CN117430609B - Purine derivative compound, preparation method and application thereof - Google Patents
Purine derivative compound, preparation method and application thereof Download PDFInfo
- Publication number
- CN117430609B CN117430609B CN202311400343.2A CN202311400343A CN117430609B CN 117430609 B CN117430609 B CN 117430609B CN 202311400343 A CN202311400343 A CN 202311400343A CN 117430609 B CN117430609 B CN 117430609B
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- formula
- reaction
- added
- purine
- substituted
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- -1 Purine derivative compound Chemical class 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 239000004009 herbicide Substances 0.000 claims abstract description 25
- 230000002363 herbicidal effect Effects 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 238000001784 detoxification Methods 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 80
- 239000002253 acid Substances 0.000 claims description 47
- 239000011230 binding agent Substances 0.000 claims description 47
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- 239000007822 coupling agent Substances 0.000 claims description 32
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 31
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 31
- 238000005406 washing Methods 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 27
- 238000010992 reflux Methods 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 24
- 230000035484 reaction time Effects 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 150000003212 purines Chemical class 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 125000005059 halophenyl group Chemical group 0.000 claims description 3
- 239000000575 pesticide Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000005826 halohydrocarbons Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 27
- 230000000694 effects Effects 0.000 abstract description 18
- 231100000674 Phytotoxicity Toxicity 0.000 abstract description 12
- MAYMYMXYWIVVOK-UHFFFAOYSA-N 2-[(4,6-dimethoxypyrimidin-2-yl)carbamoylsulfamoyl]-4-(methanesulfonamidomethyl)benzoic acid Chemical compound COC1=CC(OC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=C(CNS(C)(=O)=O)C=2)C(O)=O)=N1 MAYMYMXYWIVVOK-UHFFFAOYSA-N 0.000 abstract description 7
- 239000005577 Mesosulfuron Substances 0.000 abstract description 7
- 230000012010 growth Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 158
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 110
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 87
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 81
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- IUEISQYNCXVHTJ-UHFFFAOYSA-N 7h-purin-6-ylhydrazine Chemical compound NNC1=NC=NC2=C1NC=N2 IUEISQYNCXVHTJ-UHFFFAOYSA-N 0.000 description 46
- 239000007788 liquid Substances 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 239000012043 crude product Substances 0.000 description 33
- 239000012153 distilled water Substances 0.000 description 33
- 239000003480 eluent Substances 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- 238000003756 stirring Methods 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- 235000019441 ethanol Nutrition 0.000 description 29
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 238000001816 cooling Methods 0.000 description 25
- 238000004090 dissolution Methods 0.000 description 25
- 239000012065 filter cake Substances 0.000 description 25
- 230000001376 precipitating effect Effects 0.000 description 25
- 239000000047 product Substances 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 23
- 238000001514 detection method Methods 0.000 description 21
- 241000209140 Triticum Species 0.000 description 19
- 235000021307 Triticum Nutrition 0.000 description 19
- 238000012360 testing method Methods 0.000 description 11
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 10
- 241000196324 Embryophyta Species 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- YSKHRCGNQFWRFM-UHFFFAOYSA-N 6-chloro-9-ethylpurine Chemical compound N1=CN=C2N(CC)C=NC2=C1Cl YSKHRCGNQFWRFM-UHFFFAOYSA-N 0.000 description 7
- PLZNXQYAVUAQNV-UHFFFAOYSA-N (9-ethylpurin-6-yl)hydrazine Chemical compound N1=CN=C2N(CC)C=NC2=C1NN PLZNXQYAVUAQNV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 229930002875 chlorophyll Natural products 0.000 description 5
- 235000019804 chlorophyll Nutrition 0.000 description 5
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000005869 Pyraclostrobin Substances 0.000 description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 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 4
- 238000010227 cup method (microbiological evaluation) Methods 0.000 description 3
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 2
- KVZUCOGWKYOPID-UHFFFAOYSA-N 2,4,5-Trimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(C(O)=O)C=C1OC KVZUCOGWKYOPID-UHFFFAOYSA-N 0.000 description 2
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,5-dimethoxybenzoic acid Chemical compound COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 description 2
- WXVQURJGDUNJCS-UHFFFAOYSA-N 4-methoxy-3,5-dimethylbenzoic acid Chemical compound COC1=C(C)C=C(C(O)=O)C=C1C WXVQURJGDUNJCS-UHFFFAOYSA-N 0.000 description 2
- MHPUGCYGQWGLJL-UHFFFAOYSA-N 5-methyl-hexanoic acid Chemical compound CC(C)CCCC(O)=O MHPUGCYGQWGLJL-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001555 benzenes Chemical group 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- NIFKBBMCXCMCAO-UHFFFAOYSA-N methyl 2-[(4,6-dimethoxypyrimidin-2-yl)carbamoylsulfamoyl]-4-(methanesulfonamidomethyl)benzoate Chemical group COC(=O)C1=CC=C(CNS(C)(=O)=O)C=C1S(=O)(=O)NC(=O)NC1=NC(OC)=CC(OC)=N1 NIFKBBMCXCMCAO-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- CODFVANRHMDSSS-UHFFFAOYSA-N 1-(2-chlorophenyl)cyclopropane-1-carboxylic acid Chemical compound C=1C=CC=C(Cl)C=1C1(C(=O)O)CC1 CODFVANRHMDSSS-UHFFFAOYSA-N 0.000 description 1
- YAHLWSGIQJATGG-UHFFFAOYSA-N 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid Chemical compound C=1C=C(Cl)C=CC=1C1(C(=O)O)CC1 YAHLWSGIQJATGG-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- NDCPERCVXDYEFU-UHFFFAOYSA-N 1-fluorocyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(F)CC1 NDCPERCVXDYEFU-UHFFFAOYSA-N 0.000 description 1
- SJZATRRXUILGHH-UHFFFAOYSA-N 2,4,6-trifluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=C(F)C=C1F SJZATRRXUILGHH-UHFFFAOYSA-N 0.000 description 1
- APLNAFMUEHKRLM-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)N=CN2 APLNAFMUEHKRLM-UHFFFAOYSA-N 0.000 description 1
- SNBCBHDLGLDGRF-UHFFFAOYSA-N 2-chloro-9-ethylpurine Chemical compound N1=C(Cl)N=C2N(CC)C=NC2=C1 SNBCBHDLGLDGRF-UHFFFAOYSA-N 0.000 description 1
- RIBKWYDHQVKCIF-UHFFFAOYSA-N 2-chloro-9-propan-2-ylpurine Chemical compound N1=C(Cl)N=C2N(C(C)C)C=NC2=C1 RIBKWYDHQVKCIF-UHFFFAOYSA-N 0.000 description 1
- IJEUISLJVBUNRE-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole-4-carboxylic acid Chemical compound CC1=NOC(C)=C1C(O)=O IJEUISLJVBUNRE-UHFFFAOYSA-N 0.000 description 1
- NCTSLPBQVXUAHR-UHFFFAOYSA-N 3,5-ditert-butylbenzoic acid Chemical compound CC(C)(C)C1=CC(C(O)=O)=CC(C(C)(C)C)=C1 NCTSLPBQVXUAHR-UHFFFAOYSA-N 0.000 description 1
- NLEPZGNUPNMRGF-UHFFFAOYSA-N 3-bromo-4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(Br)=C1 NLEPZGNUPNMRGF-UHFFFAOYSA-N 0.000 description 1
- MKJBJYCBKXPQSY-UHFFFAOYSA-N 3-bromo-5-iodobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC(I)=C1 MKJBJYCBKXPQSY-UHFFFAOYSA-N 0.000 description 1
- HNJSYSWRPCCSQI-UHFFFAOYSA-N 3-iodo-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1I HNJSYSWRPCCSQI-UHFFFAOYSA-N 0.000 description 1
- QPIBHIXKUQKNFP-UHFFFAOYSA-N 4-chloro-3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(F)=C1 QPIBHIXKUQKNFP-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- ZQLDNJKHLQOJGE-UHFFFAOYSA-N 4-octylbenzoic acid Chemical compound CCCCCCCCC1=CC=C(C(O)=O)C=C1 ZQLDNJKHLQOJGE-UHFFFAOYSA-N 0.000 description 1
- OZPPUPJQRJYTNY-UHFFFAOYSA-N 4-pentoxybenzoic acid Chemical compound CCCCCOC1=CC=C(C(O)=O)C=C1 OZPPUPJQRJYTNY-UHFFFAOYSA-N 0.000 description 1
- GDFUWFOCYZZGQU-UHFFFAOYSA-N 4-propoxybenzoic acid Chemical compound CCCOC1=CC=C(C(O)=O)C=C1 GDFUWFOCYZZGQU-UHFFFAOYSA-N 0.000 description 1
- RZIIMNOJHLWYNA-UHFFFAOYSA-N 6-chloro-9-propan-2-ylpurine Chemical compound N1=CN=C2N(C(C)C)C=NC2=C1Cl RZIIMNOJHLWYNA-UHFFFAOYSA-N 0.000 description 1
- LZGHTGRSJLBTTI-UHFFFAOYSA-N 6-chloro-9-propylpurine Chemical compound N1=CN=C2N(CCC)C=NC2=C1Cl LZGHTGRSJLBTTI-UHFFFAOYSA-N 0.000 description 1
- XPCCMGJNLNAIKA-UHFFFAOYSA-N 9-benzyl-2-chloropurine Chemical compound C12=NC(Cl)=NC=C2N=CN1CC1=CC=CC=C1 XPCCMGJNLNAIKA-UHFFFAOYSA-N 0.000 description 1
- NKEFCVAMNJICJZ-UHFFFAOYSA-N 9-benzyl-6-chloropurine Chemical compound C1=NC=2C(Cl)=NC=NC=2N1CC1=CC=CC=C1 NKEFCVAMNJICJZ-UHFFFAOYSA-N 0.000 description 1
- FDRPGDDGRMEJSU-UHFFFAOYSA-N 9-butyl-6-chloropurine Chemical compound N1=CN=C2N(CCCC)C=NC2=C1Cl FDRPGDDGRMEJSU-UHFFFAOYSA-N 0.000 description 1
- NXDCWUIJNDQFAD-UHFFFAOYSA-N CCCCN1C=NC2=CN=C(N=C21)Cl Chemical compound CCCCN1C=NC2=CN=C(N=C21)Cl NXDCWUIJNDQFAD-UHFFFAOYSA-N 0.000 description 1
- IHHMUBRVTJMLQO-UHFFFAOYSA-N Pyraclonil Chemical compound C#CCN(C)C1=C(C#N)C=NN1C1=NN(CCCC2)C2=C1Cl IHHMUBRVTJMLQO-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000004495 emulsifiable concentrate Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 239000000447 pesticide residue Substances 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- 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
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P13/00—Herbicides; Algicides
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
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Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a purine derivative compound, a preparation method and application thereof. The polysubstituted purine compounds have a structure shown in a formula (I). Wherein R 1,R2 is defined in the specification. The invention also relates to an agricultural composition containing the compound or the salt thereof acceptable in the agro-pharmaceutical industry. The compound prepared by the invention has good safener activity, and can well remove the phytotoxicity of herbicide mesosulfuron to crops after use, thereby being beneficial to the growth of crops. Compared with the similar compounds, the compound provided by the invention has good detoxification effect and safety.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a purine derivative compound, a preparation method and application thereof.
Background
The herbicide safener can selectively protect crops from phytotoxicity of the herbicide on the premise of not affecting the activity of the herbicide on target weeds, and has a certain detoxification effect. These compounds have generated considerable commercial interest and motivation for research since the first herbicide safener discovery in 1947.
Safeners have the ability to enhance the selectivity of herbicides between crops and weeds and in addition have many potential use values. They can protect crops from pesticide residues, so that the flexibility of choice for crop planting in rotation is improved, which is advantageous for achieving more effective weed control by increasing the dosage of herbicide, and for using herbicide under adverse environmental conditions where crop phytotoxicity is likely to occur. Accordingly, there is a continuing need to invent novel safener compounds.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a purine derivative compound, a preparation method and application thereof, and aims to solve part of the problems in the prior art or at least alleviate part of the problems in the prior art.
The present invention has been achieved in view of the above, and a first object of the present invention is to provide a purine derivative compound having the general structural formula (I):
Wherein: r 1: an alkyl or benzyl substitution selected from the group consisting of a hydrogen atom, C 1-C6;
R 2: selected from the group consisting of substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, chloro-substituted indazolyl, isoheptyl,
Wherein the substitution refers to having one or more substituents selected from the group consisting of: halogen, phenyl, and a halogen atom,
Halogenated phenyl, alkyl of C 1-C8, alkoxy of C 1-C6, hydrogen, and the like.
A second object of the present invention is to provide a process for producing the purine derivative compound.
When R 1 is selected from C 1-C6 alkyl or benzyl, the purine derivative compounds are synthesized
The route is as follows:
Correspondingly, when R 1 is selected from C 1-C6 alkyl or benzyl, the purine derivative compound is prepared by the following method, and the method comprises the following steps:
(1) Dissolving 6-chloropurine formula (II-1) and an acid binding agent 1 in an organic solvent 1, then dropwise adding halogenated hydrocarbon for reaction, and then extracting, drying, filtering, concentrating and purifying to obtain 6-chloro-9-substituted purine compounds formula (II-2);
(2) Dissolving the 6-chloro-9-substituted purine compound formula (II-2) and hydrazine hydrate in an organic solvent 2 for reflux reaction, and obtaining 9-substituted 6-hydrazinopurine compound formula (II-3) through precipitation, suction filtration and washing;
(3) Dissolving the 9-substituted 6-hydrazinopurine compound formula (II-3) in an organic solvent 3, adding an acid binding agent 2 and a coupling agent, carrying out reflux reaction with carboxylic acid formulas (II-4) with different structures, and purifying and recrystallizing to obtain the purine derivative formula (I).
Further, in the above technical solution, the organic solvent 1, the organic solvent 2 and the organic solvent 3 may be the same, and are the same organic solvent; or can be different and is three different organic solvents. The three organic solvents can be any one of N, N-dimethylformamide, anhydrous methanol, anhydrous ethanol, isopropanol, acetonitrile and the like.
Still further, in some preferred embodiments of the present invention, the organic solvent 1 is N, N-dimethylformamide, the organic solvent 2 is absolute ethanol, and the organic solvent 3 is acetonitrile.
Further, according to the technical scheme, the acid binding agent 1 and the acid binding agent 2 can be the same and are the same acid binding agent; or two different acid binding agents. Both acid binding agents can be at least one of N, N-Diisopropylethylamine (DIEA), triethylamine, triethanolamine, ammonium chloride, potassium carbonate, sodium bicarbonate, sodium hydroxide, etc.
Further, in some preferred embodiments of the present invention, the molar ratio of the reaction of the formula (II-1) and the halogenated hydrocarbon in the step (1) is 1:1.2, the molar ratio of the formula (II-1) to the acid binding agent 1 is 1:1.2, the reaction temperature is 27-30 ℃ and the reaction time is 24 hours.
Further, in some preferred embodiments of the present invention, the reaction molar ratio of formula (II-2) to hydrazine hydrate in step (2) is 1:6, the reaction temperature is 70-80 ℃ and the reaction time is 6 hours.
Further, in some preferred embodiments of the present invention, the reaction molar ratio of formula (II-3) to formula (II-4) in step (3) is 1:1, wherein the molar ratio of the formula (II-3) to the acid binding agent 2 is 1:2, wherein the molar ratio of the formula (II-3) to the coupling agent is 1: (2-3) the reaction temperature is 70-80 ℃ and the reaction time is 10 hours.
Further, in the above technical solution, in the step (3), the coupling agent is at least one of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC), hydroxybenzotriazole (HOBt), and the like.
Further, according to the technical scheme, the solvent used for recrystallization is at least one of dichloromethane, ethyl acetate, methanol and petroleum ether.
Further, in the above technical scheme, in the step (3), the carboxylic acid formula (II-4) contains any one of a substituted or unsubstituted cyclopropyl group, an unsubstituted or substituted five-membered ring containing at least one element selected from nitrogen, oxygen and sulfur, an unsubstituted or substituted benzene ring, a substituted indazole ring, or an alkyl group; wherein the substitution refers to having one or more substituents selected from the group consisting of: halogen, phenyl, halophenyl, C 1-C8 alkyl, C 1-C6 alkoxy, hydrogen, and the like.
When R 1 is selected from hydrogen atoms, the synthetic route of the purine derivative compounds is as follows:
Correspondingly, when R 1 is selected from hydrogen atoms, the purine derivative compound is prepared by the following method, and comprises the following steps:
(A) Dissolving 6-chloropurine in formula (II-1) and hydrazine hydrate in an organic solvent 2 for reflux reaction, and obtaining 6-hydrazinopurine (II-3) through precipitation, suction filtration and washing;
(B) Dissolving the 6-hydrazinopurine (II-3) in an organic solvent 3, adding an acid binding agent 2 and a coupling agent, carrying out reflux reaction with carboxylic acid formulas (II-4) with different structures, and purifying and recrystallizing to obtain the purine derivative formula (I).
Further, in the above technical solution, the organic solvent 2 and the organic solvent 3 may be the same, and are the same organic solvent; or may be different, two different organic solvents. Both organic solvents may be any of N, N-dimethylformamide, anhydrous methanol, anhydrous ethanol, isopropanol, acetonitrile, and the like.
Still further, in some preferred embodiments of the present invention, the organic solvent 2 is absolute ethanol, and the organic solvent 3 is acetonitrile.
Further, in the above technical solution, the acid-binding agent 2 is at least one of N, N-Diisopropylethylamine (DIEA), triethylamine, triethanolamine, ammonium chloride, potassium carbonate, sodium bicarbonate, sodium hydroxide, and the like.
Further, in some preferred embodiments of the present invention, the reaction molar ratio of the formula (II-1) and hydrazine hydrate in the step (a) is 1:6, the reaction temperature is 70-80 ℃ and the reaction time is 6 hours.
Further, in some preferred embodiments of the present invention, the reaction molar ratio of formula (II-3) to formula (II-4) in step (B) is 1:1, wherein the molar ratio of the formula (II-3) to the acid binding agent 2 is 1:2, wherein the molar ratio of the formula (II-3) to the coupling agent is 1: (2-3) the reaction temperature is 70-80 ℃ and the reaction time is 10 hours.
Still further, in the above technical solution, in the step (B), the coupling agent is at least one of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC), hydroxybenzotriazole (HOBt), and the like.
Further, according to the technical scheme, the solvent used for recrystallization is at least one of dichloromethane, ethyl acetate, methanol and petroleum ether.
Further, in the above technical scheme, in the step (B), the carboxylic acid formula (II-4) contains at least one of a substituted or unsubstituted cyclopropyl group, an unsubstituted or substituted five-membered ring containing at least one element selected from nitrogen, oxygen and sulfur, an unsubstituted or substituted benzene ring, a substituted indazole ring, or an alkyl group; wherein the substitution refers to having one or more substituents selected from the group consisting of: halogen, phenyl, halophenyl, C 1-C8 alkyl, C 1-C6 alkoxy, hydrogen, and the like.
A third object of the present invention is to provide the use of a purine derivative compound as described above for combating herbicide toxicity to crops.
A fourth object of the present invention is to provide the use of a purine derivative compound as described above for the preparation of a herbicide safener composition.
Further, the herbicide safener composition comprises the purine derivative compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, and further comprises a carrier acceptable in pesticide.
In summary, the invention has the advantages and positive effects that:
the compound of the general formula (I) has excellent safety activity at low dosage, can well improve the phytotoxicity problem caused by herbicide, has good detoxification effect and is beneficial to the growth of crops. Compared with the existing similar commercialized pyraclostrobin, the compound has good safety and better detoxification effect.
The compounds of the present invention may be used alone or in combination with other known pesticides, bactericides, herbicides, plant growth regulators or fertilizers and the like. The invention also provides safener compositions comprising compounds of formula (I) as active ingredients. The safener composition comprises between 0.1 and 99% by weight of active components. The safener composition also includes an agriculturally acceptable carrier.
The compounds of the invention may be applied to seeds or foliage in the form of a formulation. Such compounds are typically dissolved in a carrier or formulated for easier dispersion when used as safeners. For example, these chemicals may be formulated as wettable powders or emulsifiable concentrates. In these compositions, a liquid or solid carrier may be added, and when necessary, a proper amount of surfactant may be added for co-use.
For certain applications, one or more additional safeners may be added to the safener composition of the present invention, thereby producing a more efficient and rapid detoxification effect.
Detailed Description
The present invention will be described in further detail with reference to the following examples, in which the apparatus and reagents used in the respective examples and test examples are commercially available unless otherwise specified. The specific embodiments described herein are to be considered in an illustrative sense only and are not intended to limit the invention.
The invention provides a purine derivative compound, a preparation method and application thereof. The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS).
Example 16 preparation of chloro-9-ethylpurine (II-2-1)
6-Chloropurine (1 eq) and an acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30ml of N, N-dimethylformamide, and bromoethane (1.2 eq) was added dropwise after stirring at room temperature for 30 mins. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether 5:1 to give 6-chloro-9-ethylpurine (formula II-2-1) in a yield of 65.2%, m.p.78.2-79.1 ℃.
Example 26 preparation of chloro-9-propylpurine (II-2-2)
6-Chloropurine (1 eq) and an acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30 ml of N, N-dimethylformamide, and after stirring for 30min at room temperature, 1-bromopropane (1.2 eq) was added dropwise. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether was 6:1 to give 6-chloro-9-propylpurine (formula II-2-2) in a yield of 63.3%, m.p.71.3-72.8deg.C.
Example 3 6 preparation of chloro-9-butylpurine (II-2-3)
6-Chloropurine (1 eq) and an acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30 ml of N, N-dimethylformamide, and after stirring for 30min at room temperature, bromo-N-butane (1.2 eq) was added dropwise. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether 5:1 to give 6-chloro-9-butylpurine (formula II-2-3) in a yield of 52.1%, m.p.67.1-68.9 ℃.
Example 46 preparation of chloro-9-isopropylpurine (II-2-4)
6-Chloropurine (1 eq) and an acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30ml of N, N-dimethylformamide, and after stirring for 30min at room temperature, bromoisopropyl (1.2 eq) was added dropwise. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether was 6:1 to give 6-chloro-9-isopropylpurine (formula II-2-4) in a yield of 49.0%, m.p.107.6-108.5 ℃.
Example 56 preparation of chloro-9-benzylpurine (II-2-5)
6-Chloropurine (1 eq) and acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30ml of N, N-dimethylformamide, and benzyl chloride (1.2 eq) was added dropwise after stirring at room temperature for 30 mins. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether was 8:1 to give 6-chloro-9-benzylpurine (formula II-2-5) in a yield of 76.4%, m.p. 86.2-87.0deg.C.
Example 6 6 preparation of cyclopropanehydrazide-purine (I-1)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, wherein TCL detection reaction is complete, cooling to room temperature, precipitating, suction-filtering, washing filter cakes with absolute ethyl alcohol and distilled water for three times respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of cyclopropanecarboxylic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6-cyclopropane hydrazide-purine (I-1), and the yield 51.3%,m.p.264.3-265.1℃;1H NMR(500MHz,TFA-d)δ(ppm)9.03(d,2H),2.05-1.74(m,1H),1.30(s,2H)1.27-1.06(d,J=8.3Hz 2H). has the structural formula as follows:
example 76 preparation of- (1-fluoro-cyclopropanehydrazide) -purine (I-2)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 1-fluorocyclopropane carboxylic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (1-fluoro-cyclopropanehydrazide) -purine (I-2), and the yield 45.7%,m.p.261.7.3-262.2℃;1H NMR(500MHz,TFA-d)δ(ppm)9.00(d,J=5.3Hz,1H),8.92(d,J=5.8Hz,1H),1.75-1.25(m,4H). has the structural formula as follows:
example 8 6 preparation of- (1-cyclopropane-4-chlorophenyl hydrazide) -purine (I-3)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 1- (4-chlorophenyl) -1-cyclopropanecarboxylic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, then the product was purified by methylene chloride: absolute methanol = 10:1 to obtain 6- (1-cyclopropane-4-chlorophenyl hydrazide) -purine (I-3), and the yield 38.6%,m.p.>300℃;1H NMR(500MHz,TFA-d)δ(ppm)9.06-8.98(m,1H),8.96(s,1H),7.60-7.33(m,4H),1.89(q,J=4.4Hz,2H),1.47(q,J=4.5Hz,2H). has the structural formula as follows:
Example 96 preparation of- (1-cyclopropane-2-chlorophenyl hydrazide) -purine (I-4)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 1- (2-chlorophenyl) -1-cyclopropanecarboxylic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: absolute methanol 50:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (1-cyclopropane-2-chlorophenyl hydrazide) -purine (I-4), and the yield 42.4%,m.p.>300℃;1H NMR(500MHz,TFA-d)δ(ppm)9.18(d,J=5.7Hz,1H),9.04(d,J=3.0Hz,1H),8.95(d,J=6.1Hz,1H),7.62-7.37(m,3H),2.19-1.87(m,2H),1.55(s,2H). has the structural formula as follows:
Example 10 preparation of 6- (3, 5-dimethyl-isoxazolyl hydrazide) -purine (I-5)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 3, 5-dimethylisoxazole-4-carboxylic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (3, 5-dimethyl-isoxazolyl hydrazide) -purine (I-5) with a yield of 31.2%, m.p. > 300 ℃;1H NMR (500 MHz, TFA-d) δ (ppm) 9.01 (d, J=2.0 Hz, 2H), 2.83 (d, J=2.1 Hz, 3H), 2.67 (d, J=2.2 Hz, 3H). The structural formula is as follows:
Example 11 preparation of 6- (5-methyl-3-phenyl-isoxazole hydrazide) -purine (I-6)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, and the mixture was refluxed at 75℃for 10 hours, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (5-methyl-3-phenyl-isoxazolyl hydrazide) -purine (I-6) with the yield of 34.2%, m.p. > 300 ℃;1H NMR (500 MHz, TFA-d) delta (ppm) 9.04-8.94 (m, 2H), 7.94-7.61 (m, 4H), 2.69 (s, 3H). The structural formula is as follows:
Example 12 preparation of 6- (3-methyl-5-phenyl-isoxazole hydrazide) -purine (I-7)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, and the reaction was refluxed at 75℃for 10 hours, with complete TCL detection, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to yield 6- (3-methyl-5-phenyl-isoxazole hydrazide) -purine (I-7) with the following structural formula:
EXAMPLE 13 preparation of 6- (1-H-pyrazole hydrazide) -purine (I-8)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of pyrazole-3-carboxylic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (1-H-pyrazole hydrazide) -purine (I-8), and the yield 58.0%,m.p.208.4-209.1℃;1H NMR(500MHz,TFA-d)δ(ppm)9.13-9.08(m,2H,),8.45-8.18(m,1H),7.50(t,J=4.4Hz,1H). has the structural formula as follows:
EXAMPLE 14 preparation of 6- (1, 3-dimethyl-pyrazole hydrazide) -purine (I-9)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq) was added, coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were reacted under reflux at 75℃for 10 hours, and the solvent was removed under reduced pressure after complete TCL detection. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: absolute methanol 50:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (1, 3-dimethyl-pyrazole hydrazide) -purine (I-9), and the yield 50.9%,m.p.241.7-243.0℃;1HNMR(500MHz,TFA-d)δ(ppm)9.00(d,J=7.2Hz,2H),7.28(s,1H),4.40(d,J=12.3Hz,3H),2.61(d,J=9.4Hz,3H). has the structural formula as follows:
EXAMPLE 15 preparation of 6- (1, 5-dimethyl-pyrazole hydrazide) -purine (I-10)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq) was added, coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were reacted under reflux at 75℃for 10 hours, and 1, 5-dimethylpyrazole-5-carboxylic acid (1 eq) was detected by TCL and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: absolute methanol 50:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (1, 5-dimethyl-pyrazole hydrazide) -purine (I-10), and the yield 55.2%,m.p.269.6-270.3℃;1HNMR(500MHz,TFA-d)δ(ppm)9.01-8.79(m,2H),7.15(s,1H),4.06(s,3H),2.46(s,3H). has the structural formula as follows:
EXAMPLE 16 preparation of 6- (5-chloroindole hydrazide) -purine (I-11)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, and the mixture was refluxed at 75℃for 10 hours, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (5-chloroindole hydrazide) -purine (I-11), and the yield 36.8%,m.p.214.9-215.7℃;1H NMR(500MHz,TFA-d)δ(ppm)9.13(s,1H),9.11(d,J=2.4Hz,1H),9.08(s,1H),9.07(d,J=2.3Hz,2H). has the structural formula as follows:
EXAMPLE 17 preparation of 6- (4-octyl-phenylhydrazide) -purine (I-12)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 4-octylbenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (4-octyl-phenyl hydrazide) -purine (I-12), and the yield 49.1%,m.p.>300℃;1H NMR(500MHz,TFA-d)δ(ppm)9.13-9.06(m,3H),8.14-7.94(m,2H),7.43-7.38(d,J=2.5Hz,1H),3.18-3.10(m,6H),1.47-1.40(m,4H),1.38-1.32(m,4H),0.94(d,3H). has the structural formula as follows:
EXAMPLE 18 preparation of 6- (3, 5-di-tert-butyl-phenylhydrazide) -purine (I-13)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 3, 5-di-tert-butylbenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: absolute methanol 50:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (3, 5-di-tert-butyl-phenyl hydrazide) -purine (I-13), and the yield 40.2%,m.p.>300℃;1H NMR(500MHz,TFA-d)δ(ppm)9.07(d,J=1.8Hz,2H),8.13-7.74(m,3H),1.43(d,J=4.2Hz,18H). has the structural formula as follows:
EXAMPLE 19 preparation of 6- (4-methoxy-phenylhydrazide) -purine (I-14)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of p-methoxybenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: absolute methanol 50:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (4-methoxy-phenylhydrazide) -purine (I-14), and the yield 57.4%,m.p.275.1-275.6℃;1H NMR(500MHz,TFA-d)δ(ppm)9.39-8.89(m,2H),8.13(t,J=8.7Hz,2H),7.27(t,J=8.6Hz,2H),4.35-3.92(m,3H). has the structural formula as follows:
EXAMPLE 20 preparation of 6- (3, 5-dimethoxy-phenylhydrazide) -purine (I-15)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 3, 5-dimethoxybenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: absolute methanol 50:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (3, 5-dimethoxy-phenyl hydrazide) -purine (I-15), and the yield 48.1%,m.p.220.2-221.4℃;1HNMR(500MHz,TFA-d)δ(ppm)9.13(d,J=4.5Hz,2H),9.09(d,J=4.9Hz,3H),3.14(s,6H). has the structural formula as follows:
EXAMPLE 21 preparation of 6- (2, 4, 5-trimethoxy-phenylhydrazide) -purine (I-16)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq) was added, coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were reacted under reflux at 75℃for 10 hours, and 2,4, 5-trimethoxybenzoic acid (1 eq) was detected by TCL and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (2, 4, 5-trimethoxy-phenylhydrazide) -purine (I-16), and the yield 39.4%,m.p.261.1-261.8℃;1H NMR(500MHz,TFA-d)δ(ppm)9.15(s,1H),8.95(s,1H),7.80(s,1H),6.84(s,1H),4.32-3.60(m,9H). has the structural formula as follows:
EXAMPLE 22 preparation of 6- (4-propoxyhydrazide) -purine (I-17)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 4-propoxybenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (4-propoxy hydrazide) -purine (I-17), and the yield 50.6%,m.p.241.0-241.7℃;1H NMR(500MHz,TFA-d)δ(ppm)9.10-9.01(m,2H),8.25-7.83(m,2H),7.17(q,J=10.3Hz,2H),4.40-3.98(m,2H),1.91(t,J=7.4Hz,2H),1.07(d,J=7.0Hz,3H). has the structural formula as follows:
EXAMPLE 23 preparation of 6- (4-pentoxy-phenylhydrazide) -purine (I-18)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 4-N-pentyloxybenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (4-pentoxy-phenylhydrazide) -purine (I-18), and the yield 49.0%,m.p.221.4-223.1℃;1H NMR(500MHz,TFA-d)δ(ppm)9.20(s,1H),9.07(d,J=6.5Hz,2H),8.97(s,1H),8.04(d,J=8.8Hz,1H),7.20(d,J=8.7Hz,1H),4.28(t,J=6.7Hz,2H),1.94(q,J=6.9Hz,2H),1.63-1.34(m,4H),1.00(t,J=7.2Hz,3H). has the structural formula as follows:
EXAMPLE 24 preparation of 6- (3-iodo-4-methoxy-phenylhydrazide) -purine (I-19)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq) was added, coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were reacted under reflux at 75℃for 10 hours, and 3-iodo-4-methoxybenzoic acid (1 eq) was detected by TCL and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (3-iodine-4-methoxy-phenyl hydrazide) -purine (I-19), and the yield 58.5%,m.p.232.7-233.0℃;1H NMR(500MHz,TFA-d)δ(ppm)8.76-8.51(m,1H),8.37-8.19(m,1H),8.12-7.90(m,2H),7.04(d,J=8.8Hz,1H),4.18-3.87(m,3H). has the structural formula as follows:
EXAMPLE 25 preparation of 6- (4-methoxy-3, 5-dimethylphenyl-hydrazide) -purine (I-20)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq) was added, coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were reacted under reflux at 75℃for 10 hours, and 3, 5-dimethyl-4-methoxybenzoic acid (1 eq) was detected by TCL and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (4-methoxy-3, 5-dimethylphenyl hydrazide) -purine (I-20), and the yield 51.2%,m.p.186.4-188.1℃;1H NMR(500MHz,TFA-d)δ(ppm)9.19(s,2H),9.15(d,J=4.1Hz,2H),4.15(s,3H),2.52(s,6H). has the structural formula as follows:
EXAMPLE 26 preparation of 6- (3-iodo-5-bromo-phenylhydrazide) -purine (I-21)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq) was added, coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were reacted under reflux at 75℃for 10 hours, and 3-bromo-5-iodobenzoic acid (1 eq) was detected by TCL and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (3-iodine-5-bromo-phenyl hydrazide) -purine (I-20) with a yield of 76.0%, m.p. > 300 ℃; 1H NMR(500MHz,DMSO-d6 ) Delta (ppm) 9.21 (s, 2H), 9.17 (s, 3H). Structural formula is as follows:
EXAMPLE 27 preparation of 6- (2, 4, 6-trifluoro-phenylhydrazide) -purine (I-22)
1. 6-Chloropurine (1 eq) was added to a three-necked flask containing 30 ml of absolute ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, detecting complete reaction of TCL, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazinopurine (formula II-3-1).
2. 6-Hydrazinopurine (formula II-3-1) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq) was added, coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were reacted under reflux at 75℃for 10 hours, and 2,4, 6-trifluorobenzoic acid (1 eq) was detected by TCL and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: anhydrous methanol was 100:1, and then passing the product through dichloromethane: absolute methanol = 10:1 to obtain 6- (2, 4, 6-trifluoro-phenyl hydrazide) -purine (I-22), and the yield 69.3%,m.p.>300℃;1H NMR(500MHz,TFA-d)δ(ppm)9.22(d,J=9.4Hz,2H),8.46(d,J=2.0Hz,1H),7.19-6.92(m,1H). has the structural formula as follows:
EXAMPLE 28 preparation of 6- (3-fluoro-4-chlorophenyl hydrazide) -9-ethylpurine (I-23)
1. 6-Chloropurine (1 eq) and an acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30ml of N, N-dimethylformamide, and bromoethane (1.2 eq) was added dropwise after stirring at room temperature for 30 mins. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether 5:1 to give 6-chloro-9-ethylpurine (formula II-2-1) in a yield of 65.2%, m.p.78.2-79.1 ℃.
2. 6-Chloro-9-ethylpurine (1 eq) was added to a three-necked flask containing 30 ml of ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, wherein TCL detection reaction is complete, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazino-9-ethylpurine (formula II-3-2).
3. 6-Hydrazino-9-ethylpurine (formula II-3-2) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), a coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 3-fluoro-4-chlorobenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: methanol is 100:1, and then passing the product through dichloromethane: methanol=10: 1 to obtain 6- (3-fluoro-4-chlorophenyl hydrazide) -9-ethylpurine (I-23), and the yield 84.2%,m.p.271.2-271.9℃;1H NMR(500MHz,TFA-d)δ(ppm)9.44-9.05(m,1H),8.82(s,1H),8.06(d,J=6.3Hz,2H),7.36(t,J=8.4Hz,1H),4.72(m,2H),1.76(q,J=6.8Hz,3H). has the following structural formula:
EXAMPLE 29 preparation of 6- (3-bromo-4-chlorophenyl hydrazide) -9-ethylpurine (I-24)
1. 6-Chloropurine (1 eq) and an acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30ml of N, N-dimethylformamide, and bromoethane (1.2 eq) was added dropwise after stirring at room temperature for 30 mins. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether 5:1 to give 6-chloro-9-ethylpurine (formula II-2-1) in a yield of 65.2%, m.p.78.2-79.1 ℃.
2. 6-Chloro-9-ethylpurine (1 eq) was added to a three-necked flask containing 30 ml of ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, wherein TCL detection reaction is complete, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazino-9-ethylpurine (formula II-3-2).
3. 6-Hydrazino-9-ethylpurine (formula II-3-2) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), a coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added, followed by reflux reaction of 3-bromo-4-chlorobenzoic acid (1 eq) at 75℃for 10 hours, complete TCL detection, and the solvent was removed under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: methanol is 100:1, and then passing the product through dichloromethane: methanol=10: 1 to obtain 6- (3-bromo-4-chlorophenyl hydrazide) -9-ethylpurine (I-24), and the yield 81.0%,m.p.256.7-257.2℃;1H NMR(500MHz,TFA-d)δ(ppm)9.34-9.23(m,1H),8.84(s,1H),8.14(t,J=4.1Hz,1H),7.91(d,J=4.0Hz,1H),7.79(t,J=4.5Hz,1H),4.74(q,J=6.7Hz,2H),1.94-1.59(m,3H). has the following structural formula:
EXAMPLE 30 preparation of 6-isoheptyl hydrazide-9-ethylpurine (I-25)
1. 6-Chloropurine (1 eq) and an acid-binding agent K 2CO3 (1.2 eq) were added to a three-necked flask containing 30ml of N, N-dimethylformamide, and bromoethane (1.2 eq) was added dropwise after stirring at room temperature for 30 mins. Then, the reaction was carried out at 27-30℃for 24 hours, and the TCL test reaction was completed. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure to give a crude product, the liquid was purified by column chromatography on silica gel, and the eluent was ethyl acetate: petroleum ether 5:1 to give 6-chloro-9-ethylpurine (formula II-2-1) in a yield of 65.2%, m.p.78.2-79.1 ℃.
2. 6-Chloro-9-ethylpurine (1 eq) was added to a three-necked flask containing 30 ml of ethanol, and after stirring and dissolution at room temperature, hydrazine hydrate (6 eq) was added. Then reflux-reacting at 78 ℃ for 6 hours, wherein TCL detection reaction is complete, cooling to room temperature, precipitating, filtering, washing filter cakes three times by ethanol and distilled water respectively, and drying to obtain a crude product of 6-hydrazino-9-ethylpurine (formula II-3-2).
3. 6-Hydrazino-9-ethylpurine (formula II-3-2) (1 eq) was added to a three-necked flask containing 40 ml of acetonitrile, and an acid-binding agent N, N-Diisopropylethylamine (DIEA) (2 eq), a coupling agent 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (1 eq) and hydroxybenzotriazole (HOBt) (1.2 eq) were added thereto, and the isoheptanoic acid (1 eq) was refluxed at 75℃for 10 hours, followed by complete TCL detection and removal of the solvent under reduced pressure. The liquid is adopted to pass through a silica gel column method, and dichloromethane is adopted as an eluent: methanol is 100:1, and then passing the product through dichloromethane: methanol=10: 1 to obtain 6-isoheptyl hydrazide-9-ethylpurine (I-25), and the yield 52.4%,m.p.187.9-188.6℃;1H NMR(500MHz,TFA-d)δ(ppm)9.16(s,1H),8.82(s,1H),4.67(m,2H),2.55(q,J=7.0Hz,1H),2.38(t,J=6.0Hz,2H),1.73(m,5H),1.37-1.34(m,4H),0.99(t,J=7.5Hz,6H). has the structural formula as follows:
example 31 concentration screening of herbicides and Compounds for testing
The stem and leaf treatment by the small cup method is adopted to carry out preliminary safety activity test on wheat seedlings which are subjected to phytotoxicity of herbicide mesosulfuron.
Herbicide concentration screening: herbicide mesosulfuron (0g a.i./hm2、15ga.i./hm2、20g a.i./hm2、25g a.i./hm2、30g a.i./hm2、35g a.i./hm2、40g a.i./hm2), with different concentrations is selected to carry out herbicide spray treatment on wheat (seedlings grow to 2-3 leaves and 1 heart period), and after 5 days of treatment, the concentration of the mesosulfuron when the mesosulfuron has a certain phytotoxicity on the wheat is screened out through measuring the root length, the root fresh weight, two She Zhu heights, the plant fresh weight and the chlorophyll content of the wheat. According to the wheat growth index measurement analysis shown in the following table 1, the effect of the phytotoxicity on the wheat crops is found to be different at each concentration, wherein the phytotoxicity of 30g of wheat treated by a.i./hm 2 is obvious.
TABLE 1 influence of different concentrations of mesosulfuron on wheat growth index
Compound concentration screening: the method comprises the steps of screening compound concentration by adopting a wheat cup method, measuring wheat subjected to phytotoxicity of herbicide fine methyl disulfuron, and detecting influence effects of the wheat on root length, root fresh weight, two She Zhu high, plant fresh weight and chlorophyll content after the compound of the formula (I) with different concentrations is applied, wherein the influence on detoxification of the phytotoxicity of the wheat crop is different under each concentration, so that the optimal detoxification concentration of the compound is determined.
Taking (I-1) as a column, the concentrations are respectively: 0mg/kg, 5mg/kg, 10mg/kg, 20mg/kg, 40mg/kg, 80mg/kg, and screening the safener concentration by a wheat cup method. The concentration of the safener is determined to be 20mg/kg by measuring the root length, root fresh weight, two She Zhu high, plant fresh weight and chlorophyll content of wheat.
TABLE 2 influence of different concentrations (I-1) on wheat
Protection effect study of purine derived compounds prepared in example 1-example 25 of the invention on 30g of a.i./hm 2 mesosulfuron-methyl phytosanitary wheat:
TABLE 3 protective effect of Compounds of general formula I and pyraclostrobin on 30g of a.i./hm 2 Methyldisulfuron phytotoxicity wheat
The amount of each compound in this table was 20mg/kg.
As can be seen from Table 3, most of the target compounds can recover the inhibition of mesosulfuron-methyl on the root, stem and chlorophyll content of wheat to a certain extent, and the detoxification effect of some of the target compounds is equivalent to that of the commercial safener pyraclostrobin, wherein the compounds I-3, I-6 and I-7 exhibit excellent safety activities, and the detoxification effect of the target compounds is even better than that of the commercial herbicide safener pyraclostrobin. Of these, the compound I-7 has the highest herbicide safener activity. The recovery rate of the fresh weight of the plant root is 85.51%, the recovery rate of the fresh weight of the plant root is 86.43%, the recovery rate of the length of the plant root is 76.67%, the recovery rate of the plant height is 90.59%, and the recovery rate of the chlorophyll content is 88.64%.
From the data, the purine derivatives prepared by the invention have higher safener activity, can effectively relieve the phytotoxicity of herbicide mesosulfuron to wheat, and has the effect of individual compounds better than that of commercial safener pyraclonil.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (7)
1. A purine derivative compound, characterized in that: the structural general formula (I) of the purine derivative compound is:
Wherein: r 1: an alkyl or benzyl substitution selected from C 1-C6;
r 2: selected from the group consisting of substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, chloro-substituted indazolyl, isoheptyl, wherein said substitution means having one or more substituents selected from the group consisting of: halogen, phenyl, halophenyl, alkyl of C 1-C8, C 1-C6 alkoxy, hydrogen.
2. The purine derivative compound of claim 1, wherein: the synthetic route of the purine derivative compound is as follows:
3. the process for producing a purine derivative compound according to claim 2, wherein: the method comprises the following steps:
(1) Dissolving 6-chloropurine formula (II-1) and an acid binding agent 1 in an organic solvent 1, then dropwise adding halogenated hydrocarbon for reaction, and then extracting, drying, filtering, concentrating and purifying to obtain 6-chloro-9-substituted purine compounds formula (II-2);
(2) Dissolving the 6-chloro-9-substituted purine compound formula (II-2) and hydrazine hydrate in an organic solvent 2 for reflux reaction, and obtaining 9-substituted 6-hydrazinopurine compound formula (II-3) through precipitation, suction filtration and washing;
(3) Dissolving the 9-substituted 6-hydrazinopurine compound formula (II-3) in an organic solvent 3, adding an acid binding agent 2 and a coupling agent, carrying out reflux reaction with carboxylic acid formulas (II-4) with different structures, and purifying and recrystallizing to obtain the purine derivative formula (I).
4. A process for the preparation of purine derivatives according to claim 3, wherein: the reaction mole ratio of the formula (II-1) and the halohydrocarbon in the step (1) is 1:1.2, the reaction temperature is 27-30 ℃ and the reaction time is 24 hours; the reaction mole ratio of the formula (II-2) to the hydrazine hydrate in the step (2) is 1:6, the reaction temperature is 70-80 ℃ and the reaction time is 6 hours; the reaction mole ratio of the formula (II-3) to the formula (II-4) in the step (3) is 1:1, the reaction temperature is 70-80 ℃ and the reaction time is 10 hours.
5. Use of a purine derivative compound according to claim 1 for the detoxification of herbicides to which crops are subjected.
6. Use of a purine derivative compound according to claim 1 in the preparation of a herbicide safener composition.
7. The use according to claim 6, characterized in that: the herbicide safener composition comprises the purine derivative compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, and further comprises a carrier acceptable in pesticide.
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