CN112898223A - 1,3, 4-oxadiazole compound containing sulfonate/carboxylate structure and preparation method and application thereof - Google Patents
1,3, 4-oxadiazole compound containing sulfonate/carboxylate structure and preparation method and application thereof Download PDFInfo
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- -1 1,3, 4-oxadiazole compound Chemical class 0.000 title claims abstract description 85
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 241000209094 Oryza Species 0.000 claims abstract description 32
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 32
- 230000001580 bacterial effect Effects 0.000 claims abstract description 32
- 235000009566 rice Nutrition 0.000 claims abstract description 32
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 241000207199 Citrus Species 0.000 claims abstract description 16
- 235000020971 citrus fruits Nutrition 0.000 claims abstract description 16
- 241000607479 Yersinia pestis Species 0.000 claims abstract description 12
- 241000238631 Hexapoda Species 0.000 claims abstract description 7
- ZANNOFHADGWOLI-UHFFFAOYSA-N ethyl 2-hydroxyacetate Chemical compound CCOC(=O)CO ZANNOFHADGWOLI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 3
- SNHCQMSIXAIOPX-UHFFFAOYSA-N O1C=[N+](N=C1)[S-] Chemical class O1C=[N+](N=C1)[S-] SNHCQMSIXAIOPX-UHFFFAOYSA-N 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 100
- 238000006243 chemical reaction Methods 0.000 claims description 71
- 239000000203 mixture Substances 0.000 claims description 31
- 238000010992 reflux Methods 0.000 claims description 27
- 241000196324 Embryophyta Species 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 208000035143 Bacterial infection Diseases 0.000 claims description 9
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 6
- 229940126062 Compound A Drugs 0.000 claims description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 6
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000000575 pesticide Substances 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 116
- 238000003786 synthesis reaction Methods 0.000 description 116
- 239000007858 starting material Substances 0.000 description 28
- LIUCWHQVLKSECA-UHFFFAOYSA-N 2-hydroxyacetohydrazide Chemical compound NNC(=O)CO LIUCWHQVLKSECA-UHFFFAOYSA-N 0.000 description 27
- VPYDKLHFZXNADD-UHFFFAOYSA-N 5-(hydroxymethyl)-3h-1,3,4-oxadiazole-2-thione Chemical compound OCC1=NN=C(S)O1 VPYDKLHFZXNADD-UHFFFAOYSA-N 0.000 description 27
- 230000000694 effects Effects 0.000 description 25
- 239000003814 drug Substances 0.000 description 21
- 230000005764 inhibitory process Effects 0.000 description 11
- RSNWORHVUOZYLT-UHFFFAOYSA-N 5-[[(2-sulfanylidene-3h-1,3,4-thiadiazol-5-yl)amino]methylamino]-3h-1,3,4-thiadiazole-2-thione Chemical compound S1C(=S)NN=C1NCNC1=NNC(=S)S1 RSNWORHVUOZYLT-UHFFFAOYSA-N 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 10
- 229910052802 copper Inorganic materials 0.000 description 10
- 239000010949 copper Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 230000002265 prevention Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 241001272684 Xanthomonas campestris pv. oryzae Species 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 244000052616 bacterial pathogen Species 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 230000003385 bacteriostatic effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000009630 liquid culture Methods 0.000 description 4
- 244000052769 pathogen Species 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- LVYJIIRJQDEGBR-UHFFFAOYSA-N 1-fluoro-2-iodoethane Chemical compound FCCI LVYJIIRJQDEGBR-UHFFFAOYSA-N 0.000 description 3
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 3
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 3
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 241000589655 Xanthomonas citri Species 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000013043 chemical agent Substances 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000004308 thiabendazole Substances 0.000 description 2
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 2
- 229960004546 thiabendazole Drugs 0.000 description 2
- 235000010296 thiabendazole Nutrition 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- 150000005072 1,3,4-oxadiazoles Chemical class 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZIZGWNOAHUCACM-UHFFFAOYSA-N 2-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=CC=C1S(Cl)(=O)=O ZIZGWNOAHUCACM-UHFFFAOYSA-N 0.000 description 1
- ZSZKAQCISWFDCQ-UHFFFAOYSA-N 2-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC=C1S(Cl)(=O)=O ZSZKAQCISWFDCQ-UHFFFAOYSA-N 0.000 description 1
- OINWZUJVEXUHCC-UHFFFAOYSA-N 3-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC(S(Cl)(=O)=O)=C1 OINWZUJVEXUHCC-UHFFFAOYSA-N 0.000 description 1
- OKYSUJVCDXZGKE-UHFFFAOYSA-N 3-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(S(Cl)(=O)=O)=C1 OKYSUJVCDXZGKE-UHFFFAOYSA-N 0.000 description 1
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 1
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 1
- DTJVECUKADWGMO-UHFFFAOYSA-N 4-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1 DTJVECUKADWGMO-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005868 Metconazole Substances 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000012271 agricultural production Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- XWPZUHJBOLQNMN-UHFFFAOYSA-N metconazole Chemical compound C1=NC=NN1CC1(O)C(C)(C)CCC1CC1=CC=C(Cl)C=C1 XWPZUHJBOLQNMN-UHFFFAOYSA-N 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- 230000001069 nematicidal effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- LRTFPLFDLJYEKT-UHFFFAOYSA-N para-isopropylaniline Chemical compound CC(C)C1=CC=C(N)C=C1 LRTFPLFDLJYEKT-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000004382 potting Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- 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
- A01N43/82—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 three ring hetero atoms
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种含磺酸酯/羧酸酯结构的1,3,4‑噁二唑类化合物及其制备方法和应用，属于化工技术与农药领域。本发明以乙醇酸乙酯为原料合成一系列含有磺酸酯/羧酸酯结构的1,3,4‑噁二唑硫醚类化合物，所合成的1,3,4‑噁二唑硫醚类化合物对农业病虫害中的水稻白叶枯病和柑橘溃疡病具有良好的抑制作用，尤其对于水稻白叶枯病菌抑制活性更高，可用于制备抗植物细菌药剂。The invention discloses a 1,3,4-oxadiazole compound containing a sulfonate/carboxylate structure and a preparation method and application thereof, belonging to the fields of chemical technology and pesticides. The present invention uses ethyl glycolate as raw material to synthesize a series of 1,3,4-oxadiazole sulfide compounds containing sulfonate/carboxylate structure, and the synthesized 1,3,4-oxadiazole sulfide The compounds have a good inhibitory effect on rice bacterial blight and citrus canker in agricultural diseases and insect pests, and especially have higher inhibitory activity on rice bacterial blight, and can be used to prepare anti-plant bacterial agents.
Description
Technical Field
The invention relates to the field of chemical technology and pesticides, in particular to a 1,3, 4-oxadiazole compound containing a sulfonate/carboxylate structure and a preparation method and application thereof.
Background
The plant bacterial diseases are a third major plant diseases which are caused by bacterial infection of plants and are only next to fungal diseases and virus diseases, and bacterial diseases such as rice bacterial blight, citrus canker and the like are all important diseases in the world. In recent years, with the change of crop cultivation systems and environmental climates in China, crop bacterial diseases such as rice bacterial blight bacteria and citrus canker bacteria tend to be predominant in China. The diseases have the characteristics of quick onset, large harm, wide distribution and the like, no effective chemical agent or other prevention and control methods exist so far, great loss is caused to agricultural production, and effective agents are urgently developed for prevention and control. Therefore, the search for a high-efficiency, low-toxicity and environment-friendly chemical agent for resisting plant bacterial diseases is an urgent problem to be solved in the field of plant protection.
Su et al (Molecules,2017,22,64.) introduced phenoxy into 1,3, 4-oxadiazole in 2017. The test result shows that: most of the synthesized compounds have certain inhibition effect on rice bacterial blight and citrus canker bacteria. Some of the compounds have excellent prevention and control effects on the treatment of the living bodies of rice, and the prevention and control effects are better than those of control drugs of bismerthiazol and thiabendazole.
1,3, 4-oxadiazole thioether is an important five-membered heterocyclic compound with diversified biological activities. Many compounds containing 1,3, 4-oxadiazole thioether have bacteriostatic, antiviral, nematicidal and other activities. It has wide application in medicine, pesticide and other fields, so its synthesis research is receiving much attention. Therefore, the 1,3,4 oxadiazole thioether has great development prospect as one of important resources in the development and research of new drugs in the future.
In conclusion, the compounds containing the 1,3, 4-oxadiazole thioether all have better biological activity, but no report about the activity of the 1,3, 4-oxadiazole thioether containing a sulfonate/carboxylate structure in resisting plant bacteria is found.
Disclosure of Invention
The invention aims to provide a 1,3, 4-oxadiazole compound containing a sulfonate/carboxylate structure, a preparation method and application thereof, so as to solve the problems in the prior art, and enable the 1,3, 4-oxadiazole thioether compound to have remarkable anti-plant bacterial activity.
In order to achieve the purpose, the invention provides the following scheme:
the invention provides a 1,3, 4-oxadiazole thioether compound, which is a 1,3, 4-oxadiazole thioether compound containing sulfonate shown in a general formula A or a 1,3, 4-oxadiazole thioether compound containing carboxylate shown in a general formula B; wherein:
R1independently selected from any one of methyl, ethyl or fluoroethyl;
R2independently selected from any one of substituted phenyl or dimethylamino;
R3independently selected from any one of substituted phenyl or dimethylamino.
More preferably, the sulfonic acid ester-containing 1,3, 4-oxadiazole sulfide compound of the general formula a and the carboxylic acid ester-containing 1,3, 4-oxadiazole sulfide compound of the general formula B are each independently selected from the following compounds:
another object of the present invention is to provide a method for preparing a 1,3, 4-oxadiazole thioether compound containing a sulfonic acid ester represented by the above general formula a, which comprises the following steps:
the synthetic route is as follows:
(1) using ethyl glycolate as a raw material, adding hydrazine hydrate (80%), and preparing 2-hydroxyacetylhydrazine (intermediate 1):
(2) preparing 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol (intermediate 2) from 2-hydroxyacetylhydrazine under alkaline conditions:
(3) 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thioether is prepared by taking 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol as a raw material (intermediate 3):
(4) preparing a 1,3, 4-oxadiazole thioether compound (target compound A) containing a sulfonate structure by using 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thioether as a raw material:
(5) preparing a 1,3, 4-oxadiazole thioether compound (target compound B) containing a carboxylic ester structure by using 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thioether as a raw material:
the invention also provides a composition comprising the 1,3, 4-oxadiazole thioether compound.
As a further preferred aspect of the present invention, the composition further comprises an agricultural adjuvant, a bactericide or an insecticide.
The fourth purpose of the invention is to provide an application of the 1,3, 4-oxadiazole thioether compound or the composition in the aspect of preventing and treating agricultural diseases and insect pests.
As a further preferred aspect of the invention, the agricultural pest is a bacterial disease of a plant.
As a further preferred aspect of the present invention, the plant bacterial disease is bacterial blight of rice or citrus canker.
The fifth purpose of the invention is to provide a method for preventing and controlling agricultural pests, which enables the 1,3, 4-oxadiazole thioether compound or the composition to act on pests of the agricultural pests or living environments thereof.
Further preferably, the agricultural pest is rice bacterial blight or citrus canker.
The invention discloses the following technical effects:
according to the invention, ethyl glycolate is used as a raw material to synthesize a series of 1,3, 4-oxadiazole thioether compounds containing sulfonate/carboxylate structures, and the synthesized 1,3, 4-oxadiazole thioether compounds have good inhibitory activity on rice bacterial blight bacteria and can be used for preparing plant bacteria resistant medicaments.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
The "parts" in the present invention are all parts by mass unless otherwise specified.
Example 1
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) benzenesulfonate (compound No. A)1) The method comprises the following steps:
(1) ethyl glycolate (0.05mol,1eq) was added to a 250mL three-necked flask at room temperature, and 100mL of absolute ethanol was added to the round-bottomed flask, followed by stirring at room temperature. Then, 80% hydrazine hydrate (0.1mol,2eq) was slowly added to the round-bottom flask with stirring at room temperature, and then heated to reflux. After the reaction is carried out for 12 hours, the reaction is stopped, the temperature is reduced by cooling, and the white intermediate product 2-hydroxyacetylhydrazine is separated out. The yield was 90%.
(2) To a 250mL three-necked round-bottomed flask, the intermediate 2-hydroxyacetylhydrazine (0.01mol,1eq) obtained in the previous step, potassium hydroxide (0.012mol,1.2eq) and 100mL of absolute ethanol were added in this order, followed by stirring and mixing. Then, after slowly adding carbon disulfide (0.012mol,1.2eq) under stirring at room temperature, the mixture was reacted at room temperature for 1 hour, then heated to 78 ℃ for reflux reaction for 6 hours, the solvent anhydrous ethanol was removed under reduced pressure on a rotary evaporator, the sample was stirred with silica gel, and the intermediate product 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol was obtained in a yield of 70% by column chromatography.
(3) In a 50mL single-neck flask, 20 mL of tetrahydrofuran as a solvent was added, followed by addition of the intermediate 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol obtained in the previous step (0.01mmol,1eq) and potassium hydroxide (0.012mmol,1.2eq), followed by stirring for dissolution, and then iodomethane (0.012mmol,1.2eq) was slowly added dropwise, followed by reaction with stirring at room temperature for 30 min. Judging that the reaction is finished by thin layer chromatography, removing the solvent under reduced pressure, mixing the sample with silica gel, and purifying by silica gel column chromatography to obtain an intermediate product, namely 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether, with the yield of 75%.
(4) To a 25mL round bottom flask was added intermediate 3(0.001mol,1eq) from the previous step at room temperatureAnd tetrahydrofuran (10mL) as a solvent, and after sufficiently dissolving the compound by stirring, sodium hydride (0.001mol,1eq) was slowly added. Stirring for 10min, slowly adding benzenesulfonyl chloride (0.0012mol,1.2eq) dropwise, reacting for 20min, tracking reaction progress by thin layer chromatography, filtering, and recrystallizing to obtain target compound A1The yield was 80%.
Example 2
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-fluorobenzenesulfonate (compound No. A)2) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 87% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ under reflux for 5 hours, giving a yield of 65%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 60min, giving a yield of 70%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-fluorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 15min, and 4-fluorobenzenesulfonyl chloride was used as a starting material, the yield was 86%.
Example 3
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzenesulfonate (compound No. A)3) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 85% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.5 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 50min, giving a yield of 80%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 30min, and 4-chlorobenzenesulfonyl chloride was used as a starting material in a yield of 76%.
Example 4
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzenesulfonate (compound No. A)4) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 88% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ under reflux for 6 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 55min, and the yield was 78%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 25min, and 4-bromobenzenesulfonyl chloride was used as a starting material in 55% yield.
Example 5
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzenesulfonate (compound No. A)5) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1 hour, and then heated to 78 ℃ under reflux for 5 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 30min, giving a yield of 70%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 15min, and 4-methoxybenzenesulfonyl chloride was used as a starting material in 66% yield.
Example 6
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-nitrobenzenesulfonate (compound No. A)6) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 85% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.3 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 35min, and the yield was 73%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-nitrobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 30min, and 4-nitrobenzenesulfonyl chloride was used as a starting material in a yield of 74%.
Example 7
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) -4- (trifluoromethyl) benzenesulfonate (compound No. A)7) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.8 hours, and then heated to 78 ℃ for reflux reaction for 6 hours, giving a yield of 60%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 60min, giving a yield of 80%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) -4- (trifluoromethyl) benzenesulfonate: the procedure is as in example 1, step (4), except that the reaction is terminated after 20min, starting from 4- (trifluoromethyl) -benzenesulfonyl chloride in 84% yield.
Example 8
(5- (methylthio) -1,3, 4-oxadiazol-2-yl) -2-fluorobenzenesulfonic acid methyl esterSynthesis of (Compound No. A)8) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: as in step (1) of example 1, the yield was 88%
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 65%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 40min, and the yield was 75%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) -2-fluorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 30min, and 2-fluorobenzenesulfonyl chloride was used as a starting material in a yield of 82%.
Example 9
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) -3-fluorobenzenesulfonate (compound No. A)9) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 85% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1 hour, and then heated to 78 ℃ for reflux reaction for 6 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 45min, giving a yield of 80%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) -3-fluorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 25min, and 3-fluorobenzenesulfonyl chloride was used as a starting material in a yield of 72%.
Example 10
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 3-chlorobenzenesulfonate (compound No. A)10) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 88% as in the step (1) of example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 50min, and the yield was 75%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) -3-chlorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 15min, and 3-chlorobenzenesulfonyl chloride was used as a starting material in a yield of 81%.
Example 11
Synthesis of methyl (5- (ethylsulfanyl) -1,3, 4-oxadiazol-2-yl) 4-fluorobenzenesulfonate (compound No. A)11) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.2 hours, and then heated to 78 ℃ for reflux reaction for 6 hours, giving a yield of 65%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-ethylsulfide: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 30min and that iodoethane was used as a starting material in a yield of 70%.
(4) Synthesis of methyl (5- (ethylsulfanyl) -1,3, 4-oxadiazol-2-yl) -4-fluorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 20min, and 4-fluorobenzenesulfonyl chloride was used as a starting material in 80% yield.
Example 12
Synthesis of methyl (5- (ethylsulfanyl) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzenesulfonate (compound No. A)12) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 85% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1 hour, and then heated to 78 ℃ for reflux reaction for 5 hours, giving a yield of 67%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-ethylsulfide: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 50min and that iodoethane was used as a starting material in a yield of 70%.
(4) Synthesis of methyl (5- (ethylsulfanyl) -1,3, 4-oxadiazol-2-yl) -4-chlorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 25min, and 4-chlorobenzenesulfonyl chloride was used as a starting material in a yield of 78%.
Example 13
Synthesis of methyl (5- (ethylsulfanyl) -1,3, 4-oxadiazol-2-yl) 4-bromobenzenesulfonate (compound No. A)13) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 88% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.5 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 55min and that iodoethane was used as a starting material in a yield of 75%.
(4) Synthesis of ethyl (5- (ethylsulfanyl) -1,3, 4-oxadiazol-2-yl) -4-bromobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 30min, and 4-bromobenzenesulfonyl chloride was used as a starting material in a yield of 72%.
Example 14
Synthesis of methyl (5- (2-fluoroethylthio) -1,3, 4-oxadiazol-2-yl) 4-fluorobenzenesulfonate (compound No. A)14) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 88% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.5 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-fluoroethylene sulfide: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 55min and 1-fluoro-2-iodoethane was used as a starting material in a yield of 75%.
(4) Synthesis of methyl (5- (2-fluoroethylthio) -1,3, 4-oxadiazol-2-yl) -4-fluorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 25min, and 4-fluorobenzenesulfonyl chloride was used as a starting material, the yield was 62%.
Example 15
Synthesis of methyl (5- (2-fluoroethylthio) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzenesulfonate (compound No. A)15) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ under reflux for 6 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-fluoroethylene sulfide: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 45min and 1-fluoro-2-iodoethane was used as a starting material in a yield of 78%.
(4) Synthesis of methyl (5- (2-fluoroethylthio) -1,3, 4-oxadiazol-2-yl) -4-chlorobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 30min, and 4-chlorobenzenesulfonyl chloride was used as a starting material in a yield of 80%.
Example 16
Synthesis of methyl (5- (2-fluoroethylthio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzenesulfonate (compound No. A)16) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ under reflux for 6 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-fluoroethylene sulfide: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 45min and 1-fluoro-2-iodoethane was used as a starting material in a yield of 80%.
(4) Synthesis of methyl (5- (2-fluoroethylthio) -1,3, 4-oxadiazol-2-yl) -4-bromobenzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 28min, and 4-bromobenzenesulfonyl chloride was used as a starting material in 80% yield.
Example 17
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) dimethylaminosulfonate (compound number A)17) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ under reflux for 6 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 45min, giving a yield of 80%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) dimethylaminosulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 30min, and dimethylaminosulfonyl chloride was used as a starting material in a yield of 80%.
Example 18
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 2- (trifluoromethyl) benzenesulfonate (compound No. A)18) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 87% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.5 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 35min, giving a yield of 80%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 2- (trifluoromethyl) benzenesulfonate: the procedure was as in (4) in example 1, except that the reaction was terminated after 28min, and 2-trifluoromethylbenzenesulfonyl chloride was used as a starting material in a yield of 64%.
Example 19
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) benzoate (Compound No. B)1) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 87% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.5 hours, and then heated to 78 ℃ for reflux reaction for 6 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 58min, giving a yield of 74%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) benzoate: the procedure was as in (4) in example 1, except that the reaction was terminated after 25min, and benzoyl chloride was used as a starting material in a yield of 77%.
Example 20
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-fluorobenzoate (Compound No. B)2) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 37min, giving a yield of 72%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-fluorobenzoate: the procedure was as in (4) in example 1, except that the reaction was terminated after 18min, and 4-fluorobenzoyl chloride was used as a starting material in a yield of 75%.
Example 21
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzoate (Compound No. B)3) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 87% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.6 hours, and then heated to 78 ℃ for reflux reaction for 6 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 60min, giving a yield of 80%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-chlorobenzoate: the procedure was as in (4) in example 1, except that the reaction was terminated after 26min, and 4-chlorobenzoyl chloride was used as a starting material in a yield of 74%.
Example 22
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzoate (compound No. B)4) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 89% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.8 hours, and then heated to 78 ℃ for reflux reaction for 5 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 58min, giving a yield of 79%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-bromobenzoate: the procedure was as in (4) in example 1, except that the reaction was terminated after 28min, and 4-bromobenzoyl chloride was used as a starting material in a yield of 70%.
Example 23
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzoate (Compound No. B)5) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 2 hours, and then heated to 78 ℃ under reflux for 6 hours, giving a yield of 70%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the procedure was as in (3) in example 1, except that the reaction was stirred at room temperature for 60min, giving a yield of 73%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-methoxybenzoate: the procedure was as in (4) in example 1, except that the reaction was terminated after 30min, and 4-methoxybenzoyl chloride was used as a starting material in 79% yield.
Example 24
Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) dimethylcarbamate (Compound No. B)6) The method comprises the following steps:
(1) 2-hydroxy acethydrazide synthesis: the yield was 90% as in the step (1) in example 1.
(2) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiol: the procedure was as in step (2) of example 1, except that the mixture was first reacted at room temperature for 1.5 hours, and then heated to 78 ℃ for reflux reaction for 5.5 hours, giving a yield of 68%.
(3) Synthesis of 5-hydroxymethyl-1, 3, 4-oxadiazole-2-thiomethyl ether: the reaction was carried out in the same manner as in example 1, step (3), except that the reaction was stirred at room temperature for 50min, whereby the yield was 78%.
(4) Synthesis of methyl (5- (methylthio) -1,3, 4-oxadiazol-2-yl) 4-fluorobenzoate: the procedure was as in (4) in example 1, except that the reaction was terminated after 20min, and dimethylcarbamoyl chloride was used as a starting material in a yield of 81%.
The physicochemical properties and mass spectrum data of the synthesized 1,3, 4-oxadiazole thioether compounds containing sulfonic ester/carboxylic ester are shown in Table 1, and the nuclear magnetic resonance hydrogen spectrum (C: (M))1H NMR) and carbon Spectroscopy (13C NMR) data are shown in table 2.
TABLE 1 physicochemical Properties of the target Compounds and their Mass spectrometric data
TABLE 2 NMR and C spectra data for target compounds
Activity test example 1: the activity test of the target compounds for inhibiting rice bacterial blight and citrus canker pathogen indoors is shown in tables 3 and 4.
Taking target compounds as medicaments, respectively adding the synthesized A and B series target compounds and two commercial medicaments of bismerthiazol and thiediazole copper into NB liquid culture media to prepare NB liquid culture media with final concentrations of 100 mu g/mL, 50 mu g/mL and 0 mu g/mL of medicaments, respectively adding 40 mu L of rice bacterial blight (Xoo) into the three groups of NB liquid culture media, wherein one group of 0 mu g/mL is set as a control. Culturing the above bacterial solution in shaking table at 28 deg.C and 180rpm for 24-48h to logarithmic growth phase, and measuring OD (OD) value on enzyme labeling instrument595) And (4) determining the OD value of the culture medium without the three bacteria-added agents as the OD value of the bacteria liquid, and deducting the OD value as a background absorption value when calculating. The activity of the citrus canker pathogen was tested as above, but the final concentrations of the three groups were set at 200. mu.g/mL and 100. mu.g, respectivelyAnd 0. mu.g/mL, again with 0. mu.g/mL being a control. The inhibitory effects (inhibition rates) of the compounds on two kinds of bacterial blight of rice and bacterial canker of citrus were measured and calculated, and the results are shown in table 3.
The inhibition rate of the compound needs to be calculated by deducting and correcting the background OD value generated by the NB liquid culture medium, and the calculation formula for correcting the OD value and the inhibition rate is as follows:
the corrected OD value (OD value of bacteria-containing culture medium liquid OD value-OD value of non-bacteria-containing culture medium compound inhibition rate) (corrected OD value of control group bacterial liquid-corrected OD value of medicine-containing bacterial liquid)/corrected OD value of control group bacterial liquid
TABLE 3 Primary screening of bacteriostatic activity of target compounds A and B against bacterial blight of rice (Xoo) and bacterial canker of citrus (Xac)
As shown in Table 3, most of the compounds A had higher antibacterial activity against rice bacterial blight bacteria than the control drugs bismerthiazol and thiediazole copper. Wherein at the concentration of 100 mu g/mL, 12 compounds A1-A5、A11-A16And B2The inhibition rate of the bacterial blight of rice is higher than 90%. When the concentration of the drug is reduced to 50 mug/mL, 3 compounds A exist1、A2、A14The inhibition rate of the bacterial blight of rice is higher than 90 percent, which is far higher than 28.3 percent of the metconazole and 30.2 percent of the thiediazole copper. At a drug concentration of 200. mu.g/mL, there were 4 compounds A1、A2、A3And A8The inhibition rate of the citrus canker pathogenic bacteria reaches more than 90 percent. At a drug concentration of 100. mu.g/mL, there were 3 compounds A1、A2And A3The inhibition effect on the citrus canker pathogenic bacteria is between 69 and 82 percent and is superior to 58.2 percent of the control drug of bismerthiazol and 53.1 percent of thiediazole copper.
Setting 5 concentration gradients for part of target compounds with good inhibitory activity, and determining EC of the target compounds on rice bacterial blight (Xoo) and citrus canker pathogen (Xac)50The value is obtained. Determination of the actual target Compounds A and A according to the above-mentioned Experimental methodsAntibacterial activity and EC of B value50The values and results are shown in Table 4.
EC against bacterial blight of rice and canker citrus of part of the target Compounds in Table 450(μM)
As shown in Table 4, there were 10 of the compounds A1-A4And A11-A16Has good inhibition effect on rice bacterial blight and EC thereof50The values ranged from 50.1 to 112.5. mu.M, which is far superior to 253.5. mu.M for bismerthiazol and 467.4. mu.M for copper thielavide. At the same time, there are 4 compounds A1-A4The inhibition effect on citrus canker pathogenic bacteria is also good. Their EC50In the range of 95.8 to 155.2. mu.M, is superior to 274.3. mu.M for bismerthiazol and 406.3. mu.M for copper thielavides.
From tables 3 and 4, it can be seen that the 1,3, 4-oxadiazole thioether compounds have more significant antibacterial activity against rice bacterial blight disease, especially compound a1、A2And A3It will be subjected to in vivo potting experiments.
Activity test example 2: highly active Compound A1、A2And A3In vivo pot culture test on rice bacterial leaf blight.
(1) Protection effect of rice bacterial leaf blight living pot experiment
Compound A with better activity to pathogenic bacteria of bacterial leaf blight of rice1、A2And A3And contrast agents of bismerthiazol and thiediazole copper are respectively prepared into medicine-containing solutions with the concentration of 200 mu g/mL by using 0.1% Tween solutions, and the medicine-containing solutions are sprayed on the surfaces of leaves of rice until liquid drops are dripped. After one day, the leaf tips were cut off with scissors with bacterial liquid of bacterial blight of rice at a distance of 1-2cm from the leaf tips, and the wounds were soaked in the bacterial liquid for about 30s, while a control group of 0.1% Tween solution without drug was provided. Each 30 rice seedlings are treated, the disease condition is checked 14 days after the application of the pesticide, the length of disease spots of rice leaves is recorded, the disease index and the prevention effect are calculated, and the result is obtainedSee table 5.
(2) Treatment effect of rice bacterial leaf blight living pot experiment
Cutting off the leaf apex at a position 1-2cm away from the leaf apex of the rice leaf by using scissors stained with pathogenic bacteria of bacterial leaf blight of rice, and soaking the wound in the bacterial liquid for about 30 s. One day later, the compound A with better activity to pathogenic bacteria of bacterial leaf blight of rice1、A2And A3And contrast agents of bismerthiazol and thiediazole copper are respectively prepared into medicine-containing solutions with the concentration of 200 mu g/mL by using 0.1% Tween solutions, and the medicine-containing solutions are sprayed on the surfaces of leaves of rice until liquid drops are dripped. Meanwhile, a 0.1% Tween solution control group without adding medicament is arranged. Each 30 rice seedlings are treated, the disease incidence condition is checked after the application of the pesticide for 14 days, the length of disease spots of the rice leaves is recorded, the disease index and the prevention effect are calculated, and the results are shown in table 6.
Control effect (%) - (control group lesion length-treatment group lesion length)/control group lesion length x 100
TABLE 5 target Compound A1、A2And A3Activity experiment result for protecting living potted plant of rice bacterial leaf blight (Xoo)
TABLE 6 target Compound A1、A2And A3Experimental result of activity of living pot culture of rice bacterial blight (Xoo)
As shown in tables 5 and 6 above, the target Compound A was tested at a drug concentration of 200. mu.g/mL2And A3The protection, prevention and control effects on the rice pot culture are respectively 68.6 percent and 62.3 percent, which are superior to 49.6 percent of the control drug bismerthiazol and 42.2 percent of the thiediazole copper. Target Compound A tested as shown in Table 61、A2And A3The treatment, prevention and control effects on the rice potted plant are respectively 44.6 percent, 62.3 percent and 56.0 percent, which are superior to the effects on leaves42.9% of cumidine and 36.1% of thiabendazole.
In conclusion, the series of 1,3, 4-oxadiazole compounds containing sulfonate/carboxylate structures have excellent antibacterial activity, and particularly the compound A1、A2、A3And A4Has the most excellent bacteriostatic activity on rice bacterial blight and citrus canker pathogen, and is superior to the bacteriostatic activity of control drugs of bismerthiazol and thiediazole copper.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
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