CN114181150A - Pyrazole amide derivative, preparation method and application thereof - Google Patents
Pyrazole amide derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN114181150A CN114181150A CN202111495272.XA CN202111495272A CN114181150A CN 114181150 A CN114181150 A CN 114181150A CN 202111495272 A CN202111495272 A CN 202111495272A CN 114181150 A CN114181150 A CN 114181150A
- Authority
- CN
- China
- Prior art keywords
- pyrazole
- methyl
- compound
- substituent
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 119
- -1 Pyrazole amide Chemical class 0.000 title claims description 152
- 150000001875 compounds Chemical class 0.000 claims abstract description 103
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 30
- 241000196324 Embryophyta Species 0.000 claims abstract description 17
- 108090000790 Enzymes Proteins 0.000 claims abstract description 16
- 102000004190 Enzymes Human genes 0.000 claims abstract description 16
- 230000012010 growth Effects 0.000 claims abstract description 13
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 231
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 201
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 177
- 238000006243 chemical reaction Methods 0.000 claims description 136
- 239000002904 solvent Substances 0.000 claims description 73
- 235000019441 ethanol Nutrition 0.000 claims description 70
- 239000000243 solution Substances 0.000 claims description 70
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 68
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 66
- 238000002390 rotary evaporation Methods 0.000 claims description 66
- 238000004809 thin layer chromatography Methods 0.000 claims description 61
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 49
- 238000001035 drying Methods 0.000 claims description 42
- 238000012544 monitoring process Methods 0.000 claims description 40
- 230000008569 process Effects 0.000 claims description 39
- 239000007788 liquid Substances 0.000 claims description 33
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 33
- 238000005406 washing Methods 0.000 claims description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 32
- 229960000583 acetic acid Drugs 0.000 claims description 30
- 239000012362 glacial acetic acid Substances 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 28
- 238000006555 catalytic reaction Methods 0.000 claims description 22
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 17
- NWHXZVJVRPCYIQ-UHFFFAOYSA-N CN1N=CC(=C1O)C(=O)O Chemical compound CN1N=CC(=C1O)C(=O)O NWHXZVJVRPCYIQ-UHFFFAOYSA-N 0.000 claims description 16
- 238000004440 column chromatography Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- OMNYXCUDBQKCMU-UHFFFAOYSA-N 2,4-dichloro-1-ethenylbenzene Chemical group ClC1=CC=C(C=C)C(Cl)=C1 OMNYXCUDBQKCMU-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 150000001413 amino acids Chemical class 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- LTOXGZKRFFELPY-UHFFFAOYSA-N CCOC(=O)C=1C=NN(C)C=1O Chemical compound CCOC(=O)C=1C=NN(C)C=1O LTOXGZKRFFELPY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- HRRWQQNTPXPXEG-UHFFFAOYSA-N 5-cyclopropyl-1,2-oxazole-4-carbonyl chloride Chemical compound C1=NOC(C2CC2)=C1C(=O)Cl HRRWQQNTPXPXEG-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 claims description 5
- KJDJPXUIZYHXEZ-UHFFFAOYSA-N hydrogen sulfate;methylaminoazanium Chemical compound CN[NH3+].OS([O-])(=O)=O KJDJPXUIZYHXEZ-UHFFFAOYSA-N 0.000 claims description 5
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical class Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 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 3
- 239000012043 crude product Substances 0.000 claims description 3
- FNASCUBBFNCFQO-UHFFFAOYSA-N ethyl 2-(ethoxymethylidene)-3-oxobutanoate Chemical compound CCOC=C(C(C)=O)C(=O)OCC FNASCUBBFNCFQO-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- SRMHVGZFDOFMKW-UHFFFAOYSA-N COC(=O)c1cnn(C)c1O Chemical compound COC(=O)c1cnn(C)c1O SRMHVGZFDOFMKW-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- KOFLVDBWRHFSAB-UHFFFAOYSA-N 1,2,4,5-tetrahydro-1-(phenylmethyl)-5,9b(1',2')-benzeno-9bh-benz(g)indol-3(3ah)-one Chemical compound C1C(C=2C3=CC=CC=2)C2=CC=CC=C2C23C1C(=O)CN2CC1=CC=CC=C1 KOFLVDBWRHFSAB-UHFFFAOYSA-N 0.000 claims 1
- HTFNVAVTYILUCF-UHFFFAOYSA-N 2-[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]anilino]-5-methyl-11-methylsulfonylpyrimido[4,5-b][1,4]benzodiazepin-6-one Chemical compound CCOc1cc(ccc1Nc1ncc2N(C)C(=O)c3ccccc3N(c2n1)S(C)(=O)=O)C(=O)N1CCC(CC1)N1CCN(C)CC1 HTFNVAVTYILUCF-UHFFFAOYSA-N 0.000 claims 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 23
- 241000219304 Portulacaceae Species 0.000 abstract description 22
- 235000001855 Portulaca oleracea Nutrition 0.000 abstract description 19
- 239000004009 herbicide Substances 0.000 abstract description 13
- IYMLUHWAJFXAQP-UHFFFAOYSA-N topramezone Chemical compound CC1=C(C(=O)C2=C(N(C)N=C2)O)C=CC(S(C)(=O)=O)=C1C1=NOCC1 IYMLUHWAJFXAQP-UHFFFAOYSA-N 0.000 abstract description 11
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- 101100339555 Zymoseptoria tritici HPPD gene Proteins 0.000 abstract 2
- 230000008635 plant growth Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- 239000003208 petroleum Substances 0.000 description 34
- 238000010898 silica gel chromatography Methods 0.000 description 26
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- QEJFOVPAFLYXGJ-UHFFFAOYSA-N 5-methyl-1-phenylpyrazole-4-carbohydrazide Chemical compound CC1=C(C(=O)NN)C=NN1C1=CC=CC=C1 QEJFOVPAFLYXGJ-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- HHPIIZJILLCOBV-UHFFFAOYSA-N 1-phenyl-5-(trifluoromethyl)pyrazole-4-carbohydrazide Chemical compound FC(F)(F)C1=C(C(=O)NN)C=NN1C1=CC=CC=C1 HHPIIZJILLCOBV-UHFFFAOYSA-N 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 8
- QOJQBWSZHCKOLL-UHFFFAOYSA-N 2,6-dimethylbenzaldehyde Chemical compound CC1=CC=CC(C)=C1C=O QOJQBWSZHCKOLL-UHFFFAOYSA-N 0.000 description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 5
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 5
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- XMCRWEBERCXJCH-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1Cl XMCRWEBERCXJCH-UHFFFAOYSA-N 0.000 description 4
- XAUUHCLUKWEZCQ-UHFFFAOYSA-N 1-(4-chlorophenyl)-5-(trifluoromethyl)pyrazole-4-carbohydrazide Chemical compound FC(F)(F)C1=C(C(=O)NN)C=NN1C1=CC=C(Cl)C=C1 XAUUHCLUKWEZCQ-UHFFFAOYSA-N 0.000 description 4
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 4
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- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- QHMTXANCGGJZRX-WUXMJOGZSA-N pymetrozine Chemical compound C1C(C)=NNC(=O)N1\N=C\C1=CC=CN=C1 QHMTXANCGGJZRX-WUXMJOGZSA-N 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
- APTZNLHMIGJTEW-UHFFFAOYSA-N pyraflufen-ethyl Chemical group C1=C(Cl)C(OCC(=O)OCC)=CC(C=2C(=C(OC(F)F)N(C)N=2)Cl)=C1F APTZNLHMIGJTEW-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- 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
- A01N43/80—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 one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- 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
Abstract
The invention discloses a 1-substituent-5-substituent-N' - (1-disubstituted) -1 with a target enzyme for inhibiting plant growth and in vitro HPPDPreparation and application of H-pyrazole-4-formylhydrazine derivative (general formula I) and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative (general formula II). The invention relates to the technical field of chemical industry and pesticides, and particularly relates to a compound which can effectively inhibit the growth of a broadleaf weed, namely purslane rhizome and has excellent inhibitory activity on HPPD enzyme. The compound B7 in the 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative has 100 percent inhibition rate to the purslane roots and stems under the dosage of 100 mu g/mL, and even under the dosage of 10 mu g/mL, the B7 still has 77.39 percent and 64.93 percent inhibition rate to the purslane roots and stems, which is better than the topramezone (53.96 percent and 43.0 percent). The compound can be used as a potential HPPD inhibitor and a broadleaf weed pre-emergence herbicide for development and use, and has the advantages of simple structure and preparation process, low production cost and wide application prospect.
Description
Technical Field
The invention relates to the field of chemical industry and pesticides, in particular to 1-substituent-5-substituent-N '- (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivatives, a preparation method of the 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivatives, and a preparation method of the 1-substituent-5-substituent-N '- (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylamino acid methyl ester derivatives The application of the (E) -methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative in medicines for inhibiting target enzymes, weed growth and the like.
Background
Weeds are one of the important components of a farmland ecosystem, and are parallel to diseases and insect pests, so that serious harm is caused to agricultural production. Weeds can compete with crops for space, sunlight, soil nutrients and moisture, resulting in reduced yield of crops and reduced quality of agricultural products. 235 billion yuan is put into China every year for weed control, still has little effect, and the yield of grains is reduced by 5 million tons due to the weed problem, so that the economic loss is nearly billion yuan. Chemical weeding is mainly used as a main body of a weed control system in China, and chemical weeding of farmlands is in a rapid development period since the 90 s of the 20 th century. Due to the wide application of chemical herbicides, the negative effects caused by the chemical herbicides are increasingly shown, and on one hand, the large-scale use of the chemical herbicides causes the problems of environmental pollution and drug residues; on the other hand, the continuous use of chemical herbicides has caused the emergence of resistant weeds and the number of resistant varieties has increased, and 44 resistant weed biotypes have been found in China at present. Therefore, the research of novel herbicides with broad spectrum, high efficiency, green and low toxicity is still a great challenge for pesticide researchers.
In recent decades, azole compounds have attracted attention from those in the agrochemical field due to their highly potent biological activity. Among various azole compounds, the pyrazole compounds have wide biological activity and play an important role in pesticides due to high efficiency, low toxicity and multi-azimuth change of substituent on a pyrazole ring. In particular, in recent years, a large number of documents report the biological activity of pyrazole derivatives, and new pyrazole pesticides have been commercialized. At present, pyrazole compounds become one of the focuses of interest in the research of creating new pesticides. The commercial herbicides such as the pyraflutole, the sulfonylopyrazole, the pyraclostrobin, the topramezone, the pyraclonil, the ipropyrazole ester, the pyraflufen-ethyl, the pyrazosulfuron-ethyl, the pyraclonil and the like all contain pyrazole structures, wherein most of the pyrazole structures are aroyl pyrazole structures, belong to p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, and have the advantages of wide weeding spectrum, good crop selectivity, capability of effectively preventing and controlling weeds which generate resistance to the herbicides such as the glyphosate and the like. The HPPD inhibitor pyrazole compound is introduced into the prevention and treatment of resistant gramineae and broadleaf weeds in wheat fields for the first time by the ciclopirox-fluridon and the topramezone developed by Qingdao original agricultural crown company, and the problems of resistance and multi-resistance of an acetolactate synthase (ALS) and an acetyl coenzyme A carboxylase (ACCase) inhibitor are perfectly solved. At present, most pyrazole HPPD inhibitors are structurally derived based on aroyl groups, and the structural transformation trend is relatively single.
The invention reserves acyl and introduces acylhydrazone and amino acid structure on the basis of leaving out inherent aroyl, aiming at exploring another new structure type of the HPPD inhibitor. The acylhydrazone compounds have wide physiological and pharmacological activities and play an important role in pesticide preparation, such as commercial herbicides diflufenzopyr, insecticides pymetrozine and metaflumizone which all contain acylhydrazone structures. Meanwhile, amino acid, which is one of five natural substances, is also the basic composition unit of protein and plays an important role in various life activities. The amino acids are diverse in types and structures, can directly participate in chemical reactions for derivatization, and many drug molecules with biological activity contain amino acid structures, such as commercial herbicides glyphosate, phosphinothricin, bialaphos and the like. Amino acid pesticides will still be one of the hot spots for creating new pesticides. In view of this, a pyrazole ring is used as a core skeleton, active units such as drug-like properties, endogenous amino acids and acylhydrazone structures are introduced based on an active substructure splicing principle, and a series of 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivatives are synthesized, so that a feasible basis is provided for the creation of a high-efficiency broad-spectrum green low-toxicity herbicide, and a potential lead structure is provided for the development of a novel HPPD inhibitor.
Disclosure of Invention
The invention aims to provide a 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative medicament which has excellent herbicidal activity, simple structure and stable compound property.
The invention also aims to provide a preparation method of the 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and the 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative.
The invention also aims at the application of the 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and the 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative in inhibiting the growth of target enzymes and weed rootstocks.
The 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine derivative (I) and the 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative (II) have the following structural general formulas:
in the formula R1Is a substituent such as methyl, trifluoromethyl and the like;
R2is phenyl, 4-chlorphenyl, 4-methylphenyl, cyclopropyl and other substituents;
R3a substituent such as a hydrogen atom or a methyl group;
R4is a substituent such as 4-fluorophenyl, 4-hydroxyphenyl, 4-methylphenyl, 2, 4-chlorophenyl, thiophen-2-yl, furan-2-yl, 3-hydroxy-4-methoxyphenyl, 2-fluoro-4-chlorophenyl, 2, 6-dimethylphenyl, etc.
In the formula R1Is a substituent such as a hydrogen atom, methyl, benzyl, isobutyl, 2-methylthio-ethyl, 3-methyl-1H-indolyl, trifluoromethyl and the like;
R2is a substituent such as a hydrogen atom, ethyl, allyl, propargyl, 4-methoxy-alpha-acetophenone, 5-cyclopropylisoxazole-4-methylcarbonyl and the like.
The invention relates to a preparation method of a 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative, which comprises the following steps:
preparation of 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine derivative:
(1) preparation of 1-substituent-5-substituent-1H-pyrazole-4-ethyl formate:
to an ethanol solution of ethyl 2-ethoxymethyleneacetoacetate or ethyl 4, 4, 4-trifluoroacetoacetate was added substituted phenylhydrazine hydrochloride, and the mixture was heated to 75 ℃ to effect a reaction. Wherein the compound molar ratio is 2-ethoxy methylene ethyl acetoacetate, 4, 4, 4-trifluoro ethyl acetoacetate: substituted phenylhydrazine hydrochloride salt ═ 1: 2. after the reaction is finished, the system is subjected to solvent removal, water washing, liquid separation, drying, concentration and column chromatography to obtain a 1-substituent-5-substituent-1H-pyrazole-4-ethyl formate intermediate;
(2) preparation of 1-substituent-5-substituent-1H-pyrazole-4-formylhydrazine:
adding excess hydrazine hydrate into ethanol solution of the intermediate of the corresponding 1-substituent-5-substituent-1H-pyrazole-4-ethyl formate, heating to 80 ℃, and monitoring the reaction progress by thin layer chromatography. After the reaction is completed, the solvent is removed by rotary evaporation, dichloromethane is used for extraction, anhydrous sodium sulfate is used for drying, and the intermediate 1-substituent-5-substituent-1H-pyrazole-4-formylhydrazine is obtained by evaporation solvent recrystallization;
(3) preparing a target compound 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine:
adding substituted aldehyde ketone into ethanol solution of 1-substituent-5-substituent-1H-pyrazole-4-formhydrazide intermediate, heating the mixture to 80 ℃, adding glacial acetic acid when the system is refluxed for 10 minutes, wherein the molar ratio is 5-substituent-1H-pyrazole-4-formhydrazide: substituted aldehyde ketones: glacial acetic acid ═ 1: 1-1.5: 2 to 3. Monitoring the reaction process by using a thin-layer chromatography, carrying out rotary evaporation to remove the solvent after the reaction is completed, washing with water, separating liquid, drying, concentrating, and then recrystallizing with absolute ethyl alcohol/ethyl acetate or purifying by using column chromatography to obtain the target compound 5-substituent-1-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine.
Preparation of (di) 1-methyl-5-substituent-1H-pyrazole-4-carboxamido acid methyl ester derivative:
(1) preparation of ethyl 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylate:
to an ethanolic solution of diethyl 2-ethoxymethylenemalonate was added methylhydrazine sulfate dissolved in a suitable amount of water in a molar ratio of diethyl 2-ethoxymethylenemalonate: methylhydrazine sulfate ═ 1: 4, the mixture is heated to 100 ℃ and the progress of the reaction is monitored by thin layer chromatography. After the reaction is completed, the solvent ethanol is removed by rotary evaporation, the solution is cooled to separate out an intermediate 1-methyl-5-hydroxy-1H-pyrazole-4-ethyl formate crude product, and the intermediate 1-methyl-5-hydroxy-1H-pyrazole-4-ethyl formate pure product is obtained by recrystallization and purification of absolute ethyl alcohol, filtration and drying.
(2) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid:
adding sodium hydroxide aqueous solution into ethanol solution of the intermediate of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester, wherein the molar ratio is 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester: sodium hydroxide ═ 1: 3, the mixture was heated to 65 ℃ and the progress of the reaction was monitored by thin layer chromatography. And after the reaction is completed, removing the solvent ethanol by rotary evaporation, adding dilute hydrochloric acid into the residual water phase to adjust the pH value to acidity, separating out a white solid, filtering, and drying to obtain the 1-methyl-5-hydroxy-1H-pyrazole-4-formic acid intermediate.
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxamido acid methyl ester:
to a solution of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid intermediate in acetonitrile mixed with N, N' -Carbonyldiimidazole (CDI) was added the corresponding amino acid methyl ester hydrochloride, the mixture was heated to 60 ℃ and catalyzed by potassium carbonate in a molar ratio of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid: CDI: amino acid methyl ester hydrochloride salt: potassium carbonate 1: 1-1.5: 1-2: 1.5 to 3. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, ethyl acetate and water are extracted, anhydrous sodium sulfate is dried, concentrated and subjected to column chromatography to obtain the intermediate of 1-methyl-5-hydroxy-1H-pyrazole-4-formylamino acid methyl ester.
(4) Preparation of the target compound 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester:
adding potassium carbonate into acetonitrile solution of intermediate 1-methyl-5-hydroxy-1H-pyrazole-4-formyl amino acid methyl ester, then adding corresponding halohydrocarbon, alpha-bromoacetophenone, 5-cyclopropyl isoxazole-4-formyl chloride and the like for substitution reaction, heating the mixture to 65 ℃, and finally adding potassium iodide for catalysis, wherein the molar ratio is as follows: 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid methyl ester: halogenated hydrocarbon, alpha-bromoacetophenone, 5-cyclopropylisoxazole-4-carbonyl chloride: potassium carbonate: potassium iodide ═ 1: 1-1.5: 1.5-3: 0.1. and after the reaction is completed, removing the acetonitrile solvent by rotary evaporation, extracting ethyl acetate with water, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography to obtain the target compound 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester.
The invention relates to an application of a 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and a 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative in preparing medicines for inhibiting the growth of target enzymes and weeds and the like.
The invention relates to a pyrazole core structure based on which amido bonds are used for linking a hydrazide pharmacophore and an amino acid pharmacophore, and provides a 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and a 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester herbicide with relatively stable physicochemical properties. Half-inhibitory concentration IC of 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine derivative on 4-hydroxyphenylpyruvate dioxygenase (HPPD)50The value range is 0.077-9.103 mu M; half inhibitory concentration IC of 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative on 4-hydroxyphenylpyruvate dioxygenase (HPPD)50The value range is 0.043-4.683 mu M, and the inhibition activity of most compounds on HPPD enzyme is better than that of a commercial herbicide topramezone (IC)500.111 μ M). In addition, under the drug dose of 100 mu g/mL, the 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine derivative has 28-74% of inhibition effect on the stem of the purslane and 34-89% of inhibition effect on the root of the purslane; the 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative has 21-100% inhibition rate on purslane stems, and 42-100% inhibition rate on purslane roots, and most compounds have better inhibition effect on broad-leaf weeds purslane than topramezone (stem inhibition rate: 59%, root inhibition rate: 57%).
Experiments prove that the 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivatives have obvious effects on inhibiting the growth of target enzymes and weeds and the like, and have the advantages of simple structure, simple preparation process, low production cost and wide application prospect.
The specific implementation mode is as follows:
example 1: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a1 comprising the steps of:
(1) preparation of ethyl 1-phenyl-5-methyl-1H-pyrazole-4-carboxylate:
ethyl 2-ethoxymethyleneacetoacetate (5g,0.03mol) was mixed with 50mL of an ethanol solution in a 100mL three-necked round-bottomed flask, and phenylhydrazine hydrochloride (7.77g,0.05mol) was added thereto to heat the system to 75 ℃ for reaction. After the reaction, the system was subjected to solvent removal, washing with water, liquid separation, drying, concentration, and silica gel column chromatography using petroleum ether/ethyl acetate (15:1/v: v) to obtain 4.30g of ethyl 1-phenyl-5-methyl-1H-pyrazole-4-carboxylate with a yield of 69.54%.
(2) Preparation of 1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1g,0.004mol) was mixed with 15mL of an ethanol solution in a 50mL three-necked round-bottomed flask, and 5mL of 80% hydrazine hydrate was added thereto, and the system was heated to 80 ℃ to carry out a reaction. After the reaction is finished, the solvent is removed by rotary evaporation, dichloromethane is used for extraction, anhydrous sodium sulfate is used for drying, and the 1-phenyl-5-methyl-1H-pyrazole-4-formylhydrazine is obtained by evaporating the solvent for recrystallization, wherein the yield is 85.19 percent.
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-fluorobenzaldehyde (0.26g, 0.002mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.17g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.26g of 1-phenyl-5-methyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 57.02%.
Example 2: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a2 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-fluorobenzaldehyde (0.21g, 0.002mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.13g, 0.002mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.27g of 1-phenyl-5-trifluoromethyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 63.43%.
Example 3: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a3 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.3g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-hydroxybenzaldehyde (0.20g, 0.002mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.17g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.32g of 1-phenyl-5-methyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 70.88%.
Example 4: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a4 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-hydroxybenzaldehyde (0.16g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.13g, 0.002mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.24g of 1-phenyl-5-trifluoromethyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 67.48%.
Example 5: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a5 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-methylbenzaldehyde (0.17g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.25g, 0.004mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.28g of 1-phenyl-5-methyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 64.30%.
Example 6: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a6 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-methylbenzaldehyde (0.13g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.20g, 0.003mol) was added after refluxing the system for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.28g of 1-phenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 66.52%.
Example 7: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a7 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 4-dichloroacetophenone (0.31g, 0.002mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.17g, 0.003mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.30g of 1-phenyl-5-methyl-N' - (1- (2, 4-dichlorophenyl) ethylidene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 55.84%.
Example 8: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. A8 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, to which was added 2, 4-dichloroacetophenone (0.17g, 0.001mol), the mixture was heated to 80 ℃ and glacial acetic acid (0.13g, 0.002mol) was added until the system refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.26g of 1-phenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylidene) -1H-pyrazole-4-formhydrazide with the yield of 61.03%.
Example 9: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a9 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 2-thiophenecarboxaldehyde (0.16g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.25g, 0.004mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with ethyl acetate to obtain 0.35g of 1-phenyl-5-methyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-formylhydrazine with the yield of 81.28%.
Example 10: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a10 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2-thiophenecarboxaldehyde (0.12g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.20g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating ethyl acetate, and recrystallizing to obtain 0.32g of 1-phenyl-5-trifluoromethyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-formylhydrazine with the yield of 79.11%.
Example 11: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a11 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2-furaldehyde (0.13g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.25g, 0.004mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.28g of 1-phenyl-5-methyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-formhydrazide with the yield of 68.58%.
Example 12: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a12 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2-furaldehyde (0.11g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ and glacial acetic acid (0.20g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.30g of 1-phenyl-5-trifluoromethyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-formhydrazide with the yield of 77.58%.
Example 13: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a13 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 3-hydroxy-4-methoxybenzaldehyde (0.21g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.25g, 0.004mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.33g of 1-phenyl-5-methyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-formhydrazide with the yield of 67.89%.
Example 14: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a14 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 3-hydroxy-4-methoxybenzaldehyde (0.17g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.20g, 0.003mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.32g of 1-phenyl-5-trifluoromethyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-formhydrazide with the yield of 71.28%.
Example 15: a process for the preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a15 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-chlorophenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2-fluoro-4-chlorobenzaldehyde (0.17g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ and glacial acetic acid (0.18g, 0.003mol) was added thereto while the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.25g of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 57.03%.
Example 16: a process for the preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a16 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 6-dimethylbenzaldehyde (0.18g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.20g, 0.003mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.24g of 1-phenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 54.78%.
Example 17: a process for the preparation of 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a17 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-methylphenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-methylbenzaldehyde (0.14g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.19g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.36g of 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 88.28%.
Example 18: a process for the preparation of 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a18 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-methylphenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.28g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 4-dichloroacetophenone (0.20g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ and glacial acetic acid (0.18g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.13g of 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-formhydrazide with the yield of 28.99%.
Example 19: a process for the preparation of 1-phenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a19 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-phenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-phenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.3g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 6-dimethylbenzaldehyde (0.22g, 0.002mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.25g, 0.004mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.32g of 1-phenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-formylhydrazine and the yield of 69.39%.
Example 20: a process for the preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a20 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-chlorophenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 4-dichloroacetophenone (0.20g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ and glacial acetic acid (0.18g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.31g of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 65.11%.
Example 21: a process for the preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a21 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-chlorophenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, 4-methylbenzaldehyde (0.13g, 0.001mol) was added thereto, the mixture was heated to 80 ℃ and glacial acetic acid (0.18g, 0.003mol) was added after the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.37g of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 92.37%.
Example 22: a process for the preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a22 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-chlorophenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 6-dimethylbenzaldehyde (0.15g, 0.001mol) was added thereto, and the mixture was heated to 80 ℃ and glacial acetic acid (0.18g, 0.003mol) was added thereto while the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.20g of 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 48.26%.
Example 23: a process for the preparation of 1-p-methylphenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a23 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-methylphenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-methylphenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 6-dimethylbenzaldehyde (0.21g, 0.002mol) was added thereto, and the mixture was heated to 80 ℃ and glacial acetic acid (0.27g, 0.005mol) was added thereto while the system was refluxed for 10 minutes. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.23g of 1-p-methylphenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 50.07%.
Example 24: a process for the preparation of 1-p-methylphenyl-5-methyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a24 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-p-methylphenyl-5-methyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-p-methylphenyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.001mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2-fluoro-4-chlorobenzaldehyde (0.27g, 0.002mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.23g, 0.004mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.25g of 1-p-methylphenyl-5-methyl-N' - (1- (2-fluoro-4-chlorphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 51.75%.
Example 25: a process for the preparation of 1-cyclopropyl-5-methyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a25 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-cyclopropyl-5-methyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.002mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2-fluoro-4-chlorobenzaldehyde (0.29g, 0.002mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.30g, 0.005mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and performing petroleum ether/ethyl acetate (5:1/v: v) column chromatography to obtain 0.24g of 1-cyclopropyl-5-methyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-formhydrazide with the yield of 44.95%.
Example 26: a process for the preparation of 1-cyclopropyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide compound No. a26 comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 1
(3) Preparation of 1-cyclopropyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide:
1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid hydrazide (0.30g,0.002mol) was mixed with 10mL of an ethanol solution in a25 mL three-necked round-bottomed flask, and 2, 6-dimethylbenzaldehyde (0.22g, 0.002mol) was added thereto, and the mixture was heated to 80 ℃ to reflux the system for 10 minutes, and glacial acetic acid (0.30g, 0.005mol) was added. Monitoring the reaction process by thin-layer chromatography, removing the solvent ethanol by rotary evaporation after the reaction is completed, washing with water, separating liquid, drying, concentrating, and recrystallizing with absolute ethanol to obtain 0.28g of 1-phenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-formylhydrazine, wherein the yield is 55.74%.
Example 27: a method for preparing 1-methyl-5-ethoxy-1H-pyrazole-4-formylglycine methyl ester (compound No. B1), comprising the steps of:
(1) preparation of ethyl 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylate:
diethyl 2-ethoxymethylenemalonate (10g, 0.05mol) was mixed with 50mL of ethanol solution in a 250mL three-necked round bottom flask, stirred at room temperature for 30 minutes, methylhydrazine sulfate (27.49g, 0.18mol) dissolved in 100mL of water was added, the system was heated to 100 ℃ and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent ethanol is removed by rotary evaporation, the water solution is cooled to separate out a crude product of the 1-methyl-5-hydroxy-1H-pyrazole-4-ethyl formate, the absolute ethanol is recrystallized and purified, and the pure product of the 1-methyl-5-hydroxy-1H-pyrazole-4-ethyl formate is obtained by suction filtration in an amount of 7g, and the yield is 88.95%.
(2) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid:
1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (5g,0.03mol) was mixed with 50mL of ethanol solution in a 250mL three-necked round-bottomed flask, NaOH (3.53g, 0.09mol) dissolved in 50mL of water was added thereto, the mixture was heated to 65 ℃ and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent ethanol is removed by rotary evaporation, dilute hydrochloric acid is added into the water phase to adjust the pH value to acidity, solid is separated out, and 3.86g of 1-methyl-5-hydroxy-1H-pyrazole-4-formic acid is obtained by suction filtration, with the yield of 92.44%.
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester:
CDI (1.71g, 0.01mol) was added to a 50mL three-necked round bottom flask containing a solution of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid (1g, 0.007mol) in 30mL acetonitrile, the mixture was stirred at room temperature for 30 minutes, glycine methyl ester hydrochloride (1.33g, 0.01mol) was added, the system was heated to 35 deg.C, potassium carbonate (0.97g, 0.007mol) was added finally to catalyze, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (1:2/v: v) to obtain 0.97g of 1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester, wherein the yield is 64.66%.
(4) Preparation of 1-methyl-5-ethoxy-1H-pyrazole-4-formylglycine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by the addition of potassium carbonate (0.49g, 0.004mol), stirring at room temperature for 30 minutes, followed by the addition of bromoethane (0.31g, 0.003mol), heating the system to 75 deg.C while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.39g of 1-methyl-5-ethoxy-1H-pyrazole-4-formylglycine methyl ester with the yield of 68.05 percent.
Example 28: a process for the preparation of 1-methyl-5-ethoxy-1H-pyrazole-4-formylleucine methyl ester (compound No. B2), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-ethoxy-1H-pyrazole-4-formylleucine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylleucine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.38g, 0.003mol), stirring at room temperature for 30 minutes, addition of bromoethane (0.24g, 0.002mol), heating the system to 75 ℃ while adding potassium iodide (0.03g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.28g of 1-methyl-5-ethoxy-1H-pyrazole-4-formylglycine methyl ester with the yield of 49.81%.
Example 29: a process for the preparation of methyl 1-methyl-5-ethoxy-1H-pyrazole-4-formylmethionine (compound No. B3), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-ethoxy-1H-pyrazole-4-formylmethionine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylmethionine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.36g, 0.003mol), stirring at room temperature for 30 minutes, addition of bromoethane (0.23g, 0.002mol), heating the system to 75 ℃ while adding potassium iodide (0.03g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.29g of 1-methyl-5-ethoxy-1H-pyrazole-4-formylmethionine methyl ester with the yield of 53.57 percent.
Example 30: a process for the preparation of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylglycine methyl ester (compound No. B4) comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylglycine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.49g, 0.004mol) was added, stirring was carried out at room temperature for 30 minutes, 3-bromopropyne (0.33g, 0.003mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.44g of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylglycine methyl ester with the yield of 73.82%.
Example 31: a method for preparing 1-methyl-5-propargyloxy-1H-pyrazole-4-formylleucine methyl ester (compound No. B5), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylleucine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylleucine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.38g, 0.003mol), stirring at room temperature for 30 minutes, addition of 3-bromopropyne (0.27g, 0.002mol), heating the system to 75 ℃ while adding potassium iodide (0.03g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.33g of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylleucine methyl ester with the yield of 57.83 percent.
Example 32: a process for the preparation of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylmethionine methyl ester (compound No. B6), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylmethionine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylmethionine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.36g, 0.003mol), stirring at room temperature for 30 minutes, addition of 3-bromopropyne (0.25g, 0.002mol), heating the system to 75 ℃ while adding potassium iodide (0.03g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.28g of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylmethionine methyl ester with the yield of 49.45 percent.
Example 33: a method for preparing 1-methyl-5-propargyloxy-1H-pyrazole-4-formyltryptophan methyl ester (compound No. B7), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-propargyloxy-1H-pyrazole-4-formyltryptophan methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formyltryptophan methyl ester (0.50g, 0.001mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.30g,0.002mol) was added thereto, the mixture was stirred at room temperature for 30 minutes, 3-bromopropyne (0.26g, 0.002mol) was added thereto, the system was heated to 75 ℃ while adding potassium iodide (0.02g, 0.0001mol) as a catalyst, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.37g of 1-methyl-5-propargyloxy-1H-pyrazole-4-formyl tryptophan methyl ester with the yield of 66.60 percent.
Example 34: a method for preparing 1-methyl-5- (alpha-oxy-p-methoxyacetophenone) -1H-pyrazole-4-formylglycine methyl ester (compound No. B8), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5- (α -oxy-p-methoxyacetophenone) -1H-pyrazole-4-formylglycine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.49g, 0.004mol) was added, after stirring at room temperature for 30 minutes, 4-methoxy- α -bromoacetophenone (1.07g, 0.005mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.44g of 1-methyl-5- (alpha-oxy-p-methoxyacetophenone) -1H-pyrazole-4-formylglycine methyl ester with the yield of 51.92 percent.
Example 35: a process for the preparation of methyl 1-methyl-5-hydroxy-1H-pyrazole-4-formylalanine (compound No. B9), comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 27
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-formylalanine methyl ester:
CDI (0.68g, 0.004mol) was added to a25 mL three necked round bottom flask charged with 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid (0.30g,0.002mol) and 15mL acetonitrile, the mixture was stirred at room temperature for 30 minutes, after which alanine methyl ester hydrochloride (0.88g, 0.006mol) was added, the system was heated to 35 deg.C and finally potassium carbonate (0.44g, 0.003mol) was added to catalyze and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (1:2/v: v) to obtain 0.21g of 1-methyl-5-hydroxy-1H-pyrazole-4-formyl alanine methyl ester, wherein the yield is 43.78%.
Example 36: a process for the preparation of methyl 1-methyl-5-hydroxy-1H-pyrazole-4-formylmethionine (compound No. B10), comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 27
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-formylmethionine methyl ester:
CDI (0.68g, 0.004mol) was added to a25 mL three-necked round bottom flask containing a solution of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid (0.30g,0.002mol) in 15mL acetonitrile, the mixture was stirred at room temperature for 30 minutes, methyl methionine hydrochloride (0.84g, 0.004mol) was added, the system was heated to 35 deg.C, potassium carbonate (0.44g, 0.003mol) was added to catalyze, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (1:2/v: v) to obtain 0.23g of 1-methyl-5-hydroxy-1H-pyrazole-4-formylmethionine methyl ester with the yield of 37.92 percent.
Example 37: a process for producing 1-methyl-5-hydroxy-1H-pyrazole-4-formylphenylalanine methyl ester (compound No. B11), which comprises the steps of:
steps (1) and (2) were carried out in the same manner as in example 27
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-formylphenylalanine methyl ester:
CDI (1.14g, 0.007mol) was added to a25 mL three-necked round bottom flask containing a solution of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid (0.50g, 0.004mol) in 15mL acetonitrile, the mixture was stirred at room temperature for 30 minutes, after which phenylalanine methyl ester hydrochloride (1.14g, 0.005mol) was added, the system was heated to 35 deg.C, and finally potassium carbonate (0.73g, 0.005mol) was added for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (1:2/v: v) to obtain 0.72g of 1-methyl-5-hydroxy-1H-pyrazole-4-formylphenylalanine methyl ester, wherein the yield is 67.47%.
Example 38: a process for the preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-formyltryptophan methyl ester (compound No. B12), which comprises the steps of:
steps (1) and (2) were carried out in the same manner as in example 27
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-formyltryptophan methyl ester:
CDI (0.68g, 0.004mol) was added to a25 mL three-necked round bottom flask containing 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid (0.30g,0.002mol) in 15mL acetonitrile, the mixture was stirred at room temperature for 30 minutes, then tryptophan methyl ester hydrochloride (0.81g, 0.003mol) was added, the system was heated to 35 deg.C, finally potassium carbonate (0.44g, 0.003mol) was added for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (1:2/v: v) to obtain 0.30g of 1-methyl-5-hydroxy-1H-pyrazole-4-formyl tryptophan methyl ester with the yield of 41.51 percent.
Example 39: a method for preparing 1-methyl-5-allyloxy-1H-pyrazole-4-formylglycine methyl ester (compound No. B13), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-allyloxy-1H-pyrazole-4-formylglycine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.49g, 0.004mol), stirring at room temperature for 30 minutes, addition of 3-bromo-1-propene (0.43g, 0.004mol), heating the system to 75 ℃ while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.41g of 1-methyl-5-allyloxy-1H-pyrazole-4-formylglycine methyl ester, wherein the yield is 69.03%.
Example 40: a process for the preparation of 1-methyl-5-allyloxy-1H-pyrazole-4-formyltryptophan methyl ester (compound No. B14), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-allyloxy-1H-pyrazole-4-formyltryptophan methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formyltryptophan methyl ester (0.50g, 0.001mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.30g,0.002mol), stirring at room temperature for 30 minutes, addition of 3-bromo-1-propene (0.27g, 0.002mol), heating the system to 75 ℃ while adding potassium iodide (0.02g, 0.0001mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.31g of 1-methyl-5-allyloxy-1H-pyrazole-4-formyl tryptophan methyl ester with the yield of 55.50 percent.
Example 41: a process for the preparation of 1-methyl-5-allyloxy-1H-pyrazole-4-formylphenylalanine methyl ester (compound No. B15), which comprises the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-allyloxy-1H-pyrazole-4-formylphenylalanine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylphenylalanine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.34g, 0.002mol) was added, and after stirring at room temperature for 30 minutes, 3-bromo-1-propene (0.30g,0.002mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.03g, 0.0002mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.25g of 1-methyl-5-allyloxy-1H-pyrazole-4-formylphenylalanine methyl ester, wherein the yield is 44.17%.
Example 42: a process for the preparation of methyl 1-methyl-5-allyloxy-1H-pyrazole-4-formylalanine (compound No. B16), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-allyloxy-1H-pyrazole-4-formylalanine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylalanine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.46g, 0.003mol), stirring at room temperature for 30 minutes, followed by addition of 3-bromo-1-propene (0.32g, 0.003mol), heating the system to 75 ℃ while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.34g of 1-methyl-5-allyloxy-1H-pyrazole-4-formylalanine methyl ester with the yield of 57.81%.
Example 43: a method for preparing 1-methyl-5-ethoxy-1H-pyrazole-4-formyltryptophan methyl ester (compound No. B17), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-ethoxy-1H-pyrazole-4-formyltryptophan methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formyltryptophan methyl ester (0.50g, 0.001mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.30g,0.002mol) was added, stirring was carried out at room temperature for 30 minutes, bromoethane (0.19g, 0.002mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.02g, 0.0001mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.33g of 1-methyl-5-ethoxy-1H-pyrazole-4-formyl tryptophan methyl ester with the yield of 61.00 percent.
Example 44: a process for the preparation of methyl 1-methyl-5-ethoxy-1H-pyrazole-4-formylalanine (compound No. B18), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-ethoxy-1H-pyrazole-4-formylalanine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylalanine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.46g, 0.003mol), stirring at room temperature for 30 minutes, addition of bromoethane (0.29g, 0.003mol), heating the system to 75 ℃ while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.42g of 1-methyl-5-ethoxy-1H-pyrazole-4-formylalanine methyl ester with the yield of 73.88 percent.
Example 45: a method for preparing 1-methyl-5-propargyloxy-1H-pyrazole-4-formylalanine methyl ester (compound No. B19), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylalanine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylalanine methyl ester (0.50g, 0.002mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.60g, 0.004mol) was added, stirring was carried out at room temperature for 30 minutes, 3-bromopropyne (0.39g, 0.003mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.31g of 1-methyl-5-propargyloxy-1H-pyrazole-4-formylalanine methyl ester with the yield of 53.11%.
Example 46: a method for preparing 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formyltryptophan methyl ester (compound number B20), comprising the following steps:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formyltryptophan methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formyltryptophan methyl ester (0.50g, 0.001mol) was mixed with 15mL of acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.40g, 0.003mol) was added, stirring was carried out at room temperature for 30 minutes, 5-cyclopropylisoxazole-4-carbonyl chloride (0.50g, 0.003mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.02g, 0.0001mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.29g of 1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formyl tryptophan methyl ester with the yield of 41.59 percent.
Example 47: a method for preparing 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formylphenylalanine methyl ester (compound No. B21), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formylphenylalanine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylphenylalanine methyl ester (0.50g, 0.002mol) was mixed with 15mL acetonitrile solution in a25 mL three-necked round-bottomed flask, potassium carbonate (0.45g, 0.003mol) was added, stirring was carried out at room temperature for 30 minutes, 5-cyclopropylisoxazole-4-carbonyl chloride (0.57g, 0.003mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.03g, 0.0002mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.32g of 1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formylphenylalanine methyl ester with the yield of 44.28%.
Example 48: a method for preparing 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formylmethionine methyl ester (compound No. B22), comprising the steps of:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formylmethionine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylmethionine methyl ester (0.50g, 0.002mol) was mixed with 15mL acetonitrile solution in a25 mL three-necked round-bottomed flask, followed by addition of potassium carbonate (0.48g, 0.003mol), stirring at room temperature for 30 minutes, followed by addition of 5-cyclopropylisoxazole-4-carbonyl chloride (0.60g, 0.003mol), heating the system to 75 ℃ while adding potassium iodide (0.03g, 0.00012mol) for catalysis, and monitoring the progress of the reaction by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.30g of 1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formylmethionine methyl ester with the yield of 40.81 percent.
Example 49: a method for preparing 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formylalanine methyl ester (compound No. B23), comprising the following steps:
steps (1) to (3) were carried out in the same manner as in example 27
(4) Preparation of 1-methyl-5- (5-cyclopropylisoxazol-4-carbomethoxy) -1H-pyrazole-4-formylalanine methyl ester:
1-methyl-5-hydroxy-1H-pyrazole-4-formylalanine methyl ester (0.50g, 0.002mol) and 15mL acetonitrile solution were mixed in a25 mL three-necked round bottom flask, potassium carbonate (0.61g, 0.004mol) was added, stirring was carried out at room temperature for 30 minutes, 5-cyclopropylisoxazole-4-carbonyl chloride (0.76g, 0.004mol) was added, the system was heated to 75 ℃ while adding potassium iodide (0.04g, 0.0002mol) for catalysis, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the solvent acetonitrile is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (5:1/v: v) to obtain 0.48g and 60.20% of 1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formyl alanine methyl ester.
Example 50: a method for preparing 1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester (compound No. B24), comprising the steps of:
steps (1) and (2) were carried out in the same manner as in example 27
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester:
CDI (1.71g, 0.01mol) was added to a 50mL three-necked round bottom flask containing a solution of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid (1g, 0.007mol) in 30mL acetonitrile, the mixture was stirred at room temperature for 30 minutes, glycine methyl ester hydrochloride (1.33g, 0.01mol) was added, the system was heated to 35 deg.C, potassium carbonate (0.97g, 0.007mol) was added finally to catalyze, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, the product is washed by water, extracted by ethyl acetate, dried by anhydrous sodium sulfate, and subjected to silica gel column chromatography by using petroleum ether/ethyl acetate (1:2/v: v) to obtain 0.97g of 1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester, wherein the yield is 64.66%.
The physicochemical properties and the spectrum data of the target compound obtained in the above example are shown in table 1:
TABLE 1 physicochemical Properties and spectral data of the target Compounds obtained in examples 1 to 50
Test example 1: activity test of target compounds to inhibit the target enzyme HPPD:
the test adopts an arabidopsis thaliana p-hydroxyphenylpyruvate dioxygenase (HPPD) enzyme-linked immunoassay kit to measure the in-vitro inhibition effect of the compound on the HPPD. Topramezone served as a positive control. Topramezone and all compounds are dissolved in DMSO, and experimental operation is strictThe method is carried out according to the kit specification, and blank holes (blank reference holes are not added with samples and enzyme labeling reagents, and the rest steps are operated in the same way), standard holes and sample holes to be detected are respectively arranged. The standard sample is accurately loaded by 50 mu L on the enzyme-labeled coating plate, 40 mu L of sample diluent is loaded in the sample hole to be detected, and then 10 mu L of sample to be detected is loaded (the final dilution of the sample is 5 times). And adding the sample to the bottom of the hole of the enzyme label plate, keeping the sample from touching the hole wall as much as possible, and slightly shaking and uniformly mixing the sample and the hole wall. The plates were sealed with a sealing plate and incubated at 37 ℃ for 30 minutes. Carefully uncovering the sealing plate membrane, discarding liquid, spin-drying, filling washing liquid into each hole, standing for 30 seconds, then discarding, repeating the steps for 5 times, and adding 50 mu L of enzyme-labeled reagent into each hole after drying, except blank holes. After repeated incubation and washing, 50 mu L of color-developing agent A is added into each hole, 50 mu L of color-developing agent B is added, the mixture is gently shaken and evenly mixed, and the mixture is subjected to light-shielding color development for 10 minutes at 37 ℃. Then, 50. mu.L of a stop solution was added thereto to stop the reaction. Zeroing with blank well, sequentially measuring absorbance (OD value) of each well at 450nm wavelength with microplate reader, and calculating half maximal Inhibitory Concentration (IC) according to standard curve with standard substance concentration as abscissa and OD value as ordinate50)。
Test example 2: the target compound inhibits the growth of the rhizome of broad-leaf weed purslane:
according to the experiment, broad-leaved weed purslane is used as an object to be tested, purslane seeds are germinated to expose white under a constant temperature condition, then 2 pieces of filter paper are laid in a culture dish (12-hole plate), 4-6 exposed white seeds with consistent amplification are placed in each dish (each hole), a compound is dissolved by DMF to be prepared into medicaments with the concentrations of 100 mu g/mL and 10 mu g/mL, the medicaments are added into the holes, each treatment is repeated for three times, the culture dish is placed in an artificial climate incubator after the treatment is finished, and the illumination period is day at 28 ℃, the illumination is 5000lx, and the illumination period is day: night is 16: 8. culturing for 5 days under the condition of 70-80% of relative humidity, measuring the root length and stem length of 4 seeds with basically consistent growth vigor, respectively calculating the growth inhibition rate of each treatment group to the weed seeds, and expressing the root length and stem length of the purslane by using L, wherein the formula is as follows:
growth inhibition ratio (%) ═ L(blank group)–L(treatment group)/L(blank group)×100％
Examples were determined as described above1-50 purslane growth inhibitory Activity and HPPD enzyme inhibition IC of target Compounds50The values and results are shown in Table 2.
TABLE 2 purslane growth inhibitory Activity and enzyme inhibition IC of the target Compounds of examples 1-5050Value of
aInhibition is the mean ± standard deviation (SE) of 3 replicates.
As can be seen from Table 2, most of the compounds show obvious inhibition effect on purslane rhizomes, and at the concentration of 100 mug/mL, the inhibition rates of the compounds A11, B2, B6, B7, B13 and B16 on the growth of purslane stems are all more than 70%, which is better than that of the commercial HPPD inhibitor topramezone (58.76%). The compounds B2, B7, B13, B15, B16, B20 and B23 have stronger herbicidal activity on purslane, and the inhibition rate on purslane roots is more than 90% and better than topramezone (57.12%) under the dosage of 100 mu g/mL. Wherein, the compounds B2, B7, B13 and B16 have obvious inhibition effect on stems and roots, and the inhibition rate is 100%. In addition, compounds A1, A5, A6, A8, B5, B7, B10, B17 and B24 showed excellent inhibitory effects on HPPD with IC50 values of 0.088. mu.M, 0.095. mu.M, 0.077. mu.M, 0.092. mu.M, 0.043. mu.M, 0.095. mu.M, 0.064. mu.M, 0.098. mu.M and 0.072. mu.M, respectively, superior to topramezone (0.111. mu.M).
In conclusion, the series of 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine and 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivatives show certain inhibition effects on the rhizome growth of purslane and HPPD enzyme. On average, the inhibition effect of the 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative on the growth of purslane rhizomes is better than that of the 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine derivative, wherein the compound B7 shows the most excellent inhibition activity. Compound B7 showed 100% inhibition of both purslane roots and stems at 100 μ g/mL dose, and even at 10 μ g/mL dose, B7 showed 77.39% and 64.93% inhibition of purslane roots and stems, which was better than topramezone (53.96% and 43.0%).
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 (4)
1. The invention discloses a preparation method and application of a 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine derivative (I) and a 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester derivative (II), wherein the structural general formula is as follows:
in the formula R1Is a substituent such as methyl, trifluoromethyl and the like;
R2is phenyl, 4-chlorphenyl, 4-methylphenyl, cyclopropyl and other substituents;
R3a substituent such as a hydrogen atom or a methyl group;
R4is a substituent such as 4-fluorophenyl, 4-hydroxyphenyl, 4-methylphenyl, 2, 4-chlorophenyl, thiophen-2-yl, furan-2-yl, 3-hydroxy-4-methoxyphenyl, 2-fluoro-4-chlorophenyl, 2, 6-dimethylphenyl, etc.
In the formulaR1Is a substituent such as a hydrogen atom, methyl, benzyl, isobutyl, 2-methylthio-ethyl, 3-methyl-1H-indolyl, trifluoromethyl and the like;
R2is a substituent such as a hydrogen atom, ethyl, allyl, propargyl, 4-methoxy-alpha-acetophenone, 5-cyclopropylisoxazole-4-methylcarbonyl and the like.
2. The 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-carboxylic acid hydrazide derivative and the 1-methyl-5-substituent-1H-pyrazole-4-carboxylic acid methyl ester derivative according to claim 1, wherein the partially synthesized compound is as follows:
compound A1 1-phenyl-5-methyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A2, 1-phenyl-5-trifluoromethyl-N' - (1- (4-fluorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a3 1-phenyl-5-methyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a4 1-phenyl-5-trifluoromethyl-N' - (1- (4-hydroxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A5, 1-phenyl-5-methyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A6, 1-phenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A7, 1-phenyl-5-methyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A8, 1-phenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A9, 1-phenyl-5-methyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A10, 1-phenyl-5-trifluoromethyl-N' - (1- (2-thienyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A11, 1-phenyl-5-methyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A12, 1-phenyl-5-trifluoromethyl-N' - (1- (2-furyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a13 1-phenyl-5-methyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a14 1-phenyl-5-trifluoromethyl-N' - (1- (3-hydroxy-4-methoxyphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a15, 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a16 1-phenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A17, 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A18, 1-p-methylphenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a19 1-phenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A20, 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 4-dichlorophenyl) ethylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A21, 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (4-methylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A22, 1-p-chlorophenyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound A23, 1-p-methylphenyl-5-methyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a24, 1-p-methylphenyl-5-methyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a25 1-cyclopropyl-5-methyl-N' - (1- (2-fluoro-4-chlorophenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound a26, 1-cyclopropyl-5-trifluoromethyl-N' - (1- (2, 6-dimethylphenyl) methylene) -1H-pyrazole-4-carboxylic acid hydrazide;
compound B1 methyl-1-methyl-5-ethoxy-1H-pyrazole-4-formylglycine methyl ester;
compound B2 methyl 1-methyl-5-ethoxy-1H-pyrazole-4-formylleucine;
compound B3 methyl 1-methyl-5-ethoxy-1H-pyrazole-4-formylmethionine;
compound B4 methyl 1-methyl-5-propargyloxy-1H-pyrazole-4-formylglycine methyl ester;
compound B5 methyl 1-methyl-5-propargyloxy-1H-pyrazole-4-formylleucine;
compound B6 methyl 1-methyl-5-propargyloxy-1H-pyrazole-4-formylmethionine;
compound B7, 1-methyl-5-propargyloxy-1H-pyrazole-4-formyltryptophan methyl ester;
compound B8, 1-methyl-5- (alpha-oxy-p-methoxyacetophenone) -1H-pyrazole-4-formylglycine methyl ester;
compound B9 methyl 1-methyl-5-hydroxy-1H-pyrazole-4-carboxamidoalanine;
compound B10 methyl 1-methyl-5-hydroxy-1H-pyrazole-4-formylmethionine;
compound B11, 1-methyl-5-hydroxy-1H-pyrazole-4-formylphenylalanine methyl ester;
compound B12, 1-methyl-5-hydroxy-1H-pyrazole-4-formyltryptophan methyl ester;
compound B13 methyl 1-methyl-5-allyloxy-1H-pyrazole-4-formylglycine methyl ester;
compound B14 methyl-1-methyl-5-allyloxy-1H-pyrazole-4-formyltryptophan methyl ester;
compound B15 methyl-1-methyl-5-allyloxy-1H-pyrazole-4-formylphenylalanine methyl ester;
compound B16 methyl 1-methyl-5-allyloxy-1H-pyrazole-4-formylalanine methyl ester;
compound B17 methyl-1-methyl-5-ethoxy-1H-pyrazole-4-formyltryptophan methyl ester;
compound B18 methyl 1-methyl-5-ethoxy-1H-pyrazole-4-formylalanine methyl ester;
compound B19 methyl 1-methyl-5-propargyloxy-1H-pyrazole-4-formylalanine methyl ester;
compound B20 methyl-1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formyltryptophan methyl ester;
compound B21 methyl-1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formylphenylalanine methyl ester;
compound B22 methyl-1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formylmethionine;
compound B23 methyl 1-methyl-5- (5-cyclopropylisoxazole-4-carbomethoxy) -1H-pyrazole-4-formylalanine methyl ester;
compound B24 methyl 1-methyl-5-hydroxy-1H-pyrazole-4-formylglycine methyl ester.
3. The process for producing a 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-carboxylic acid hydrazide derivative and a 1-methyl-5-substituent-1H-pyrazole-4-carboxylic acid methyl ester derivative according to claim 1 or 2, which comprises the steps of:
preparation of 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine derivative:
(1) preparation of 1-substituent-5-substituent-1H-pyrazole-4-ethyl formate:
to an ethanol solution of ethyl 2-ethoxymethyleneacetoacetate or ethyl 4, 4, 4-trifluoroacetoacetate was added substituted phenylhydrazine hydrochloride, and the mixture was heated to 75 ℃ to effect a reaction. Wherein the compound molar ratio is 2-ethoxy methylene ethyl acetoacetate, 4, 4, 4-trifluoro ethyl acetoacetate: substituted phenylhydrazine hydrochloride salt ═ 1: 2. after the reaction is finished, the system is subjected to solvent removal, water washing, liquid separation, drying, concentration and column chromatography to obtain a 1-substituent-5-substituent-1H-pyrazole-4-ethyl formate intermediate;
(2) preparation of 1-substituent-5-substituent-1H-pyrazole-4-formylhydrazine:
adding excess hydrazine hydrate into ethanol solution of the intermediate of the corresponding 1-substituent-5-substituent-1H-pyrazole-4-ethyl formate, heating to 80 ℃, and monitoring the reaction progress by thin layer chromatography. After the reaction is completed, the solvent is removed by rotary evaporation, dichloromethane is used for extraction, anhydrous sodium sulfate is used for drying, and the intermediate 1-substituent-5-substituent-1H-pyrazole-4-formylhydrazine is obtained by evaporation solvent recrystallization;
(3) preparing a target compound 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine:
adding substituted aldehyde ketone into ethanol solution of 1-substituent-5-substituent-1H-pyrazole-4-formhydrazide intermediate, heating the mixture to 80 ℃, adding glacial acetic acid when the system is refluxed for 10 minutes, wherein the molar ratio is 5-substituent-1H-pyrazole-4-formhydrazide: substituted aldehyde ketones: glacial acetic acid ═ 1: 1-1.5: 2 to 3. Monitoring the reaction process by using a thin-layer chromatography, carrying out rotary evaporation to remove the solvent after the reaction is completed, washing with water, separating liquid, drying, concentrating, and then recrystallizing with absolute ethyl alcohol/ethyl acetate or purifying by using column chromatography to obtain the target compound 5-substituent-1-substituent-N' - (1-disubstituted) -1H-pyrazole-4-formylhydrazine.
Preparation of (di) 1-methyl-5-substituent-1H-pyrazole-4-carboxamido acid methyl ester derivative:
(1) preparation of ethyl 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylate:
to an ethanolic solution of diethyl 2-ethoxymethylenemalonate was added methylhydrazine sulfate dissolved in a suitable amount of water in a molar ratio of diethyl 2-ethoxymethylenemalonate: methylhydrazine sulfate ═ 1: 4, the mixture is heated to 100 ℃ and the progress of the reaction is monitored by thin layer chromatography. After the reaction is completed, the solvent ethanol is removed by rotary evaporation, the solution is cooled to separate out an intermediate 1-methyl-5-hydroxy-1H-pyrazole-4-ethyl formate crude product, and the intermediate 1-methyl-5-hydroxy-1H-pyrazole-4-ethyl formate pure product is obtained by recrystallization and purification of absolute ethyl alcohol, filtration and drying.
(2) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid:
adding sodium hydroxide aqueous solution into ethanol solution of the intermediate of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester, wherein the molar ratio is 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester: sodium hydroxide ═ 1: 3, the mixture was heated to 65 ℃ and the progress of the reaction was monitored by thin layer chromatography. And after the reaction is completed, removing the solvent ethanol by rotary evaporation, adding dilute hydrochloric acid into the residual water phase to adjust the pH value to acidity, separating out a white solid, filtering, and drying to obtain the 1-methyl-5-hydroxy-1H-pyrazole-4-formic acid intermediate.
(3) Preparation of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxamido acid methyl ester:
to a solution of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid intermediate in acetonitrile mixed with N, N' -Carbonyldiimidazole (CDI) was added the corresponding amino acid methyl ester hydrochloride, the mixture was heated to 60 ℃ and catalyzed by potassium carbonate in a molar ratio of 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid: CDI: amino acid methyl ester hydrochloride salt: potassium carbonate 1: 1-1.5: 1-2: 1.5 to 3. After the reaction is completed, the solvent acetonitrile is removed by rotary evaporation, ethyl acetate and water are extracted, anhydrous sodium sulfate is dried, concentrated and subjected to column chromatography to obtain the intermediate of 1-methyl-5-hydroxy-1H-pyrazole-4-formylamino acid methyl ester.
(4) Preparation of the target compound 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester:
adding potassium carbonate into acetonitrile solution of intermediate 1-methyl-5-hydroxy-1H-pyrazole-4-formyl amino acid methyl ester, then adding corresponding halohydrocarbon, alpha-bromoacetophenone, 5-cyclopropyl isoxazole-4-formyl chloride and the like for substitution reaction, heating the mixture to 65 ℃, and finally adding potassium iodide for catalysis, wherein the molar ratio is as follows: 1-methyl-5-hydroxy-1H-pyrazole-4-carboxylic acid methyl ester: halogenated hydrocarbon, alpha-bromoacetophenone, 5-cyclopropylisoxazole-4-carbonyl chloride: potassium carbonate: potassium iodide ═ 1: 1-1.5: 1.5-3: 0.1. and after the reaction is completed, removing the acetonitrile solvent by rotary evaporation, extracting ethyl acetate with water, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography to obtain the target compound 1-methyl-5-substituent-1H-pyrazole-4-formylamino acid methyl ester.
4. The use of the 1-substituent-5-substituent-N' - (1-disubstituted) -1H-pyrazole-4-carboxylic acid hydrazide and 1-methyl-5-substituent-1H-pyrazole-4-carboxylic acid methyl ester derivatives according to claim 1 or 2 in the preparation of medicaments for inhibiting the target enzyme HPPD and weed growth.
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| CN114989142A (en) * | 2022-05-09 | 2022-09-02 | 沈阳万菱生物技术有限公司 | Preparation method of pyrazole compound |
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