CN116283822A - 噻唑和咪唑并[1,2-a]吡啶酰腙类化合物及应用 - Google Patents
噻唑和咪唑并[1,2-a]吡啶酰腙类化合物及应用 Download PDFInfo
- Publication number
- CN116283822A CN116283822A CN202310073525.7A CN202310073525A CN116283822A CN 116283822 A CN116283822 A CN 116283822A CN 202310073525 A CN202310073525 A CN 202310073525A CN 116283822 A CN116283822 A CN 116283822A
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- CN
- China
- Prior art keywords
- hydrogen
- carbohydrazide
- pyridine
- imidazo
- thiazole
- 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
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 80
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title claims abstract description 13
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 title claims description 10
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 11
- 241000196324 Embryophyta Species 0.000 claims abstract description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 241000209140 Triticum Species 0.000 claims abstract description 7
- 235000021307 Triticum Nutrition 0.000 claims abstract description 7
- 239000003899 bactericide agent Substances 0.000 claims abstract description 7
- 239000002917 insecticide Substances 0.000 claims abstract description 6
- 240000007594 Oryza sativa Species 0.000 claims abstract description 5
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000009566 rice Nutrition 0.000 claims abstract description 5
- 244000061456 Solanum tuberosum Species 0.000 claims abstract description 4
- 235000002595 Solanum tuberosum Nutrition 0.000 claims abstract description 4
- -1 (E) -N' - (4- (trifluoromethoxy) benzylidene) thiazole-4-carbohydrazide Chemical compound 0.000 claims description 125
- 239000001257 hydrogen Substances 0.000 claims description 78
- 229910052739 hydrogen Inorganic materials 0.000 claims description 78
- 150000002431 hydrogen Chemical class 0.000 claims description 78
- 229910052736 halogen Inorganic materials 0.000 claims description 46
- 150000002367 halogens Chemical class 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 42
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 42
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 42
- 229910052794 bromium Inorganic materials 0.000 claims description 42
- 125000004432 carbon atom Chemical group C* 0.000 claims description 42
- 229910052801 chlorine Inorganic materials 0.000 claims description 42
- 239000000460 chlorine Substances 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
- 125000001188 haloalkyl group Chemical group 0.000 claims description 36
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 36
- 229910052731 fluorine Inorganic materials 0.000 claims description 33
- 239000011737 fluorine Substances 0.000 claims description 33
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 33
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 24
- PZCUPAZNRMQILK-UHFFFAOYSA-N 1,3-thiazole-4-carbohydrazide Chemical compound NNC(=O)C1=CSC=N1 PZCUPAZNRMQILK-UHFFFAOYSA-N 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 15
- 125000005336 allyloxy group Chemical group 0.000 claims description 14
- RHZQESDITRQWDU-UHFFFAOYSA-N imidazo[1,2-a]pyridine-2-carbohydrazide Chemical compound C1=CC=CC2=NC(C(=O)NN)=CN21 RHZQESDITRQWDU-UHFFFAOYSA-N 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000005819 alkenylalkoxy group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 241001124076 Aphididae Species 0.000 claims description 7
- 239000000575 pesticide Substances 0.000 claims description 7
- 241000238631 Hexapoda Species 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 5
- 229910052799 carbon Inorganic materials 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 206010039509 Scab Diseases 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
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- 150000003839 salts Chemical class 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
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- 239000007787 solid Substances 0.000 description 22
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- GGQJRQPMZGEWFR-UHFFFAOYSA-N C(=O)NN.N1=CC=CC=C1 Chemical compound C(=O)NN.N1=CC=CC=C1 GGQJRQPMZGEWFR-UHFFFAOYSA-N 0.000 description 9
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- CASRSOJWLARCRX-UHFFFAOYSA-N 3,5-dichlorobenzaldehyde Chemical compound ClC1=CC(Cl)=CC(C=O)=C1 CASRSOJWLARCRX-UHFFFAOYSA-N 0.000 description 2
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 2
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- WDTUCEMLUHTMCB-UHFFFAOYSA-N 5-chloro-2-fluorobenzaldehyde Chemical compound FC1=CC=C(Cl)C=C1C=O WDTUCEMLUHTMCB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- 150000007857 hydrazones Chemical class 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- PQQRHWFRZHFGFM-UHFFFAOYSA-N 1,3-thiazole-4-carboxamide Chemical compound NC(=O)C1=CSC=N1 PQQRHWFRZHFGFM-UHFFFAOYSA-N 0.000 description 1
- YSFBEAASFUWWHU-UHFFFAOYSA-N 2,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(Cl)=C1 YSFBEAASFUWWHU-UHFFFAOYSA-N 0.000 description 1
- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- FABVMBDCVAJXMB-UHFFFAOYSA-N 3,5-dichloro-2-hydroxybenzaldehyde Chemical compound OC1=C(Cl)C=C(Cl)C=C1C=O FABVMBDCVAJXMB-UHFFFAOYSA-N 0.000 description 1
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- 239000005747 Chlorothalonil Substances 0.000 description 1
- 241001292317 Clausena Species 0.000 description 1
- 239000005759 Diethofencarb Substances 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- CRQQGFGUEAVUIL-UHFFFAOYSA-N chlorothalonil Chemical compound ClC1=C(Cl)C(C#N)=C(Cl)C(C#N)=C1Cl CRQQGFGUEAVUIL-UHFFFAOYSA-N 0.000 description 1
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- XDOKFEJMEJKVGX-UHFFFAOYSA-N ethyl 1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC=N1 XDOKFEJMEJKVGX-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
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- HZRSNVGNWUDEFX-UHFFFAOYSA-N pyraclostrobin Chemical compound COC(=O)N(OC)C1=CC=CC=C1COC1=NN(C=2C=CC(Cl)=CC=2)C=C1 HZRSNVGNWUDEFX-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- A01N43/74—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 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
-
- 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
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Abstract
本发明公开了噻唑和咪唑并[1,2‑a]吡啶酰腙类化合物及应用,该类化合物具有
Description
技术领域
本发明属于农药化学领域,具体涉及噻唑和咪唑并[1,2-a]吡啶酰腙类化合物及应用,对植物病源真菌、东方黏虫和蚜虫的有效抑制,以及这类化合物在防治农业病原性真菌感染和常见虫害中的用途。
背景技术
植物真菌病是指由植物病原真菌引起的病害,主要包括稻瘟菌、灰霉病菌、锈菌属真菌、禾谷镰孢、尖刀镰孢、布氏白粉菌、炭疽菌、玉米黑粉菌等。一种作物上可发现几种甚至几十种真菌病害。农作物病虫害也是主要农业灾害之一,我国农作物常见的病虫害有东方黏虫、玉米螟、棉铃虫、棉蚜、麦蚜、麦红蜘蛛、蝗虫等。植物真菌病和农作物虫害已严重影响我国农业生产。
近年来,稠杂环化合物逐渐发展成为新药物开发中闪光点。酰腙是一类含有酰胺和亚胺官能团结构的化合物。N-酰腙结构具有拟肽性质,可以被多种不同受体识别。又因酰腙氮、氧原子具有使其配位能力极强,有利于与多数的金属离子形成配合物。通过修饰其化学结构,可以获得更多高活性的杂环取代酰腙类化合物,其在农业、医药以及工业等各个领域都被广泛应用。在农业方面,酰腙类化合物用途广泛,被用作除草剂、杀菌剂及杀虫剂等。在医药方面,杂环取代酰腙类化合物具有多种生理活性,酰腙及其金属配合物已经被广泛用于医药、分析和功能材料等领域。酰腙类化合物具有抗菌、抗寄生虫、抗肿瘤以及酶抑制活性等。在工业方面,酰腙类化合物被应用于生物材料的荧光分析、发光材料、染色剂以及荧光探针材料等。
目前国内应用广泛的杀菌剂包括吡唑醚菌酯、百菌清、噻呋酰胺和乙霉威等。螺螨酯、虫酰肼和氟啶脲等,是市场上活性较好的杀虫剂。但随着社会的发展,耐药性是现有杀菌杀虫剂常见的问题,而杀菌杀虫剂的不规范使用是导致农药效用下降的主要原因。因此设计和开发新的新型的杂环酰腙类化合物对人类生命健康和粮食安全事业发展具有重要意义。
发明内容
本发明的目的在于探索一类新型高效的新型杂环酰腙类杀菌杀虫剂,提供具有抗植物病原菌和杀虫活性的杂环酰腙类衍生物。
本发明的技术方案如下:
噻唑和咪唑并[1,2-a]吡啶酰腙类化合物,所述的化合物包括:
式I的化合物或其药学上可接受的盐:
式I中R1选自氢、烷基、卤素、羟基和卤代烷基;
R2选自氢、烷基、卤素、羟基和卤代烷基;
R3选自氢、烷基、卤素、羟基、卤代烷氧基、卤代烷基、烯基烷氧基和卤代烯基烷氧基;
R4选自氢、烷基、卤素、羟基和卤代烷基;
R5选自氢、烷基、卤素、羟基和卤代烷基;
和/或式Ⅱ的化合物或其药学上可接受的盐:
式Ⅱ中R1选自氢、烷基、卤素、羟基和卤代烷基;
R2选自氢、烷基、卤素、羟基和卤代烷基;
R3选自氢、烷基、卤素、羟基、卤代烷氧基、卤代烷基、烯基烷氧基和卤代烯基烷氧基;
R4选自氢、烷基、卤素、羟基和卤代烷基;
R5选自氢、烷基、卤素、羟基和卤代烷基;
R'1选自氢、烷基、卤素、羟基和卤代烷基;
R'2选自氢、烷基、卤素、羟基和卤代烷基;
R'3选自氢、烷基、卤素、羟基和卤代烷基。
可选的,所述的烷基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;
所述的卤代烷基为具有1-6个碳原子的直链或支链饱和烃基,或为具有3-6个碳原子的环状饱和烃基,或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中一个或多个碳原子被一个或多个卤原子取代;
所述的烷氧基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被氧取代;
所述的烯基、炔基为具有1-6个碳原子的直链或支链的含有双键或三键的不饱和烃基;
所述的卤素选自氟、氯、溴和碘的取代;
所述的卤代不饱和烃基为如上定义的烯基或炔基中一个或多个碳原子被一个或多个卤原子取代;
所述的卤代烷基为如上定义的烷基与卤素连接;
所述的卤代烷氧基为如上定义的烷氧基与卤素连接;
所述的烯基烷氧基为如上定义的不饱和烃基烷氧基连接;
所述的卤代烯基烷氧基为如上定义的卤代不饱和烃基烷氧基连接。
可选的,所述式I中R1选自氢、氟、氯、溴和羟基;
R2选自氢、氟、氯和溴;
R3选自氢、氟、氯、溴、三氟甲基、三氟甲氧基和烯丙氧基;
R4选自氢、氟、氯、溴和三氟甲基;
R5选自氢、氟、氯和溴。
可选的,所述式Ⅱ中R1选自氢、氟、氯、溴和羟基;
R2选自氢、氟、氯和溴;
R3选自氢、氟、氯、溴、三氟甲基、三氟甲氧基和烯丙氧基;
R4选自氢、氟、氯、溴和三氟甲基;
R5选自氢、氟、氯和溴;
R'1选自氢、氯、溴和苄氧基;
R'2选自氢、氯和溴;
R'3选自氢、氯和溴。
可选的,通式I的化合物优选以下结构化合物:
(E)-N'-(4-(三氟甲氧基)亚苄基)噻唑-4-碳酰肼(I-1);
(E)-N'-(5-氯-2-氟亚苄基)噻唑-4-碳酰肼(I-2);
(E)-N'-(2,4-二氯亚苄基)噻唑-4-碳酰肼(I-3);
(E)-N'-(3,5-二氯亚苄基)噻唑-4-碳酰肼(I-4);
(E)-N'-(4-(烯丙氧基)亚苄基)噻唑-4-碳酰肼(I-5);
(E)-N'-(3-氯亚苄基)噻唑-4-碳酰肼(I-6);
(E)-N'-(2,6-氯亚苄基)噻唑-4-碳酰肼(I-7);
(E)-N'-(3,5-二氯-2-羟基亚苄基)噻唑-4-碳酰肼(I-8);
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-9);
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-10)。
可选的,通式Ⅱ的化合物优选以下结构化合物:
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-1);
(E)-N'-(3-氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-2);
(E)-N'-(5-氯-2-氟亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-3);
(E)-N'-(2,6-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-4);
(E)-N'-(3,5-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-5);
(E)-N'-(4-(烯丙氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-6);
(E)-N'-(2-溴亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-7);
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-8);
(E)-N'-(4-(三氟甲氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-9)。
本发明所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物用于制备植物杀菌剂的应用。
可选的,所述的杀菌剂用于防治包括番茄灰霉病、马铃薯干腐病、苹果炭疽病、苹果腐烂病、水稻稻瘟病和/或小麦赤霉病。
本发明所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物用于制备植物杀虫剂的应用。
可选的,所述的杀虫剂用于防治包括黏虫和/或蚜虫。
本发明的化合物活性测试结果表示通式Ⅰ和Ⅱ的化合物对马铃薯干腐病菌(Fusarium solani)、番茄灰霉病菌(Botrytis cinerea)、小麦赤霉病菌(Fusariumgraminearum)、苹果腐烂病菌(Cytospora sp.)、苹果炭疽病菌(Colletotrichumgloeosporioides)和水稻稻瘟病菌(Magnaporthe grisea)具有优良的抑制活性,可以用于植物杀菌剂的制备。
活性测试结果表示通式Ⅰ和Ⅱ的化合物对东方黏虫具有优良的抑制活性,可以用于植物杀虫剂的制备。
具体实施方式
下面将结合本发明实施例对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物的两种通式包括:
式I的化合物或其药学上可接受的盐:
式I中R1选自氢、烷基、卤素和羟基;
R2选自氢、烷基、卤素和羟基;
R3选自氢、烷基、卤素、羟基、卤代烷氧基、卤代烷基和烷氧基烯基;
R4选自氢、烷基、卤素、羟基和卤代烷基;
R5选自氢、烷基、卤素和羟基;
和/或式Ⅱ的化合物或其药学上可接受的盐:
式Ⅱ中R1选自氢、烷基、卤素和羟基;
R2选自氢、烷基、卤素和羟基;
R3选自氢、烷基、卤素、羟基、卤代烷氧基、卤代烷基、烯基烷氧基和卤代烯基烷氧基;
R4选自氢、烷基、卤素、羟基和卤代烷基;
R5选自氢、烷基、卤素和羟基;
R'1选自氢、烷基、卤素和烷氧基;
R'2选自氢、烷基、卤素和烷氧基;
R'3选自氢、烷基、卤素和烷氧基。
烷基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;
卤代烷基为具有1-6个碳原子的直链或支链饱和烃基,或为具有3-6个碳原子的环状饱和烃基,或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中一个或多个碳原子被一个或多个卤原子取代;
烷氧基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被氧取代;
烯基、炔基为具有1-6个碳原子的直链或支链的含有双键或三键的不饱和烃基;
卤素主要选自氟、氯、溴和碘的取代;
卤代不饱和烃基为如上定义的烯基或炔基中一个或多个碳原子被一个或多个卤原子取代;
卤代烷基为如上定义的烷基与卤素连接;
卤代烷氧基为如上定义的烷氧基与卤素连接;
烯基烷氧基为如上定义的不饱和烃基烷氧基连接;
卤代烯基烷氧基为如上定义的卤代不饱和烃基烷氧基连接。
本发明的优选方案在于:
式I中R1选自氢、氟、氯、溴和羟基;
R2选自氢、氟、氯和溴;
R3选自氢、氟、氯、溴、三氟甲基、三氟甲氧基和烯丙氧基;
R4选自氢、氟、氯、溴和三氟甲基;
R5选自氢、氟、氯和溴;
式Ⅱ中R1选自氢、氟、氯、溴和羟基;
R2选自氢、氟、氯和溴;
R3选自氢、氟、氯、溴、三氟甲基、三氟甲氧基和烯丙氧基;
R4选自氢、氟、氯、溴和三氟甲基;
R5选自氢、氟、氯和溴;
R'1选自氢、氯、溴和苄氧基;
R'2选自氢、氯和溴;
R'3选自氢、氯和溴。
通式I的化合物优选以下结构化合物:
(E)-N'-(4-(三氟甲氧基)亚苄基)噻唑-4-碳酰肼(I-1);
(E)-N'-(5-氯-2-氟亚苄基)噻唑-4-碳酰肼(I-2);
(E)-N'-(2,4-二氯亚苄基)噻唑-4-碳酰肼(I-3);
(E)-N'-(3,5-二氯亚苄基)噻唑-4-碳酰肼(I-4);
(E)-N'-(4-(烯丙氧基)亚苄基)噻唑-4-碳酰肼(I-5);
(E)-N'-(3-氯亚苄基)噻唑-4-碳酰肼(I-6);
(E)-N'-(2,6-氯亚苄基)噻唑-4-碳酰肼(I-7);
(E)-N'-(3,5-二氯-2-羟基亚苄基)噻唑-4-碳酰肼(I-8);
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-9);
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-10)。
通式Ⅱ的化合物优选以下结构化合物:
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-1);(E)-N'-(3-氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-2);
(E)-N'-(5-氯-2-氟亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-3);
(E)-N'-(2,6-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-4);
(E)-N'-(3,5-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-5);
(E)-N'-(4-(烯丙氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-6);
(E)-N'-(2-溴亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-7);
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-8);(E)-N'-(4-(三氟甲氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-9)。本发明的化合物制备方法如下:
Scheme1杂环酰腙类化合物Ⅰ的合成方法。(1)杂环酯类原料;(2)合成中间体;(3)醛类原料;(4)酰腙类衍生物;
Scheme2杂环酰腙类化合物Ⅱ的合成方法。(1)吡啶类原料;(2、3)合成中间体;(4)醛类原料;(5)酰腙类衍生物;
本发明的方案中,如无特殊说明,提到的比例或百分含量均以质量计。
I类化合物的一般制备方法:
(I)在10mL茄形瓶中加入噻唑-4-羧酸乙酯(100mg,0.64mmol)的无水EtOH(6.4ml)溶液,加入NH2-NH2·H2O(0.2ml,10-15eq),室温搅拌,反应过夜。真空浓缩,硅胶色谱柱纯化DCM:MeOH(50:1~10:1)得中间体化合物2(噻唑-4-甲酰肼),白色固体。
(II)在25ml茄形瓶加入2(噻唑-4-甲酰肼)和3的甲醇溶液(5ml),加入2滴冰醋酸,反应混合物在室温搅拌过夜。真空浓缩,硅胶色谱柱纯化DCM:MeOH(50:1~10:1)得到目标化合物。
Ⅱ类化合物的一般制备方法:
(I)在25mL茄形瓶中加入吡啶类原料1(500mg,5.31mmol)和无水EtOH(10ml),冰浴搅拌,加入3-溴丙酮酸乙酯(1.55g,7.97mmol),回流24h;冷却后真空浓缩,硅胶色谱柱纯化DCM:MeOH(100:1~50:1)得中间体化合物2,淡黄色固体。
在10mL茄形瓶中加入中间体化合物2(50mg,0.26mmol),加入NH2-NH2·H2O(0.5ml,过量),搅拌均匀后69℃回流2h。真空浓缩,硅胶色谱柱纯化,DCM:MeOH(50:1~10:1)得到中间体化合物3,白色固体。
(II)在25ml茄形瓶加入中间体化合物3和醛类原料4的甲醇溶液(5ml),加入2滴冰醋酸,室温搅拌过夜。真空浓缩,硅胶色谱柱纯化DCM:MeOH(50:1~10:1)得到目标化合物。
实施例1:
(E)-N'-(4-(三氟甲氧基)亚苄基)噻唑-4-碳酰肼(I-1);
以通式I的制备方法,用噻唑-4-甲酰肼和4-三氟甲氧基苯甲醛制得目标化合物I-1,得黄色固体,产率88.63%。1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),9.27(d,J=2.0Hz,1H),8.61(s,1H),8.54(d,J=2.0Hz,1H),7.85–7.82(m,2H),7.47–7.44(m,2H).13CNMR(100MHz,DMSO-d6)δ157.14,155.33,149.51,149.33,147.08,133.65,129.05,126.16,121.37.
实施例2:
(E)-N'-(5-氯-2-氟亚苄基)噻唑-4-碳酰肼(I-2);
以通式I的制备方法,用噻唑-4-甲酰肼和5-氯-2-氟苯甲醛制得目标化合物I-2,得黄色固体,产率96.39%。1NMR(400MHz,DMSO-d6)δ12.32(s,1H),9.28(d,J=2.0Hz,1H),8.80(s,1H),8.57(d,J=2.0Hz,1H),7.89(dd,J=6.2,2.8Hz,1H),7.55(ddd,J=8.9,4.5,2.8Hz,1H),7.38(dd,J=10.1,8.9Hz,1H).13C NMR(100MHz,DMSO-d6)δ159.75(d,J=323Hz),157.24,155.37,149.27,139.91(d,J=4.0Hz),131.45(d,J=9.0Hz),129.00,126.50,125.39(d,J=3.0Hz),123.88(d,J=12.0Hz),118.24(d,J=23.0Hz).
实施例3:
(E)-N'-(2,4-二氯亚苄基)噻唑-4-碳酰肼(I-3);
以通式I的制备方法,用噻唑-4-甲酰肼和2,4-二氯苯甲醛制得目标化合物I-3,得白色固体,产率78.39%。1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),9.28(d,J=2.0Hz,1H),8.99(s,1H),8.56(d,J=2.0Hz,1H),8.02(d,J=8.5Hz,1H),7.72(d,J=2.1Hz,1H),7.54–7.49(m,1H).13C NMR(100MHz,DMSO-d6)δ157.25,155.31,149.38,143.61,135.12,134.03,130.91,129.40,128.18,128.02,126.38.
实施例4:
(E)-N'-(3,5-二氯亚苄基)噻唑-4-碳酰肼(I-4);
以通式I的制备方法,用噻唑-4-甲酰肼和3,5-二氯苯甲醛制得目标化合物I-4,得黄色固体,产率96.98%。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),9.28(d,J=2.0Hz,1H),8.56(d,J=2.0Hz,1H),8.54(s,1H),7.73(d,J=1.9Hz,2H),7.68(t,J=1.9Hz,1H).13C NMR(100MHz,DMSO-d6)δ157.27,155.36,149.30,145.50,138.09,134.66,129.12,126.45,125.36.
实施例5:
(E)-N'-(4-(烯丙氧基)亚苄基)噻唑-4-碳酰肼(I-5);
以通式I的制备方法,用噻唑-4-甲酰肼和4-烯丙氧基苯甲醛制得目标化合物I-5,得黄色固体,产率88.33%。1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),9.26(d,J=2.0Hz,1H),8.52(s,1H),8.50(d,J=2.0Hz,1H),7.68–7.61(m,2H),7.06–7.00(m,2H),6.05(s,1H),5.41(dq,J=17.3,1.7Hz,1H),5.28(dq,J=10.5,1.5Hz,1H),4.62(dt,J=5.3,1.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ159.80,156.85,155.15,149.77,148.49,133.42,128.76,127.03,125.61,117.67,115.03,68.30.
实施例6:
(E)-N'-(3-氯亚苄基)噻唑-4-碳酰肼(I-6);
以通式I的制备方法,用噻唑-4-甲酰肼和3-氯苯甲醛制得目标化合物I-6,得白色固体,产率95.64%。1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),9.28(d,J=2.0Hz,1H),8.57(s,1H),8.55(d,J=2.0Hz,1H),7.75(d,J=2.0Hz,1H),7.66(ddd,J=4.7,3.3,1.5Hz,1H),7.50(dd,J=4.0,2.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ157.16,155.30,149.45,146.98,136.60,133.68,130.81,129.78,126.24,126.20,125.96.
实施例7:
(E)-N'-(2,6-二氯亚苄基)噻唑-4-碳酰肼(I-7);
以通式I的制备方法,用噻唑-4-甲酰肼和2,6-二氯苯甲醛制得目标化合物I-7,得黄色固体,产率89.58%。1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),12.53(s,1H),9.30(d,J=2.0Hz,1H),8.73(s,1H),8.61(d,J=2.0Hz,1H),7.60(dd,J=19.0,2.5Hz,2H).13CNMR(100MHz,DMSO-d6)δ157.22,155.34,149.36,144.04,133.94,131.26,130.82,129.06,126.43.
实施例8:
(E)-N'-(3,5-二氯-2-羟基亚苄基)噻唑-4-碳酰肼(I-8);
以通式I的制备方法,用噻唑-4-甲酰肼和3,5-二氯-2-羟基苯甲醛制得目标化合物I-8,得黄色固体,产率91.15%。1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),9.29(d,J=2.0Hz,1H),8.79(s,1H),8.55(d,J=2.0Hz,1H),7.58(d,J=0.9Hz,1H),7.56(s,1H),7.47–7.43(m,1H).13C NMR(100MHz,DMSO-d6)δ157.16,155.63,152.34,148.64,148.04,130.36,128.49,127.05,122.97,121.54,120.81.
实施例9:
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-9);
以通式I的制备方法,用噻唑-4-甲酰肼和2-氟-4-三氟甲基苯甲醛制得目标化合物I-9,得黄色固体,产率93.48%。1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),9.29(d,J=2.0Hz,1H),8.88(s,1H),8.58(d,J=2.0Hz,1H),8.16(t,J=7.7Hz,1H),7.79(dd,J=10.6,1.8Hz,1H),7.68(dd,J=8.2,1.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.50(dd,J=297Hz),157.28,155.34,149.25,139.86(d,J=5.0Hz),131.34(dd,J=33.0,8.5Hz),127.64(d,J=3.0Hz),126.53,126.17(d,J=10.0Hz),123.23(q,J=269Hz),121.70(t,J=4Hz),113.71(dd,J=24.0,4.0Hz).
实施例10:
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-10);
以通式I的制备方法,用噻唑-4-甲酰肼和2-氟-5-(三氟甲基)苯甲醛制得目标化合物I-10,得黄色固体,产率92.96%。1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),9.29(d,J=2.0Hz,1H),8.88(s,1H),8.58(d,J=2.0Hz,1H),8.21(dd,J=6.6,2.4Hz,1H),7.89(td,J=5.0,4.5,2.3Hz,1H),7.57(t,J=9.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ162.43(d,J=248.0Hz),157.29,155.39,149.20,139.78(d,J=3.0Hz),128.83(d,J=5.0Hz),126.55,125.87(dd,J=32.0,3.0Hz),124.09(t,J=190Hz),123.54–123.25(m),122.32,117.71(d,J=22.0Hz).
实施例11:
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-1);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和2-氟-5-三氟甲基苯甲醛制得目标化合物Ⅱ-1,得黄色固体,产率98.31%。1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.89(s,1H),8.62(d,J=6.8Hz,1H),8.59(s,1H),8.21(dd,J=6.5,2.5Hz,1H),7.90–7.85(m,1H),7.65(d,J=9.2Hz,1H),7.56(t,J=9.4Hz,1H),7.40(ddd,J=8.9,6.8,1.3Hz,1H),7.03(t,J=6.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ162.32(d,J=233.0Hz),158.95,144.05,139.03(d,J=4.0Hz),138.14,129.66,129.16–128.53(m),127.79,126.83,125.86(dd,J=33.0,3.0Hz),123.55–123.18(m),122.37(d,J=270.0Hz),117.71(d,J=23.0Hz),117.35,116.30,113.54.
实施例12:
(E)-N'-(3-氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-2);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和3-氯苯甲醛制得目标化合物Ⅱ-2,得白色固体,产率89.86%。1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.62(dt,J=6.9,1.2Hz,1H),8.57(d,J=11.0Hz,2H),7.75(q,J=1.5Hz,1H),7.68–7.61(m,2H),7.54–7.45(m,2H),7.39(ddd,J=9.2,6.7,1.3Hz,1H),7.03(td,J=6.8,1.1Hz,1H).13CNMR(100MHz,DMSO-d6)δ158.77,146.34,144.03,138.36,136.80,133.70,130.85,129.67,127.80,126.80,126.16,125.93,117.35,116.09,113.51.
实施例13:
(E)-N'-(5-氯-2-氟亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-3);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和5-氯-2-氟苯甲醛制得目标化合物Ⅱ-3,得白色固体,产率91.39%。1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.81(s,1H),8.62(dt,J=6.9,1.2Hz,1H),8.57(s,1H),7.90(dd,J=6.1,2.8Hz,1H),7.65(dq,J=9.3,1.0Hz,1H),7.56–7.52(m,1H),7.42–7.35(m,2H),7.03(td,J=6.8,1.2Hz,1H).13CNMR(100MHz,DMSO-d6)δ159.45(d,J=270.0Hz),158.91,144.05,139.22(d,J=4.0Hz),138.20,131.30(d,J=8.0Hz),129.00(d,J=3.0Hz),127.80,126.83,125.36(d,J=2.0Hz),124.08(d,J=12.0Hz),118.25(d,J=23.0Hz),117.36,116.25,113.54.
实施例14:
(E)-N'-(2,6-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-4);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和2,6-二氯苯甲醛制得目标化合物Ⅱ-4,得白色固体,产率95.18%。1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),8.80(s,1H),8.65–8.61(m,1H),8.56–8.54(m,1H),7.65(dd,J=9.2,1.2Hz,1H),7.59–7.56(m,2H),7.47–7.44(m,1H),7.40(ddd,J=9.2,6.7,1.3Hz,1H),7.03(td,J=6.8,1.2Hz,1H).13C NMR(100MHz,DMSO-d6)δ158.84,144.05,143.43,138.30,133.97,131.21,130.98,129.08,127.82,126.81,117.38,116.19,113.53.
实施例15:
(E)-N'-(3,5-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-5);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和3,5-二氯苯甲醛制得目标化合物Ⅱ-5,得白色固体,产率91.22%。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),8.62(dt,J=6.9,1.3Hz,1H),8.56(d,J=5.3Hz,2H),7.72(d,J=2.0Hz,2H),7.68(t,J=1.9Hz,1H),7.64(dt,J=9.1,1.1Hz,1H),7.39(ddd,J=9.2,6.7,1.3Hz,1H),7.03(td,J=6.7,1.2Hz,1H).13C NMR(100MHz,DMSO-d6)δ158.89,144.85,144.03,138.28,138.21,134.68,129.00,127.80,126.83,125.29,117.36,116.21,113.54.
实施例16:
(E)-N'-(4-(烯丙氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-6);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和4-烯丙氧基苯甲醛制得目标化合物Ⅱ-6,得白色固体,产率98.04%。1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),8.61(dd,J=6.9,1.3Hz,1H),8.54–8.52(m,2H),7.65–7.62(m,3H),7.40–7.36(m,1H),7.05–7.01(m,3H),6.06(m,1H),5.41(dq,J=17.3,1.7Hz,1H),5.28(dq,J=10.5,1.5Hz,1H),4.62(dt,J=5.3,1.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ159.72,158.41,147.84,143.97,138.70,133.47,128.68,127.75,127.21,126.66,117.71,117.30,115.77,115.05,113.39,68.31.
实施例17:
(E)-N'-(2-溴亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-7);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和2-溴苯甲醛制得目标化合物Ⅱ-7,得白色固体,产率82.14%。1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.99(s,1H),8.62(d,J=6.6Hz,1H),8.56(s,1H),8.01(dd,J=7.9,1.8Hz,1H),7.73–7.59(m,2H),7.47(t,J=7.6Hz,1H),7.43–7.32(m,2H).13C NMR(100MHz,DMSO-d6)δ158.91,146.48,144.04,138.44,133.49,133.21,131.67,128.11,127.79,127.37,126.77,123.63,117.37,116.12,113.50.
实施例18:
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-8);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和2-氟-4-三氟甲基苯甲醛制得目标化合物Ⅱ-8,得黄色固体,产率93.28%。1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.89(s,1H),8.62(d,J=6.9Hz,1H),8.58(s,1H),8.16(t,J=7.7Hz,1H),7.81–7.76(m,1H),7.69–7.64(m,2H),7.42–7.37(m,1H),7.03(t,J=6.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.24(d,J=251.0Hz),158.96,144.06,139.16(d,J=4.0Hz),138.17,133.19,127.82,127.59(d,J=3.0Hz),126.86,126.39(d,J=11.0Hz),121.75(d,J=5.0Hz),117.38,116.31,114.08–113.60(m),113.57.
实施例19:
(E)-N'-(4-(三氟甲氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-9);
以通式Ⅱ的制备方法,用咪唑并[1,2-a]吡啶-2-甲酰肼和4-三氟甲氧基苯甲醛制得目标化合物Ⅱ-9,得黄色固体,产率98.14%。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.62(d,J=7.3Hz,2H),8.55(s,1H),7.83(d,J=8.5Hz,2H),7.64(d,J=9.2Hz,1H),7.45(d,J=8.3Hz,2H),7.39(dd,J=9.2,6.5Hz,1H),7.02(t,J=6.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ158.75,149.25,146.43,144.04,138.43,133.84,128.97,127.81,126.81,122.40(q,J=126Hz),121.40,117.36,116.05,113.51.
本发明中的化合物均可用上述或类似上述的方法制备得到,根据取代基的不同和取代基位置的不同选用相应的原料即可。
(I)活性测试结果表示通式Ⅰ和Ⅱ的化合物对马铃薯干腐病菌(Fusariumsolani)、番茄灰霉病菌(Botrytis cinerea)、小麦赤霉病菌(Fusarium graminearum)、苹果腐烂病菌(Cytospora sp.)、苹果炭疽病菌(Colletotrichum gloeosporioides)和水稻稻瘟病菌(Magnaporthe grisea)具有优良的抑制活性。
下面是部分活性评价实验及结果
所有化合物用菌丝生长速率法测定对不同植物源真菌的抑制活性,并与阳性对照药物进行比较,筛选出活性好的化合物。
具体方法:将待筛选化合物配置成10mg/m L的母液,取75μL(50ppm,下同)加入20mL固体培养基中并迅速混合均匀。供试菌株需预先活化,用内径5mm的打孔器制取足够数量的菌饼备用。用无菌接种针把菌饼放在凝固好的培养基上,含菌丝面朝下,轻轻按压使菌饼与培养基紧密接触,每个培养皿内放三个同一株病原真菌的菌饼。接菌完成的培养皿放入26℃-28℃的恒温培养箱中黑暗培养,48~96h后用直尺测量真菌菌落的径向长度(十字交叉法,取平均值)。
以相应的DMSO溶剂体系作为空白对照,以多菌灵为阳性对照。抑制率(%)=抑制率(%)=(C–T)/(C–5mm)×100%,C为空白对照组的菌落直径(mm),T为处理组或阳性对照组的菌落直径(mm)。LC50值由不同浓度梯度的抑制率确定,拟合作图用IBM SPSSStatistics 21计算。
表1部分化合物对部分化合物对番茄灰霉病菌、马铃薯干腐病菌和苹果炭疽病菌的毒力测定
表2部分化合物对部分化合物对苹果腐烂病菌、水稻稻瘟病菌和小麦赤霉病菌的毒力测定
(II)活性测试结果表示通式Ⅰ和Ⅱ的化合物对东方黏虫具有优良的抑制活性。
所有化合物用浸叶法测定对3龄东方黏虫的抑制活性,并与空白组、阴性组进行比较,筛选出活性好的化合物。
具体方法:选择大小匀称、健康状态良好的3龄东方黏虫置于24孔板内,将待筛选化合物配置成1mg/m L的母液,取适量新鲜干净的叶子,分切为0.5mm的正方形备用。将叶片浸于待测药剂溶液中,10s后取出置于培养皿中晾干,等量放置于含有东方黏虫的24孔板中。待24h和48h后观察并记录结果。
下面是部分活性评价实验及结果:
表3化合物在1.0mg/mL浓度时对三龄东方黏虫的杀虫活性
a 10.0mg/mL时,苦皮藤素V(CV)对东方黏虫的死亡率
表4处理48小时后部分化合物对东方黏虫(3龄)的LD50值
(III)活性测试结果表示通式Ⅰ和Ⅱ的化合物对蚜虫具有优良的抑制活性。
测试所有化合物对无翅豌豆成蚜的抑制活性,并与空白组、阴性组进行比较,筛选出活性好的化合物。
具体方法:随机选择健康状态良好的20-30头无翅豌豆成蚜置于豌豆叶片,0.1mg的待筛选化合物利用200μL丙酮进行溶解,并利用0.1%tween 80%水溶液将药剂稀释,配置成100mg/L的母液,将叶片置于药液中10s,24h后检测试虫死亡情况并记录结果。
下面是部分活性评价实验及结果:
表5处理24小时后部分化合物对无翅豌豆成蚜的LD50值
以上详细描述了本公开的优选实施方式,但是,本公开并不限于上述实施方式中的具体细节,在本公开的技术构思范围内,可以对本公开的技术方案进行多种简单变型,这些简单变型均属于本公开的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本公开对各种可能的组合方式不再另行说明。
此外,本公开的各种不同的实施方式之间也可以进行任意组合,只要其不违背本公开的思想,其同样应当视为本公开所公开的内容。
Claims (10)
1.噻唑和咪唑并[1,2-a]吡啶酰腙类化合物,其特征在于,所述的化合物包括:
式I的化合物或其药学上可接受的盐:
式I中R1选自氢、烷基、卤素、羟基和卤代烷基;
R2选自氢、烷基、卤素、羟基和卤代烷基;
R3选自氢、烷基、卤素、羟基、卤代烷氧基、卤代烷基、烯基烷氧基和卤代烯基烷氧基;
R4选自氢、烷基、卤素、羟基和卤代烷基;
R5选自氢、烷基、卤素、羟基和卤代烷基;
和/或式Ⅱ的化合物或其药学上可接受的盐:
式Ⅱ中R1选自氢、烷基、卤素、羟基和卤代烷基;
R2选自氢、烷基、卤素、羟基和卤代烷基;
R3选自氢、烷基、卤素、羟基、卤代烷氧基、卤代烷基、烯基烷氧基和卤代烯基烷氧基;
R4选自氢、烷基、卤素、羟基和卤代烷基;
R5选自氢、烷基、卤素、羟基和卤代烷基;
R'1选自氢、烷基、卤素、羟基和卤代烷基;
R'2选自氢、烷基、卤素、羟基和卤代烷基;
R'3选自氢、烷基、卤素、羟基和卤代烷基。
2.根据权利要求1所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物,其特征在于,所述的烷基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;
所述的卤代烷基为具有1-6个碳原子的直链或支链饱和烃基,或为具有3-6个碳原子的环状饱和烃基,或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中一个或多个碳原子被一个或多个卤原子取代;
所述的烷氧基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被氧取代;
所述的烯基、炔基为具有1-6个碳原子的直链或支链的含有双键或三键的不饱和烃基;
所述的卤素选自氟、氯、溴和碘的取代;
所述的卤代不饱和烃基为如上定义的烯基或炔基中一个或多个碳原子被一个或多个卤原子取代;
所述的卤代烷基为如上定义的烷基与卤素连接;
所述的卤代烷氧基为如上定义的烷氧基与卤素连接;
所述的烯基烷氧基为如上定义的不饱和烃基烷氧基连接;
所述的卤代烯基烷氧基为如上定义的卤代不饱和烃基烷氧基连接。
3.根据权利要求1所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物,其特征在于,所述式I中R1选自氢、氟、氯、溴和羟基;
R2选自氢、氟、氯和溴;
R3选自氢、氟、氯、溴、三氟甲基、三氟甲氧基和烯丙氧基;
R4选自氢、氟、氯、溴和三氟甲基;
R5选自氢、氟、氯和溴。
4.根据权利要求1所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物,其特征在于,所述式Ⅱ中R1选自氢、氟、氯、溴和羟基;
R2选自氢、氟、氯和溴;
R3选自氢、氟、氯、溴、三氟甲基、三氟甲氧基和烯丙氧基;
R4选自氢、氟、氯、溴和三氟甲基;
R5选自氢、氟、氯和溴;
R'1选自氢、氯、溴和苄氧基;
R'2选自氢、氯和溴;
R'3选自氢、氯和溴。
5.根据权利要求1所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物,其特征在于,
通式I的化合物优选以下结构化合物:
(E)-N'-(4-(三氟甲氧基)亚苄基)噻唑-4-碳酰肼(I-1);
(E)-N'-(5-氯-2-氟亚苄基)噻唑-4-碳酰肼(I-2);
(E)-N'-(2,4-二氯亚苄基)噻唑-4-碳酰肼(I-3);
(E)-N'-(3,5-二氯亚苄基)噻唑-4-碳酰肼(I-4);
(E)-N'-(4-(烯丙氧基)亚苄基)噻唑-4-碳酰肼(I-5);
(E)-N'-(3-氯亚苄基)噻唑-4-碳酰肼(I-6);
(E)-N'-(2,6-氯亚苄基)噻唑-4-碳酰肼(I-7);
(E)-N'-(3,5-二氯-2-羟基亚苄基)噻唑-4-碳酰肼(I-8);
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-9);
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)噻唑-4-碳酰肼(I-10)。
6.根据权利要求1所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物,其特征在于,通式Ⅱ的化合物优选以下结构化合物:
(E)-N'-(2-氟-5-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-1);
(E)-N'-(3-氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-2);
(E)-N'-(5-氯-2-氟亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-3);
(E)-N'-(2,6-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-4);
(E)-N'-(3,5-二氯亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-5);
(E)-N'-(4-(烯丙氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-6);
(E)-N'-(2-溴亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-7);
(E)-N'-(2-氟-4-(三氟甲基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-8);
(E)-N'-(4-(三氟甲氧基)亚苄基)咪唑并[1,2-a]吡啶-2-碳酰肼(Ⅱ-9)。
7.权利要求1-6任一项所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物用于制备植物杀菌剂的应用。
8.根据权利要求7所述的应用,其特征在于,所述的杀菌剂用于防治包括番茄灰霉病、马铃薯干腐病、苹果炭疽病、苹果腐烂病、水稻稻瘟病和/或小麦赤霉病。
9.权利要求1-6任一项所述的噻唑和咪唑并[1,2-a]吡啶酰腙类化合物用于制备植物杀虫剂的应用。
10.根据权利要求9所述的应用,其特征在于,所述的杀虫剂用于防治包括黏虫和/或蚜虫。
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