CN115583916A - 一种含取代杂环的双酰胺类化合物及其制备方法与应用 - Google Patents
一种含取代杂环的双酰胺类化合物及其制备方法与应用 Download PDFInfo
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- CN115583916A CN115583916A CN202211292660.2A CN202211292660A CN115583916A CN 115583916 A CN115583916 A CN 115583916A CN 202211292660 A CN202211292660 A CN 202211292660A CN 115583916 A CN115583916 A CN 115583916A
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- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 24
- -1 bisamide compound Chemical class 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000006482 condensation reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 81
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical class CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
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- 239000003905 agrochemical Substances 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
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- 238000002156 mixing Methods 0.000 claims description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
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- 239000004480 active ingredient Substances 0.000 claims description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 4
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- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
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- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-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
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000000749 insecticidal effect Effects 0.000 abstract description 11
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 230000004071 biological effect Effects 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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- 241000123650 Botrytis cinerea Species 0.000 description 3
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- 239000005788 Fluxapyroxad Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 241000918585 Pythium aphanidermatum Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- SXSGXWCSHSVPGB-UHFFFAOYSA-N fluxapyroxad Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=CC=C1C1=CC(F)=C(F)C(F)=C1 SXSGXWCSHSVPGB-UHFFFAOYSA-N 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 3
- 229940080818 propionamide Drugs 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
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- JREJQAWGQCMSIY-UHFFFAOYSA-N 1-methyl-pyrazole-5-carboxylic acid Chemical compound CN1N=CC=C1C(O)=O JREJQAWGQCMSIY-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
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- 229920001817 Agar Polymers 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- 239000005657 Fenpyroximate Substances 0.000 description 2
- 239000005901 Flubendiamide Substances 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
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- 229940056881 imidacloprid Drugs 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
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- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 1
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- 239000005886 Chlorantraniliprole Substances 0.000 description 1
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- 241000258937 Hemiptera Species 0.000 description 1
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- PSOVNZZNOMJUBI-UHFFFAOYSA-N chlorantraniliprole Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl PSOVNZZNOMJUBI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
-
- 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
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered 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
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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Abstract
本发明公开了一种含取代杂环的双酰胺类化合物及其制备方法与应用。本发明含取代杂环的双酰胺类化合物,其结构式如下式Ia、式Ib、Ic或式Id所示。本发明将氨基进行保护通过缩合反应即能制备得到含取代杂环的双酰胺类化合物。本发明具有新颖的结构、较好的杀虫、杀螨、杀菌活性,其工艺路线短、反应条件温和、制备简单。
Description
技术领域
本发明涉及一种含取代杂环的双酰胺类化合物及其制备方法与应用,属于农用化学杀虫剂、杀菌剂的发现及合成技术领域。
背景技术
随着人口的增长、人均可耕种面积减少,全球粮食供应面临严峻考验。农药作为一种重要物资在社会经济和人类生产中发挥着重要作用。随着人们对农药的认识越来越深刻,寻求结构新奇、低毒和对环境友好的农药活性化合物成为新农药创制的方向。近年来,一些含酰胺结构的化合物因其结构新颖、作用机制特别、高活性,且对哺乳动物具有较高的安全性等特点,已发展成为重要的农药活性分子,例如美国杜邦公司发现的氯虫苯甲酰胺和德国巴斯夫公司发现的氟唑菌酰胺,因此含酰胺结构的活性分子的设计与合成已成为当今各农药研发的热点。杂环化合物由于其结构的特殊性和生物活性的多样性使得其在农药的研发中也受到广泛的关注,尤其是含氮杂环化合物。吡唑和吡啶类结构均是具有广泛生物活性的含氮杂环化合物,它们已包含在医药、农药、兽药、化妆品等各种领域的活性分子的结构中。因此,寻求在吡唑和吡啶环上不同位置连接不同的取代基,以合成具有不同的生物活性的吡唑和吡啶类结构的化合物具有重要的意义。
发明内容
本发明的目的是提供一种含取代杂环的双酰胺类化合物及其制备方法与应用。本发明具有新颖的结构、较好的杀虫、杀螨、杀菌活性,其工艺路线短、反应条件温和、制备简单。
本发明提供了一种含取代杂环的双酰胺类化合物,其结构式如下式Ia、式Ib、Ic或式Id所示:
式Ia、式Ib、Ic和式Id中,R1是C1-C6的烷基;
R2是H、F或甲氧基;
R3是H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基;
R4、R5均为H、C1-C6的烷基或取代的C1-C6烷基,R4与R5为相同或不同的基团;
R6是H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基、取代的C1-C6烷基、烷氧基或酯基;
Y是烷氧基、H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基。
本发明中,所述取代的C1-C6烷基指的是本领域中公知的常识,即C1-C6烷基被各种常见的取代基取代。
上述的含取代杂环的双酰胺类化合物中,所述卤素为氟、氯、溴或碘;
所述C1-C6的烷基为C1-C6的直链或支链烷基;
所述酯基为甲酸酯、二甲酸酯、乙酸酯和异丙酸酯中的至少一种。
本发明还提供了上述的含取代杂环的双酰胺类化合物的制备方法,包括如下步骤:
1)在有机溶剂中,将式II所示化合物中的氨基进行保护反应,得到式III所示的化合物;
式II和式III中,R1是C1-C6的烷基;
2)在有机溶剂中,将所述式III所示的化合物和式IV所示的化合物混合进行氨基缩合反应,得到式V所示的化合物;
式IV和式V中,R1是C1-C6的烷基;
R2是H、F或甲氧基;
Y是烷氧基、H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基;
3)在有机溶剂中,将所述式V所示的化合物中的氨基保护基进行脱去反应,得到式VI所示的化合物;
式VI中,R1是C1-C6的烷基;
R2是H、F或甲氧基;
Y是烷氧基、H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基;
4)在有机溶剂中,将所述式VI所示的化合物和式VIIa、式VIIb、式VIIc或式VIId所示的化合物混合进行缩合反应,即得到所述式Ia、式Ib、Ic或式Id所示的化合物;
R3是H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基;
R4、R5均为H、C1-C6的烷基或取代的C1-C6烷基,R4与R5为相同或不同的基团;
R6是H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基、取代的C1-C6烷基、烷氧基或酯基。
本发明的反应方程式如下所示:
上述的制备方法中,步骤1)中加入氨基保护剂进行所述氨基的保护;
所述氨基保护剂选自氯甲酸苄酯、二碳酸二叔丁酯、芴甲氧羰酰氯、对甲氧基氯苄和对甲苯磺酰氯中的至少一种;
所述氨基保护剂与所述式II所示的化合物的摩尔比可为1~10:1,具体可为1:1或1~5:1;
所述保护反应的温度可为-10℃至所述有机溶剂的沸点,具体可为室温,时间可为0.5~48小时,具体可为2h、0.5~2小时、2~48小时、2~12小时或1~30小时。
上述的制备方法中,步骤1)-4)中,所述有机溶剂为相同或不同的溶剂,均选自水、二氯甲烷、氯仿、四氯化碳、苯、甲苯、二甲苯、环己烷、正己烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺和二甲基亚砜中的至少一种。
本发明方法中,步骤1)得到式III所示化合物的后处理采用本领域中常规的方法处理,具体可为:反应完毕,旋蒸脱溶,柠檬酸溶液调节pH,乙酸乙酯萃取,收集有机相后无水硫酸钠干燥,旋蒸脱溶即得。
上述的制备方法中,步骤2)中,所述式III所示的化合物与所述式IV所示的化合物的摩尔比可为1:1~10,具体可为1:1、1~5:1或1~8:1;
所述氨基缩合反应中加入缩合剂;
所述缩合剂选自二环己基碳二亚胺(英文缩写为DCC)、二异丙基碳二亚胺(英文缩写为DIC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(英文缩写为EDCI)和1-羟基苯并三唑(英文缩写为HoBT)中的至少一种;
所述缩合剂与所述式III所示的化合物的摩尔比可为1~20:1,具体可为1:1.5、1~1.5:1、1.5~10:1或1~15:1;
所述氨基缩合反应的温度可为-10℃至所述有机溶剂的沸点,具体可为室温,时间可为0.5~48小时,具体可为12h、0.5~12小时、12~48小时或5~30小时。
本发明方法中,步骤2)得到式V所示化合物的后处理采用本领域中常规的方法处理,具体可为:反应完毕,将反应液依次用饱和碳酸氢钠溶液洗涤和饱和氯化钠溶液洗涤,收集有机相无水硫酸钠干燥、减压蒸馏脱溶、残留物柱层析纯化。
上述的制备方法中,步骤3)中,加入酸脱去所述氨基保护基;
所述酸选自三氟乙酸、对甲苯磺酸、盐酸、叔丁基二甲硅基三氟甲磺酸酯和溴化锌中的至少一种;
所述酸与所述式V所示的化合物的摩尔比可为1~20:1,具体可为6:1、1~6:1、6~20:1或5~10:1;
所述脱去反应的温度可为-10℃至所述有机溶剂的沸点,具体可为室温,时间可为0.5~48小时,具体可为12h、0.5~12小时、12~48小时或5~30小时。
本发明方法中,步骤3)得到式VI所示化合物的后处理采用本领域中常规的方法处理,具体可为:反应结束后减压蒸馏脱除溶剂,残留液用饱和碳酸氢钠溶液调节pH至中性,收集有机相无水硫酸钠干燥,减压蒸馏脱溶即得。
上述的制备方法中,步骤4)中,所述式VI所示的化合物与所述式VIIa、式VIIb、式VIIc或式VIId所示的化合物的摩尔比可为1:1~10,具体可为1:1、1~5:1或1~8:1;
所述缩合反应中加入缩合剂;
所述缩合剂选自二环己基碳二亚胺(英文缩写为DCC)、二异丙基碳二亚胺(英文缩写为DIC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(英文缩写为EDCI)和1-羟基苯并三唑(英文缩写为HoBT)中的至少一种;
所述缩合剂与所述式VI所示的化合物的摩尔比可为1~20:1,具体可为1:1.5、1~1.5:1、1.5~10:1或1~15:1;
所述缩合反应的温度可为-10℃至所述有机溶剂的沸点,具体可为室温,时间可为0.5~48小时,具体可为12h、0.5~12小时、12~48小时或5~30小时。
本发明方法中,步骤4)得到式Ia、式Ib、Ic或式Id所示的化合物的后处理采用本领域中常规的方法处理,具体可为:反应完毕,将反应液依次用饱和碳酸氢钠溶液洗涤和饱和氯化钠溶液洗涤,收集有机相无水硫酸钠干燥,减压蒸馏脱溶,残留物柱层析。
本发明方法中,所述室温为本领域中公知的常识,指的是10~30℃。
本发明所述式Ⅰa、式Ib、式Ic和、式Id中至少一种所示的含取代杂环的双酰胺类化合物用于制备农用化学杀虫剂中。
本发明所述式Ⅰa、式Ib、式Ic和、式Id用于农业上适用的盐和/或其立体异构体在制备农用化学杀虫剂中。
本发明进一步提供了一种杀虫剂,它由活性成分和农业可以接受的助剂组成;
所述活性成分为所述式Ⅰa、式Ib、式Ic和、式Id中至少一种所示的含取代杂环的双酰胺类化合物和/或其在农业上适用的盐,和/或其立体异构体。
本发明具有以下优点:
本发明化合物具有新颖的结构和显著的杀虫、杀螨、杀菌活性;且本发明制备路线短、反应条件温和、对设备要求低,后处理方便、制备简单。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
下述实施例中,二碳酸二叔丁酯,2-甲基-4-七氟异丙基苯胺,吡唑,二环己基碳二亚胺,1-(3-二甲氨基丙基)-3-乙基碳二亚胺和1-羟基苯并三唑等均购自伊诺凯科技有限公司;1,4-二氧六环和二氯甲烷等其余常规试剂均购自北京化学试剂公司。
实施例1、
衍生物N-(1-((2-甲氧基-4-(全氟丙烷-2-基)苯基)氨基)-1-氧代丙烷-2-基)-1-甲基-1H-吡唑-5-甲酰胺:
步骤A:制备(叔丁氧羰基)丙氨酸。
500mL三口瓶,加入DL-丙氨酸(17.8g,200mmol)、100mL水以及100mL1,4-二氧六环,0℃搅拌下缓慢加入氢氧化钠(16g,400mmol),添加完毕,搅拌15min。然后滴加二碳酸二叔丁酯(43.6g,200mmol),滴毕搅拌至反应结束。反应液旋蒸脱溶,柠檬酸溶液调节反应液pH,然后乙酸乙酯萃取,合并的有机相经无水硫酸钠干燥后,旋蒸脱溶得(叔丁氧羰基)丙氨酸(35.6g,190mmol),产率95%。
1H NMR(500MHz,Chloroform-d)δ11.11(s,1H),6.78(s,0.45H),5.11(s,0.55H),4.46–3.92(m,1H),1.37(d,J=9.3Hz,12H).
步骤B:制备N-(1-((2-甲氧基-4-七氟异丙基苯基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯。
500mL三口瓶,加入(叔丁氧羰基)丙氨酸(5.6g,30mmol)以及250mL干燥二氯甲烷,0℃下,然后加入二环己基碳二亚胺(9.13g,45mmol)和4-二甲氨基吡啶(0.72g,6mmol)。接着在0℃下搅拌30min后,加入2-甲氧基-4-七氟异丙基苯胺(8.6g,30mmol)。然后转移至室温25℃反应12h。反应完毕,将反应液过滤,滤液依次用饱和碳酸氢钠溶液洗涤和饱和氯化钠溶液洗涤,收集的有机相经无水硫酸钠干燥、旋蒸脱溶、残留物经柱层析得到N-(1-((2-甲氧基-4-七氟异丙基苯基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(11.37g,24.6mmol),产率82%。
1H NMR(500MHz,Chloroform-d)δ8.67(s,1H),8.43(d,J=8.6Hz,1H),7.11(d,J=8.6Hz,1H),6.97(s,1H),5.18(s,1H),4.30(s,1H),3.82(s,3H),1.38(d,J=10.6Hz,12H).
步骤C:制备2-氨基-N-(2-甲氧基-4-七氟异丙基苯基)丙酰胺。
250mL三口瓶,将(1-((2-甲氧基-4-七氟异丙基苯基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(6.93g,15mmol)溶于45mL二氯甲烷和45mL三氟乙酸中。室温25℃搅拌反应2h。反应完毕,将反应液旋蒸脱溶,加入乙酸乙酯溶解后,滤液依次用饱和碳酸氢钠溶液洗涤和饱和氯化钠溶液洗涤,收集的有机相经无水硫酸钠干燥,旋蒸脱溶得2-氨基-N-(2-甲氧基-4-七氟异丙基苯基)丙酰胺(5.21g,14.4mmol),产率96%。
1H NMR(500MHz,Chloroform-d)δ10.01(s,1H),8.54(d,J=8.6Hz,1H),7.19(d,J=8.6Hz,1H),7.05(s,1H),3.93(s,3H),3.66(q,J=7.0Hz,1H),1.62(s,2H),1.44(d,J=7.0Hz,3H).
步骤D:制备N-(1-((2-甲氧基-4-七氟异丙基苯基)氨基)-1-氧代丙烷-2-基)-1-甲基-1H-吡唑-5-甲酰胺。
100mL三口瓶,将1-甲基-1H-吡唑-5-羧酸(0.35g,2.76mmol)溶于50mL二氯甲烷中,0℃搅拌下,将1-(3-二甲氨基丙基)-3-乙基碳二亚胺(0.53g,2.76mmol)、1-羟基苯并三唑(0.357g,2.76mmol)和N,N-二异丙基乙胺(0.36g,2.76mmol)依次加入反应瓶中,搅拌反应60min,再将2-氨基-N-(2-甲氧基-4-七氟异丙基苯基)丙酰胺(1g,2.76mmol)加至反应瓶中。加毕,转移至室温25℃反应12h。反应结束,将反应液用柠檬酸溶液调节pH,然后依次用饱和碳酸氢钠溶液洗涤和饱和氯化钠溶液洗涤,收集的有机相经无水硫酸钠干燥、旋蒸脱溶、残留物柱层析得N-(1-((2-甲氧基-4-七氟异丙基苯基)氨基)-1-氧代丙烷-2-基)-1-甲基-1H-吡唑-5-甲酰胺(0.73g,1.55mmol),产率56%。
N-(1-((2-甲氧基-4-七氟异丙基苯基)氨基)-1-氧代丙烷-2-基)-1-甲基-1H-吡唑-5-甲酰胺结构确证如下:
1H NMR(500MHz,Chloroform-d)δ8.53(s,1H),8.47(d,J=8.6Hz,1H),7.46(d,J=2.1Hz,1H),7.21(d,J=8.7Hz,1H),7.07(s,1H),6.93(d,J=9.2Hz,1H),6.65(d,J=2.1Hz,1H),4.83(m,1H),4.17(s,3H),3.93(s,3H),1.58(d,J=7.0Hz,3H).
现将根据以上实施例的制备方法而采用不同的原料制备的本发明式(I)表示的典型化合物列在表1a、表1b、表1c和表1d中,但是它们绝不限制本发明的范围。
表1a含杂环取代的双酰胺类化合物结构及其熔点
表1b含杂环取代的双酰胺类化合物结构及其熔点
表1c含杂环取代的双酰胺类化合物结构及其熔点
表1d含杂环取代的双酰胺类化合物结构及其熔点
以下表2为表1a、表1b、表1c和表1d中所述部分化合物的核磁数据。
注:表2中所述化合物编号与表1中所述化合物编号相对应。其中s为单峰,d为双峰,dd为双二重峰,dq为双四重峰,t为三重峰,q为四重峰,m为多重峰。
表2含取代杂环的双酰胺类化合物的1H NMR数据
实施例2、
利用本发明实施例1中提供的含取代杂环的双酰胺类化合物测试其对害虫生物的生物活性:
下面给出使用本发明的化合物进行生物活性测定的实例,需要指出的是本发明并不仅仅局限在下述实例的范围内。
杀虫活性评价试验根据下列方法进行:
称取一定质量本发明实施例1中化合物(具体可为表1中NO.1)溶于1mL二甲基亚砜(DMSO),加入100mL水和0.1g表面活性剂曲拉通X-100,混合成为均一水相,使用时可用水稀释配置成测定所需的浓度。
测试对象和测试方法如下:
(1)对小菜蛾的生物活性评价:以氟苯虫酰胺原药为阳性对照。配制好的待测药液,用直头眼科镊子浸渍甘蓝叶片(6cm×2cm),时间5s,甩掉余液。按样品标记顺序依次放在底部铺有滤纸的培养皿(9cm)上,自然阴干,每个处理接入10头2-3龄小菜蛾幼虫,将试验处理置于标准处理室内,48h检查死活虫数,以拨针轻触虫体,不动者为死亡,并进行统计分析,计算致死率;
(2)对大豆蚜的生物活性评价:以吡虫啉原药为阳性对照。采集虫口密度大的大豆叶,仔细挑选使健康的3龄若蚜(20头)留在叶面上,将带虫的大豆叶浸入配制好的待测药液5s后拿开,沥干后放入底部铺有保湿滤纸的培养皿(6cm)中,放置在温度为25℃,相对湿度为78%,光照时间为14/10h的人工气候箱中继续饲养,36h后记录死亡情况,并进行统计分析,计算致死率。
(3)对红蜘蛛的生物活性评价:以唑螨酯原药为阳性对照。将带虫量30头的豇豆叶浸入配制好的待测药液5s后拿开,沥干后放入底部铺有保湿滤纸的培养皿(6cm)中,放置在温度为25℃,相对湿度为50%,光照时间为14/10h的人工气候箱中继续饲养,48h后在双目镜下记录死亡情况,并进行统计分析,计算致死率。
试验统计:统计各个处理的死虫数和活虫数,计算死亡率
空白对照组死亡率<15%,试验结果可信,试验结果进行校正,空白对照组死亡率<5%,试验结果可不校正。
生测实验结果表明:本发明化合物具有良好的杀虫活性。
如表3所示,本发明化合物对鳞翅目害虫(小菜蛾)具有较好杀虫活性:400mg/L浓度下,化合物12、27、32对小菜蛾死亡率53%、50%、60%。
如表4所示,本发明化合物对同翅目害虫(大豆蚜)具有显著地杀虫活性:400mg/L浓度下,化合物02、07、17对大豆蚜的死亡率为90%、85%、88%;200mg/L浓度下,化合物02、07、17对大豆蚜的死亡率为73%、63%、77%;100mg/L浓度下,化合物02、17对大豆蚜死亡率55%、58%。
如表5所示,本发明化合物对螨类害虫(红蜘蛛)具有较好杀虫活性:400mg/L浓度下,化合物13、20、42对红蜘蛛死亡率79%、82%、53%;200mg/L浓度下,化合物13、20对红蜘蛛死亡率60%、66%。
注,上述mg/L均指每毫克活性化合物/升。
将本发明实施例1中表1所示的编号的部分化合物与对照化合物氟苯虫酰胺的杀虫活性(小菜蛾)进行比较,结果列于表3。
表3杀虫活性比较
将本发明实施例1中表1所示的编号的部分化合物与对照化合物吡虫啉的杀虫活性(大豆蚜)进行比较,结果列于表4。
表4杀虫活性比较
将本发明实施例1中表1所示的编号的部分化合物与对照化合物唑螨酯的杀虫活性(红蜘蛛)进行比较,结果列于表5。
表5杀虫活性比较
实施例3、
利用本发明实施例1中提供的含取代杂环的双酰胺类化合物测试其对农业病菌的生物活性:
下面给出使用本发明的化合物进行生物活性测定的实例,需要指出的是本发明并不仅仅局限在下述实例的范围内。
杀虫活性评价试验根据下列方法进行:
称取一定质量本发明实施例1中所述化合物(具体可为表1中NO.1)溶于5mL二甲基亚砜(DMSO),使用时可用培养液稀释配置成测定所需的浓度。
测试对象和测试方法如下:
(1)测试对象:油菜菌核病菌(Sclerotinia sclerotiorum)、苹果腐烂病菌(Valsamali)、小麦赤霉病菌(Fusarium graminearum)、水稻纹枯病菌(Rhizoctonia solani)、瓜果腐霉病菌(Pythium aphanidermatum)和番茄灰霉病菌(Botrytis cinerea)。
(2)测试方法:
①制备PDA培养基:按每200g马铃薯,1L去离子水,20g琼脂条,20g葡萄糖的配比制备马铃薯葡萄糖琼脂(PDA)培养基,并用高压灭菌锅灭菌,备用。
②配制试验药剂:分别称取50mg目标化合物与氟唑菌酰胺原药,5mL二甲基亚砜溶解,配制成浓度为10000mg/L的药液备用。
③试验方法:无菌条件下,用移液枪分别吸取上述制备好的10000mg/L的药液,加入到准备好的已灭菌的PDA培养基中,充分混匀,制备成50mg/L带药培养基。然后将其倒入直径为9cm的培养皿中,每个药剂3次重复。待皿中带药培养基冷却固化后,制备成带药PDA平板。DMSO为溶剂对照,无菌水为空白对照。将准备好的病原菌平板,沿菌落边缘制备直径5mm的菌饼,分别接种于带药和对照PDA平板中间,置于25℃培养箱中避光培养。
试验统计:待对照PDA平板中的菌落充分生长后,以十字交叉法测量各菌落直径,取其平均值。抑制率计算公式如下:
生测实验结果表明:本发明化合物具有良好的杀菌活性。
如表6所示,本发明化合物对各类真菌病害具有较好杀菌活性:50mg/L浓度下,化合物02、18、32、43对油菜菌核病菌的抑制率分别为65%、70%、65%和67%;化合物18、22、32对小麦赤霉病菌的抑制率分别为45%、50%和58%;化合物02、22、32对水稻纹枯病菌的抑制率分别为74%、65%和61%;化合物02、18、32对苹果腐烂病菌的抑制率分别为68%、77%和71%;化合物02、22、32对瓜果腐霉病菌的抑制率分别为34%、29%和35%;化合物22、32、59对番茄灰霉病菌的抑制率分别为37%、37%、和48%。
注:上述mg/L均指每毫克活性化合物/升。
将本发明实施例1中表1所示的编号的部分化合物与对照化合物氟唑菌酰胺的杀菌活性进行比较,结果列于表6。
表6杀菌活性比较
Claims (10)
2.根据权利要求1所述的含取代杂环的双酰胺类化合物,其特征在于,所述卤素为氟、氯、溴或碘;
所述C1-C6的烷基为C1-C6的直链或支链烷基;
所述酯基为甲酸酯、二甲酸酯、乙酸酯和异丙酸酯中的至少一种。
3.权利要求1或2所述的含取代杂环的双酰胺类化合物的制备方法,包括如下步骤:
1)在有机溶剂中,将式II所示化合物中的氨基进行保护反应,得到式III所示的化合物;
式II和式III中,R1是C1-C6的烷基;
2)在有机溶剂中,将所述式III所示的化合物和式IV所示的化合物混合进行氨基缩合反应,得到式V所示的化合物;
式IV和式V中,R1是C1-C6的烷基;
R2是H、F或甲氧基;
Y是烷氧基、H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基;
3)在有机溶剂中,将所述式V所示的化合物中的氨基保护基进行脱去反应,得到式VI所示的化合物;
式VI中,R1是C1-C6的烷基;
R2是H、F或甲氧基;
Y是烷氧基、H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基;
4)在有机溶剂中,将所述式VI所示的化合物和式VIIa、式VIIb、式VIIc或式VIId所示的化合物混合进行缩合反应,即得到所述式Ia、式Ib、Ic或式Id所示的化合物;
R3是H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基或取代的C1-C6烷基;
R4、R5均为H、C1-C6的烷基或取代的C1-C6烷基,R4与R5为相同或不同的基团;
R6是H、卤素、氰基、三氟甲基、二氟甲基、C1-C6的烷基、取代的C1-C6烷基、烷氧基或酯基。
4.根据权利要求3所述的制备方法,其特征在于,步骤1)中加入氨基保护剂进行所述氨基的保护;
所述氨基保护剂选自氯甲酸苄酯、二碳酸二叔丁酯、芴甲氧羰酰氯、对甲氧基氯苄和对甲苯磺酰氯中的至少一种;
所述氨基保护剂与所述式II所示的化合物的摩尔比为1~10:1;
所述保护反应的温度为-10℃至所述有机溶剂的沸点;
步骤1)-4)中,所述有机溶剂为相同或不同的溶剂,均选自水、二氯甲烷、氯仿、四氯化碳、苯、甲苯、二甲苯、环己烷、正己烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺和二甲基亚砜中的至少一种。
5.根据权利要求3或4所述的制备方法,其特征在于,步骤2)中,所述式III所示的化合物与所述式IV所示的化合物的摩尔比为1:1~10;
所述氨基缩合反应中加入缩合剂;
所述缩合剂选自二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺和1-羟基苯并三唑中的至少一种;
所述缩合剂与所述式III所示的化合物的摩尔比为1~20:1;
所述氨基缩合反应的温度为-10℃至所述有机溶剂的沸点,时间可为0.5~48小时。
6.根据权利要求3-5中任一项所述的制备方法,其特征在于,步骤3)中,加入酸脱去所述氨基保护基;
所述酸选自三氟乙酸、对甲苯磺酸、盐酸、叔丁基二甲硅基三氟甲磺酸酯和溴化锌中的至少一种;
所述酸与所述式V所示的化合物的摩尔比为1~20:1;
所述脱去反应的温度为-10℃至所述有机溶剂的沸点,时间可为0.5~48小时。
7.根据权利要求3-6中任一项所述的制备方法,其特征在于,步骤4)中,所述式VI所示的化合物与所述式VIIa、式VIIb、式VIIc或式VIId所示的化合物的摩尔比为1:1~10;
所述缩合反应中加入缩合剂;
所述缩合剂选自二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺和1-羟基苯并三唑中的至少一种;
所述缩合剂与所述式VI所示的化合物的摩尔比可为1~20:1;
所述缩合反应的温度可为-10℃至所述有机溶剂的沸点,时间可为0.5~48小时。
8.权利要求1或2所述式Ⅰa、式Ib、式Ic和、式Id中至少一种所示的含取代杂环的双酰胺类化合物在制备农用化学杀虫剂中的应用。
9.权利要求1或2所述式Ⅰa、式Ib、式Ic和、式Id在农业上适用的盐和/或其立体异构体在制备农用化学杀虫剂中的应用。
10.一种杀虫剂,它由活性成分和农业可以接受的助剂组成;
所述活性成分为权利要求1或2所述式Ⅰa、式Ib、式Ic和、式Id中至少一种所示的含取代杂环的双酰胺类化合物和/或其在农业上适用的盐,和/或其立体异构体。
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