thiazolidinone, the preparation method of which includes:

[0201] The starting materials 2-thio-4-thiazolidinone (1.276 g, 11 mmol) and ammonium acetate (2.310 g, 30 mmol) were dissolved in 100 mL of toluene. Then, 4-methyl-3-acetyl-2-oxo-1-oxaspiro[4,5]dec-3-ene (compound 2) (2.080 g, 10 mmol) was added. The mixture was refluxed at 110 °C and stirred for 15 h. After the reaction was completed by TLC monitoring, the solvent was removed by rotary evaporation under reduced pressure. Then, ethyl acetate and water were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate and petroleum ether (boiling range 60-90 °C, volume ratio 1:6) to obtain 1.807 g of yellow solid with a melting point of 118-119 °C and a yield of 56%.

[0202] 1 H NMR (300MHz, CDCl3) δ: 10.31 (brs, 1H), 2.53, 2.13 (s, 3H), 1.96, 1.91 (s, 3H), 1.88-1.46 (m, 10H).

[0203] In this invention, other intermediate compounds shown in Formula 3 can be obtained by replacing different raw materials, and other intermediate compounds shown in Formula 3 can also be obtained, which will not be listed here.

[0204] Example 2: Preparation of the compound represented by formula I

[0205] This embodiment provides a compound (E)-2-(3′,4′-dichloro-5-fluoro-[1,1′-biphenyl]-2-amino)-5–(4-phenyl-2-oxo-1-oxaspiro[4,5]-dec-3-en-3-ethylene)-thiazolyl-4-one, the preparation method of which includes:

[0206] (1) 5-(4-phenyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-2-thio-4-thiazolidinone (3.850 g, 10 mmol) was dissolved in 100 mL of acetonitrile, and potassium carbonate (2.070 g, 15 mmol) and methyl iodoform (1.704 g, 12 mmol) were added. The mixture was stirred at room temperature for 8 h. After the reaction was completed by TLC monitoring, potassium carbonate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure. The residue was recrystallized from ethyl acetate to give (E)-2-methylthio-5-(4-phenyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-thiazolidinone (compound 4), 3.352 g of yellow solid with a melting point of 141-143 °C and a yield of 84%. 1 H NMR(300MHz, CDCl3)δ:7.41-7.33(m,3H),7.18-7.11(m,2H),2.72(s,3H),2.11-2.00(m,1H),1.91(s,3H),1.90-1.64(m,8H),1.54-1.44(m,1H). 13 C NMR(75MHz, CDCl3)δ:190.52,176.08,169.04,166.82,137.92,132.05,131.89,1 29.40,129.11,128.81,127.34,88.96,33.41,33.13,26.14,24.64,22.22,15.83.

[0207] (2) (E)-2-methylthio-5–(4-phenyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-thiazolyl-4-one (0.399 g, 1 mmol) was dissolved in a mixture of 1.5 mL glacial acetic acid and 13.5 mL toluene. 3′,4′-dichloro-5-fluoro-[1,1′-biphenyl]-2-amine (0.383 g, 1.5 mmol) was added. The mixture was refluxed at 110 °C and stirred for 12 h. After the reaction was completed by TLC monitoring, the solvent was removed by rotary evaporation under reduced pressure. The residue was separated by silica gel column chromatography (eluting agents were ethyl acetate and petroleum ether (boiling range 60-90 °C), volume ratio 1:6) to obtain 0.551 g of red solid with melting point 161-163 °C, yield 91%.

[0208] 1 H NMR (300MHz, CDCl3) δ: 10.16 (brs, 1H), 7.49-7.29 (m, 5H), 7.20-6.88 (m, 6H), 2.00-0.96 (m, 10H), 1.72 (s, 3H). 13 C NMR(75MHz, CDCl3)δ:169.54,166.52,165.17,160.40(d, 1 J CF =243.9Hz), 151.35, 140.86(d, 4 J CF =2.7Hz),138.01,134.40,134.29,132.29,131.93,131.77,130.92,130.25,129.46,129.09,128.90,128.63,127.35,125.97,123.22(d, 3 J CF =8.3Hz), 117.13(d, 2 J CF =22.9Hz), 115.78(d, 2 J CF =22.1Hz),89.01,33.39,33.00,24.63,22.83,22.20.HRMS m / z:C 32 H 25 Cl2FN2O3S6O7.1022[M+H] + (calcd[M+H] + 607.1020).

[0209] Example 3: Preparation of the compound represented by formula I

[0210] This embodiment provides a compound (E)-2-(2′,3′,4′-trifluoro-[1,1′-biphenyl]-2-amino)-5-(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-en-3-ethylene)-thiazolyl-4-one, the preparation method of which includes:

[0211] (1) The intermediate 5-(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-2-thio-4-thiazolidinone (3.230 g, 10 mmol) was dissolved in 100 mL of acetonitrile, and potassium carbonate (2.070 g, 15 mmol) and iodomethane (1.704 g, 12 mmol) were added. The mixture was stirred at room temperature for 8 h. After the reaction was completed by TLC monitoring, the potassium carbonate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure. The residue was recrystallized from ethyl acetate to give 2.966 g of (E)-2-methylthio-5–(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-thiazolidinone yellow solid with a melting point of 142-144 °C and a yield of 88%. 1 H NMR(300MHz, CDCl3)δ:2.72(s,3H),2.56,2.22(s,3H),1.93,1.86(s,3H),1.88-1.67(m,9H),1.30-1.19(m,1H).

[0212] (2) (E)-2-methylthio-5-(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-thiazolyl-4-one (0.337 g, 1 mmol) was dissolved in a mixed solution of 1.5 mL glacial acetic acid and 13.5 mL toluene. 2′,3′,4′-trifluoro-[1,1′-biphenyl]-2-amine (0.335 g, 1.5 mmol) was added, and the mixture was refluxed and stirred at 110 °C for 12 h. After the reaction was completed by TLC monitoring, the solvent was removed by rotary evaporation under reduced pressure. The residue was separated by silica gel column chromatography (eluting agents were ethyl acetate and petroleum ether (boiling range 60-90 °C), volume ratio 1:6) to obtain 0.440 g of orange solid with melting point 138-139 °C and yield 86%. 1 H NMR (300MHz, CDCl3) δ: 9.86 (brs, 1H), 7.43-7.17 (m, 3H), 7.05-6.80 (m, 3H), 2.48, 2.02 (s, 3H), 1.87, 1.86 (s, 3H), 1.85-1.41 (m, 10H).

[0213] Example 4: Preparation of the compound represented by formula I

[0214] This embodiment provides a compound (E)-2-(4′-trifluoromethoxy-[1,1′-biphenyl]-2-amino)-5–(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-en-3-ethylene)-thiazolyl-4-one, the preparation method of which includes:

[0215] (1) (E)-2-methylthio-5-(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-thiazolyl-4-one was prepared by using step (1) of Example 3;

[0216] (2) (E)-2-methylthio-5–(4-methyl-2-oxo-1-oxaspiro[4,5]-dec-3-ene-3-ethylene)-thiazolyl-4-one (0.337 g, 1 mmol) was dissolved in a mixture of 1.5 mL glacial acetic acid and 13.5 mL toluene. 4′-trifluoromethoxy-[1,1′-biphenyl]-2-amine (0.380 g, 1.5 mmol) was added, and the mixture was refluxed at 110 °C with stirring for 14 h. After the reaction was completed by TLC monitoring, the solvent was removed by rotary evaporation under reduced pressure. The residue was separated by silica gel column chromatography (eluting agents were ethyl acetate and petroleum ether (boiling range 60-90 °C), volume ratio 1:6) to obtain 0.493 g of yellow solid with melting point 146-148 °C and yield 91%.

[0217] 1 H NMR (300MHz, CDCl3) δ: 9.81 (brs, 1H), 7.41-7.08 (m, 7H), 7.02-6.87 (m, 3 = 1H), 2.48, 2.02 (s, 3H), 1.85 (s, 3H), 1.84-1.41 (m, 10H). HRMS m / z: C 28 H 25 F3N2O4S 543.1562[M+H] + (calcd[M+H] + 543.1560).

[0218] In this invention, other compounds represented by general formula I can be obtained by replacing them with different raw materials, which will not be listed here.

[0219] Test case

[0220] 1. Bactericidal activity assay

[0221] The compounds of this invention were used to conduct in vitro fungicidal activity or in vivo protective effect tests on various fungal diseases of plants. The results of the fungicidal activity determination are shown in the following examples.

[0222] (1) Determination of in vitro bactericidal activity

[0223] The determination method is as follows: This experiment was conducted in accordance with the agricultural industry standard of the People's Republic of China (NY / T1156.2-2006), using the mycelial growth rate method.

[0224] A certain amount of the original drug was weighed using an analytical balance, and DMSO was used as the dissolving solvent to prepare a solution with a mass concentration of 5000 mg / L. This solution was then diluted with potato dextrose agar (PDA) to prepare 50 mg / L PDA plates for testing. Various pathogenic bacteria were cultured and inoculated into the center of the drug-containing PDA plates under aseptic conditions, with the mycelial side down. The plates were covered and incubated in the dark at 24°C for 2-3 days. The mycelial growth of the pathogenic bacteria was investigated based on the growth of colonies in the blank control plates. After the colonies in the blank control had fully grown, the colony diameter of each treatment was measured using the cross-sectional method. Each sample was measured in triplicate, and the average value was taken. Carbendazim, thifluzamide, and cyazofamid were used as control agents. The inhibition rate of mycelial growth of each agent on various pathogenic bacteria was calculated by the ratio of the difference between the colony diameter of the blank control and the colony diameter of the agent-treated bacteria to the colony diameter of the blank control, as shown in Table 2.

[0225] Table 2. In vitro bactericidal activity (inhibition rate / %) of some intermediates and compounds

[0226]

[0227] As shown in the table above, at a concentration of 50 mg / L, the compounds and intermediates exhibit high inhibition rates against wheat scab, rice bakanae disease pathogens, and rapeseed sclerotinia pathogens. Some compounds can even completely inhibit the growth of pathogenic fungi, demonstrating excellent antibacterial activity.

[0228] 2. Toxicity testing

[0229] Compounds with an initial inhibition rate greater than 70% were subjected to precise toxicity assays. The test compounds were diluted into five concentration gradients on PDA medium and inoculated with the corresponding pathogenic fungi. Each concentration gradient was repeated three times. The EC50 of the compounds was calculated using SPSS software. 50 and EC 90 (mg / L) are shown in Table 3.

[0230] Table 3. In vitro antibacterial activity of some intermediates and compounds against plant pathogens (EC) 50 and EC 90 (mg / L)

[0231]

[0232]

[0233] Among them, compounds 3-1 and 3-14 have EC50 inhibitory effects against the wheat scab pathogen. 50 See the photograph of the measurement plate. Figure 1 Cyazofamid and compounds 3-5 provided by this invention have EC50 effects against wheat scab pathogens. 50 See the photograph of the measurement plate. Figure 2 Cyazofamid and compound 3-1 provided by this invention have EC50 inhibitory effects on rice bakanae disease pathogens. 50 See the photograph of the measurement plate. Figure 3 Compounds 3-5 and 3-22 have EC50 activity against the pathogenic fungus *Bakanae nil* of rice. 50 See the photograph of the measurement plate. Figure 4 .

[0234] In this invention, other compounds have similar effects to the compounds described above, and are not listed here.

[0235] 3. In vitro bactericidal activity test

[0236] The in vitro fungicidal activity of compound 3-1 against cyazofamid resistant strains was tested. Photographs of test plates showing the interaction between high concentrations (50 mg / L) of cyazofamid and resistant strains T2-5, T10, and T32 are shown below. Figure 5 Photographs of test plates for resistant strains T18, T48, and T79 can be found in [link to image]. Figure 6 Further tests were conducted on low concentrations (0.5 mg / L and 1 mg / L) of compound 3-1 against standard strain 2021, resistant strain T10, resistant strain T2-5, resistant strain T32, resistant strain T13, and resistant strain T12. Plate images are shown below. Figure 7 and Figure 8 .

[0237] The results showed that compound 3-1 could completely inhibit the growth of all resistant strains at a concentration of 50 mg / L. At concentrations of 1 mg / L and 0.5 mg / L, the inhibition rate of this compound against resistant strains was the same as that against standard wild-type Fusarium graminearum strains, which fully demonstrates that this type of compound does not have cross-resistance with cyazofamid, laying the foundation for subsequent field applications.

[0238] The resistant strain numbers are derived from the following literature:

[0239] [1] Li, B.; Zheng, ZT.; Liu, XM.; Cai, YQ.; Mao, XW.; Zhou, MG. Genotypes and Characteristics of Phenamacril-Resistant Mutants in Fusarium asiaticum. PlantDisease, 2016, 100, 1754-1761.

[0240] 4. In vivo protective activity assay

[0241] The determination method is as follows: A live pot test method is used. The chemical sample to be tested is dissolved in a small amount of solvent (the type of solvent is such as acetone, methanol, DMF, etc., and the choice is based on its solubility in the sample; the volume ratio of solvent to spray volume is equal to or less than 0.05), and then diluted with water containing 0.1% Tween 80 to prepare the test solution of the required concentration. The test solution is sprayed onto the diseased host plants (standard potted seedlings cultivated in a greenhouse) using a crop sprayer. Disease inoculation is performed 24 hours later. Based on the characteristics of the disease, diseased plants requiring temperature and humidity control are inoculated and placed in an artificial climate chamber for cultivation. After the disease has fully infected the plants, they are transferred to a greenhouse for cultivation. Diseased plants not requiring humidity control are directly inoculated and cultivated in the greenhouse. The disease control effect of the compound is evaluated after the control group has fully developed the disease (usually one week).

[0242] The in vivo protective activity test results for some compounds at a drug concentration of 400 mg / L are as follows:

[0243] Compound I-7-5 showed a 95% control efficacy against cucumber downy mildew, while I-12-15 showed a 93% control efficacy against cucumber downy mildew.

[0244] Compound I-6-9 showed an efficacy of 88% against wheat powdery mildew, I-14-6 showed an efficacy of 85% against wheat powdery mildew, and I-16-7 showed an efficacy of 81% against wheat powdery mildew.

[0245] Compound I-3-5 showed an efficacy of 86% against corn rust, while I-10-17 showed an efficacy of 89% against corn rust.

[0246] Other compounds of general formula I and other intermediate compounds of general formula 3 of the present invention were tested according to the above-described bioactivity assay method, and they also had activities comparable to those of the compounds listed above, which will not be listed one by one here.

[0247] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A butenolactone compound containing a thiazolidinone structure, characterized in that, It has the following structure: ； Compound I-5-11: R1, R2 = -(CH2)5-, R3 = 4-FPh, R4 = ; Compound I-9-5: R1, R2 = -(CH2)5-, R3 = 4-OCH3Ph, R4 = n -C4H 9； Compound I-15-13: R1, R2 = -(CH2)5-, R3 = 3-FPh, R4 = ; Compound I-20-3: R1, R2 = -(CH2)5-, R3 = 2-ClPh, R4 = C2H5.

2. A butenolactone intermediate containing a thiazolidinone structure, characterized in that, It has the following structure: ； 3 Intermediate 3-1: R1, R2 = -(CH2)5-, R3 = CH3, R = S; Intermediates 3-5: R1, R2 = -(CH2)5-, R3 = 4F-Ph, R = S; Intermediate 3-14: R1, R2 = -(CH2)5-, R3 = 3Cl-Ph, R = S; Intermediate 3-15: R1, R2 = -(CH2)5-, R3 = 3F-Ph, R = S; Intermediate 3-17: R1, R2 = -(CH2)5-, R3 = 3NO2-Ph, R = S; Intermediate 3-22: R1, R2 = -CH2CH2CH(OCH3)CH2CH2-, R3 = CH3, R = S; Intermediate 3-24: R1, R2 = -CH2CH2C(NOCH3)CH2CH2-, R3 = CH3, R = S.

3. The method for preparing the butenolactone compound containing a thiazolidinone structure according to claim 1, characterized in that, The compound was synthesized via the following route: In the formula, R1, R2, R3, and R4 are defined as described in claim 1, and R is S.

4. The method for preparing butenolactone compounds containing a thiazolidinone structure according to claim 3, characterized in that, Includes the following steps: (1) In a first solvent, the intermediate compound represented by general formula 3 is methylated under the action of a base to give compound 4; the base is selected from one or more of potassium carbonate, cesium carbonate, sodium hydride, sodium ethoxide and sodium hydroxide, the first solvent is selected from acetonitrile and / or acetone, and the reaction temperature is heated from room temperature to reflux temperature; (2) In a second solvent, compound 4 reacts with NH2-R4 under reflux conditions with acid catalysis to obtain the compound shown in general formula I; the second solvent is selected from toluene and / or xylene, and the acid is selected from one or more of oxalic acid, acetic acid and propionic acid.

5. The method for preparing the butenolactone intermediate containing a thiazolidinone structure according to claim 2, characterized in that, The synthesis route is as follows: ； In the formula, R, R1, R2, and R3 are defined as described in claim 2.

6. The method for preparing the butenolactone intermediate containing a thiazolidinone structure according to claim 5, characterized in that, include: 1) Compound 1 reacts with diketene in the presence of a catalyst to give 3-acetylbutenolactone compound 2, wherein the catalyst is selected from triethylamine and / or diisopropylethylamine; 2) In the third solvent, compound 2 and The intermediate compound of general formula 3 is obtained by reflux reaction under the action of an organic base; the organic base is selected from one or more of ethanolamine, piperidine, pyridine, sodium acetate and ammonium acetate, and the third solvent is selected from toluene and / or xylene.

7. The use of a butenolactone compound containing a thiazolidinone structure as described in claim 1 or an intermediate of a butenolactone compound containing a thiazolidinone structure as described in claim 2 in the preparation of a fungicide, wherein the fungicide is at least one of a fungicide for controlling wheat scab pathogen and a fungicide for controlling rice bakanae disease pathogen.

8. The application according to claim 7, characterized in that, The formulations of the fungicides include at least one of the following: emulsifiable concentrate, wettable powder, suspension concentrate, powder, soluble powder, aqueous solution, water-dispersible granules, fumigant, granules, and seed coating agent.

Images