CN117567508A - Bisphosphonate containing hydroxamic acid and preparation method and application thereof - Google Patents
Bisphosphonate containing hydroxamic acid and preparation method and application thereof Download PDFInfo
- Publication number
- CN117567508A CN117567508A CN202311530096.8A CN202311530096A CN117567508A CN 117567508 A CN117567508 A CN 117567508A CN 202311530096 A CN202311530096 A CN 202311530096A CN 117567508 A CN117567508 A CN 117567508A
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- CN
- China
- Prior art keywords
- compound
- formula
- hydroxamic acid
- reaction
- bisphosphonate
- 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
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000002253 acid Substances 0.000 title claims abstract description 35
- 229940122361 Bisphosphonate Drugs 0.000 title claims abstract description 34
- 150000004663 bisphosphonates Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 239000004009 herbicide Substances 0.000 claims abstract description 14
- 239000003619 algicide Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 8
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims abstract description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 192
- 239000003054 catalyst Substances 0.000 claims description 23
- 238000006482 condensation reaction Methods 0.000 claims description 15
- 150000007530 organic bases Chemical class 0.000 claims description 15
- 238000006845 Michael addition reaction Methods 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000006264 debenzylation reaction Methods 0.000 claims description 13
- 238000006297 dehydration reaction Methods 0.000 claims description 13
- 230000002363 herbicidal effect Effects 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 229940126062 Compound A Drugs 0.000 claims description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 claims description 8
- 150000007524 organic acids Chemical group 0.000 claims description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- -1 bisphosphonate compound Chemical class 0.000 abstract description 11
- 230000002353 algacidal effect Effects 0.000 abstract description 3
- 238000009333 weeding Methods 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 2
- 238000005481 NMR spectroscopy Methods 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000004896 high resolution mass spectrometry Methods 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- IVIIAEVMQHEPAY-UHFFFAOYSA-N tridodecyl phosphite Chemical compound CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC IVIIAEVMQHEPAY-UHFFFAOYSA-N 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 241000196324 Embryophyta Species 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 239000011148 porous material Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000001963 growth medium Substances 0.000 description 8
- 241000195493 Cryptophyta Species 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 230000009036 growth inhibition Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 239000003899 bactericide agent Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000003760 magnetic stirring Methods 0.000 description 5
- 241000219195 Arabidopsis thaliana Species 0.000 description 4
- 241000607479 Yersinia pestis Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108700003863 Arabidopsis ENT1 Proteins 0.000 description 3
- 241000192043 Echinochloa Species 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
- RPQWXGVZELKOEU-UHFFFAOYSA-N 3,4-difluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1F RPQWXGVZELKOEU-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FPJRZKFBYYRPKI-UHNVWZDZSA-N [(2r,3r)-2,3-dihydroxy-3-methyl-4-oxobutyl] dihydrogen phosphate Chemical compound O=C[C@@](O)(C)[C@H](O)COP(O)(O)=O FPJRZKFBYYRPKI-UHNVWZDZSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000007598 dipping method Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- CZHLPWNZCJEPJB-UHFFFAOYSA-N 1-chloro-3-methylbutane Chemical compound CC(C)CCCl CZHLPWNZCJEPJB-UHFFFAOYSA-N 0.000 description 1
- KURKJXZWCPWPFX-UHFFFAOYSA-N 2,2-difluoroacetyl chloride Chemical compound FC(F)C(Cl)=O KURKJXZWCPWPFX-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- SIFIJQFBERMWMU-UHFFFAOYSA-N 2,4,6-trifluorobenzoyl chloride Chemical compound FC1=CC(F)=C(C(Cl)=O)C(F)=C1 SIFIJQFBERMWMU-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- POIAZJJVWRVLBO-UHFFFAOYSA-N 2-chloro-4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(Cl)=C1 POIAZJJVWRVLBO-UHFFFAOYSA-N 0.000 description 1
- VTXNOVCTHUBABW-UHFFFAOYSA-N 3,4-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C(Cl)=C1 VTXNOVCTHUBABW-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- HPHZOCIBMCWXCQ-UHFFFAOYSA-N 3-bromo-4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1Br HPHZOCIBMCWXCQ-UHFFFAOYSA-N 0.000 description 1
- OXZYBOLWRXENKT-UHFFFAOYSA-N 4-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=C(C(Cl)=O)C=C1 OXZYBOLWRXENKT-UHFFFAOYSA-N 0.000 description 1
- KHZDUKKKWXLPFY-UHFFFAOYSA-N 4-chloro-2,6-difluorobenzoyl chloride Chemical compound FC1=CC(Cl)=CC(F)=C1C(Cl)=O KHZDUKKKWXLPFY-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- OEYHURRIOWWRMD-UHFFFAOYSA-N 4-fluoro-2-(trifluoromethyl)benzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(C(F)(F)F)=C1 OEYHURRIOWWRMD-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010001557 Albinism Diseases 0.000 description 1
- 241000219194 Arabidopsis Species 0.000 description 1
- 101100375585 Arabidopsis thaliana YAB1 gene Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000107955 Microcystis aeruginosa FACHB-905 Species 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000005791 algae growth Effects 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MYHOHFDYWMPGJY-UHFFFAOYSA-N pentafluorobenzoyl chloride Chemical compound FC1=C(F)C(F)=C(C(Cl)=O)C(F)=C1F MYHOHFDYWMPGJY-UHFFFAOYSA-N 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- 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
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/26—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-nitrogen bonds
- A01N57/28—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-nitrogen bonds containing acyclic or cycloaliphatic radicals
-
- 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
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/26—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-nitrogen bonds
- A01N57/30—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-nitrogen bonds containing aromatic radicals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P13/00—Herbicides; Algicides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
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Abstract
The invention relates to the field of plant protection, and discloses a bisphosphonate compound containing hydroxamic acid, and a preparation method and application thereof. The structural formula of the bisphosphonate containing hydroxamic acid is shown as formula (I), wherein R 1 And R is 2 Each independently selected from hydrogen, alkyl, alkoxyalkyl or acyloxyalkyl, R 3 Selected from hydrogen, alkyl, difluoromethyl, phenyl, substituted phenyl or benzyl. The bisphosphonate containing hydroxamic acid has good weeding and algicidal activity and good application prospect in the aspects of preparing herbicides and algicides.
Description
Technical Field
The invention relates to the field of plant protection, in particular to a bisphosphonate compound containing hydroxamic acid, a preparation method and application thereof.
Background
With the increase of resistance of the miscellaneous herbal medicines and the enhancement of environmental protection consciousness, new herbicides are created as urgent demands for sustainable development of agriculture. Recent studies have found that 2C-methylerythrose-4-phosphate (MEP) is widely available in bacteria and plants as a novel bactericide and a target for action of herbicides, and among them, a bactericide against DXR, a second key enzyme in the production process, has been intensively studied, but studies on herbicides targeting DXR have been quite rare.
Currently there are two main natural products for the development of bactericides for DXR enzymes: fosfos and FR900098 (FR) are used as lead structures, and structurally comprise three units of phosphonic acid, hydroxamic acid and a connecting chain, and have high inhibition activity on DXR enzyme, but have not been applied to clinic due to low lipophilicity and bioavailability. Modification of the structure of FOS and FR may reveal some FOS analogs that are more lipophilic, antibacterial or antimalarial active. Therefore, the development of design and synthesis researches of novel herbicides and bactericides aiming at FOS and FR will have important significance.
Disclosure of Invention
The invention aims to solve the problems of low herbicidal activity, low bioavailability and serious environmental pollution of herbicides in the prior art, and provides a bisphosphonate compound containing hydroxamic acid, which has high herbicidal activity and algicidal activity and can be applied as a herbicide and an algicide.
In order to achieve the above object, in one aspect, the present invention provides a bisphosphonate containing hydroxamic acid, which has a structural formula as shown in formula (I),
wherein R is 1 And R is 2 Each independently selected from hydrogen, alkyl, alkoxyalkyl or acyloxyalkyl, R 3 Selected from hydrogen, alkyl, difluoromethyl, phenyl, substituted phenylOr benzyl.
Preferably, R 1 And R is 2 Each independently selected from hydrogen or ethyl, R 3 Selected from hydrogen, alkyl, difluoromethyl, phenyl, substituted phenyl or benzyl.
Preferably, the bisphosphonate containing hydroxamic acid is at least one of the following compounds:
compound I-1: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is H;
compound I-2: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 3 ；
Compound I-3: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 2 CH 3 ；
Compound I-4: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is- (CH) 2 ) 2 CH 3 ；
Compound I-5: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-C (CH) 3 ) 3 ；
Compound I-6: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CHF 2 ；
Compound I-7: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-Ph;
compound I-8: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-CH 3 -Ph；
Compound I-9: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-OCH 3 -Ph；
Chemical combinationObject I-10: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 4-F-Ph;
compound I-11: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 4-Cl-Ph;
compound I-12: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-CF 3 -Ph；
Compound I-13: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 3,4-diF-Ph;
compound I-14: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 3, 4-dich-Ph;
compound I-15: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 2-Cl-4-F-Ph;
compound I-16: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 3-Br-4-F-Ph;
compound I-17: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 2-CF 3 -4-F-Ph；
Compound I-18: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 2,6-diF-4-Cl-Ph;
compound I-19: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 2,4, 6-tri-F-Ph;
compound I-20: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is pentaF-Ph;
compound I-21: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 2 Ph；
Compound I-22: r is R 1 Is H, R 2 Is H, R 3 4-F-Ph;
compound I-23: r is R 1 Is H, R 2 Is H, R 3 3,4-diF-Ph.
In a second aspect, the present invention provides a process for preparing the above-described hydroxamic acid-containing bisphosphonate, comprising the steps of:
s1: carrying out condensation reaction on a compound shown in a formula (1) and paraformaldehyde, and then carrying out dehydration reaction to obtain a compound shown in a formula (2);
s2: carrying out Michael addition reaction on a compound shown in the formula (2) and O-benzyl hydroxylamine to obtain a compound shown in the formula (3);
s3: reacting a compound shown in a formula (3) with a compound A to obtain a compound shown in a formula (4), wherein the compound A is carboxylic acid or acyl chloride;
s4: debenzylating a compound shown in a formula (4) with hydrogen;
wherein R is 1 、R 2 And R is 3 The definition of (a) is the same as that described above.
Preferably, in step S1, the condensation reaction is carried out in the presence of a first organic base and the dehydration reaction is carried out in the presence of a first catalyst.
Preferably, the amount of the first organic base is 1 to 2 molar equivalents relative to 1 molar equivalent of the amount of the compound represented by formula (1).
Preferably, the first catalyst is an organic acid, and the amount of the organic acid is 0.05% to 1% by mole equivalent with respect to 1 mole equivalent of the amount of the compound represented by formula (1).
Preferably, the conditions of the condensation reaction include: the temperature is 60-100deg.C, and the time is 10-16h.
Preferably, the conditions of the dehydration reaction include: the temperature is 100-130 ℃ and the time is 12-36h.
Preferably, in step S2, the O-benzyl hydroxylamine is used in an amount of 1.1 to 1.5 molar equivalents relative to 1 molar equivalent of the compound of formula (2).
Preferably, the conditions of the michael addition reaction include: the temperature is 10-30 ℃ and the time is 4-6h.
Preferably, in step S3, the reaction is carried out in the presence of a second organic base.
Preferably, the carboxylic acid or acid chloride is used in an amount of 1.1 to 1.5 molar equivalents relative to 1 molar equivalent of the compound of formula (3).
Preferably, the reaction conditions include: the temperature is 10-30 ℃ and the time is 6-12h.
Preferably, in step S4, the debenzylation reaction is carried out in the presence of a second catalyst.
Preferably, the second catalyst is a metal catalyst, and the metal catalyst is used in an amount of 0.05 to 0.2 molar equivalents with respect to 1 molar equivalent of the compound represented by formula (4).
Preferably, the pressure of the hydrogen is 1 to 4atm.
Preferably, the conditions of the debenzylation reaction include: the temperature is 10-30 ℃ and the time is 2-4h.
In a third aspect, the present invention provides the use of a bisphosphonate containing hydroxamic acid as described above in the preparation of a herbicide.
In a fourth aspect, the present invention provides the use of a bisphosphonate as described above containing hydroxamic acid for the preparation of an algicide.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) The bisphosphonate containing hydroxamic acid has high herbicidal activity and high blue algae inhibition activity;
(2) The method for preparing the bisphosphonate containing hydroxamic acid is efficient and quick, and can be used for industrial production;
(3) The bisphosphonate containing hydroxamic acid can be used as herbicide and algicide.
Drawings
FIG. 1 is EC 50 An experimental group of 14 compounds of formula (I) and compound FOS below 100mg/L and a blank reference group showed inhibitory effects on Arabidopsis at different concentrations.
Detailed Description
The following describes specific embodiments of the present invention in detail with reference to the drawings. It should be understood that the detailed description and specific examples, while indicating and illustrating the invention, are not intended to limit the invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
In the description of the present application, the terms "first", "second" are used for descriptive purposes only and are not to be construed as indicating relative importance or implicitly indicating the number of technical features indicated.
In one aspect, the invention provides a bisphosphonate containing hydroxamic acid having a structural formula as shown in formula (I),
wherein R is 1 And R is 2 Each independently selected from hydrogen, alkyl, alkoxyalkyl or acyloxyalkyl, R 3 Selected from hydrogen, alkyl, difluoromethyl, phenyl, substituted phenyl or benzyl.
In a preferred embodiment, R 1 And R is 2 Each independently selected from hydrogen or ethyl, R 3 Selected from hydrogen, alkyl (e.g. methyl, ethyl, propyl or tert-butyl), difluoromethyl, phenyl, substituted phenyl (e.g. 4-methyl)-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl or 4-trifluoromethyl-phenyl) or benzyl.
In a more preferred embodiment, R 1 And R is 2 Are all hydrogen or ethyl, R 3 Selected from hydrogen, methyl, ethyl, propyl, t-butyl, difluoromethyl, phenyl, substituted phenyl or benzyl.
In a preferred embodiment, the hydroxamic acid-containing bisphosphonate is at least one of the following compounds:
compound I-1: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is H;
compound I-2: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 3 ；
Compound I-3: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 2 CH 3 ；
Compound I-4: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is- (CH) 2 ) 2 CH 3 ；
Compound I-5: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-C (CH) 3 ) 3 ；
Compound I-6: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CHF 2 ；
Compound I-7: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-Ph;
compound I-8: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-CH 3 -Ph；
Compound I-9: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-OCH 3 -Ph；
Compound I-10: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 4-F-Ph;
compound I-11: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 4-Cl-Ph;
compound I-12: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-CF 3 -Ph；
Compound I-13: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 3,4-diF-Ph;
compound I-14: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 3, 4-dich-Ph;
compound I-15: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 2-Cl-4-F-Ph;
compound I-16: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 3-Br-4-F-Ph;
compound I-17: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 2-CF 3 -4-F-Ph；
Compound I-18: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 2,6-diF-4-Cl-Ph;
compound I-19: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 2,4, 6-tri-F-Ph;
compound I-20: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is pentaF-Ph；
Compound I-21: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 2 Ph；
Compound I-22: r is R 1 Is H, R 2 Is H, R 3 4-F-Ph;
compound I-23: r is R 1 Is H, R 2 Is H, R 3 3,4-diF-Ph.
In the present invention, "4-CH 3 -Ph "is" 4-methyl-phenyl ","4-OCH 3 -Ph "is" 4-methoxy-phenyl ","4-F-Ph "is" 4-fluoro-phenyl ","4-Cl-Ph "is" 4-chloro-phenyl ","4-CF 3 -Ph "is" 4-trifluoromethyl-phenyl ","3,4-diF-Ph "is" 3, 4-difluoro-phenyl ","3,4-di Cl-Ph "is" 3, 4-dichloro-phenyl ","2-Cl-4-F-Ph "is" 2-chloro-4-fluoro-phenyl ","3-Br-4-F-Ph "is" 3-bromo-4-fluoro-phenyl ","2-CF " 3 -4-F-Ph "is" 2-trifluoromethyl-4-fluoro-phenyl ","2,6-diF-4-Cl-Ph "is" 2, 6-difluoro-4-chloro-phenyl ","2,4,6-tri F-Ph "is" 2,4, 6-trifluoro-phenyl "," pentaF-Ph "is" pentafluoro-phenyl "," -CH 2 Ph "is" methylene-phenyl ".
In a second aspect, the present invention provides a process for preparing the above-described hydroxamic acid-containing bisphosphonate, comprising the steps of:
s1: carrying out condensation reaction on a compound shown in a formula (1) and paraformaldehyde, and then carrying out dehydration reaction to obtain a compound shown in a formula (2);
s2: carrying out Michael addition reaction on a compound shown in the formula (2) and O-benzyl hydroxylamine to obtain a compound shown in the formula (3);
s3: reacting a compound shown in a formula (3) with a compound A to obtain a compound shown in a formula (4), wherein the compound A is carboxylic acid or acyl chloride;
s4: debenzylating a compound shown in a formula (4) with hydrogen;
wherein R is 1 、R 2 And R is 3 Is as defined above.
In the method of the present invention, the synthetic route of the bisphosphonate containing hydroxamic acid is shown below.
In the present invention, all the reactions are carried out in the presence of an organic solvent, which is not particularly limited, and the organic solvent conventional in the art may be, for example, methanol, toluene or methylene chloride.
In the present invention, "Ph" is "phenyl" and "Bn" is "benzyl".
In a preferred embodiment, in step S1, the condensation reaction is carried out in the presence of a first organic base.
In a preferred embodiment, in the condensation reaction of step S1, the first organic base is used in an amount of 1 to 2 molar equivalents relative to 1 molar equivalent of the compound represented by formula (1); specifically, it may be 1 molar equivalent, 1.5 molar equivalents or 2 molar equivalents.
In a preferred embodiment, in step S1, the conditions of the condensation reaction include: the temperature is 60-100 ℃ and the time is 10-16h; specifically, the temperature may be 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ or 100 ℃; the time may be 10 hours, 12 hours, 14 hours or 16 hours.
In the present invention, there is no particular requirement for the first organic base, and the organic base conventional in the art may be, for example, triethylamine, diethylamine or pyridine.
In a preferred embodiment, in step S1, the dehydration reaction is carried out in the presence of a first catalyst, which is an organic acid; specifically, the organic acid may be p-toluenesulfonic acid, benzenesulfonic acid or oxalic acid.
In a preferred embodiment, in the dehydration reaction of step S1, the organic acid is used in an amount of 0.05 to 1% molar equivalent with respect to 1 molar equivalent of the compound of formula (1); specifically, it may be 0.05% molar equivalent, 0.1% molar equivalent, 0.3% molar equivalent, 0.5% molar equivalent, 0.7% molar equivalent or 1% molar equivalent.
In a preferred embodiment, the conditions of the dehydration reaction include: the temperature is 100-130 ℃ and the time is 12-36h; specifically, the temperature may be 100 ℃, 110 ℃, 120 ℃ or 130 ℃; the time may be 12 hours, 24 hours or 36 hours.
In a specific embodiment, the preparation process of step S1 includes: dissolving a compound shown in a formula (1), paraformaldehyde and a first organic base (such as diethylamine) in an organic solvent (such as methanol) for magnetic stirring, tracking the progress of a condensation reaction by TLC until the condensation reaction is finished, cooling the mixture after the condensation reaction to room temperature, concentrating, mixing with toluene, adding a first catalyst (such as p-toluenesulfonic acid), heating, stirring overnight for dehydration reaction, cooling to room temperature, adding a saturated NaCl aqueous solution and extracting with toluene, combining organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain the compound shown in the formula (2).
In a preferred embodiment, in the Michael addition reaction of step S2, the amount of O-benzylhydroxylamine is 1.1 to 1.5 molar equivalents relative to 1 molar equivalent of the compound of formula (2); specifically, it may be 1.1 molar equivalent, 1.2 molar equivalent, 1.3 molar equivalent, 1.4 molar equivalent or 1.5 molar equivalent.
In a preferred embodiment, in step S2, the conditions of the michael addition reaction include: the temperature is 10-30 ℃ and the time is 4-6h; specifically, the temperature may be 10 ℃, 20 ℃ or 30 ℃; the time may be 4 hours, 5 hours or 6 hours.
In a specific embodiment, the preparation process of step S2 includes: dissolving the compound shown in the formula (2) in an organic solvent (such as dichloromethane), slowly dropwise adding O-benzyl hydroxylamine, stirring at room temperature, performing Michael addition reaction, tracking the Michael addition reaction progress by TLC until the Michael addition reaction is finished, adding a saturated sodium chloride aqueous solution, extracting with dichloromethane, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography to obtain the compound shown in the formula (3).
In a preferred embodiment, in step S3, the reaction is carried out in the presence of a second organic base.
In a preferred embodiment, in the reaction of step S3, the carboxylic acid or acid chloride is used in an amount of 1.1 to 1.5 molar equivalents relative to 1 molar equivalent of the compound of formula (3); specifically, it may be 1.1 molar equivalent, 1.2 molar equivalent, 1.3 molar equivalent, 1.4 molar equivalent or 1.5 molar equivalent.
In a preferred embodiment, in step S3, the reaction conditions include: the temperature is 10-30 ℃ and the time is 6-12h; specifically, the temperature may be 10 ℃, 20 ℃ or 30 ℃; the time may be 6h, 7h, 8h, 9h, 10h, 11h or 12h.
In the present invention, there is no particular requirement for the second organic base, and the organic base conventional in the art may be, for example, triethylamine, N-methylmorpholine or N, N-diisopropylethylamine.
In the present invention, there is no particular requirement for the carboxylic acid or acid chloride, and carboxylic acid or acid chloride conventionally used in the art may be used, for example, the carboxylic acid may be formic acid or acetic acid; the acid chloride may be acetyl chloride, benzoyl chloride, phenylacetyl chloride, chloroacetyl chloride or trichloroacetyl chloride.
In a specific embodiment, the preparation process of step S3 includes: dissolving a compound shown in a formula (3) and a second organic base (such as triethylamine) in an organic solvent (such as dichloromethane), slowly dropwise adding a compound A (such as carboxylic acid or acyl chloride), stirring at room temperature, reacting, tracking the reaction progress by TLC until the reaction is finished, adding a saturated sodium chloride aqueous solution, extracting with dichloromethane, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography to obtain the compound shown in the formula (4).
In a preferred embodiment, in step S4, the debenzylation reaction is carried out in the presence of a second catalyst, which is a metal catalyst; specifically, the metal catalyst may be a palladium catalyst, a nickel catalyst or a platinum catalyst.
In a preferred embodiment, in the debenzylation reaction of step S4, the metal catalyst is used in an amount of 0.05 to 0.2 molar equivalent relative to 1 molar equivalent of the compound represented by formula (4); specifically, it may be 0.05 molar equivalent, 0.1 molar equivalent, 0.15 molar equivalent or 0.2 molar equivalent.
In a preferred embodiment, the pressure of the hydrogen is 1 to 4atm; specifically, it may be 1atm, 2atm, 3atm or 4atm.
In a preferred embodiment, the conditions of the debenzylation reaction comprise: the temperature is 10-30 ℃ and the time is 2-4h; the temperature may be 10 ℃, 20 ℃ or 30 ℃; the time may be 2 hours, 3 hours or 4 hours.
In the present invention, the "pressure" is "absolute pressure".
In a specific embodiment, the preparation process of step S4 includes: dissolving the compound shown in the formula (4) in an organic solvent (such as methanol), adding a second catalyst (such as a metal palladium catalyst), introducing 1atm of hydrogen, stirring at room temperature, carrying out debenzylation reaction, tracking the progress of the debenzylation reaction by TLC until the debenzylation reaction is finished, filtering, concentrating, and carrying out column chromatography to obtain the compound shown in the formula (I).
In a third aspect, the present invention provides the use of a bisphosphonate containing hydroxamic acid as described above in the preparation of a herbicide.
In a preferred embodiment, the bisphosphonate containing hydroxamic acid can be used alone as a herbicide, or mixed with other acceptable carriers or diluents on plant protection to be formulated into a mixture, granule or aqueous emulsion, or compounded with other pesticide bactericides, insecticides, herbicides or plant growth regulators.
In a fourth aspect, the present invention provides the use of a bisphosphonate as described above containing hydroxamic acid for the preparation of an algicide.
In a preferred embodiment, the bisphosphonate containing hydroxamic acid can be used alone as an algicide, or mixed with other acceptable carriers or diluents on plant protection to be formulated into a mixture, granule or emulsion in water, or compounded with other algicides.
The following examples are given to further illustrate the hydroxamic acid-containing bisphosphonates of the present invention, their preparation and use, and are not intended to limit the scope of the invention to the following examples.
The experimental methods in the following examples and comparative examples, unless otherwise specified, are all conventional in the art; the experimental materials used in the examples described below are commercially available unless otherwise specified.
In the following examples and comparative examples, the determination of nuclear magnetic data was performed by using a Quantum-IPlus400MHz type nuclear magnetic resonance spectrometer, and High Resolution Mass Spectrometry (HRMS) was performed by an Agilent 6224TOF LC/MS type mass spectrometer.
Examples 1 to 23
Examples 1 to 23 are for the preparation of the hydroxamic acid-containing bisphosphonates according to the invention, i.e.the compounds of formula (I), wherein R is 1 、R 2 And R is 3 The specific choices of (a) are shown in table 1, and in step (3), the specific choices of compound a are shown in table 2;
TABLE 1
TABLE 2
| Numbering device | Compound A | Numbering device | Compound A |
| Example 1 | Formic acid | Example 13 | 3, 4-Difluorobenzoyl chloride |
| Example 2 | Acetyl chloride | Example 14 | 3, 4-dichlorobenzoyl chloride |
| Example 3 | Propionyl chloride | Example 15 | 2-chloro-4-fluorobenzoyl chloride |
| Example 4 | Isopentyl chloride | Example 16 | 3-bromo-4-fluorobenzoyl chloride |
| Example 5 | Pivaloyl chloride | Example 17 | 2-trifluoromethyl-4-fluorobenzoyl chloride |
| Example 6 | Difluoro acetyl chloride | Example 18 | 2, 6-difluoro-4-chlorobenzoyl chloride |
| Example 7 | Benzoyl chloride | Example 19 | 2,4, 6-trifluoro-benzoyl chloride |
| Example 8 | Para-methylbenzoyl chloride | Example 20 | Pentafluorobenzoyl chloride |
| Example 9 | P-methoxybenzoyl chloride | Example 21 | Phenylacetyl chloride |
| Example 10 | Para-fluorobenzoyl chloride | Example 22 | Para-fluorobenzoyl chloride |
| Example 11 | P-chlorobenzoyl chloride | Example 23 | 3, 4-Difluorobenzoyl chloride |
| Example 12 | 4-Trifluoromethylbenzoyl chloride |
The specific preparation process for examples 1-23 is as follows:
s1: in a dried 100mL round bottom flask, a compound shown in a formula (1) (specific structure is shown in Table 1) (14 mmol), paraformaldehyde (70 mmol) and diethylamine (14 mmol) are dissolved in methanol (50 mL), magnetic stirring is carried out for 12h under reflux, TLC tracks the progress of the condensation reaction until the condensation reaction is finished, the reacted mixture is cooled to room temperature, concentrated and then dissolved in toluene (60 mL), p-toluenesulfonic acid (0.014 mmol) is added and stirred at 110 ℃ for 24 hours for dehydration reaction, after the dehydration reaction is finished, the cooled to room temperature, saturated NaCl aqueous solution (30 mL) is added and extracted with toluene, organic phases are combined, anhydrous sodium sulfate is dried and concentrated to obtain the compound shown in a formula (2) (specific structure is shown in Table 1);
s2: dissolving the compound (specific structure shown in table 1) (10 mmol) shown in formula (2) prepared in step S1 in dichloromethane (50 mL) in a dry 100mL round bottom flask, slowly dropwise adding O-benzyl hydroxylamine (12 mmol), maintaining the michael addition reaction for 4 hours at room temperature under magnetic stirring, tracking the michael addition reaction progress by TLC until the michael addition reaction is finished, adding saturated aqueous sodium chloride solution (30 mL) and extracting with dichloromethane, drying the organic phase over anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography using dichloromethane/methanol (50:1, v/v) to obtain the compound shown in formula (3) (specific structure shown in table 1);
s3: in a dry 100mL round bottom flask, the compound (specific structure shown in Table 1) (5 mmol) and triethylamine (7.5 mmol) of formula (3) prepared in step S2 are dissolved in dichloromethane (50 mL), compound A (specific selection shown in Table 2) (6 mmol) is slowly added dropwise, the reaction is maintained at room temperature under magnetic stirring for 6 hours, TLC tracks the reaction progress until the reaction is finished, saturated aqueous sodium chloride solution (30 mL) is added and extracted with dichloromethane, the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography using dichloromethane/methanol (50:1, v/v) to obtain the compound (specific structure shown in Table 1) of formula (4);
s4: in a dry 50mL round bottom flask, the compound of formula (4) (specific structure shown in Table 1) (1 mmol) prepared in step S3 was dissolved in methanol (10 mL), a metallic palladium catalyst (10% by weight of palladium) (0.2 mmol) was added, and 1atm hydrogen was introduced, the debenzylation reaction was maintained at room temperature under magnetic stirring for 2 hours, TLC followed by debenzylation reaction progress until the debenzylation reaction was completed, then filtration through celite, concentration, and then column chromatography purification using methylene chloride/methanol (50:1, v/v) was performed to obtain the compound of formula (I) (specific structure shown in Table 1).
Test example 1
The product prepared in the above example was characterized and the results were as follows:
compound I-1: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ8.34(s,1H),4.24-4.19(m,8H),4.13-4.09(m,2H),2.97-2.88(m,1H),1.39-1.36(m,12H). 13 C NMR(100MHz,CD 3 OD)δ158.7,63.3(d,J＝42.2Hz),46.5,42.1,15.3；
HRMS m/z calcd for C 11 H 25 NO 8 P 2 [M-H] - 360.0983,found 360.0986；
compound I-2: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ4.22-4.16(m,8H),4.15-4.11(m,2H),3.01(t,J＝22.8Hz,1H),2.15(s,3H),1.38(t,J＝8.0Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ171.4,62.3(d,J＝23.6Hz),42.6,32.5(t,J＝90.4Hz),18.3,14.5；
HRMS m/z calcd for C 12 H 27 NO 8 P 2 [M-H] - 374.1139,found 374.1140；
compound I-3: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ4.24-4.16(m,10H),3.08-2.97(m,1H),2.51(q,J＝7.6Hz,2H),1.38(t,J＝7.2Hz,12H),1.13(t,J＝7.6Hz,3H). 13 C NMR(100MHz,CD 3 OD)δ175.2,63.1(d,J＝21.4Hz),43.7,33.4(t,J＝90.6Hz),25.2,15.3,7.7；
HRMS m/z calcd for C 13 H 29 NO 8 P 2 [M-H] - 388.1296,found 388.1300；
compound I-4: colorless oily form; 1 H NMR(400MHz,CDCl 3 )δ4.24-4.16(m,10H),3.08-2.97(m,1H),2.46(t,J＝7.6Hz,2H),1.65(q,J＝7.6Hz,2H),1.37(t,J＝7.2Hz,12H),0.96(t,J＝7.6Hz,3H). 13 C NMR(100MHz,CD 3 OD)δ174.4,63.1(d,J＝21.4Hz),43.7,33.9(t,J＝66.8Hz),32.6,17.6,15.3,12.9；
HRMS m/z calcd for C 14 H 31 NO 8 P 2 [M-H] - 402.1452,found 402.1458；
compound I-5: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ4.25-4.15(m,10H),3.14-3.03(m,1H),1.38(q,J＝9.0Hz,12H),1.28(s,9H). 13 C NMR(100MHz,CD 3 OD)δ177.9,63.2(d,J＝20.6Hz),45.9,38.6,33.9(t,J＝90.0Hz),26.0,15.3；
HRMS m/z calcd for C 15 H 33 NO 8 P 2 [M-H] - 416.1609,found 416.1611；
compound I-6: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ9.90(s,1H),6.40(t,J＝53.6Hz,1H),4.25-4.14(m,10H),2.95(t,J＝22.8Hz,1H),1.40-1.34(m,12H). 13 C NMR(100MHz,CD 3 OD)δ162.1,106.4,63.3(d,J＝24.8Hz),43.9,32.9(t,J＝90.8Hz),15.2；
HRMS m/z calcd for C 12 H 25 F 2 NO 8 P 2 [M-H] - 410.0951,found 410.0956；
compound I-7: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CD 3 OD)δ7.68(d,J＝6.4Hz,2H),7.49-7.47(m,1H),7.43(d,J＝7.6Hz,2H),4.32-4.27(m,2H),4.19(d,J＝7.6Hz,8H),3.35-3.34(m,1H),1.33(t,J＝4.0Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ170.0 133.9,130.4,128.3,127.5,63.2(d,J＝21.2Hz),45.2,33.4(t,J＝90.6Hz),15.2；
HRMS m/z calcd for C 17 H 29 NO 8 P 2 [M-H] - 436.1296,found 436.1299；
compound I-8: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝7.6Hz,2H),7.19(d,J＝8.0Hz,2H),4.36-4.34(d,J＝8.0Hz,2H),4.29-4.18(m,8H),3.21(t,J＝23.2Hz,1H),2.37(s,3H),1.40-1.34(m,12H). 13 C NMR(100MHz,CD 3 OD)δ170.0,141.0,130.9,128.5,128.1,63.2(d,J＝27.6Hz),45.4,33.4(t,J＝90.0Hz),20.1,15.3；
HRMS m/z calcd for C 18 H 31 NO 8 P 2 [M-H] - 450.1452,found 450.1453；
compound I-9: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.4Hz,2H),6.89(d,J＝8.8Hz,2H),4.30-4.19(m,10H),3.84(s,3H),3.22(t,J＝22.8Hz,1H),1.40-1.35(m,12H). 13 C NMR(100MHz,CD 3 OD)δ169.5,161.8,130.7,125.6,112.7,63.2(d,J＝26.4Hz),54.5,45.5,33.4(t,J＝90.4Hz),15.3；
HRMS m/z calcd for C 18 H 31 NO 9 P 2 [M-H] - 466.1401,found 466.1400.
compound I-10: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ8.12-8.09(m,1H),7.83-7.80(m,1H),7.13(t,J＝8.4Hz,1H),7.05(d,J＝8.4Hz,1H),4.34-4.25(m,2H),4.23-4.18(m,8H),3.22(t,J＝23.2Hz,1H),1.39(t,J＝8.0Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ166.8(d,J＝589.2Hz),163.2,131.1(d,J＝100.6Hz),131.1,114.4(d,J＝22.2Hz),63.2(d,J＝26.6Hz),45.2,33.4(t,J＝90.6Hz),15.3；
HRMS m/z calcd for C 17 H 28 FNO 8 P 2 [M-H] - 454.1201,found 454.1205；
compound I-11: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝7.2Hz,2H),7.44-7.39(m,2H),4.37-4.22(m,2H),4.25-4.20(m,8H),3.30-3.15(m,1H),1.38(d,J＝7.6Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ170.0,133.9,130.5,128.3,127.6,63.3(d,J＝24.0Hz),45.1,33.3(t,J＝90.6Hz),15.3；
HRMS m/z calcd for C 17 H 28 ClNO 8 P 2 [M-H] - 470.0906,found 470.0910；
compound I-12: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.81(t,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,1H),7.06-7.01(m,1H),4.37-4.33(m,2H),4.24-4.18(m,8H),3.18-3.06(m,1H),1.40-1.37(m,12H). 13 C NMR(100MHz,CD 3 OD)δ167.2,131.6(d,J＝30.2Hz),130.1(d,J＝6.2Hz),130.1,116.4(d,J＝25.8Hz),114.0(dd,J＝122.4,21.8Hz),63.3(d,J＝19.6Hz),44.0,33.6(t,J＝90.4Hz),15.3；
HRMS m/z calcd for C 18 H 28 F 3 NO 8 P 2 [M-H] - 504.1169,found 504.1168；
compound I-13: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.71-7.66(m,1H),7.62-7.58(m,1H),7.17(q,J＝8.8Hz,1H),4.35-4.27(m,2H),4.26-4.19(m,8H),3.18(t,J＝22.8Hz,1H),1.39(t,J＝8.4Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ167.2,151.5(dd,J＝251.6,12.6Hz),149.3(dd,J＝247.2,13.0Hz),131.0,125.9,118.1(d,J＝19.2Hz),116.6(d,J＝16.8Hz),63.2(d,J＝26.8Hz),45.0,33.4(t,J＝90.8Hz),15.3；
HRMS m/z calcd for C 17 H 27 F 2 NO 8 P 2 [M-H] - 472.1107,found 472.1108；
compound I-14: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.41-7.38(m,2H),7.30-7.27(m,1H),4.35-4.23(m,10H),3.15(t,J＝12.8Hz,1H),1.39(t,J＝7.6Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ169.9,133.9,131.6,130.4,128.3,127.6,126.9,63.2(d,J＝27.2Hz),45.2,33.4(t,J＝90.2Hz),15.3；
HRMS m/z calcd for C 17 H 27 Cl 2 NO 8 P 2 [M-H] - 504.0516,found 504.0517；
compound I-15: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.85(d,J＝7.6Hz,1H),7.65(d,J＝8.0Hz,2H),4.37-4.29(m,2H),4.25-4.15(m,8H),3.18(t,J＝22.8Hz,1H),1.41-1.35(m,12H). 13 C NMR(150MHz,CD 3 OD)δ168.5,138.0,131.7(d,J＝32.6Hz),128.9,127.8(d,J＝40.2Hz),124.5,63.2(d,J＝27.6Hz),44.5,33.3(t,J＝90.2Hz),15.2；
HRMS m/z calcd for C 17 H 27 ClFNO 8 P 2 [M-H] - 488.0812,found 488.0811；
compound I-16: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CD 3 OD)δ7.77(s,1H),7.16(t,J＝8.4Hz,2H),4.33-4.26(m,2H),4.19(d,J＝15.2Hz,8H),3.34(s,1H),1.33(t,J＝6.8Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ168.0,163.2(d,J＝175.4Hz),131.3,130.3,129.2,114.2(d,J＝22.4Hz),113.6(d,J＝21.8Hz),62.5(d,J＝28.8Hz),44.4,32.5(t,J＝90.0Hz),14.5；
HRMS m/z calcd for C 17 H 27 BrFNO 8 P 2 [M-H] - 532.0307,found 532.0308；
compound I-17: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ7.46(t,J＝7.2Hz,1H),7.38(d,J＝8.8Hz,1H),7.28-7.27(m,1H),4.34-4.19(m,10H),3.15-2.99(m,1H),1.39(t,J＝7.2Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ167.7,163.2,161.6,130.7(d,J＝8.4Hz),130.3,118.5(d,J＝21.6Hz),113.3(d,J＝25.4Hz),63.3(d,J＝17.6Hz),44.0,15.3；
HRMS m/z calcd for C 18 H 27 F 4 NO 8 P 2 [M-H] - 522.1075,found 522.1076；
compound I-18: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 ) 1 H NMR(400MHz,CDCl 3 )δ7.18(d,J＝7.6Hz,1H),7.11-7.03(m,1H),4.36-4.17(m,10H),3.17-3.02(m,1H),1.40(t,J＝6.4Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ165.2,154.9(d,J＝46.2Hz),153.3(d,J＝41.6Hz),123.0(d,J＝66.8Hz),117.8(d,J＝26.8Hz),116.5(d,J＝18.2Hz),115.6,63.3(d,J＝19.2Hz),44.1,32.3(t,J＝90.6Hz),15.3；
HRMS m/z calcd for C 17 H 26 ClF 2 NO 8 P 2 [M-H] - 506.0717,found 506.0718；
compound I-19: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ6.68(t,J＝8.4Hz,2H),4.30-4.19(m,10H),3.15-3.04(m,1H),1.39(q,J＝6.4Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ163.5(d,J＝170.2Hz),161.1,159.6(d,J＝170.2Hz),100.1,100.1(d,J＝33.2Hz),63.3(d,J＝8.6Hz),44.2,33.8(t,J＝90.6Hz),15.2；
HRMS m/z calcd for C 17 H 26 F 3 NO 8 P 2 [M-H] - 490.1013,found 490.1015；
compound I-20: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,CDCl 3 )δ4.30-4.20(m,10H),3.14-3.01(m,1H),1.42-1.38(m,12H). 13 C NMR(100MHz,CD 3 OD)δ158.3,143.1(d,J＝170.2Hz),141.8(d,J＝170.2Hz),137.4(d,J＝168.4Hz),110.8,63.3(d,J＝6.8Hz),44.3,33.8(t,J＝90.2Hz),15.2；
HRMS m/z calcd for C 17 H 24 F 5 NO 8 P 2 [M-H] - 526.0825,found 526.0827；
compound I-21: the color of the product is colorless, the color is colorless, 1 H NMR(400MHz,DMSO-d 6 )δ7.32-7.20(m,5H),4.10-3.99(m,10H),3.70(s,2H),3.03(t,J＝24.4Hz,1H),1.21(t,J＝3.4Hz,12H). 13 C NMR(100MHz,CD 3 OD)δ172.4,134.9,129.2,128.0,126.4,63.2(d,J＝20.6Hz),43.9,38.7,33.5(t,J＝90.6Hz),15.3；
HRMS m/z calcd for C 18 H 31 NO 8 P 2 [M-H] - 450.1452,found 450.1450；
compound I-22: a white solid was used as a solid, 1 H NMR(400MHz,D 2 O)δ7.62(t,J＝7.2Hz,2H),7.19(t,J＝7.2Hz,2H),4.25(s,2H),2.97-2.82(m,1H). 13 C NMR(100MHz,D 2 O)δ169.4,163.7(d,J＝246.2Hz),131.2(d,J＝9.8Hz),130.1(d,J＝68.8Hz),115.1(d,J＝19.8Hz),47.0,39.1(t,J＝142.8Hz). 31 P NMR(162MHz,D 2 O)δ16.71；
HRMS m/z calcd for C 9 H 12 FNO 8 P 2 [M-H] - 341.9949,found 341.9952；
compound I-23: a white solid was used as a solid, 1 H NMR(400MHz,D 2 O)δ7.56(t,J＝7.6Hz,1H),7.44(s,1H),7.36-7.30(m,1H),4.21(s,2H),2.57-2.43(m,1H). 13 C NMR(100MHz,D 2 O)δ168.2,152.6(d,J＝9.2Hz),150.3(d,J＝46.8Hz),130.3,125.2,117.7,116.9,46.8,37.5(t,J＝92.8Hz). 31 P NMR(162MHz,D 2 O)δ16.73；
HRMS m/z calcd for C 9 H 11 F 2 NO 8 P 2 [M-H] - 359.9855,found 359.9853。
test example 2
The products prepared in examples 1 to 23 were tested for herbicidal activity, and Arabidopsis thaliana inhibitory activity was tested using the method reported in the reference (Pest Manag. Sci.2023.DOI:10.1002/ps. 7810) with the compound FOS (Pest Manag. Sci.2023.DOI:10.1002/ps. 7810) as a comparative compound;
weighing a certain mass of a compound to be tested, dissolving with little DMF as possible, diluting with distilled water to prepare solutions to be tested with the concentration of 1000mg/L, 500mg/L, 250mg/L, 100mg/L and 10mg/L, and preparing the solutions with DMF and water as blank references;
0.62g of 1/2MS medium and 3mg of FeSO 4 7H 2 2.5g of O and 2.5g of sucrose are dissolved in 250mL of deionized water, the pH is adjusted to 5.8-6.0 by adding sodium hydroxide, and then 0.125g of 2-morpholinoethanesulfonic acid and 2.0g of agar powder are added into the solution to prepare the growth medium. Sterilizing a growth culture medium at high temperature and high pressure, moving the growth culture medium into a super clean bench after ultraviolet sterilization, sucking 0.9mL of the growth culture medium into a 24-pore plate in the super clean bench, adding 0.1mL of prepared solutions to be tested with different concentrations into each pore to ensure that the testing concentration is 100mg/L, 50mg/L, 25mg/L, 10mg/L and 1mg/L, taking a proper amount of seeds into a 1.5mL centrifuge tube, adding 75% (volume fraction) alcohol into the centrifuge tube, shaking for 30 seconds, washing 2-3 times with water (sterilized), sucking the seeds onto filter paper by a pipette, naturally airing, solidifying the 24-pore plate growth culture medium, dipping the seeds to the surface of the growth culture medium, uniformly dipping 6 seeds into each pore, and carrying out three groups of parallel experiments on each compound to be tested;
placing the 24 pore plates in a refrigerator at 4 ℃ for 2 days, taking out the 24 pore plates after 2 days, and placing the 24 pore plates in a climatic chamber, wherein the growth conditions in the first stage are that the temperature is 25 ℃, the humidity is 60%, the illumination time is 16h, and the illumination intensity is 7k lux; the second stage has a temperature of 25deg.C, a humidity of 60%,8 hours at night; growing for 8-10 days, stopping culturing when 5 th leaf is about to grow out, shooting the growth condition of each pore plate by using a digital camera, treating the shot picture with Adobe Photoshop, measuring the green channel pixel value of each pore Arabidopsis, calculating the inhibition rate, wherein the inhibition rate is = (1-experimental group pixel value/reference group pixel value) ×100%, calculating the concentration of the compound to be tested with 50% inhibition rate according to the growth inhibition rate of the compound to be tested to Arabidopsis at different concentrations, and using EC 50 (mg/L) shows the test results shown in Table 3, FIG. 1 is EC 50 An experimental group of 14 compounds of formula (I) and compound FOS below 100mg/L and a blank reference group showed inhibitory effects on Arabidopsis at different concentrations.
TABLE 3 Table 3
| Compounds of formula (I) | EC 50 (mg/L) | Compounds of formula (I) | EC 50 (mg/L) | Compounds of formula (I) | EC 50 (mg/L) |
| I-1 | >100 | I-9 | >100 | I-17 | 53.6±3.2 |
| I-2 | >100 | I-10 | 1.6±0.2 | I-18 | 52.5±4.8 |
| I-3 | >100 | I-11 | 33.4±3.4 | I-19 | >100 |
| I-4 | >100 | I-12 | 20.4±3.5 | I-20 | >100 |
| I-5 | >100 | I-13 | 1.1±0.2 | I-21 | 15.7±1.7 |
| I-6 | >100 | I-14 | 11.1±1.4 | I-22 | 42.1±3.5 |
| I-7 | 9.4±1.1 | I-15 | 2.0±0.3 | I-23 | 30.8±2.9 |
| I-8 | 51.2±4.2 | I-16 | 6.5±1.0 | FOS | 28.8±2.5 |
As can be seen from Table 3, the compounds prepared in examples 7 to 8, examples 10 to 18 and examples 21 to 23 have a remarkable inhibitory effect on Arabidopsis thaliana, EC 50 Between 1.1 and 53.6mg/L, wherein the compounds prepared in example 7, example 10, examples 12-16 and example 21 have better inhibitory activity against Arabidopsis thaliana than the compound FOS.
As can be seen from FIG. 1, all the test compounds showed concentration-dependent growth inhibition and albinism on Arabidopsis thaliana as the compound FOS, and the growth inhibition activity increased with the increase of the concentration, and the compound I-10, the compound I-13 and the compound I-15 showed strong inhibition on Arabidopsis thaliana at the concentration of 10mg/L, whereas the compound FOS showed only a low inhibition.
Test example 3
The products prepared in examples 1 to 23 were tested for pre-emergence herbicidal activity using the compound FOS (Pest Manag. Sci.2023.DOI: 10.1002/ps.7810) as a control compound and the methods reported in the reference (J. Agric. Food chem.2020,68,3071) were used for pre-emergence herbicidal activity testing;
weighing a certain mass of a compound to be tested, dissolving the compound with a small amount of DMF (dimethyl formamide), adding a drop of Tween-80 emulsifier, diluting the compound with distilled water to prepare solutions to be tested with the concentration of 100mg/L, 50mg/L, 25mg/L, 10mg/L and 1mg/L, and preparing the solutions with Tween-80, DMF and water as blank references;
the weeding activity is tested by a culture dish method, the model plants are dicotyledonous plants (rape) and monocotyledonous plants (barnyard grass), filter paper with the diameter of 9cm is paved in the culture dish, 9mL of compound solution to be tested is sucked and added into different culture dishes, then seeds of 10-15 model plants are placed on the filter paper and are transferred into a climatic chamber for culture, the culture condition is that the temperature is 25 ℃ and the humidity is 70%, the culture is firstly carried out for 3 days in the dark at constant temperature, then the illumination is carried out for 12 hours (illuminance is 10 Klux) each day, the darkness is carried out for 12 hours, and the culture is continued for 4 days. Randomly selecting 3 plants of two modes from each culture dish, measuring root and stem lengths, respectively, and calculating inhibition ratio = (1-experiment group root/stem length +.reference group root/stem length) ×100%, calculating concentration of compound to be tested with 50% growth inhibition ratio according to growth inhibition ratio of compound to be tested to root and stem of mode plant, using EC 50 (mg/L) and the test results are shown in Table 4.
TABLE 4 Table 4
As can be seen from Table 4, the compounds prepared in examples 4-18 and examples 20-23 have significant pre-emergence inhibitory activity on both roots and stems of the model plants rape and barnyard grass, which inhibitory activity is higher or comparable to that of the comparative compound FOS, and the compounds I-10, I-13 and I-16 have EC on rape roots 50 The value is less than 1mg/L, and the EC of the rape stem is controlled 50 The values were 6.6, 7.5 and 13.2mg/L, respectively, whereas the compound FOS corresponds to EC 50 Values as high as 28.5 and 31.8mg/L; in addition, compound I-10 and Compound I-13 against barnyard grassEC of grass root 50 The values are 8.7 and 16.6mg/L, respectively, and EC against barnyard grass stems 50 Values of 3.8 and 8.5mg/L, respectively, lower than the corresponding EC for the compound FOS 50 Values.
Test example 4
The products prepared in examples 1-23 were tested for algicidal activity, and blue algae inhibitory activity was tested using the method reported in reference (J.Agric.food chem.2019,67,12538) with the compound FOS (Pest Manag.Sci.2023.DOI: 10.1002/ps.7810) as a control compound;
use of commercial algicides CuSO 4 As a blank reference, inhibition activities of test compounds on Agrocytococcus PCC6803 and Microcystis aeruginosa FACHB905 were measured using 96-well plates, blue algae were cultured in BG11 growth medium to logarithmic phase, then 1mL of blue algae culture solution was diluted 100 times and transferred to fresh BG11 growth medium with test compound concentrations of 100. Mu.M, 50. Mu.M, 25. Mu.M, 10. Mu.M and 1. Mu.M, respectively, after 7 days of culture, absorbance (OD) at 680 nm wavelength was measured for each well 680 ) And the inhibition ratio was calculated, inhibition ratio= (1-experimental group OD 680 Reference group OD 680 ) X 100%, calculating the concentration of the compound to be tested with 50% blue algae inhibition rate according to the inhibition rate of the compound to be tested with different concentrations, and using EC 50 (. Mu.M) shows the test results shown in Table 5.
TABLE 5
As can be seen from Table 5, the hydroxamic acid-containing bisphosphonates of the present invention have overall higher inhibitory activity against FACHB905 than PCC6803, while the compounds prepared in examples 6-8, examples 10-13 and examples 15-16 have better inhibitory activity against blue algae growth than the comparative compound FOS. Wherein, compound I-7, compound I-10 and Compound I-13 are directed to FACHB905EC 50 The values were 2.5. Mu.M, 1.8. Mu.M and 1.7. Mu.M, respectively, with higher inhibitory activity than the commercial algicide CuSO 4 Or equivalent thereto.
In conclusion, the bisphosphonate containing hydroxamic acid has obvious growth inhibition effect on the mode plants and blue algae, has high growth inhibition activity on the mode plants and blue algae, and has good application prospect in the aspects of preparing herbicides and algicides.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (10)
1. A bisphosphonate containing hydroxamic acid is characterized in that the structural formula is shown as formula (I),
wherein R is 1 And R is 2 Each independently selected from hydrogen, alkyl, alkoxyalkyl or acyloxyalkyl, R 3 Selected from hydrogen, alkyl, difluoromethyl, phenyl, substituted phenyl or benzyl.
2. The hydroxamic acid-containing bisphosphonate according to claim 1, wherein R 1 And R is 2 Each independently selected from hydrogen or ethyl, R 3 Selected from hydrogen, alkyl, difluoromethyl, phenyl, substituted phenyl or benzyl.
3. The hydroxamic acid-containing bisphosphonate according to claim 1 or 2, characterized in that the hydroxamic acid-containing bisphosphonate is at least one of the following compounds:
compounds of formula (I)I-1：R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is H;
compound I-2: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 3 ；
Compound I-3: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 2 CH 3 ；
Compound I-4: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is- (CH) 2 ) 2 CH 3 ；
Compound I-5: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-C (CH) 3 ) 3 ；
Compound I-6: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CHF 2 ；
Compound I-7: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-Ph;
compound I-8: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-CH 3 -Ph；
Compound I-9: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-OCH 3 -Ph；
Compound I-10: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 4-F-Ph;
compound I-11: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 4-Cl-Ph;
compound I-12: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 4-CF 3 -Ph；
Compound I-13: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 3,4-diF-Ph;
compound I-14: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 3, 4-dich-Ph;
compound I-15: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 2-Cl-4-F-Ph;
compound I-16: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 3-Br-4-F-Ph;
compound I-17: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is 2-CF 3 -4-F-Ph；
Compound I-18: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 2,6-diF-4-Cl-Ph;
compound I-19: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 2,4, 6-tri-F-Ph;
compound I-20: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 Is pentaF-Ph;
compound I-21: r is R 1 is-CH 2 CH 3 ，R 2 is-CH 2 CH 3 ，R 3 is-CH 2 Ph；
Compound I-22: r is R 1 Is H, R 2 Is H, R 3 4-F-Ph;
compound I-23: r is R 1 Is H, R 2 Is H, R 3 3,4-diF-Ph.
4. A process for preparing a hydroxamic acid-containing bisphosphonate according to any of claims 1-3, characterized in that the process comprises the steps of:
s1: carrying out condensation reaction on a compound shown in a formula (1) and paraformaldehyde, and then carrying out dehydration reaction to obtain a compound shown in a formula (2);
s2: carrying out Michael addition reaction on a compound shown in the formula (2) and O-benzyl hydroxylamine to obtain a compound shown in the formula (3);
s3: reacting a compound shown in a formula (3) with a compound A to obtain a compound shown in a formula (4), wherein the compound A is carboxylic acid or acyl chloride;
s4: debenzylating a compound shown in a formula (4) with hydrogen;
wherein R is 1 、R 2 And R is 3 Is as defined in claim 1.
5. The method according to claim 4, wherein in step S1, the condensation reaction is performed in the presence of a first organic base, and the dehydration reaction is performed in the presence of a first catalyst;
preferably, the amount of the first organic base is 1 to 2 molar equivalents relative to 1 molar equivalent of the amount of the compound represented by formula (1);
preferably, the first catalyst is an organic acid, and the amount of the organic acid is 0.05% -1% molar equivalent to 1 molar equivalent of the compound represented by formula (1);
preferably, the conditions of the condensation reaction include: the temperature is 60-100 ℃ and the time is 10-16h;
preferably, the conditions of the dehydration reaction include: the temperature is 100-130 ℃ and the time is 12-36h.
6. The method according to claim 4, wherein in the step S2, the O-benzylhydroxylamine is used in an amount of 1.1 to 1.5 molar equivalents relative to 1 molar equivalent of the compound represented by the formula (2);
preferably, the conditions of the michael addition reaction include: the temperature is 10-30 ℃ and the time is 4-6h.
7. The process according to claim 4, wherein in step S3, the reaction is carried out in the presence of a second organic base;
preferably, the carboxylic acid or acid chloride is used in an amount of 1.1 to 1.5 molar equivalents relative to 1 molar equivalent of the compound of formula (3);
preferably, the reaction conditions include: the temperature is 10-30 ℃ and the time is 6-12h.
8. The process according to claim 4, wherein in step S4, the debenzylation reaction is carried out in the presence of a second catalyst;
preferably, the second catalyst is a metal catalyst, and the amount of the metal catalyst is 0.05 to 0.2 molar equivalents with respect to the amount of the compound represented by the formula (4) of 1 molar equivalent;
preferably, the pressure of the hydrogen is 1-4atm;
preferably, the conditions of the debenzylation reaction include: the temperature is 10-30 ℃ and the time is 2-4h.
9. Use of a bisphosphonate containing hydroxamic acid according to any of claims 1-3 in the preparation of a herbicide.
10. Use of a bisphosphonate containing hydroxamic acid according to any of claims 1-3 in the preparation of an algicide.
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