CN114989123B - Flavone-3-carboxylic acid compound, bactericidal composition containing same and application thereof - Google Patents
Flavone-3-carboxylic acid compound, bactericidal composition containing same and application thereof Download PDFInfo
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- CN114989123B CN114989123B CN202210542091.6A CN202210542091A CN114989123B CN 114989123 B CN114989123 B CN 114989123B CN 202210542091 A CN202210542091 A CN 202210542091A CN 114989123 B CN114989123 B CN 114989123B
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- China
- Prior art keywords
- carboxylic acid
- reaction
- flavone
- mmol
- acid compound
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 56
- -1 Flavone-3-carboxylic acid compound Chemical class 0.000 title claims abstract description 50
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 59
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 39
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical class ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 32
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 17
- 239000013067 intermediate product Substances 0.000 claims description 16
- 239000002994 raw material Substances 0.000 claims description 14
- 239000005711 Benzoic acid Substances 0.000 claims description 11
- 235000010233 benzoic acid Nutrition 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000005917 acylation reaction Methods 0.000 claims description 4
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004495 emulsifiable concentrate Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000004530 micro-emulsion Substances 0.000 claims description 2
- 239000004562 water dispersible granule Substances 0.000 claims description 2
- 239000004563 wettable powder Substances 0.000 claims description 2
- 150000001559 benzoic acids Chemical class 0.000 claims 2
- 239000000725 suspension Substances 0.000 claims 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims 1
- 241001313857 Bletilla striata Species 0.000 claims 1
- 241000723346 Cinnamomum camphora Species 0.000 claims 1
- 244000061176 Nicotiana tabacum Species 0.000 claims 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims 1
- 240000007594 Oryza sativa Species 0.000 claims 1
- 235000007164 Oryza sativa Nutrition 0.000 claims 1
- 241000918585 Pythium aphanidermatum Species 0.000 claims 1
- 240000008042 Zea mays Species 0.000 claims 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims 1
- 229960000846 camphor Drugs 0.000 claims 1
- 229930008380 camphor Natural products 0.000 claims 1
- 235000005822 corn Nutrition 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
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- 235000009566 rice Nutrition 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 241000233866 Fungi Species 0.000 abstract description 6
- 239000003899 bactericide agent Substances 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 3
- 241000238631 Hexapoda Species 0.000 abstract description 2
- 241000607479 Yersinia pestis Species 0.000 abstract description 2
- 230000000843 anti-fungal effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 29
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical class CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 22
- 239000010410 layer Substances 0.000 description 21
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- BLFGQHDZMHMURV-UHFFFAOYSA-N 4-oxo-2-phenylchromene-3-carboxylic acid Chemical class O1C2=CC=CC=C2C(=O)C(C(=O)O)=C1C1=CC=CC=C1 BLFGQHDZMHMURV-UHFFFAOYSA-N 0.000 description 16
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- 239000007787 solid Substances 0.000 description 14
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- 238000000967 suction filtration Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
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- 238000010992 reflux Methods 0.000 description 11
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- 238000005406 washing Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 9
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 230000001580 bacterial effect Effects 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 6
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 6
- 238000004896 high resolution mass spectrometry Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- FUUCTBPASNZPKE-UHFFFAOYSA-N 2-chloro-3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1Cl FUUCTBPASNZPKE-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000000855 fungicidal effect Effects 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 3
- MWOVVGIHWSYVMD-UHFFFAOYSA-N 3,5-bis(3-methylbut-3-enyl)benzoyl chloride Chemical compound CC(CCC1=CC(CCC(C)=C)=CC(C(Cl)=O)=C1)=C MWOVVGIHWSYVMD-UHFFFAOYSA-N 0.000 description 3
- WSJZRPQLFKDILG-UHFFFAOYSA-N 4-chloropyrimidine-5-carbonyl chloride Chemical compound ClC(=O)C1=CN=CN=C1Cl WSJZRPQLFKDILG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- WNGYYRCTIGAIQX-UHFFFAOYSA-N Frutinone A Natural products O=C1Oc2ccccc2C3Oc4ccccc4C(=O)C13 WNGYYRCTIGAIQX-UHFFFAOYSA-N 0.000 description 3
- RFWULRHBGYKEEZ-UHFFFAOYSA-N Frutinone A Chemical compound O1C2=CC=CC=C2C(=O)C2=C1C(C=CC=C1)=C1OC2=O RFWULRHBGYKEEZ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- 150000001558 benzoic acid derivatives Chemical class 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- SJUXLKYJKQBZLM-UHFFFAOYSA-N ethyl 3-(4-fluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(F)C=C1 SJUXLKYJKQBZLM-UHFFFAOYSA-N 0.000 description 3
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
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- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- OLNAFSKQRRSJNG-UHFFFAOYSA-N 2-(4-methoxyphenyl)-4-oxochromene-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1=C(C(O)=O)C(=O)C2=CC=CC=C2O1 OLNAFSKQRRSJNG-UHFFFAOYSA-N 0.000 description 2
- KHGDFAIHCDPNRU-UHFFFAOYSA-N 3,5-bis(3-methylbut-3-enyl)benzoic acid Chemical compound CC(CCC1=CC(CCC(C)=C)=CC(C(O)=O)=C1)=C KHGDFAIHCDPNRU-UHFFFAOYSA-N 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
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- KRAHENMBSVAAHD-UHFFFAOYSA-N ethyl 3-(4-methoxyphenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(OC)C=C1 KRAHENMBSVAAHD-UHFFFAOYSA-N 0.000 description 1
- HMHGOWYKZQPERA-UHFFFAOYSA-N ethyl 4-oxo-2-phenylchromene-3-carboxylate Chemical class O1C2=CC=CC=C2C(=O)C(C(=O)OCC)=C1C1=CC=CC=C1 HMHGOWYKZQPERA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- FGHVAWYQLUNBDP-UHFFFAOYSA-N formic acid;pyrimidine Chemical compound OC=O.C1=CN=CN=C1 FGHVAWYQLUNBDP-UHFFFAOYSA-N 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RUUOPSRRIKJHNH-UHFFFAOYSA-N pyridazine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=N1 RUUOPSRRIKJHNH-UHFFFAOYSA-N 0.000 description 1
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- WJXZJIAOEKEAER-UHFFFAOYSA-N tetrazine-5-carboxylic acid Chemical compound OC(=O)c1cnnnn1 WJXZJIAOEKEAER-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a flavone-3-carboxylic acid compound, a bactericidal composition containing the compound and application thereof, the structural general formula of the bactericidal composition is shown as formula (I),Wherein, X 1、X2、X3、X4 and R' groups are defined in the specification, the series of compounds have good antifungal activity and high biological activity, can be used for preventing and controlling crop diseases and insect pests caused by fungi, and widens the selection range of bactericides.
Description
Technical Field
The invention relates to the field of crop control, in particular to a flavone-3-carboxylic acid compound, a bactericidal composition containing the compound and application thereof.
Background
Bush-senone (Frutinones) is a natural product of chromones, which was first isolated from the plant Hamamelis virginiana of the genus Polygala by Paolo et al in 1989, thereafter, it was isolated from shrubs such as P.gazensis, P. teretifolia and P.fruticosa, and three natural products Frutinone A, frutinone B and Frutinone C have been isolated and reported. Studies show that Frutinone A has biological activities of resisting cucumber cladosporium cucumerinum and candida albicans, resisting oxidization, inhibiting cytochrome P4501A2 (CYP 1A 2) and the like, and is a potential bactericide drug molecule and lead compound.
In the process of researching Frutinone A and the synthesis and bactericidal activity of analogues thereof, an intermediate of the flavonoid-3-carboxylic acid compound is found to be used for treating plant pathogenic fungi: anthracis, saprophytic fungus, fusarium pseudograminearum, rhizoctonia solani, pyricularia and Fusarium moniliforme all exhibit excellent bactericidal activity.
However, there have been few studies on structural modification and agricultural applications of flavone-3-carboxylic acid compounds so far, and the molecular structure types of flavone-3-carboxylic acid compounds which can achieve the purpose of effective sterilization have yet to be widened.
Disclosure of Invention
The invention aims to provide a flavone-3-carboxylic acid compound, a bactericidal composition containing the compound and application thereof, enrich the structure of the flavone-3-carboxylic acid compound and widen the selection range of bactericides.
In order to achieve the technical purpose, the application adopts the following technical scheme:
In a first aspect, the application provides a flavone-3-carboxylic acid compound, which has a structural general formula shown in formula (I):
Wherein, X 1、X2、X3 and X 4 are respectively and independently selected from C, CH or N;
R and R' are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, di (C 1-10 alkyl) amino, halogenated C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylthio, halogenated C 1-10 alkoxy, halogenated C 1-10 alkylthio, N-heterocyclyl, wherein N-heterocyclyl includes, but is not limited to, pyrrolidinyl, methylpyrrolyl, methylmorpholino, and the like.
Preferably, it is a compound of formula (II):
Wherein X 1、X2、X3, R and R' are as defined above, W 1、W2 is independently selected from the group consisting of alkyl of H, C 1-10, or W 1、W2 forms a cyclic structure.
Preferably, R represents R 1、R2、R3 and R 4, R' represents R 5、R6、R7、R8 and R 9, which are compounds of formula (III),
Wherein R 1、R2、R3、R4、R5、R6、R7、R8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, di (C 1-10 alkyl) amino, halogenated C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylthio, halogenated C 1-10 alkoxy, halogenated C 1-10 alkylthio, N-heterocyclyl, more preferably N-heterocyclyl is selected from pyrrolidinyl, methylpyrrolinyl and methylmorpholine.
In a second aspect, the present application provides a method for preparing a flavone-3-carboxylic acid compound, comprising the steps of: s1, carrying out an acylation reaction by taking substituted benzoic acid and oxalyl chloride as raw materials to obtain an intermediate product a; s2, taking the intermediate product a and ethyl acetoacetate as raw materials, and carrying out nucleophilic substitution reaction to obtain an intermediate product b; s3, carrying out an acylation reaction by taking carboxylic acid compounds with chlorine substituted on beta carbon and oxalyl chloride as raw materials to obtain an intermediate product c; s4, carrying out cyclization reaction by taking the intermediate product b and the intermediate product c as raw materials and taking sodium tert-butoxide and cesium carbonate as catalysts to obtain an intermediate product d; s5, hydrolyzing the intermediate product d by lithium hydroxide to obtain a compound e with a general formula (I);
in a third aspect, the present application provides a fungicidal composition comprising a flavone-3-carboxylic acid compound.
In a fourth aspect, the application provides an application of a flavone-3-carboxylic acid compound in controlling crop diseases.
The beneficial effects of the application are as follows: the application provides a series of flavone-3-carboxylic acid compounds with brand new structures, which have good antifungal activity and high biological activity, can be used for preventing and controlling crop diseases and insect pests caused by fungi, and widens the selection range of bactericides; the application realizes the framework transformation of the flavone-3-carboxylic acid, enriches the structure of the flavone-3-carboxylic acid compound, has low cost and easy obtainment of synthesis raw materials, avoids expensive raw materials or noble metal catalysts involved in the existing method, and has simple operation, mild reaction conditions, environmental protection and easy recovery and reuse of solvents.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and all other embodiments obtained by those skilled in the art without making any creative effort based on the embodiments of the present invention are within the protection scope of the present invention.
The flavone-3-carboxylic acids of the present invention are illustrated by the compounds listed in Table 1 below, wherein X 1、 X2、X3 and X 4 are not illustrated by default to C, but are not limiting to the present invention.
TABLE 1 list of flavone-3-carboxylic acids
The embodiment of the application also provides a preparation method of the flavone-3-carboxylic acid compound, which comprises the following steps: the substituted benzoic acid reacts with oxalyl chloride serving as an acylating reagent to prepare a compound shown in a formula a, wherein R groups of the substituted benzoic acid represent that hydrogen at different positions on a benzene ring is mono-substituted or poly-substituted by groups such as fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, tertiary butyl, nitro, trifluoromethyl, cyano and the like; and then nucleophilic substitution reaction is carried out on the compound shown in the formula a and ethyl acetoacetate to prepare the compound shown in the formula b: substituted ethyl benzoylacetate; and then reacting the carboxylic acid analogue with chlorine substituted on beta carbon with oxalyl chloride serving as an acylating agent to prepare the compound shown in the formula c. The carboxylic acid compound comprises benzoic acid, picolinic acid, pyrimidine formic acid, pyridazine carboxylic acid, triazine carboxylic acid or tetrazine carboxylic acid substances; then nucleophilic substitution is carried out on the prepared compound shown in the formula b and the compound shown in the formula c, and meanwhile [3+3] cyclization reaction is carried out under a sodium tert-butoxide and cesium carbonate double-base system to synthesize an intermediate 4-oxo-2-phenyl-4H-chromene-3-carboxylic acid ethyl ester analogue, wherein the intermediate is shown in the formula d; finally, the compound shown in the formula d is hydrolyzed by lithium hydroxide to obtain the flavone-3-carboxylic acid analogue shown in the formula e. The reaction mechanism is as follows:
In other embodiments, the method further comprises the steps of: s6, taking a compound e, paraformaldehyde and an amine compound as raw materials to perform a Mannich reaction to obtain a compound f with a general formula (II), wherein the reaction mechanism is as follows:
The embodiment also provides a bactericidal composition containing the flavone-3-carboxylic acid compound, and when the bactericidal composition containing the flavone-3-carboxylic acid compound is applied, the bactericidal composition is matched with auxiliary materials acceptable in agriculture and pharmacy to form bactericidal preparations with different dosage forms, wherein the dosage forms of the bactericidal composition are suspending agents, water dispersible granules, wettable powder, oil suspending agents, emulsifiable concentrates, microemulsions, aqueous emulsions, suspending agents or solutions.
The fungicidal composition further comprises at least one carrier, in which the fungicidal composition is usually processed into a concentrate form and used for transportation, diluted by the user before application, the presence of a small amount of surfactant aids the dilution process, at least one carrier in the composition of the application is preferably a surfactant, for example the composition may contain at least two carriers, at least one of which is a surfactant, the carriers in the fungicidal composition of the application being substances that satisfy the following conditions: it is formulated with the active ingredient for ease of application to the locus to be treated, for example, it may be a plant, seed or soil; or to facilitate storage, transport or handling. The carrier may be a solid or a liquid, including substances that are normally gaseous but which have been compressed into a liquid, and commonly used in formulating insecticidal and fungicidal compositions. Suitable solid carriers include: natural or synthetic clays and silicates, such as diatomaceous earth, talc, attapulgite, kaolin, montmorillonite and mica; calcium carbonate; calcium sulfate; synthetic silica, calcium silicate and aluminum silicate; elements such as carbon or sulfur; natural or synthetic resins such as coumarone resins; polyvinyl chloride and styrene polymers or copolymers; solid polychlorinated phenol; asphalt; waxes such as beeswax or paraffin wax. Suitable liquid carriers include: water; alcohols such as ethanol or isopropanol; ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone or cyclohexanone; an ether; aromatic hydrocarbons such as benzene, toluene, xylene or solvent oils; petroleum fractions such as kerosene or mineral oil; biological material oil; in general, mixtures of these liquids are also suitable.
The embodiment also provides the application of the flavone-3-carboxylic acid compound in preventing and controlling crop diseases, in particular, the disease includes at least one of diseases caused by fungi of the oomycetes, basidiomycetes, ascomycetes and fungi of the fungi half-known.
The invention is further illustrated by the following examples.
Example 1
Synthesis of 4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (flavone-3-carboxylic acid)
The synthetic route is as follows:
The preparation method comprises the following specific preparation steps: s1, benzoic acid (10 mmol), 5 drops of DMF and 50ml of dichloromethane are added into a 100ml single-port bottle, oxalyl chloride (12 mmol) is slowly added at room temperature, and the mixture is heated to reflux for reaction for 3h. After the reaction is finished, the benzoyl chloride (1 a) is obtained by distilling and desolventizing by a water pump under reduced pressure at 70 ℃, and is stored in a closed manner and immediately used for the next reaction; s2, a solution of 16.6mmol of sodium tert-butoxide (t-Buona) and toluene (50 mL) was added to a 250mL double-necked flask, and a solution of ethyl acetoacetate (8.3 mmol) and toluene (5 mL) was slowly added dropwise at 0℃and stirred for 15 minutes, and then a solution of benzoyl chloride (10 mmol) and toluene (10 mL) was added dropwise to the above mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃to room temperature for 0.5-3 hours. After the reaction, adding 1.5 times hydrochloric acid (12 mol/L), adjusting the pH to about 7, adding water into the reaction solution for extraction, extracting the separated water layer with toluene for three times, combining the organic layers, washing with saturated saline water, drying with anhydrous Na 2SO4, filtering, and distilling under reduced pressure to remove the solvent to obtain an intermediate ethyl benzoylacetate (1 b); s3, adding 2-chlorobenzoic acid (10 mmol), 50ml of dichloromethane and 5 drops of DMF into a 100ml single-port bottle, slowly adding oxalyl chloride (12 mmol) at room temperature, and carrying out heating reflux reaction for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 2-chloro-benzoyl chloride (1 c), and the 2-chloro-benzoyl chloride is stored in a sealed manner and immediately used for the next reaction. To a 50ml single flask was added 2-chlorobenzoic acid (10 mmol), 5 drops of DMF and 50ml of dichloromethane, and oxalyl chloride (12 mmol) was slowly added at room temperature and the reaction was heated under reflux for 3h. After the reaction is finished, the benzoyl chloride (1 c) is obtained by decompression and desolventizing at 70 ℃, and the benzoyl chloride is stored in a closed manner and is immediately used for the next reaction; s4, in a 100mL double-port bottle, t-Buona (8.3 mmol), CS 2CO3 (8.3 mmol) and dimethylacetamide (DMAC, 10 mL) were added, and a solution of ethyl benzoylacetate (8.3 mmol) and DMAC (2.5 mL) was slowly dropped at 0℃and stirred for 15min, and a solution of 2-chloro-benzoyl chloride (10 mmol) and DMAC (5 mL) was dropped at 0℃into the above mixture. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. After the completion of the reaction, the temperature was lowered to room temperature, 1.5 times hydrochloric acid (12 mol/L) was added, the pH was adjusted to about 7, the reaction solution was extracted with water, the separated aqueous layer was extracted three times with toluene, the organic layers were combined and washed with saturated brine, dried over anhydrous Na 2SO4, filtered, and desolventized by distillation under reduced pressure to give intermediate 1d (crude mixture). Column chromatography to obtain flavone-3-ethyl formate ：1H-NMR (600MHz,Chloroform-d)δ8.29(m,J＝8.0,1.8Hz,1H),7.79–7.77(m,2H),7.74(m,J＝8.4,7.2,1.8Hz,1H),7.60–7.57(m,1H),7.56–7.52(m,3H),7.47 (m,J＝8.4,7.2,1H),4.30(q,J＝7.2Hz,2H),1.19(t,J＝7.2Hz,3H).13C-NMR (101MHz,Chloroform-d)δ175.08(1C),165.06(1C),163.12(1C),155.84(1C),134.36(1C),133.22(1C),132.25(1C),131.63(1C),131.33(1C)128.77(1C), 128.10(1C),126.65(1C),126.11(1C),125.71(1C),123.15(1C),118.08(1C), 61.91(1C),13.84(1C).HR-MS(ESI+)m/z Calcd for C16H8O4(M+H)+295.0965, found 295.0959;S5., dissolving intermediate 1d in 15ml methanol at room temperature in 50ml single-port bottle, stirring, adding 15ml water, stirring, adding lithium hydroxide (83 mmol), stirring at room temperature for 4 hr, vacuum distilling at 60deg.C to remove methanol, adding 25ml water, suction filtering, adding hydrochloric acid into water layer to adjust pH to 2-3, filtering to obtain white solid 1e, namely flavone-3-carboxylic acid ：1H-NMR(600MHz, Chloroform-d)δ8.14(m,J＝7.8,1.8Hz,1H,Benzene-H),7.77–7.70(m,3H,Benzene-H),7.62–7.56(m,1H,Benzene-H),7.48(t,J＝7.8Hz,2H,Benzene-H), 7.42–7.37(m,1H,Benzene-H),7.35(d,J＝8.4Hz,1H,Benzene-H).13C-NMR (151MHz,Chloroform-d)δ200.84(1C),178.09(1C),159.60(1C),155.15(1C),137.88(1C),136.11(1C),132.54(1C),128.36(2C),127.91(2C),125.59(1C), 124.46(1C),117.10(1C),115.23(1C),100.70(1C).HR-MS(ESI+)m/z Calcd for C16H8O4(M+H)-265.0506,found 265.0506.
Example 2
Synthesis of 8-methyl-4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (2 e)
The synthetic route is as follows:
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The preparation method comprises the following specific steps: steps S1, S2 are the same as steps S1, S2 in example 1 to give ethyl benzoylacetate (1 b); s3, adding 2-chloro-3-methyl-benzoic acid (10 mmol), 50ml dichloromethane and 5 drops of DMF into a 100ml single-port bottle, slowly adding oxalyl chloride (12 mmol) at room temperature, and carrying out heating reflux reaction for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 2-chloro-3-methyl-benzoyl chloride (2 c), and the 2c is stored in a closed manner and immediately used for the next reaction; s4.100mL double flask was charged with t-Buona (8.3 mmol), cs2CO3 (8.3 mmol) and DMAc (10 mL), a solution of DMAc (2.5 mL) containing ethyl benzoylacetate (8.3 mmol) was added at 0deg.C, and after stirring for 15min, a solution of DMAc (5 mL) containing 2-chloro-3-methylbenzoyl chloride (10 mmol) was added dropwise to the above mixture at 0deg.C. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to 7, separating the reaction solution with toluene and water, extracting the separated water layer with toluene for three times, washing the combined extract with brine, drying with anhydrous Na 2SO4, and concentrating under reduced pressure to obtain intermediate 2d (crude product mixture); s5, adding the intermediate 2d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction is finished, the methanol is distilled and removed under reduced pressure at 60 ℃, 25ml of water is added, the filtration is carried out, the pH value of the water layer is adjusted to 2-3 by adding hydrochloric acid, and the white solid is obtained by suction filtration 2e：1H-NMR (600MHz,Chloroform-d)δ8.06–7.93(m,1H,Benzene-H),7.80–7.66(m,2H,Benzene-H),7.60–7.58(m,1H,Benzene-H),7.54–7.44(m,2H,Benzene-H), 7.34–7.23(m,2H,Benzene-H),2.48(s,3H,-CH3).13C-NMR(151MHz, Chloroform-d)δ178.22(1C),168.85(1C),159.63(1C),153.52(1C),137.25(1C),134.51(1C),132.50(1C),129.47(1C),129.43(1C),128.40(2C),127.87(2C), 126.64(1C),126.14(1C),124.02(1C),123.11(1C),100.45(1C),15.50(1C).HR-MS(ESI+)m/z Calcd for C16H8O4(M+H)-279.0663,found 279.0664.
Example 3
Synthesis of 2- (4-fluorophenyl) -8-methyl-4-oxo-4H-chromene-3-carboxylic acid (3 e)
The synthetic route is as follows:
the specific synthesis steps are as follows: step S1 and step S2 are the same as step S1 and step S2 in example 1 except that the raw material benzoic acid is replaced with p-fluorobenzoic acid to obtain ethyl p-fluorobenzoylacetate (3 b); step S3 is the same as step S3 in example 2 to give 2-chloro-3-methylbenzoyl chloride (2 c); s4, adding t-Buona (8.3 mmol), CS 2CO3 (8.3 mmol) and DMAC (10 mL) into a 100mL double-mouth bottle, slowly dropwise adding a solution prepared from ethyl p-fluorobenzoylacetate (8.3 mmol) and DMAC (2.5 mL) at 0 ℃, stirring for 15min, and dropwise adding a solution prepared from 2-chloro-3-methylbenzoyl chloride (10 mmol) and DMAC (5 mL) into the mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to 7, extracting with water, extracting the separated water layer with toluene for three times, mixing the organic layers, washing with saturated saline, drying with anhydrous Na 2SO4, and removing solvent by reduced pressure distillation to obtain intermediate 3d (crude product mixture); s5, adding the intermediate 3d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction is finished, the methanol is distilled and removed under reduced pressure at 60 ℃, 25ml of water is added, the suction filtration is carried out, the pH value of the water layer is adjusted to 2-3 by adding hydrochloric acid, and the suction filtration is carried out, thus obtaining white solid 3e：1H-NMR (600MHz,Chloroform-d)δ7.81(m,J＝7.8,1.8Hz,1H),7.49–7.42(m,1H),7.26(t,J＝7.8Hz,1H),7.20–7.15(m,4H),2.47(s,3H).13C-NMR(151MHz, Chloroform-d)δ171.65(1C),171.22(1C),167.22(1C),165.53(1C),138.32(1C),134.70(1C),133.93(1C),132.94(1C),132.88(1C),129.58(1C),126.14(1C), 125.48(1C),125.46(1C),115.82(1C),115.68(1C),20.77(1C).HR-MS(ESI+) m/z Calcd for C16H8O4(M+H)-297.0569,found 297.0408.
Example 4
Synthesis of 2- (4-methoxyphenyl) -4-oxo-4H-chromene-3-carboxylic acid (4 e)
The synthetic route is as follows:
The specific synthesis steps are as follows: step S1 and step S2 are the same as the other contents of step S1 and step S2 in example 1, except that the raw material benzoic acid is replaced by p-methoxyphenyl acid to obtain methoxy ethyl benzoyl acetate (4 b); step S3 is the same as step S3 in example 1 to obtain 2-chloro-benzoyl chloride (4 c); s4, in a 100mL double-port bottle, t-Buona (8.3 mmol), CS 2CO3 (8.3 mmol) and DMAC (10 mL) were added, and a solution of ethyl p-methoxybenzoyl acetate (8.3 mmol) and DMAC (2.5 mL) was slowly added dropwise at 0℃and stirred for 15min, and a solution of 2-chloro-benzoyl chloride (10 mmol) and DMAC (5 mL) was added dropwise to the above mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to 7, extracting with water, extracting the separated water layer with toluene for three times, mixing the organic layers, washing with saturated saline, drying with anhydrous Na 2SO4, and removing solvent by reduced pressure distillation to obtain intermediate 4d (crude product mixture); s5, adding the intermediate 4d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction is finished, the methanol is distilled and removed under reduced pressure at 60 ℃, 25ml of water is added, the suction filtration is carried out, the pH value of the water layer is adjusted to 2-3 by adding hydrochloric acid, and the suction filtration is carried out, thus obtaining white solid 4e：1H-NMR(600MHz, Chloroform-d)δ8.04–8.03(m,1H),7.52–7.49(m,3H),7.44(m,J＝7.8,7.2,1.8 Hz,1H),7.38(m,J＝7.8,7.2,1.8Hz,2H),7.36–7.30(m,1H),3.90(s,3H).13C-NMR(151MHz,Chloroform-d)δ170.62(1C),169.06(1C),165.62(1C), 160.89(1C),153.88(1C),134.70(1C),133.52(1C),132.45(1C),132.44(1C),131.67(1C),131.48(1C),128.54(1C),126.69(1C),121.39(1C),113.81(1C), 106.13(1C),55.52(1C).HR-MS(ESI+)m/z Calcd for C16H8O4(M+H)-295.0612, found 295.0615.
Example 5
Synthesis of 5-chloro-4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (5 e)
The synthetic route is as follows:
The specific synthesis steps are as follows: steps S1, S2 are the same as steps S1, S2 in example 1 to give ethyl benzoylacetate (1 b); s3, adding 2, 6-dichloro-benzoic acid (10 mmol), 50ml dichloromethane and 5 drops of DMF into a 100ml single-port bottle, slowly adding oxalyl chloride (12 mmol) at room temperature, and carrying out heating reflux reaction for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 2, 6-dichloro-benzoyl chloride (5 c), and the 2, 6-dichloro-benzoyl chloride is stored in a closed manner and immediately used for the next reaction; s4, adding t-Buona (8.3 mmol), CS 2CO3 (8.3 mmol) and DMAC (10 mL) into a 100mL double-mouth bottle, slowly dropwise adding a solution prepared from ethyl benzoylacetate (8.3 mmol) and DMAC (2.5 mL) at 0 ℃, stirring for 15min, and dropwise adding a solution prepared from 2, 6-dichlorobenzoyl chloride (10 mmol) and DMAC (5 mL) into the mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to 7, extracting with water, extracting the separated water layer with toluene three times, mixing the organic layers, washing with saturated saline, drying with anhydrous Na 2SO4, and removing solvent by reduced pressure distillation to obtain intermediate 5d (crude product mixture); s5, adding the intermediate 5d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction is finished, the methanol is distilled and removed under reduced pressure at 60 ℃, 25ml of water is added, the suction filtration is carried out, the pH value of the water layer is adjusted to 2-3 by adding hydrochloric acid, and the suction filtration is carried out, thus obtaining white solid 5e：1H-NMR(600 MHz,Chloroform-d)δ7.75–7.69(m,2H,Benzene-H),7.60(q,J＝8.4Hz,2H,Benzene-H),7.49(t,J＝7.8Hz,2H,Benzene-H),7.40(d,J＝7.8Hz,1H, Benzene-H),7.30–7.26(m,1H,Benzene-H).13C-NMR(151MHz,Chloroform-d) δ200.73(1C),179.81(1C),158.47(1C),156.71(1C),137.37(1C),135.16(1C),134.34(1C),132.73(1C),128.45(2C),128.06(1C),127.96(2C),116.39(1C),113.32(1C),100.53(1C).HR-MS(ESI+)m/z Calcd for C16H8O4(M+H)-299.0116, found 299.0117.
Example 6
Synthesis of 8- ((dimethylamino) methyl) -4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (1 f)
The synthetic route is as follows:
The specific synthesis steps are as follows: the other steps are the same as in example 1 except that step S6. The prepared 4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (1 e) (10 mmol) is dissolved in ethanol, 37% aqueous formaldehyde solution (20 mmol) is added and heated to 65℃and stirred, dimethylamine (11 mmol) is added after 30min of reaction, the reaction is carried out for 1 to 5H, filtration, recrystallisation from absolute ethanol or separation from chromatographic column to give product 1f.
Example 7
Synthesis of 4-oxo-2-phenyl-8- (pyrrolidin-1-ylmethyl) -4H-chromen-3-carboxylic acid (2 f)
The synthetic route is as follows:
the specific synthesis steps are as follows: the other steps are the same as in example 1 except that step S6. The prepared 4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (1 e) (10 mmol) is dissolved in ethanol, 37% aqueous formaldehyde solution (20 mmol) is added and heated to 65℃and stirred, after 30min of reaction, tetrahydropyrrole (11 mmol) is added and reacted for 1 to 5H, filtered, recrystallized from absolute ethanol or separated by chromatography column to give product 2f.
Example 8
Synthesis of 8- (morpholinomethyl) -4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (3 f)
The synthetic route is as follows:
the specific synthesis steps are as follows: the other steps are the same as in example 1 except that step S6. The prepared 4-oxo-2-phenyl-4H-chromene-3-carboxylic acid (1 e) (10 mmol) is dissolved in ethanol, 37% aqueous formaldehyde solution (20 mmol) is added and heated to 65℃and stirred, morpholine (11 mmol) is added after 30min of reaction, reaction is carried out for 1 to 5H, filtration is carried out, and the product 3f is obtained by recrystallisation from absolute ethanol or separation from a chromatographic column.
Example 9
Synthesis of 2- (2, 4-bis (3-methylbuten-2-butenyl) phenyl) -4-oxo-4H-chromen-3-carboxylic acid (6 e)
The synthetic route is as follows:
The specific synthesis steps are as follows: step S1 and step S2 are the same as those in step S1 and step S2 in example 1 except that the raw material benzoic acid is replaced with 2-chlorobenzoic acid to obtain 2-chlorobenzoyl acetoacetate (9 b); s3, adding benzoic acid (10 mmol), potassium carbonate (11.5 mmol), 40ml acetone and a small amount of tetrabutylammonium bromide serving as a phase transfer catalyst into a three-necked flask, dropwise adding isopentenyl bromide (20 mmol), carrying out reflux reaction for 8h, desolventizing, and separating by column chromatography to obtain 3, 5-diisopentenylbenzoic acid; to a 100ml single-necked flask was added 3, 5-diisopentenylbenzoic acid. (10 mmol), 50ml of dichloromethane and 5 drops of DMF, oxalyl chloride (12 mmol) was slowly added at room temperature and the reaction was heated under reflux for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 3, 5-diisopentenyl benzoyl chloride (9 c), and the 3, 5-diisopentenyl benzoyl chloride is stored in a closed manner and immediately used for the next reaction; s4, adding t-Buona (8.3 mmol), CS2CO3 (8.3 mmol) and DMAC (10 mL) into a 100mL double-mouth bottle, slowly dropwise adding a solution prepared from ethyl 2-chlorobenzoylacetate (8.3 mmol) and DMAC (2.5 mL) at 0 ℃, stirring for 15min, and dropwise adding a solution prepared from 3, 5-diisopentenyl benzoyl chloride (10 mmol) and DMAC (5 mL) into the mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to about 7, extracting with water, extracting the separated water layer with toluene for three times, mixing the organic layers, washing with saturated saline, drying with anhydrous Na 2SO4, and spin-drying to obtain intermediate 9d (crude mixture); s5, adding the intermediate 17d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction, removing methanol under reduced pressure at 60 ℃, adding 25ml of water, suction filtering, adding hydrochloric acid into a water layer to adjust the pH value to 2-3, and suction filtering to obtain white solid 9e.
Example 10
(10 E) Synthesis of 4-oxo-2-phenyl-4H-pyrano [2,3-b ] pyridine-3-carboxylic acid
The synthetic route is as follows:
The specific synthesis steps are as follows: steps S1, S2 are the same as in example 1 to give ethyl benzoylacetate (1 b); s3, adding 2-chloro-3-picolinic acid (10 mmol), 50ml dichloromethane and 5 drops of DMF into a 100ml single-port bottle, slowly adding oxalyl chloride (12 mmol) at room temperature, and carrying out heating reflux reaction for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 2-chloro-3-pyridine formyl chloride (10 c), and the 2-chloro-3-pyridine formyl chloride is stored in a closed manner and immediately used for the next reaction; s4, in a 100mL double-port bottle, t-Buona (8.3 mmol), CS 2CO3 (8.3 mmol) and DMAC (10 mL) were added, and a solution of ethyl benzoylacetate (8.3 mmol) and DMAC (2.5 mL) was slowly added dropwise at 0℃and stirred for 15min, and a solution of 2-chloro-3-pyridine formyl chloride (10 mmol) and DMAC (5 mL) was added dropwise to the above mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to about 7, extracting with water, extracting the separated water layer with toluene for three times, mixing the organic layers, washing with saturated saline, drying with anhydrous Na 2SO4, and spin-drying to obtain intermediate 10d (crude mixture); s5, adding the intermediate 10d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction is finished, the methanol is distilled and removed under reduced pressure at 60 ℃, after spin drying, 25ml of water is added, suction filtration is carried out, the pH of the water layer is adjusted to 2-3 by adding hydrochloric acid, and the white solid 10e is obtained by suction filtration.
Example 11
Synthesis of 6-fluoro-4-oxo-2-phenyl-4H-pyrano [2,3-c ] pyridine-3-carboxylic acid (11 e)
The synthetic route is as follows:
The specific synthesis steps are as follows: steps S1, S2 are the same as in example 1 to give ethyl benzoylacetate (1 b); s3, adding 2-chloro-5-fluoro-4-picolinic acid (10 mmol), 50ml dichloromethane and 5 drops of DMF into a 100ml single-port bottle, slowly adding oxalyl chloride (12 mmol) at room temperature, and heating and refluxing for reaction for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 2-chloro-5-fluoro-4-pyridine formyl chloride (11 c), and the 2-chloro-5-fluoro-4-pyridine formyl chloride is stored in a closed manner and immediately used for the next reaction; s4, adding t-Buona (8.3 mmol), CS2CO3 (8.3 mmol) and DMAC (10 mL) into a 100mL double-mouth bottle, slowly dropwise adding a solution prepared from ethyl benzoylacetate (8.3 mmol) and DMAC (2.5 mL) at 0 ℃, stirring for 15min, and dropwise adding a solution prepared from 2-chloro-5-fluoro-4-pyridine formyl chloride (10 mmol) and DMAC (5 mL) into the mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to 7, extracting with water, extracting the separated water layer with toluene three times, mixing the organic layers, washing with saturated saline, drying with anhydrous Na 2SO4, filtering, and spin-drying to obtain intermediate 11d (crude mixture); s5, adding the intermediate 19d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction is finished, the methanol is distilled and removed under reduced pressure at 60 ℃, after the mixture is dried by spin, 25ml of water is added, suction filtration is carried out, the pH value of the water layer is adjusted to 2-3 by adding hydrochloric acid, suction filtration is carried out, and white solid is obtained, thus obtaining white solid 11e.
Example 12
Synthesis of 5, 7-dimethyl-4-oxo-2-phenyl-4H-pyrano [2,3-b ] pyridine-3-carboxylic acid (12 e)
The synthetic route is as follows:
/>
The method comprises the following specific steps: steps S1, S2 are the same as in example 1 to give ethyl benzoylacetate (1 b); s3, adding 2-chloro-4, 6-dimethyl-3-picolinic acid (10 mmol), 50ml dichloromethane and 5 drops of DMF into a 100ml single-port bottle, slowly adding oxalyl chloride (12 mmol) at room temperature, and carrying out heating reflux reaction for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 2-chloro-4, 6-dimethyl-3-pyridine formyl chloride (12 c), and the 2-chloro-4, 6-dimethyl-3-pyridine formyl chloride is stored in a sealed manner and immediately used for the next reaction; s4, in a 100mL double-mouth bottle, t-Buona (8.3 mmol), CS 2CO3 (8.3 mmol) and DMAC (10 mL) are added, a solution prepared from ethyl benzoylacetate (8.3 mmol) and DMAC (2.5 mL) is slowly added dropwise at 0 ℃, after stirring for 15min, a solution prepared from 2-chloro-4, 6-dimethyl-3-pyridine formyl chloride (10 mmol) and DMAC (5 mL) is added dropwise to the mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to about 7, extracting with water, extracting the separated water layer with toluene for three times, mixing the organic layers, washing with saturated saline, drying with anhydrous Na 2SO4, and spin-drying to obtain intermediate 12d (crude mixture); s5, adding the intermediate 20d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, uniformly stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), and stirring for 4h. After the reaction is finished, the methanol is distilled and removed under reduced pressure at 60 ℃, after spin drying, 25ml of water is added, suction filtration is carried out, the pH of the water layer is adjusted to 2-3 by adding hydrochloric acid, and the white solid 12e is obtained by suction filtration.
Example 13
Synthesis of 5-oxo-7-phenyl-5H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid (13 e)
The synthetic route is as follows:
The method comprises the following specific steps: steps S1, S2 are the same as in example 1 to give ethyl benzoylacetate (1 b); s3, adding 4-chloropyrimidine-5-carboxylic acid (10 mmol), 50ml dichloromethane and 5 drops of DMF into a 100ml single-port bottle, slowly adding oxalyl chloride (12 mmol) at room temperature, and carrying out heating reflux reaction for 3h. After the reaction is finished, the solvent is removed by reduced pressure distillation at 70 ℃ to obtain 4-chloro-pyrimidine 5-carbonyl chloride (13 c), and the 4-chloro-pyrimidine 5-carbonyl chloride is stored in a closed manner and immediately used for the next reaction; s4, adding t-Buona (8.3 mmol), cs 2CO3 (8.3 mmol) and DMAc (10 mL) into a 100mL double-mouth bottle, slowly dropwise adding a solution prepared from ethyl benzoylacetate (8.3 mmol) and DMAc (2.5 mL) at 0 ℃, stirring for 15min, and dropwise adding a solution prepared from 4-chloro-pyrimidine 5-carbonyl chloride (10 mmol) and DMAc (5 mL) into the mixture at 0 ℃. After the addition was completed, the resulting mixture was stirred at 0℃for 0.5h, then heated to 110℃and reacted at a constant temperature for 16h. Cooling to room temperature, adding 1.5 times hydrochloric acid (12 mol/L), adjusting pH to 7, separating the reaction solution with toluene and water, extracting the separated water layer with toluene for three times, washing the combined extract with brine, drying with anhydrous Na 2 SO4, and concentrating under reduced pressure to obtain intermediate 13d (crude product mixture); s5, adding the intermediate 13d into a 50ml single-port bottle at room temperature, adding 15ml of methanol for dissolution, stirring, adding 15ml of water, uniformly stirring, adding lithium hydroxide (83 mmol), stirring for 4h, monitoring by a dot plate, and ending the reaction. Removing methanol at 60 ℃, spin-drying, adding 25ml of water, suction-filtering, adding hydrochloric acid into the water layer to adjust Ph to 2-3, and suction-filtering to obtain white solid 13e.
Other compounds were synthesized as described above.
Test of bactericidal Activity
The compounds of the present application were used to test the bactericidal activity against a variety of fungal diseases. The experimental method is as follows: the compounds were dissolved in acetone or dichloromethane or DMSO to prepare 2000 μm mother liquor. Under aseptic conditions, the prepared 2000. Mu.M mother liquor was diluted with medium to 200. Mu.M plates of toxic medium, and experiments were repeated 3 times each with no drug-treated blank.
The mycelium growth rate method is adopted for measurement according to the agricultural industry standard of the people's republic of China (NY/T1156.2-2006). Cutting bacterial cakes from the edge of bacterial colony under aseptic operation condition with sterilizing puncher with diameter of 5mm, inoculating bacterial cakes in the center of the medicated plate with the inoculant with mycelium facing downwards, covering the dish cover, and culturing in incubator at 25deg.C.
The growth condition of pathogenic bacteria hypha is investigated according to the growth condition of bacterial colonies in a blank control culture dish, after the bacterial colonies in the blank control are fully grown, the diameter of each treated bacterial colony is measured by a crisscross method, the growth diameter of the bacterial colonies is calculated by adopting the following formula, and the average value is obtained:
Colony growth diameter = colony diameter-cake diameter.
The measurement results were calculated by the following method, and the hypha growth inhibition ratios of the respective chemical treatments to various pathogenic bacteria were calculated from the blank colony growth diameter and the chemical-treated colony growth diameter (see the following formulas).
Hypha growth inhibition (%) = [ (control colony growth diameter-agent treated colony growth diameter)/blank colony growth diameter ] ×100, partial compound test results are shown in table 2 (wherein compound numbers correspond to numbers in table 1, example 1 product is 4-oxo-2-phenyl-4H-chromene-3-carboxylic acid, i.e., flavone-3-carboxylic acid):
table 2: results of test for the bactericidal Activity of some Compounds
The known starting materials used in the present invention may be synthesized by methods known in the art or purchased through conventional commercial means. The preparation of the compounds of the present invention may be accomplished by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed above, embodiments formed in combination with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
Claims (6)
1. The flavone-3-carboxylic acid compound is characterized in that the structural general formula is shown in the formula (1):
（I）
the flavone-3-carboxylic acid compound is one of the following structural formulas:
，/>，/>，，/>。
2. a process for the preparation of a flavone-3-carboxylic acid compound as claimed in claim 1, comprising the steps of:
S1, carrying out an acylation reaction by taking substituted benzoic acid and oxalyl chloride as raw materials to obtain an intermediate product a, wherein the reaction formula is as follows:
Wherein R' in the substituted benzoic acid is as defined in claim 1;
S2, taking the intermediate product a and ethyl acetoacetate as raw materials, and carrying out nucleophilic substitution reaction to obtain an intermediate product b, wherein the reaction formula is as follows:
s3, carrying out an acylation reaction by taking carboxylic acid compounds with chlorine substituted on beta carbon and oxalyl chloride as raw materials to obtain an intermediate product c, wherein the reaction formula is as follows:
Wherein in the carboxylic acid compound with hydrogen on the beta carbon replaced by chlorine, X 1、X2、X3、X4 and R are defined as in claim 1;
s4, carrying out a cyclization reaction by taking the intermediate product b and the intermediate product c as raw materials and taking sodium tert-butoxide and cesium carbonate as catalysts to obtain an intermediate product d, wherein the reaction formula is as follows:
s5, hydrolyzing the intermediate product d by lithium hydroxide to obtain a flavone-3-carboxylic acid compound e, wherein the reaction formula is as follows:
。
3. A bactericidal composition containing the flavone-3-carboxylic acid compound of claim 1.
4. A bactericidal composition according to claim 3 in the form of a suspension, water dispersible granule, wettable powder, oil suspension, emulsifiable concentrate, microemulsion, aqueous emulsion, suspension or soluble formulation.
5. A bactericidal composition according to claim 3, further comprising at least one carrier.
6. Use of a flavone-3-carboxylic acid compound as claimed in claim 1 for controlling crop diseases including tobacco damping-off, rice bakanae disease, camphor anthracnose, corn stalk rot and bletilla striata southern blight.
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