CN113773306B - 3,3-二取代吲哚酮类化合物及其制备方法和应用 - Google Patents
3,3-二取代吲哚酮类化合物及其制备方法和应用 Download PDFInfo
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- CN113773306B CN113773306B CN202111275629.3A CN202111275629A CN113773306B CN 113773306 B CN113773306 B CN 113773306B CN 202111275629 A CN202111275629 A CN 202111275629A CN 113773306 B CN113773306 B CN 113773306B
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- -1 3,3-disubstituted indolone compound Chemical class 0.000 title abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 241000588724 Escherichia coli Species 0.000 claims abstract description 8
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 8
- 230000000844 anti-bacterial effect Effects 0.000 claims description 11
- 241000894006 Bacteria Species 0.000 claims description 9
- 239000003899 bactericide agent Substances 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 8
- 244000063299 Bacillus subtilis Species 0.000 abstract description 7
- 235000014469 Bacillus subtilis Nutrition 0.000 abstract description 7
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 7
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 230000001954 sterilising effect Effects 0.000 abstract description 2
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 229930195735 unsaturated hydrocarbon Chemical group 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 238000001228 spectrum Methods 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 5
- 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 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 5
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 4
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 235000005513 chalcones Nutrition 0.000 description 4
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 4
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 3
- 238000005882 aldol condensation reaction Methods 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
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- 230000004048 modification Effects 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 239000007787 solid 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
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 102000002852 Vasopressins Human genes 0.000 description 2
- 108010004977 Vasopressins Proteins 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 229960003726 vasopressin Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- NJXZWIIMWNEOGJ-WEWKHQNJSA-N (2s,4r)-1-[(3r)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-4-hydroxy-n,n-dimethylpyrrolidine-2-carboxamide Chemical compound COC1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(Cl)C=C2[C@@](N2[C@@H](C[C@@H](O)C2)C(=O)N(C)C)(C=2C(=CC=CC=2)OC)C1=O NJXZWIIMWNEOGJ-WEWKHQNJSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- GKODDAXOSGGARJ-UHFFFAOYSA-N 5-Fluoroisatin Chemical compound FC1=CC=C2NC(=O)C(=O)C2=C1 GKODDAXOSGGARJ-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010010369 HIV Protease Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- 239000001888 Peptone Substances 0.000 description 1
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- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
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- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
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- 238000011534 incubation Methods 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000003997 social interaction Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及杀菌领域,具体是一种3,3‑二取代吲哚酮类化合物及其制备方法和应用,所述3,3‑二取代吲哚酮类化合物的通式为式中:R选自氢原子、烷基、烷氧基、卤素原子中的一种;R1选自氢原子、烷基、苄基、不饱和烃基中的一种;R2选自芳基。该化合物方法简单,易于合成,生产成本低,对大肠杆菌、绿脓杆菌、枯草芽孢杆菌、金黄色葡萄球菌均有较好的抑制作用。
Description
技术领域
本发明涉及杀菌领域,具体是一种3,3-二取代吲哚酮类化合物及其制备方法和应用。
背景技术
有机合成杀菌剂是目前农用杀菌剂中的主体部分,也是现代农药工业的重要组成部分。但随着有机合成杀菌剂的大量使用,病原菌表现出了不同程度的耐药性或抗药性。为解决这一问题,不断地开发出各种新型杀菌剂是农药工业面临的一个问题。
关于3,3-二取代吲哚酮类化合物,已有许多报道其具有多种生物活性:日本正大药物公司的Chaki(2006)等人报道了一种3,3-二取代吲哚酮类化合物,作为抗利尿激素V1B受体拮抗剂在多种焦虑动物模型中显示出抗焦虑作用[T.Shimazaki,M.Iijima,S.Chaki.The pituitary mediates the anxiolytic-like effects of the vasopressinV1B receptor antagonist,SSR149415,in a social interaction test in rats[J].European Journal of Pharmacology,2006,543(1-3):63-67];普渡大学的Ghosh(2006)人合成了一类新型的3,3-二取代吲哚酮,作为HIV-1蛋白酶抑制剂,大部分对HIV蛋白酶表现出较低的纳米摩尔抑制能力[A.K.Ghosh,G.Schiltz,R.S.Perali,等.Design andsynthesis of novel HIV-1protease inhibitors incorporating oxyindoles as theP2'-ligands[J].Bioorganic Medicinal Chemistry Letters,2006,16(7):1869-1873];Beccalli(2020)等人合成的3,3-二取代吲哚酮类化合物,体外抗肿瘤活性实验表明,在低微摩尔范围的所有癌症细胞系中显示出强的抗癌作用[M.S.Christodoulou,F.Nicoletti,K.Mangano,等.Novel 3,3-disubstituted oxindole derivatives.Synthesis andevaluation of the anti-proliferative activity[J].Bioorg Med Chem Lett,2020,30(2):1268-1245];但未见3,3-二取代吲哚酮类化合物用于细菌杀菌活性物质的相关报道。
发明内容
本发明的目的之一在于克服现有技术的不足,提供一种新的3,3-二取代吲哚酮类化合物,以至少达到化合物合成方法简单,易于合成,生产成本低,对大肠杆菌、绿脓杆菌、枯草芽孢杆菌、金黄色葡萄球菌均有较好的抑制作用。
本发明的目的是通过以下技术方案来实现的:
一种3,3-二取代吲哚酮类化合物或其立体异构体、手性异构体或其盐,结构通式如式(I):
式中:
R选自氢原子、卤素原子、烷基和烷氧基中的一种;
R1选自氢原子、烷基、苄基、烯丙基和炔丙基中的一种;
R2选自芳基;所述芳基所述芳基分别被一个或多个各自独立的氢原子、烷基、卤素、硝基、烷氧基取代。
在一些较优的实施例中,R选自氢原子、氟原子中的一种;R1选自氢原子、正丁基中的一种;R2选自苯基、噻吩和呋喃中的一种;所述苯基、噻吩和呋喃分别被一个或多个各自独立的氢原子、烷基、卤素、硝基、烷氧基取代。
在一些更优的实施例中,R2选自苯基、2-甲氧基苯基、3-甲氧基苯基、4-硝基苯基、2-噻吩、2-呋喃、3,4-二甲氧基苯中的一种。
本发明的目的之二在于,提供一种所述式(I)化合物的制备方法,包括以下步骤:
提供化合物A和化合物B,所述化合物A的通式为化合物B的通式为:
所述化合物A、所述化合物B和经过迈克尔加成反应得到所述式(I)化合物。
进一步的,所述迈克尔加成反应是在碱和反应介质的存在下进行的;
所述碱包括叔丁醇钠或叔丁醇钾;
所述反应介质包括N,N-二甲基甲酰胺;
进一步的,当所述碱为叔丁醇钠、反应介质为N,N-二甲基甲酰时,所述化合物A、化合物B、N,N-二甲基甲酰和叔丁醇盐的摩尔比为1:2.2:76-78:2。
进一步的,所述化合物B的合成方法为:
将芳香族甲醛、芳香族乙酮混合,进行羟醛缩合反应,得到所述化合物B。
进一步的,所述羟醛缩合反应是在碱性条件下进行的;
所述碱包括氢氧化钠或氢氧化钾;
和/或,所述或羟醛缩合反应的溶剂包括乙醇或甲醇;
和/或,所述芳香族甲醛包括邻甲氧基苯甲醛、间甲氧基苯甲醛、对硝基苯甲醛、糠醛、2-噻吩甲醛、3,4-二甲氧基苯甲醛、苯甲醛中的一种;
和/或,所述芳香族乙酮包括苯乙酮或取代苯乙酮。
进一步的,所述芳香族乙酮:芳香族甲醛:乙醇:氢氧化钠的摩尔比为1:1:340-360:30-35。
进一步的,所述化合物A的合成方法包括:
提供化合物C,所述化合物C的通式为将所述化合物C和吡唑酮混合,经过亲核加成消除反应,得到化合物A。
其中,所述吡唑酮的合成方法为:将无水乙醇和水合肼在冰浴条件下混合,然后加入丙烯酸甲酯,然后真空减压蒸馏去除无水乙醇即得。
进一步的,所述亲核加成消除反应使用的溶剂包括甲醇或乙醇;
和/或,所述化合物C和吡唑酮的摩尔比为1.0:1.5-3.0。
进一步的,所述化合物C的合成方法包括:
提供化合物D,所述化合物D的通式为将所述化合物D、碱和不饱和卤代物混合,经过亲核取代反应,得到化合物C。
进一步的,所述亲核取代反应的溶剂为N,N-二甲基甲酰胺或四氢呋喃;
和/或,所述碱包括氢氧化钠、氢氧化钾和氢化钠中的一种;
和/或,所述不饱和卤代物包括:卤化苄、卤化烯、卤化炔中的一种。
进一步的,所述化合物D、碱和不饱和卤代物的摩尔比为1:1.2-1.5:1.5-2.0。
本发明的目的之三在于,提供所述式(I)化合物、或其立体异构体、手性异构体或其盐在制备杀菌剂或抑菌剂的应用。
进一步的,所述杀菌剂或抑菌剂中的菌为细菌;所述细菌包括但不限于大肠杆菌(Escherichia coli)、绿脓杆菌(Pseudomonas aeruginosa)、枯草芽孢杆菌(Bacillussubtilis)、金黄色葡萄球菌(Staphylococcus aureus)。
本发明的有益效果是:
(1)本发明的化合物结构简单,易于合成,反应快速,生产成本低,实际应用前景广泛;
(2)对多种细菌具有抗菌活性,可进行结构改造和优化,在杀菌剂领域应用前景广泛。
附图说明
图1为实施例1的氢谱图;图2为实施例1的碳谱图;图3为实施例1的质谱图;
图4为实施例2的氢谱图;图5为实施例2的碳谱图;图6为实施例2的质谱图;
图7为实施例3的氢谱图;图8为实施例3的碳谱图;图9为实施例3的质谱图;
图10为实施例4的氢谱图;图11为实施例4的碳谱图;图12为实施例4的质谱图;
图13为实施例5的氢谱图;图14为实施例5的碳谱图;图15为实施例5的质谱图;
图16为实施例6的氢谱图;图17为实施例6的碳谱图;图18为实施例6的质谱图;
图19为实施例7的氢谱图;图20为实施例7的碳谱图;图21为实施例7的质谱图;
图22为实施例8的氢谱图;图23为实施例8的碳谱图;图24为实施例8的质谱图;
图25为实施例9的氢谱图;图26为实施例9的碳谱图;图27为实施例9的质谱图;
图28为实施例10的氢谱图;图29为实施例10的碳谱图;图30为实施例10的质谱图;
图31为实施例2的氟谱图。
具体实施方式
下面结合附图进一步详细描述本发明的技术方案,但本发明的保护范围不局限于以下所述。
实施例1
制备(±)-(S)-3-((R)-1-(2-methoxyphenyl)-3-oxo-3-phenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法如下:
1)取10%的氢氧化钠水溶液(18mL)加入到100mL的圆底烧瓶中,再加入15mL乙醇和苯乙酮(50mmol),室温搅拌半小时后,缓慢滴加邻甲氧基苯甲醛(50mmol),室温反应,薄层层析(TLC)监测反应进程。反应完毕后,加入稀盐酸调pH至中性,反应液置冰水30min后减压抽滤收集固体,用水和少量冰乙醇洗涤固体,抽干即得到查尔酮粗产品。查尔酮粗产品用乙醇重结晶,真空水泵减压抽滤,少量冰乙醇洗涤滤饼,油泵干燥滤饼既得查尔酮;
2)在250mL的圆底烧瓶中加入乙醇(100mL),冰浴条件下快速加入水合肼(100mmol),搅拌几分钟后缓慢滴加丙烯酸甲酯(110mmol),滴加完毕后,冷凝回流12h。真空减压蒸馏去除无水乙醇,由于浓缩后的吡唑酮会进一步分解,得到淡黄色的油状液体不能久存,需立即进行下一步反应。
称量靛红(20mmol)加入100mL圆底烧瓶中,加入适量甲醇,搅拌均匀后加入上述合成的吡唑酮(60mmol),回流反应,TLC监测反应进程,待反应完毕后,用布氏漏斗减压抽滤,用冰无水乙醇冲洗滤饼数次,收集滤饼,油泵干燥滤饼得到靛红N,N'-环状偶氮次甲基亚胺;
3)将靛红N,N'-环状偶氮次甲基亚胺(1.0mmol)、查尔酮(2.2mmol)和N,N-二甲基甲酰胺(6.0mL)加入25mL反应试管中室温搅拌均匀、快速称量叔丁醇钠(2.0mmol)加入反应液,观察颜色变化,TLC监测反应进程,待反应完全后处理既得目标产物;产物为白色粉末,产率67%。
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),10.08(s,1H),7.78(d,J=7.6Hz,2H),7.61-7.55(m,3H),7.48(ψt,J=7.4Hz,2H),7.23(d,J=7.2Hz,1H),7.00(t,J=7.6Hz,1H),6.95(ψt,J=8.0Hz,1H),6.85(ψt,J=7.4Hz,1H),6.70(ψt,J=7.4Hz,1H),6.55(d,J=8.0Hz,1H),6.48(d,J=7.6Hz,1H),5.55(d,J=2.0Hz,1H),5.49(dd,J=11.2,2.4Hz,1H),4.14(dd,J=17.2,11.2Hz,1H),3.50(s,3H),3.07(dd,J=17.2,2.4Hz,1H);13C NMR(100MHz,DMSO-d6):δ198.3,174.1,162.5,157.3,140.7,137.1,133.6,130.7,129.3,129.2(2C),128.5,128.1,127.6,126.0,125.9,121.1,120.1,110.8,109.3,91.9,71.2,55.2,37.4(The peak of one carbon was masked by the peak of DMSO);HRMS(ESI):m/zcalcd for C27H23N3O4Na[M+Na]+476.1586,found 476.1685.
实施例2
制备(±)-(S)-3-((R)-1-(3-methoxyphenyl)-3-oxo-3-phenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例1。不同点为用间甲氧基苯甲醛替代实施例7中的邻甲氧基苯甲醛。
产物为白色粉末,产率48%。
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),10.06(s,1H),7.82(d,J=7.2Hz,2H),7.62-7.58(m,3H),7.48(ψt,J=7.4Hz,2H),7.09(t,J=7.4Hz,1H),6.99-6.92(m,2H),6.65(d,J=7.2Hz,1H),6.60-6.58(m,3H),5.58(d,J=1.2Hz,1H),4.77(d,J=11.6Hz,1H),4.22(dd,J=17.2,11.6Hz,1H),3.53(s,3H),3.02(d,J=17.2Hz,1H);13C NMR(100MHz,DMSO-d6):δ198.1,173.8,162.5,158.7,141.1,138.8,137.0,133.7,130.8,129.7,129.4,129.3,128.9,128.1,125.6,122.1,121.8,115.6,112.7,110.0,92.2,71.0,55.1,46.9,37.0;HRMS(ESI):m/z calcd for C27H23N3O4Na[M+Na]+476.1586,found 476.1690.
实施例3
制备(±)-(S)-3-((R)-1-(4-nitrophenyl)-3-oxo-3-phenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例1。不同点为用对硝基苯甲醛替代实施例7中的邻甲氧基苯甲醛。
产物为黄色粉末,产率44%。
1H NM R(400MHz,DMSO-d6)δ10.26(s,1H),9.30(s,1H),8.14(d,J=8.4Hz,2H),7.54(ψd,J=8.0Hz,4H),7.47(d,J=7.6Hz,1H),7.36(ψt,J=7.2Hz,2H),7.25(t,J=7.4Hz,1H),7.19(ψt,J=7.4Hz,1H),7.01(ψt,J=7.4Hz,1H),6.56(d,J=8.0Hz,1H),4.85(d,J=3.2Hz,1H),4.45-4.33(m,2H),2.99(dd,J=17.2,8.0Hz,1H),2.61(dd,J=17.2,10.0Hz,1H);13C NMR(100MHz,DMSO-d6):δ197.8,173.3,162.6,146.7,145.7,140.8,136.7,133.9,131.1,130.1,129.3,128.7,128.1,125.5,123.0,122.5,110.2,92.5,70.6,46.7,37.0;HRMS(ESI):m/z calcd for C26H20N4O5Na[M+Na]+491.1331,found 491.1377.
实施例4
制备(±)-(S)-3-((S)-1-(4-nitrophenyl)-3-oxo-3-phenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例3。不同点为两个产物立体构型不一样。
产物为黄色粉末,产率9%。
1H NMR(400MHz,DMSO-d6):δ10.31(br s,1H),10.04(br s,1H),8.01(d,J=7.6Hz,1H),7.98(d,J=7.8Hz,2H),7.91(d,J=8.8Hz,2H),7.63(t,J=7.4Hz,1H),7.50(ψt,J=7.8Hz,2H),7.37(ψt,J=7.8Hz,1H),7.31(d,J=2.4Hz,1H),7.23(ψt,J=7.4Hz,1H),7.10(d,J=8.4Hz,2H),6.69(d,J=7.6Hz,1H),5.59(d,J=2.4Hz,1H),4.89(d,J=11.2Hz,1H),3.98(dd,J=17.6,11.2Hz,1H),3.59(d,J=17.6Hz,1H);13C NMR(100MHz,DMSO-d6):δ197.3,173.9,162.2,147.0,145.7,142.9,136.5,134.0,131.3,131.1,130.6,129.2,128.6,128.0,125.2,122.9,122.7,110.6,93.0,71.3,45.3,38.4;HRMS(ESI):m/z calcdfor C26H20N4O5Na[M+Na]+491.1331,found 491.1319.
实施例5
制备(±)-(S)-3-((R)-1-(furan-2-yl)-3-oxo-3-phenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例1。不同点为用糠醛替代实施例7中的邻甲氧基苯甲醛。
产物为白色固体,产率11%。
1H NMR(400MHz,DMSO-d6)δ10.43(br s,1H),9.99(br s,1H),7.99(d,J=7.6Hz,2H),7.82(d,J=7.8Hz,1H),7.62(ψt,J=6.8Hz,1H),7.53-7.48(m,2H),7.33-7.27(m,4H),6.75(d,J=7.6Hz,1H),6.15(ψs,1H),5.69(d,J=2.4Hz,1H),5.58(d,J=1.6Hz,1H),4.88(d,J=10.4Hz,1H),3.87(dd,J=17.2,11.6Hz,1H),3.35(d,J=15.6Hz,1H);13C NMR(100MHz,DMSO-d6):δ197.4,174.3,162.1,151.6,143.0,142.4,136.6,133.8,130.6,130.4,129.2,128.5,128.5,126.1,122.3,110.7,110.2,108.1,92.9,70.5,39.5,37.3;HRMS(ESI):m/z calcd for C24H19N3O4Na[M+Na]+436.1273,found 436.1250.
实施例6
制备(±)-(S)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-3-((S)-3-oxo-3-phenyl-1-(thiophen-2-yl)propyl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例1。不同点为用2-噻吩甲醛替代实施例7中的邻甲氧基苯甲醛。
产物为白色粉末,产率34%。
1H NMR(400MHz,DMSO-d6)δ10.75(br s,1H),10.03(br s,1H),7.82(d,J=7.2Hz,2H),7.62(t,J=7.2Hz,1H),7.52-7.49(m,3H),7.45(d,J=7.6Hz,1H),7.17-7.12(m,2H),7.00-6.96(m,2H),6.64(d,J=7.6Hz,1H),6.61(dd,J=5.0,1.0Hz,1H),5.54(d,J=2.8Hz,1H),4.88(dd,J=11.2,2.4Hz,1H),4.09(dd,J=17.4,11.2Hz,1H),2.95(dd,J=17.4,2.4Hz,1H);13C NMR(100MHz,DMSO-d6):δ198.1,173.8,162.4,141.4,138.1,137.0,133.7,130.7,129.9,129.3,129.2,128.7,128.1,125.5,125.1,123.8,122.2,110.1,92.1,70.8,42.2,37.7;HRMS(ESI):m/z calcd for C24H19N3O3SNa[M+Na]+452.1045,found 452.1088.
实施例7
制备(±)-(S)-3-((S)-1-(3,4-dimethoxyphenyl)-3-oxo-3-phenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例1。不同点为用3,4-二甲氧基苯甲醛替代实施例7中的邻甲氧基苯甲醛。
产物为白色粉末,产率21%。
1H NMR(400MHz,CDCl3)δ10.17(s,1H),9.96(s,1H),7.97-7.95(m,3H),7.61(d,J=7.4Hz,1H),7.49(ψt,J=7.6Hz,2H),7.37(d,J=2.4Hz,1H),7.34(dd,J=7.8,1.0Hz,1H),7.21(td,J=7.6,0.8Hz,1H),6.69(d,J=7.6Hz,1H),6.64(d,J=8.4Hz,1H),6.49(dd,J=8.4,2.0Hz,1H),6.08(d,J=1.6Hz,1H),5.59(d,J=2.4Hz,1H),4.65(dd,J=11.2,1.6Hz,1H),3.81(dd,J=17.2,11.2Hz,1H),3.61(s,3H),3.45(dd,J=17.2,1.6Hz,1H),3.28(s,3H);13C NMR(100MHz,DMSO-d6):δ197.9,174.4,161.9,148.1,147.8,143.4,136.9,133.8,130.5,130.3,129.2,128.5,127.9,126.3,123.2,122.2,112.2,111.0,110.4,92.8,71.9,55.6,55.2,45.0,38.9;HRMS(ESI):m/zcalcd for C28H25N3O5Na[M+Na]+506.1692,found506.1658.
实施例8
制备(±)-(S)-1-butyl-3-((R)-3-oxo-1,3-diphenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
1)冰水浴(0℃)下将靛红(10mmol)溶解于N,N-二甲基甲酰胺溶液(20mL)中,搅拌均匀后,快速称量氢化钠(15mmol)并分批加入反应液中,继续0℃搅拌约半小时后,向反应液中缓慢滴加碘丁烷(15mmol),反应液搅拌均匀至室温反应,TLC监测反应进程。处理后得N-正丁基取代靛红。
其余制备方法同实施例1。不同点为用苯甲醛替代实施例7中的邻甲氧基苯甲醛。
产物为白色粉末,产率55%。
1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),7.81(d,J=7.2Hz,2H),7.66(d,J=7.2Hz,1H),7.60(t,J=7.4Hz,1H),7.55(d,J=2.4Hz,1H),7.49(ψt,J=7.8Hz,2H),7.16(td,J=7.6,0.8Hz,1H),7.03(ψt,J=7.4Hz,1H),6.97(ψs,5H),6.76(d,J=8.0Hz,1H),5.56(d,J=2.4Hz,1H),4.78(dd,J=11.6,2.6Hz,1H),4.25(dd,J=17.6,11.6Hz,1H),3.65-3.58(m,1H),3.53-3.45(m,1H),3.02(dd,J=17.6,2.6Hz,1H),1.38-1.33(m,2H),1.26-1.10(m,2H),0.86(t,J=7.2Hz,3H);13C NMR(100MHz,DMSO-d6):δ198.1,171.7,162.6,141.9,137.0,136.9,133.8,130.9,129.8,129.6,129.3,128.7,128.1,127.9,127.3,125.2,122.8,109.2,92.2,70.2,47.0,39.9,36.9,29.2,20.1,14.1;HRMS(ESI):m/zcalcd for C30H29N3O3Na[M+Na]+502.2107,found502.2026.
实施例9
制备(±)-(S)-1-butyl-3-((S)-3-oxo-1,3-diphenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例8。不同点为两个产物立体构型不一样。
产物为白色粉末,产率27%。
1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.02(d,J=7.2Hz,1H),7.97(d,J=7.6Hz,2H),7.61(t,J=7.4Hz,1H),7.49(ψt,J=7.8Hz,2H),7.45(t,J=8.0Hz,1H),7.34(dJ=2.4Hz,1H),7.28(ψt,J=7.4,Hz,1H),7.04(ψt,J=7.2Hz,1H),6.98(ψt,J=7.4Hz,2H),6.88(d,J=8.0Hz,1H),6.71(d,J=7.2Hz,2H),5.59(d,J=2.4Hz,1H),4.78(dd,J=11.2,1.6Hz,1H),3.85(dd,J=17.6,11.2Hz,1H),3.54(dd,J=17.6,1.6Hz,1H),3.33-3.28(m,1H),3.14-3.09(m,1H),0.90-0.76(m,4H),0.69(t,J=6.6Hz,3H);13C NMR(100MHz,DMSO-d6):δ197.6,172.7,162.0,144.1,137.0,136.8,133.9,130.8,130.4,129.8,129.2,128.5,127.9,127.6(2C),125.3,122.8,109.5,92.9,71.3,45.4,39.4,38.9,28.9,19.7,14.1;HRMS(ESI):m/z calcd for C30H29N3O3Na[M+Na]+502.2107,found 502.2031.
实施例10
制备(±)-(S)-5-fluoro-3-((S)-3-oxo-1,3-diphenylpropyl)-3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl)indolin-2-one,其化学结构式如下所示:
制备方法同实施例1。不同点为用5-氟靛红替代实施例7中的靛红。
产物为白色粉末,产率26%。
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.99(s,1H),8.00(d,J=8.4Hz,2H),7.94(dd,J=8.4,2.4Hz,1H),7.61(t,J=7.4Hz,1H),7.49(ψt,J=7.8Hz,2H),7.46(d,J=2.4Hz,1H),7.16(td,J=8.8Hz,1H),7.09-7.01(m,3H),6.85(ψd,J=6.4Hz,2H),6.63(dd,J=8.4,4.4Hz,1H),5.61(d,J=2.4Hz,1H),4.70(dd,J=11.2,1.6Hz,1H),3.94(dd,J=18.0,11.2Hz,1H),3.50(dd,J=18.0,1.6Hz,1H);13C NMR(100MHz,DMSO-d6):δ198.0,173.6,162.5,137.2(d),137.1,137.0,133.8,131.0,129.6,129.3,128.1,127.4,116.2,116.0,113.3,113.1,109.9(2C),92.5,71.2(d),46.8,37.0;19F NMR(376MHz,DMSO-d6):-120.9;HRMS(ESI):m/z calcd for C26H20N3O3FNa[M+Na]+464.1386,found 464.1322.
实验例一
分别对实施例1-10中的3,3-二取代吲哚酮类化合物进行生物抗菌活性测定。
采用对倍稀释法测定大肠杆菌(Escherichia coli)、绿脓杆菌(Pseudomonasaeruginosa)、枯草芽孢杆菌(Bacillus subtilis)、金黄色葡萄球菌(Staphylococcusaureus)4种供试菌的最小抑菌浓度。菌种均由四川农业大学无公害农药研究实验室提供。
取10支无菌EP管,除第1管加入1000μL的浓度为1000μg/mL DMSO化合物溶液外,其余每管依次加入液体培养基(牛肉膏(4g),蛋白胨(8g),NaCl(4g),1mol/LNaOH溶液调pH=7.5-7.6)500μL,然后从第1个EP管吸取500μL溶液至第2个EP管,用移液枪混匀后再吸取500μL混合液至第3个EP管,如此连续倍比稀释至第8个EP管,并从第8个EP管中吸取500μL丢弃,第9个EP管为DMSO溶剂空白对照,第10管为阳性对照。每管再加入500μL 105CFU/mL待测菌液,充分混匀使化合物最终浓度为500μg/mL~4μg/mL。用保鲜膜将10支EP管包好置于烧杯中,在恒温培养振荡箱中37℃培养18h后观察结果,以肉眼见不到浑浊的最低药物浓度为该化合物的最小抑菌浓度(MIC)。EP管溶液浑浊则代表未抑制细菌生长,溶液透亮清澈则表示该浓度的化合物对细菌有抑制生长作用。
实施例1-10中的3,3-二取代吲哚酮类化合物4种细菌的最小抑菌浓度结果如表1所示。
表1
表1结果说明实施例1-10制备的3,3-二取代吲哚酮类化合物对大肠杆菌、绿脓杆菌、枯草芽孢杆菌、金黄色葡萄球菌均具有一定抑制作用。
以上所述仅是本发明的优选实施方式,应当理解本发明并非局限于本文所披露的形式,不应看作是对其他实施例的排除,而可用于各种其他组合、修改和环境,并能够在本文所述构想范围内,通过上述教导或相关领域的技术或知识进行改动。而本领域人员所进行的改动和变化不脱离本发明的精神和范围,则都应在本发明所附权利要求的保护范围内。
Claims (2)
1.以下化合物用于制备杀菌剂或抑菌剂的应用,所述菌为绿脓杆菌,
2.以下化合物用于制备杀菌剂或抑菌剂的应用,所述菌为大肠杆菌,
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