CN117964549A - Synthesis and antibacterial application of novel thymol derivative containing piperidine and sulfonamide active fragments - Google Patents
Synthesis and antibacterial application of novel thymol derivative containing piperidine and sulfonamide active fragments Download PDFInfo
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- CN117964549A CN117964549A CN202410015455.4A CN202410015455A CN117964549A CN 117964549 A CN117964549 A CN 117964549A CN 202410015455 A CN202410015455 A CN 202410015455A CN 117964549 A CN117964549 A CN 117964549A
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 239000012634 fragment Substances 0.000 title claims abstract description 31
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 30
- 150000003456 sulfonamides Chemical class 0.000 title claims abstract description 30
- DBEFONQGRSUFQO-UHFFFAOYSA-N 3-(2-Methylpropanoyloxy)-8-(2-methylbutanoyloxy)-9,10-epoxy-p-mentha-1,3,5-triene Chemical compound C=1C=C(C)C=C(OC(=O)C(C)C)C=1C1(COC(=O)C(C)CC)CO1 DBEFONQGRSUFQO-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 230000000844 anti-bacterial effect Effects 0.000 title description 20
- 230000015572 biosynthetic process Effects 0.000 title description 6
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 241000233654 Oomycetes Species 0.000 claims abstract description 18
- 241000233866 Fungi Species 0.000 claims abstract description 16
- 125000003639 thymyl group Chemical class C1(=CC(C)=CC=C1C(C)C)* 0.000 claims abstract description 10
- 241000196324 Embryophyta Species 0.000 claims description 15
- 241000228197 Aspergillus flavus Species 0.000 claims description 12
- 241000233616 Phytophthora capsici Species 0.000 claims description 12
- 241000813090 Rhizoctonia solani Species 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 241000222201 Colletotrichum capsici Species 0.000 claims description 6
- 235000007164 Oryza sativa Nutrition 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 235000009566 rice Nutrition 0.000 claims description 6
- 241001480007 Phomopsis Species 0.000 claims description 5
- 239000000417 fungicide Substances 0.000 claims description 5
- 241000221662 Sclerotinia Species 0.000 claims description 4
- 230000000855 fungicidal effect Effects 0.000 claims description 4
- 244000298697 Actinidia deliciosa Species 0.000 claims description 3
- 235000009436 Actinidia deliciosa Nutrition 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 241000223195 Fusarium graminearum Species 0.000 claims description 2
- 230000002538 fungal effect Effects 0.000 claims 2
- 235000009434 Actinidia chinensis Nutrition 0.000 claims 1
- 241001465180 Botrytis Species 0.000 claims 1
- 240000007594 Oryza sativa Species 0.000 claims 1
- 230000000843 anti-fungal effect Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 238000000338 in vitro Methods 0.000 abstract description 6
- 229940121375 antifungal agent Drugs 0.000 abstract description 4
- 244000052616 bacterial pathogen Species 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract 1
- 150000002611 lead compounds Chemical class 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 112
- 150000001875 compounds Chemical class 0.000 description 28
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 239000007787 solid Substances 0.000 description 18
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 238000006467 substitution reaction Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 241000894006 Bacteria Species 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000004293 19F NMR spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000005730 Azoxystrobin Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000221696 Sclerotinia sclerotiorum Species 0.000 description 6
- WFDXOXNFNRHQEC-GHRIWEEISA-N azoxystrobin Chemical compound CO\C=C(\C(=O)OC)C1=CC=CC=C1OC1=CC(OC=2C(=CC=CC=2)C#N)=NC=N1 WFDXOXNFNRHQEC-GHRIWEEISA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- TWFZGCMQGLPBSX-UHFFFAOYSA-N Carbendazim Natural products C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 241001330975 Magnaporthe oryzae Species 0.000 description 5
- 241000209094 Oryza Species 0.000 description 5
- 239000006013 carbendazim Substances 0.000 description 5
- JNPZQRQPIHJYNM-UHFFFAOYSA-N carbendazim Chemical compound C1=C[CH]C2=NC(NC(=O)OC)=NC2=C1 JNPZQRQPIHJYNM-UHFFFAOYSA-N 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- -1 indazole sulfenamid Chemical compound 0.000 description 5
- 230000020477 pH reduction Effects 0.000 description 5
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000223218 Fusarium Species 0.000 description 4
- 239000005844 Thymol Substances 0.000 description 4
- 241000209140 Triticum Species 0.000 description 4
- 235000021307 Triticum Nutrition 0.000 description 4
- 239000003899 bactericide agent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CZYUGTLMFHDODF-UHFFFAOYSA-N tert-butyl 4-(methylamino)piperidine-1-carboxylate Chemical compound CNC1CCN(C(=O)OC(C)(C)C)CC1 CZYUGTLMFHDODF-UHFFFAOYSA-N 0.000 description 4
- 229960000790 thymol Drugs 0.000 description 4
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 3
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 241000123650 Botrytis cinerea Species 0.000 description 2
- 241001290235 Ceratobasidium cereale Species 0.000 description 2
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 2
- 240000006365 Vitis vinifera Species 0.000 description 2
- 235000014787 Vitis vinifera Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 241000894007 species Species 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IAQLCKZJGNTRDO-UHFFFAOYSA-N 1-(4-{4-[5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone Chemical compound CC1=CC(C(F)(F)F)=NN1CC(=O)N1CCC(C=2SC=C(N=2)C=2CC(ON=2)C=2C(=CC=CC=2F)F)CC1 IAQLCKZJGNTRDO-UHFFFAOYSA-N 0.000 description 1
- ZEXXEODAXHSRDJ-UHFFFAOYSA-N 2-[(ethanesulfonyl)amino]-5-fluoro-4-[4-methyl-5-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzene-1-carbothioamide Chemical compound CS(=O)(=O)OC1=CC=CC(Cl)=C1C1ON=C(C=2N=C(SC=2)C2CCN(CC2)C(=O)CN2C(=CC(=N2)C(F)F)C(F)F)C1 ZEXXEODAXHSRDJ-UHFFFAOYSA-N 0.000 description 1
- 150000005360 2-phenylpyridines Chemical class 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
- 241000223600 Alternaria Species 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
- 235000006008 Brassica napus var napus Nutrition 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- 241000222199 Colletotrichum Species 0.000 description 1
- 208000035240 Disease Resistance Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000005812 Oxathiapiprolin Substances 0.000 description 1
- 241001281803 Plasmopara viticola Species 0.000 description 1
- 239000002535 acidifier Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- WURGXGVFSMYFCG-UHFFFAOYSA-N dichlofluanid Chemical compound CN(C)S(=O)(=O)N(SC(F)(Cl)Cl)C1=CC=CC=C1 WURGXGVFSMYFCG-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a thymol derivative containing piperidine and sulfonamide active fragments as shown in a formula I. The invention further provides a synthesis method of the derivative. Part of the novel thymol derivatives show excellent in-vitro antifungal activity on nine plant fungi/oomycete germs, have good in-vivo anti-sclerotium rolfsii activity on rape crops, and can be used as potential antifungal lead compounds.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to synthesis and antibacterial application of a novel thymol derivative containing piperidine and sulfonamide active fragments.
Background
Plant fungi/oomycete diseases pose a significant threat to the yield and quality of various crops worldwide and cause huge agricultural economic losses. At present, various technologies including biological, physical and chemical aspects have been widely used for controlling plant fungi/oomycete diseases. Among them, chemical control is the most direct and efficient method. However, with the wide and large use of chemical pesticides, problems such as disease resistance of plant fungi/oomycetes and environmental pollution are endangered. Therefore, development of a novel antifungal/oomycete germ agent with high efficiency, low toxicity and low residual amount is urgent. Thymol, piperidine and sulfonamide active fragments are ubiquitous in a wide variety of natural products, medicines and pesticides, with a broad range of biological activities. Such as the commercial fungicides dichlofluanid, sulfenamid and indazole sulfenamid, and the commercial egg bactericides Oxathiapiprolin and Fluoxapiprolin, all contain these active fragments. Therefore, the novel thymol derivative containing the piperidine and sulfonamide active fragments is constructed by designing a simple, efficient and green synthetic route, and has a certain practical significance.
The invention aims to design and synthesize a novel thymol derivative containing piperidine and sulfonamide active fragments, and discuss antifungal activity of the thymol derivative.
Disclosure of Invention
The invention aims at designing a synthetic method for constructing novel thymol derivatives containing piperidine and sulfonamide active fragments and application of the thymol derivatives as antifungal/oomycete active ingredients. The target product has a novel skeleton structure, has excellent antibacterial activity on nine plant fungi/oomycetes such as phytophthora capsici, colletotrichum capsici, aspergillus flavus, rhizoctonia solani, sclerotium rot of colza, rice blast, gibberella wheat, phomopsis kiwi fruit and the like, and has good living anti-sclerotium rot activity on rape crops.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a thymol derivative containing piperidine and sulfonamide active fragments, which is shown in a formula I:
Wherein R is selected from (hetero) aryl, (hetero) alkyl.
The invention also provides application of the thymol derivative containing the piperidine and sulfonamide active fragments in preventing and treating plant fungi/oomycetes diseases.
Preferably, the plant fungi/oomycetes comprise nine species of phytophthora capsici, colletotrichum capsici, aspergillus flavus, rhizoctonia solani, sclerotium bacteria, grape vine cavity bacteria, rice blast bacteria, gibberella wheat bacteria and phomopsis actinomycetes.
Preferably, the novel thymol derivatives containing piperidine and sulfonamide active fragments are used at a concentration of 50 μg/mL.
The invention also provides a fungicide, which comprises thymol derivatives containing piperidine and sulfonamide active fragments according to the technical scheme.
The beneficial effects of the invention are as follows:
The thymol derivative containing the piperidine and sulfonamide active fragments provided by the invention has good antibacterial effect on phytophthora capsici, aspergillus flavus, rhizoctonia solani, sclerotinia sclerotiorum, botrytis cinerea, rice blast fungus and other plant fungi/oomycetes. In particular, the compounds 5a, 5b, 5c, 5f, 5g, 5i, 5l, 5n, 5q, 5u, 5v described later have excellent antibacterial effects against phytophthora capsici; the compounds 5b, 5d, 5f, 5g, 5l, 5m, 5o, 5q, 5s and 5v have excellent antibacterial effect on aspergillus flavus bacteria; the compounds 5l, 5p and 5q have excellent antibacterial effect on Rhizoctonia solani; the compounds 5f, 5g, 5h, 5i, 5l, 5m, 5u and 5v have excellent antibacterial effect on sclerotinia sclerotiorum; the compounds 5f, 5m, 5o and 5q have excellent antibacterial effects on the plasmopara viticola; the compounds 5b and 5o have excellent antibacterial effect against rice blast bacteria.
Detailed Description
The invention provides a thymol derivative containing piperidine and sulfonamide active fragments, wherein the structural general formula of the thymol derivative containing piperidine and sulfonamide active fragments is shown as formula I:
Wherein R is selected from (hetero) aryl, (hetero) alkyl.
In the present invention, the pyrrolidone-containing 2-phenylpyridine derivative is preferably prepared according to the following synthetic route:
Reagents and conditions: (a) 1, 3-dibromopropane, K 2CO3, acetone, reflux; (b) 1-Boc-4-methylaminopiperidine, K 2CO3, acetonitrile, r.t.; (c) HCl, CH 3OH,r.t.;(d)RSO2Cl,Et3N,CH2Cl2, r.t. 1) Synthesis of Compound 2 from Compound 1 (substitution reaction)
The synthesis of compound 2 from compound 1 is preferably: thymol 1 is subjected to substitution reaction with 1, 3-dibromopropane under the condition of K 2CO3 as a base, thereby obtaining a compound 2.
The amount of 1, 3-dibromopropane used in the substitution reaction is preferably 1.5 times the amount of compound 1.
As the solvent used in the substitution reaction, acetone is preferable as the solvent.
As the temperature of the substitution reaction, room temperature is preferably selected.
The time for the substitution reaction is preferably 6 to 12 hours.
2) Synthesis of Compound 3 from Compound 2 (substitution reaction)
The synthesis of compound 3 from compound 2 is preferably: under the condition of K 2CO3 as a base, carrying out substitution reaction on the compound 2 and 1-Boc-4-methylaminopiperidine to obtain a compound 3.
As the amount of 1-Boc-4-methylaminopiperidine used in the substitution reaction, 1.0 equivalent (molar ratio) to the amount of compound 1 is preferably used.
As the solvent used in the substitution reaction, acetonitrile is preferable as the solvent.
As the temperature of the substitution reaction, room temperature is preferably selected.
The time for the substitution reaction is preferably 3 hours. .
3) Synthesis of Compound 4 from Compound 3 (acidification reaction)
The synthesis of compound 4 from compound 3 is preferably: compound 3 is acidified in the presence of hydrochloric acid to remove Boc groups to give compound 4.
As the deprotection reaction, hydrochloric acid is preferably used as an acidifying agent.
As the amount of hydrochloric acid used in the above-mentioned acidification reaction, 1.2 times equivalent (molar ratio) to the amount of compound 3 is preferably used.
As the solvent used in the above-mentioned acidification reaction, methanol is preferable as the solvent.
The temperature of the acidification reaction is preferably room temperature.
The time for the acidification reaction is preferably 2 hours.
4) Synthesis of Compound 5 from Compound 4 (substitution reaction)
The synthesis of compound 5 from compound 1 is preferably: under the action of triethylamine, the compound 4 and RSO 2 Cl undergo substitution reaction to obtain a compound 5.
As the amount of the above-mentioned RSO 2 Cl, 1.0 equivalent (molar ratio) to the amount of the compound 1 is preferably used.
As the amount of triethylamine, 1 is preferably used relative to the amount of compound 1.2 equivalents (molar ratio).
The temperature of the substitution reaction is preferably room temperature.
The time for the substitution reaction is preferably 2 hours.
The invention also provides application of the novel thymol derivative containing the piperidine and sulfonamide active fragments in preventing and treating plant fungi/oomycetes diseases. In the invention, the weeds preferably comprise nine species of phytophthora capsici, colletotrichum capsici, aspergillus flavus, rhizoctonia solani, sclerotinia sclerotiorum, pyricularia oryzae, gibberella aestiva and Rhizoctonia cerealis. In the present invention, the novel thymol derivatives containing piperidine and sulfonamide active fragments are used at a concentration of 50 μg/mL.
The invention also provides a fungicide, which comprises the novel thymol derivative containing piperidine and sulfonamide active fragments. The dosage form of the fungicide is not particularly limited in the present invention, and a novel thymol derivative containing piperidine and sulfonamide active fragments may be used as an acceptable dosage form. The preparation method of the herbicide is not particularly limited, and the herbicide is prepared by adopting a conventional preparation method.
The present invention will be described in detail with reference to examples for further illustration of the invention, but they should not be construed as limiting the scope of the invention.
The chemical reagents used in the examples below, unless otherwise specified, were all commercially available.
In the following examples, nuclear magnetic data were measured by using a Bruker ASCEND 400 (400 MHz) nuclear magnetic resonance spectrometer, and mass spectrometry data were measured by using a Thermo Fisher Q Exactive mass spectrometer.
Example 1
This example is intended to illustrate the preparation of novel thymol derivatives containing piperidine and sulfonamide active fragments according to the present invention, and examples of representative compounds include the following steps:
(1) Synthesis of Compound 2:
Thymol 1 (10.00 g,66.57 mmol) and 1, 3-dibromopropane (26.88 g,133.14 mmol) were added to a round bottom flask containing 80mL of acetone (CH 3 CN) at room temperature, followed by K 2CO3 (18.40 g,133.14 mmol) and stirred well. The reaction was refluxed for 12 hours, monitored by TLC, cooled to room temperature, the solid was filtered off, and the organic solution was concentrated under reduced pressure to give crude product 2, which was used directly in the next step.
(2) Synthesis of Compound 3:
After dissolving compound 2 (18.00 g,63.57 mmol) with acetonitrile (CH 3 CN) followed by the addition of 1-Boc-4-methylaminopiperidine (14.22 g,63.57 mmol) and K 2CO3 (11.00 g,76.28 mmol), respectively, at room temperature for 3 hours, the reaction was monitored by TLC, cooled to room temperature, the solid was filtered off, the organics concentrated under reduced pressure and the mixture was isolated by column chromatography using petroleum ether/ethyl acetate (20:1-5:1) eluent to give compound 3.
(3) Synthesis of Compound 4:
compound 3 (16.70 g,41.28 mmol) was dissolved in 60mL of methanol at room temperature, followed by addition of 20mL of hydrochloric acid and stirring was continued at room temperature for 2 hours. The reaction was monitored by TLC and the organic solution was concentrated under reduced pressure to give crude product 4, which was used directly in the next step.
(4) Synthesis of Compound 5:
Compound 4 (2.93 mmol) was dissolved in DCM (15 mL) at room temperature and a solution of triethylamine (4.40 mmol) was slowly added and stirred for 10min, RSO 2 Cl (2.93 mmol) was slowly added dropwise to the reaction solution, after continuing the reaction for 2h, TLC monitored the reaction, the organic solution was concentrated under reduced pressure and the mixture was separated by column chromatography using petroleum ether/ethyl acetate (10:1-2:1) eluent to give the final product 5.
The structural formula of the target compound 5 prepared in example 1 of the present invention is shown below, and the compounds 5a to 5y can be obtained by the synthetic steps of (1) to (4).
Chemical structure of novel thymol derivatives containing piperidine and sulfonamide active fragments
5A colorless viscous liquid, yield :53％.1H NMR(400MHz,CDCl3)δ7.78–7.75(m,2H),7.61–7.51(m,3H),7.09–7.06(m,1H),6.72(d,J＝7.2Hz,1H),6.62(s,1H),4.01–3.93(m,2H),3.86–3.81(m,2H),3.30–3.18(m,1H),2.68–2.58(m,2H),2.31–2.25(m,2H),2.30(s,3H),2.23(s,3H),1.92–1.85(m,2H),1.80–1.76(m,2H),1.69–1.59(m,3H),1.18(d,J＝7.0Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,136.3,136.3,133.9,132.7,129.0,127.7,125.9,121.0,112.2,65.7,60.2,50.4,46.1,37.7,27.7,27.3,26.6,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C25H36N2O3SH 445.2519;Found 445.2523.
5B colorless viscous liquid, yield :75％.1H NMR(400MHz,CDCl3)δ7.68–7.66(m,2H),7.37–7.35(m,2H),7.06(d,J＝7.6Hz,1H),6.71(d,J＝7.6Hz,1H),6.63(s,1H),3.95(t,J＝6.0Hz,2H),3.86–3.81(m,2H),3.27–3.19(m,1H),3.01–2.94(m,1H),2.60(t,J＝7.2Hz,2H),2.34–2.27(m,2H),2.29(s,3H),2.23(s,3H),1.97–1.85(m,3H),1.80–1.76(m,2H),1.68–1.58(m,2H),1.27(d,J＝6.8Hz,6H),1.17(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ205.1,156.0,136.3,133.9,132.7,129.0,127.7,125.9,121.0,112.2,65.8,60.2,50.4,46.1,37.6,34.2,28.0,27.3,26.7,23.7,22.8,21.3.HRMS(ESI):calcd for C20H17Cl2F4N3O2[M+H]+Calcd for C28H42N2O3S 487.2989;Found 487.2998.
5C white solid, yield 71%, melting point :179–180℃.1H NMR(400MHz,CDCl3)δ7.62–7.59(m,2H),7.47–7.43(m,2H),6.99(d,J＝7.6Hz,1H),6.64(d,J＝8.0Hz,1H),6.55(s,1H),3.88(t,J＝6.0Hz,2H),3.79–3.74(m,2H),3.19–3.12(m,1H),2.53(t,J＝7.2Hz,2H),2.25–2.18(m,2H),2.22(s,3H),2.16(s,3H),1.85–1.78(m,2H),1.73–1.69(m,3H),1.62–1.51(m,2H),1.27(s,9H),1.10(d,J＝7.0Hz,6H).13C NMR(101MHz,CDCl3)δ156.4,156.0,136.3,134.0,133.4,127.6,126.0,125.9,121.0,112.2,65.7,60.2,50.4,46.1,37.6,35.2,31.1,27.8,27.3,26.6,22.8,21.3.HRMS(ESI):[M+H]+Calcd for C29H44N2O3SH 501.3145;Found 501.3167.
5D colorless viscous liquid, yield :73％.1H NMR(400MHz,CDCl3)δ7.70–7.67(m,2H),7.07(d,J＝7.6Hz,1H),7.00–6.97(m,2H),6.72(d,J＝7.8Hz,1H),6.63(s,1H),3.95(t,J＝6.0Hz,2H),3.86(s,3H),3.83–3.78(m,2H),3.29–3.18(m,1H),2.60(t,J＝7.2Hz,2H),2.33–2.21(m,2H),2.30(s,3H),2.24(s,3H),1.96–1.86(m,3H),1.80–1.76(m,2H),1.68–1.58(m,2H),1.18(d,J＝7.2Hz,6H).13CNMR(101MHz,CDCl3)δ163.0,156.0,136.3,133.9,129.8,127.9,125.9,121.0,114.2,112.2,65.8,60.2,55.6,50.4,46.1,37.7,27.8,27.3,26.7,22.8,21.3.HRMS(ESI):[M+H]+Calcd for C26H38N2O4SH 475.2625;Found 475.2630.
5E pale yellow solid, yield 98%, melting point :87–88℃.1H NMR(400MHz,CDCl3)δ8.38–8.35(m,2H),7.95–7.92(m,2H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.0Hz,1H),6.62(s,1H),3.95(t,J＝6.0Hz,2H),3.87–3.83(m,2H),3.28–3.18(m,1H),2.61(t,J＝7.2Hz,2H),2.40–2.33(m,2H),2.30(s,3H),2.24(s,3H),1.92–1.86(m,2H),1.84–1.80(m,3H),1.71–1.61(m,2H),1.18(d,J＝6.8Hz,6H).13CNMR(101MHz,CDCl3)δ156.0,150.2,142.5,136.3,133.9,128.8,125.9,124.3,121.1,112.1,65.6,59.9,50.4,46.0,37.7,27.7,27.4,26.6,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C25H35N3O5SH 490.2370;Found 490.2369.
5F white solid, yield 79%, melting point :72–73℃.1H NMR(400MHz,CDCl3)δ7.71–7.67(m,2H),7.51–7.48(m,2H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝8.0Hz,1H),6.63(s,1H),3.95(t,J＝6.0Hz,2H),3.83–3.78(m,2H),3.29–3.18(m,1H),2.60(t,J＝7.2Hz,2H),2.35–2.25(m,1H),2.30(s,3H),2.24(s,3H),1.92–1.82(m,3H),1.82–1.77(m,2H),1.69–1.59(m,2H),1.18(d,J＝7.0Hz,6H).13CNMR(101MHz,CDCl3)δ156.0,139.3,136.3,134.8,133.9,129.4,129.1,125.9,121.0,112.2,65.7,60.1,50.4,46.0,37.7,27.7,27.3,26.7,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C25H35ClN2O3SH 479.2129;Found 479.2130.
5G of pale yellow solid, 67 percent of yield and melting point :173–174℃.1H NMR(400MHz,CDCl3)δ7.68–7.65(m,2H),7.63–7.59(m,2H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.8Hz,1H),6.63(s,1H),3.95(t,J＝6.0Hz,2H),3.83–3.78(m,2H),3.29–3.18(m,1H),2.61(t,J＝7.2Hz,2H),2.35–2.25(m,2H),2.30(s,3H),2.24(s,3H),1.92–1.86(m,2H),1.82–1.76(m,3H),1.69–1.59(m,2H),1.18(d,J＝7.2Hz,6H).13CNMR(101MHz,CDCl3)δ156.0,136.3,135.3,133.9,132.4,129.2,127.8,125.9,121.0,112.2,65.7,60.1,50.4,46.0,37.7,27.7,27.3,26.6,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C25H35BrN2O3SH 523.1625;Found 523.1624.
5H of pale yellow solid, yield 88%, melting point :76–77℃.1H NMR(400MHz,CDCl3)δ7.88–7.81(m,4H),7.07(d,J＝7.6Hz,1H),6.73(d,J＝8.0Hz,1H),6.62(s,1H),3.95(t,J＝6.0Hz,2H),3.86–3.81(m,2H),3.28–3.18(m,1H),2.61(t,J＝7.2Hz,2H),2.37–2.31(m,2H),2.30(s,3H),2.24(s,3H),1.93–1.86(m,3H),1.84–1.79(m,2H),1.70–1.60(m,2H),1.18(d,J＝7.2Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,140.9,136.3,133.9,132.9,128.2,125.9,121.1,117.3,116.5,112.2,65.6,60.0,50.4,46.0,37.6,27.7,27.3,26.6,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C26H35N3O3SH 470.2471;Found 470.2480.
5 I-white solid, 98% yield, melting point :181–182℃.1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.2Hz,2H),7.80(d,J＝8.4Hz,2H),7.07(d,J＝8.0Hz,1H),6.72(d,J＝8.0Hz,1H),6.63(s,1H),3.95(t,J＝6.0Hz,2H),3.88–3.82(m,2H),3.28–3.18(m,1H),2.61(t,J＝7.2Hz,2H),2.36–2.31(m,2H),2.30(s,3H),2.24(s,3H),1.92–1.86(m,2H),1.83–1.79(m,3H),1.70–1.60(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,140.2,136.3,134.3(q,J＝32.9Hz),133.9,128.1,126.2(q,J＝3.7Hz),125.9,123.3(q,J＝274.2Hz),121.1,112.2,65.7,60.0,50.4,46.0,37.6,27.8,27.4,26.7,22.8,21.3.19F NMR(377MHz,CDCl3)δ-63.1.HRMS(ESI):[M+H]+Calcd for C26H35F3N2O3SH 513.2393;Found 513.2393.
5J white solid, yield 89%, melting point :182–183℃.1H NMR(400MHz,CDCl3)δ7.57–7.54(m,2H),7.43–7.38(m,2H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,1H),6.63(s,1H),3.95(t,J＝6.0Hz,2H),3.85–3.81(m,2H),3.29–3.18(m,1H),2.60(t,J＝7.2Hz,2H),2.43(s,3H),2.34–2.36(m,2H),2.30(s,3H),2.24(s,3H),1.92–1.86(m,2H),1.80–1.76(m,3H),1.69–1.59(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,139.2,136.3,136.2,134.0,133.5,128.9,128.0,125.9,124.9,121.0,112.2,65.8,60.2,50.4,46.1,37.6,27.8,27.3,26.7,22.8,21.4,21.3.HRMS(ESI):[M+H]+Calcd for C26H38N2O3SH 459.2676;Found459.2679.
5K white solid, yield 79%, melting point :118–119℃.1H NMR(400MHz,CDCl3)δ7.56–7.45(m,3H),7.32–7.27(m,1H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,1H),6.63(s,1H),3.95(t,J＝6.0Hz,2H),3.85–3.81(m,2H),3.29–3.18(m,1H),2.61(t,J＝7.2Hz,2H),2.35–2.32(m,2H),2.30(s,3H),2.24(s,3H),1.93–1.86(m,2H),1.82–1.77(m,3H),1.69–1.59(m,2H),1.18(d,J＝6.8Hz,6H).13CNMR(101MHz,CDCl3)δ162.5(d,J＝252.9Hz),156.0,138.6(d,J＝6.6Hz),136.3,133.9,130.8(d,J＝7.5Hz),125.9,123.4(d,J＝3.1Hz),121.1,119.9(d,J＝21.2Hz),114.9(d,J＝24.1Hz),112.2,65.7,60.1,50.4,46.0,37.7,27.8,27.3,26.7,22.8,21.3.19F NMR(377MHz,CDCl3)δ-109.6.HRMS(ESI):[M+H]+Calcd for C25H35FN2O3SH 463.2425;Found 463.2425.
5L of colorless viscous liquid, yield :88％.1H NMR(400MHz,CDCl3)δ7.90–7.88(m,1H),7.64–7.54(m,1H),7.46–7.38(m,1H),7.32–7.28(m,2H),7.07(d,J＝8.0Hz,1H),6.72(d,J＝7.6Hz,1H),6.64–6.62(m,1H),3.98–3.93(m,2H),3.83–3.75(m,2H),3.30–3.18(m,1H),2.66–2.63(m,1H),2.62(s,3H),2.61–2.58(m,1H),2.47–2.39(m,2H),2.30(s,3H),2.26(s,3H),2.24–2.21(m,1H)(s,1H),1.94–1.85(m,2H),1.82–1.76(m,2H),1.68–1.51(m,2H),1.18(d,J＝7.0Hz,6H).13C NMR(101MHz,CDCl3)δ156.1,138.0,136.3,133.9,132.8,130.2,129.6,127.8,126.1,125.9,121.0,112.2,65.8,60.5,50.3,46.1,45.1,37.8,27.7,26.7,22.8,21.4,20.7.HRMS(ESI):[M+H]+Calcd for C26H38N2O3SH 459.2676;Found 459.2679.
5M colorless viscous liquid, yield :83％.1HNMR(400MHz,CDCl3)δ8.05(dd,J＝8.0,1.6Hz,1H),7.53–7.45(m,2H),7.40–7.36(m,1H),7.07(d,J＝8.0Hz,1H),6.72(d,J＝8.4Hz,1H),6.64(s,1H),3.97(t,J＝6.0Hz,2H),3.93–3.87(m,2H),3.30–3.19(m,1H),2.78–2.71(m,2H),2.63(t,J＝7.2Hz,2H),2.50–2.42(m,1H),2.30(s,3H),2.26(s,3H),1.95–1.88(m,2H),1.81–1.77(m,2H),1.64–1.54(m,2H),1.18(d,J＝7.2Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,136.6,136.3,134.0,133.5,132.3,132.2,132.0,126.9,125.9,121.0,112.2,65.8,60.5,50.4,45.5,37.7,27.8,26.7,22.8,21.3.HRMS(ESI):[M+H]+Calcd for C25H35ClN2O3SH 479.2130;Found 479.2131.
5N, colorless viscous liquid, yield :77％.1H NMR(400MHz,CDCl3)δ7.86–7.82(m,1H),7.59–7.53(m,1H),7.29–7.25(m,1H),7.23–7.18(m,1H),7.09–7.06(m,1H),6.72(d,J＝7.6Hz,1H),6.63(s,1H),3.96(t,J＝6.0Hz,2H),3.94–3.89(m,2H),3.30–3.19(m,1H),2.62(t,J＝7.2Hz,2H),2.59–2.52(m,2H),2.46–2.37(m,1H),2.30(s,3H),2.25(s,3H),1.94–1.87(m,2H),1.83–1.78(m,2H),1.68–1.57(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ160.0(d,J＝256.8Hz),156.0,136.3,134.9(d,J＝8.6Hz),133.9,131.3,125.9,125.7(d,J＝14.4Hz),124.4(d,J＝4.1Hz),121.0,117.3(d,J＝22.0Hz),112.2,65.7,60.3,50.4,45.7,45.7,37.7,27.6,26.7,22.8,21.4.19F NMR(377MHz,CDCl3)δ-107.5.HRMS(ESI):[M+H]+Calcd for C25H35FN2O3SH 463.2425;Found 463.2433.
5O, colorless viscous liquid, yield :87％.1H NMR(400MHz,CDCl3)δ8.13–8.09(m,1H),7.88–7.84(m,1H),7.71–7.64(m,2H),7.07(d,J＝8.0Hz,1H),6.72(d,J＝7.6Hz,1H),6.64(s,1H),3.97(t,J＝6.0Hz,2H),3.88–3.83(m,2H),3.30–3.20(m,1H),2.74–2.61(m,2H),2.63(t,J＝7.2Hz,2H),2.50–2.43(m,1H),2.30(s,3H),2.26(s,3H),1.95–1.88(m,2H),1.82–1.78(m,2H),1.65–1.55(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.1,138.1,136.3,134.0,132.6,132.2,131.9,128.6(q,J＝6.6Hz),127.9(q,J＝33.2Hz),125.9,122.6(q,J＝275.5Hz),121.0,112.3,65.8,60.4,50.4,45.5,37.7,27.8,27.7,26.7,22.8,21.3.19F NMR(377MHz,CDCl3)δ-57.4.HRMS(ESI):[M+H]+Calcd for C26H35F3N2O3SH 513.2393;Found 513.2402.
5P colorless viscous liquid, yield :59％.1H NMR(400MHz,CDCl3)δ7.07(d,J＝7.6Hz,1H),6.94(s,2H),6.72(d,J＝7.6Hz,1H),6.64(s,1H),3.97(t,J＝6.0Hz,2H),3.65–3.60(m,2H),3.29–3.19(m,1H),2.78–2.72(m,3H),2.64(d,J＝7.2Hz,2H),2.61(s,6H),2.52–2.45(m,1H),2.30–2.27(m,9H),1.96–1.89(m,2H),1.83–1.78(m,2H),1.55–1.45(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,142.5,140.5,136.3,133.9,131.9,131.8,125.9,121.0,112.2,65.7,60.8,50.3,44.0,37.9,27.7,27.5,26.7,22.8,22.8,21.4,21.0.HRMS(ESI):[M+H]+Calcd for C28H42N2O3SH 487.2989;Found 487.2991.
5Q colorless viscous liquid, yield :62％.1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.24–7.17(m,2H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,1H),6.64(s,1H),3.97(t,J＝6.0Hz,2H),3.80–3.74(m,2H),3.29–3.19(m,1H),2.64–2.56(m,4H),2.56(s,3H),2.46–2.39(m,1H),2.36(s,3H),2.30(s,3H),2.26(s,3H),1.94–1.88(m,2H),1.82–1.77(m,2H),1.61–1.51(m,2H),1.18(d,J＝6.8Hz,6H).13CNMR(101MHz,CDCl3)δ156.0,136.3,135.9,135.6,134.8,133.9,133.5,132.7,130.6,125.9,121.0,112.2,65.7,60.5,50.4,45.1,37.8,27.8,27.6,26.7,22.8,21.4,20.9,20.2.HRMS(ESI):[M+H]+Calcd for C27H40N2O3SH 473.2832;Found473.2849.
5R pale yellow solid, yield 76%, melting point :96–97℃.1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.2Hz,1H),7.92(d,J＝9.0Hz,1H),7.87(s,1H),7.07(d,J＝7.6Hz,1H),6.73(d,J＝6.8Hz,1H),6.64(s,1H),3.98(t,J＝6.0Hz,2H),3.92–3.86(m,2H),3.30–3.20(m,1H),2.85–2.78(m,2H),2.64(t,J＝7.2Hz,2H),2.53–2.45(m,1H),2.30(s,3H),2.27(s,3H),1.96–1.89(m,2H),1.87–1.82(m,2H),1.68–1.58(m,2H),1.18(d,J＝7.0Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,148.2,136.3,135.7,135.6,133.9,132.0,128.4(q,J＝14.8Hz),125.9,121.9(q,J＝274.7Hz),121.5(q,J＝4.0Hz),121.0,112.2,65.6,60.1,50.4,45.9,37.7,27.8,26.7,22.8,21.4.19F NMR(377MHz,CDCl3)δ-63.3.HRMS(ESI):[M+H]+Calcd for C26H34F3N3O5SH 558.2244;Found 558.2250.
5S pale yellow solid, yield 63%, melting point :78–79℃.1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.8Hz,1H),7.11–7.08(m,1H),7.06–7.05(m,1H),6.72(d,J＝7.4Hz,1H),6.64(s,1H),3.97(t,J＝6.0Hz,2H),3.90(s,3H),3.86–3.81(m,2H),3.30–3.20(m,1H),2.75–2.68(m,2H),2.63(t,J＝7.2Hz,2H),2.48–2.41(m,1H),2.30(s,3H),2.26(s,3H),1.95–1.88(m,2H),1.83–1.79(m,2H),1.66–1.56(m,2H),1.19(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ163.1,156.0,149.7,136.3,133.9,132.8,125.9,122.9,121.0,116.3,112.2,109.8,65.7,60.3,56.4,50.4,45.7,37.7,27.8,27.6,26.7,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C26H37N3O6SH 520.2476;Found 520.2484.
5T pale yellow solid, 92% yield, melting point :101–102℃.1H NMR(400MHz,CDCl3)δ8.49–8.44(m,2H),8.20(d,J＝8.6Hz,1H),7.07(d,J＝7.6Hz,1H),7.07(d,J＝7.6Hz,1H),6.64(s,1H),3.97(t,J＝6.0Hz,2H),3.92–3.86(m,2H),3.30–3.19(m,1H),2.88–2.81(m,2H),2.64(t,J＝7.2Hz,2H),2.53–2.46(m,1H),2.30(s,3H),2.27(s,3H),1.95–1.91(m,2H),1.89–1.83(m,2H),1.68–1.58(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,149.7,148.3,137.8,136.3,133.9,132.6,126.0,125.9,121.1,119.7,112.2,65.6,60.0,50.4,45.9,37.7,27.8,27.7,26.7,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C25H34N4O7SH 535.2221;Found 535.2230.
5U yellow solid, 94% yield, melting point :110–111℃.1H NMR(400MHz,CDCl3)δ8.05(d,J＝2.2Hz,1H),7.85(dd,J＝8.4,2.2Hz,1H),7.68(d,J＝8.4Hz,1H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,1H),6.63(s,1H),3.96(t,J＝6.0Hz,2H),3.86–3.81(m,2H),3.29–3.18(m,1H),2.62(t,J＝7.2Hz,2H),2.38–2.32(m,3H),2.30(s,3H),2.25(s,3H),1.93–1.87(m,2H),1.85–1.80(m,2H),1.71–1.61(m,2H),1.18(d,J＝7.0Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,137.3,136.3,136.0,133.9,132.5,131.8,129.5(q,J＝32.4Hz),126.8(q,J＝5.5Hz),125.9,121.9(q,J＝275.0Hz),121.1,112.2,65.6,59.9,50.4,46.0,37.7,27.7,27.3,26.6,22.8,21.4.19F NMR(376MHz,CDCl3)δ-63.0.HRMS(ESI):[M+H]+Calcd for C26H34ClF3N2O3SH 547.2004;Found 547.1997.
5V white solid, 61% yield, melting point :176–177℃.1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.99–7.95(m,2H),7.93–7.91(m,1H),7.75(dd,J＝8.6,2.0Hz,1H),7.67–7.59(m,2H),7.05(d,J＝7.6Hz,1H),6.70(d,J＝7.8Hz,1H),6.61(s,1H),3.94–3.89(m,4H),3.27–3.16(m,1H),2.58(t,J＝7.2Hz,2H),2.35–2.32(m,2H),2.28(s,3H),2.22(s,3H),1.90–1.83(m,2H),1.81–1.74(m,3H),1.70–1.60(m,2H),1.16(d,J＝7.2Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,136.3,134.9,133.9,133.4,132.2,129.3,129.2,128.9,128.8,128.0,127.6,125.8,123.0,121.0,112.2,65.7,60.1,50.4,46.2,37.7,27.7,27.3,26.6,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C29H38N2O3SH 495.2676;Found 495.2684.
5W white solid, 96% yield, melting point :85–86℃.1H NMR(400MHz,CDCl3)δ7.60(dd,J＝5.0,1.2Hz,1H),7.52(dd,J＝3.6,1.6Hz,1H),7.14–7.12(m,1H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.2Hz,1H),6.63(s,1H),3.96(t,J＝6.0Hz,2H),3.86–3.81(m,2H),3.29–3.19(m,1H),2.62(t,J＝7.2Hz,2H),2.41–2.34(m,2H),2.30(s,3H),2.25(s,3H),1.94–1.87(m,2H),1.85–1.79(m,3H),1.73–1.62(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,136.6,136.3,133.9,132.3,131.9,127.6,125.9,121.0,112.2,65.7,60.1,50.4,46.1,37.7,27.7,27.2,26.6,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C23H34N2O3S2H451.2084;Found 451.2083.
5X white solid, 97% yield, melting point :87–88℃.1H NMR(400MHz,CDCl3)δ8.98(dd,J＝2.4,0.8Hz,1H),8.82(dd,J＝4.8,1.6Hz,1H),8.06–8.03(m,1H),7.50–7.46(m,1H),7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.0Hz,1H),6.62(s,1H),3.95(t,J＝6.0Hz,2H),3.88–3.83(m,2H),3.28–3.18(m,1H),2.61(t,J＝7.2Hz,2H),2.39–2.32(m,3H),2.30(s,3H),2.24(s,3H),1.93–1.86(m,2H),1.84–1.80(m,2H),1.68–1.61(m,2H),1.18(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,153.3,148.4,136.3,135.3,133.9,133.2,125.9,123.7,121.0,112.2,65.6,60.0,50.4,45.9,37.7,27.7,27.3,26.6,22.8,21.4.HRMS(ESI):[M+H]+Calcd for C24H35N3O3SH 446.2472;Found 446.2483.
5Y white solid, yield 43%, melting point :75–76℃.1H NMR(400MHz,CDCl3)δ7.07(d,J＝7.6Hz,1H),6.72(d,J＝7.8Hz,1H),6.64(s,1H),3.98(t,J＝6.0Hz,2H),3.30–3.20(m,2H),2.82–2.81(m,1H),2.81(s,1H),2.79(s,6H),2.78–2.75(m,1H),2.65(t,J＝7.2Hz,2H),2.50–2.43(m,1H),2.30(s,3H),2.28(s,3H),1.96–1.90(m,2H),1.82–1.78(m,2H),1.62–1.51(m,2H),1.19(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ156.0,136.3,133.9,125.9,121.0,112.2,65.8,60.6,50.4,46.2,38.2,37.8,27.8,27.8,26.7,22.8,21.3.HRMS(ESI):[M+H]+Calcd for C21H37N3O3SH 412.2628;Found 412.2632.
Example 2
The isolated antifungal activity of the target compounds against plant fungi/oomycetes including phytophthora capsici, colletotrichum capsici, aspergillus flavus, rhizoctonia solani, sclerotinia viticola, pyricularia oryzae, gibberella wheat and Phomopsis actinomyces is shown in Table 1.
The mycelium growth rate method is adopted to carry out in-vitro antifungal activity measurement on nine representative plant fungi/oomycetes including phytophthora capsici, colletotrichum glomerocladium, aspergillus flavus, rhizoctonia solani, sclerotinia rot, botrytis cinerea, rice blast pathogen, wheat gibberella zeae, kiwi fruit phomopsis and the like. The common commercial drugs azoxystrobin and carbendazim with broad-spectrum bactericidal activity are used as positive controls. Dissolving target compound with dimethyl sulfoxide (DMSO) to obtain mother solution with high concentration, diluting to desired concentration according to volume of Tween-80 water and fungus culture medium PDA of 0.1%, pouring the medicated culture medium into culture dish, cooling to room temperature, and inoculating different strains of 5mm diameter bacterial cakes at the central position of the culture dish. Culturing in biochemical incubator at 27+ -1deg.C for 3-6 days, measuring mycelium growth diameter with vernier caliper, and recording. As a negative control group, the same dose of inhibitor-free solvent (dmso+0.1% tween-80 water) was used, and each treatment was repeated three times, all in a sterile ultra clean bench.
The formula for calculating the inhibition rate of the compound to fungi is as follows:
inhibition (%) = [ (blank diameter-treatment diameter)/(blank diameter-0.5) ] x100
TABLE 1 antifungal Activity of thymol derivatives containing piperidine and sulfonamide active fragments
a Pc (phytophthora capsici), cf (colletotrichum capsici), af (aspergillus flavus), rs (Rhizoctonia solani), ss (Sclerotinia sclerotiorum), bd (Portland cavity germ), pg (Pyricularia oryzae), gz (Alternaria tritici), ps (Rhizoctonia cerealis).
As shown in Table 1, at a concentration of 50. Mu.g/mL, a part of the compounds show good antibacterial effect on plant fungi/oomycetes such as phytophthora capsici, aspergillus flavus, rhizoctonia solani, sclerotinia sclerotiorum, sclerotinia viticola, pyricularia oryzae and the like, and are superior to thymol as an initial substrate. Wherein, the compounds 5a, 5b, 5c, 5f, 5g, 5i, 5l, 5n, 5q, 5u and 5v show inhibitory activity of more than 60% on phytophthora capsici, especially the compounds 5b, 5f and 5q have inhibitory activity of more than 90% on phytophthora capsici, which are superior to the in vitro inhibitory activity of commercial bactericides azoxystrobin and carbendazim; the compounds 5b, 5d, 5f, 5g, 5l, 5m, 5o, 5q, 5s and 5v have excellent antibacterial effect on aspergillus flavus bacteria, wherein the compounds 5f and 5s have higher than 90% of inhibition activity on the aspergillus flavus bacteria, and are better than the in-vitro inhibition activity of commercial bactericides azoxystrobin and carbendazim; the compounds 5l, 5p and 5q show the inhibition activity of more than 60% on the Rhizoctonia solani, and are superior to the in-vitro inhibition activity of the commercial bactericide azoxystrobin; the compounds 5f, 5g, 5h, 5i, 5l, 5m, 5u and 5v show 61-88% of in-vitro inhibition activity on sclerotinia sclerotiorum, which is superior to that of the commercial azoxystrobin; the compounds 5f, 5m, 5o and 5q have 67-74% of antibacterial effect on the grape vine cavity germs, and are superior to the commercial medicine carbendazim; the compounds 5b and 5o have about 66% of antibacterial effect on rice blast bacteria, and are better than the commercial medicines azoxystrobin and carbendazim. In general, the novel thymol derivative containing piperidine and sulfonamide active fragments has certain application prospect and reference value in the aspect of advancing the development of antifungal medicaments.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (5)
1. The novel thymol derivative containing piperidine and sulfonamide active fragments is characterized in that the structural general formula of the derivative containing piperidine and sulfonamide active fragments is shown as formula I:
Wherein R is selected from (hetero) aryl, (hetero) alkyl.
2. Use of a novel thymol derivative containing piperidine and sulfonamide active fragments according to claim 1 for controlling plant fungal/oomycete diseases.
3. The use of novel thymol derivatives containing piperidine and sulfonamide active fragments according to claim 2 for controlling plant fungi/oomycete diseases, wherein the fungi/oomycetes include phytophthora capsici, colletotrichum capsici, aspergillus flavus, rhizoctonia solani, sclerotinia rot, botrytis, rice blast, gibberella zeae and phomopsis kiwi.
4. Use of a novel thymol derivative containing piperidine and sulfonamide active fragments according to claim 2 for controlling plant fungal/oomycete diseases, characterized in that said novel thymol derivative containing piperidine and sulfonamide active fragments is used at a concentration of 50 μg/mL.
5. A fungicide comprising a novel thymol derivative comprising piperidine and sulfonamide active fragments according to claims 1 to 4.
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