CN114213403A - 1,2, 4-oxadiazole-5-formamide derivatives and preparation method and application thereof - Google Patents
1,2, 4-oxadiazole-5-formamide derivatives and preparation method and application thereof Download PDFInfo
- Publication number
- CN114213403A CN114213403A CN202111553516.5A CN202111553516A CN114213403A CN 114213403 A CN114213403 A CN 114213403A CN 202111553516 A CN202111553516 A CN 202111553516A CN 114213403 A CN114213403 A CN 114213403A
- Authority
- CN
- China
- Prior art keywords
- oxadiazole
- carboxamide
- pyridin
- ethyl
- preparation
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 80
- RCOJRSOHHFTHDJ-UHFFFAOYSA-N 1,2,4-oxadiazole-5-carboxamide Chemical class NC(=O)C1=NC=NO1 RCOJRSOHHFTHDJ-UHFFFAOYSA-N 0.000 title claims abstract description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 123
- -1 oxalyl chloride monoethyl ester Chemical class 0.000 claims abstract description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 30
- 241000196324 Embryophyta Species 0.000 claims abstract description 27
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 240000007594 Oryza sativa Species 0.000 claims abstract description 19
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 19
- 235000009566 rice Nutrition 0.000 claims abstract description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 18
- 241000134843 Aphelenchoides besseyi Species 0.000 claims abstract description 14
- 241000243786 Meloidogyne incognita Species 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 13
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims abstract description 12
- 240000003768 Solanum lycopersicum Species 0.000 claims abstract description 12
- 241000243771 Bursaphelenchus xylophilus Species 0.000 claims abstract description 8
- 241000244203 Caenorhabditis elegans Species 0.000 claims abstract description 8
- 238000007792 addition Methods 0.000 claims abstract description 7
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 62
- 238000006243 chemical reaction Methods 0.000 claims description 55
- 238000005406 washing Methods 0.000 claims description 54
- 239000007787 solid Substances 0.000 claims description 38
- 230000002829 reductive effect Effects 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 34
- 238000004440 column chromatography Methods 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 32
- 239000003208 petroleum Substances 0.000 claims description 31
- 238000001035 drying Methods 0.000 claims description 29
- 230000008569 process Effects 0.000 claims description 25
- 241000244206 Nematoda Species 0.000 claims description 23
- 239000007788 liquid Substances 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 229920006395 saturated elastomer Polymers 0.000 claims description 19
- 235000002639 sodium chloride Nutrition 0.000 claims description 19
- 238000000967 suction filtration Methods 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 15
- 230000000843 anti-fungal effect Effects 0.000 claims description 12
- 230000002147 killing effect Effects 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical class N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- WWTUOASJEXMWFG-UHFFFAOYSA-N O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NC(C=CC(Cl)=C1)=C1Cl Chemical compound O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NC(C=CC(Cl)=C1)=C1Cl WWTUOASJEXMWFG-UHFFFAOYSA-N 0.000 claims description 5
- QTMPSJXLOUBMEC-UHFFFAOYSA-N O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NCC(C=CC(F)=C1)=C1F Chemical compound O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NCC(C=CC(F)=C1)=C1F QTMPSJXLOUBMEC-UHFFFAOYSA-N 0.000 claims description 5
- ZHNWMIHNNDUMOD-UHFFFAOYSA-N O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NCCC1=NC=CC=C1 Chemical compound O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NCCC1=NC=CC=C1 ZHNWMIHNNDUMOD-UHFFFAOYSA-N 0.000 claims description 5
- BCCAPNRWKFGDTA-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CS2)=NO1)NCC(C=CC(F)=C1)=C1F Chemical compound O=C(C1=NC(C2=CC=CS2)=NO1)NCC(C=CC(F)=C1)=C1F BCCAPNRWKFGDTA-UHFFFAOYSA-N 0.000 claims description 5
- PQYBWXXLMMDWBE-UHFFFAOYSA-N O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NC(C=CC(Cl)=C1)=C1Cl Chemical compound O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NC(C=CC(Cl)=C1)=C1Cl PQYBWXXLMMDWBE-UHFFFAOYSA-N 0.000 claims description 5
- BWVLSRSLTZBNEK-UHFFFAOYSA-N O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NCC(C=CC(F)=C1)=C1F Chemical compound O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NCC(C=CC(F)=C1)=C1F BWVLSRSLTZBNEK-UHFFFAOYSA-N 0.000 claims description 5
- ACJHIAJXJGSQEV-UHFFFAOYSA-N O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl Chemical compound O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl ACJHIAJXJGSQEV-UHFFFAOYSA-N 0.000 claims description 5
- QXQDRWIGGXKPHV-UHFFFAOYSA-N O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NCCC1=NC=CC=C1 Chemical compound O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)NCCC1=NC=CC=C1 QXQDRWIGGXKPHV-UHFFFAOYSA-N 0.000 claims description 5
- VIHRPIDUJKPZIZ-UHFFFAOYSA-N CC(C=C1)=CC=C1C1=NOC(C(NC(C=CC(Cl)=C2)=C2Cl)=O)=N1 Chemical compound CC(C=C1)=CC=C1C1=NOC(C(NC(C=CC(Cl)=C2)=C2Cl)=O)=N1 VIHRPIDUJKPZIZ-UHFFFAOYSA-N 0.000 claims description 4
- ZBPUXGQPZSWAML-UHFFFAOYSA-N CC(C=C1)=CC=C1C1=NOC(C(NCC(C=CC(F)=C2)=C2F)=O)=N1 Chemical compound CC(C=C1)=CC=C1C1=NOC(C(NCC(C=CC(F)=C2)=C2F)=O)=N1 ZBPUXGQPZSWAML-UHFFFAOYSA-N 0.000 claims description 4
- QKLFLLNVZWMKIW-UHFFFAOYSA-N CC(C=C1)=CC=C1C1=NOC(C(NCCC2=NC=C(C(F)(F)F)C=C2Cl)=O)=N1 Chemical compound CC(C=C1)=CC=C1C1=NOC(C(NCCC2=NC=C(C(F)(F)F)C=C2Cl)=O)=N1 QKLFLLNVZWMKIW-UHFFFAOYSA-N 0.000 claims description 4
- PVLKGJVMNULWSD-UHFFFAOYSA-N CC(C=C1)=CC=C1C1=NOC(C(NCCC2=NC=CC=C2)=O)=N1 Chemical compound CC(C=C1)=CC=C1C1=NOC(C(NCCC2=NC=CC=C2)=O)=N1 PVLKGJVMNULWSD-UHFFFAOYSA-N 0.000 claims description 4
- YTOVCTSOGBYKMS-UHFFFAOYSA-N O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NC(C=CC(Cl)=C1)=C1Cl Chemical compound O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NC(C=CC(Cl)=C1)=C1Cl YTOVCTSOGBYKMS-UHFFFAOYSA-N 0.000 claims description 4
- BIYPZESYSJFGJM-UHFFFAOYSA-N O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NCC(C=CC(F)=C1)=C1F Chemical compound O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NCC(C=CC(F)=C1)=C1F BIYPZESYSJFGJM-UHFFFAOYSA-N 0.000 claims description 4
- CGTOXAQKHVOUQB-UHFFFAOYSA-N O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NCCC1=NC=CC=C1 Chemical compound O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NCCC1=NC=CC=C1 CGTOXAQKHVOUQB-UHFFFAOYSA-N 0.000 claims description 4
- BKSXDSBIJQWCDB-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CC=C2)=NO1)NC(C=CC(Cl)=C1)=C1Cl Chemical compound O=C(C1=NC(C2=CC=CC=C2)=NO1)NC(C=CC(Cl)=C1)=C1Cl BKSXDSBIJQWCDB-UHFFFAOYSA-N 0.000 claims description 4
- UNWKEUUFZHPLGK-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CC=C2)=NO1)NCC(C=CC(F)=C1)=C1F Chemical compound O=C(C1=NC(C2=CC=CC=C2)=NO1)NCC(C=CC(F)=C1)=C1F UNWKEUUFZHPLGK-UHFFFAOYSA-N 0.000 claims description 4
- KGDGMCNVYBFNFV-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CC=C2)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl Chemical compound O=C(C1=NC(C2=CC=CC=C2)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl KGDGMCNVYBFNFV-UHFFFAOYSA-N 0.000 claims description 4
- NRGQWSDDHVKXGM-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CS2)=NO1)NC(C=CC(Cl)=C1)=C1Cl Chemical compound O=C(C1=NC(C2=CC=CS2)=NO1)NC(C=CC(Cl)=C1)=C1Cl NRGQWSDDHVKXGM-UHFFFAOYSA-N 0.000 claims description 4
- RSUIWQSXTREURV-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CS2)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl Chemical compound O=C(C1=NC(C2=CC=CS2)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl RSUIWQSXTREURV-UHFFFAOYSA-N 0.000 claims description 4
- ACBMFCVRVRTPFI-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CS2)=NO1)NCCC1=NC=CC=C1 Chemical compound O=C(C1=NC(C2=CC=CS2)=NO1)NCCC1=NC=CC=C1 ACBMFCVRVRTPFI-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 150000003948 formamides Chemical class 0.000 claims description 4
- 241000221696 Sclerotinia sclerotiorum Species 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229940121375 antifungal agent Drugs 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 241000221662 Sclerotinia Species 0.000 abstract description 20
- 235000006008 Brassica napus var napus Nutrition 0.000 abstract description 17
- 239000000575 pesticide Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 240000000385 Brassica napus var. napus Species 0.000 abstract description 4
- 206010059866 Drug resistance Diseases 0.000 abstract description 2
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 24
- 230000005764 inhibitory process Effects 0.000 description 18
- 241000233866 Fungi Species 0.000 description 16
- 244000060924 Brassica campestris Species 0.000 description 15
- 230000001069 nematicidal effect Effects 0.000 description 13
- 239000005783 Fluopyram Substances 0.000 description 12
- KVDJTXBXMWJJEF-UHFFFAOYSA-N fluopyram Chemical compound ClC1=CC(C(F)(F)F)=CN=C1CCNC(=O)C1=CC=CC=C1C(F)(F)F KVDJTXBXMWJJEF-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- 239000013641 positive control Substances 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 6
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 6
- 241000243770 Bursaphelenchus Species 0.000 description 6
- KLKDWFJWOMSDKZ-UHFFFAOYSA-N O1C(C(=O)Cl)=NC(C=2C=CC=CC=2)=N1 Chemical compound O1C(C(=O)Cl)=NC(C=2C=CC=CC=2)=N1 KLKDWFJWOMSDKZ-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000001681 protective effect Effects 0.000 description 6
- 150000001408 amides Chemical group 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 150000003141 primary amines Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- IHNSIFFSNUQGQN-UHFFFAOYSA-N tioxazafen Chemical compound C1=CSC(C=2ON=C(N=2)C=2C=CC=CC=2)=C1 IHNSIFFSNUQGQN-UHFFFAOYSA-N 0.000 description 5
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 4
- AHZQBNLUGQVHBV-UHFFFAOYSA-N CC(C=C1)=CC=C1C1=NOC(C(Cl)=O)=N1 Chemical compound CC(C=C1)=CC=C1C1=NOC(C(Cl)=O)=N1 AHZQBNLUGQVHBV-UHFFFAOYSA-N 0.000 description 4
- UBTNMUDJFYKECW-UHFFFAOYSA-N O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)Cl Chemical compound O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)Cl UBTNMUDJFYKECW-UHFFFAOYSA-N 0.000 description 4
- OPJBZQYESNKXPY-UHFFFAOYSA-N O=C(C1=NC(C(C=C2)=NC=C2Br)=NO1)Cl Chemical compound O=C(C1=NC(C(C=C2)=NC=C2Br)=NO1)Cl OPJBZQYESNKXPY-UHFFFAOYSA-N 0.000 description 4
- AKKXCODPRFFZFR-UHFFFAOYSA-N O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl Chemical compound O=C(C1=NC(C(C=N2)=CC=C2Br)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl AKKXCODPRFFZFR-UHFFFAOYSA-N 0.000 description 4
- LOIWPXNWHBEBSR-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CS2)=NO1)Cl Chemical compound O=C(C1=NC(C2=CC=CS2)=NO1)Cl LOIWPXNWHBEBSR-UHFFFAOYSA-N 0.000 description 4
- STZXKGQNQGTUMH-UHFFFAOYSA-N O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)Cl Chemical compound O=C(C1=NC(C2=NC=C(C(F)(F)F)C=C2Cl)=NO1)Cl STZXKGQNQGTUMH-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 230000000855 fungicidal effect Effects 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000005645 nematicide Substances 0.000 description 4
- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 description 3
- OMPOBDCBGHUPBD-UHFFFAOYSA-N 3-phenyl-1,2,4-oxadiazole-5-carboxylic acid Chemical compound O1C(C(=O)O)=NC(C=2C=CC=CC=2)=N1 OMPOBDCBGHUPBD-UHFFFAOYSA-N 0.000 description 3
- 240000008067 Cucumis sativus Species 0.000 description 3
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 3
- 239000005531 Flufenacet Substances 0.000 description 3
- FJKRPJQNQBGLAG-UHFFFAOYSA-N O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl Chemical compound O=C(C1=NC(C(C=C2)=CC=C2Cl)=NO1)NCCC1=NC=C(C(F)(F)F)C=C1Cl FJKRPJQNQBGLAG-UHFFFAOYSA-N 0.000 description 3
- VNMLFNRQYTVSFG-UHFFFAOYSA-N O=C(C1=NC(C2=CC=CC=C2)=NO1)NCCC1=NC=CC=C1 Chemical compound O=C(C1=NC(C2=CC=CC=C2)=NO1)NCCC1=NC=CC=C1 VNMLFNRQYTVSFG-UHFFFAOYSA-N 0.000 description 3
- 239000003899 bactericide agent Substances 0.000 description 3
- VDEUYMSGMPQMIK-UHFFFAOYSA-N benzhydroxamic acid Chemical compound ONC(=O)C1=CC=CC=C1 VDEUYMSGMPQMIK-UHFFFAOYSA-N 0.000 description 3
- IANUJLZYFUDJIH-UHFFFAOYSA-N flufenacet Chemical compound C=1C=C(F)C=CC=1N(C(C)C)C(=O)COC1=NN=C(C(F)(F)F)S1 IANUJLZYFUDJIH-UHFFFAOYSA-N 0.000 description 3
- 239000000417 fungicide Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- IGLWCQMNTGCUBB-UHFFFAOYSA-N 3-methylidenepent-1-ene Chemical compound CCC(=C)C=C IGLWCQMNTGCUBB-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 2
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 229940054066 benzamide antipsychotics Drugs 0.000 description 2
- 150000003936 benzamides Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- GELVILJIMYOEPI-UHFFFAOYSA-N 3-thiophen-2-yl-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical class O1C(C(F)(F)F)=NC(C=2SC=CC=2)=N1 GELVILJIMYOEPI-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 1
- 239000005660 Abamectin Substances 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 235000014698 Brassica juncea var multisecta Nutrition 0.000 description 1
- 235000006618 Brassica rapa subsp oleifera Nutrition 0.000 description 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- AVEZUJSJNYYIDD-UHFFFAOYSA-N Cc1ncccc1C(=O)Nc2ccccn2 Chemical group Cc1ncccc1C(=O)Nc2ccccn2 AVEZUJSJNYYIDD-UHFFFAOYSA-N 0.000 description 1
- 241000222199 Colletotrichum Species 0.000 description 1
- 102000015833 Cystatin Human genes 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- 241001115619 Diaporthe sterilis Species 0.000 description 1
- 208000035240 Disease Resistance Diseases 0.000 description 1
- 239000005959 Fosthiazate Substances 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 244000284380 Hibiscus rosa sinensis Species 0.000 description 1
- 241001330975 Magnaporthe oryzae Species 0.000 description 1
- 241000243785 Meloidogyne javanica Species 0.000 description 1
- 239000005950 Oxamyl Substances 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 241000233679 Peronosporaceae Species 0.000 description 1
- 241000233614 Phytophthora Species 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
- 241001281803 Plasmopara viticola Species 0.000 description 1
- 241000500441 Plutellidae Species 0.000 description 1
- 241000221300 Puccinia Species 0.000 description 1
- 239000005869 Pyraclostrobin Substances 0.000 description 1
- 241001361634 Rhizoctonia Species 0.000 description 1
- 235000000664 Rosa chinensis Nutrition 0.000 description 1
- 241000256247 Spodoptera exigua Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 241000219094 Vitaceae Species 0.000 description 1
- 229950008167 abamectin Drugs 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 108050004038 cystatin Proteins 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- GIGKBTJPLNTFON-UHFFFAOYSA-N ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate Chemical compound O1C(C(=O)OCC)=NC(C=2C=CC=CC=2)=N1 GIGKBTJPLNTFON-UHFFFAOYSA-N 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- DUFVKSUJRWYZQP-UHFFFAOYSA-N fosthiazate Chemical compound CCC(C)SP(=O)(OCC)N1CCSC1=O DUFVKSUJRWYZQP-UHFFFAOYSA-N 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000021021 grapes Nutrition 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- KZAUOCCYDRDERY-UHFFFAOYSA-N oxamyl Chemical compound CNC(=O)ON=C(SC)C(=O)N(C)C KZAUOCCYDRDERY-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000012015 potatoes Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HZRSNVGNWUDEFX-UHFFFAOYSA-N pyraclostrobin Chemical compound COC(=O)N(OC)C1=CC=CC=C1COC1=NN(C=2C=CC(Cl)=CC=2)C=C1 HZRSNVGNWUDEFX-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the field of chemical industry and pesticides, in particular to a 1,2, 4-oxadiazole-5-formamide derivative, a preparation method of the 1,2, 4-oxadiazole-5-formamide derivative and application of the 1,2, 4-oxadiazole-5-formamide derivative in preparation of drugs for preventing and treating plant diseases such as rice sheath blight, tomato gray mold, sclerotinia rot of colza, meloidogyne incognita, pine wood nematode, aphelenchoides besseyi and caenorhabditis elegans, wherein the derivative is prepared by taking substituted arylnitrile, hydroxylamine hydrochloride, sodium hydroxide, oxalyl chloride monoethyl ester, triethylamine, lithium hydroxide, oxalyl chloride and primary amine as raw materials through addition, cyclization, hydrolysis, chloracylation and substitution reaction respectively, has low toxicity, high yield, easy degradation and good environmental compatibility, high safety, simple preparation process, low production cost, simple structure and difficult generation of drug resistance.
Description
Technical Field
The invention relates to the field of chemical industry and pesticides, in particular to a 1,2, 4-oxadiazole-5-carboxamide derivative, a preparation method of the 1,2, 4-oxadiazole-5-carboxamide derivative, and application of the 1,2, 4-oxadiazole-5-carboxamide derivative in preparation of a drug for preventing and treating plant diseases such as rice sheath blight disease, tomato gray mold, sclerotinia rot, meloidogyne incognita, pine wood nematode, aphelenchoides besseyi and caenorhabditis elegans.
Background
In recent years, plant diseases caused by fungi and nematodes have become increasingly serious, and the viability and health of plants are greatly threatened. Worse still, the combination of fungi and nematodes tends to produce a synergistic effect, with crop losses greater than those caused by each pathogen alone or both. Up to now, more than 8000 fungi have been known to cause plant diseases, the most serious of which include gray mold, sclerotinia rot of colza, rice sheath blight, saprolegniasis, anthracnose, fusarium, puccinia, phytophthora and magnaporthe oryzae, which cause 85% of plant diseases, and these fungi cause economic losses of crops worldwide. Meanwhile, meloidogyne incognita, aphelenchoides besseyi and bursaphelenchus xylophilus are plant parasitic nematodes which cause serious damage to agriculture and forestry, respectively. Worldwide agricultural losses due to plant parasitic nematodes are reported to be as high as $ 1570 million each year. To date, the most effective and useful methods for controlling fungi and nematodes remain chemical agents. However, abuse of existing pesticides has led to the emergence of resistant microorganisms, further exacerbating the overall management of this situation, and lack of reports on co-control of fungi and nematodes. Therefore, it is essential to develop efficient, low-toxic, non-drug resistant pesticides to effectively control these plant diseases.
In recent years, 1,2, 4-oxadiazole compounds are also found to have better plant nematode killing activity, wherein representative compounds such as Tioxazafen are found to have better control effect on crop root-knot nematodes through field experiments, and are considered to be the currently most promising 1,2, 4-oxadiazole nematicides in market development by the industry. In addition, fluopyram serving as a succinate dehydrogenase inhibitor containing an amide structure not only has antibacterial activity but also has nematicidal activity, and no cross resistance is found between fluopyram and other bactericides or succinate dehydrogenase inhibitors, but the field application cost is high. Therefore, there is a need to develop new agents with novel structure and low cost, which can kill bacteria and nematodes.
The inventor C, Brown, P-Y, Croullanden, C, Duboster, H, Racharis, S, Mekring, A-S, Rabosker, P, Heynolf, Zetian' S disease, U, Vochestofu-Newman, Chinese publication No. CN104470896A discloses a fungicidal 3- [ (pyridin-2-ylmethoxyimino) (phenyl) methyl ] -2-substituted-1, 2, 4-oxadiazol-5 (2H) -one derivative on 25/03/2015. Most of the compounds have good protective activity (> 70%) against tomato late blight at 500ppm and show more than 70% control effect against plasmopara viticola at 10 ppm.
The inventor has good luck, Liu Lian, Huenchen, Huan Qi, Wang Ming Hui, China publication No. CN108794462A in 2018, 11.13.8, discloses an oxadiazole insecticidal bactericide containing fluorine cyanimine thiazolidine substituent, a preparation method and application thereof, the compounds have good inhibitory activity on rice sheath blight bacteria, pepper colletotrichum, wheat gibberellic disease and Chinese rose downy mildew bacteria, wherein the inhibition rate of the compounds on the rice sheath blight bacteria is 76.7% at 50 mu g/mL; in addition, the compound also shows a certain insecticidal activity on diamond back moths and beet armyworms.
The inventor W.J.sWammySec, W.P.Xiaohakenson, China publication No. CN108371182A discloses a 3, 5-disubstituted-4, 5-dihydro-1, 2, 4-oxadiazole compound in 2018 at 08.07.h, and finds that the number of the root gall of cucumber seedlings treated by 8ppm of the compound is 0 through a small greenhouse experiment, and the grade score of the root gall of part of the compound is obviously lower than that of oxamyl and abamectin when the concentration is reduced to 1 ppm.
The inventor has discovered that ethylthio-pyridine-1, 2, 4-oxadiazole substituted benzamides have good biological activity on cucumber gray mold at a concentration of 100ppm, and the inhibition rate of part of the compounds is more than 60% but lower than that of positive control pyraclostrobin (81.4%) in Tanshizu, Tianxiayu, Yansen, Daili, and Zhangli, China publication No. CN111943944A at 11/17/2020.
The inventor has discovered 14 1,2, 4-oxadiazole bipyridyl substituted benzamides compounds in China publication No. CN111592533A in 28.08/2020 in narrow province, beautiful in summer, beautiful in field, and the preparation method and application thereof, and the series of compounds have better activity on sclerotinia rot of colza, gray mold of cucumber and rice sheath blight disease under 50ppm measured by a hypha growth inhibition method, wherein the inhibition rates of the compounds with the optimal activity on the three fungi are respectively 80.8, 90.5 and 84.8%.
The inventor T.J.Hoffman, D.Sterili, R.Lajen, Chinese publication No. CN112714764A discloses 3- (2-thienyl) -5- (trifluoromethyl) -1,2, 4-oxadiazole derivatives which can be used as agricultural chemical fungicides in 2021, 05 and 27, and the prevention effect of the compounds on brown induced diseases is determined by adopting a leaf disc method, and the therapeutic activity and the protective activity of most compounds on the brown induced diseases at 200ppm are more than 80 percent; in addition, the compound also shows good fungicidal activity on soybean rust and anthracnose.
The inventor, Stefin, Reye, Michel, Paul, Waoke, Chinese publication No. CN1665395A, published on 9/07 2005, discloses a synergistic fungicide composition of N- (2-pyridyl) methyl-3-pyridinecarboxylic acid amide derivatives and one or more other fungicides for controlling fungal diseases, which can compete well with fungi on potatoes, grapes and tomatoes.
In summary, the drug small molecule containing the 1,2, 4-oxadiazole structure not only has nematicidal activity but also has fungicidal activity, so that the structure has attracted extensive attention in pesticide creation. In addition, the amide structure is an important structure created by pesticide small molecules, and has wide-spectrum biological activity, such as fungus killing, nematode killing, insect killing and the like. However, these 1,2, 4-oxadiazole derivatives have the following problems: firstly, in the aspect of antifungal activity, part of compounds have good in-vitro antifungal activity, but the evaluation of in-vivo experiments is lacked, and the compounds are found to have higher dosage in the in-vivo experiments and are difficult to apply in fields; secondly, in the aspect of killing nematodes, the targeted nematodes are single, the main target is meloidogyne incognita, but the killing effect on other plant nematodes is unknown, for example, the killing activity on the pine wood nematodes and the aphelenchoides besseyi is not evaluated, and Tioxazafen serving as a nematicide is a rigid compound and lacks certain flexibility, so that the flexibility of the drug micromolecule is reduced; finally, it is found that the 1,2, 4-oxadiazole derivative has few reports on the aspects of plant fungus resistance and nematode disease resistance. Therefore, Tioxazafen is used as a lead compound, an amide group is skillfully introduced, a series of 1,2, 4-oxadiazole-5-formamide derivatives are synthesized, and the application of the 1,2, 4-oxadiazole-5-formamide derivatives in the aspects of plant fungus resistance and nematode resistance is reported.
Disclosure of Invention
The invention aims to overcome the defects and provide a 1,2, 4-oxadiazole-5-formamide derivative with excellent activity of resisting plant fungi and nematodes and simple structure, and a preparation method and application thereof.
The specific technical scheme is as follows:
the first purpose of the invention is to provide a 1,2, 4-oxadiazole-5-formamide derivative, which has the following structural general formula (I):
in the formula R1Is phenyl, 4-methylphenyl, 4-chlorophenyl, thienyl, 6-bromo-3 pyridyl or 3-chloro-5-trifluoromethylpyridyl;
R2is pyridyl, 3-chloro-5-trifluoromethylpyridyl, 2, 4-difluorobenzyl or 2, 4-dichlorophenyl;
n is 0, 1 or 2.
Preferably, the 1,2, 4-oxadiazole-5-carboxamide derivatives include the following compounds:
compound F1: n- (2- (pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide;
compound F2: n- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide;
compound F3: n- (2, 4-difluorobenzyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide;
compound F4: n- (2, 4-dichlorophenyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide;
compound F5: n- (2- (pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F6: n- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F7: n- (2, 4-difluorobenzyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F8: n- (2, 4-dichlorophenyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F9: n- (2- (pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F10: n- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F11: n- (2, 4-difluorobenzyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F12: n- (2, 4-dichlorophenyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F13: n- (2- (pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide;
compound F14: n- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide;
compound F15: n- (2, 4-difluorobenzyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide;
compound F16: n- (2, 4-dichlorophenyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide;
compound F17: 3- (6-bromopyridin-3-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F18: 3- (6-bromopyridin-3-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F19: 3- (6-bromopyridin-3-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F20: 3- (6-bromopyridin-3-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F21: 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F22: 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F23: 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide;
compound F24: 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide.
The invention also aims to provide a preparation method of the 1,2, 4-oxadiazole-5-formamide derivative, which is synthesized by taking substituted aromatic nitrile, hydroxylamine hydrochloride, sodium hydroxide, oxalyl chloride monoethyl ester, triethylamine, lithium hydroxide, oxalyl chloride and primary amine as raw materials through five steps of addition, cyclization, hydrolysis, chloric acylation and substitution reaction respectively;
the synthetic route of the 1,2, 4-oxadiazole-5-formamide derivative is as follows:
the preparation method of the 1,2, 4-oxadiazole-5-formamide derivatives specifically comprises the following steps:
(1) preparation of N-hydroxy-substituted formamide (intermediate a):
uniformly mixing a hydroxylamine hydrochloride system, sodium hydroxide system and ethanol system, dripping substituted formonitrile at room temperature, heating and refluxing for 5-7h after dripping, washing, separating liquid, drying, filtering, decompressing and desolventizing a reaction system to obtain an N-hydroxy substituted formamide intermediate, and counting as an intermediate a;
(2) preparation of ethyl 3-substituted-1, 2, 4-oxadiazole-5-carboxylate (intermediate b):
adding the intermediate a, triethylamine and acetonitrile into a three-neck flask, dropwise adding oxalyl chloride monoethyl ester under ice bath, continuously keeping the temperature, uniformly stirring, and heating and refluxing for 6-9 h; after the reaction is finished, removing the generated solid by suction filtration, decompressing the filtrate to remove the solvent, extracting by ethyl acetate, washing by water and saturated saline, drying by anhydrous sodium sulfate, and carrying out column chromatography to obtain a white solid 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester which is counted as an intermediate b;
(3) preparation of 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid (intermediate c):
dissolving the intermediate b in ethanol, adding a lithium hydroxide solution to adjust the pH to be alkaline after dissolving at room temperature, hydrolyzing for 0.5-1 hour at room temperature, decompressing to remove the solvent, adding water to dissolve, adding HCl to adjust the pH to be acidic under ice bath until a large amount of solid is generated, performing suction filtration on the system, washing a filter cake with a large amount of ice water or petroleum ether to obtain a white solid 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid, and counting as an intermediate c;
(4) preparation of 3-substituted-1, 2, 4-oxadiazole-5-carbonyl chloride (intermediate d):
adding the intermediate c and dried dichloromethane into a single-mouth bottle, dropwise adding oxalyl chloride under ice bath, then adding 1 drop of N, N' -Dimethylformamide (DMF), uniformly stirring, then transferring to room temperature to react for 6-8h, directly performing reduced pressure desolventization by a rotary evaporator after the reaction is finished to obtain oily liquid 3-substituted-1, 2, 4-oxadiazole-5-carbonyl chloride, and counting as an intermediate d;
(5) preparation of target compound 1,2, 4-oxadiazole-5-carboxamide:
adding substituted primary amine, triethylamine and dry dichloromethane into a single-mouth bottle, uniformly stirring, dropwise adding the intermediate d at room temperature, and reacting for 9 hours; and (3) washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and desolventizing under reduced pressure, and performing column chromatography to obtain a white solid 1,2, 4-oxadiazole-5-formamide derivative.
In the step (1), the molar ratio of the substituted formonitrile to the hydroxylamine hydrochloride to the sodium hydroxide is substituted formonitrile: and (3) hydroxylamine hydrochloride: sodium hydroxide ═ 1: 1.2: 1.2; the amount of the ethanol solution is calculated according to 0.8-1mL of ethanol added in each millimole of the substituted formonitrile.
In the step (2), the molar ratio of the intermediate a to oxalyl chloride monoethyl ester to triethylamine is that the intermediate a: oxalyl chloride monoethyl ester: triethylamine 1: 1.2: 1.5; the dosage of the acetonitrile solution is calculated according to the addition of 0.7-1mL of acetonitrile in each millimole of the intermediate a; the mobile phase of the column chromatography is petroleum ether: and (10-30) 1.
In step (4), the intermediate c: oxalyl chloride ═ 1: 1.5.
in the step (5), the mole ratio of the primary amine, the intermediate d and the triethylamine is primary amine: intermediate d: 1.5 parts of triethylamine, (1-1.5) and 1.5 parts of triethylamine; the dosage of the dichloromethane is calculated according to the addition of 2-3mL of dichloromethane to millimole of primary amine; the mobile phase of the column chromatography is petroleum ether: and (30-60) ethyl acetate is 1.
The invention further aims to provide application of the 1,2, 4-oxadiazole-5-carboxamide derivative in preventing and treating plant diseases such as tomato gray mold, rice sheath blight disease, sclerotinia sclerotiorum, meloidogyne incognita, pine wood nematode, aphelenchoides besseyi and caenorhabditis elegans.
The 1,2, 4-oxadiazole-5-formamide derivative has antifungal activity and plant nematode resistance, and is applied to preparation of a medicament with antifungal and plant nematode killing functions.
The 1,2, 4-oxadiazole-5-formamide derivatives are applied to preparation of pharmaceutical preparations or pharmaceutical compositions for preventing and treating plant diseases such as tomato gray mold, rice sheath blight disease, sclerotinia rot of colza, meloidogyne incognita, pine wood nematode, aphelenchoides besseyi and caenorhabditis elegans.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, an amide functional group is introduced into a 1,2, 4-oxadiazole structure, so that the activity combination and the pharmaceutical property improvement of a '1, 2, 4-oxadiazole' and 'amide' pharmacophore are realized, and a 1,2, 4-oxadiazole-5-formamide antifungal and nematocidal drug with relatively stable physicochemical property and excellent pharmaceutical property is created. When the concentration is 50 mu g/mL, the inhibitor has a good inhibition effect on the tomato gray mold, and specifically shows an inhibition rate of 20.9-58.2%; middle concentration EC for inhibiting rice sheath blight50The value range is 5.01-29.84 mu g/mL, and the activity is superior to that of the prior commercial contrast medicament fluopyram (A)>50. mu.g/mL); EC for sclerotinia rot of colza50The value range is 2.89-20.75 mu g/mL, is higher than that of a control medicament fluthiamide (4.25 mu g/mL) and is close to that of fluopyram (1.23 mu g/mL); at 200 mu g/mL, the rate of inhibition on meloidogyne incognita is 11.6-93.2%, which is mostly better than that of the existing commercial contrast medicament Tioxazafen (23.9%), the rate of inhibition on pine wood nematodes is 5.5-41.2%, which is mostly better than that of the existing commercial contrast medicament Tioxazafen (13.5%), and the activity on aphelenchoides besseyi is slightly inferior.
Experiments prove that the 1,2, 4-oxadiazole-5-carboxamide derivatives have remarkable effects in preventing and treating plant diseases such as tomato gray mold, rice sheath blight disease, sclerotinia rot of colza, meloidogyne incognita, pine wood nematode, aphelenchoides besseyi and the like, and show that the derivatives not only aim at a certain single plant disease, but also show good prevention and treatment effects on the three plant fungal diseases and the three plant nematode diseases.
The derivative has the characteristics of low toxicity, high yield, easy degradation, good environmental compatibility, high safety, simple preparation process, low production cost, simple structure and difficult generation of drug resistance, and the amide group is introduced, so that the flexibility of the oxadiazole is improved, the flexibility of the micromolecule is increased, and the drug effect is remarkable.
Drawings
FIG. 1: a synthetic route of 1,2, 4-oxadiazole-5-formamide derivatives.
Detailed Description
The synthetic routes for the 1,2, 4-oxadiazole-5-carboxamide derivatives provided in examples 1-24 are as follows:
example 1: a process for the preparation of N- (2- (pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide (compound No. F1) comprising the steps of:
(1) preparation of N-hydroxybenzamide:
mixing hydroxylamine hydrochloride (4.04g, 58.18mmol), sodium hydroxide (2.33g, 58.18mmol) and ethanol (48.48mL) in a 100mL three-necked bottle, dripping substituted carbonitrile (5g, 48.48mmol) at room temperature, and heating and refluxing for 6h after dripping; after the reaction is finished, the reaction system is washed, separated, dried, filtered and desolventized under reduced pressure to obtain 5.54g of an N-hydroxybenzamide intermediate with the yield of 83.92 percent;
(2) preparation of ethyl 3-phenyl-1, 2, 4-oxadiazole-5-carboxylate:
adding N-hydroxybenzamide (5g, 36.72mmol), triethylamine (4.45g, 55.08mmol) and acetonitrile (36.72mL) into a three-necked bottle, dropwise adding oxalyl chloride monoethyl ester (6.02g, 44.06mmol) under ice bath, keeping the temperature, stirring for 0.5h, and then heating and refluxing for 8 h; after the reaction is finished, removing generated solid by suction filtration, removing the solvent from the filtrate under reduced pressure, diluting the residue by ethyl acetate, washing the residue by water and saturated saline solution, extracting and layering, drying by anhydrous sodium sulfate, and adding petroleum ether: ethyl acetate 10:1 as a mobile phase, and performing column chromatography to obtain 6.01g of white solid ethyl 3-phenyl-1, 2, 4-oxadiazole-5-carboxylate, wherein the yield is 66.47%;
(3) preparation of 3-phenyl-1, 2, 4-oxadiazole-5-carboxylic acid:
dissolving 3-phenyl-1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester (6.00g, 24.37mmol) in ethanol, dissolving at room temperature, adding 2mol/L lithium hydroxide solution to adjust the pH to be alkaline, hydrolyzing at room temperature for 0.8h, removing the solvent under reduced pressure, adding water to dissolve, adding 6mol/L HCl to adjust the pH to be acidic under ice bath until a large amount of solid is generated, performing suction filtration, washing a filter cake with a large amount of ice water to obtain 3.00g of white solid 3-phenyl-1, 2, 4-oxadiazole-5-carboxylic acid, wherein the yield is 56.43%;
(4) preparation of 3-phenyl-1, 2, 4-oxadiazole-5-carbonyl chloride:
adding 3-phenyl-1, 2, 4-oxadiazole-5-carboxylic acid (0.50g, 2mmol) and dried dichloromethane into a single-mouth bottle, dropwise adding oxalyl chloride (0.44g, 3mmol) under ice bath, then adding 1 drop of DMF, stirring uniformly, transferring to room temperature for reaction for 6h, directly performing reduced pressure desolventization by a rotary evaporator after the reaction is finished to obtain 0.30g of oily liquid 3-phenyl-1, 2, 4-oxadiazole-5-carbonyl chloride, and directly putting into the next step without purification;
(5) preparation of the target compound N- (2- (pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide:
adding 2- (pyridine-2-yl) ethyl-1-amine (0.18g, 1.44mmol), triethylamine (0.22g, 2.16mmol) and 2.88mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-phenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.44mmol) at room temperature, keeping the temperature for reaction for 9h, washing the reaction system with water, saturated sodium bicarbonate, saturated brine, separating liquid, drying, suction filtering and desolventizing under reduced pressure, adding petroleum ether: column chromatography using ethyl acetate 30:1 as the mobile phase gave 0.28g of N- (2- (pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide as a white solid in 66.15% yield. (Note: dichloromethane used: 1.5+1.5mL)
Example 2: a process for the preparation of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide (compound No. F2) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide:
adding 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl-1-amine (0.32g, 1.44mmol), triethylamine (0.22g, 2.16mmol) and 2.88mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-phenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.44mmol) at room temperature, keeping the temperature for reaction for 9h, washing the reaction system with water, saturated sodium bicarbonate, saturated saline, separating, drying, suction filtering and desolventizing under reduced pressure, adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.29g of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide as a white solid in 68.51% yield.
Example 3: a process for the preparation of N- (2, 4-difluorobenzyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide (compound No. F3) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of target compound N- (2, 4-difluorobenzyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide:
adding 2, 4-difluorobenzylamine (0.21g, 1.44mmol), triethylamine (0.22g, 2.16mmol) and 2.88mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-phenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.44mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating liquid, drying, performing suction filtration and reduced pressure desolventization, and adding petroleum ether: column chromatography using ethyl acetate 30:1 as the mobile phase gave 0.24g of N- (2, 4-difluorobenzyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide as a white solid in 52.93% yield.
Example 4: a process for the preparation of N- (2, 4-dichlorophenyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide (compound No. F4) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of target compound N- (2, 4-dichlorophenyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide:
adding 2, 4-dichloroaniline (0.23g, 1.44mmol), triethylamine (0.22g, 2.16mmol) and 2.88mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-phenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.44mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating liquid, drying, carrying out suction filtration, and carrying out desolventizing under reduced pressure, adding petroleum ether: ethyl acetate 35:1 as the mobile phase was subjected to column chromatography) to give N- (2, 4-dichlorophenyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide as a white solid in 0.24g, 49.94% yield.
Example 5: a process for the preparation of N- (2- (pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F5) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2- (pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (pyridine-2-yl) ethyl-1-amine (0.16g, 1.35mmol), triethylamine (0.20g, 2.02mmol) and 2.70mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-p-methylphenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.35mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating liquid, drying, suction filtering and desolventizing under reduced pressure, adding petroleum ether: column chromatography using ethyl acetate 30:1 as the mobile phase gave 0.17g of N- (2- (pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 40.91% yield.
Example 6: a process for the preparation of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F6) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl-1-amine (0.30g, 1.35mmol), triethylamine (0.20g, 2.02mmol) and 2.70mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-p-methylphenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.35mmol) at room temperature, reacting for 9h while keeping the temperature, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating liquid, drying, suction filtering and desolventizing under reduced pressure, and then adding petroleum ether: ethyl acetate 30:1 as a mobile phase was subjected to column chromatography to give 0.30g of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 54.20% yield;
example 7: a process for the preparation of N- (2, 4-difluorobenzyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F7) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of target compound N- (2, 4-difluorobenzyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-difluorobenzylamine (0.19g, 1.35mmol), triethylamine (0.20g, 2.02mmol) and 2.70mL of dried dichloromethane into a single-neck bottle, uniformly stirring, adding 3-p-methylphenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.35mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and reduced pressure desolventizing, and then adding petroleum ether: ethyl acetate 30:1 as a mobile phase was subjected to column chromatography to give 0.19g of N- (2, 4-difluorobenzyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 42.82% yield;
example 8: a process for the preparation of N- (2, 4-dichlorophenyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F8) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2, 4-dichlorophenyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-dichloroaniline (0.22g, 1.35mmol), triethylamine (0.20g, 2.02mmol) and 2.70mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-p-methylphenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.30g, 1.35mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and reduced pressure desolventizing, and adding petroleum ether: ethyl acetate 30:1 as a mobile phase was subjected to column chromatography to give 0.21g of N- (2, 4-dichlorophenyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 44.76% yield;
example 9: a process for the preparation of N- (2- (pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F9) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2- (pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (pyridine-2-yl) ethyl-1-amine (0.15g, 1.19mmol), triethylamine (0.18g, 1.79mmol) and 2.38mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-p-chlorophenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.29g, 1.19mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating liquid, drying, suction filtering and desolventizing under reduced pressure, adding petroleum ether: ethyl acetate 30:1 as a mobile phase, and by column chromatography, 0.22g of N- (2- (pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide was obtained as a white solid, with a yield of 56.08%;
example 10: a process for the preparation of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F10) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl-1-amine (0.27g, 1.19mmol), triethylamine (0.18g, 1.79mmol) and 2.38mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-p-chlorophenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.29g, 1.19mmol) at room temperature, reacting for 9h while maintaining the temperature, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating, drying, suction filtering and desolventizing under reduced pressure, and then adding petroleum ether: ethyl acetate 30:1 as a mobile phase was subjected to column chromatography to give 0.22g of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 42.76% yield;
example 11: a process for the preparation of N- (2, 4-difluorobenzyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F11) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of target compound N- (2, 4-difluorobenzyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-difluorobenzylamine (0.17g, 1.19mmol), triethylamine (0.18g, 1.79mmol) and 2.38mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-p-chlorophenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.29g, 1.19mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and reduced pressure desolventizing, and then adding petroleum ether: ethyl acetate 30:1 as a mobile phase was subjected to column chromatography to give N- (2, 4-difluorobenzyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide 0.23g as a white solid in 55.12% yield.
Example 12: a process for the preparation of N- (2, 4-dichlorophenyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F12) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2, 4-dichlorophenyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-dichloroaniline (0.19g, 1.19mmol), triethylamine (0.18g, 1.79mmol) and 2.38mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3-p-chlorophenyl-1, 2, 4-oxadiazole-5-carbonyl chloride (0.29g, 1.19mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and reduced pressure desolventizing, and adding petroleum ether: column chromatography using ethyl acetate 30:1 as the mobile phase gave 0.25g of N- (2, 4-dichlorophenyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 56.84% yield.
Example 13: a process for the preparation of N- (2- (pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F13) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2- (pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (pyridine-2-yl) ethyl-1-amine (0.14g, 1.16mmol), triethylamine (0.18g, 1.75mmol) and 2.32mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3- (thiophene-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.25g, 1.16mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating, drying, suction filtering and desolventizing under reduced pressure, and then adding petroleum ether: ethyl acetate 30:1 as the mobile phase through the column layer gave 0.20g of N- (2- (pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 57.17% yield.
Example 14: a process for the preparation of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F14) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl-1-amine (0.26g, 1.16mmol), triethylamine (0.18g, 1.75mmol) and 2.32mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3- (thiophene-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.25g, 1.16mmol) at room temperature, reacting for 9h while maintaining the temperature, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating, drying, suction filtering and desolventizing under reduced pressure, and then adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.26g of N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 55.42% yield.
Example 15: a process for the preparation of N- (2, 4-difluorobenzyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F15) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2, 4-difluorobenzyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-difluorobenzylamine (0.17g, 1.16mmol), triethylamine (0.18g, 1.75mmol) and 2.32mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3- (thiophene-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.25g, 1.16mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and reduced pressure desolventizing, and adding petroleum ether: column chromatography using ethyl acetate 30:1 as the mobile phase gave 0.25g of N- (2, 4-difluorobenzyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 66.80% yield.
Example 16: a process for the preparation of N- (2, 4-dichlorophenyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F16) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound N- (2, 4-dichlorophenyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-dichloroaniline (0.19g, 1.16mmol), triethylamine (0.18g, 1.75mmol) and 2.32mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding 3- (thiophene-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.25g, 1.16mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and reduced pressure desolventizing, and then adding petroleum ether: column chromatography using ethyl acetate 30:1 as the mobile phase gave 0.21g of N- (2, 4-dichlorophenyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 53.00% yield.
Example 17: a process for the preparation of 3- (6-bromopyridin-3-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F17) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (6-bromopyridin-3-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (pyridine-2-yl) ethyl-1-amine (0.09g, 0.76mmol), triethylamine (0.12g, 1.14mmol) and 1.52mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding newly prepared 3- (5-bromopyridine-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.22g, 0.76mmol) at room temperature, keeping the temperature for reaction for 9h, washing the reaction system with water, saturated sodium bicarbonate, saturated common salt water, separating liquid, drying, suction filtering and desolventizing under reduced pressure, and then adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.15g of 3- (6-bromopyridin-3-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 52.56% yield.
Example 18: a process for the preparation of 3- (6-bromopyridin-3-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F18) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (6-bromopyridin-3-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl-1-amine (0.17g, 0.76mmol), triethylamine (0.12g, 1.14mmol) and 1.52mL of dried dichloromethane into a single-neck flask, stirring uniformly, adding newly prepared 3- (5-bromopyridin-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.22g, 0.76mmol) at room temperature, reacting for 9h while maintaining the temperature, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating, drying, suction filtering and desolventizing under reduced pressure, adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.16g of 3- (6-bromopyridin-3-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 44.02% yield.
Example 19: a process for the preparation of 3- (6-bromopyridin-3-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F19) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (6-bromopyridin-3-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide:
2, 4-difluorobenzylamine (0.11g, 0.76mmol), triethylamine (0.12g, 1.14mmol) and 1.52mL of dried dichloromethane were added to a single-neck flask, and after stirring uniformly, freshly prepared 3- (5-bromopyridin-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.22g, 0.76mmol) was added at room temperature, and after reaction at this temperature for 9 hours, the reaction system was washed with water, saturated sodium bicarbonate, saturated brine, separated, dried, suction filtered and desolventized under reduced pressure, and then treated with petroleum ether: column chromatography using ethyl acetate 30:1 as the mobile phase gave 0.16g of 3- (6-bromopyridin-3-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 53.09% yield.
Example 20: a process for the preparation of 3- (6-bromopyridin-3-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F20) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (6-bromopyridin-3-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-dichloroaniline (0.12g, 0.76mmol), triethylamine (0.12g, 1.14mmol) and 1.52mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding newly prepared 3- (5-bromopyridin-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.22g, 0.76mmol) at room temperature, keeping the temperature for reaction for 9 hours, washing the reaction system with water, saturated sodium bicarbonate, saturated salt water, separating, drying, performing suction filtration and reduced pressure desolventizing, and then adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.17g of 3- (6-bromopyridin-3-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 53.84% yield.
Example 21: a process for the preparation of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F21) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (pyridine-2-yl) ethyl-1-amine (0.20g, 1.60mmol), triethylamine (0.24g, 2.40mmol) and 3.22mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding newly prepared 3- (3-chloro-5- (trifluoromethyl) pyridine-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.50g, 1.60mmol) at room temperature, keeping the temperature, reacting for 9h, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated common salt water, separating liquid, drying, suction filtering and desolventizing under reduced pressure, adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.36g of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 61.56% yield.
Example 22: a process for the preparation of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F22) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl-1-amine (0.36g, 1.60mmol), triethylamine (0.24g, 2.40mmol) and 3.22mL of dried dichloromethane into a single-neck flask, stirring uniformly, adding newly prepared 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.50g, 1.60mmol) at room temperature, reacting for 9h while keeping the temperature, washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating, drying, suction filtering and desolventizing under reduced pressure, and then adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.40g of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 49.91% yield.
Example 23: a process for the preparation of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F23) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide:
2, 4-difluorobenzylamine (0.23g, 1.60mmol), triethylamine (0.24g, 2.40mmol) and 3.22mL of dried dichloromethane were charged into a single-neck flask, and after stirring uniformly, freshly prepared 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.50g, 1.60mmol) was added at room temperature, and after reaction for 9 hours while maintaining the temperature, the reaction system was washed with water, saturated sodium bicarbonate, saturated brine, separated, dried, suction filtered and desolventized under reduced pressure, and then treated with petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.34g of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 50.67% yield.
Example 24: a process for the preparation of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide (compound No. F24) comprising the steps of:
steps (1) to (4) were the same as in example 1;
(5) preparation of the target compound 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide:
adding 2, 4-dichloroaniline (0.26g, 1.60mmol), triethylamine (0.24g, 2.40mmol) and 3.22mL of dried dichloromethane into a single-neck bottle, stirring uniformly, adding fresh 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -1,2, 4-oxadiazole-5-carbonyl chloride (0.50g, 1.60mmol) at room temperature, keeping the temperature for reaction for 9h, washing the reaction system with water, saturated sodium bicarbonate, saturated saline, separating, drying, suction filtering and desolventizing under reduced pressure, adding petroleum ether: ethyl acetate 30:1 as the mobile phase was subjected to column chromatography to give 0.44g of 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide as a white solid in 62.75% yield.
The structural formula and the molecular formula of the target compound prepared in the above example are shown in table 1, and the physicochemical properties and the spectrum information thereof are shown in table 2.
TABLE 1 structural formulas and molecular formulas of target compounds obtained in examples 1 to 24
TABLE 2 physicochemical Properties and spectral data of the target Compounds obtained in examples 1 to 24
And (3) testing the activities of the tomato gray mold, the rice sheath blight and the rape sclerotinia rot:
respectively inoculating pathogenic fungi of tomato gray mold, rice sheath blight and rape sclerotinia sclerotiorum on potato glucose agar (PDA) plate, culturing in biochemical incubator at 25 + -1 deg.C for 1-4 days, and determining antifungal activity with new myceliumAnd (4) sex. Dissolving target compounds F1-F24 and a commercial contrast medicament in 100 mu L of DMF, and then adding the solution into a PDA culture medium to ensure that the final concentration is 50 mu g/mL; cutting off a bacterium dish with the diameter of about 5mm from the culture medium, picking the bacterium dish by using a sterile inoculating needle, and inoculating the bacterium dish in the middle of a PDA flat plate in a sterile environment; then, carrying out primary screening of fungal activity; selecting commercially available bactericide fluopyram as a positive control, and preparing a negative control group without a compound by the same method; the test was repeated three times; when the diameter of the mycelium of the blank control reaches 5.0-5.5 cm, measuring and recording the radial growth of the fungal colony; by measuring EC50Values, compounds with excellent activity were further evaluated; final data were analyzed using SPSS v.25.0; the inhibition rate of the fungus was calculated using the following formula;
inhibition (%) × 100 [ (mycelium diameter of negative control-treated mycelium diameter)/(mycelium diameter of negative control-0.5) ];
5 corresponding concentration gradients are set for partial target compounds, and the EC of the target compounds for rice sheath blight disease and sclerotinia rot of colza is measured50A value;
the bacteriostatic activity and EC of the target compounds of examples F1-F24 were determined as described above50The values and results are shown in tables 3 to 4
TABLE 3 examples 1-24 test for bacteriostatic activity against fungi at 50. mu.g/mL for the target compounds
As can be seen from table 3, 1,2, 4-oxadiazole-5-carboxamide has good inhibitory activity against the above three fungi; firstly, when the concentration is 50 mu g/mL, the compound has good inhibition effect on the gray mold of tomatoes, and the inhibition rate is 20.9-58.2%; secondly, the compounds F1, F3, F5, F9, F13, F14 and F15 show good antifungal activity on rice sheath blight, and the inhibition rates are 69.1%, 84.2%, 72.7%, 86.7%, 64.9%, 75.8% and 87.6% respectively, and are obviously superior to fluopyram (23.8%); meanwhile, F1, F3, F9, F14 and F15 show remarkable antifungal activity on sclerotinia rot of colza, and the inhibition rates are 73.2%, 84.8%, 61.1%, 65.2% and 89.3% respectively, which are equivalent to that of positive control fluthiamide (86.7%).
TABLE 4 inhibition of rice sheath blight and sclerotinia rot of colza EC by some target compounds50Value of
As shown in Table 4, EC of compounds F1, F3, F5, F9, F13, F14 and F15 against Rhizoctonia solani50Values of 20.03,5.61,20.84,10.02,29.84,9.73, 5.01. mu.g/mL, respectively, are much higher than that of the positive control fluopyram (128.8. mu.g/mL); meanwhile, EC of F1, F3, F9, F14 and F15 on sclerotinia rot of colza50The values were 20.75, 5.41, 18.66, 15.27 and 2.89. mu.g/mL, respectively, which are superior to the positive control fluthiamide (4.25. mu.g/mL).
From tables 3 and 4, it can be seen that the derivatives have more significant activity on sclerotinia rot of colza, especially N- (2, 4-difluorobenzyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide (compound F15), and a semi-living experiment is carried out on the derivatives.
Test example 2: semi-living test of high-activity compound F15 on sclerotinia rot of colza
(1) Semi-living test protection effect of sclerotinia rot of colza
Leaves of uniform size and similar shape were cut from healthy canola plants, sterilized with 1% sodium hypochlorite for 1 minute, then rinsed with sterile water and blotted dry with sterile filter paper. 100, 50, 25. mu.g/mL of test compound F15 was sprayed onto the leaves until the liquid flowed, and after 24 hours, 5mm dishes were inoculated into the widest center of the rape leaf surface, avoiding placing them on the main veins. Fluopyram and sterile distilled water were used as positive and negative controls, respectively. All inoculated leaves were placed in an illumination incubator at 25 ℃ with a relative humidity of 85% and an illumination time of 16 hours. The mean diameter of the lesions was measured by the crisscross method at 72 hours after application and the control effect was calculated and the results are shown in table 5.
(2) Semi-living test treatment effect of sclerotinia rot of colza
Leaves of uniform size and similar shape were cut from healthy canola plants, sterilized with 1% sodium hypochlorite for 1 minute, then rinsed with sterile water and blotted dry with sterile filter paper. A5 mm dish was inoculated in the center of the widest leaf surface of rape, avoiding placing it on the main vein, and after 24 hours of inoculation, compound F15 was sprayed on the leaf surface at 100, 50, 25. mu.g/mL until the liquid flowed. Fluopyram and sterile distilled water were used as positive and negative controls, respectively. All inoculated leaves were placed in an illumination incubator at 25 ℃ with a relative humidity of 85% and an illumination time of 16 hours. The mean diameter of the lesions was measured by the crisscross method at 72 hours after application and the control effect was calculated and the results are shown in table 5.
Control effect (%) - (control group lesion length-treatment group lesion length)/control group lesion length x 100
TABLE 5 semi-living test result of target compound F15 on sclerotinia rot of colza
As can be seen from table 5, compound F15 exhibited excellent therapeutic and protective activities, with therapeutic activities at 100, 50, 25 μ g/mL of 62.3%, 50.0%, and 27.7%, respectively; the protective activity is 71.0%, 66.0% and 56.3%, which is close to fluopyram. Notably, the protective or therapeutic effect of compound F15 showed concentration dependence and was safe for canola leaves at high concentrations.
Test example 3 determination of in vitro nematicidal Activity
Table 6 examples 1-24 in vitro nematicidal activity of target compounds against meloidogyne incognita (m.incognitia) and caenorhabditis elegans (c.elegans)
Table 7 examples 1-24 in vitro nematicidal activity of target compounds against pine wood nematodes (b.xylophilus) and aphelenchoides besseyi (a.besseyi)
The nematicidal activity of the novel 1,2, 4-oxadiazole-5-carboxamides containing an amide substructure are shown in tables 6 and 7. Overall, some of these target compounds showed significant nematicidal activity, and it is evident that F11 has excellent nematicidal activity against meloidogyne incognita at 48h, with a corrected mortality rate of 93.2% at 200 μ g/mL, higher than the positive control Tioxazfen (23.9%). Meanwhile, F3, F6, F10, F13, F14 and F20 show good nematicidal activity to caenorhabditis elegans under the same concentration, the mortality rate is 100%, and F3 and F6 also show excellent nematicidal activity to caenorhabditis elegans when the concentration is reduced to 50 mu g/mL, the mortality rate is 100%, and the nematicidal activity is close to that of the commercial nematicidal agents, namely fosthiazate and fluopyram. In addition, the series of compounds have certain nematicidal activity to pine wood nematodes and aphelenchoides besseyi at high concentration.
In conclusion, the series of 1,2, 4-oxadiazole-5-formamide derivatives have excellent antifungal activity, particularly the compounds F1, F3, F9, F14 and F15 show the most excellent in-vitro antifungal activity on rice sheath blight disease and sclerotinia rot of colza, firstly, the inhibition rate of the compounds F3, F9 and F15 on the rice sheath blight is more than 80% at 50 mu g/mL, and the inhibition rate is obviously better than that of the fluorine-containing cyanimine thiazolidine substituted oxadiazole compounds (76.7%); secondly, the inhibition rates of a compound F15 with better activity in the derivatives to rice sheath blight and sclerotinia rot of colza are respectively 87.6 and 89.3% at 50 mu g/mL, which are superior to 1,2, 4-oxadiazole bipyridyl substituted benzamide compounds, and the inhibition rates of the compounds with the optimal activity in the series of compounds to the two fungi are respectively 80.8 and 84.8% at the dosage. At the same time, compound F15 also showed excellent therapeutic and protective activity against sclerotinia rot of colza, which was 62.3%, 71.0% at 100 μ g/mL, respectively, comparable to fluopyram (74.1% and 75.6%). In addition, the compounds also show good plant nematode killing activity, such as meloidogyne incognita, aphelenchoides besseyi and pine wood nematodes, and obviously have a plant nematode killing spectrum superior to that of the existing 3, 5-disubstituted-4, 5-dihydro-1, 2, 4-oxadiazole compounds, mainly aiming at meloidogyne incognita and lack the evaluation on the nematode killing activity of other plant nematodes, such as aphelenchoides besseyi and pine wood nematodes. Therefore, the series of 1,2, 4-oxadiazole-5-formamide derivatives not only have excellent antifungal activity, but also have good nematicidal activity.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.
Claims (9)
1,2, 4-oxadiazole-5-formamide derivatives, which are characterized in that the structural general formula of the derivatives is shown as the formula (I):
wherein: r1Is phenyl, 4-methylphenyl, 4-chlorophenyl, thienyl, 6-bromo-3 pyridyl or 3-chloro-5-trifluoromethylpyridyl; r2Is pyridyl, 3-chloro-5-trifluoromethylpyridyl, 2, 4-difluorobenzyl or 2, 4-dichlorobenzeneA group; n is 0, 1 or 2.
2. The 1,2, 4-oxadiazole-5-carboxamide derivative of claim 1, which comprises the following compounds: n- (2- (pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide, N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide, N- (2, 4-difluorobenzyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide, N- (2, 4-dichlorophenyl) -3-phenyl-1, 2, 4-oxadiazole-5-carboxamide, N- (2- (pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide, N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide, N- (2, 4-difluorobenzyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide, N- (2, 4-dichlorophenyl) -3- (p-tolyl) -1,2, 4-oxadiazole-5-carboxamide, N- (2- (pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide, n- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide, N- (2, 4-difluorobenzyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide, N- (2, 4-dichlorophenyl) -3- (p-chlorophenyl) -1,2, 4-oxadiazole-5-carboxamide, N- (2- (pyridin-2-yl) ethyl) -3- (thiophen-2-yl) -1,2, 4-oxadiazole-5-carboxamide, N- (2- (3-chloro-5- (trifluoromethyl) pyridine- 2-yl) ethyl) -3- (thien-2-yl) -1,2, 4-oxadiazole-5-carboxamide, N- (2, 4-difluorobenzyl) -3- (thien-2-yl) -1,2, 4-oxadiazole-5-carboxamide, N- (2, 4-dichlorophenyl) -3- (thien-2-yl) -1,2, 4-oxadiazole-5-carboxamide, 3- (6-bromopyridin-3-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide, 3- (6-bromopyridin-3-yl) -N- (2- (3-chloro-5-carboxamide - (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide, 3- (6-bromopyridin-3-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide, 3- (6-bromopyridin-3-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide, 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide, 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) -1,2, 4-oxadiazole-5-carboxamide, 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-difluorobenzyl) -1,2, 4-oxadiazole-5-carboxamide, 3- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -N- (2, 4-dichlorophenyl) -1,2, 4-oxadiazole-5-carboxamide.
3. The method for preparing the 1,2, 4-oxadiazole-5-carboxamide derivative of claim 1 or 2, wherein the substituted aromatic nitrile, hydroxylamine hydrochloride, sodium hydroxide, oxalyl chloride monoethyl ester, triethylamine, lithium hydroxide, oxalyl chloride and primary amine are used as raw materials, and the synthesis is carried out by five steps of addition, cyclization, hydrolysis, chloric acylation and substitution reaction.
4. A process for the preparation of 1,2, 4-oxadiazole-5-carboxamide derivatives according to claim 3, comprising the steps of:
(1) preparation of N-hydroxy substituted formamide:
uniformly mixing a hydroxylamine hydrochloride system, sodium hydroxide system and ethanol system, dripping substituted formonitrile at room temperature, heating and refluxing for 5-7h after dripping, washing, separating liquid, drying, filtering, decompressing and desolventizing a reaction system to obtain an N-hydroxy substituted formamide intermediate, and counting as an intermediate a;
(2) preparation of ethyl 3-substituted-1, 2, 4-oxadiazole-5-carboxylate:
adding the intermediate a, triethylamine and acetonitrile into a three-neck flask, dropwise adding oxalyl chloride monoethyl ester under ice bath, continuously keeping the temperature, uniformly stirring, and heating and refluxing for 6-9 h; after the reaction is finished, removing the generated solid by suction filtration, decompressing the filtrate to remove the solvent, extracting by ethyl acetate, washing by water and saturated saline, drying by anhydrous sodium sulfate, and carrying out column chromatography to obtain a white solid 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester which is counted as an intermediate b;
(3) preparation of 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid:
dissolving the intermediate b in ethanol, adding a lithium hydroxide solution to adjust the pH to be alkaline after dissolving at room temperature, hydrolyzing for 0.5-1 hour at room temperature, decompressing to remove the solvent, adding water to dissolve, adding HCl to adjust the pH to be acidic under ice bath until a large amount of solid is generated, performing suction filtration on the system, washing a filter cake with a large amount of ice water or petroleum ether to obtain a white solid 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid, and counting as an intermediate c;
(4) preparation of 3-substituted-1, 2, 4-oxadiazole-5-carbonyl chloride:
adding the intermediate c and dried dichloromethane into a single-mouth bottle, dropwise adding oxalyl chloride under ice bath, then adding 1 drop of N, N' -dimethylformamide, uniformly stirring, transferring to room temperature to react for 6-8h, directly performing reduced pressure desolventization by a rotary evaporator after the reaction is finished to obtain oily liquid 3-substituted-1, 2, 4-oxadiazole-5-carbonyl chloride, and counting as an intermediate d;
(5) preparation of target compound 1,2, 4-oxadiazole-5-carboxamide:
adding substituted primary amine, triethylamine and dry dichloromethane into a single-mouth bottle, uniformly stirring, dropwise adding the intermediate d at room temperature, and reacting for 9 hours; and (3) washing the reaction system with water, washing with saturated sodium bicarbonate, washing with saturated salt water, separating liquid, drying, performing suction filtration and desolventizing under reduced pressure, and performing column chromatography to obtain a white solid 1,2, 4-oxadiazole-5-formamide derivative.
5. The method for preparing the 1,2, 4-oxadiazole-5-carboxamide derivative of claim 4, wherein in step (1), the molar ratio of the substituted carbonitrile to hydroxylamine hydrochloride to sodium hydroxide is: and (3) hydroxylamine hydrochloride: sodium hydroxide ═ 1: 1.2: 1.2; the dosage of the ethanol solution is calculated according to 800-1000 mL of ethanol added to each mole of substituted carbonitrile.
6. The process for preparing 1,2, 4-oxadiazole-5-carboxamide derivative according to claim 4, wherein in step (2), the molar ratio of intermediate a, oxalyl chloride monoethyl ester and triethylamine is intermediate a: oxalyl chloride monoethyl ester: triethylamine 1: 1.2: 1.5; the dosage of the acetonitrile solution is calculated according to the addition of 700-1000 mL of acetonitrile in each mole of the intermediate a; the mobile phase of the column chromatography is petroleum ether: ethyl acetate is 10:1 to 30: 1.
7. The method for preparing the 1,2, 4-oxadiazole-5-carboxamide derivative of claim 4, wherein in step (5), the molar ratio of the primary amine, intermediate d, triethylamine is primary amine: intermediate d: 1: 1-1.5: 1.5 of triethylamine; the dosage of the dichloromethane is calculated according to the addition of 2000-3000 mL of dichloromethane to each mole of primary amine; the mobile phase of the column chromatography is petroleum ether: ethyl acetate is 30:1 to 60: 1.
8. Use of the 1,2, 4-oxadiazole-5-carboxamide derivative of claim 1 or 2 for the preparation of a medicament having both antifungal and plant nematode killing properties.
9. The use of the 1,2, 4-oxadiazole-5-carboxamide derivative of claim 1 or 2 for the preparation of a medicament for the control of plant diseases such as tomato gray mold, rice sheath blight, sclerotinia sclerotiorum, meloidogyne incognita, pine wood nematode, aphelenchoides besseyi and caenorhabditis elegans.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111553516.5A CN114213403B (en) | 2021-12-17 | 2021-12-17 | 1,2,4-oxadiazole-5-formamide derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111553516.5A CN114213403B (en) | 2021-12-17 | 2021-12-17 | 1,2,4-oxadiazole-5-formamide derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114213403A true CN114213403A (en) | 2022-03-22 |
| CN114213403B CN114213403B (en) | 2022-10-25 |
Family
ID=80703701
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111553516.5A Active CN114213403B (en) | 2021-12-17 | 2021-12-17 | 1,2,4-oxadiazole-5-formamide derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114213403B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114933573A (en) * | 2022-05-06 | 2022-08-23 | 贵州大学 | 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid derivative, and preparation method and application thereof |
| CN115093377A (en) * | 2022-06-20 | 2022-09-23 | 贵州大学 | Haloalkyl-containing 1,2, 4-oxadiazole derivative and preparation method and application thereof |
| CN116354900A (en) * | 2023-03-03 | 2023-06-30 | 中国农业大学 | Chlorothiazole compound containing maleic acid structure, and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104672162A (en) * | 2015-02-13 | 2015-06-03 | 贵州大学 | Preparation method and use of pentadiene ketone compound containing 1,3,4-oxadiazole sulfo-ethyoxyl |
| US20150315199A1 (en) * | 2010-04-02 | 2015-11-05 | Euroscreen S.A. | Novel nk-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in nk-3 receptors mediated disorders |
| WO2017135137A1 (en) * | 2016-02-01 | 2017-08-10 | 住友化学株式会社 | Pest control composition and pest control method |
| CN107033098A (en) * | 2017-05-03 | 2017-08-11 | 贵州大学 | 1,3,4 oxadiazole sulphur/oxygen ether compound of amide bond and preparation method and application |
| CN110407824A (en) * | 2019-08-08 | 2019-11-05 | 安徽医科大学 | Aryl methanamide compounds and preparation method thereof, pharmaceutical composition and purposes |
-
2021
- 2021-12-17 CN CN202111553516.5A patent/CN114213403B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150315199A1 (en) * | 2010-04-02 | 2015-11-05 | Euroscreen S.A. | Novel nk-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in nk-3 receptors mediated disorders |
| CN104672162A (en) * | 2015-02-13 | 2015-06-03 | 贵州大学 | Preparation method and use of pentadiene ketone compound containing 1,3,4-oxadiazole sulfo-ethyoxyl |
| WO2017135137A1 (en) * | 2016-02-01 | 2017-08-10 | 住友化学株式会社 | Pest control composition and pest control method |
| CN107033098A (en) * | 2017-05-03 | 2017-08-11 | 贵州大学 | 1,3,4 oxadiazole sulphur/oxygen ether compound of amide bond and preparation method and application |
| CN110407824A (en) * | 2019-08-08 | 2019-11-05 | 安徽医科大学 | Aryl methanamide compounds and preparation method thereof, pharmaceutical composition and purposes |
Non-Patent Citations (1)
| Title |
|---|
| COLUMBUS，OHIO，US: ""REGISTRY[online]"", 《STN检索报告 US REGISTRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114933573A (en) * | 2022-05-06 | 2022-08-23 | 贵州大学 | 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid derivative, and preparation method and application thereof |
| CN114933573B (en) * | 2022-05-06 | 2023-10-20 | 贵州大学 | 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid derivative, and preparation method and application thereof |
| CN115093377A (en) * | 2022-06-20 | 2022-09-23 | 贵州大学 | Haloalkyl-containing 1,2, 4-oxadiazole derivative and preparation method and application thereof |
| CN116354900A (en) * | 2023-03-03 | 2023-06-30 | 中国农业大学 | Chlorothiazole compound containing maleic acid structure, and preparation method and application thereof |
| CN116354900B (en) * | 2023-03-03 | 2024-03-12 | 中国农业大学 | Chlorothiazole compound containing maleic acid structure, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114213403B (en) | 2022-10-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114213403B (en) | 1,2,4-oxadiazole-5-formamide derivative and preparation method and application thereof | |
| CN110015977B (en) | Malononitrile oxime ether compound and its use | |
| JP6811000B2 (en) | Phenoxyhalogen phenylamidines and their use as fungicides | |
| RU2443110C2 (en) | Agent for treatment of soil or seeds including compounds of quinoline or their salts as active ingredient, or method to prevent plant diseases using this agent | |
| CN114933573B (en) | 3-substituted-1, 2, 4-oxadiazole-5-carboxylic acid derivative, and preparation method and application thereof | |
| CN107848959A (en) | The phenoxyphenylamidineand of halogen substitution and its purposes as fungicide | |
| MX2015003727A (en) | Herbicidal and fungicidal 5-oxy-substituted 3-phenylisoxazoline-5 -carboxamides and 5-oxy-substituted 3-phenylisoxazoline-5-thioami des. | |
| JP2764265B2 (en) | Microbicide composition | |
| JPH0656796A (en) | N-iodopropargylhydantoin compound, composition, production, and use as antimicrobial agent | |
| CN103922990B (en) | A kind of molecular modification of Natural occurring compounds and the method for weeding | |
| CN109320471B (en) | 3- (2, 6-difluorophenyl) -1,2, 4-oxadiazole compound and application thereof | |
| CN106008496A (en) | S-(5-substituted-1, 3, 4-thiadiazole)-(5-substituted phenyl)-2-furancarbothioic acid ester compound, preparation method and application thereof | |
| KR900006746B1 (en) | Process for producing new amide derivatives and fungicides comprising these compounds as active ingredient | |
| TW201208569A (en) | Novel heterocyclic alkanol derivatives | |
| CN108059629B (en) | Pyrimidine-containing substituted pyrazole compound and preparation method and application thereof | |
| CN108191786B (en) | 2, 5-substituent-1, 3, 4-oxadiazole disulfone derivative, preparation method and application thereof | |
| KR20170132743A (en) | Triazole derivatives as agrochemicals and plant growth regulators | |
| Pasteris et al. | Oxysterol‐binding protein inhibitors: oxathiapiprolin–A new Oomycete fungicide that targets an oxysterol‐binding protein | |
| CN114195772B (en) | 1,2, 4-oxadiazole derivative containing 1,3, 4-thiadiazole unit, and preparation method and application thereof | |
| SU1450737A3 (en) | Method of producing derivatives of 9.10-phenanthredione | |
| CN109535153A (en) | Benzisothiazolinone isoxazole acetamide derivative and synthetic method and application thereof | |
| CN115521267A (en) | Benzenesulfonamide compound containing N-5-chloroisoxazole malonate structure, preparation method and application | |
| GB2127817A (en) | 3-aryl-5, 6-dihydro-1,4,2-oxathiazines and their oxides] | |
| JPH0368566A (en) | Derivative of 5-substituted 3-aryl inoxazole, its preparation and expellant medicine for controlling harmful organism containing same | |
| JP4153092B2 (en) | Pest control composition and pest control method |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20220322 Assignee: LIUZHOU HUINONG CHEMICALS CO.,LTD. Assignor: Guizhou University Contract record no.: X2024980017614 Denomination of invention: 1,2,4-Oxadiazole-5-Formamide Derivatives and Their Preparation Methods and Applications Granted publication date: 20221025 License type: Common License Record date: 20241009 |