CN117384105A - 麝香草酚衍生物及其用途 - Google Patents
麝香草酚衍生物及其用途 Download PDFInfo
- Publication number
- CN117384105A CN117384105A CN202311232805.4A CN202311232805A CN117384105A CN 117384105 A CN117384105 A CN 117384105A CN 202311232805 A CN202311232805 A CN 202311232805A CN 117384105 A CN117384105 A CN 117384105A
- Authority
- CN
- China
- Prior art keywords
- thymol
- cycloalkyl
- alkyl
- triazole
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 125000003639 thymyl group Chemical class C1(=CC(C)=CC=C1C(C)C)* 0.000 title claims description 12
- 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 claims abstract description 23
- 241000223221 Fusarium oxysporum Species 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000000575 pesticide Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 239000005844 Thymol Substances 0.000 claims description 17
- 229960000790 thymol Drugs 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 150000003852 triazoles Chemical class 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 241000234435 Lilium Species 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- AFBBKYQYNPNMAT-UHFFFAOYSA-N 1h-1,2,4-triazol-1-ium-3-thiolate Chemical group SC=1N=CNN=1 AFBBKYQYNPNMAT-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000022 bacteriostatic agent Substances 0.000 abstract description 3
- QMPFMODFBNEYJH-UHFFFAOYSA-N methyl 1h-1,2,4-triazole-5-carboxylate Chemical compound COC(=O)C1=NC=NN1 QMPFMODFBNEYJH-UHFFFAOYSA-N 0.000 abstract description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 abstract description 2
- QBDXSEYWEKKYSH-UHFFFAOYSA-N 3,4-dimethyl-1,2,4-triazole Chemical compound CC1=NN=CN1C QBDXSEYWEKKYSH-UHFFFAOYSA-N 0.000 abstract description 2
- FRAKFBWDPXYIQO-UHFFFAOYSA-N 3,5-dibromo-1h-1,2,4-triazole Chemical compound BrC1=NNC(Br)=N1 FRAKFBWDPXYIQO-UHFFFAOYSA-N 0.000 abstract description 2
- PZBQVZFITSVHAW-UHFFFAOYSA-N 5-chloro-2h-benzotriazole Chemical compound C1=C(Cl)C=CC2=NNN=C21 PZBQVZFITSVHAW-UHFFFAOYSA-N 0.000 abstract description 2
- LRUDIIUSNGCQKF-UHFFFAOYSA-N 5-methyl-1H-benzotriazole Chemical compound C1=C(C)C=CC2=NNN=C21 LRUDIIUSNGCQKF-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000223218 Fusarium Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- -1 thymol ethyl triazole derivative Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
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- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
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- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
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- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- 239000012470 diluted sample Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
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- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 239000000174 gluconic acid Substances 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
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- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
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- 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
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01P3/00—Fungicides
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
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Abstract
本发明公开了一种如式I所示的麝香草酚衍生物，其中R优选为3‑巯基‑1，2，4‑三唑(1a)、3，4‑二甲基‑1，2，4‑三唑(1b)、1，2，3‑三唑(1c)、3，5‑二溴‑1，2，4‑三唑(1d)、6‑甲基‑1H‑苯并‑1，2，3‑三唑(1e)、3‑甲氧甲酰基‑1，2，4‑三唑(1f)、6‑氯‑1H‑苯并‑1，2，3‑三唑(1g)；本发明还提供了该麝香草酚衍生物的药用盐；本发明还提供了该麝香草酚衍生物的制备方法，以及提供了所述麝香草酚衍生物及其药用盐作为抗尖孢镰刀菌的抑菌剂用于制备农药的用途。
Description
技术领域
本发明属于新型天然产物改造药物开发技术领域，尤其涉及一种麝香草酚衍生物及其的制备方法与应用。
背景技术
麝香草酚(Thymol)，又称百里香酚，是源于百里香属植物挥发油的天然产物。其结构如所示，在苯酚的2位和5位分别引入异丙基和甲基即可得到。作为一个天然产物，其用途十分广泛。在医药领域，可以作为外用药物用于痱子、疱疹及皮肤瘙痒症的治疗；在农业领域，可以作为杀虫剂和抗真菌剂用于控制植物病虫害；在畜牧业领域，它还可以作为饲料添加剂，减少动物腹泻，增强繁殖率和哺乳性能。
尖孢镰刀菌(Fusarium oxysporum)属于半知菌类镰刀菌属(Fusarium)真菌，是引起植物枯萎病的主要病原菌，可引起150多种植物产生枯萎病，包括棉花、番茄、香蕉、西瓜、草莓、甘蓝、鹰嘴豆、豌豆、苜蓿、百合等的枯萎病。
目前，对尖孢镰刀菌引起的植物病害的防治，主要有生物防治和化学防治两类方法。生物防治一般是利用一些能产生抗生物质的微生物(细菌、真菌或放线菌)来抑制尖孢镰刀菌的生长。虽然生物防治，取得了一些进展，但大多未规模化，主要的原因是田间应用时防治效果不稳定、缺少广谱性、产品生产储存要求严格、对比化学制剂见效慢和效果不突出、价格昂贵等。目前情况下，化学防治仍然是防治尖孢镰刀菌的主要策略。化学防治主要是使用唑类、甲酯类、酰胺类等农药。但总体来说，目前使用的化学农药防治效果并不理想，容易产生抗药性，长期使用会导致土壤酸化、重金属超标，而且价格也相对较贵。因此，研发高效低毒廉价的抗尖孢镰刀菌新型农药十分必要。
本发明对麝香草酚的抗尖孢镰刀菌活性进行了研究，发现其对尖孢镰刀菌有明显的活性，其EC50(半数有效抑制浓度)为40.1μg/mL。但比起现有报道的抗菌剂，仍有一定差距。因此，本发明合成了一种麝香草酚衍生物，用于作为抗尖孢镰刀菌的抑菌剂用于制备农药，所制备的农药用于百合枯萎病的防治。
发明内容
本发明的目的之一就是提供一系列麝香草酚衍生物及其合成方法；本发明的另一目的是公开所述衍生物作为抗尖孢镰刀菌的抑菌剂用于制备农药的用途。在一些实施方式中，所述麝香草酚衍生物是一种麝香草酚乙基三唑衍生物。
一方面，本发明提供了如式I所示的麝香草酚衍生物，
其中R为
R1和R2各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；
R3和R4各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；或R3和R4与它们所键合的碳原子一起形成环烷基团，所述环状基团是五元环或六元环，所述环状基团未被取代或任选地被Cm-n烷基和/或卤素取代；
R8和R9各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；
R5和R6各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；或R5和R6与它们所键合的氮原子、碳原子一起形成杂环基团，所述杂环基团是五元环或六元环，所述环状基团未被取代或任选地被Cm-n烷基和/或卤素取代；所述杂环基团是只有一个杂原子的基团；
R7是Cm-n烷基或Cx-y环烷基；
在一些实施方式中，所述Cm-n烷基是C1-10烷基，所述Cx-y环烷基是C3-8环烷基；
在一些实施方式中，所述Cm-n烷基和Cx-y环烷基未被取代或任选地被卤素取代。
在一些实施方式中，所述Cm-n烷基是C1-6烷基，所述Cx-y环烷基是C5-8环烷基。
在一些实施方式中，所述Cm-n烷基是甲基、乙基或丙基；所述Cx-y环烷基是C5-6环烷基。
在一些实施方式中，R1和R2不同时是-COOR7；在另一些实施方式中，R1和R2不是环烷基和-COOR7的组合。
在一些实施方式中，R3和R4不同时是-COOR7；在另一些实施方式中，R3和R4不是环烷基和-COOR7的组合。
在一些实施方式中，R5和R6不同时是-COOR7；在另一些实施方式中，R5和R6不是环烷基和-COOR7的组合。
在一些实施方式中，R8和R9不同时是-COOR7；在另一些实施方式中，R8和R9不是环烷基和-COOR7的组合。
“烷基”是指具有碳原子链的直链或支链的、饱和的脂族基团。
“卤素”是指氟、氯、溴或碘。“卤代”是指氟代、氯代、溴代或碘代。
除非另行说明，“任选取代的”是指给定的基团可以仅由通过可用化合价的氢取代基组成。
“环烷基”是指非芳族的饱和的环基团。
“杂原子”是指不是碳原子和氢原子的原子。
在一些实施方式中，R8和R9不是环烷基和-COOR7的组合，也不同时是-COOR7；和/或，R3和R4不是环烷基和-COOR7的组合，也不同时是-COOR7；和/或，R5和R6不是环烷基和-COOR7的组合，也不同时是-COOR7。
在一些具体实施方式中，所述麝香草酚衍生物是化合物1a-1g，其中R是3-巯基-1，2，4-三唑(1a)、3，4-二甲基-1，2，4-三唑(1b)、1，2，3-三唑(1c)、3，5-二溴-1，2，4-三唑(1d)、6-甲基-1H-苯并-1，2，3-三唑(1e)、3-甲氧甲酰基-1，2，4-三唑(1f)、6-氯-1H-苯并-1，2，3-三唑(1g)，R的结构如式1a-1g所示，：
一方面，本发明还提供了如上所述麝香草酚衍生物的药用盐。可药用盐是指本发明化合物的盐是可药用的，并具有所需药理学活性。此类盐包括与无机酸形成的酸加成盐，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等；或与有机酸形成的酸加成盐，所述有机酸如乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、邻-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1，2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、2-萘磺酸、对甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]辛-2-烯-1-甲酸、葡庚糖酸、4，4’-亚甲基双(3-羟基-2-烯-1-甲酸)(4，4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid))、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、三氟乙酸、月桂基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、粘康酸等。
可药用盐还包括碱加成盐，其可以在存在的酸性质子能够与无机碱或有机碱反应时形成。可接受的无机碱包括氢氧化钠、碳酸钠、氢氧化钾、氢氧化铝和氢氧化钙。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、α-甲基葡糖胺等。
一方面,本发明提供了如上所述麝香草酚衍生物的方法,该方法包括的步骤(如图1)包括：
(1)麝香草酚(化合物2)在碱存在下，和二溴乙烷发生取代反应得麝香草酚氧乙基溴(化合物3)；
(2)化合物3与三唑或三唑衍生物(化合物4)在碳酸盐存在下回流反应，制备得到如式1所示的麝香草酚衍生物(化合物1)。
在一些具体实施方式中，所述三唑或衍生物是
其中，R1、R2、R3、R4、R5、R6、R8、R9如前所述。
图1中数字1指化合物1，即本文所述的麝香草酚衍生物；数字2指化合物2，即麝香草酚；数字3指化合物3，即麝香草酚氧乙基溴；数字4指化合物4，即三唑或其衍生物。
在一些具体实施方式中，三唑或其衍生物是化合物4a-4g，得到的麝香草酚衍生物是如式1所示的化合物，其中R如1a-1g所示。
在一些具体实施方式中，步骤(1)中所述碱为氢氧化钠或氢氧化钾；优选地，所述碱为氢氧化钠，
在一些具体实施方式中，步骤(2)中所述碳酸盐是碳酸钠或碳酸钾；优选的，所述碳酸盐是碳酸钾。
一方面，本发明还提供了上述麝香草酚衍生物在抑制抗尖孢镰刀菌方面的应用。
具体地，所述应用是在制备抗尖孢镰刀菌抗菌剂方面的用途；
具体地，所述应用可以是将上述麝香草酚衍生物作为有效成分用于制备农药，该农药用于百合枯萎病的防治。
一方面，本发明提供了一种抑制抗尖孢镰刀菌的方法，所述方法是使抗尖孢镰刀菌与上述麝香草酚衍生物接触。
本发明提供的麝香草酚衍生物具有以下优点:在体外生物活性测试中,本发明提供的麝香草酚衍生物具有抗尖孢镰刀菌活性,其中化合物1a的抑制率明显高于麝香草酚。
附图说明
图1是麝香草酚衍生物的制备流程；
图2是化合物1的抗尖孢镰刀菌活性
具体实施方式
本发明是通过下面的具体实施例进行描述,通过具体实施例可以更好的理解本发明,但本发明的范围不受这些实施例的限制。
实施例1:麝香草酚氧乙基溴(化合物3)的制备
具体合成方法：向500mL的三颈烧瓶中加入麝香草酚(10g，67mmol),然后向烧瓶中缓慢加入150mL纯水，搅拌，再依次加入氢氧化钠(NaOH,4g，100mmol)、四丁基溴化铵(TBAB，2.2g，6.7mmol)、碘化钾(KI，1.1g，6.7mmol),加热使其完全溶解，当温度达到90℃时，向反应液中缓慢加入1，2-二溴乙烷(12mL，134mmol)，使温度保持在100℃左右，继续搅拌12h。薄层色谱(TLC)监测反应，待反应结束后，过滤，收集油状液体，然后用2％的NaOH水溶液、饱和食盐水分别洗涤3次，最后用乙酸乙酯萃取，将收集到的有机层溶液用无水硫酸钠干燥，滤液浓缩后以石油醚/乙酸乙酯(V/V＝40/1)为洗脱剂柱层析分离即得化合物3。
化合物3，无色油状液体，1HNMR(600M,CDCl3)δppm:7.12(d,J＝7.7Hz,1H),6.79(d,J＝7.7Hz,1H),4.30(t,J＝6.1Hz,2H),3.67(t,J＝6.1Hz,2H),3.33(m,1H),2.33(s,3H),1.23(d,J＝6.7Hz,6H)。
实施例2:麝香草酚衍生物(化合物1)的制备通法
向50mL反应瓶中加入麝香草酚氧乙基溴(化合物3，500mg，2.07mmol),然后加入25mL乙腈，搅拌，加入碳酸钾(572mg，4.14mmol),最后加入3-巯基-1，2，4-三唑(316mg，3.12mmol)在80℃下加热回流12h。薄层色谱(TLC)监测反应结束后，先将沉淀过滤，用50mL乙腈将沉淀洗涤三次，滤液减压浓缩后以石油醚/乙酸乙酯(V/V＝1/1)为洗脱剂柱层析分离纯化，即得到目标产物1a。化合物1b-1g的合成方法与此相同。
化合物1a-1g的理化数据如下：
化合物1a，白色粉末状固体，1HNMR(600M,CDCl3)δppm:8.24(s,1H),7.13(d,J＝7.6Hz,1H),6.80(d,J＝7.6Hz,1H),6.71(s,1H),4.30(t,J＝6.4Hz,2H),3.60(t,J＝6.4Hz,2H),3.29(m,1H),2.33(s,3H),2.22(s,1H,-NH),1.23(d,J＝7.1Hz,6H)；13CNMR(150M,CDCl3)δppm:155.5,155.3,136.3,136.2,134.1,126.0,121.7,112.5,66.8,31.8,26.5,22.7,22.7,21.2.
化合物1b，白色粉末状固体，1HNMR(600M,CDCl3)δppm:7.06(d,J＝7.7Hz,1H),6.75(d,J＝7.7Hz,1H),6.58(s,1H)4.38(t,J＝6.4Hz,2H),4.31(t,J＝6.4Hz,2H),3.06(m,1H),2.47(s,3H),2.31(s,3H),2.28(s,3H),1.10(d,J＝6.9Hz,6H)；13CNMR(150M,CDCl3)δppm:159.7,155.1,153.1,136.4,133.9,125.9,122.0,112.4,66.3,47.7,26.3,22.7,22.7,21.2,13.7,11.7.
化合物1c，无色油状液体，1HNMR(600M,CDCl3)δppm:7.65(s,2H),7.09(d,J＝7.7Hz,1H),6.78(d,J＝7.7Hz,1H),6.67(s,1H),4.88(t,J＝5.6Hz,2H),4.50(t,J＝5.6Hz,2H),3.16(m,1H),2.33(s,3H),1.11(d,J＝7.0Hz,6H).；13CNMR(150M,CDCl3)δppm:155.3,136.3,134.4,134.4,126.1,121.9,112.5,66.0,54.2,26.5,22.7,22.7,21.3.
化合物1d，无色针晶(甲醇)，1HNMR(600M,CDCl3)δppm:7.08(d,J＝7.7Hz,1H),6.78(d,J＝7.7Hz,1H),6.60(s,1H),4.57(t,J＝5.1Hz,2H),4.36(t,J＝5.1Hz,2H),3.29(m,1H),2.31(s,3H),1.10(d,J＝6.9Hz,6H).；13CNMR(150M,CDCl3)δppm:154.6,140.4,136.2,134.0,130.6,125.9,122.0,112.0,65.0,49.4,26.2,22.5,22.5,21.1.
化合物1e，白色块状固体，1HNMR(600M,CDCl3)δppm:7.74(dd,J＝8.7,0.8Hz,1H),7.60(s,1H),7.21(d,J＝8.8,1H),7.03(d,J＝7.7Hz,1H),6.74(d,J＝7.8Hz,1H),6.66(ds,1H),5.10(t,J＝5.6Hz,2H),4.62(t,J＝5.6Hz,2H),3.07(m,1H),2.49(s,3H),2.29(s,3H),0.99(d,J＝6.9Hz,6H).；13CNMR(150M,CDCl3)δppm:155.5,145.5,143.6,136.9,136.7,134.9,129.7,126.5,122.4,117.8,116.7,113.0,66.7,56.1,26.8,23.0,23.0,22.5,21.7..
化合物1f，白色块状固体，1HNMR(600M,CDCl3)δppm:8.00(s,1H),7.04(d,J＝8.0Hz,1H),6.74(d,J＝8.0,1H),6.59(m,1H),5.11(t,J＝5.3Hz,2H),4.37(t,J＝5.3Hz,2H),4.01(s,3H),3.00(m,1H),2.29(s,3H),1.06(d,J＝6.9Hz,6H).；13CNMR(150M,CDCl3)δppm:158.8,155.4,151.4,145.1,136.8,134.5,126.4,122.3,112.5,66.4,53.5,50.7,26.8,23.1,23.1,21.7.
化合物1g，无色油状液体，1HNMR(600M,CDCl3)δppm:7.87(s,1H),7.81(d,J＝9.1Hz,1H),7.34(d,J＝9.0,1H),7.04(d,J＝7.7Hz,1H),6.75(d,J＝7.7Hz,1H),6.66(s,1H),5.12(t,J＝5.5Hz,2H),4.63(t,J＝5.5Hz,2H),3.04(m,1H),2.30(s,3H),0.98(dt,J＝7.0,1.4Hz,6H)；13CNMR(150M,CDCl3)δppm:154.8,144.6,142.8,136.1,134.2,132.0,127.8,125.9,121.8,119.0,116.9,112.3,65.8,55.9,26.2,22.3,22.3,21.1.
实施例3:化合物1抗尖孢镰刀菌活性测定
采用有毒培养基法测定抗尖孢镰刀菌活性
(1)供试菌种
尖孢镰刀菌(Fusarium oxysporum)购自北京北纳创联生物技术研究院。
(2)待测样品溶液的配制：
5mg样品加入500μL DMSO完全溶解后，再加入9500μL无菌水得到500μg/mL的待测样品溶液。
(3)测定方法
将以上稀释好的10mL待测样品溶液加入到90mL的PDA(60-70℃)培养基中，待培养基冷却凝固后，用直径5mm的无菌打孔器打取生长期为5-6天的尖孢镰刀菌菌饼，将打取的5mm菌饼接种至含有待测样品的PDA培养基中心，即为样品处理组，以不含待测样品溶液的PDA培养基作为空白对照组。以上接种完毕后，置于30℃恒温培养箱培养4-5天，测量菌落直径，计算抑制率。
dc:空白对照组菌落直径；d0:菌饼直径；ds:样品处理组菌落直径
(4)化合物1抗尖孢镰刀菌活性结果
化合物1及麝香草酚的抗尖孢镰刀菌活性结果见图2及表1。可以看出
表1.化合物1的抗尖孢镰刀菌活性
Claims (10)
1.一种如式I所示的麝香草酚衍生物，
其中R为
R1和R2各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；
R3和R4各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；或R3和R4与它们所键合的碳原子一起形成环烷基团，所述环状基团是五元环或六元环，所述环状基团未被取代或任选地被Cm-n烷基和/或卤素取代；
R8和R9各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；
R5和R6各自独立地是H、卤素、Cm-n烷基、Cx-y环烷基或-COOR7；或R5和R6与它们所键合的氮原子、碳原子一起形成杂环基团，所述杂环基团是五元环或六元环，所述环状基团未被取代或任选地被Cm-n烷基和/或卤素取代；所述杂环基团是只有一个杂原子的基团；
R7是Cm-n烷基或Cx-y环烷基；
所述Cm-n烷基是C1-10烷基，所述Cx-y环烷基是C3-8环烷基；
所述Cm-n烷基和Cx-y环烷基未被取代或任选地被卤素取代。
2.如权利要求1所述的麝香草酚衍生物，其特征在于，所述Cm-n烷基是C1-6烷基，所述Cx-y环烷基是C5-8环烷基。
3.如权利要求1所述的麝香草酚衍生物，其特征在于，所述Cm-n烷基是甲基、乙基或丙基；所述Cx-y环烷基是C5-6环烷基。
4.如权利要求1所述的麝香草酚衍生物，其特征在于，R如式1a-1g所示：
5.如权利要求1-4任一项所述麝香草酚衍生物的药用盐。
6.一种制备如权利要求1-4任一项所述麝香草酚衍生物的方法,其包括如下步骤：
(1)麝香草酚在碱存在下，和二溴乙烷发生取代反应得麝香草酚氧乙基溴；
(2)所述麝香草酚氧乙基溴与三唑或三唑衍生物在碳酸盐存在下回流反应，制备得到所述麝香草酚衍生物；
所述三唑或三唑衍生物是
7.如权利要求6所述的方法,其特征在于，所述三唑或三唑衍生物的结构如式4a-4g所示：
8.如权利要求6所述的方法,其特征在于，所述碱是氢氧化钠。
9.如权利要求6所述的方法,其特征在于，所述碳酸盐是碳酸钾。
10.麝香草酚衍生物及其药用盐的用途，其特征在于，所述麝香草酚衍生物是权利要求1-4任一项所述的麝香草酚衍生物，所述用途是：
(1)在制备抗尖孢镰刀菌抗菌剂方面的用途；和/或，
(2)在制备农药方面的用途，所述农药是用于百合枯萎病防治的农药，所述麝香草酚衍生物作为有效成分是有效成分。
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