CN106749262B - 1,2,4- triazole ring simultaneously [4,3-a] condense piperazine Mannich base analog derivative and its preparation method and application - Google Patents
1,2,4- triazole ring simultaneously [4,3-a] condense piperazine Mannich base analog derivative and its preparation method and application Download PDFInfo
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- CN106749262B CN106749262B CN201610993675.XA CN201610993675A CN106749262B CN 106749262 B CN106749262 B CN 106749262B CN 201610993675 A CN201610993675 A CN 201610993675A CN 106749262 B CN106749262 B CN 106749262B
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- mannich
- piperazine
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- triazole
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 title claims abstract description 14
- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 241000196324 Embryophyta Species 0.000 claims abstract description 8
- 241000233866 Fungi Species 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- -1 Substituted-phenyl Chemical group 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 150000003852 triazoles Chemical class 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
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- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- 230000000694 effects Effects 0.000 abstract description 16
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- 235000018262 Arachis monticola Nutrition 0.000 abstract description 5
- 241000555706 Botryosphaeria dothidea Species 0.000 abstract description 5
- 241001157813 Cercospora Species 0.000 abstract description 5
- 241000223195 Fusarium graminearum Species 0.000 abstract description 5
- 235000007688 Lycopersicon esculentum Nutrition 0.000 abstract description 5
- 235000020232 peanut Nutrition 0.000 abstract description 5
- 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 abstract description 4
- 240000008067 Cucumis sativus Species 0.000 abstract description 4
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 abstract description 4
- 241000223218 Fusarium Species 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 4
- 238000005556 structure-activity relationship Methods 0.000 abstract description 4
- 238000010276 construction Methods 0.000 abstract description 3
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- 238000004659 sterilization and disinfection Methods 0.000 abstract description 3
- 241001290235 Ceratobasidium cereale Species 0.000 abstract description 2
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- 230000002363 herbicidal effect Effects 0.000 abstract description 2
- 240000003768 Solanum lycopersicum Species 0.000 abstract 1
- 125000001425 triazolyl group Chemical group 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- 241000192043 Echinochloa Species 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 238000000034 method Methods 0.000 description 5
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- 206010001497 Agitation Diseases 0.000 description 3
- 239000005496 Chlorsulfuron Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- VJYIFXVZLXQVHO-UHFFFAOYSA-N chlorsulfuron Chemical compound COC1=NC(C)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CC=2)Cl)=N1 VJYIFXVZLXQVHO-UHFFFAOYSA-N 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 238000013461 design Methods 0.000 description 3
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- 239000000575 pesticide Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
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- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 description 3
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical group N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
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- 229940079593 drug Drugs 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
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- 239000001257 hydrogen Substances 0.000 description 2
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- 238000005286 illumination Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 2
- 229960004034 sitagliptin Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- 150000000178 1,2,4-triazoles Chemical class 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-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
- KZAQTVQJVOALDK-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-1,2,4-triazole Chemical compound FC(F)(F)C=1N=CNN=1 KZAQTVQJVOALDK-UHFFFAOYSA-N 0.000 description 1
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
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- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
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- 101710148054 Ketol-acid reductoisomerase (NAD(+)) Proteins 0.000 description 1
- 101710099070 Ketol-acid reductoisomerase (NAD(P)(+)) Proteins 0.000 description 1
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
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- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
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- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 244000144980 herd Species 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- GDBREXONAMPGBA-FJCMUPJRSA-N kassinin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=CC=C1 GDBREXONAMPGBA-FJCMUPJRSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- PTVWPYVOOKLBCG-ZDUSSCGKSA-N levodropropizine Chemical compound C1CN(C[C@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-ZDUSSCGKSA-N 0.000 description 1
- 229960002265 levodropropizine Drugs 0.000 description 1
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- IVRLZJDPKUSDCF-UHFFFAOYSA-N pyrazin-2-ylhydrazine Chemical compound NNC1=CN=CC=N1 IVRLZJDPKUSDCF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
1,2,4- of one kind triazole ring simultaneously [4,3-a] condense piperazine Mannich (Mannich) bases derivative, have the structural formula as shown in general formula I:
Description
Technical field
The invention belongs to farm weedings, the synthesis and application in fungicide field, and in particular to 1,2,4- of one kind triazole ring is simultaneously
[4,3-a] condenses Mannich (Mannich) bases derivative and its preparation method and application of piperazine.
Background technique
The prevention and treatment of phytopathogen and weeds agriculture, woods, herd, the realization of the every profession and trades such as secondary, fishing and public health during
It is extremely important.As people are to environmental problem pay attention to day by day, scientists is needed constantly to carry out innovation research, and then developed new
Efficient, less toxic, safe and with different role mode pesticide species.
Piperazine is a kind of important heterocyclic compound, and many derivatives containing piperazine have been directed to multiple in the research of medicine
Field is developed very rapid.Studies have shown that the compound containing piperazine and N- substitution often shows extensive bioactivity, such as
Antimicrobial, anti-hypertension, anticancer, antidepression, antianxiety, anti-inflammatory and analgesic etc..So far, it has developed many and has contained piperazine
Medical kind, such as Ciprofloxacin, Levodropropizine, Dasatinib, sitagliptin of piperazine heterocycle etc..Many heterocycle Mannich
(Mannich) alkaloid compound is also play an important role in medicament research and development due to its extensive bioactivity, however current double
The synthesis of heterocyclic compound and bioactivity research have become an important development direction of heterocyclic pesticide.Anellated triazoles class is derivative
Object is a kind of important dipeptides with the compound that amino acid acts on because its unique physiological activity is got the attention
Base peptidase-iv inhibitors and human nerve kassinin kinin-I antagonist, can be used for the diseases such as diabetes B, obesity and hypertension
It prevents and treats
In order to find 1 with superelevation bioactivity, 2,4- triazole ring annelated heterocycles pass through the sterilization to being commercialized
Agent structure, active site and the mechanism of action further appreciate that, herein based on this, utilize active fragment splicing principle and medicine
Object derivatization method is derived from 1,2,4- triazole rings in sitagliptin and simultaneously [4,3-a] condenses piperazine segment, and design has synthesized a system for the first time
Column 1,2,4- triazole ring simultaneously [4,3-a] condense Mannich (Mannich) bases derivative of piperazine, and it is corresponding raw to test it
Object activity (activity of weeding, bactericidal activity and KARI enzyme inhibition activity), summarizes its structure-activity relationship, to design and developing 1,2,4-
Triazole ring annelated heterocycles provide great reference, and are beneficial to the initiative efficient newtype drug of excess of export, are novel
Medicine and pesticide provide new opportunities and challenges, therefore related 1, and there are also very big for 2,4- triazole ring annelated heterocycles design aspects
Potentiality.
Summary of the invention
It is an object of the invention to analyze in view of the above technology, a kind of 1,2,4- triazole rings are provided and simultaneously [4,3-a] condense piperazine
Different substituent group is imported 1,2,4- triazoles by Mannich base analog derivative of piperazine and its preparation method and application, the preparation method
Ring simultaneously [4,3-a] condenses piperazine and prepares substitutive derivative, the higher new construction of discovery bioactivity, summarize new structure-activity relationship and
It is regular between bioactivity；The Mannich base analog derivative of preparation is the environment friendly agricultural with superelevation activity of weeding, bactericidal activity, can
Applied to the integrated control to crop smothering and fungus damage on various crops.
Technical solution of the present invention:
1,2,4- of one kind triazole ring simultaneously [4,3-a] condenses Mannich (Mannich) bases derivative of piperazine, has as logical
Structural formula shown in Formulas I:
In formula:
In general formula: R1It is CH3Or CF3；
R2Heteroaryl or the heteroaryl with 1-3 substituent group, the substituent group be low alkyl group, low-grade halogenated alkyl,
Phenyl, substituted-phenyl, halogen atom, the substitution be it is monosubstituted or polysubstituted, substituent group on substituted-phenyl is lower alkyl
Base, low-grade halogenated alkyl or halogen atom, heteroaryl are containing the furan in heteroatomic 5 member ring of one or more N, O, S or 6 member rings
It mutters, thiophene, pyrazoles, imidazoles, triazole, pyridine, pyrimidine, pyrazine, pyridazine；
" low alkyl group " be methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl,
Cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
The carbon skeleton of " low-grade halogenated alkyl " is identical as above-mentioned " low alkyl group ", herein under the premise of low-grade halogenated alkyl
It is the hydrogen moiety on low alkyl group or is all replaced by halogen atom；
The halogen atom is fluorine, chlorine, bromine or iodine.
A kind of 1,2,4- triazole ring simultaneously [4,3-a] condense piperazine Mannich (Mannich) bases derivative system
Preparation Method is shown below:
Specific step is as follows:
1) Formula II compound 1,2,4- triazole ring simultaneously [4,3-a] is condensed into piperazine and formula III compound 4- (4- substituted aryl
Methylene amino) -5- substitution -4H-1,2,4- triazole -3- mercaptan mix with organic solvent, and 37wt% formalin, stirring is added
Reaction filters the solid being born or filters out solid after concentration, and reaction temperature is 10-80 DEG C, and the reaction time is 2-10 hours；
2) above-mentioned solid ethyl alcohol or ethanol-water mixture are recrystallized, or directly uses ethanol washing, Formulas I chemical combination is made
Object, wherein the volume ratio of ethyl alcohol and water is 1:0.1-0.5 in ethanol-water mixture；
The organic solvent is methanol, ethyl alcohol, propyl alcohol, methylene chloride, tetrahydrofuran, 1,4- dioxane or N, N- diformazan
Base formamide；The Formula II compound represented, formula III compound represented, the molar ratio of organic solvent and formaldehyde are 1: 1-
1.2:1-3:1.5-2；
Compounds of formula II is prepared according to document (J.Med.Chem.2008,51,589-602.) operation, general formula
The compound of III is prepared according to the method in document (J.Agric.Food.Chem., 2010,58,5515-5522.).
A kind of 1,2,4- triazole ring Mannich (Mannich) the bases derivative that simultaneously [4,3-a] condenses piperazine is answered
With withered to cucumber fusarium axysporum, peanut Cercospora bacteria, Botryosphaeria berengeriana f. sp, wheat line for controlling plant fungus damage and crop smothering
Germ, tomato early blight bacterium and fusarium graminearum in vitro inhibitory activity with higher.
The invention has the advantages that
Different substituent group is imported 1,2,4- triazole ring and simultaneously [4,3-a] condenses piperazine preparation substitution derivative by the preparation method
Object, the higher new construction of discovery bioactivity are summarized regular between new structure-activity relationship and bioactivity；The Mannich bases of preparation
Derivative bactericidal activity with higher and activity of weeding, to cucumber fusarium axysporum, peanut Cercospora bacteria, Botryosphaeria berengeriana f. sp,
The phytopathogens such as rhizoctonia cerealis, tomato early blight bacterium and fusarium graminearum have high in vitro inhibitory activity, can be used for controlling
Plant fungus damage processed and crop smothering further include agricultural, forestry, acceptable carrier in health in the sterilization or Herbicidal combinations.
Specific embodiment
Further illustrate the present invention with reference to embodiments, the purpose is to be better understood when that the contents of the present invention are body
Existing substantive distinguishing features of the invention, therefore the cited case is not construed as limiting the scope of the invention.Here it also refers in particular to
Specific experiment method and apparatus involved in embodiment unless otherwise specified, is conventional method or says according to manufacturer out
The condition of bright book suggestion is implemented, and related reagent is commercially available without specified otherwise.
Embodiment 1:
1,2,4- of one kind triazole ring simultaneously [4,3-a] condense piperazine Mannich (Mannich) bases derivative, the bases
Derivative is (E) -4- ((R2—Methylene) amino) -5-R1- 2- ((3- (trifluoromethyl) -5,6- dihydro-[1,2,4] triazole [4,
3-a] piperazine -7 (8H)-yl) methyl) -2,4- dihydro -3H-1,2,4- triazole -3- thioketones, general formula of the chemical structure is as follows:
Preparation method, steps are as follows:
(1) 3- (trifluoromethyl) -1, the preparation of 2,4- triazols [4,3-a] pyrazine,
Its preparation process are as follows:
Its preparation step is as follows:
1) 31.3g (80wt%, 50mmol) hydrazine hydrate is added in 100mL three-necked bottle, is warming up to 60 DEG C, magnetic agitation
Under be slowly added dropwise 11.5g (100mmol) 2- chloropyrazine, keep temperature 60 C to react 10h, be cooled to 2 DEG C after completion of the reaction, be precipitated
Solid, filtering, dry white solid 6.63g, yield 60.5%；
2) 6.0g (55mmol) 2- diazanyl pyrazine is added in 250mL three-necked bottle, ice water is cooled to 0 DEG C, magnetic agitation
Under 28.6g (136mmol) trifluoroacetic anhydride is slowly added dropwise, be then warmed to room temperature reaction 2h, the poly phosphorus that diluted of 35mL be added
Acid (dilution of 10g water is added in every 100g polyphosphoric acids), is heated to 80 DEG C of reaction 10h, after being cooled to room temperature, is added to residue
30mL ice water, it is 7-8 that sodium hydroxide solution, which is slowly added dropwise, and adjusts pH, and ethyl acetate extraction merges organic layer, organic phase saturation
Sodium-chloride water solution washing, anhydrous sodium sulfate is dry, is condensed organic layer, obtains light yellow solid 6.7g, yield 65.1%.
(2) preparation of (trifluoromethyl) -5,6,7,8- tetrahydro [1,2,4] triazol [4,3-a] piperazine
It is by 5.0g (26.6mmol) 3- (trifluoromethyl) -1,2,4- triazol [4,3-a] pyrazine 3.0g and mass fraction
The palladium charcoal of its 5wt% is added in the 100mL three-neck flask of dress 50mL dehydrated alcohol, is passed through hydrogen under 30 DEG C of magnetic agitations,
Normal pressure hydrogenation 20h, is filtered after completion of the reaction, and filtrate chromatographs through decolorizing with activated carbon through column, obtains yellowish-brown liquid 3.5g, yield
68.5%.
(3) (E) -4- ((R2—Methylene) amino) -5-R1- 2- ((3- (trifluoromethyl) -5,6- dihydro-[1,2,4] triazole
[4,3-a] piperazine -7 (8H)-yl) methyl) preparation of -2,4- dihydro -3H-1,2,4- triazole -3- thioketones
In the round-bottomed flask of 50mL, it is added 0.17g (0.90mmol) (trifluoromethyl) -5,6,7,8- tetrahydros [1,2,4]
Triazol [4,3-a] piperazine, the formalin and 15mL dehydrated alcohol of 2.0g mass fraction 37%, is stirred at room temperature 15min, so
4- ((R is added afterwards2—Methylene) amino) -5-R11h is stirred at room temperature in -2,4- dihydro -3H-1,2,4- triazole -3- mercaptan, filters,
It is washed with dehydrated alcohol, target solids product is made.
In above-mentioned preparation method, R1、R2Table 1 is included in using the analog derivative physical property prepared by different raw materials,
Partial derivatives1H NMR data is included in table 2.
The physical property of 1 target compound of table
The hydrogen nuclear magnetic resonance modal data of 2 target compound of table
Prepared 1,2,4- triazole ring Mannich (Mannich) bases derivative that simultaneously [4,3-a] condenses piperazine is used for
Control plant fungus damage and crop smothering.
1) measurement of activity of weeding selects chlorsulfuron to compare:
Rape Plating: completing the filter paper of a diameter 5.6cm respectively in the culture dish of two groups of diameter 6cm, and 2 millis are added
The test compounds solution (solvent DMF) of 100 μ g/mL is risen, is added at rape seed 10,28 ± 1 DEG C of seed soaking 6 hours, it is black
Dark culture measured radicle length after 72 hours, detected chemical combination to the growth inhibition of rape radicle by compound under dark condition
The activity of weeding of object, each processing is repeated twice, and the rate of being inhibited (formula) is compared with blank control group.Activity refers to
Mark: embryo root colonization (%) the results are shown in Table 3.
Barnyard grass small-radius curve track: after completing bead and filter paper respectively in two groups 50 milliliters of small beaker, 6 milliliter of 100 μ is added
The test compounds solution (solvent DMF) of g/mL, at 10,28 ± 1 DEG C, the barnyard grass seed just to have showed money or valuables one carries unintentionally, illumination cultivation 72 hours
The height for measuring seedling afterwards, by compound under illumination condition to growth inhibition the removing come detection compound of barnyard grass Seedling Height
Careless activity, each processing is repeated twice, and the rate of being inhibited (formula) is compared with blank control group.Activity index: plant height
Growth inhibition ratio (%), the results are shown in Table 3.
The activity of weeding (inhibiting rate %, 100 μ g/mL) of 3. part of compounds of table
| No. | Rape | Barnyard grass | No | Rape | Barnyard grass |
| 01 | 38.3 | 10.0 | 10 | 13.9 | 0 |
| 02 | 51.1 | 10.0 | 11 | 35.1 | 10.0 |
| 03 | 16.1 | 5.0 | 12 | 32.0 | 10.0 |
| 04 | 52.7 | 17.0 | 13 | 20.1 | 0 |
| 05 | 25.3 | 3.0 | 14 | 4.9 | 0 |
| 06 | 33.5 | 5.0 | 15 | 59.8 | 8.0 |
| 07 | 31.8 | 5.0 | 16 | 21.5 | 0 |
| 08 | 35.2 | 13.0 | Chlorsulfuron | 74.7 | 66.7 |
| 09 | 0 | 12.0 |
Conclusion: compared with comparison medicine chlorsulfuron, the activity of weeding of compound has a certain distance with it, but compound
02,0.4,15 rape activity of weeding has been more than 50%, this also implies this series compound, and there are this potential weeding is living
Property, it can advanced optimize, to improve activity of weeding.
2) Antifungal Activity in Vitro test is carried out using derivative provided by the invention:
Test target: under 50mg/L concentration, cucumber fusarium axysporum, peanut Cercospora bacteria, Botryosphaeria berengeriana f. sp, wheat line
The frequently seen plants such as blight bacterium, tomato early blight bacterium and fusarium graminearum disease fungus has carried out antibacterial test.
Test method: mycelial growth rate method is used.Compound is dissolved in dimethyl sulfoxide, be made into concentration be 3.0 ×
104The solution of mg/L is diluted to the test fluid of concentration 50mg/L with tween solution.It takes 1mL access for trying strain, blank pair is set
According to.After cultivating 72h at 25 ± 1 DEG C, colony diameter is measured, and the rate of being inhibited (formula) is compared with blank control group,
And triazolone is selected to compare, it the results are shown in Table 4:
The bacteriostatic activity (inhibiting rate %, 50mg/L) of 4. part of compounds of table
Conclusion: compared with comparison medicine triazolone, this series compound part of compounds is to individual strain (cercospora brown spots of peanut
Bacterium, Botryosphaeria berengeriana f. sp, tomato early blight bacterium and fusarium graminearum) inhibitory activity it is suitable with triazolone, even more than three
Oxazolone, and there is broad spectrum activity (01 and 04), bactericidal activity is excellent.
Claims (3)
1. one kind 1,2,4- triazole ring simultaneously [4,3-a] condenses Mannich (Mannich) bases derivative of piperazine, it is characterised in that
With the structural formula as shown in general formula I:
General formula I:
In formula:
In general formula: R1It is CH3Or CF3；
R2Heteroaryl or the heteroaryl with 1-3 substituent group, the substituent group be low alkyl group, low-grade halogenated alkyl, phenyl,
Substituted-phenyl, halogen atom, the substitution be it is monosubstituted or polysubstituted, substituent group on substituted-phenyl is low alkyl group, low
Grade halogenated alkyl or halogen atom, heteroaryl are containing furans, the thiophene in heteroatomic 5 member ring of one or more N, O, S or 6 member rings
Pheno, pyrazoles, imidazoles, triazole, pyridine, pyrimidine, pyrazine, pyridazine；
" low alkyl group " is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, cyclopropyl
Base, cyclobutyl, cyclopenta or cyclohexyl；
The carbon skeleton of " low-grade halogenated alkyl " is identical as above-mentioned " low alkyl group ", herein under the premise of low-grade halogenated alkyl be
Hydrogen moiety on low alkyl group is all replaced by halogen atom；
The halogen atom is fluorine, chlorine, bromine or iodine.
2. a kind of Mannich (Mannich) bases that simultaneously [4,3-a] condenses piperazine of 1,2,4- triazole ring as described in claim 1 spreads out
The preparation method of biology, it is characterised in that be shown below:
Specific step is as follows:
1) Formula II compound 1,2,4- triazole ring simultaneously [4,3-a] is condensed into piperazine and formula III compound 4- (4- substituted aryl methylene
Amino) -5- substitution -4H-1,2,4- triazole -3- mercaptan mix with organic solvent, and 37wt% formalin is added, and stirring is anti-
It answers, filter the solid being born or filters out solid after concentration, reaction temperature is 10-80 DEG C, and the reaction time is 2-10 hours；
2) above-mentioned solid ethyl alcohol or ethanol-water mixture are recrystallized, or directly use ethanol washing, compound of formula I is made,
The volume ratio of ethyl alcohol and water is 1:0.1-0.5 in middle ethanol-water mixture；
The organic solvent is methanol, ethyl alcohol, propyl alcohol, methylene chloride, tetrahydrofuran, 1,4- dioxane or N, N- dimethyl methyl
Amide；The Formula II compound represented, formula III compound represented, the molar ratio of organic solvent and formaldehyde are 1: 1-1.2:
1-3∶1.5-2。
3. a kind of Mannich (Mannich) bases that simultaneously [4,3-a] condenses piperazine of 1,2,4- triazole ring as described in claim 1 spreads out
The application of biology, it is characterised in that: for controlling plant fungus damage and crop smothering.
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