CN118026932A - Cerbera manghas aldehyde derivative, and preparation method and application and pharmaceutical composition thereof - Google Patents
Cerbera manghas aldehyde derivative, and preparation method and application and pharmaceutical composition thereof Download PDFInfo
- Publication number
- CN118026932A CN118026932A CN202410182925.6A CN202410182925A CN118026932A CN 118026932 A CN118026932 A CN 118026932A CN 202410182925 A CN202410182925 A CN 202410182925A CN 118026932 A CN118026932 A CN 118026932A
- Authority
- CN
- China
- Prior art keywords
- compound
- cerbera
- preparation
- organic solvent
- manghas
- 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.)
- Pending
Links
- 241001247436 Cerbera manghas Species 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 title claims abstract 6
- 241000700605 Viruses Species 0.000 claims abstract description 21
- 241000196324 Embryophyta Species 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000011814 protection agent Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 76
- 229940126214 compound 3 Drugs 0.000 claims description 47
- 239000003960 organic solvent Substances 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- 241001247435 Cerbera Species 0.000 claims description 25
- 150000007530 organic bases Chemical class 0.000 claims description 24
- AEDDIBAIWPIIBD-ZJKJAXBQSA-N mangiferin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(OC=2C(=CC(O)=C(O)C=2)C2=O)C2=C1O AEDDIBAIWPIIBD-ZJKJAXBQSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- -1 carbodiimide compound Chemical class 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 229940125782 compound 2 Drugs 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims description 13
- 238000007112 amidation reaction Methods 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- 238000005886 esterification reaction Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000002917 insecticide Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 4
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 4
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 230000000844 anti-bacterial effect Effects 0.000 claims description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000003899 bactericide agent Substances 0.000 claims description 3
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 claims description 3
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims description 3
- 229910000071 diazene Inorganic materials 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 2
- 235000015110 jellies Nutrition 0.000 claims 1
- 239000008274 jelly Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 61
- 230000000694 effects Effects 0.000 abstract description 22
- 241000500437 Plutella xylostella Species 0.000 abstract description 11
- 241001124076 Aphididae Species 0.000 abstract description 10
- 241000723873 Tobacco mosaic virus Species 0.000 abstract description 10
- 239000000575 pesticide Substances 0.000 abstract description 9
- 230000001665 lethal effect Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 96
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000007788 liquid Substances 0.000 description 26
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 25
- 238000002844 melting Methods 0.000 description 25
- 230000008018 melting Effects 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000000926 separation method Methods 0.000 description 23
- 150000001299 aldehydes Chemical class 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 15
- 239000012071 phase Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 238000010828 elution Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 230000002147 killing effect Effects 0.000 description 7
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 7
- 229960000329 ribavirin Drugs 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000002274 desiccant Substances 0.000 description 6
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- QVBVQHTXLPNXEY-ZMFCMNQTSA-N (4r)-6-[2-[4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 QVBVQHTXLPNXEY-ZMFCMNQTSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 4
- 241000238631 Hexapoda Species 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- LPNRUMVKXCLEBE-JXVRESAISA-L (3r)-4-[[(e)-2-[5-ethyl-4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethenyl]-oxidophosphoryl]-3-hydroxybutanoate Chemical compound CCC1=C(C=2C=CC=CC=2)N=C(C(C)C)C(\C=C\P([O-])(=O)C[C@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 LPNRUMVKXCLEBE-JXVRESAISA-L 0.000 description 3
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 3
- YLLRPQWLASQXSI-UHFFFAOYSA-N 3-(4b,8a,9,9a-tetrahydro-4aH-pyrido[2,3-b]indol-4-ylamino)phenol Chemical compound Oc1cccc(NC2=CC=NC3NC4C=CC=CC4C23)c1 YLLRPQWLASQXSI-UHFFFAOYSA-N 0.000 description 3
- LIDUGWDLSDKCLM-CSKARUKUSA-N 4-[[3-[[[(e)-6,6-dimethylhept-2-en-4-ynyl]-ethylamino]methyl]phenoxy]methyl-dimethylsilyl]benzonitrile Chemical compound CC(C)(C)C#C/C=C/CN(CC)CC1=CC=CC(OC[Si](C)(C)C=2C=CC(=CC=2)C#N)=C1 LIDUGWDLSDKCLM-CSKARUKUSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- 238000012271 agricultural production Methods 0.000 description 3
- 239000003905 agrochemical Substances 0.000 description 3
- 229940125872 compound 4d Drugs 0.000 description 3
- 229940126115 compound 4f Drugs 0.000 description 3
- 229940125880 compound 4j Drugs 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- YWKVMGDEOUPQGN-UHFFFAOYSA-N ethyl 2-[4-[2-(3-hydroxy-1-azabicyclo[2.2.2]octan-3-yl)ethynyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OCC)=CC=C1C#CC1(O)C(CC2)CCN2C1 YWKVMGDEOUPQGN-UHFFFAOYSA-N 0.000 description 3
- 230000000749 insecticidal effect Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 3
- 229940080817 rotenone Drugs 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical class CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- 240000006677 Vicia faba Species 0.000 description 2
- 235000010749 Vicia faba Nutrition 0.000 description 2
- 235000002098 Vicia faba var. major Nutrition 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000000287 crude extract Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- PNHQFFOWCUDBPX-UHFFFAOYSA-N methyl 7-formylcyclopenta[c]pyran-4-carboxylate Chemical compound COC(=O)C1=COC=C2C(C=O)=CC=C12 PNHQFFOWCUDBPX-UHFFFAOYSA-N 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- KRIWIRSMQRQYJG-DLBZAZTESA-N (2s,3s)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol Chemical compound C=1C(N[C@@H](CO)[C@H](O)CO)=NC2=C(C(C)C)C=NN2C=1NCC1=CC=CC=C1 KRIWIRSMQRQYJG-DLBZAZTESA-N 0.000 description 1
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 240000007124 Brassica oleracea Species 0.000 description 1
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 description 1
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 1
- 235000001169 Brassica oleracea var oleracea Nutrition 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- 241000724252 Cucumber mosaic virus Species 0.000 description 1
- 241000219112 Cucumis Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- 241000219104 Cucurbitaceae Species 0.000 description 1
- 241000256113 Culicidae Species 0.000 description 1
- 241000371644 Curvularia ravenelii Species 0.000 description 1
- 244000111489 Gardenia augusta Species 0.000 description 1
- 235000018958 Gardenia augusta Nutrition 0.000 description 1
- 241000255967 Helicoverpa zea Species 0.000 description 1
- 244000017020 Ipomoea batatas Species 0.000 description 1
- 235000002678 Ipomoea batatas Nutrition 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 241000723994 Maize dwarf mosaic virus Species 0.000 description 1
- 241001477931 Mythimna unipuncta Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000346285 Ostrinia furnacalis Species 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 235000016761 Piper aduncum Nutrition 0.000 description 1
- 235000017804 Piper guineense Nutrition 0.000 description 1
- 244000203593 Piper nigrum Species 0.000 description 1
- 235000008184 Piper nigrum Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000231139 Pyricularia Species 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 241000344246 Tetranychus cinnabarinus Species 0.000 description 1
- 241000016010 Tomato spotted wilt orthotospovirus Species 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 150000002796 natural product derivatives Chemical class 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000021251 pulses Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002728 pyrethroid Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of pesticides, in particular to cerbera manghas aldehyde derivatives, a preparation method and application thereof, and a pharmaceutical composition. The cerbera manghas excellent lethal activity on aphids and plutella xylostella larvae, also has excellent tobacco mosaic virus resistance activity, and part of compounds reach the activity level of commercial varieties and have good application prospects as plant protection agents, especially in the aspects of resisting plant virus agents and pesticides. The preparation method of cerbera manghas the advantages of high yield and purity of the target compound, simple synthesis method, simple operation, easy preparation, low production cost and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of pesticides, in particular to cerbera manghas aldehyde derivatives, a preparation method and application thereof, and a pharmaceutical composition.
Background
In agricultural production, various crop diseases and insect pests frequently occur, and the characteristics of disasters and great harm are presented, so that huge losses are brought to the agricultural production, and serious threats are formed to grain safety. The use of pesticides for active control can save 30-40% of the total crop yield loss worldwide. Therefore, the pesticide is the most economical and effective means for improving the unit yield of the grains, and is a protective umbrella for agricultural production. The problems of resistance, re-increase rampant (resurgence) and residue (residue) generated in the process of preventing and controlling plant diseases and insect pests are continuously aggravated, and the requirements of the public on pesticides are increasingly improved, so that the green pesticide with high efficiency, safety and environmental friendliness is attracting attention.
Natural active substances have historically been the main source of agricultural control of weeds, pathogens and pests, and modern times are continually inspiring the discovery and development of new pesticides. Natural products generally have complex chemical structures, often have a plurality of chiral centers, and most natural products are unstable in the environment and have toxicity, insecticidal spectrum, light stability or production problems, so that synthesis and structural modification are required by chemical means. The synthesis of natural product derivatives also provides tools for the study of chemical biology, and can determine the relationship between structure and biological activity, and understand the action mode of natural products and biological targets. For example, pyrethroid insecticides and neonicotinoid insecticides are all agricultural chemical varieties that have been successfully developed by natural product derived designs. Therefore, the natural active substances are used as lead compounds, new agricultural chemical varieties safe to the ecological environment are developed through structural diversity derivatization, and the method is an effective way for realizing the creation of green efficient new agricultural chemical.
Cerbera Manghas L (cerbinal) can be isolated from bark of Cerbera Manghas Linnaeus (Cerbera manghas L.) and Gardenia jasminoides Ellis. Cerbera Manghas has bactericidal activity on Helminthosporium, pyricularia, and Leptosporium of Cucurbitaceae. Cerbera Manghas aldehyde has 100% inhibiting activity on herba Avenae Fatuae, semen Tritici Aestivi, herba Alii Fistulosi and herba Trigonellae Purpureae in the concentration range of 0.75-4 μg/mL. Chinese patent CN110156685A discloses a cerbera manghas derivative-aromatic cyclopentenopyridine for inhibiting tobacco mosaic virus, rice virus, pepper virus, tomato virus, sweet potato virus, potato virus and melon virus and maize dwarf mosaic virus, and in addition, shows activity against plutella xylostella and tetranychus cinnabarinus. However, no cerbera's aldehyde derivatives with aphidicidal activity have been reported.
Disclosure of Invention
In view of the above, the invention aims to provide cerbera manghas derivatives, and a preparation method, application and a pharmaceutical composition thereof. The cerbera manghas excellent lethal activity on aphids and plutella xylostella larvae and also has excellent tobacco mosaic virus resistance activity.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a cerbera mangiferin derivative, which has a structure shown in a formula I:
R in the formula I comprises-COOH, -COOR 1、-COXR2 or CONR 3R3';
R 1 in the-COOR 1 comprises any one of the following structures:
X in the-COXR 2 comprises oxygen or sulfur, and R 2 comprises any one of the following structures:
R 3 in CONR 3R3 'comprises hydrogen or methyl, and R 3' comprises methyl, ethyl or any one of the following structures:
the invention provides a preparation method of cerbera manghas aldehyde derivatives, which comprises the following steps when R is-COOH:
carrying out hydrolysis reaction on the compound 2 to obtain cerbera manghas aldehyde derivative with R as-COOH, and marking the cerbera manghas aldehyde derivative as a compound 3;
when R is-COOR 1, the preparation method comprises the following steps:
Mixing the compound 3, a first organic base, R 1 Br and a second organic solvent, and carrying out substitution reaction to obtain cerbera mangiferin derivatives; r 1 in R 1 Br is the same as R 1 in formula I;
when R is-COXR 2, the preparation method comprises the following steps:
Mixing the compound 3, R 2 XH, a first catalyst and a third organic solvent, and carrying out esterification reaction to obtain cerbera mangiferin derivatives; r 2 and X in R 2 XH are the same as R 2 and X in formula I;
when R is CONR 3R3', the preparation method comprises the following steps:
Mixing the compound 3, R 3R3' NH, a second catalyst and a fourth organic solvent, and carrying out amidation reaction to obtain cerbera mangiferin derivatives; r 3 and R 3 ' in R 3R3 ' NH are the same as R 3 and R 3 ' in formula I.
Preferably, the hydrolysis reaction is carried out in the presence of an inorganic alkaline agent and a solvent;
the inorganic alkaline reagent comprises one or more of alkali metal hydroxide and alkali metal carbonate;
The molar ratio of the compound 2 to the inorganic alkaline reagent is 1:1 to 5;
The solvent comprises a first organic solvent and water, wherein the first organic solvent comprises one or more of tetrahydrofuran, 1, 4-dioxane, methanol, ethanol and acetonitrile, and the volume ratio of the first organic solvent to the water is 3-1: 1.
Preferably, the temperature of the hydrolysis reaction is 0-60 ℃ and the time is 1-10 h.
Preferably, the first organic base comprises one or more of 1, 8-diazabicyclo undec-7-ene, triethylene diamine and triethylamine;
The molar ratio of the compound 3 to the first organic base is 1:2 to 6;
The molar ratio of the compound 3 to R 1 Br is 1:1.5 to 4;
the second organic solvent comprises one or more of N, N-dimethylformamide, acetone, toluene and methylene dichloride;
The temperature of the substitution reaction is 0-60 ℃ and the time is 2-15 h.
Preferably, the molar ratio of compound 3 to R 2 XH is 1:1.1 to 4;
The first catalyst comprises a carbodiimide compound and a second organic base; the carbodiimide compound comprises one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; the second organic base comprises one or more of N, N-lutidine, 1-hydroxybenzotriazole, 4-pyrrolidinylpyridine and N-hydroxyphthalimide;
the third organic solvent comprises N, N-dimethylformamide and/or dichloromethane;
the temperature of the esterification reaction is 0-60 ℃ and the time is 3-20 h.
Preferably, the molar ratio of compound 3 to R 3R3' NH is 1:1.1 to 4;
The second catalyst comprises a coupling reagent and a third organic base; the coupling reagent comprises one or more of benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride; the third organic base comprises one or more of triethylamine, pyridine and diisopropylamine;
the fourth organic solvent comprises one or more of dichloromethane, N-dimethylformamide, chloroform and toluene;
the amidation reaction temperature is 0-40 deg.c and the amidation reaction time is 2-20 hr.
The invention provides application of the cerbera mangiferin derivative in the technical scheme or the cerbera mangiferin derivative prepared by the preparation method in the technical scheme in preparation of plant protection agents.
Preferably, the plant protection agent comprises one or more of an anti-plant virus agent, an insecticide and a bactericide.
The invention provides a pharmaceutical composition, which comprises an active component and pharmaceutically acceptable auxiliary materials, wherein the active component comprises cerbera manghas aldehyde derivatives prepared by the technical scheme or cerbera manghas aldehyde derivatives prepared by the preparation method.
The cerbera manghas excellent lethal activity on aphids and plutella xylostella larvae, also has excellent tobacco mosaic virus resistance activity, and part of compounds reach the activity level of commercial varieties and have good application prospects as plant protection agents, especially in the aspect of resisting plant virus agents and pesticides. As shown by the test results of the examples, most of the compounds showed good anti-TMV activity, and compound 3, compound 2, compound 4a, compound 4b, compound 4f, compound 4i, compound 4j, compound 4l, compound 4m, compound 4o, compound 4p, compound 4v and compound 4x showed higher activity levels than ribavirin at a concentration of 500 μg/mL. In addition, all compounds showed plutella xylostella larva killing activity, and most of the compounds showed activity against aphids. In terms of plutella xylostella larva killing, most of the compounds show high activity at the concentration of 600 mug/mL, and seven compounds (compound 3, compound 4d, compound 4g, compound 4i, compound 4n, compound 4q and compound 4 s) show mortality rate of more than or equal to 30% at the concentration of 200 mug/mL. In terms of aphid killing, most compounds exhibit higher levels of activity than the botanical insecticide rotenone.
The preparation method of cerbera manghas the advantages of high yield and purity of the target compound, simple synthesis method, simple operation, easy preparation, low production cost and suitability for industrial production.
Detailed Description
The invention provides a cerbera mangiferin derivative, which has a structure shown in a formula I:
R in the formula I comprises-COOH, -COOR 1、-COXR2 or CONR 3R3';
R 1 in the-COOR 1 comprises any one of the following structures:
X in the-COXR 2 comprises oxygen or sulfur, and R 2 comprises any one of the following structures:
R 3 in CONR 3R3 'comprises hydrogen or methyl, and R 3' comprises methyl, ethyl or any one of the following structures:
In the invention, the cerbera manghas derivative comprises one or more of a compound 3 (R is-COOH), a compound 4 a-4 j (R is-COOR 1), a compound 4 k-4 n (R is-COXR 2) and a compound 4 o-4 x (R is CONR 3R3'):
the structure of R corresponding to compound 3 and compounds 4a to 4x is as follows:
The invention provides a preparation method of cerbera manghas aldehyde derivatives, which is described in the following cases.
When R is-COOH, the preparation method of the cerbera manghas aldehyde derivative (compound 3) comprises the following steps: carrying out hydrolysis reaction on the compound 2 to obtain cerbera manghas aldehyde derivative (compound 3) with R being-COOH;
The materials and equipment used in the present invention are preferably commercially available in the art unless otherwise specified.
In the present invention, the hydrolysis reaction is preferably carried out in the presence of an inorganic alkaline agent and a solvent. In the present invention, the inorganic alkaline agent preferably includes an alkali metal hydroxide and/or an alkali metal carbonate; the alkali metal hydroxide preferably comprises one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide; the alkali metal carbonate preferably comprises sodium carbonate and/or potassium carbonate. In the present invention, the molar ratio of the compound 2 to the inorganic alkaline agent is preferably 1:1 to 5, more preferably 1:1.5 to 3, further 1:1.5 to 2.
In the present invention, the solvent preferably includes a first organic solvent and water, the first organic solvent preferably includes one or more of tetrahydrofuran, 1, 4-dioxane, methanol, ethanol and acetonitrile, and the volume ratio of the first organic solvent to water is preferably 3 to 1:1, more preferably 3 to 2:1.
In the present invention, the mixing preferably includes: dissolving an inorganic alkaline reagent in water to obtain alkali liquor; dissolving the compound 2 in a first organic solvent to obtain a compound 2 solution; the solution of compound 2 is mixed with an alkaline solution. In the present invention, the ratio of the amount of the substance of the compound 2 to the volume of the first organic solvent is preferably 1mol:10 to 100L, more preferably 1mol: 15-30L.
In the present invention, the temperature of the hydrolysis reaction is preferably 0 to 60 ℃, more preferably 20 to 40 ℃, still more preferably room temperature; the hydrolysis reaction time is preferably 1 to 10 hours, more preferably 2 to 5 hours, and the extent of the hydrolysis reaction is preferably tracked by TLC in the embodiment of the present invention.
After the hydrolysis reaction is completed, the present invention preferably further comprises: sequentially adjusting the pH value of the obtained hydrolysis reaction liquid to 2-3, concentrating and carrying out solid-liquid separation, washing the obtained solid product with water and drying to obtain the cerbera mangiferin derivative (compound 3) with R being-COOH. The acid used for the adjustment of the pH value in the present invention is not particularly limited, and may be any acid known to those skilled in the art, and specifically, for example, a hydrochloric acid solution having a concentration of preferably 0.1 to 5mol/L, more preferably 1 to 2mol/L. The concentration of the present invention is not particularly limited, and the first organic solvent may be removed by any concentration means known to those skilled in the art, and specifically, the concentration means may be rotated under reduced pressure. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method well known to those skilled in the art, such as suction filtration, filtration or centrifugal separation. The drying conditions are not particularly limited, and the drying may be carried out until the weight is constant.
When R is preferably-COOR 1, the cerbera strap aldehyde derivative preparation method comprises the following steps: mixing the compound 3, a first organic base, R 1 Br and a second organic solvent, and carrying out substitution reaction to obtain cerbera mangiferin derivatives; r 1 in R 1 Br is the same as R 1 in formula I.
In the present invention, the first organic base preferably includes one or more of 1, 8-diazabicyclo undec-7-ene (DBU), triethylenediamine and triethylamine. In the present invention, the molar ratio of the compound 3 to the first organic base is preferably 1:2 to 6, more preferably 1:3 to 5, more preferably 1:4.
In the present invention, the molar ratio of the compound 3 to R 1 Br is preferably 1:1.5 to 4, more preferably 1:2 to 4, more preferably 1:3 to 4.
In the present invention, the second organic solvent preferably includes one or more of N, N-dimethylformamide, acetone, toluene, and methylene chloride. In the present invention, the ratio of the amount of the substance of the compound 3 to the volume of the second organic solvent is preferably 1mol:5 to 80L, more preferably 1mol: 44-45L.
In the present invention, the mixing preferably includes: the compound 3 is dissolved in a second organic solvent, the first organic base is added under ice water bath condition to mix for 3-60 min (more preferably 30 min), and then R 1 Br is added to mix.
In the present invention, the temperature of the substitution reaction is preferably 0 to 60 ℃, more preferably 20 to 40 ℃, still more preferably room temperature; the time of the substitution reaction is preferably 2 to 15 hours, more preferably 3 to 7 hours, and the extent of the substitution reaction is preferably tracked by TLC in the embodiment of the present invention.
After completion of the substitution reaction, the present invention preferably further comprises: and (3) quenching the obtained substitution reaction liquid with water, extracting with ethyl acetate, sequentially washing the obtained organic phase with water, washing with saturated saline, drying with a desiccant, and separating solid from liquid, concentrating the obtained liquid component, and then rapidly separating by a column to obtain the cerbera mangiferin derivative. In the present invention, the number of times of extraction with ethyl acetate is preferably 1 to 4 times, more preferably 2 to 3 times. In the present invention, the drying agent preferably includes anhydrous sodium sulfate and/or anhydrous magnesium sulfate. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method well known to those skilled in the art, such as suction filtration, filtration or centrifugal separation. The concentration is not particularly limited, and the solvent may be removed by concentration means well known to those skilled in the art, and, for example, by rotation under reduced pressure. In the invention, the eluent used for the rapid column separation preferably comprises one or more of petroleum ether, ethyl acetate, methylene dichloride and methanol, more preferably petroleum ether-ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate is 9:1-1:1, and the elution mode is preferably gradient elution.
When R is-COXR 2, the preparation method of the cerbera manghas derivative comprises the following steps: mixing the compound 3, R 2 XH, a first catalyst and a third organic solvent, and carrying out esterification reaction to obtain cerbera mangiferin derivatives; r 2 and X in R 2 XH are the same as R 2 and X in formula I.
In the present invention, the molar ratio of compound 3 to R 2 XH is preferably 1:1.1 to 4, more preferably 1:1.5 to 3, more preferably 1:1.8 to 2.
In the present invention, the first catalyst preferably includes a carbodiimide compound and a second organic base; the carbodiimide compound preferably comprises one or more of Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI); the second organic base preferably includes one or more of N, N-lutidine (DMAP), 1-hydroxybenzotriazole (HOBt), 4-pyrrolidinylpyridine (4-PPY), and N-hydroxyphthalimide (NHPI). In the present invention, the molar ratio of the compound 3 to the carbodiimide compound is preferably 1:1.1 to 5, more preferably 1:1.5 to 2. In the present invention, the molar ratio of the compound 3 to the second organic base is preferably 1:0.05 to 0.5, more preferably 1:0.1 to 0.2.
In the present invention, the third organic solvent preferably includes N, N-dimethylformamide and/or dichloromethane. In the present invention, the ratio of the amount of the substance of the compound 3 to the volume of the third organic solvent is preferably 1mol:10 to 60L, more preferably 1mol: 25-30L.
In the present invention, the mixing preferably includes dissolving the compound 3 in a third organic solvent, adding the first catalyst and mixing with R 2 XH.
In the present invention, the temperature of the esterification reaction is preferably 0 to 60 ℃, more preferably 20 to 40 ℃, still more preferably room temperature; the time for the esterification reaction is preferably 3 to 20 hours, more preferably 5 to 10 hours, and still more preferably 6 to 7 hours.
After completion of the esterification reaction, the present invention preferably further comprises: quenching the obtained esterification reaction liquid with water, separating to obtain an organic phase and a water phase, and washing the water phase with dichloromethane to obtain a dichloromethane phase; and combining the organic phase and the dichloromethane phase, sequentially performing water washing, saturated saline water washing, drying by a drying agent and solid-liquid separation, concentrating the obtained liquid component, and then performing rapid column separation to obtain the cerbera mangiferin derivative. In the present invention, the number of times of the dichloromethane extraction is preferably 1 to 5 times, more preferably 2 to 3 times. In the present invention, the drying agent preferably includes anhydrous sodium sulfate and/or anhydrous magnesium sulfate. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method well known to those skilled in the art, such as suction filtration, filtration or centrifugal separation. The concentration is not particularly limited, and the solvent may be removed by concentration means well known to those skilled in the art, and, for example, by rotation under reduced pressure. In the invention, the eluent used for the rapid column separation preferably comprises one or more of petroleum ether, ethyl acetate, methylene dichloride and methanol, more preferably petroleum ether-ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate is 9:1-1:2, and the elution mode is preferably gradient elution.
When R is CONR 3R3', the preparation method of the cerbera manghas derivative comprises the following steps: mixing the compound 3, R 3R3' NH, a second catalyst and a fourth organic solvent, and carrying out amidation reaction to obtain cerbera mangiferin derivatives; r 3 and R 3 ' in R 3R3 ' NH are the same as R 3 and R 3 ' in formula I.
In the present invention, the molar ratio of compound 3 to R 3R3' NH is preferably 1:1.1 to 4, more preferably 1:1.5 to 3, more preferably 1:1.8 to 2.
In the present invention, the second catalyst preferably includes a coupling reagent and a third organic base; the coupling reagent preferably comprises one or more of benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate (BOPreagent), benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N' -tetramethyluronium tetrafluoroborate (TBTU), 1-hydroxybenzotriazole (HOBt) and 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (edc·hcl); the third organic base preferably comprises one or more of triethylamine, pyridine and diisopropylamine. In the present invention, the molar ratio of the compound 3 to the coupling agent is preferably 1:1 to 4, more preferably 1:1.2 to 1.5. In the present invention, the molar ratio of the compound 3 to the third organic base is preferably 1:1 to 4, more preferably 1:2 to 3.
In the present invention, the fourth organic solvent preferably includes one or more of methylene chloride, N-dimethylformamide, chloroform and toluene. In the present invention, the ratio of the amount of the substance of the compound 3 to the volume of the fourth organic solvent is preferably 1mol:10 to 60L, more preferably 1mol: 25-30L.
In the present invention, the temperature of the amidation reaction is preferably 0 to 40 ℃, more preferably 10 to 30 ℃, still more preferably room temperature; the amidation reaction time is preferably 2 to 20 hours, more preferably 3 to 10 hours, and still more preferably 3 to 5 hours.
After completion of the amidation reaction, the present invention preferably further comprises: quenching the obtained amidation reaction liquid with water, separating the liquid to obtain an organic phase and a water phase respectively, and washing the water phase with dichloromethane to obtain a dichloromethane phase; and combining the organic phase and the dichloromethane phase, sequentially performing water washing, saturated saline water washing, drying by a drying agent and solid-liquid separation, concentrating the obtained liquid component, and then performing rapid column separation to obtain the cerbera mangiferin derivative. In the present invention, the number of times of the dichloromethane extraction is preferably 1 to 4 times, more preferably 2 to 3 times. In the present invention, the drying agent preferably includes anhydrous sodium sulfate and/or anhydrous magnesium sulfate. The solid-liquid separation is not particularly limited, and may be performed by a solid-liquid separation method well known to those skilled in the art, such as suction filtration, filtration or centrifugal separation. The concentration is not particularly limited, and the solvent may be removed by concentration means well known to those skilled in the art, and, for example, by rotation under reduced pressure. In the invention, the eluent used for the rapid column separation preferably comprises one or more of petroleum ether, ethyl acetate, methylene dichloride and methanol, more preferably petroleum ether-ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate is 4:1-1:2, and the elution mode is preferably gradient elution.
The invention provides application of the cerbera mangiferin derivative in the technical scheme or the cerbera mangiferin derivative prepared by the preparation method in the technical scheme in preparation of plant protection agents. In the present invention, the plant protecting agent preferably includes one or more of an anti-plant virus agent, an insecticide and a bactericide. In the present invention, the plant virus preferably includes one or more of tobacco mosaic virus, tomato spotted wilt virus and cucumber mosaic virus. In the present invention, the insecticide preferably includes one or more of aphids, plutella xylostella larvae, armyworms, cotton bollworms, corn borers and mosquito larvae.
The invention also provides a pharmaceutical composition, which comprises an active component and pharmaceutically acceptable auxiliary materials, wherein the active component comprises the cerbera manghas aldehyde derivative according to the technical scheme or the cerbera manghas aldehyde derivative prepared by the preparation method according to the technical scheme. The pharmaceutically acceptable auxiliary materials are not particularly limited, and can be used as is well known to those skilled in the art. The dosage form of the pharmaceutical composition is not particularly limited in the present invention, and the dosage form of the pharmaceutical composition known to those skilled in the art may be employed.
For further explanation of the present invention, cerbera manghas derivatives, and methods for preparing and using the same, are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Synthesis of cerbera manghas aldehyde derivative (compound 3).
Compound 2 (5.82 mmol) was dissolved in 90mL tetrahydrofuran and 30mL aqueous lithium hydroxide (11.65 mmol) was added with stirring at room temperature and TLC followed until the reaction was complete (2 h). The pH of the reaction system was adjusted to 2 to 3 with 1M hydrochloric acid, tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the obtained solid product was suction-filtered, washed with water and dried to constant weight to give Compound 3 (yellow solid, 1.62g, yield 94%). Melting point 187～189℃;1H NMR(400MHz,DMSO-d6)δ13.42(s,1H),9.88(s,1H),9.14(s,1H),8.37(d,J＝1.0Hz,1H),7.95(d,J＝3.7Hz,1H),7.75(d,J＝8.9Hz,2H),7.19(d,J＝8.9Hz,2H),7.09(d,J＝3.6Hz,1H),3.87(s,3H);13C NMR(100MHz,DMSO-d6)δ183.00,166.33,159.70,136.99,133.61,131.05,125.80,120.13,116.14,115.07,108.37,55.65.HRMS(ESI)calcd for C17H14NO4[M+H]+296.0917,found 296.0984.
Example 2
Synthesis of cerbera Manghas aldehyde derivatives (Compounds 4a to 4 j).
TABLE 1 Structure of R 1 in Compounds 4 a-4 j and R 1 Br
Compound 3 (0.68 mmol) was dissolved in 30 ln, n-dimethylformamide, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU, 2.71 mmol) was added under ice-water bath, after stirring for 30min, bromohydrocarbon R 1 Br (2.71 mmol) was added, stirring was continued until compound 3 disappeared (3-7 h), the reaction was quenched with water, extraction was performed twice with ethyl acetate, the organic phase was combined, water-washed, saturated brine-washed, dried over anhydrous magnesium sulfate, suction filtration was performed, the resulting liquid fractions were desolventized, and flash column separation (gradient elution, petroleum ether and ethyl acetate volume ratios were 9:1, 4:1, 2:1 and 1:1, respectively) to give compounds 4a to 4j.
Compound 4a: the yield was 80%; melting point 164～165℃;1H NMR(400MHz,CDCl3)δ9.93(s,1H),9.25(s,1H),8.35(d,J＝1.3Hz,1H),7.96(d,J＝3.7Hz,1H),7.46(d,J＝8.9Hz,2H),7.17(d,J＝3.6Hz,1H),7.07(d,J＝8.9Hz,2H),4.50(q,J＝7.1Hz,2H),3.90(s,3H),1.48(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ184.71,165.85,160.48,144.55,137.31,134.09,134.04,130.89,126.89,125.67,121.29,116.34,115.39,109.53,61.65,55.91,14.53.HRMS(ESI)calcd for C19H18NO4[M+H]+324.1230,found 324.1244.
Compound 4b: the yield was 50%; melting point 163～164℃;1H NMR(400MHz,CDCl3)δ9.94(s,1H),9.27(s,1H),8.40(s,1H),7.99(d,J＝3.6Hz,1H),7.47(d,J＝8.9Hz,2H),7.20(d,J＝3.6Hz,1H),7.08(d,J＝8.8Hz,2H),5.60(s,2H),3.91(s,3H),3.61(s,3H).13C NMR(100MHz,CDCl3)δ184.71,165.23,160.34,144.74,137.05,134.12,133.71,131.16,126.77,125.53,121.22,115.48,115.25,109.43,91.39,58.09,55.80.HRMS(ESI)calcd for C19H18NO5[M+H]+340.1180,found 340.1275.
Compound 4c: the yield thereof was found to be 75%; melting point 136～137℃;1H NMR(400MHz,CDCl3)δ9.93(s,1H),9.25(s,1H),8.40(d,J＝1.5Hz,1H),7.98(d,J＝3.7Hz,1H),7.49-7.44(m,2H),7.21(d,J＝3.5Hz,1H),7.09-7.04(m,2H),4.96(s,2H),3.90(s,3H),3.82(s,3H).13C NMR(100MHz,CDCl3)δ184.83,168.13,165.03,160.46,145.02,137.16,134.23,133.71,131.38,126.89,125.65,121.44,115.36,114.87,109.65,61.35,55.90,52.56.HRMS(ESI)calcd for C20H18NO6[M+H]+368.1129,found368.1216.
Compound 4d: the yield thereof was found to be 72%; melting point 132～133℃;1H NMR(400MHz,CDCl3)δ9.91(s,1H),9.24(s,1H),8.34(s,1H),7.95(d,J＝3.6Hz,1H),7.46(d,J＝8.8Hz,2H),7.16(d,J＝3.6Hz,1H),7.07(d,J＝8.8Hz,2H),5.37(dt,J＝12.4,6.2Hz,1H),3.89(s,3H),1.45(d,J＝6.2Hz,6H).13C NMR(100MHz,CDCl3)δ184.59,165.28,160.29,144.39,137.15,134.07,133.94,130.77,126.75,125.54,121.01,116.61,115.21,109.45,69.35,55.78,22.07.HRMS(ESI)calcd for C20H20NO4[M+H]+338.1387,found 338.1311.
Compound 4e: the yield thereof was found to be 82%; melting point 98～99℃;1H NMR(400MHz,CDCl3)δ9.93(s,1H),9.26(s,1H),8.36(s,1H),7.97(d,J＝3.4Hz,1H),7.46(d,J＝8.4Hz,2H),7.12(d,J＝3.6Hz,1H),7.08(d,J＝8.4Hz,2H),4.72(t,J＝5.6Hz,1H),4.64-4.57(m,3H),3.91(s,3H),2.34-2.18(m,2H).13C NMR(100MHz,CDCl3)δ184.68,165.68,160.33,144.57,137.06,134.06,133.71,130.96,126.74,125.51,121.16,115.78,115.25,109.26,81.53,79.88,61.65,61.60,55.80,29.99,29.79.19F NMR(376MHz,CDCl3)δ-221.82.HRMS(ESI)calcd for C20H19FNO4[M+H]+356.1293,found 356.1206.
Compound 4f: the yield was 50%; melting point 127～128℃;1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.24(s,1H),8.34(d,J＝1.5Hz,1H),7.94(d,J＝3.7Hz,1H),7.48-7.43(m,2H),7.12(d,J＝3.6Hz,1H),7.10-7.05(m,2H),4.61(t,J＝6.2Hz,2H),3.90(s,3H),3.83(t,J＝6.0Hz,2H),2.13-2.04(m,2H).13C NMR(100MHz,CDCl3)δ184.65,166.11,160.32,144.56,137.06,134.01,133.82,130.96,126.74,125.49,121.09,115.85,115.25,109.35,62.43,59.16,55.79,31.87.HRMS(ESI)calcd for C20H20NO5[M+H]+354.1336,found 354.1346.
Compound 4g: the yield thereof was found to be 74%; melting point 150～151℃;1H NMR(400MHz,CDCl3)δ9.94(s,1H),9.25(s,1H),8.36(s,1H),8.00(d,J＝3.6Hz,1H),7.46(d,J＝8.8Hz,2H),7.14(d,J＝3.5Hz,1H),7.09(d,J＝8.8Hz,2H),5.07(s,2H),3.91(s,3H).13C NMR(100MHz,CDCl3)δ184.88,163.99,160.48,145.20,136.85,134.34,132.83,131.53,126.78,125.51,121.62,115.36,114.20,113.33,109.34,55.82,49.01.HRMS(ESI)calcd for C19H15N2O4[M+H]+335.1026,found 335.0953.
Compound 4h: the yield thereof was found to be 47%; melting point 203～205℃;1H NMR(400MHz,CDCl3)δ9.93(s,1H),9.25(s,1H),8.38(d,J＝1.5Hz,1H),7.98(d,J＝3.7Hz,1H),7.49-7.44(m,2H),7.21(d,J＝3.7Hz,1H),7.11-7.05(m,2H),5.03(d,J＝2.4Hz,2H),3.91(s,3H),2.56(t,J＝2.4Hz,1H).13CNMR(100MHz,CDCl3)δ184.85,164.93,160.47,144.97,137.15,134.23,133.68,131.25,126.87,125.66,121.40,115.37,115.10,109.61,75.65,55.92,52.91.HRMS(ESI)calcd for C20H16NO4[M+H]+334.1074,found 334.1068.
Compound 4i: the yield thereof was found to be 67%; melting point 147～149℃;1H NMR(400MHz,CDCl3)δ9.92(s,1H),9.25(s,1H),8.37(s,1H),7.97(d,J＝3.4Hz,1H),7.46(d,J＝8.7Hz,2H),7.18(d,J＝3.4Hz,1H),7.08(d,J＝8.7Hz,2H),4.79(dd,J＝12.3,2.4Hz,1H),4.26(dd,J＝12.2,6.4Hz,1H),3.91(s,3H),3.41(d,J＝2.7Hz,1H),2.94(t,J＝4.3Hz,1H),2.79-2.75(m,1H).13C NMR(100MHz,CDCl3)δ184.83,165.46,160.50,144.91,137.18,134.23,133.83,131.19,126.88,125.68,121.37,115.45,115.39,109.60,66.05,55.92,49.52,44.90.HRMS(ESI)calcd for C20H18NO5[M+H]+352.1180,found 352.1169.
Compound 4j: the yield thereof was found to be 87%; melting point 146～148℃;1H NMR(400MHz,CDCl3)δ9.94(s,1H),9.27(s,1H),8.38(s,1H),7.99(d,J＝3.6Hz,1H),7.47(d,J＝8.8Hz,2H),7.18-7.07(m,4H),6.16(d,J＝15.8Hz,1H),5.12(d,J＝3.7Hz,2H),3.91(s,3H),3.77(s,3H).13C NMR(100MHz,CDCl3)δ184.76,166.12,165.05,160.37,144.79,141.06,137.02,134.16,133.49,131.08,126.75,125.55,122.59,121.31,115.28,115.13,109.37,63.47,55.81,51.85.HRMS(ESI)calcd for C22H20NO6[M+H]+394.1285,found 394.1194.
Example 3
Cerbera manghas aldehyde derivative (compounds 4 k-4 n) synthesis.
TABLE 2 Structure of X and R 2 in Compounds 4k to 4n and R 2 XH
Compound 3 (1.02 mmol) was dissolved in 30mL of dichloromethane, EDCI (2.03 mmol), DMAP (0.10 mmol) and R 2 XH (substituted phenol or substituted thiophenol, 2.03 mmol) were then added, stirred at room temperature for 7h, then 20mL of water was added for quenching reaction, the organic phase and the aqueous phase were obtained separately, the aqueous phase was washed twice with dichloromethane to obtain the dichloromethane phase, the organic phase and the chloromethane phase were combined, saturated brine wash, dried over anhydrous magnesium sulfate, suction filtered, the obtained liquid fractions were desolventized, and the rapid column separation (gradient elution, petroleum ether and ethyl acetate in the volume ratio of 9:1, 3:1, 1:1 and 1:2) was performed, respectively, to obtain compounds 4k to 4n.
Compound 4k: the yield thereof was found to be 51%; melting point 87-88℃;1H NMR(400MHz,CDCl3)δ9.96(s,1H),9.31(s,1H),8.52(s,1H),8.01(d,J＝3.6Hz,1H),7.53-7.45(m,4H),7.35-7.26(m,4H),7.09(d,J＝8.8Hz,2H),3.91(s,3H).13C NMR(100MHz,CDCl3)δ184.84,164.21,160.39,150.52,145.00,137.05,134.23,133.68,131.51,129.68,126.84,126.29,125.58,121.72,121.41,115.29,115.12,109.62,55.82.HRMS(ESI)calcd for C23H18NO4[M+H]+372.1230,found 372.1142.
Compound 4l: the yield thereof was found to be 63%; melting point 193-194℃;1H NMR(400MHz,CDCl3)δ9.96(s,1H),9.30(s,1H),8.51(s,1H),8.01(d,J＝3.6Hz,1H),7.50(d,J＝8.8Hz,2H),7.26-7.22(m,3H),7.15(t,J＝8.5Hz,2H),7.10(d,J＝8.8Hz,2H),3.91(s,3H).13C NMR(100MHz,CDCl3)δ184.83,164.21,161.71,160.40,159.28,146.30,146.27,145.03,136.99,134.24,133.52,131.53,126.83,125.54,123.20,123.11,121.44,116.46,116.22,115.30,114.79,109.55,55.81.HRMS(ESI)calcd for C23H17FNO4[M+H]+367.1288,found 367.1203.
Compound 4m: the yield thereof was found to be 58%; melting point 201-202℃;1HNMR(400MHz,CDCl3)δ9.97(s,1H),9.31(s,1H),8.52(s,1H),8.02(d,J＝3.4Hz,1H),7.75(d,J＝8.5Hz,2H),7.50(d,J＝8.8Hz,2H),7.42(d,J＝8.3Hz,2H),7.23(d,J＝3.4Hz,1H),7.10(d,J＝8.8Hz,2H),3.92(s,3H).13CNMR(100MHz,CDCl3)δ184.89,163.68,160.46,152.99,145.19,136.95,134.33,133.40,131.71,128.75,128.43,127.04(q,J＝3.7Hz),126.88,125.55,125.18,122.48,122.31,121.53,115.34,114.44,109.57,55.82.HRMS(ESI)calcd for C24H17F3NO4[M+H]+440.1104,found440.1006.
Compound 4n: the yield thereof was found to be 34%; melting point 203-204℃;1H NMR(400MHz,CDCl3)δ9.95(s,1H),9.27(s,1H),8.37(s,1H),8.00(d,J＝3.7Hz,1H),7.54(dd,J＝8.2,5.4Hz,2H),7.50(d,J＝8.5Hz,2H),7.24-7.17(m,3H),7.11(d,J＝8.5Hz,2H),3.92(s,3H).13C NMR(100MHz,CDCl3)δ187.97,184.95,165.09,162.60,160.44,145.02,137.27,137.18,136.99,134.19,131.61,129.00,127.01,125.55,122.47,121.91,121.87,121.58,116.90,116.68,115.35,109.50,55.83.HRMS(ESI)calcd for C23H17FNO3S[M+H]+406.0908,found 406.0809.
Example 4
Cerbera manghas aldehyde derivative (compound 4 o-4 x) synthesis.
TABLE 3 structures of R 3 and R 3 'in compounds 4 o-4 x and R 3R3' NH
Compound 3 (1.02 mmol) was dissolved in 30mL of dichloromethane, TBTU (1.22 mmol), triethylamine (2.03 mmol) and substituted amine R 3R3' NH (1.02 mmol) were then added, stirred at room temperature for 4h, then 20mL of water was added for quenching reaction, the organic phase and the aqueous phase were obtained separately, the aqueous phase was washed twice with dichloromethane to obtain the dichloromethane phase, the organic phase and the dichloromethane phase were combined, saturated brine wash, dried over anhydrous magnesium sulfate, suction filtered, the resulting liquid fractions were desolventized, and flash column separation (gradient elution, petroleum ether and ethyl acetate in the volume ratios 4:1, 2:1, 1:2) were performed, respectively, to obtain compounds 4o to 4x.
Compound 4o: the yield was 86%; melting point 203～205℃;1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.24(s,1H),8.23(s,1H),7.89(d,J＝3.7Hz,1H),7.44(d,J＝8.8Hz,2H),7.05(d,J＝8.9Hz,2H),6.72(d,J＝3.7Hz,2H),3.89(s,3H),3.13(d,J＝4.8Hz,3H).13C NMR(100MHz,CDCl3)δ184.66,166.25,160.29,142.97,137.07,133.87,132.62,128.79,126.17,125.43,121.24,121.08,115.19,105.66,55.76,26.93.HRMS(ESI)calcd for C18H17N2O3[M+H]+309.1234,found 309.1161.
Compound 4p: the yield thereof was found to be 78%; melting point 165～167℃;H NMR(400MHz,CDCl3)δ9.94(s,1H),9.28(s,1H),8.24(d,J＝1.5Hz,1H),7.92(d,J＝3.8Hz,1H),7.46(d,J＝8.9Hz,2H),7.06(d,J＝8.9Hz,2H),6.72(d,J＝3.7Hz,1H),6.63(s,1H),3.90(s,3H),3.69-3.55(m,2H),1.35(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ184.69,165.38,160.29,142.85,137.11,133.88,132.57,128.80,126.14,125.46,121.30,121.23,115.18,105.48,55.76,35.10,14.95.HRMS(ESI)calcd for C19H19N2O3[M+H]+323.1390,found 323.1471.
Compound 4q: the yield was 95%; melting point 66～67℃;1H NMR(400MHz,CDCl3)δ9.89(s,1H),9.22(s,1H),7.88(d,J＝3.8Hz,1H),7.74(s,1H),7.46(d,J＝8.9Hz,2H),7.05(d,J＝8.9Hz,2H),6.51(d,J＝3.7Hz,1H),3.89(s,3H),3.21(s,3H),3.03(s,3H).13C NMR(100MHz,CDCl3)δ184.50,167.70,160.24,142.62,137.21,133.61,133.25,125.91,125.50,125.02,123.58,120.92,115.17,106.83,55.76,39.17,35.43.HRMS(ESI)calcd for C19H19N2O3[M+H]+323.1390,found 323.1318.
Compound 4r: the yield was 50%; melting point 250～252℃;1H NMR(400MHz,CDCl3)δ9.94(s,1H),9.29(s,1H),8.26(d,J＝1.5Hz,1H),7.95(d,J＝3.8Hz,1H),7.46(d,J＝8.9Hz,2H),7.12-7.04(m,3H),6.86(d,J＝3.7Hz,1H),4.02(q,J＝5.8Hz,2H),3.90(s,3H),3.69(t,J＝5.6Hz,2H).13C NMR(100MHz,CDCl3)δ184.73,165.61,160.36,143.27,137.06,134.05,132.33,129.07,126.28,125.48,121.46,120.43,115.22,105.74,55.78,41.69,32.45.HRMS(ESI)calcd for C19H18BrN2O3[M+H]+401.0495,found 401.0401.
Compound 4s: the yield thereof was found to be 56%; melting point 161～162℃;1H NMR(400MHz,CDCl3)δ9.94(s,1H),9.29(s,1H),8.26(s,1H),7.95(d,J＝3.6Hz,1H),7.46(d,J＝8.8Hz,2H),7.22(s,1H),7.07(d,J＝8.8Hz,2H),6.90(d,J＝3.5Hz,1H),4.38(d,J＝4.9Hz,2H),3.90(s,3H),3.85(s,3H).13CNMR(100MHz,CDCl3)δ184.90,170.39,165.69,160.45,143.53,137.19,134.13,132.52,129.16,126.43,125.60,121.55,120.21,115.33,106.03,55.90,52.76,41.99.HRMS(ESI)calcd for C20H19N2O5[M+H]+367.1288,found 367.1203.
Compound 4t: the yield thereof was found to be 73%; melting point 197～199℃;1H NMR(400MHz,CDCl3)δ9.92(s,1H),9.27(s,1H),8.23(d,J＝1.4Hz,1H),7.91(d,J＝3.7Hz,1H),7.46(d,J＝8.9Hz,2H),7.06(d,J＝8.9Hz,2H),6.70(d,J＝3.7Hz,1H),6.55(d,J＝7.5Hz,1H),4.11(dt,J＝16.7,6.2Hz,1H),3.90(s,3H),2.11(dd,J＝12.0,3.0Hz,2H),1.83-1.76(m,2H),1.54-1.25(m,6H).13C NMR(100MHz,CDCl3)δ184.75,164.61,160.44,142.92,137.28,133.96,132.82,128.88,126.26,125.58,121.67,121.41,115.32,105.55,55.88,49.05,33.26,25.67,24.89.HRMS(ESI)calcd for C23H25N2O3[M+H]+377.1860,found 377.1849.
Compound 4u: the yield was 64%; melting point 168～169℃;1H NMR(400MHz,CDCl3)δ9.92(s,1H),9.28(s,1H),8.29(s,1H),7.88(d,J＝3.8Hz,1H),7.46(d,J＝8.9Hz,2H),7.44-7.37(m,4H),7.34(d,J＝6.7Hz,1H),7.06(d,J＝8.9Hz,2H),6.97-6.91(m,1H),6.67(d,J＝3.7Hz,1H),4.77(d,J＝5.7Hz,2H),3.90(s,3H).13C NMR(100MHz,CDCl3)δ184.74,165.50,160.31,143.06,137.71,137.06,133.96,132.48,129.03,128.95,127.89,127.83,126.20,125.46,121.32,120.82,115.19,105.61,55.78,44.31.HRMS(ESI)calcd for C24H21N2O3[M+H]+385.1547,found385.1455.
Compound 4v: the yield thereof was found to be 84%; melting point 221～223℃;1H NMR(400MHz,CDCl3)δ9.92(s,1H),9.26(s,1H),8.46(s,1H),8.27(s,1H),7.93(d,J＝3.6Hz,1H),7.72(d,J＝7.9Hz,2H),7.43(dd,J＝18.2,8.4Hz,4H),7.20(t,J＝7.4Hz,1H),7.05(d,J＝8.8Hz,2H),6.82(d,J＝3.6Hz,1H),3.90(s,3H).13C NMR(100MHz,CDCl3)δ184.80,163.64,160.36,143.15,137.59,137.01,134.03,132.24,129.27,128.99,126.21,125.41,125.01,121.57,121.36,120.21,115.25,105.44,55.78.HRMS(ESI)calcd for C23H19N2O3[M+H]+371.1390,found 371.1471.
Compound 4w: the yield is 67%; melting point 173～175℃;1HNMR(400MHz,CDCl3)δ9.94(s,1H),9.28(s,1H),8.80(s,1H),8.60(d,J＝5.3Hz,2H),8.29(s,1H),7.97(d,J＝3.3Hz,1H),7.74(d,J＝5.2Hz,2H),7.45(d,J＝8.5Hz,2H),7.06(d,J＝8.5Hz,2H),6.81(d,J＝3.4Hz,1H),3.90(s,3H).13C NMR(100MHz,DMSO-d6)δ183.51,165.17,160.20,150.83,146.19,137.54,133.85,128.98,126.34,124.93,120.83,120.67,119.58,115.58,114.46,110.12,108.11,56.24.HRMS(ESI)calcd for C22H18N3O3[M+H]+372.1343,found 372.1250.
Compound 4x: the yield was 33%; melting point 221～223℃;1HNMR(400MHz,CDCl3)δ9.97(s,1H),9.32(s,1H),8.36(s,1H),8.30(s,1H),7.97(d,J＝3.7Hz,1H),7.68(dd,J＝8.7,4.7Hz,2H),7.48(d,J＝8.8Hz,2H),7.12(t,J＝8.6Hz,2H),7.08(d,J＝8.8Hz,2H),6.81(d,J＝3.7Hz,1H),3.91(s,3H).13C NMR(100MHz,CDCl3)δ184.79,163.68,160.98,160.36,158.55,143.18,136.95,134.02,133.63,133.60,132.25,128.95,126.19,125.38,122.09,122.01,121.53,121.16,116.06,115.83,115.25,105.51,55.78.HRMS(ESI)calcd for C23H18FN2O3[M+H]+389.1296,found 389.1204.
Test example 1
Test for anti-tobacco mosaic virus (Tobacco mosaic virus, TMV) activity.
The virus purification and concentration measurement are carried out by compiling tobacco mosaic virus SOP standard according to a measuring room generated by elements of university of south China. After 2 times of polyethylene glycol centrifugation treatment, the concentration of the virus crude extract is measured, and the virus crude extract is refrigerated at 4 ℃ for standby.
And respectively adding the compounds 2-3 and the compounds 4 a-4 x into DMF (dimethyl formamide) for dissolution to prepare a compound mother solution with the concentration of 1 multiplied by 10 5 mu g/mL, and then diluting the compound mother solution with an aqueous solution containing 1 per mill of Tween-80 to obtain cerbera mangiferin derivative solutions with the concentration of 500 mu g/mL and 100 mu g/mL. The positive control ribavirin solution was diluted to a concentration of 500. Mu.g/mL and 100. Mu.g/mL to give a ribavirin solution.
In vivo passivation: selecting 3-5 She Qishan Xiyan with uniform growth vigor, mixing and passivating a medicament solution (cerbera manghas derivative solution or ribavirin solution) with an equal volume of virus juice for 30min, performing friction inoculation, washing with running water after inoculation, repeating for 3 times, and setting 1%o Tween-80 aqueous solution for comparison. And counting the number of lesions after 3 days, and calculating a result.
In vivo therapeutic action: 3-5 She Qishan Xiyan with uniform growth vigor is selected, the whole leaf of the writing brush is inoculated with virus, the virus concentration is 10 mug/mL, and the whole leaf is washed by running water after inoculation. After leaf surface is dried, the whole plant is sprayed and applied (cerbera manghas derivative solution or ribavirin solution), each group is treated for 3 times, and 1 permillage Tween-80 water solution is used for comparison. And recording the number of the lesions after 3 days, and calculating the control effect.
Living body protecting action: 3-5 She Qishan Xiyan with uniform growth vigor is selected, the whole plant is sprayed and applied (cerbera manghas aldehyde derivative solution or ribavirin solution), each group is treated for 3 times, and 1 per mill tween-80 water solution is used for comparison. After 24h, the leaf surface is spread with silicon carbide (500 meshes), the whole leaf surface is dipped with a virus liquid by a writing brush, the whole leaf surface is lightly rubbed for 2 times along the branch pulse direction, the lower part of the leaf surface is supported by a palm, the virus concentration is 10 mug/mL, and the leaf surface is washed by running water after inoculation. And recording the number of the lesions after 3 days, and calculating the control effect.
Inhibition ratio (%) = [ (control number of dried spots-number of treated dried spots)/control number of dried spots ] ×100%.
Table 4 results of Tobacco Mosaic Virus (TMV) activity test of cerbera manghas derivatives (n=3)
/>
As can be seen from the data in table 4, most of the compounds exhibited good anti-TMV activity, compound 3, compound 2, compound 4a, compound 4b, compound 4f, compound 4i, compound 4j, compound 4l, compound 4m, compound 4o, compound 4p, compound 4v and compound 4x exhibited higher levels of activity than ribavirin at a concentration of 500 μg/mL.
Test example 2
And (5) testing insecticidal activity.
The activity test method of the plutella xylostella larvae comprises the following steps: leaf dipping proposed by the International Commission on resistance action (IRAC) was used. 2mg of the drug (compound 2 to 3, compound 4a to 4x, positive control rotenone) was weighed on an analytical balance in a 10mL small beaker, and dissolved in 50. Mu.L of dimethylformamide (analytically pure), and 10mL of water was added to prepare 200mg/kg of a drug solution. The cabbage leaves are immersed in the liquid medicine for 2 to 3 seconds by using straight ophthalmic forceps, and the superfluous liquid medicine is thrown away. 1 tablet at a time, 3 tablets per sample. Sequentially placed on the treated paper in the order of sample marking. After the liquid medicine is dried, the liquid medicine is put into a straight pipe with a length of 10cm and a mark, 2-year-old plutella xylostella larvae are inoculated, and the pipe orifice is covered by gauze. The test treatment was placed in a standard treatment chamber and the results were checked after 96 hours. Each compound was repeated 3 times. The control was prepared by adding only the emulsifier and solvent to distilled water and stirring well.
The aphid killing activity determination method comprises the following steps: dissolving the medicine in 1mLDMF, adding two drops of Tween-20 emulsifier, adding distilled water, and stirring to obtain medicinal liquid with concentration of 600 μg/mL, 200 μg/mL and 100 μg/mL respectively. Soaking aphid (about 60) broad bean leaves in the medicament for 5 seconds, taking out, lightly spin-drying, sucking excessive liquid medicine by using filter paper, then inserting broad bean branches into the water-absorbing sponge, covering the branches by using a glass cover, sealing by using gauze, and checking the result for 96 hours, wherein each compound is repeated for 3 times. Control was prepared by adding only the emulsifier and solvent DMF to distilled water and stirring well.
Mortality (%) = [ (number of control insects-number of surviving insects)/number of control insects ] ×100%.
TABLE 5 insecticidal Activity test results of Cerbera Manghas Aldol derivatives
/>
As can be seen from the data in table 5, all compounds exhibited plutella xylostella larva killing activity, and most compounds exhibited activity against aphids. In terms of plutella xylostella larva killing, most of the compounds show high activity at the concentration of 600 mug/mL, and seven compounds (compound 3, compound 4d, compound 4g, compound 4i, compound 4n, compound 4q and compound 4 s) show mortality rate of more than or equal to 30% at the concentration of 200 mug/mL. In terms of aphid killing, most compounds exhibit higher levels of activity than the botanical insecticide rotenone.
While the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments of the invention can be made and still fall within the scope of the invention without undue effort.
Claims (10)
1. Cerbera manghas aldehyde derivative which is characterized by having a structure shown in a formula I:
R in the formula I comprises-COOH, -COOR 1、-COXR2 or CONR 3R3';
R 1 in the-COOR 1 comprises any one of the following structures:
X in the-COXR 2 comprises oxygen or sulfur, and R 2 comprises any one of the following structures:
R 3 in CONR 3R3 'comprises hydrogen or methyl, and R 3' comprises methyl, ethyl or any one of the following structures:
2. A method for preparing a cerbera manghas derivative according to claim 1, wherein when R is-COOH, the method comprises the steps of:
carrying out hydrolysis reaction on the compound 2 to obtain cerbera manghas aldehyde derivative with R as-COOH, and marking the cerbera manghas aldehyde derivative as a compound 3;
when R is-COOR 1, the preparation method comprises the following steps:
Mixing the compound 3, a first organic base, R 1 Br and a second organic solvent, and carrying out substitution reaction to obtain cerbera mangiferin derivatives; r 1 in R 1 Br is the same as R 1 in formula I;
when R is-COXR 2, the preparation method comprises the following steps:
Mixing the compound 3, R 2 XH, a first catalyst and a third organic solvent, and carrying out esterification reaction to obtain cerbera mangiferin derivatives; r 2 and X in R 2 XH are the same as R 2 and X in formula I;
when R is CONR 3R3', the preparation method comprises the following steps:
Mixing the compound 3, R 3R3' NH, a second catalyst and a fourth organic solvent, and carrying out amidation reaction to obtain cerbera mangiferin derivatives; r 3 and R 3 ' in R 3R3 ' NH are the same as R 3 and R 3 ' in formula I.
3. The method according to claim 2, wherein the hydrolysis reaction is carried out in the presence of an inorganic alkaline agent and a solvent;
the inorganic alkaline reagent comprises one or more of alkali metal hydroxide and alkali metal carbonate;
The molar ratio of the compound 2 to the inorganic alkaline reagent is 1:1 to 5;
The solvent comprises a first organic solvent and water, wherein the first organic solvent comprises one or more of tetrahydrofuran, 1, 4-dioxane, methanol, ethanol and acetonitrile, and the volume ratio of the first organic solvent to the water is 3-1: 1.
4. A process according to claim 2 or 3, wherein the hydrolysis reaction is carried out at a temperature of 0 to 60 ℃ for a period of 1 to 10 hours.
5. The preparation method according to claim 2, wherein the first organic base comprises one or more of 1, 8-diazabicyclo undec-7-ene, triethylenediamine and triethylamine;
The molar ratio of the compound 3 to the first organic base is 1:2 to 6;
The molar ratio of the compound 3 to R 1 Br is 1:1.5 to 4;
the second organic solvent comprises one or more of N, N-dimethylformamide, acetone, toluene and methylene dichloride;
The temperature of the substitution reaction is 0-60 ℃ and the time is 2-15 h.
6. The preparation method according to claim 2, wherein the molar ratio of the compound 3 to R 2 XH is 1:1.1 to 4;
The first catalyst comprises a carbodiimide compound and a second organic base; the carbodiimide compound comprises one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; the second organic base comprises one or more of N, N-lutidine, 1-hydroxybenzotriazole, 4-pyrrolidinylpyridine and N-hydroxyphthalimide;
the third organic solvent comprises N, N-dimethylformamide and/or dichloromethane;
the temperature of the esterification reaction is 0-60 ℃ and the time is 3-20 h.
7. The preparation method according to claim 2, wherein the molar ratio of the compound 3 to R 3R3' NH is 1:1.1 to 4;
The second catalyst comprises a coupling reagent and a third organic base; the coupling reagent comprises one or more of benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride; the third organic base comprises one or more of triethylamine, pyridine and diisopropylamine;
the fourth organic solvent comprises one or more of dichloromethane, N-dimethylformamide, chloroform and toluene;
the amidation reaction temperature is 0-40 deg.c and the amidation reaction time is 2-20 hr.
8. Use of a cerbera jelly aldehyde derivative according to claim 1 or prepared by a preparation method according to any one of claims 2 to 7 for the preparation of a plant protection agent.
9. The use according to claim 8, wherein the plant protection agent comprises one or more of an anti-plant virus agent, an insecticide and a bactericide.
10. A pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises a cerbera mangiferin derivative as claimed in claim 1 or a cerbera mangiferin derivative as produced by the method of any one of claims 2 to 7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410182925.6A CN118026932A (en) | 2024-02-19 | 2024-02-19 | Cerbera manghas aldehyde derivative, and preparation method and application and pharmaceutical composition thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410182925.6A CN118026932A (en) | 2024-02-19 | 2024-02-19 | Cerbera manghas aldehyde derivative, and preparation method and application and pharmaceutical composition thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118026932A true CN118026932A (en) | 2024-05-14 |
Family
ID=90985268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410182925.6A Pending CN118026932A (en) | 2024-02-19 | 2024-02-19 | Cerbera manghas aldehyde derivative, and preparation method and application and pharmaceutical composition thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118026932A (en) |
-
2024
- 2024-02-19 CN CN202410182925.6A patent/CN118026932A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104744460B (en) | β carbolines, dihydro β carbolines and tetrahydro-beta-carboline alcaloid-derivatives and preparation method thereof and the application in terms of preventing and treating plant virus, sterilization, desinsection | |
| CN110092776B (en) | Pyrazole oxime ester compound containing pyridine-difluoride pyrazole structure and preparation method and application thereof | |
| CN105884634B (en) | The preparation of gossypol derivative and they, application and anticancer activity on pesticide | |
| KR20020058089A (en) | Pyrazolecarboxamide and pyrazolethioamide as fungicide | |
| CN110407828B (en) | Pyrazole-5-amide derivative containing oxazole structure and preparation method and application thereof | |
| CN110922397B (en) | Preparation method and application of 3- (pyrazole biphenyl methoxy) pyrazole derivative containing substituted isoxazole unit | |
| CN110845487B (en) | 3- (triazole biphenyl methoxyl) pyrazole amide compound containing isoxazole structure and preparation method and application thereof | |
| CN110845488B (en) | Preparation method and application of 3- (benzotriazole benzyloxy) pyrazole derivative containing aryl isoxazole | |
| EP0268892A2 (en) | Substituted-amido derivatives, method for preparation of the same and phytopathogenic fungicides containing the same | |
| CN113773233B (en) | Methyl guanidinyl urea derivative and preparation method and application thereof | |
| CN100556896C (en) | Coupling substance of growth hormone and agricultural chemicals and preparation method thereof and application as agricultural chemicals | |
| CN118026932A (en) | Cerbera manghas aldehyde derivative, and preparation method and application and pharmaceutical composition thereof | |
| CN114409664B (en) | Spiro heterocyclic tetrahydropyran compound and preparation method and application thereof | |
| CN108191665B (en) | Eugenol ester analogue, preparation method thereof and pesticide | |
| CN109422734A (en) | Nortopsentin Alkaloid derivative and its preparation and the application in prevention and treatment pest and disease damage | |
| KR20050000419A (en) | 4˝-Deoxy-4˝-(S)-amido avermectin derivatives | |
| CN109896973A (en) | A kind of cinnamamide derivative and application thereof | |
| KR20030074794A (en) | Pyrrolecarboxamides for the use as fungicides | |
| CN110156685A (en) | The cyclopenta pyridine and its synthetic method of fragrance and application | |
| CN110759911A (en) | Carboline derivative, preparation method thereof and application thereof in preventing and treating plant viruses, killing bacteria and killing insects | |
| CN111620837B (en) | Cedar ketone thiazole amide compound, and preparation method and application thereof | |
| CN111560015B (en) | Preparation and application of 1,2,3-triazole benzyloxy pyrazole derivative containing 1,2,4-oxadiazole unit | |
| CN111560010B (en) | Preparation and application of pyrazole oxime derivative containing triazole aryl methoxy pyrazole unit | |
| CN111675704B (en) | 2-substituent imidazole alkane compound containing oxadiazole heterocyclic structure and preparation method and application thereof | |
| CN111675699B (en) | Preparation method and application of pyrazole derivative containing 2-substituent imidazolidine structural unit |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |