CN110183386B - 地克珠利衍生物及其应用和含有该衍生物的杀菌剂 - Google Patents
地克珠利衍生物及其应用和含有该衍生物的杀菌剂 Download PDFInfo
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- CN110183386B CN110183386B CN201910420685.8A CN201910420685A CN110183386B CN 110183386 B CN110183386 B CN 110183386B CN 201910420685 A CN201910420685 A CN 201910420685A CN 110183386 B CN110183386 B CN 110183386B
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- diclazuril
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- ZSZFUDFOPOMEET-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenyl]acetonitrile Chemical class C1=CC(Cl)=CC=C1C(C#N)C1=C(Cl)C=C(N2C(NC(=O)C=N2)=O)C=C1Cl ZSZFUDFOPOMEET-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 24
- 239000003899 bactericide agent Substances 0.000 title claims abstract description 22
- 240000008067 Cucumis sativus Species 0.000 claims abstract description 15
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 claims abstract description 15
- 241000196324 Embryophyta Species 0.000 claims abstract description 13
- 102000019259 Succinate Dehydrogenase Human genes 0.000 claims abstract description 11
- 108010012901 Succinate Dehydrogenase Proteins 0.000 claims abstract description 11
- 208000031888 Mycoses Diseases 0.000 claims abstract description 9
- 230000002438 mitochondrial effect Effects 0.000 claims abstract description 8
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 claims abstract description 5
- 241000221785 Erysiphales Species 0.000 claims abstract description 5
- 241000233679 Peronosporaceae Species 0.000 claims abstract description 5
- 240000007594 Oryza sativa Species 0.000 claims abstract description 3
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 3
- 235000009566 rice Nutrition 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 174
- 230000000855 fungicidal effect Effects 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
- 239000000417 fungicide Substances 0.000 claims description 9
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 claims description 3
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
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- 239000000725 suspension Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 22
- 239000000575 pesticide Substances 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 232
- 239000000460 chlorine Substances 0.000 description 103
- 238000002844 melting Methods 0.000 description 54
- 230000008018 melting Effects 0.000 description 54
- 125000001309 chloro group Chemical group Cl* 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 22
- -1 nitro, cyano, monobromomethyl Chemical group 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 14
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
- 229960000248 diclazuril Drugs 0.000 description 13
- 229910052736 halogen Inorganic materials 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 102000000570 Succinate Cytochrome c Oxidoreductase Human genes 0.000 description 7
- 108010041797 Succinate Cytochrome c Oxidoreductase Proteins 0.000 description 7
- 125000001246 bromo group Chemical group Br* 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 125000004438 haloalkoxy group Chemical group 0.000 description 5
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 241000224483 Coccidia Species 0.000 description 4
- 206010017533 Fungal infection Diseases 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 208000024386 fungal infectious disease Diseases 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 150000002989 phenols Chemical class 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 229910014265 BrCl Inorganic materials 0.000 description 3
- 208000003495 Coccidiosis Diseases 0.000 description 3
- 102100030497 Cytochrome c Human genes 0.000 description 3
- 108010075031 Cytochromes c Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010023076 Isosporiasis Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000282898 Sus scrofa Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- AAYPOQCLSJJZGA-UHFFFAOYSA-N [1-butoxy-3-ethoxy-3-methoxy-2-methyl-1-(2-methylpropoxy)-1-propan-2-yloxy-3-propoxypropan-2-yl] hypofluorite Chemical compound CCCCOC(OCC(C)C)(OC(C)C)C(C)(OF)C(OC)(OCC)OCCC AAYPOQCLSJJZGA-UHFFFAOYSA-N 0.000 description 3
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
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- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- KOFLVDBWRHFSAB-UHFFFAOYSA-N 1,2,4,5-tetrahydro-1-(phenylmethyl)-5,9b(1',2')-benzeno-9bh-benz(g)indol-3(3ah)-one Chemical compound C1C(C=2C3=CC=CC=2)C2=CC=CC=C2C23C1C(=O)CN2CC1=CC=CC=C1 KOFLVDBWRHFSAB-UHFFFAOYSA-N 0.000 description 2
- FZPHMACGWIAGFA-UHFFFAOYSA-N 6-decylubiquinol Chemical compound CCCCCCCCCCC1=C(C)C(O)=C(OC)C(OC)=C1O FZPHMACGWIAGFA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 102000015782 Electron Transport Complex III Human genes 0.000 description 2
- 108010024882 Electron Transport Complex III Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- FBWADIKARMIWNM-UHFFFAOYSA-N N-3,5-dichloro-4-hydroxyphenyl-1,4-benzoquinone imine Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1N=C1C=CC(=O)C=C1 FBWADIKARMIWNM-UHFFFAOYSA-N 0.000 description 2
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 239000001384 succinic acid Substances 0.000 description 2
- VMAATSFMXSMKPG-UHFFFAOYSA-N 1,3-dichloro-2-fluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=C(F)C(Cl)=C1 VMAATSFMXSMKPG-UHFFFAOYSA-N 0.000 description 1
- XRIGPWYPAMUKOE-UHFFFAOYSA-N 2,2,2-trichloro-n-[4-oxo-2-(phenoxymethyl)quinazolin-3-yl]acetamide Chemical compound N=1C2=CC=CC=C2C(=O)N(NC(=O)C(Cl)(Cl)Cl)C=1COC1=CC=CC=C1 XRIGPWYPAMUKOE-UHFFFAOYSA-N 0.000 description 1
- DXINALIRZBGSTJ-UHFFFAOYSA-N 3,5-dichloro-n-[4-(4-fluorophenyl)-1,2,5-oxadiazol-3-yl]-4-methoxybenzamide Chemical compound C1=C(Cl)C(OC)=C(Cl)C=C1C(=O)NC1=NON=C1C1=CC=C(F)C=C1 DXINALIRZBGSTJ-UHFFFAOYSA-N 0.000 description 1
- WNMBUQJSKBDZAJ-UHFFFAOYSA-N 3-chloro-4-(3-chloro-4-methoxyanilino)-1-[3-(trifluoromethyl)phenyl]pyrrole-2,5-dione Chemical compound C1=C(Cl)C(OC)=CC=C1NC1=C(Cl)C(=O)N(C=2C=C(C=CC=2)C(F)(F)F)C1=O WNMBUQJSKBDZAJ-UHFFFAOYSA-N 0.000 description 1
- MBDUKNCPOPMRJQ-UHFFFAOYSA-N 4-amino-2-chlorobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C(Cl)=C1 MBDUKNCPOPMRJQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 241000223924 Eimeria Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000283903 Ovis aries Species 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001165 anti-coccidial effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000004382 potting Methods 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 210000001563 schizont Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及农药领域,公开了一种地克珠利衍生物及其应用和含有该衍生物的杀菌剂,该衍生物具有式(1)或式(2)所示的结构。本发明提供的前述地克珠利衍生物能够作为线粒体琥珀酸脱氢酶抑制剂被应用,并且具有抗植物真菌病的作用,更具体地,本发明的前述地克珠利衍生物能够用于防治水稻纹枯病、黄瓜灰霉病、黄瓜霜霉病和黄瓜白粉病等。
Description
本申请为申请日为2016年6月2日、申请号为201610387500.4、名称为“地克珠利衍生物及其应用和含有该衍生物的杀菌剂”的中国发明专利申请的分案申请。
技术领域
本发明涉及农药领域,具体地,涉及一种地克珠利衍生物、地克珠利衍生物作为线粒体琥珀酸脱氢酶抑制剂的应用、地克珠利衍生物在抗植物真菌病中的应用以及一种用于抗植物真菌病的杀菌剂。
背景技术
2012年全球杀菌剂销售额占全球农药销售额的26.3%,达到了140.1亿美元,其中以琥珀酸脱氢酶为靶标的杀菌剂在2012年的增长率达到了20%,是增速最快的一类杀菌剂,占总的杀菌剂市场份额的5.4%。这类杀菌剂具有高效、广谱的杀菌活性和较低的抗性风险等优点,是目前最有前景的杀菌剂之一。
但是,现有的商品化琥珀酸脱氢酶抑制剂类杀菌剂都属于酰胺类,这一类杀菌剂在结构和作用机制上都比较类似,因此这类化合物面临着较高的抗性风险。从而,寻找具有全新骨架的琥珀酸脱氢酶抑制剂具有非常重要的意义。
地克珠利(Diclazuril)是由比利时杨森公司在1986年报道的抗球虫药物,在结构上属于三嗪苯乙腈类化合物,用于禽类的抗球虫病。地克珠利主要用于鸡球虫病的防治,属于高效的抗球虫药物,同时还具有广谱、低毒、耐药性低和用量小等优点。临床试验证明,地克珠利对鸭球虫及兔球虫等均有很好的效果,同时对其它药物产生耐药性的球虫也有着非常好的效果,目前世界上已经有超过40个国家使用地克珠利来防治相应的病害。
地克珠利目前的作用机制尚不明确,目前对其作用机理的研究只是基于细胞和亚细胞水平。Taylor等报道了地克珠利对感染羔羊的艾美耳球虫的第一代和第二代分裂体和配子体阶段有效,它还能影响球虫核酸的合成。
发明内容
根据对地克珠利的研究,本发明提供了一系列具有线粒体琥珀酸脱氢酶抑制作用的地克珠利衍生物,本发明提供的地克珠利衍生物具有较明显的线粒体琥珀酸脱氢酶抑制活性以及抗植物真菌病的作用。
为了实现上述目的,第一方面,本发明提供一种地克珠利衍生物,该衍生物具有式(1)或式(2)所示的结构,
其中,在式(1)和式(2)中,
R11和R12分别选自H、C1-4的烷基、C1-4的烷氧基、卤素、硝基、氰基、一溴代甲基、一氯代甲基、一氟代甲基、三氟甲基和三氟甲氧基;
R21、R22、R23和R24分别选自H、C1-4的烷基、C1-4的烷氧基和卤素;
R3选自H、C1-6的烷基、C1-6的卤代烷基、C1-6的烷氧基、C1-6的卤代烷氧基、C1-6的烷硫基、C1-6的卤代烷硫基、硝基、氰基和卤素中的至少一种;
当R11、R21和R24为H,R22和R23为Cl,W为O时;R3不为4-Cl或4-OCH3。
第二方面,本发明提供前述地克珠利衍生物作为线粒体琥珀酸脱氢酶抑制剂的应用。
第三方面,本发明提供前述地克珠利衍生物在抗植物真菌病中的应用。
第四方面,本发明提供一种用于抗植物真菌病的杀菌剂,该杀菌剂的活性成分为本发明前述的地克珠利衍生物中的至少一种,以所述杀菌剂的总重量计,所述活性成分的含量为0.1-100重量%。
本发明前述提供的地克珠利衍生物能够作为线粒体琥珀酸脱氢酶抑制剂用于抗植物真菌病中。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不用于限制本发明。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
第一方面,本发明提供了一种地克珠利衍生物,该衍生物具有式(1)或式(2)所示的结构,
其中,在式(1)和式(2)中,
R11和R12分别选自H、C1-4的烷基、C1-4的烷氧基、卤素、硝基、氰基、一溴代甲基、一氯代甲基、一氟代甲基、三氟甲基和三氟甲氧基;
R21、R22、R23和R24分别选自H、C1-4的烷基、C1-4的烷氧基和卤素;
R3选自H、C1-6的烷基、C1-6的卤代烷基、C1-6的烷氧基、C1-6的卤代烷氧基、C1-6的烷硫基、C1-6的卤代烷硫基、硝基、氰基和卤素中的至少一种;
当R11、R21和R24为H,R22和R23为Cl,W为O时;R3不为4-Cl或4-OCH3。
所述“C1-4的烷基”表示碳原子总数为1-4的烷基。
所述“C1-4的烷氧基”表示碳原子总数为1-4的烷氧基。
所述“C1-6的烷基”表示碳原子总数为1-6的烷基。
所述“C1-6的卤代烷基”表示碳原子总数为1-6的烷基,且烷基中至少一个氢原子被卤原子取代。
所述“C1-6的烷氧基”表示碳原子总数为1-6的烷氧基。
所述“C1-6的卤代烷氧基”表示碳原子总数为1-6的烷氧基,且烷氧基中至少一个氢原子被卤原子取代。
所述“C1-6的烷硫基”表示碳原子总数为1-6的烷硫基。
所述“C1-6的卤代烷硫基”表示碳原子总数为1-6的烷硫基,且烷硫基中至少一个氢原子被卤原子取代。
所述“卤素”或者“卤原子”均包括氟、氯、溴和碘中的任意一种或多种。
优选地,在式(1)和式(2)中,R11和R12分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、氟、氯、溴、硝基、氰基、一溴代甲基、一氯代甲基、一氟代甲基、三氟甲基和三氟甲氧基;更优选
R11和R12分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、氟、氯、溴、三氟甲基和三氟甲氧基;特别优选
R11和R12分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和三氟甲基。
优选地,在式(1)和式(2)中,R21、R22、R23和R24分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、氟、氯和溴;更优选
R21、R22、R23和R24分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和氯;特别优选
R21、R22、R23和R24分别选自H、甲基、乙基、正丙基、异丙基和氯。
优选地,R3选自H、C1-4的烷基、C1-4的卤代烷基、C1-4的烷氧基、C1-4的卤代烷氧基、C1-4的烷硫基、C1-4的卤代烷硫基、硝基、氰基和卤素中的至少一种;更优选
R3选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、叔丁硫基、硝基、氰基和卤素中的至少一种;特别优选
R3选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、叔丁硫基、硝基、氰基和卤素中的至少一种。
针对本发明的式(1)或式(2)所示的结构的地克珠利衍生物,本发明提供以下几种具体的实施方式:
具体实施方式1:在式(1)和式(2)中,
R11和R12分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、氟、氯、溴、硝基、氰基、一溴代甲基、一氯代甲基、一氟代甲基、三氟甲基和三氟甲氧基;
R21、R22、R23和R24分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、氟、氯和溴;
R3选自H、C1-4的烷基、C1-4的卤代烷基、C1-4的烷氧基、C1-4的卤代烷氧基、C1-4的烷硫基、C1-4的卤代烷硫基、硝基、氰基和卤素中的至少一种;并且当R11、R21和R24为H,R22和R23为Cl,W为O时;R3不为4-Cl或4-OCH3。
具体实施方式2:在式(1)和式(2)中,
R11和R12分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、氟、氯、溴、三氟甲基和三氟甲氧基;
R21、R22、R23和R24分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和氯;
R3选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、叔丁硫基、硝基、氰基和卤素中的至少一种;并且
当R11、R21和R24为H,R22和R23为Cl,W为O时;R3不为4-Cl或4-OCH3。
具体实施方式3:在式(1)和式(2)中,
R11和R12分别选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和三氟甲基;
R21、R22、R23和R24分别选自H、甲基、乙基、正丙基、异丙基和氯;
R3选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、叔丁硫基、硝基、氰基和卤素中的至少一种;并且
当R11、R21和R24为H,R22和R23为Cl,W为O时;R3不为4-Cl或4-OCH3。
具体实施方式4:所述地克珠利衍生物为以下化合物中的至少一种;且化合物A1-A28以及化合物B1-B16具有式(1)所示的结构;化合物C1-C12具有式(2)所示的结构;
化合物A1:R11、R21和R24为H;R22和R23为Cl;R3为2-Cl;W为O;
化合物A2:R11、R21和R24为H;R22和R23为Cl;R3为2-Br;W为O;
化合物A3:R11、R21和R24为H;R22和R23为Cl;R3为2-SCH3;W为O;
化合物A4:R11、R21和R24为H;R22和R23为Cl;R3为3-C2H5;W为O;
化合物A5:R11、R21和R24为H;R22和R23为Cl;R3为4-F;W为O;
化合物A6:R11、R21和R24为H;R22和R23为Cl;R3为4-tC4H9;W为O;
化合物A7:R11、R21和R24为H;R22和R23为Cl;R3为2,4-(tC4H9)2;W为O;
化合物A8:R11、R21和R24为H;R22和R23为Cl;R3为2-Cl-4-tC4H9;W为O;
化合物A9:R11、R21和R24为H;R22和R23为Cl;R3为2-Br-4-tC4H9;W为O;
化合物A10:R11、R21和R24为H;R22和R23为Cl;R3为2-CH3-4-tC4H9;W为O;
化合物A11:R11、R21和R24为H;R22和R23为Cl;R3为3,5-(CH3)2;W为O;
化合物A12:R11、R21和R24为H;R22和R23为Cl;R3为2,6-Cl2;W为O;
化合物A13:R11、R21和R24为H;R22和R23为Cl;R3为2,5-Cl2;W为O;
化合物A14:R11、R21和R24为H;R22和R23为Cl;R3为2,4,6-Cl3;W为O;
化合物A15:R11、R21和R24为H;R22和R23为Cl;R3为3,4-(CH3)2;W为O;
化合物A16:R11、R21和R24为H;R22和R23为Cl;R3为2,3-F2;W为O;
化合物A17:R11、R21和R24为H;R22和R23为Cl;R3为3-Br-4-F;W为O;
化合物A18:R11、R21和R24为H;R22和R23为Cl;R3为2-CH3-5-F;W为O;
化合物A19:R11、R21和R24为H;R22和R23为Cl;R3为2-Cl-4-CH3;W为O;
化合物A20:R11、R21和R24为H;R22和R23为Cl;R3为3,4-Cl2;W为O;
化合物A21:R11为CH3;R21和R24为H;R22和R23为Cl;R3为2-Cl;W为O;
化合物A22:R11为tC4H9;R21和R24为H;R22和R23为Cl;R3为2-Br;W为O;
化合物A23:R11为CF3;R21和R24为H;R22为CH3;R23为Cl;R3为2-SCH3;W为O;
化合物A24:R11为H;R21和R24为CH3;R22和R23为Cl;R3为2-Cl;W为O;
化合物A25:R11和R23为H;R21为CH3;R22为Cl;R24为iCH(CH3)2;R3为2-Br;W为O;
化合物A26:R11、R21、R22和R24为H;R23为Cl;R3为2-NO2;W为O;
化合物C1:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2-Cl-4-CH3;
化合物C2:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,5-Cl2;
化合物C3:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2-Cl;
化合物C4:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,3-F2;
化合物C5:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为3-CH3;
化合物C6:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,4-(tC4H9)2;
化合物C7:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,6-Cl2;
化合物C8:R11、R21和R24为H;R12为ClCH2;R22和R23为Cl;R3为4-tC4H9;
化合物C9:R11为C2H5;R12、R22和R23为Cl;R21和R24为H;R3为4-CN;
化合物C10:R11和R24为H;R12为CN;R21为CH3;R22和R23为Cl;R3为2,4,6-Cl3;
化合物C11:R11、R21、R23和R24为H;R12为NO2;R22为Cl;R3为2-Cl-4-tC4H9;
化合物C12:R11、R22和R24为H;R12和R21为CH3;R23为Cl;R3为2-CH3-4-tC4H9。
需要特别说明的是,在上述化合物中,关于R3取代基,例如在化合物A8中,“R3为2,4-(tC4H9)2”表示在2位和4位上均有一个tC4H9取代基;例如在化合物A9中,“R3为2-Cl-4-tC4H9”表示在2位和4位上分别有一个氯原子取代基和一个tC4H9取代基,其余与此相似。
第二方面,本发明提供了前述地克珠利衍生物作为线粒体琥珀酸脱氢酶抑制剂的应用。
第三方面,本发明提供了前述地克珠利衍生物在抗植物真菌病中的应用。
在本发明的第二方面和第三方面中,所涉及的地克珠利衍生物与本发明的第一方面中所述的地克珠利衍生物的结构和可选范围完全相同,为了避免重复,本发明在此不再赘述,本领域技术人员不应理解为对本发明的限制。
优选地,所述植物真菌病为水稻纹枯病、黄瓜灰霉病、黄瓜霜霉病和黄瓜白粉病中的至少一种。
第四方面,本发明提供了一种用于抗植物真菌病的杀菌剂,该杀菌剂的活性成分为为本发明前述的地克珠利衍生物中的至少一种,以所述杀菌剂的总重量计,所述活性成分的含量为0.1-100重量%。
在本发明的第四方面中,所涉及的地克珠利衍生物与本发明的第一方面中所述的地克珠利衍生物的结构和可选范围完全相同,为了避免重复,本发明在此不再赘述,本领域技术人员不应理解为对本发明的限制。
优选地,在所述杀菌剂中,活性成分的含量为1-98重量%;更优选为5-90重量%。
优选地,所述杀菌剂的剂型选自水合剂、粉剂、乳剂、悬浮剂和粒剂。
本发明的前述式(1)和式(2)所示的结构的地克珠利衍生物可以通过实验室合成制得。本发明的实例中示例性地提供了各类化合物的制备方法,本领域技术人员不应理解为对本发明的限定。
以下将通过制备例和测试例对本发明进行详细描述。以下制备例和测试例中,在没有特别说明的情况下,所使用的各种原料均来自商购。
制备例1
步骤1:式H-2化合物的制备
在50mL圆底烧瓶中加入7.14mmol的3,5-二氯-4-氟硝基苯(H-1化合物),9.29mmol取代的苯酚(根据R3的不同,取代的苯酚中的取代基不同)和9.29mmol的碳酸钾,再加入20mL的DMF后升温至100℃。TLC监测原料反应完全后停止反应,加入50mL的乙醚后用30mL的2M的NaOH水溶液洗两次后再用50mL的饱和食盐水洗1次,减压除去溶剂后得式H-2化合物。
步骤2:式H-3化合物的制备
在100mL的圆底烧瓶中加入3.1mmol式H-2化合物和3.1mmol的氯化铵,再加入50mL的乙醇和6mL的水,加热至回流后加入9.3mmol还原铁粉,TLC监测原料反应完毕后停止反应,硅藻土过滤后将滤液减压浓缩,减压除去大部分溶剂后加入50mL乙酸乙酯萃取,有机相用饱和食盐水洗后加入无水硫酸钠干燥,除去溶剂后得式H-3化合物。
步骤3:式H-5化合物的制备
在100mL圆底烧瓶中加入3.1mmol式H-3化合物,10mL醋酸和1mL浓盐酸,控制温度为4℃,缓慢滴加亚硝酸钠的水溶液(包括3.4mmol的亚硝酸钠和1mL的水),滴加完毕后继续搅拌半小时,加入0.635g的NaOAc和0.915g的CH2(CONHCOOEt)2,随后将反应体系移至室温。反应半小时后再加入0.212g的NaOAc,升温至回流,TLC监测原料反应完毕,得到含有式H-4化合物的产物;然后向其中加入5mL浓盐酸,继续反应,TLC监测水解完毕后停止反应,减压除去大部分溶剂后加入50mL水,有大量固体析出,抽滤得式H-5化合物,不提纯直接进行下一步反应。
步骤4:式H-6化合物的制备
在50mL圆底烧瓶中加入式H-5化合物和5mL巯基乙酸,加热至150℃,TLC监测原料反应完全后停止反应,冷却后加入NaHCO3水溶液中和过量的巯基乙酸,析出大量固体,抽滤得目标化合物粗产品,干燥后柱层析即得式H-6化合物。
具体地,本发明根据制备例1的方法通过采用不同的原料制备化合物A1-A26。
各化合物的表征数据如下:
化合物A1:熔点为189-192℃.1H NMR(600MHz,CDCl3)δ9.37(s,1H),7.72(s,2H),7.64(s,1H),7.48(d,J=7.9Hz,1H),7.13(t,J=7.8Hz,1H),7.04(t,J=7.7Hz,1H),6.51(d,J=8.2Hz,1H).13C NMR(151MHz,DMSO)δ157.32,151.75,148.02,145.37,138.76,137.30,131.27,129.06,128.46,126.96,124.65,121.62,114.73.HRMS(ESI)理论值C15H8Cl3N3O3[M+H]+:383.9704.测得值:383.9702。
化合物A2:熔点为170-173℃.1H NMR(600MHz,DMSO)δ12.54(s,1H),7.88(s,2H),7.75(d,J=9.4Hz,1H),7.74(s,1H),7.30(t,J=7.8Hz,1H),7.07(t,J=7.5Hz,1H),6.56(d,J=8.2Hz,1H).13CNMR(151MHz,CDCl3)δ155.55,152.77,146.77,136.76,136.45,133.92,129.80,128.33,125.11,124.06,114.20,111.48.HRMS(ESI)理论值C15H8BrCl2N3O3[M+H]+427.9199,测得值:427.9191。
化合物A3:熔点为174-175℃.1H NMR(400MHz,CDCl3)δ9.69(s,1H),7.71(s,2H),7.64(s,1H),7.31(d,J=5.6Hz,1H),7.07(d,J=6.0Hz,2H),6.39(d,J=7.2Hz,1H),2.54(s,3H).13C NMR(101MHz,CDCl3)δ155.47,153.31,146.83,146.70,136.56,136.39,129.92,127.59,126.98,125.98,125.09,123.37,112.31,15.18.HRMS(ESI)理论值C16H11Cl2N3O3S[M+H]+:395.9971.测得值:395.9971。
化合物A4:熔点为148-150℃.1H NMR(400MHz,CDCl3)δ10.38(s,1H),7.69(s,2H),7.64(s,1H),7.18(t,J=7.5Hz,1H),6.91(d,J=6.7Hz,1H),6.75(s,1H),6.60(d,J=6.8Hz,1H),2.62(d,J=7.2Hz,2H),1.21(t,J=6.4Hz,3H).13C NMR(101MHz,CDCl3)δ156.37,155.96,147.02,146.92,146.33,136.39,136.30,130.04,129.34,125.11,122.38,114.65,111.77,28.64,15.25.HRMS(ESI)理论值C17H13Cl2N3O3[M+H]+:378.0406.测得值:378.0400。
化合物A5:熔点为107-108℃.1H NMR(600MHz,DMSO)δ12.53(s,1H),7.85(s,2H),7.73(s,1H),7.20(t,J=8.7Hz,2H),6.91(dd,J=9.1,4.1Hz,2H).13C NMR(151MHz,CDCl3)δ159.18,157.58,155.67,152.43,147.05,146.88,136.57,136.49,130.07,125.26,116.31,116.25,116.20,116.15.HRMS(ESI)理论值C15H8Cl2FN3O3[M+H]+:367.9999.测得值:367.9992。
化合物A6:熔点为185-186℃.1H NMR(400MHz,CDCl3)δ10.12(s,1H),7.68(s,2H),7.64(s,1H),7.30(d,J=7.9Hz,2H),6.78(d,J=7.8Hz,2H),1.30(s,9H).13C NMR(101MHz,CDCl3)δ155.81,154.16,147.20,146.97,145.54,136.41,136.29,130.15,126.47,125.14,114.38,34.17,31.42.HRMS(ESI)理论值C19H17Cl2N3O3[M+H]+:406.0719.测得值:406.0716。
化合物A7:熔点为185-186℃.1H NMR(600MHz,CDCl3)δ9.28(s,1H),7.75(s,2H),7.65(d,J=3.6Hz,2H),7.64(s,1H),6.95(d,J=8.4Hz,2H).13C NMR(151MHz,DMSO)δ159.56,157.30,148.01,144.57,138.98,137.34,135.32,128.50,126.93,118.87,116.29,106.25.HRMS(ESI)理论值C16H8Cl2N4O3[M+H]+:375.0046.测得值375.0042。
化合物A8:熔点为180-182℃.1H NMR(600MHz,CDCl3)δ10.45(s,1H),7.70(s,2H),7.65(s,1H),7.42(s,1H),7.00(d,J=8.4Hz,1H),6.20(d,J=8.4Hz,1H),1.54(s,9H),1.30(s,9H).13C NMR(151MHz,DMSO)δ157.42,152.86,148.13,145.56,144.65,138.29,137.27,135.86,128.92,127.05,124.60,124.29,111.80,40.40,40.27,40.13,35.23,34.55,31.83,30.27.HRMS(ESI)理论值C23H25Cl2N3O3[M+H]+:462.1346.测得值462.1356。
化合物A9:熔点为185-187℃.1H NMR(600MHz,DMSO)δ12.54(s,1H),7.87(s,2H),7.74(s,1H),7.56(d,J=2.1Hz,1H),7.26(dd,J=8.7,2.1Hz,1H),6.49(d,J=8.7Hz,1H),1.26(s,9H).13C NMR(101MHz,CDCl3)δ155.81,154.16,147.20,146.97,145.54,136.41,136.29,130.15,126.47,125.14,114.38,34.17,31.42.HRMS(ESI)理论值C19H16Cl3N3O3[M+H]+:439.0330.测得值439.0341。
化合物A10:熔点为177-178℃.1H NMR(600MHz,DMSO)δ12.52(s,1H),7.86(s,2H),7.74(s,1H),7.69(d,J=2.4Hz,1H),7.31(dd,J=9.0,1.8Hz,1H),6.45(d,J=9.0Hz,1H),1.26(s,9H).13C NMR(151MHz,CDCl3)δ155.46,150.51,147.36,147.06,146.72,136.67,136.43,130.98,129.90,125.23,125.08,113.65,110.92,34.33,31.29.HRMS(ESI)理论值C19H16BrCl2N3O3[M+Na]+:505.9644.测得值505.9648。
化合物A11:熔点为172-173℃.1H NMR(600MHz,DMSO)δ12.50(s,1H),7.83(s,1H),7.72(s,1H),7.33(s,1H),7.09(d,J=10.2Hz,1H),6.23(d,J=9.0Hz,1H),2.39(s,3H),1.25(s,9H).13C NMR(151MHz,DMSO)δ157.46,152.52,148.13,146.44,145.30,138.21,137.21,128.86,128.75,126.84,125.40,124.06,111.84,34.28,31.69,16.58.HRMS(ESI)理论值C20H19Cl2N3O3[M+H]+:420.0876.测得值420.0879。
化合物A12:熔点为231-233℃.1H NMR(600MHz,DMSO)δ12.53(s,1H),7.83(s,2H),7.73(s,1H),6.74(s,1H),6.45(s,2H),2.23(s,6H).13C NMR(151MHz,DMSO)δ156.88,156.14,147.61,145.27,139.46,137.84,136.80,128.42,126.39,124.54,112.07,20.90.HRMS(ESI)理论值C17H13Cl2N3O3[M+Na]+:400.0226.测得值400.0223。
化合物A13:熔点为171-173℃.1H NMR(600MHz,DMSO)δ12.50(s,1H),7.75(s,2H),7.71(s,1H),7.58(d,J=8.2Hz,2H),7.28(t,J=8.1Hz,1H).13C NMR(151MHz,DMSO)δ157.32,148.02,147.60,146.95,137.18,137.04,130.24,126.90,125.97,125.25.HRMS(ESI)理论值C15H7Cl4N3O3[M+H]+:417.9314.测得值417.9311。
化合物A14:熔点为248-250℃.1H NMR(600MHz,DMSO)δ12.46(s,1H),7.72(s,2H),7.69(s,1H),7.56(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,1H).13C NMR(151MHz,DMSO)δ157.26,152.26,147.99,144.73,139.03,137.36,133.03,132.49,128.20,126.90,124.77,120.77,114.74.HRMS(ESI)理论值C15H7Cl4N3O3[M+H]+:417.9314.测得值417.9319。
化合物A15:熔点为147-149℃.1H NMR(600MHz,DMSO)δ12.50(s,1H),7.83(s,2H),7.76(s,2H),7.71(s,1H).13C NMR(151MHz,CDCl3)δ155.66,147.65,147.08,146.76,136.30,135.28,129.73,128.96,127.27,126.42,125.07.HRMS(ESI)理论值C15H6Cl5N3O3[M+H]+:451.8925.测得值451.8922。
化合物A16:熔点为168-170℃.13C NMR(151MHz,CDCl3)δ155.84,154.50,147.12,146.96,138.24,136.40,136.28,130.94,130.44,130.15,125.14,116.18,111.75,19.98,18.90.HRMS(ESI)理论值C17H13Cl2N3O3[M+Na]+:400.0226.测得值400.0227。
化合物A17:熔点为194-196℃.1H NMR(600MHz,DMSO)δ12.54(s,1H),7.88(s,2H),7.74(s,1H),7.22(d,J=7.2Hz,1H),7.14(d,J=8.4Hz,1H),6.56(t,J=7.8Hz,1H).13C NMR(151MHz,DMSO)δ157.29,152.02,150.32,148.00,145.38,145.00,141.17,139.52,138.95,137.33,128.36,126.90,125.04,112.23,111.44.HRMS(ESI)理论值C15H7Cl2F2N3O3[M+H]+:385.9905.测得值385.9909。
化合物A18:熔点为161-163℃.1H NMR(600MHz,DMSO)δ12.53(s,1H),7.86(s,2H),7.74(s,1H),7.38(t,J=9.0Hz,1H),7.33(dd,J=5.4,3.1Hz,1H),6.92(dd,J=8.0,4.8Hz,1H).13C NMR(151MHz,CDCl3)δ155.19,151.89,146.74,146.53,136.78,136.42,130.92,129.85,127.62,125.12,123.72,122.75,114.40.HRMS(ESI)理论值C15H7BrCl2FN3O3[M+H]+:444.9032.测得值:444.9035。
化合物A19:熔点为200-202℃.1H NMR(600MHz,CDCl3)δ9.09(s,1H),7.72(s,2H),7.64(s,1H),7.21–7.15(m,1H),6.70(td,J=8.4,2.4Hz,1H),6.11(dd,J=9.6,2.4Hz,1H),2.41(s,3H).13CNMR(151MHz,CDCl3)δ162.25,160.63,155.59,154.93,154.87,146.89,146.77,136.63,136.42,131.66,131.60,129.80,125.14,122.27,109.17,109.04,100.82,100.65,15.53.HRMS(ESI)理论值C16H10Cl2FN3O3[M+H]+:382.0156.测得值382.0148。
化合物A20:熔点为177-179℃.1H NMR(600MHz,CDCl3)δ9.00(s,1H),7.71(s,2H),7.63(s,1H),7.29(s,1H),6.91(d,J=8.4Hz,1H),6.39(d,J=8.4Hz,1H),2.30(s,3H).13CNMR(151MHz,CDCl3)δ155.15,149.71,146.93,146.48,136.60,136.32,133.53,131.22,129.80,127.98,125.04,122.18,114.09,20.35.HRMS(ESI)理论值C16H10Cl3N3O3[M+H]+:397.9861.测得值397.9863。
化合物A21:熔点为203-205℃.1H NMR(600MHz,DMSO)δ12.52(s,1H),7.84(s,2H),7.73(s,1H),6.15(s,2H),3.69(s,6H),3.61(s,3H).13C NMR(151MHz,DMSO)δ157.33,154.10,152.99,148.04,145.45,138.36,137.25,133.59,128.86,126.79,92.97,60.56,56.45.HRMS(ESI)理论值C18H15Cl2N3O6[M+H]+:440.0411.测得值440.0408。
化合物A22:熔点为205-207℃.1H NMR(600MHz,DMSO)δ12.50(s,1H),7.84(s,2H),7.71(s,1H),7.19(d,J=7.2Hz,1H),7.10(d,J=8.4Hz,1H),6.51(t,J=7.8Hz,1H).13C NMR(151MHz,DMSO)δ156.87,155.22,147.58,144.42,138.46,136.90,132.32,131.69,128.10,126.52,125.31,117.19,115.05.HRMS(ESI)理论值C15H7Cl4N3O3[M+H]+:417.9314.测得值417.9310。
化合物A23:熔点为194-195℃.1H NMR(600MHz,DMSO)δ12.51(s,1H),7.76(s,1H),7.57(s,1H),7.35(d,J=7.8Hz,1H),7.17(dd,J=7.2,4.8Hz,1H),7.07(dd,J=8.4,4.2Hz,1H),7.04(d,J=7.8Hz,1H),2.53(s,3H),2.15(s,3H).13C NMR(151MHz,DMSO)δ160.11,152.83,148.45,148.32,146.02,132.14,129.18,126.56,125.91,124.87,122.34,122.06,119.76,119.13,118.79,113.96,15.15,14.33.HRMS(ESI)理论值C18H13F3ClN3O3S[M+H]+:444.0318.测得值444.0317。
化合物A24:熔点为211-213℃.1H NMR(600MHz,DMSO)δ12.51(s,1H),7.50(s,1H),7.45(d,J=7.2Hz,1H),7.29(dd,J=8.4,4.8Hz,1H),7.11(dd,J=7.8,4.2Hz,1H),7.08(d,J=7.2Hz,1H),2.21(s,6H).13C NMR(151MHz,DMSO)δ157.16,151.95,148.34,142.12,138.98,135.52,133.14,130.95,126.51,125.83,124.01,123.22,120.53,14.21.HRMS(ESI)理论值C17H12Cl3N3O3[M+H]+:411.9944.测得值411.9946。
化合物A25:熔点为198-199℃.1H NMR(600MHz,DMSO)δ12.48(s,1H),7.56(d,J=7.2Hz,1H),7.51(s,1H),7.35(dd,J=7.2,4.8Hz,1H),7.06(dd,J=8.4,4.2Hz,1H),7.03(d,J=7.8Hz,1H),6.96(s,1H)2.88-2.87(m,1H),2.25(s,3H),1.20(d,J=7.2Hz,6H).13CNMR(151MHz,DMSO)δ157.12,154.09,147.58,148.32,147.13,139.30,138.92,134.81,132.56,127.42,124.02,122.83,114.75,112.05,111.84,28.36,23.36,14.28.HRMS(ESI)理论值C19H17BrClN3O3[M+H]+:450.0142.测得值450.0143。
化合物A26:熔点为224-245℃.1H NMR(600MHz,DMSO)δ12.46(s,1H),8.22(d,J=7.8Hz,1H),7.95(s,1H),7.81(d,J=7.2Hz,1H),7.80(dd,J=9.0,4.8Hz,1H),7.78(dd,J=9.0,4.8Hz,1H),7.65(s,1H),7.50(s,1H),7.20(s,1H).13C NMR(151MHz,DMSO)δ157.12,149.74,148.31,147.56,138.98,138.69,134.55,132.28,126.64,126.07,124.15,122.73,121.76,119.13,117.45.HRMS(ESI)理论值C15H9ClN4O5[M+H]+:361.0261.测得值361.0262。
测试例1
琥珀酸细胞色素c氧化还原酶(Succinate-cytochrome c reductase,SCR)是复合物II和复合物III的混合物。SCR中SQR活性的测试是使用琥珀酸和二氯酚吲哚酚钠(dichlorophenolindophenol,DCIP)作为底物来测定的,而复合物III活性的测定是使用decylubiquinol(DBH2)和细胞色素c(cytochrome c)作为底物,SCR酶活性的测试是用琥珀酸和细胞色素c作为底物。按照化合物酶抑制活性测试方法,测试了化合物A1-A26的活性,活性测试结果如表1中所示。
并且,表1中还提供了现有商品S-地克珠利的活性测试结果。
表1
编号 | IC<sub>50</sub>(μM) | 编号 | IC<sub>50</sub>(μM) |
A1 | 31.46±1.21 | A15 | 16.23±1.09 |
A2 | 4.20±0.15 | A16 | 22.96±1.14 |
A3 | 34.23±1.08 | A17 | 0.61±0.12 |
A4 | 26.74±1.28 | A18 | 19.06±1.13 |
A5 | 5.07±1.25 | A19 | 6.30±0.11 |
A6 | 2.16±0.15 | A20 | 23.77±1.03 |
A7 | 0.0116±0.00114 | A21 | 1.36±0.11 |
A8 | 0.40±0.01 | A22 | 1.51±0.12 |
A9 | 1.30±0.14 | A23 | 1.25±0.18 |
A10 | 1.39±0.11 | A24 | 2.18±0.19 |
A11 | 1.25±0.16 | A25 | 5.23±1.05 |
A12 | 15.14±1.10 | A26 | 4.26±0.14 |
A13 | 3.89±1.21 | S-地克珠利 | 36.22±1.50 |
A14 | 0.18±0.01 |
从酶抑制活性测试结果中可以看出,本发明的化合物对猪心来源SCR都表现出了良好的抑制活性,并且多数化合物的效果优于商品化的对照药剂地克珠利。
测试例2
采用温室盆栽实验对所合成的化合物A1-A26中的部分目标化合物进行活体水平的杀菌活性的测定。测试结果如表2中所示。
表2
从表2的结果可以看出,本发明的化合物在200mg/L浓度下对水稻纹枯病、黄瓜白粉病和黄瓜灰霉病并未全部表现出显著的活性,但是本发明的上述化合物在200mg/L浓度下对黄瓜霜霉病均表现出较好的防效。
制备例2
步骤1:式G-2化合物的制备
在100mL圆底烧瓶中加入10mmol的式G-1化合物(根据R3取代基的不同,选择不同种类的原料),50mL干燥的二氯甲烷和20mmol的吡啶,冰浴条件下缓慢滴加氯甲酸甲酯的二氯甲烷溶液(10mmol/20mL),反应1h后TLC监测原料反应完毕,用2M的盐酸中和至反应体系至中性,饱和食盐水洗涤后无水硫酸钠干燥,减压除去溶剂得式G-2化合物,不经过提纯直接进行下一步反应。
步骤2:式G-3化合物的制备
在50mL圆底烧瓶中加入5mmol的式G-2化合物,30mL干燥的DMF,冰浴下加入7.5mmol的60重量%的NaH,反应半小时后将5mmol的式G-4化合物溶解在10mL干燥的DMF,缓慢滴加至反应体系,滴加完毕后常温反应半小时后升温至120℃,反应6小时后TLC监测原料反应完全,停止反应后将体系倒入150mL冰水中,析出大量固体,将其柱层析后即得式G-3化合物。
具体地,本发明通过采用相应的原料根据制备例2的方法制备化合物C1-C12。
各化合物的表征数据如下:
化合物C1:熔点为169-171℃;1H NMR(600MHz,DMSO)δ12.73(s,1H),7.78(s,2H),7.44(s,1H),7.09(d,J=7.8Hz,1H),6.45(s,1H),6.40(d,J=8.4Hz,1H),2.27(s,3H).13CNMR(151MHz,DMSO)δ161.78,151.74,150.55,145.30,139.87,139.64,139.38,134.17,132.50,132.26,130.76,128.04,124.42,122.04,120.48,120.22,118.41,116.59,114.00,100.62,21.21.HRMS(ESI)理论值C18H10Cl3F3N2O3[M+H]+:464.9782.测得值464.9788。
化合物C2:熔点为178-181℃;1H NMR(600MHz,DMSO)δ12.76(s,1H),7.84(s,2H),7.71(d,J=8.4Hz,1H),7.28(d,J=8.4Hz,1H),6.52(d,J=1.8Hz,1H),6.46(s,1H).13C NMR(151MHz,DMSO)δ161.78,151.77,150.59,145.32,139.90,139.66,139.41,134.21,132.53,132.30,130.79,128.07,124.45,122.08,120.51,120.26,118.43,116.61,114.03,100.68.HRMS(ESI)理论值C17H7Cl4F3N2O3[M+H]+:484.9236.测得值484.9226。
化合物C3:熔点为192-193℃;1H NMR(600MHz,DMSO)δ12.73(s,1H),7.81(s,2H),7.62(d,J=7.8Hz,1H),7.31(t,J=7.8Hz,1H),7.15(t,J=7.8Hz,1H),6.53(d,J=8.4Hz,1H),6.46(s,1H).13CNMR(151MHz,DMSO)δ161.77,151.27,150.59,145.86,139.82,139.58,133.81,130.94,130.60,128.70,128.27,124.27,121.26,120.24,118.42,114.14,100.68.HRMS(ESI)理论值C17H8Cl3F3N2O3[M+H]+:450.9625.测得值450.9632。
化合物C4:熔点为184-187℃;1H NMR(600MHz,DMSO)δ12.74(s,1H),7.82(s,2H),7.26–7.21(m,1H),7.20–7.13(m,1H),6.48(t,J=7.8Hz,1H),6.46(s,1H).13C NMR(151MHz,DMSO)δ161.79,151.62,150.62,150.05,149.99,145.56,144.92,140.71,139.91,139.67,139.17,134.08,130.66,128.19,124.76,120.26,118.44,111.92,111.81,110.93,109.58,100.68.HRMS(ESI)理论值C17H7Cl2F5N2O3[M+H]+:452.9827.测得值452.9820。
化合物C5:熔点为159-161℃;1H NMR(600MHz,DMSO)δ12.71(s,1H),7.76(s,2H),7.25(t,J=7.8Hz,1H),6.93(d,J=7.8Hz,1H),6.72(s,1H),6.57(d,J=7.8Hz,1H),6.45(s,1H),2.30(s,3H).13CNMR(151MHz,DMSO)δ161.81,156.07,150.62,146.11,139.93,133.32,130.42,129.82,128.67,123.76,115.19,111.34,100.69,21.01.HRMS(ESI)理论值C18H11Cl2F3N2O3[M+H]+:431.0172.测得值431.0179。
化合物C6:熔点为188-191℃;1H NMR(600MHz,DMSO)δ12.72(s,1H),7.77(s,2H),7.40(d,J=2.4Hz,1H),7.16(dd,J=8.4,2.4Hz,1H),6.45(s,1H),6.13(d,J=8.5Hz,1H),1.54(s,9H),1.30(s,9H).13C NMR(151MHz,DMSO)δ160.61,152.32,151.11,145.99,144.29,135.40,133.54,130.14,128.80,124.15,123.95,111.15,103.27,31.36,29.80.HRMS(ESI)理论值C26H27Cl2F3N2O3[M+H]+:529.1267.测得值529.1263。
化合物C7:熔点为163-164℃;13C NMR(151MHz,DMSO)δ161.76,150.58,147.31,147.22,139.76,139.51,131.77,130.47,129.77,126.57,125.69,124.92,120.24,118.42,100.63.HRMS(ESI)理论值C17H7Cl4F3N2O3[M+H]+:484.9236.测得值484.9233。
化合物C8:熔点为187-188℃;1H NMR(600MHz,DMSO)δ12.61(s,1H),7.71(s,2H),7.55(d,J=2.4Hz,2H),7.25(d,J=2.4Hz,2H),5.70(s,1H),4.05(s,2H),1.33(s,9H).13CNMR(151MHz,DMSO)δ165.61,153.92,153.71,149.83,144.42,142.34,128.62,127.44,124.79,119.85,115.36,103.45,40.93,34.23,31.37.HRMS(ESI)理论值C21H19Cl3N2O3[M+H]+:453.0461.测得值453.0465。
化合物C9:熔点为192-194℃;1H NMR(600MHz,DMSO)δ12.47(s,1H),7.85(d,J=2.4Hz,2H),7.74(s,2H),7.16(d,J=2.4Hz,2H),2.44(q,J=3.0Hz,2H),1.33(t,J=2.4Hz,3H).13C NMR(151MHz,DMSO)δ161.32,159.92,153.03,142.36,131.95,128.64,127.46,119.87,118.62,118.21,108.23,105.74,24.23,21.37.HRMS(ESI)理论值C19H12Cl3N3O3[M+H]+:435.9944.测得值435.9945。
化合物C10:熔点为178-180℃;1H NMR(600MHz,DMSO)δ12.50(s,1H),7.66(s,1H),7.33(s,2H),6.22(s,1H),2.24(s,3H).13C NMR(151MHz,DMSO)δ165.32,153.02,144.88,142.25,133.29,131.45,130.22,130.02,128.23,127.06,125.13,124.47,119.71,115.23,114.56,28.47.HRMS(ESI)理论值C18H8Cl5N3O3[M+H]+:489.9008.测得值489.9006。
化合物C11:熔点为203-204℃;1H NMR(600MHz,DMSO)δ12.62(s,1H),7.83(s,1H),7.45(s,1H),7.38(d,J=2.4Hz,1H),7.22(d,J=3.0Hz,1H),7.03(d,J=2.4Hz,1H),6.86(d,J=2.4Hz,1H),6.77(s,1H),1.32(s,9H).13C NMR(151MHz,DMSO)δ165.04,161.59,153.06,148.87,147.56,144.52,127.89,127.21,126.04,125.63,124.56,123.18,122.84,121.74,119.15,99.45,33.79,31.32.HRMS(ESI)理论值C20H17Cl2N3O5[M+H]+:450.0545.测得值450.0544。
化合物C12:熔点为182-184℃;1H NMR(600MHz,DMSO)δ12.48(s,1H),7.78(s,1H),7.41(s,1H),7.35(d,J=2.4Hz,1H),7.25(d,J=2.4Hz,1H),6.93(s,1H),5.43(s,1H),2.31(s,3H),2.12(s,3H),2.08(s,3H),1.28(s,9H).13C NMR(151MHz,DMSO)δ166.04,151.49,151.36,149.84,147.46,146.92,133.47,130.12,127.31,126.64,123.63,121.76,121.68,117.94,117.05,102.14,34.52,19.21,18.65,17.85,17.29.HRMS(ESI)理论值C20H17Cl2N3O5[M+H]+:450.0545.测得值450.0544。
测试例3
采用与测试例1相同的方法测试化合物C1-C12的酶抑制活性,其活性结果如表3中所示。
表3
从表3的结果可以看出,本发明的化合物C1-C12对猪心来源的SCR都表现出了良好的抑制活性,并且化合物的效果明显优于商品化的对照药剂地克珠利。
制备例3
步骤1:式K-2化合物的制备
在100mL圆底烧瓶中加入3.1mmol的2-氯-4-氨基苯甲酸(式K-1化合物),10mL的醋酸和1mL的浓盐酸,控制温度在4℃,缓慢滴加亚硝酸钠的水溶液(含有3.4mmol的亚硝酸钠和1mL的水),滴加完毕后继续搅拌半小时,加入0.635g的NaOAc和0.915g的CH2(CONHCOOEt)2,随后将反应体系移至室温反应半小时后再加入0.212g的NaOAc升温至回流,TLC监测原料反应完毕后加入5mL浓盐酸,继续反应,TLC监测水解完毕后停止反应,减压除去大部分溶剂后加入50mL的水,有大量固体析出,抽滤得式K-2化合物,不提纯直接进行下一步反应。
步骤2:式K-4化合物的制备
在50mL圆底烧瓶中加入式K-2化合物和5mL巯基乙酸,加热至150℃,TLC监测原料反应完毕后停止反应,得到含有式K-3化合物的产物,待冷却后加入NaHCO3水溶液中和过量的巯基乙酸,析出大量固体,抽滤得目标化合物粗产品,干燥后即得式K-4化合物。
步骤3:式K-5化合物的制备
在50mL圆底烧瓶中加入1.87mmol的式K-4化合物和10mL氯化亚砜,加热至回流,反应3h后减压蒸馏除去过量氯化亚砜,再加入30mL干燥的二氯甲烷将其溶解,缓慢滴加至2.80mmol取代的苯酚(根据R3基团的不同,取代的苯酚原料不同)及5.7mmol的三乙胺的二氯甲烷溶液中,滴加完毕后反应2小时,TLC监测原料反应完毕后停止反应,饱和食盐水洗后无水硫酸钠干燥,减压除去溶剂后柱层析得式K-5化合物。
具体地,本发明通过采用相应的原料根据制备例3的方法制备化合物B1-B16。
各化合物的表征数据如下:
化合物B1:熔点为159-161℃;1H NMR(600MHz,DMSO)δ12.51(s,1H),8.25(d,J=8.5Hz,1H),7.88(d,J=1.4Hz,1H),7.80–7.69(m,2H),7.57(d,J=8.8Hz,2H),7.40(d,J=8.8Hz,2H).13CNMR(151MHz,DMSO)δ162.53,156.82,149.03,147.56,143.86,137.25,132.86,132.49,130.50,129.61,126.81,126.69,123.84,123.43.HRMS(ESI)理论值C16H9Cl2N3O4[M+H]+:378.0043.测得值378.0048。
化合物B2:熔点为179-180℃;1H NMR(600MHz,DMSO)δ12.50(s,1H),8.31(d,J=8.4Hz,1H),7.91(s,1H),7.79(d,J=7.8Hz,1H),7.77(s,1H),7.67(d,J=7.8Hz,1H),7.54(d,J=8.4Hz,1H),7.49(t,J=7.2Hz,1H),7.40(t,J=7.8Hz,1H).13C NMR(151MHz,DMSO)δ161.63,156.81,147.56,146.27,144.14,137.31,133.15,132.57,130.28,128.71,128.13,126.99,125.86,124.35,123.57.HRMS(ESI)理论值C16H9Cl2N3O4[M+H]+:378.0043.测得值378.0040。
化合物B3:熔点为176-178℃;1H NMR(600MHz,DMSO)δ12.51(s,1H),8.19(d,J=8.4Hz,1H),7.87(d,J=1.Hz,1H),7.76(s,1H),7.74(dd,J=8.4,1.8Hz,1H),6.97(s,1H),6.94(s,2H),2.32(s,6H).13C NMR(151MHz,DMSO)δ162.96,156.82,150.19,147.56,143.65,139.10,137.20,132.48,132.10,127.71,127.42,126.78,123.52,119.20,20.77.HRMS(ESI)理论值C18H14ClN3O4[M+H]+:372.0746.测得值372.0759。
化合物B4:熔点为180-182℃;1H NMR(600MHz,dmso)δ12.51(s,1H),8.27(d,J=8.4Hz,1H),7.89(d,J=1.8Hz,1H),7.79–7.74(m,2H),7.27(d,J=7.8Hz,1H),7.13(d,J=7.8Hz,2H),2.91(m,1H),2.17(s,3H),1.21(d,J=6.6Hz,6H).13C NMR(151MHz,DMSO)δ162.87,156.57,150.23,147.59,143.73,139.31,137.45,132.44,132.30,127.67,127.75,126.91,123.58,117.35,35.31,30.12,20.19.HRMS(ESI)理论值C20H18ClN3O4[M+H]+:400.1059.测得值400.1054。
化合物B5:熔点为193-196℃;1H NMR(600MHz,dmso)δ12.52(s,1H),8.29(d,J=8.4Hz,1H),7.90(d,J=1.8Hz,1H),7.79(dd,J=8.4,1.8Hz,1H),7.77(s,1H),7.44(d,J=7.8Hz,1H),7.37(t,J=7.2Hz,1H),7.31(m,2H),2.46(s,3H).13C NMR(151MHz,DMSO)δ161.94,156.82,147.57,146.97,143.96,137.27,133.04,132.33,131.43,127.26,127.00,126.75,126.41,125.90,123.58,122.59,14.12.HRMS(ESI)理论值C17H12ClN3O4S[M+H]+:390.0310.测得值390.0298。
化合物B6:熔点为182-184℃;1H NMR(600MHz,dmso)δ12.51(s,1H),8.21(d,J=8.4Hz,1H),7.87(s,1H),7.75(d,J=8.4Hz,2H),7.29(d,J=7.2Hz,2H),7.21(d,J=7.8Hz,2H),2.34(s,3H).13CNMR(151MHz,DMSO)δ163.45,161.57,159.12,156.45,150.22,149.42,147.81,144.11,137.85,132.99,127.23,126.98,126.33,123.88,113.75,110.67,17.49.HRMS(ESI)理论值C17H12ClN3O4[M+H]+:358.0589.测得值358.0593。
化合物B7:熔点为212-214℃;1H NMR(600MHz,dmso)δ12.51(s,1H),8.29(d,J=8.4Hz,1H),7.89(d,J=2.4Hz,1H),7.77(t,J=7.2Hz,2H),7.45–7.39(m,1H),7.31(dd,J=9.0,2.4Hz,1H),7.14(td,J=9.8,7.2Hz,1H),2.19(s,3H).13C NMR(151MHz,DMSO)δ162.11,161.27,159.65,156.83,149.27,149.19,147.57,143.92,137.26,132.82,132.42,132.01,126.92,126.61,126.15,123.58,113.37,113.23,110.07,109.91,15.28.HRMS(ESI)理论值C17H11ClFN3O4[M+H]+:376.0495.测得值376.0490。
化合物B8:熔点为223-224℃;1H NMR(600MHz,dmso)δ12.51(s,1H),8.33(d,J=9.0Hz,1H),7.93(d,J=1.8Hz,1H),7.84(d,J=2.4Hz,1H),7.80(dd,J=8.4,1.8Hz,1H),7.76(s,1H),7.75(d,J=9.0Hz,1H),7.53(dd,J=8.4,2.4Hz,1H),2.18(s,6H).13C NMR(151MHz,DMSO)δ163.06,156.83,148.18,147.56,143.63,137.84,137.20,134.28,132.45,132.12,130.29,127.46,126.81,123.56,122.42,118.75,18.84.HRMS(ESI)理论值C18H14ClN3O4[M+H]+:372.0746.测得值372.0746。
化合物B9:熔点为192-194℃;1H NMR(600MHz,dmso)δ12.52(s,1H),8.32(d,J=9.0Hz,1H),7.92(d,J=1.8Hz,1H),7.82(d,J=2.4Hz,1H),7.80(dd,J=8.4,1.8Hz,1H),7.78(s,1H),7.72(d,J=9.0Hz,1H),7.51(dd,J=8.4,2.4Hz,1H).13C NMR(151MHz,DMSO)δ161.21,156.79,147.55,146.84,144.29,137.34,133.37,132.77,132.34,131.39,128.12,126.99,125.40,125.06,124.67,123.52.HRMS(ESI)理论值C16H8Cl3N3O4[M+H]+:411.9653.测得值411.9652。
化合物B10:熔点为205-207℃;1H NMR(600MHz,dmso)δ12.52(s,1H),8.32(d,J=8.4Hz,1H),7.91(d,J=2.4Hz,1H),7.79(dd,J=8.4,24Hz,1H),7.77(s,1H),7.72(dd,J=8.4,3.0Hz,1H),7.63(dd,J=9.0,5.4Hz,1H),7.40(td,J=8.4,3.0Hz,1H).13C NMR(151MHz,DMSO)δ163.11,157.71,148.59,146.84,143.45,138.74,135.58,134.34,132.53,131.42,129.41,128.21,126.21,125.76,125.67,124.10.HRMS(ESI)理论值C16H8Cl2FN3O4[M+H]+:395.9949.测得值395.9943。
化合物B11:熔点为209-210℃;1H NMR(600MHz,dmso)δ12.51(s,1H),8.42(d,J=8.4Hz,1H),7.87(s,1H),7.53(d,J=8.4,1H),7.48(d,J=8.4Hz,2H),7.46(d,J=8.4,2H),2.07(s,3H).13C NMR(151MHz,DMSO)δ165.21,160.14,148.39,147.53,146.03,144.38,135.21,131.98,131.15,130.36,128.34,127.45,121.92,119.61,18.74.HRMS(ESI)理论值C17H11Cl2N3O4[M+H]+:392.0127.测得值392.0125。
化合物B12:熔点为195-197℃;1H NMR(600MHz,dmso)δ12.54(s,1H),8.42(d,J=8.4Hz,1H),7.87(s,1H),7.53(d,J=8.4,1H),7.24(s,1H)),7.23(s,2H),2.27(s,6H),1.69-1.68(m,1H),1.21(d,J=8.4Hz,6H).13C NMR(151MHz,DMSO)δ165.21,160.42,158.35,148.39,146.53,144.39,140.68,135.21,131.98,127.74,127.43,121.96,119.61,119.36,29.25,21.63,18.24.HRMS(ESI)理论值C21H20ClN3O4[M+H]+:314.1142.测得值314.1145。
化合物B13:熔点为211-212℃;1H NMR(600MHz,dmso)δ12.52(s,1H),8.45(d,J=8.4Hz,1H),7.86(s,1H),7.56(d,J=8.4,1H),7.43(d,J=8.4,1H),7.23(dd,J=8.4,2.4Hz,1H),7.22(dd,J=8.4,2.4Hz,1H),7.13(d,J=8.4,1H),2.46(s,3H).13C NMR(151MHz,DMSO)δ165.31,160.12,148.35,146.09,144.53,135.91,135.28,131.95,127.43,127.21,126.47,125.7,125.5,121.95,121.86,119.71,119.66,16.24.HRMS(ESI)理论值C21H20ClN3O4[M+H]+:314.1142.测得值314.1145。
化合物B14:熔点为198-200℃;1H NMR(600MHz,dmso)δ12.46(s,1H),7.66(s,1H),7.56(d,J=8.4,1H),7.50(s,1H),7.40(dd,J=8.4,3.0Hz,1H),7.31(d,J=8.4,1H),7.29(dd,J=8.4,3.0Hz,1H),2.21(s,3H),2.12(s,3H).13C NMR(151MHz,DMSO)δ165.29,157.14,148.39,147.53,146.39,138.93,135.21,132.28,131.65,131.08,129.14,127.33,127.26,127.21,126.95,124.17,21.63,18.24.HRMS(ESI)理论值C18H13Cl2N3O4[M+H]+:406.0238.测得值406.0240。
化合物B15:熔点为178-179℃;1H NMR(600MHz,dmso)δ12.43(s,1H),7.76(s,1H),7.66(d,J=8.4,1H),7.51(s,1H),7.46(dd,J=8.4,3.0Hz,1H),7.26(d,J=8.4,1H),7.24(dd,J=8.4,3.0Hz,1H),2.87-2.86(m,1H),1.2(d,J=8.4,6H).13C NMR(151MHz,DMSO)δ165.27,157.14,148.89,148.33,143.39,139.53,138.91,135.28,133.25,131.28,128.14,127.73,127.06,126.21,123.81,116.43,28.09,23.63,18.74.HRMS(ESI)理论C20H17BrClN3O4[M+H]+:478.0091.测得值478.0079。
化合物B16:熔点为194-196℃;1H NMR(600MHz,dmso)δ12.47(s,1H),8.33(d,J=8.4,1H),8.02(s,2H),7.96(dd,J=8.4,3.0Hz,1H),7.91(dd,J=8.4,3.0Hz,1H),7.63(d,J=8.4,1H),7.51(s,1H).13C NMR(151MHz,DMSO)δ165.23,157.54,148.39,145.33,140.39,138.97,136.91,136.68,135.25,128.74,127.73,126.21,124.81,120.43.HRMS(ESI)理论C16H8Cl2N4O6[M+H]+:422.9821.测得值422.9826。
测试例4
采用与测试例1相同的方法测试化合物B1-B16的酶抑制活性,其活性结果如表4中所示。
表4
编号 | IC<sub>50</sub>(μM) |
B1 | >100 |
B2 | >100 |
B3 | >100 |
B4 | 4.13±1.44 |
B5 | 10.55±1.13 |
B6 | >100 |
B7 | >100 |
B8 | 18.01±1.27 |
B9 | >100 |
B10 | >100 |
B11 | 4.36±1.41 |
B12 | 5.26±1.12 |
B13 | 1.25±1.36 |
B14 | 5.89±1.10 |
B15 | 1.29±1.41 |
B16 | 1.87±1.25 |
从酶抑制活性测试结果中可以看出,本发明的大部分化合物对猪心来源SCR都表现出了良好的抑制活性,并且多数化合物的效果优于商品化的对照药剂地克珠利。
测试例5
采用与测试例2相同的方法测试化合物B1-B16中的部分化合物的杀菌活性,其活性结果如表5中所示。
表5
从表5的结果可以看出,本发明的化合物在200mg/L浓度下对水稻纹枯病、黄瓜白粉病和黄瓜灰霉病并未全部表现出显著的活性,但是本发明的上述化合物在200mg/L浓度下对黄瓜霜霉病均表现出较好的防效。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (8)
1.一种地克珠利衍生物,该衍生物具有式(2)所示的结构,
所述地克珠利衍生物为以下化合物中的至少一种:
化合物C1:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2-Cl-4-CH3;
化合物C2:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,5-Cl2;
化合物C3:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2-Cl;
化合物C4:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,3-F2;
化合物C5:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为3-CH3;
化合物C6:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,4-(tC4H9)2;
化合物C7:R11、R21和R24为H;R12为CF3;R22和R23为Cl;R3为2,6-Cl2;
化合物C8:R11、R21和R24为H;R12为ClCH2;R22和R23为Cl;R3为4-tC4H9;
化合物C9:R11为C2H5;R12、R22和R23为Cl;R21和R24为H;R3为4-CN;
化合物C10:R11和R24为H;R12为CN;R21为CH3;R22和R23为Cl;R3为2,4,6-Cl3;
化合物C11:R11、R21、R23和R24为H;R12为NO2;R22为Cl;R3为2-Cl-4-tC4H9;
化合物C12:R11、R22和R24为H;R12和R21为CH3;R23为Cl;R3为2-CH3-4-tC4H9。
2.权利要求1所述的地克珠利衍生物作为线粒体琥珀酸脱氢酶抑制剂的应用。
3.权利要求1所述的地克珠利衍生物在抗植物真菌病中的应用。
4.根据权利要求3所述的应用,其中,所述植物真菌病为水稻纹枯病、黄瓜灰霉病、黄瓜霜霉病和黄瓜白粉病中的至少一种。
5.一种用于抗植物真菌病的杀菌剂,其特征在于,该杀菌剂的活性成分为权利要求1所述的地克珠利衍生物中的至少一种,以所述杀菌剂的总重量计,所述活性成分的含量为0.1-100重量%。
6.根据权利要求5所述的杀菌剂,其中,以所述杀菌剂的总重量计,所述活性成分的含量为1-98重量%。
7.根据权利要求5中所述的杀菌剂,其中,以所述杀菌剂的总重量计,所述活性成分的含量为5-90重量%。
8.根据权利要求5-7中任意一项所述的杀菌剂,其中,所述杀菌剂的剂型选自水合剂、粉剂、乳剂、悬浮剂和粒剂。
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