CN115246825A - Isoxazoline derivative containing amide structure, preparation thereof and application of isoxazoline derivative as insecticide and bactericide - Google Patents
Isoxazoline derivative containing amide structure, preparation thereof and application of isoxazoline derivative as insecticide and bactericide Download PDFInfo
- Publication number
- CN115246825A CN115246825A CN202110452545.6A CN202110452545A CN115246825A CN 115246825 A CN115246825 A CN 115246825A CN 202110452545 A CN202110452545 A CN 202110452545A CN 115246825 A CN115246825 A CN 115246825A
- Authority
- CN
- China
- Prior art keywords
- cdcl
- nmr
- room temperature
- under reduced
- reduced pressure
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002547 isoxazolines Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 125000003368 amide group Chemical group 0.000 title abstract 3
- 239000002917 insecticide Substances 0.000 title description 8
- 230000000844 anti-bacterial effect Effects 0.000 title description 5
- 239000003899 bactericide agent Substances 0.000 title description 3
- 241000500437 Plutella xylostella Species 0.000 claims abstract description 12
- 241000346285 Ostrinia furnacalis Species 0.000 claims abstract description 11
- 241000607479 Yersinia pestis Species 0.000 claims abstract description 9
- 241000256251 Spodoptera frugiperda Species 0.000 claims abstract description 5
- 241000255967 Helicoverpa zea Species 0.000 claims abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 66
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 30
- 239000007864 aqueous solution Substances 0.000 claims description 23
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 22
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 150000001408 amides Chemical group 0.000 claims description 15
- UYBQBUZXULIDMQ-UHFFFAOYSA-N 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC(F)(F)C(=C)C1=CC(Cl)=CC(Cl)=C1 UYBQBUZXULIDMQ-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 241001477931 Mythimna unipuncta Species 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- DKYRKAIKWFHQHM-UHFFFAOYSA-N (3,5-dichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=CC(Cl)=C1 DKYRKAIKWFHQHM-UHFFFAOYSA-N 0.000 claims description 7
- 241001124076 Aphididae Species 0.000 claims description 7
- MOFRJTLODZILCR-UHFFFAOYSA-N 2-fluoro-5-formylbenzonitrile Chemical compound FC1=CC=C(C=O)C=C1C#N MOFRJTLODZILCR-UHFFFAOYSA-N 0.000 claims description 6
- -1 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2- (1H-1,2,4-triazol-1-yl) benzoic acid Chemical compound 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- 240000007594 Oryza sativa Species 0.000 claims description 6
- 235000007164 Oryza sativa Nutrition 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 241000344246 Tetranychus cinnabarinus Species 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 235000009566 rice Nutrition 0.000 claims description 6
- 241000209140 Triticum Species 0.000 claims description 5
- 235000021307 Triticum Nutrition 0.000 claims description 5
- 244000000003 plant pathogen Species 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 240000008067 Cucumis sativus Species 0.000 claims description 4
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 claims description 4
- 240000008042 Zea mays Species 0.000 claims description 4
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 4
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 235000005822 corn Nutrition 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- FFTOUVYEKNGDCM-OWOJBTEDSA-N (e)-1,3,3-trifluoroprop-1-ene Chemical compound F\C=C\C(F)F FFTOUVYEKNGDCM-OWOJBTEDSA-N 0.000 claims description 3
- KWAOOHWHBJHUTC-UHFFFAOYSA-N 5-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-fluorobenzonitrile Chemical compound C1=C(C#N)C(F)=CC=C1C1=NOC(C(F)(F)F)(C=2C=C(Cl)C=C(Cl)C=2)C1 KWAOOHWHBJHUTC-UHFFFAOYSA-N 0.000 claims description 3
- 235000017060 Arachis glabrata Nutrition 0.000 claims description 3
- 244000105624 Arachis hypogaea Species 0.000 claims description 3
- 235000010777 Arachis hypogaea Nutrition 0.000 claims description 3
- 235000018262 Arachis monticola Nutrition 0.000 claims description 3
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims description 3
- 241000233616 Phytophthora capsici Species 0.000 claims description 3
- 240000003768 Solanum lycopersicum Species 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 235000020232 peanut Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 2
- 244000241235 Citrullus lanatus Species 0.000 claims description 2
- 235000012828 Citrullus lanatus var citroides Nutrition 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 241001128004 Demodex Species 0.000 claims description 2
- 241000790252 Otodectes cynotis Species 0.000 claims description 2
- 241001558929 Sclerotium <basidiomycota> Species 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 claims description 2
- 241000223218 Fusarium Species 0.000 claims 2
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 claims 1
- 241000255925 Diptera Species 0.000 claims 1
- 241000620639 Psoroptes cervinus Species 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 35
- 241000196324 Embryophyta Species 0.000 abstract description 14
- 230000002147 killing effect Effects 0.000 abstract description 7
- 241000256113 Culicidae Species 0.000 abstract description 4
- 241000409991 Mythimna separata Species 0.000 abstract description 4
- 244000052616 bacterial pathogen Species 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 22
- 239000003814 drug Substances 0.000 description 21
- 238000001035 drying Methods 0.000 description 21
- 238000004949 mass spectrometry Methods 0.000 description 21
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- 238000005406 washing Methods 0.000 description 20
- 238000012360 testing method Methods 0.000 description 19
- 239000007788 liquid Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 241001147381 Helicoverpa armigera Species 0.000 description 11
- 238000000034 method Methods 0.000 description 8
- 238000002791 soaking Methods 0.000 description 8
- 239000000575 pesticide Substances 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- XURKAMDMPSCECA-UHFFFAOYSA-N 2-fluoro-5-(hydroxyiminomethyl)benzonitrile Chemical compound ON=CC1=CC=C(F)C(C#N)=C1 XURKAMDMPSCECA-UHFFFAOYSA-N 0.000 description 5
- 241000238631 Hexapoda Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- QKBKGNDTLQFSEU-UHFFFAOYSA-N 2-bromo-3,3,3-trifluoroprop-1-ene Chemical compound FC(F)(F)C(Br)=C QKBKGNDTLQFSEU-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 241000256054 Culex <genus> Species 0.000 description 3
- 241000256059 Culex pipiens Species 0.000 description 3
- 241000144210 Culex pipiens pallens Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 240000006677 Vicia faba Species 0.000 description 3
- 235000010749 Vicia faba Nutrition 0.000 description 3
- 235000002098 Vicia faba var. major Nutrition 0.000 description 3
- 238000007598 dipping method Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- MLBZKOGAMRTSKP-UHFFFAOYSA-N fluralaner Chemical compound C1=C(C(=O)NCC(=O)NCC(F)(F)F)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 MLBZKOGAMRTSKP-UHFFFAOYSA-N 0.000 description 3
- 229960004498 fluralaner Drugs 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 230000000749 insecticidal effect Effects 0.000 description 3
- 231100000225 lethality Toxicity 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241001600407 Aphis <genus> Species 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000005747 Chlorothalonil Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- CRQQGFGUEAVUIL-UHFFFAOYSA-N chlorothalonil Chemical compound ClC1=C(Cl)C(C#N)=C(Cl)C(C#N)=C1Cl CRQQGFGUEAVUIL-UHFFFAOYSA-N 0.000 description 2
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000003971 isoxazolinyl group Chemical group 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- DBNFKWRZLGVLSH-UHFFFAOYSA-N 2-amino-n-(2,2,2-trifluoroethyl)acetamide;hydrochloride Chemical compound Cl.NCC(=O)NCC(F)(F)F DBNFKWRZLGVLSH-UHFFFAOYSA-N 0.000 description 1
- UUYDPHCMCYSNAY-UHFFFAOYSA-N 2-amino-n-methylacetamide Chemical compound CNC(=O)CN UUYDPHCMCYSNAY-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- WOYZXEVUWXQVNV-UHFFFAOYSA-N 4-phenoxyaniline Chemical compound C1=CC(N)=CC=C1OC1=CC=CC=C1 WOYZXEVUWXQVNV-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- KIRTWJNAASMOKG-UHFFFAOYSA-N 5-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-(1,2,4-triazol-1-yl)benzonitrile Chemical compound N=1OC(C(F)(F)F)(C=2C=C(Cl)C=C(Cl)C=2)CC=1C(C=C1C#N)=CC=C1N1C=NC=N1 KIRTWJNAASMOKG-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 1
- 240000007124 Brassica oleracea Species 0.000 description 1
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 description 1
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 1
- 235000001169 Brassica oleracea var oleracea Nutrition 0.000 description 1
- TWFZGCMQGLPBSX-UHFFFAOYSA-N Carbendazim Natural products C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 239000005901 Flubendiamide Substances 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000258242 Siphonaptera Species 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- DMVOXQPQNTYEKQ-UHFFFAOYSA-N biphenyl-4-amine Chemical group C1=CC(N)=CC=C1C1=CC=CC=C1 DMVOXQPQNTYEKQ-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 239000006013 carbendazim Substances 0.000 description 1
- JNPZQRQPIHJYNM-UHFFFAOYSA-N carbendazim Chemical compound C1=C[CH]C2=NC(NC(=O)OC)=NC2=C1 JNPZQRQPIHJYNM-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 235000007240 daidzein Nutrition 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 235000005489 dwarf bean Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ZGNITFSDLCMLGI-UHFFFAOYSA-N flubendiamide Chemical compound CC1=CC(C(F)(C(F)(F)F)C(F)(F)F)=CC=C1NC(=O)C1=CC=CC(I)=C1C(=O)NC(C)(C)CS(C)(=O)=O ZGNITFSDLCMLGI-UHFFFAOYSA-N 0.000 description 1
- KLEJZTLSRWJZLH-UHFFFAOYSA-N formamide phthalic acid Chemical compound C(C=1C(C(=O)O)=CC=CC1)(=O)O.C(=O)N KLEJZTLSRWJZLH-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- ZTUJDPKOHPKRMO-UHFFFAOYSA-N hydron;2,2,2-trifluoroethanamine;chloride Chemical compound Cl.NCC(F)(F)F ZTUJDPKOHPKRMO-UHFFFAOYSA-N 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- XMIAFAKRAAMSGX-UHFFFAOYSA-N quinolin-5-amine Chemical compound C1=CC=C2C(N)=CC=CC2=N1 XMIAFAKRAAMSGX-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention relates to an isoxazoline derivative containing an amide structure, a preparation method thereof and application thereof in the aspect of preventing and controlling pests and plant germs. The isoxazoline derivative containing the amide structure shows good activity of killing diamondback moth, oriental armyworm, spodoptera frugiperda, cotton bollworm, corn borer and mosquito larvae and activity of inhibiting plant germs.
Description
Technical Field
The invention relates to a novel isoxazoline derivative containing an amide structure, a preparation method thereof and application thereof in pest and plant germ prevention and control, belonging to the technical field of agricultural protection and pest prevention and control.
Background
The Food and Agricultural Organization (FAO) statistical data of the United nations show that the world food loss caused by the diseases and the insect pests accounts for about 1/3 of the total yield each year. The application of the pesticide greatly reduces the damage of farmland diseases, pests and weeds and lightens the global famine. Pests are the most important cause of crop reduction in recent decades, however, with the widespread use of insecticides, the emergence of insects resistant to various insecticides has become a serious problem worldwide. To facilitate management of pesticide resistance in agriculture and to meet the food demand of the rapidly growing population, there is an urgent need to develop green pesticides (org. Processes. Dev.2020,24, 1024-1031) that act on new targets or new sites in targets.
Since 2005 japanese daidzein chemical co-Ltd reported isoxazoline compounds as insecticides (w.o. 2005085216), they have become a focus and frontier in the field of insecticide research due to their unique insecticidal mechanism, high selectivity, no significant cross-resistance with existing insecticides, etc. as a new class of insecticides discovered in the 21 st century. Numerous research institutes have conducted extensive studies on this isoxazoline structure, and many highly active compounds have been found in extensive screening. To date, four commercial veterinary and two agricultural pesticides (formula one) (ChemMedChem 2016,11,270-276.) have been available for isoxazoline structures. Therefore, starting from the isoxazoline skeleton, the design and development of a novel high-efficiency low-toxicity isoxazoline pesticide have important significance.
The amide structure is an important active fragment, and is widely present in a plurality of pesticide molecules and natural products, such as flubendiamide, m-acid amide, phthalic acid formamide, o-formamido benzamide and the like, which all contain an active group with an amide structure.
Disclosure of Invention
The invention aims to provide novel isoxazoline derivatives containing an amide structure, preparation thereof and application thereof in the aspect of preventing and controlling pests and plant germs. The derivatives which are based on the conversion of cyano groups in high-activity molecules DP-9 reported by DuPont company into carboxylic acid and amide are found to have better activity for killing diamondback moth, oriental armyworm, spodoptera frugiperda, cotton bollworm, corn borer, mosquito larvae, flea, mite and tick and have activity for inhibiting plant germs for the first time by combining an intermediate derivatization method. The invention lays a foundation for creating novel, broad-spectrum and high-efficiency pesticide and has good creativity.
The isoxazoline derivative I containing the amide structure is a compound (structural formula II) shown as I-1 to I-20
The synthesis method of the chemical structural formulas I-1 to I-20 is as follows:
synthesis of isoxazoline derivatives I-1 to I-20 containing amide structures: according to the method shown in the equation I, 3,5-dichlorophenylboronic acid (1) and 2-bromo-3,3-trifluoropropene (2) are used as raw materials, sodium carbonate is used as alkali, bis-triphenylphosphine palladium chloride is used as a catalyst, and a coupling product 3,5-dichloro-1- (1-trifluoromethylvinyl) benzene (3) is obtained by refluxing in tetrahydrofuran and water. Taking 2-fluoro-5-formyl benzonitrile (4) as a raw material, reacting with hydroxylamine hydrochloride to generate oxime (5) in methanol and water under the catalysis of sodium carbonate, and then oxidizing and cyclizing Oxone with the synthesized 3 in water in the presence of KCl to generate 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2-fluorobenzonitrile (6). And then carrying out nucleophilic substitution on the potassium carbonate serving as a base and 1,2,3-triazole under the catalysis of cuprous iodide to obtain a compound DP-9. Then heating, refluxing and hydrolyzing in sodium hydroxide water solution to obtain 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2- (1H-1,2,4-triazol-1-yl) benzoic acid (7), and finally condensing and reacting with corresponding amine in the presence of HOBt, EDCl and triethylamine to generate I-1-I-20.
R in the above equation 1 ,R 2 Are respectively groups shown in structures I-1 to I-20.
The isoxazoline derivatives I-1-I-20 containing the amide structures show good killing activity on diamondback moth, armyworm, spodoptera frugiperda, cotton bollworm, corn borer, mosquito larvae, aphid, tetranychus cinnabarinus adults, fleas, ticks, demodex, scabies, earmites, culex pipiens pale subspecies and the like.
The isoxazoline derivatives I-1 to I-20 containing the amide structures show good activity of resisting plant pathogens, and can well inhibit 14 plant pathogens of cucumber wilt, peanut brown spots, apple ring lines, wheat sharp eyedrops, corn small spots, watermelon anthracnose, rice bakanae disease, tomato early blight, wheat scab, rice blast, phytophthora capsici leonian, rape sclerotium, cucumber gray mold and rice sheath blight.
Detailed Description
The following examples and biological test results are provided to further illustrate the invention and are not meant to limit the invention.
Example 1: synthesis of isoxazoline derivative I-1 containing amide structure
In the first step, 3,5-dichloro-1- (1-trifluoromethylvinyl) benzene (3) was synthesized. 3,5-dichlorophenylboronic acid (1) (57.25g, 300mmol), dichlorobis (triphenylphosphine) palladium (6.32g, 9mmol) were charged into a 2L dry three-necked flask, argon was replaced three times, and then 200mL of 3.0M aqueous potassium carbonate and 600mL of tetrahydrofuran were added via syringe, followed by 2-bromo-3,3,3-trifluoropropene (2) (37.4mL, 360mmol), and heated under reflux for 4h. After the reaction is finished, the mixture is cooled to room temperature, ice water is added, the water phase is extracted for 3 times by ethyl acetate, the combined organic phase is washed by water for 2 times, saturated sodium chloride is washed for 1 time, anhydrous sodium sulfate is dried, the mixture is concentrated under reduced pressure, and the colorless oily matter is obtained by PE column chromatography, wherein the yield is 64 percent.
Second step, synthesis of 2-fluoro-5 ((hydroxyimino) methyl) benzonitrile (5). 2-fluoro-5-formylbenzonitrile (14.91g, 100mmol) and hydroxylamine hydrochloride (10.43g, 150mmol) were dissolved in a 500mL flask containing 200mL of water and 100mL of methanol, and sodium carbonate (19.08g, 180mmol) was slowly added and stirred at room temperature overnight. Most of the methanol was removed by rotary removal under reduced pressure, and then the reaction solution was poured into 300mL of ice water to precipitate a large amount of white solid, which was filtered by suction to obtain a fluffy white powder 12.29g with a yield of 75%. 1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),7.88–7.79(m,3H),7.25(t,J＝8.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ163.7(d,J＝262.8Hz),147.3,133.4(d,J＝8.7Hz),132.0,129.7(d,J＝4.2Hz),117.2(d,J＝20.3Hz),113.5,102.4(d,J＝16.2Hz).
And step three, synthesizing 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2-fluorobenzonitrile (6). 3,5-dichloro-1- (1-trifluoromethylvinyl) benzene (3) (60.00g, 250mmol), 2-fluoro-5 ((hydroxyimino) methyl) benzonitrile (5) (16.4 g, 100mmol) and KCl (7.46g, 100mmol) were charged to a 1L round bottom flask, followed by 750mL of water, and finally Oxone (92.2 g, 150mmol) with stirring and stirred at room temperature for 4h. The mixture was poured into a separatory funnel, the aqueous phase was extracted 3 times with dichloromethane, the combined organic phases were washed 2 times with water, 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed by PE/EA =10/1 column to give 5.40g of a white solid with a yield of 67%. 1 H NMR(400MHz,CDCl 3 )δ7.98(dd,J＝8.4,5.6Hz,1H),7.89(d,J＝5.6Hz,1H),7.49(s,2H),7.44(s,1H),7.32(t,J＝8.4Hz,1H),4.07(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ164.3(d,J＝265.2Hz),153.7,138.5,135.9,133.4(d,J＝8.9Hz),132.1,130.1,125.4(d,J＝4.1Hz),125.3,123.7(q,J＝282.5Hz),117.7(d,J＝20.6Hz),112.9,102.8(d,J＝16.4Hz),88.0(q,J＝30.7Hz),43.8.
The fourth step, the synthesis of 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2- (1H-1,2,4-triazol-1-yl) benzonitrile (DP-9). Reacting 5- (5- (3,5-dichlorophenyl) -5- (trifluoro-phenyl)Methyl) -4,5-dihydroisoxazol-3-yl) -2-fluorobenzonitrile (6) (33.78g, 84mmol), 1,2,4-triazole (8.12g, 117.6mmol), cuI (3.20g, 16.8mmol) and potassium carbonate (23.22g, 168mmol) were charged to a dry 250mL flask containing 160mL of ldmf, replaced with argon gas three times, and stirred with heating at 120 ℃ for 24h. The reaction mixture was cooled to room temperature, ethyl acetate was added, filtration was performed with celite, 300mL of water was added, extraction was performed with ethyl acetate 3 times, the combined organic phases were washed with water several times, washed with saturated sodium chloride 1 time, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography with PE/EA =1/1 to obtain 34.15g of a white solid with a yield of 90%. 1 H NMR(400MHz,CDCl 3 )δ8.86(s,1H),8.16(s,1H),8.11–8.04(m,2H),7.92–7.87(m,1H),7.48(d,J＝1.6Hz,2H),7.41(t,J＝1.6Hz,1H),4.13(d,J＝17.2Hz,1H),3.77(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ153.7,153.4,143.1,139.8,138.3,135.8,132.8,132.3,130.1,128.6,125.2,125.0,123.5(q,J＝282.7Hz),115.4,106.3,88.1(q,J＝30.8Hz),43.4.
The fifth step, synthesis of 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2- (1H-1,2,4-triazol-1-yl) benzoic acid (7). Intermediate DP-9 (18.04g, 40mmol) and sodium hydroxide (8.00g, 200mmol) were heated to reflux in a mixture of 100mL ethanol and 300mL water at 120 deg.C until the reaction was complete, and monitored by TLC plates. After the reaction is finished, cooling the mixture to room temperature, adding 500mL of water, extracting with a proper amount of ether, collecting a water phase, slowly dropwise adding 5M hydrochloric acid under vigorous stirring till the pH value is about 5, separating out a large amount of solid, and performing suction filtration to obtain 14.38g of white solid, wherein the yield is 76 percent, and the melting point is 141-144 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.62(s,1H),8.16(s,1H),8.09(s,1H),7.95(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.50(d,J＝1.6Hz,2H),7.43(t,J＝1.6Hz),4.14(d,J＝17.2Hz,1H),3.77(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ167.2,154.7,150.8,144.9,138.7,137.4,135.8,130.7,130.1,129.2,128.3,127.5,125.4,123.5(q,J＝282.5Hz),88.0(q,J＝30.4Hz),43.8. 19 F NMR(376MHz,DMSO-d 6 )δ-79.51(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 19 H 12 Cl 2 F 3 N 4 O 3 [M+H] + 471.0239,found,471.0233.
And step six, synthesizing I-1. To a solution of 7 (470.0mg, 1.0mmol) and aniline (0.1mL, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6 mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:1) to obtain yellow solid 346.7mg, yield 64%, melting point 242-244 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.48–8.35(m,2H),8.06(s,1H),7.95(s,1H),7.89(d,J＝7.2Hz,1H),7.53–7.47(m,3H),7.44(d,J＝1.2Hz,1H),7.40(d,J＝7.2Hz,2H),7.28(t,2H),7.13(t,J＝7.2Hz,1H),4.10(d,J＝17.2Hz,1H),3.74(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ163.4,154.6,153.1,144.7,138.6,137.1,135.9,135.5,133.3,130.1,129.6,129.4,129.3,128.6,126.9,125.5,125.4,123.7(q,J＝282.7Hz),120.4,88.0(q,J＝30.3Hz),43.8. 19 F NMR(376MHz,CDCl 3 )δ-79.55(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 25 H 17 Cl 2 F 3 N 5 O 2 [M+H] + 546.0711,found,546.0713.
example 2: i-2 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and 2-aminopyridine (103.5mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16h. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain yellow solid 175.5mg, yield 33%, melting point 134-136 deg.C; 1 H NMR(400MHz,CDCl 3 )δ10.31(s,1H),8.51(s,1H),8.17(d,J＝8.4Hz,1H),8.05(s,1H),8.00(dd,J＝8.4,1.6Hz,1H),7.85(s,1H),7.68–7.59(m,3H),7.52(s,2H),7.46(d,J＝1.6Hz,1H),6.91(t,J＝6.0Hz,1H),4.07(t,J＝17.2Hz,1H),3.72(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ164.6,154.6,153.0,151.2,147.3,144.0,139.0,138.7,136.0,135.8,132.2,130.1,129.6,128.8,127.9,126.0,125.5,123.7(q,J＝282.6Hz),120.6,115.1,88.0(q,J＝30.6Hz),43.8. 19 F NMR(376MHz,CDCl 3 )δ-79.52(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 24 H 16 Cl 2 F 3 N 6 O 2 [M+H] + 547.0664,found,547.0658.
example 3: i-3 synthesis. To a solution of 7 (470.0mg, 1.0 mmol) and 5-aminoquinoline (125.6mg, 1.10 mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5 mmol), HOBt (202.7mg, 1.5 mmol), and triethylamine (0.28mL, 2.0 mmol), and the mixture was stirred at room temperature for 16h. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain white solid 314.1mg, yield 53%, melting point 163-165 deg.C; 1 H NMR(400MHz,CDCl 3 )δ10.11(s,1H),8.73(d,J＝7.2Hz,1H),8.68(dd,J＝4.0,1.2Hz,1H),8.57(s,1H),8.15(dd,J＝8.4,1.2Hz,1H),8.08(d,J＝1.6Hz,1H),8.03–7.98(m,2H),7.70(d,J＝8.4Hz,1H),7.59–7.50(m,4H),7.46–7.41(m,2H),4.17(d,J＝17.2Hz,1H),3.81(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ163.9,154.7,153.0,148.5,144.1,138.7,138.4,136.5,136.0,135.8,133.8,132.6,130.0,129.5,128.8,128.0,128.0,127.3,126.1,125.4,123.7(q,J＝282.6Hz),122.9,122.0,117.3,87.9(q,J＝30.5Hz),43.8. 19 F NMR(376MHz,CDCl 3 )δ-79.46(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 28 H 18 Cl 2 F 3 N 6 O 2 [M+H] + 597.0820,found,597.0822.
example 4: i-4 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and 4-amino-1,1' -biphenyl (169.2mg, 1.1mmol) in methylene chloride (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:1) to obtain white pigment621.1mg of a colored solid, 60% of yield and 194-196 ℃ of melting point; 1 H NMR(400MHz,CDCl 3 )δ8.49(s,1H),8.36(s,1H),8.14(s,1H),8.03(d,J＝1.6Hz,1H),7.94(dd,J＝8.4,1.6Hz,1H),7.56–7.49(m,9H),7.45–7.40(m,3H),7.34(dd,J＝7.2,1.6Hz,1H),4.13(d,J＝17.2Hz,1H),3.76(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ163.5,154.7,153.0,144.6,140.2,138.5,138.3,136.4,135.9,135.6,133.1,130.1,129.5,129.2,129.0,128.4,127.8,127.5,127.0,126.6,125.4,123.7(q,J＝282.5Hz),120.7,88.0(q,J＝30.7Hz),43.7. 19 F NMR(376MHz,CDCl 3 )δ-79.56(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 31 H 21 Cl 2 F 3 N 5 O 2 [M+H] + 622.1024,found,622.1015.
example 5: i-5 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and 4-aminodiphenyl ether (185.2mg, 1.1mmol) in methylene chloride (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:1) to obtain white solid 409.5mg, yield 64%, melting point 112-115 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.48(s,1H),8.23(s,1H),8.13(s,1H),8.01(d,J＝2.0Hz,1H),7.94(dd,J＝8.4,2.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.50(d,J＝1.6Hz,2H),7.44(t,J＝1.6Hz,1H),7.39(dt,J＝9.2,2.4Hz,2H),7.36–7.30(m,2H),7.10(tt,J＝7.2,0.8Hz,1H),7.01–6.97(m,2H),6.97–6.93(m,2H),4.13(d,J＝17.2Hz,1H),3.77(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ163.5,157.2,154.7,154.5,152.9,144.5,138.5,135.8,135.5,132.9,132.5,130.1,129.9,129.4,129.0,128.3,126.4,125.4,123.7(q,J＝283.1Hz),123.5,122.1,119.5,118.8,87.9(q,J＝30.4Hz),43.7. 19 F NMR(376MHz,CDCl 3 )δ-79.55(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 31 H 21 Cl 2 F 3 N 5 O 3 [M+H] + 638.0974,found,638.0966.
example 6: i-6 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and N-methylaniline (117.9mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain 332.8mg as brown solid with yield of 60% and melting point of 92-95 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.25(s,1H),8.11(s,1H),7.74–7.68(m,2H),7.49(d,J＝1.6Hz,2H),7.45(t,J＝2.0Hz,1H),7.34(d,J＝8.4Hz,1H),7.11–7.06(m,3H),6.63(dd,J＝6.4,3.2Hz,2H),4.03(d,J＝17.2Hz,1H),3.66(d,J＝17.2Hz,1H),3.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ167.0,154.6,152.8,143.1,142.1,138.8,135.9,135.2,131.8,130.1,129.3,128.6,128.5,127.9,127.4,126.2,125.4,124.0,123.7(q,J＝282.7Hz),87.7(q,J＝30.6Hz),43.9,37.4. 19 F NMR(376MHz,CDCl 3 )δ-79.51(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 26 H 19 Cl 2 F 3 N 5 O 2 [M+H] + 560.0868,found,560.0863.
example 7: i-7 synthesis. EDCI hydrochloride (287.6 mg,1.5 mmol), HOBt (202.7 mg,1.5 mmol), and triethylamine (0.28mL, 2.0 mmol) were added to a solution of 7 (470.0mg, 1.0mmol) and benzylamine (117.9mg, 1.1mmol) in dichloromethane (5 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:1) to obtain yellow solid 457.9mg, with yield 82%, melting point 68-71 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.38(s,1H),7.94(s,1H),7.87(t,J＝9.4Hz,1H),7.54–7.47(m,3H),7.43(t,J＝2.0Hz,1H),7.33–7.26(m,3H),7.15(d,J＝6.8Hz,2H),6.65(s,1H),4.42(d,J＝5.6Hz,2H),4.11(d,J＝17.2Hz,1H),3.74(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ165.4,154.7,152.8,144.5,138.6,137.0,135.8,135.7,133.0,130.0,129.2,129.0,128.9,128.1,128.0,128.0,126.6,125.4,123.7(q,J＝282.8Hz),87.9(q,J＝30.4Hz),44.5,43.8. 19 F NMR(376MHz,CDCl 3 )δ-79.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 26 H 19 Cl 2 F 3 N 5 O 2 [M+H] + 560.0868,found,560.0869.
example 8: i-8 synthesis. To a solution of 7 (470.0mg, 1.0 mmol) and 2-aminomethylpyridine (119.0mg, 1.10 mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5 mmol), HOBt (202.7mg, 1.5 mmol), and triethylamine (0.28mL, 2.0 mmol), and the mixture was stirred at room temperature for 16h. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (dichloromethane) = V (methanol) = 30) to obtain white solid 460.4mg, yield 82%, melting point 107-110 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.44–8.27(m,3H),7.93(s,1H),7.88(s,1H),7.83(d,J＝8.0Hz,1H),7.52(d,J＝7.6Hz,1H),7.50–7.45(m,3H),7.41(s,2H),7.21(t,J＝4.4Hz,1H),4.41(d,J＝5.2Hz,2H),4.10(d,J＝17.2Hz,1H),3.75(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ165.8,154.8,152.7,149.2,149.0,144.3,138.5,136.0,135.8,135.7,133.2,132.7,130.0,129.3,128.9,127.9,126.3,125.3,123.8,123.7(q,J＝282.3Hz),87.9(q,J＝30.4Hz),43.7,41.7. 19 F NMR(376MHz,CDCl 3 )δ-79.56(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 25 H 18 Cl 2 F 3 N 6 O 2 [M+H] + 561.0820,found,561.0818.
example 9: i-9 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and methylamine hydrochloride (74.3mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.42mL, 3.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain white solid 370.5mg, yield 77%, melting point 189-190 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.47(s,1H),8.11(s,1H),7.92–7.87(m,2H),7.59–7.56(m,1H),7.50(d,J＝1.2Hz,2H),7.45(t,J＝1.6Hz,1H),6.22(s,1H),4.12(d,J＝17.2Hz,1H),3.76(d,J＝17.2Hz,1H),2.85(d,J＝4.8Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ166.3,154.8,152.8,144.4,138.6,135.8,135.7,132.7,130.0,129.1,128.7,127.8,126.3,125.3,123.7(q,J＝282.7Hz),87.8(q,J＝30.5Hz),43.7,26.9. 19 FNMR(376MHz,CDCl 3 )δ-79.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 20 H 15 Cl 2 F 3 N 5 O 2 [M+H] + 484.0555,found,484.0552.
example 10: i-10 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and trifluoroethylamine hydrochloride (149.1mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.42mL, 3.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain white solid 453.9mg, with yield 82% and melting point 158-160 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.39(s,1H),8.08(s,1H),7.93(s,2H),7.53(d,J＝8.8Hz,1H),7.49(s,2H),7.44(t,J＝1.6Hz,1H),7.00(s,1H),4.12(d,J＝17.2Hz,1H),3.99–3.89(m,2H),3.76(d,J＝17.2Hz,1H). 13 CNMR(100MHz,CDCl 3 )δ165.9,154.6,152.9,144.4,138.5,135.8,135.6,131.9,130.1,129.8,129.2,128.2,126.6,125.3,123.8(q,J＝276.8Hz),123.7(q,J＝282.6Hz),88.0(q,J＝30.4Hz),43.7,41.2(q,J＝34.7Hz). 19 F NMR(376MHz,CDCl 3 )δ-71.99(s),-79.52(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 21 H 14 Cl 2 F 6 N 5 O 2 [M+H] + 552.0429,found,552.0419.
example 11: synthesis of I-11. To a solution of 7 (470.0mg, 1.0mmol) and cyclopropylamine (62.8mg, 1.1mmol) in methylene chloride (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile matter under reduced pressureExtracting the fermentation product with dichloromethane, washing the organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain white solid 416.6mg, with yield of 82% and melting point of 153-155 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.43(s,1H),8.11(s,1H),7.90(dd,J＝8.4,2.0Hz,1H),7.87(d,J＝2.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.50(d,J＝1.6Hz,2H),7.44(t,J＝1.6Hz,1H),6.19(s,1H),4.12(d,J＝17.2Hz,1H),3.75(d,J＝17.2Hz,1H),2.78–2.69(m,2H),0.78(q,J＝6.4Hz,2H),0.42(q,J＝5.2Hz,2H). 13 CNMR(100MHz,CDCl 3 )δ166.9,154.7,152.9,144.6,138.6,135.9,135.7,133.2,130.1,129.3,129.1,128.1,126.7,125.2,123.7(q,J＝280.3Hz)87.9(q,J＝30.5Hz),43.8,23.3,6.7. 19 F NMR(376MHz,CDCl 3 )δ-79.55(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 22 H 17 Cl 2 F 3 N 5 O 2 [M+H] + 510.0711,found,570.0712.
example 12: i-12 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and propargylamine (60.6mg, 1.1mmol) in methylene chloride (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain pale yellow solid 364.0mg, yield 72%, melting point 93-96 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.43(s,1H),8.09(s,1H),7.92–7.86(m,2H),7.55(d,J＝8.8Hz,1H),7.49(d,J＝1.2Hz,2H),7.43(t,J＝1.6Hz,1H),6.74(s,1H),4.12(d,J＝17.2Hz,1H),4.06(dd,J＝4.8,2.4Hz,2H),3.75(d,J＝17.2Hz,1H),2.25(t,J＝2.4Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ165.2,154.6,153.1,144.6,138.6,135.9,135.8,132.3,130.1,129.6,129.1,128.2,126.6,125.4,123.7(q,J＝282.6Hz),88.0(q,J＝30.5Hz),78.3,72.6,43.8,30.0. 19 F NMR(376MHz,CDCl 3 )δ-79.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 22 H 15 Cl 2 F 3 N 5 O 2 [M+H] + 508.0555,found,508.0550.
example 13: i-13 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and allylamine hydrochloride (102.9mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain pale yellow solid 474.6mg, yield 93%, melting point 140-143 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.44(s,1H),8.09(s,1H),7.89(dd,J＝7.2,2.0Hz,2H),7.56(dd,J＝9.2,2.0Hz,2H),7.49(d,J＝1.6Hz,2H),7.44(t,J＝2.0Hz,1H),6.30(t,J＝5.6Hz,1H),5.73(ddt,J＝16.4,10.4,5.6Hz,1H),5.12(tq,J＝9.6,1.6Hz,2H),4.12(d,J＝17.2Hz,1H),3.90(tt,J＝5.6,1.2Hz,2H),3.75(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ165.5,154.7,152.8,144.4,138.6,135.8,135.6,133.0,132.8,130.0,129.2,128.8,127.9,126.4,125.3,123.7(q,J＝282.7Hz),117.5,87.8(q,J＝30.5Hz),43.7,42.62. 19 F NMR(376MHz,CDCl 3 )δ-79.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 22 H 17 Cl 2 F 3 N 5 O 2 [M+H] + 510.0711,found,510.0710.
example 14: i-14 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and 2-methoxyethylamine (82.6mg, 1.1mmol) in methylene chloride (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (dichloromethane) = V (methanol) = 1:1) to obtain white solid 389.0mg, with yield of 74% and melting point of 85-87 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.44(s,1H),8.08(s,1H),7.88(d,J＝7.6Hz,2H),7.57(d,J＝8.8Hz,1H),7.49(d,J＝1.2Hz,2H),7.43(t,J＝1.6Hz,1H),6.47(s,1H),4.11(d,J＝17.2Hz,1H),3.75(d,J＝17.2Hz,1H),3.46(q,J＝5.2Hz,2H),3.37(t,J＝5.2Hz,2H),3.28(s,3H). 13 C NMR(100MHz,CDCl 3 )δ165.7,154.7,152.8,144.3,138.6,135.7,135.6,132.7,130.0,129.1,128.7,127.8,126.3,125.3,123.7(q,J＝282.7Hz),87.8(q,J＝30.5Hz),70.5,58.7,43.7,39.9. 19 F NMR(376MHz,CDCl 3 )δ-79.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 22 H 19 Cl 2 F 3 N 5 O 3 [M+H] + 528.0817,found,528.0811.
example 15: i-15 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and glycine methyl ester hydrochloride (138.1mg, 1.1mmol) in methylene chloride (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.42mL, 3.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain light yellow solid 432.0mg, yield 80%, melting point 186-189 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.49(s,1H),8.11(s,1H),7.96–7.92(m,2H),7.61(dd,J＝8.8,0.8Hz,1H),7.50(d,J＝1.6Hz,2H),7.44(t,J＝1.6Hz,1H),6.70(t,J＝4.4Hz,1H),4.13(d,J＝17.2Hz,1H),4.09(d,J＝5.2Hz,2H),3.76(s,3H),3.75(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.6,165.8,154.7,153.0,144.6,138.6,135.9,135.8,131.8,130.1,129.6,128.9,128.1,126.6,125.4,123.7(q,J＝282.7Hz),87.9(q,J＝30.5Hz),52.7,43.8,41.8. 19 F NMR(376MHz,CDCl 3 )δ-79.53(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 22 H 17 Cl 2 F 3 N 5 O 4 [M+H] + 542.0610,found,542.0601.
example 16: i-16 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and 2-amino-N-methylacetamide (96.9mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile matter under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressurePerforming column chromatography (V (dichloromethane) = 40) to obtain 433.2mg white solid, the yield is 80%, and the melting point is 115-118 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.49(s,1H),7.97(s,1H),7.84–7.79(m,2H),7.70(t,J＝5.6Hz,1H),7.53(d,J＝8.4Hz,1H),7.45(d,J＝1.6Hz,2H),7.39(t,J＝1.6Hz,1H),6.89(q,J＝4.8Hz,1H),4.10(d,J＝17.2Hz,1H),3.85(d,J＝5.6Hz,2H),3.76(d,J＝17.2Hz,1H),2.71(d,J＝4.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ169.0,166.5,154.8,152.6,144.1,138.5,135.8,135.7,131.6,130.0,129.4,128.6,127.6,125.5,125.3,123.7(q,J＝282.6Hz),87.9(q,J＝30.4Hz),43.6,43.5,26.2. 19 F NMR(376MHz,CDCl 3 )δ-79.56(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 22 H 18 Cl 2 F 3 N 6 O 3 [M+H] + 541.0770,found,541.0762.
example 17: i-17 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and 2-amino-N- (2,2,2-trifluoroethyl) acetamide hydrochloride (211.8mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), triethylamine (0.42mL, 3.0mmol), and the mixture was stirred at room temperature for 16h. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain white solid 476.8mg, yield 78%, melting point 101-104 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.49(s,1H),8.07(s,1H),7.93–7.89(m,2H),7.58(d,J＝8.0Hz,1H),7.49(d,J＝1.2Hz,2H),7.44(t,J＝2.0Hz,1H),7.13(s,1H),7.06(s,1H),4.12(d,J＝17.0Hz,1H),4.07(d,J＝5.6Hz,2H),3.99–3.89(m,2H),3.75(d,J＝17.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.8,166.5,154.5,153.1,144.1,138.6,135.9,135.8,131.6,130.1,129.8,129.1,127.8,125.9,125.4,123.9(q,J＝276.8Hz),123.7(q,J＝282.7Hz),88.0(d,J＝30.6Hz),43.8,43.7,40.85(d,J＝35.0Hz). 19 F NMR(376MHz,CDCl 3 )δ-72.21(s),-79.62(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 23 H 17 Cl 2 F 6 N 6 O 3 [M+H] + 604.0643,found,604.0634.
example 18: i-18 synthesis. To a solution of 7 (470.0mg, 1.0 mmol) and diethylamine (80.4mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6 mg,1.5 mmol), HOBt (202.7mg, 1.5 mmol), and triethylamine (0.28mL, 2.0 mmol), and the mixture was stirred at room temperature for 16h. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain white solid 418.9mg, yield 80%, melting point 65-67 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.55(s,1H),8.09(s,1H),7.84(dd,J＝8.4,1.2Hz,1H),7.72(d,J＝8.4Hz,1H),7.68(d,J＝1.6Hz,1H),7.50(d,J＝1.6Hz,2H),7.43(t,J＝1.6Hz,1H),4.10(dd,J＝17.2,6.8Hz,1H),3.73(dd,J＝17.2,6.8Hz,1H),3.59(t,J＝6.4Hz,1H),3.33(t,J＝6.4Hz,1H),2.97(dd,J＝18.4,6.8Hz,2H),1.13(t,J＝7.2Hz,3H),0.83(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ166.7,154.7,152.9,144.0,138.7,135.8,135.0,132.2,123.0,128.5,128.3,126.2,125.3,125.2,123.7(q,J＝282.8Hz),87.7(q,J＝30.5Hz),43.8,43.1,39.4,13.6,12.3. 19 F NMR(375MHz,CDCl 3 )δ-79.44(s),-79.60(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 23 H 21 Cl 2 F 3 N 5 O 2 [M+H] + 526.1024,found,526.1019.
example 19: i-19 synthesis. EDCI hydrochloride (287.6 mg,1.5 mmol), HOBt (202.7 mg,1.5 mmol) and triethylamine (0.28mL, 2.0 mmol) were added to a solution of 7 (470.0mg, 1.0mmol) and morpholine (95.8mg, 1.1mmol) in dichloromethane (5 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. Removing volatile under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (petroleum ether) = V (ethyl acetate) = 1:2) to obtain white solid 345.6mg, yield 64%, melting point 79-81 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.52(s,1H),8.13(s,1H),7.88(dd,J＝8.4,2.0Hz,1H),7.71(d,J＝2.0Hz,1H),7.68(d,J＝8.4Hz,1H),7.50(s,2H),7.44(t,J＝2.0Hz,1H),4.11(dd,J＝17.2,4.8Hz,1H),3.84–3.77(m,1H),3.77–3.68(m,2H),3.63–3.47(m,3H),3.20–3.10(m,2H),3.00–2.92(m,1H). 13 C NMR(100MHz,CDCl 3 )δ166.1,154.5,153.2,143.5,138.7,138.6,135.9,135.3,131.2,130.1,128.8,128.8,126.7,127.7,125.4,124.9,123.7(q,J＝282.5Hz),87.9(q,J＝30.4Hz),66.4,66.2,47.3,43.8,42.3. 19 F NMR(375MHz,CDCl 3 )δ-79.40(s),-79.57(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 23 H 19 Cl 2 F 3 N 5 O 3 [M+H] + 540.0817,found,540.0814.
example 20: i-20 synthesis. To a solution of 7 (470.0mg, 1.0mmol) and N-methylpiperazine (110.2mg, 1.1mmol) in dichloromethane (5 mL) at room temperature were added EDCI hydrochloride (287.6mg, 1.5mmol), HOBt (202.7mg, 1.5mmol), and triethylamine (0.28mL, 2.0mmol), and the mixture was stirred at room temperature for 16 hours. Removing volatile matter under reduced pressure, extracting with dichloromethane, washing organic phase with saturated sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography (V (dichloromethane) = V (methanol) = 40) to obtain pale yellow solid 495.2mg, yield 90%, melting point 106-108 deg.C; 1 H NMR(400MHz,CDCl 3 )δ8.50(s,1H),8.09(s,1H),7.86(dt,J＝8.4,2.0Hz,1H),7.71–7.66(m,2H),7.48(s,2H),7.42(t,J＝2.0Hz,1H),4.10(dd,J＝17.2,5.6Hz,1H),3.85–3.76(m,1H),3.72(dd,J＝17.2,4.0Hz,1H),3.62–3.51(m,1H),3.17–3.06(m,1H),2.99–2.89(m,1H),2.48–2.40(m,1H),2.25–2.15(m,5H),1.75–1.64(m,1H). 13 C NMR(100MHz,CDCl 3 )δ165.8,154.6,152.9143.5,138.7,138.6,135.7,135.1,131.3,123.0,129.9,128.7,128.6,126.6,126.6,125.3,124.8,123.7(q,J＝282.8Hz),87.7(q,J＝30.6Hz),54.4,54.2,46.8,45.9,43.8,41.8. 19 F NMR(376MHz,CDCl 3 )δ-79.39(s),-79.58(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C 24 H 22 Cl 2 F 3 N 6 O 2 [M+H] + 553.1133,found,553.1133.
example 21: the isoxazoline amide compounds I-1 to I-20 are used for measuring the insecticidal activity of diamondback moth (Plutella xylostella), armyworm (Mythimna separata), cotton bollworm (Helicoverpa armigera), corn borer (0 strinia nubilalis), culex pipiens pallidus (Culex pipiens pallens), aphid (Aphis lambanus Kaltenbach) and the acaricidal activity of Tetranyhus cinnabarinus (Tetranyhus cinnabarinus), and the measuring programs are as follows:
testing the activity of armyworm: armyworm (Mythimna separata Walker), a normal population raised indoors. The test method comprises the following steps: the leaf soaking method comprises soaking folium Maydis in medicinal liquid prepared from acetone, inoculating 10-head larvae of 3 years old after the medicinal liquid is dried, mainly performing stomach poisoning and contact killing, and observing feeding phenomenon of the larvae. Mortality was checked for 72 h. Each compound was repeated 3 times.
Mortality (%) = (number of dead insects applied/total number of insects applied) × 100
Corrected mortality (%) = [ (drug application mortality-blank mortality)/(1-blank mortality) ] × 100
Cotton bollworm activity test: helicoverpa armigera (Helicoverpa armigera), a normal population raised indoors. The test method comprises the following steps: leaf soaking method. Soaking corn leaf in liquid medicine prepared from acetone, inoculating 10 larvae of 3 years old after the liquid medicine is dried, mainly performing stomach toxicity and contact killing, and observing feeding phenomenon of the larvae. Mortality was checked after 72 h. Each compound was repeated 3 times.
Activity test of corn borer: corn borer (0 strinia nubilalis Hubner), a normal population raised indoors. The test method comprises the following steps: leaf soaking method. Soaking corn leaf in liquid medicine prepared from acetone, inoculating 10 larvae of 3 years old after the liquid medicine is dried, mainly performing stomach toxicity and contact killing, and observing feeding phenomenon of the larvae. Mortality was checked after 72 hours. Each compound was repeated 3 times.
Activity test of plutella xylostella: diamondback moth (Plutella xylostella), a normal population raised indoors. The test method comprises the following steps: leaf soaking. Dipping the cabbage leaves into the liquid medicine with proper concentration by using straight-head ophthalmic forceps for 3-5 seconds, and throwing off residual liquid. One sheet at a time, 3 sheets per sample, were placed on the treatment paper in order of sample label. After the liquid medicine is dried, the liquid medicine is put into a straight pipe with the length of 10cm and provided with a mark, 10 second-instar larvae are inoculated, and the pipe openings of the second-instar larvae are covered by gauze. The experimental treatments were placed in a standard room and the results were checked after 4 days. Each compound was repeated 3 times.
Activity test of culex larvae: culex pipiens pallens (culex pallens), a normal population raised indoors. 10 larvae of culex 3 instars were selected and placed in a beaker of 100mL of the prepared desired concentration. Treatments were placed in a standard treatment room and mortality was checked after 72 h. An aqueous solution containing 1mL of test solvent was used as a blank. Each compound was repeated 3 times.
Aphid activity test: aphid (Aphis laburnii Kaltenbach), a normal population raised by laboratory broad bean leaves. Weighing the medicines, adding 1ml of DMMF to dissolve, adding two drops of Tween-20 emulsifier, adding a certain amount of distilled water, and stirring uniformly to prepare the liquid medicine with the required concentration. Soaking the leaves of broad beans with aphids (about 60) in the medicament for 5 seconds, taking out, slightly drying, sucking the redundant medicament with filter paper, inserting the branches of the broad beans into water-absorbing sponge, covering the branches with glass covers, sealing with gauze, checking the result after 96 hours, and repeating each compound for 3 times. The control was prepared by adding the emulsifier and solvent to distilled water and stirring the mixture uniformly.
Testing the activity of tetranychus cinnabarinus adults: when Tetranychus cinnabarinus (Tetranychus cinnabarinus) for experiments grows to two true leaves of dwarf beans, plants with regular growth vigor, 4-5 square centimeters of leaf area and about 10 centimeters of plant height are selected for grafting, and the quantity of each plant is controlled to be about 60-100. And (5) after inoculating the insects for 2h, carrying out medicament treatment. The medicament treatment adopts a plant dipping method, and the dipping time is 5 seconds. After the plants are taken out of the liquid medicine, the plants are shaken slightly to throw off the redundant liquid medicine, then the plants are moved into a water culture tank and placed at room temperature. The results were examined under binoculars 24h after treatment. Each compound was repeated 3 times.
TABLE 1 Activity test results of Compounds I-1 to I-20 against armyworm, diamondback moth, heliothis armigera and corn borer
a Activities at 200mg/L. b Activities at 100mg/L. c Activities at 10mg/L d Activities at 1mg/L, e Activities at 0.1mg/L.
TABLE 2 Activity test results of Compounds I-1 to I-20 against mosquito larvae, helicoverpa armigera, corn borer
a Activities at 200mg/L. b Activities at 100mg/L. c Activities at 5mg/L, d Activities at 2mg/L. e Activities at 1mg/L. f Activities at 0.5mg/L, g Activities at 0.25mg/L. h Activities at 0.1mg/L. i Activities at0.05 mg/L, j Activities at0.025 mg/L.
The commercial varieties Fluralaner and DP-9 are used as a control to test the insecticidal activity of diamondback moth, armyworm, spodoptera frugiperda, cotton bollworm, corn borer, culex pipiens L.sp.pipiens, aphid and the mite-killing activity of Tetranychus cinnabarinus. The test result shows that most of the derivatives show higher activity. The compounds I-3, I-7, I-9-I-12, I-16, I-18 and I-20 have 100 percent of lethality to armyworms at the concentration of 200 mg/L; the compounds I-11 and I-16 have a lethality rate of more than 80 percent to diamondback moth at a concentration of 1 mg/L; the compounds I-7 and I-18 have 100 percent of lethality to culex pipiens pallens larvae at the concentration of 0.1 mg/L; most compounds show certain activity for killing cotton bollworms and corn borers.
Example 22: antibacterial activity test, the determination procedure is as follows:
ex vivo sterilization test, cell growth rate assay (plate method):
dissolving a certain amount of medicament in a proper amount of acetone, then diluting the solution to a required concentration by using an emulsifier aqueous solution containing 200 mug/mL, sucking 1mL of liquid medicine respectively, injecting the liquid medicine into a culture dish, adding 9mL of culture medium respectively, shaking the liquid medicine uniformly to prepare a medicine-containing plate with 50 mug/mL, and taking the plate added with 1mL of sterilized water as a blank control. Cutting the plate with a punch with diameter of 4mm along the outer edge of the hypha, and transferring to a medicated plate. Each treatment was repeated three times. The culture dish is placed in a constant temperature incubator at 24 +/-1 ℃ for culture. And after 48 hours, investigating the expansion diameter of each treated bacterium disc, calculating an average value, and comparing with a blank control to calculate the relative bacteriostasis rate.
TABLE 3 Activity test results of Compounds I-1 to I-20 on plant pathogens
The activity test of 14 plant fungi is carried out by taking broad-spectrum bactericides carbendazim, chlorothalonil, fluralaner and DP-9 as controls, and the test result shows that part of compounds show broad-spectrum inhibitory activity to 14 tested bacteria under the condition that the test concentration is 50 mg/L. Wherein, the inhibition rate of the derivatives I-10, I-11 and I-18-I-20 on the peanut brown spot pathogen is superior to DP-9 (51%), fluralaner (30%), chlorothalonil (44%) and pyrimethamine (18%), and the inhibition rate of most derivatives on the wheat sheath blight pathogen reaches more than 90%. I-17 has higher bactericidal activity to tomato early blight bacteria than or equal to that of a control sample; the inhibition rate of I-7, I-11 and I-20 on the ring rot of apple reaches more than 90 percent; the inhibition rate of I-3 to phytophthora capsici reaches 79%.
Claims (4)
1. The isoxazoline derivative I containing the amide structure is a compound shown in the following structure, and specifically is a compound shown in I-1 to I-20:
2. the method for producing isoxazoline derivatives I-1 to I-20 having an amide structure according to claim 1, which comprises: firstly, using 3,5-dichlorophenylboronic acid (1) and 2-bromo-3,3-trifluoropropene (2) as raw materials, sodium carbonate as alkali, bis-triphenylphosphine palladium chloride as a catalyst, and refluxing in tetrahydrofuran and water to obtain a coupling product 3,5-dichloro-1- (1-trifluoromethylvinyl) benzene (3); taking 2-fluoro-5-formyl benzonitrile (4) as a raw material, reacting with hydroxylamine hydrochloride to generate oxime (5) in methanol and water under the catalysis of sodium carbonate, and then oxidizing and cyclizing with Oxone in water and KCl to generate 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2-fluorobenzonitrile (6) in water with the synthesized 3; then carrying out nucleophilic substitution on potassium carbonate serving as alkali and 1,2,3-triazole under the catalysis of cuprous iodide to obtain a compound DP-9; then heating, refluxing and hydrolyzing in sodium hydroxide aqueous solution to obtain 5- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2- (1H-1,2,4-triazol-1-yl) benzoic acid (7), and finally condensing and reacting with corresponding amine in the presence of HOBt, EDCl and triethylamine to generate I-1-I-20
R 1 And R 2 Respectively represent groups shown in structures I-1 to I-20.
3. The application of the isoxazoline derivative I-1 to I-20 containing the amide structure in the claim 1 in pest control is characterized in that the pests are diamondback moth, armyworm, spodoptera frugiperda, cotton bollworm, corn borer, mosquito larva, aphid, tetranychus cinnabarinus adult mite, flea, tick, demodex, scabies mite and earmite.
4. The application of the isoxazoline derivatives I-1 to I-20 containing the amide structures in the claim 1 in preventing and treating plant pathogens, which is characterized in that the plant pathogens are cucumber fusarium wilt, peanut brown spots, apple ring rot, wheat sharp eyespot, corn small spot, watermelon anthracnose, rice bakanae disease, tomato early blight, wheat gibberella, rice blast, phytophthora capsici, sclerotium napellum, cucumber gray mold or rice sheath blight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110452545.6A CN115246825A (en) | 2021-04-26 | 2021-04-26 | Isoxazoline derivative containing amide structure, preparation thereof and application of isoxazoline derivative as insecticide and bactericide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110452545.6A CN115246825A (en) | 2021-04-26 | 2021-04-26 | Isoxazoline derivative containing amide structure, preparation thereof and application of isoxazoline derivative as insecticide and bactericide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115246825A true CN115246825A (en) | 2022-10-28 |
Family
ID=83696063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110452545.6A Pending CN115246825A (en) | 2021-04-26 | 2021-04-26 | Isoxazoline derivative containing amide structure, preparation thereof and application of isoxazoline derivative as insecticide and bactericide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115246825A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007016017A (en) * | 2005-06-06 | 2007-01-25 | Nissan Chem Ind Ltd | Substituted isoxazoline compound and pest control agent |
| CN101331127A (en) * | 2005-12-16 | 2008-12-24 | 杜邦公司 | 5-aryl isoxazolines for controlling invertebrate pests |
-
2021
- 2021-04-26 CN CN202110452545.6A patent/CN115246825A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007016017A (en) * | 2005-06-06 | 2007-01-25 | Nissan Chem Ind Ltd | Substituted isoxazoline compound and pest control agent |
| CN101331127A (en) * | 2005-12-16 | 2008-12-24 | 杜邦公司 | 5-aryl isoxazolines for controlling invertebrate pests |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110092776B (en) | Pyrazole oxime ester compound containing pyridine-difluoride pyrazole structure and preparation method and application thereof | |
| JP6710273B2 (en) | Cyclic amine compound and pest control agent | |
| JP2006290883A (en) | Substituted heterocycle carboxylic anilide derivative, its intermediate and chemical for agriculture and horticulture and method for using the same | |
| CN110128409B (en) | Preparation and application of difluoromethylpyrazole oxime derivative containing pyridine bipyrazole structure | |
| WO2006022225A1 (en) | Optically active phthalamide derivative, agricultural or horticultural insecticide, and method of using the same | |
| WO2007108483A1 (en) | N-2-(hetero)arylethylcarboxamide derivative, and pest-controlling agent comprising the same | |
| WO2007125984A1 (en) | Isoxazoline derivative, pest-controlling agent, and use of the pest-controlling agent | |
| EA019243B1 (en) | Insecticidal compounds | |
| WO2014187298A1 (en) | N-pyridine amide compound, preparation method therefor, and application thereof | |
| WO2014187297A1 (en) | N-pyridine(hetero)aromatic amide compound and preparation method and use thereof | |
| EP3889137A1 (en) | Cyclic amine compound and pest control agent | |
| CN110407831B (en) | Preparation and application of pyrazole oxime ester derivative containing N- (3-chloropyridine-2-yl) pyrazole structure | |
| CN106243039B (en) | Preparation method and application of pyrazole oxime compound containing 1-methyl-3-ethyl-4-chloro-5-formylpyrazole structure | |
| JP2008222709A (en) | Pest control agent composition and use of the same | |
| CN110407813B (en) | Pyrazole oxime compound containing 1- (3-chloropyridine-2-yl) pyrazole structure and preparation method and application thereof | |
| KR20220015388A (en) | Pyridinium salts and pest control agents | |
| KR20220016459A (en) | Pyridinium salts and pest control agents | |
| WO2017069154A1 (en) | Amide compound and pest control agent | |
| CN115246825A (en) | Isoxazoline derivative containing amide structure, preparation thereof and application of isoxazoline derivative as insecticide and bactericide | |
| CN115246795B (en) | Isoxazoline compound containing ether structure at 4-phenyl para-position, preparation method thereof and application thereof as insecticidal and bactericidal agent | |
| JP2004269515A (en) | Substituted heterocyclic amide derivative, its intermediate, agricultural and horticultural agent and method for using them | |
| US7994339B2 (en) | Phthalamide derivative, agricultural or horticultural pesticide, and use of the pesticide | |
| CN109232534B (en) | Heterocyclic diarylamine-containing pyrazole formamide compound and preparation method and application thereof | |
| CN115246826B (en) | Quaternary ammonium salt isoxazoline compound, its preparation and application as insecticidal and bactericidal agent | |
| CN111978306A (en) | Furanol pyrazole formamide derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |