CN101747322A - Pyridazinone derivatives with 1,2,4-triazole schiff base, preparation method and application thereof - Google Patents
Pyridazinone derivatives with 1,2,4-triazole schiff base, preparation method and application thereof Download PDFInfo
- Publication number
- CN101747322A CN101747322A CN 201010041815 CN201010041815A CN101747322A CN 101747322 A CN101747322 A CN 101747322A CN 201010041815 CN201010041815 CN 201010041815 CN 201010041815 A CN201010041815 A CN 201010041815A CN 101747322 A CN101747322 A CN 101747322A
- Authority
- CN
- China
- Prior art keywords
- triazole
- phenyl
- compound
- trimethoxyphenyl
- pyridazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 1,2,4-triazole schiff base Chemical class 0.000 title claims abstract description 31
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000002262 Schiff base Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 239000002994 raw material Substances 0.000 claims abstract description 18
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims abstract description 12
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical class NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940067157 phenylhydrazine Drugs 0.000 claims abstract description 7
- LUMLZKVIXLWTCI-NSCUHMNNSA-N (e)-2,3-dichloro-4-oxobut-2-enoic acid Chemical compound OC(=O)C(\Cl)=C(/Cl)C=O LUMLZKVIXLWTCI-NSCUHMNNSA-N 0.000 claims abstract description 6
- 229940074391 gallic acid Drugs 0.000 claims abstract description 6
- 235000004515 gallic acid Nutrition 0.000 claims abstract description 6
- ZAKLKBFCSHJIRI-UHFFFAOYSA-N mucochloric acid Natural products OC1OC(=O)C(Cl)=C1Cl ZAKLKBFCSHJIRI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003935 benzaldehydes Chemical class 0.000 claims abstract description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 4
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 15
- 238000001953 recrystallisation Methods 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Natural products COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- WUGMUGFWKHXWPK-UHFFFAOYSA-N 4-chloro-2-phenylpyridazin-3-one Chemical class O=C1C(Cl)=CC=NN1C1=CC=CC=C1 WUGMUGFWKHXWPK-UHFFFAOYSA-N 0.000 claims description 11
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 10
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 6
- 125000005323 thioketone group Chemical group 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 230000002507 anti-phytoviral effect Effects 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- HZNQSWJZTWOTKM-UHFFFAOYSA-N 2,3,4-trimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1OC HZNQSWJZTWOTKM-UHFFFAOYSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
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- 239000012043 crude product Substances 0.000 claims description 3
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- 230000006698 induction Effects 0.000 claims description 3
- 238000007603 infrared drying Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
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- 238000003756 stirring Methods 0.000 claims description 3
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- 238000009156 water cure Methods 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- VKWCOHVAHQOJGU-UHFFFAOYSA-N 4,5-dichloro-2-phenylpyridazin-3-one Chemical compound O=C1C(Cl)=C(Cl)C=NN1C1=CC=CC=C1 VKWCOHVAHQOJGU-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 230000036961 partial effect Effects 0.000 claims description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 45
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- 230000002401 inhibitory effect Effects 0.000 abstract description 15
- 241000724252 Cucumber mosaic virus Species 0.000 abstract description 13
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 abstract description 12
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Abstract
The invention discloses a preparation method and bioactivity of a compound with anti-plant virus function, namely pyridazinone derivatives with 1,2,4-triazole schiff base, and the compound structure is indicated by the following formulas. The invention introduces a method for using mucochloric acid, gallic acid, 1,3-thiocarbohydrazide, substituted benzaldehyde, phenylhydrazine and the like as raw materials to prepare compound pyridazinone derivatives with 1,2,4-triazole schiff base after the five reaction steps of etherification, triazole ring closure, imidization, pyridazine ring closure and thiolation. The compounds (d, f, g and h) of the invention possess high treating and inhibiting effects on the cucumber mosaic virus (CMV) disease, and show a better anti-plant virus activity.
Description
Technical field: what the present invention relates to have the Antiphytoviral effect contains 1,2,4-triazole Schiff's base pyridazinone derivative and preparation method thereof.
Background technology: pyridazinone compound is that a class has the active heterogeneous ring compound of good biological, with the pyridazinone ring is that to carry out structural modification be that new field has been opened up in novel pesticide initiative to parent. at present, existing many commercial pyridazinone agricultural chemicals comprise plant-growth regulator, weedicide, sterilant, desinsection (killing mite) agent, insect growth adjusting (IGRs) etc.The pyridazinone agricultural chemicals has active characteristics such as high, environmentally friendly, is bringing into play important effect aspect the integrated control of disease and pest and the reduction agricultural chemicals environmental pollution.
(Luo Tiejun such as Luo Tiejun in 1999; Ou Xiaoming; Luo Zhenli. the synthetic and biological activity [J] of pyridazinone acetamides. organic chemistry .1999; 19; 190-194) on the structure of the 2-tertiary butyl-4-chloro-5-hydroxyl-3 (2)-ketone, introduce the ethanamide ether structure; obtain the acetamides of a series of novel pyridazinones; active testing is found; the compound 2-tertiary butyl-5-[(N, N-diacetyl) oxygen base]-4-chloro-pyridazine-3 (2H)-ketone and the 2-tertiary butyl-5-[(acetyl piperidine) the oxygen base]-4-chloro-pyridazine-3 (2H)-ketone reaches 65.6% and 60.2% respectively to the inhibiting rate of red spider.
(Zou Xiajuan such as calendar year 2001 Zou Xiajuan, Jin Guiyu, Yang Zhao .1-substituted-phenyl-1, synthetic and the activity of resisting tobacco mosaic virus [J] of 4-dihydro-6-methyl-4-pyridazinone-3-hydrazides. applied chemistry .2001,18 (8), 599-601) synthetic 1-substituted-phenyl-1,4-dihydro-6-methyl-4-pyridazinone-3-hydrazide compound.The biological activity determination data presentation, target compound is through active testing, find that major part has the activity of certain resisting tobacco mosaic virus (TMV), wherein compound 1-(2, the 6-dichlorophenyl)-1, the biological activity of 4-dihydro-6-methyl-4-pyridazinone-3-formyl hydrazine is considerably beyond external commercial contrast medicine DHT (2,4-dioxy Hexahydrotriazine), 1-phenyl-1, the activity and the DHT of 4-dihydro-6-methyl-4-pyridazinone-3-formyl hydrazine compound are suitable, and compound 1-(4-chloro-phenyl-)-1,4-dihydro-6-methyl-4-pyridazinone-3-formyl hydrazine carries out the rice sheath blight disease inhibiting rate and is respectively 74.5% and 79.6%.
Eddy in 2002, (Eddy, S. such as S.; Nuria, F.; Matilde, Y.; Vicente, T.; Reyes, L.; Ernesto, C.; Enrique, Ravin.Pyridazines part XXIX:synthesis and platelet aggregation inhibition activity of5-substituted-6-phenyl-3 (2H)-pyridazinones.novel aspects oftheir biological actions[J] .Bioorganic ﹠amp; Medicinal Chemistry.2002,10 (9), be raw material 2873-2882) with 5-replacement-6-phenyl-3 (2)-pyridazinone, hydrazine hydrate, refluxing in ethanol system prepared 6-phenyl-4 in 3 hours, and 5-two replaces-3 (2H)-pyridazinones, and yield is 63%.The same year (Yang Huazheng such as Yang Huazheng; Wang Xiang; Hu Fangzhong; Yang Xiu phoenix .3-aryloxy-6-replaces the synthetic and weeding activity [J] of pyridazine. SCI .2002; 23 (12); 2261-2263.) reported that a series of 3-aryloxy-6-replaces the synthetic of pyridazine; and measured its weeding activity; found that the equal tool of institute's synthetic compound all has activity to rape (B.campestrisL.) and barnyard grass grass (E.acrus-galli); wherein compound 6-(2; the 4-dichlorophenoxy)-3-(N; the N-dimethyl) activity of pyridazine is the highest; the result finds that also the variation of the R group that links to each other with the O atom is very big to active influence, and the growth of carbochain and shorten and all can make active the reduction.(Ren Kangtai such as Ren Kangtai, Hu Fangzhong, Wang Xiang, Yang Xiufeng, Yang Huazheng. the synthetic and weeding activity [J] of aryloxy pyridazine class derivative. applied chemistry .2002,19 (9), 827-831) reported the synthetic of aryloxy pyridazine class derivative, and reported its weeding activity test, found that this compounds all has medium weeding activity.Charlotta, L. waiting design to synthesize a series of pyridazine analogues, to find when micromolar concentrations albumen to be coughed up propylhomoserin phosphorylation (PTP1B) inhibited, compound 3-amino-6 wherein, 8-dihydro-2-(4-isopropyl phenyl)-2H-sulfo-[3,4-c] pyridazine-4-nitrile has higher selectivity to PTP1B.
The beautiful grade of Zou Xia (Zou Xiajuan in 2003, the beautiful .1-substituted-phenyl-1 in gold osmanthus, synthetic and the biological activity [J] of 4-dihydro-6-methyl-4-pyridazinone-3-hydrazide derivatives. organic chemistry .2003,23 (1), 62-65) with 1-substituted-phenyl-3-carbonyl hydrazide-1,4-dihydro-6-methyl-4-pyridazinone is a raw material, carries out derivation, synthesize the acylhydrazone class novel cpd of 6 pyridazinones, and studied its biological activity.Preliminary biological activity test shows that target compound is when mass concentration is 500 μ g/mL, the acylhydrazone compounds has certain restraining effect to tobacco mosaic virus (TMV) (TMV), especially compound N '-(3-anisole methylene radical)-1-(3-chloro-phenyl-)-1,4-dihydro-6-methyl-4-pyridazinone-3-acylhydrazone reaches 60% to its inhibiting rate of tobacco mosaic virus (TMV) (TMV).
(Wang Zhanpings such as Wang Zhanping in 2004, Hu Fangzhong, Zou Xiaomao, Yang Xiufeng, the synthetic and weeding activity research [J] of the polished .3-aryloxy of Yang Hua-6-chlorine (or fluorine) pyridazine compound. Pesticide Science journal .2004,6 (2), 15-19) from 3, the 6-dichloro-pyridazine sets out, and obtains 3 by fluoro, 6-difluoro pyridazine.With 3,6-dichloro-pyridazine, 3,6-difluoro pyridazine respectively with the fortified phenol condensation, obtained 18 3-aryloxy-12 3-aryloxy of 6-chlorine pyridazine-6-fluorine pyridazine.Preliminary bioassay results shows, target compound has weeding activity in various degree, and wherein compound 3-(3-methylphenoxy)-6-chlorine pyridazine, 3-(3-sells phenoxyl)-6-chlorine pyridazine and 3-(3-methylphenoxy)-6-fluorine pyridazine reach 95.7%, 96.1% and 91.2% respectively to the inhibiting rate of barnyard grass grass (E.acrus-galli) when concentration is 100 μ g/mL; When formulation rate drops to 10 μ g/mL, inhibiting rate remains on more than 60%.
(Qi Chuanmin such as the neat people of biography in 2004, Chen Wanyi, Yang Lingchun, Jiang Mingliang. new chemical hybridization agent pyridazinone derivative synthetic and to wheat castration activity research [J]. organic chemistry .2004,24 (6), 645-649) prepared 1 with the linked reaction of different aryl diazonium salts from pyrone, 4-dihydro-3-carboxyl pyridazine-4-ketone compounds, and be that raw material is respectively with thiosemicarbazide and hydrazine or phenylhydrazine encircles and reaction has obtained two classes and castrates chemical crossbred agent heterogeneous ring compound-pyridazinone aminothiazole and pyridazine pyrazolone compounds with them first, the preliminary activity experiment of castrating shows that pyridazinone aminothiazole hydrochloride compounds has the activity of castration when higher concentration, and the castration rate reaches about 99% when dosage is 2100g/ha.
(Liu Weidong such as Liu Wei east in 2005, Li Zhiwei, Li Zhongying, Wang Xiaoguang, Gao Bida .N-methoxyl group-N-{2-[2-replacement-4-chloro-3 (2) pyridazinones-5-oxygen (sulphur) methylene radical] phenyl } Urethylane [J]. synthetic chemistry .2005,13 (1), 33-36) 16 Urethylanes that contain the pyridazine ring with novel texture have been synthesized in design, adopt the mycelial growth rate method to these compounds the sterilization of exsomatizing screen, when 50mg/L, majority of compounds is to wheat scab (F.gyaminearum), Pyricularia oryzae (P.grisea) and botrytis cinerea pers (B.cinerea) have bacteriostatic activity preferably.Compound N-methoxyl group-N-{2-[2-phenyl-4-chloro-3 (2) pyridazinones-5-sulphur methylene radical wherein] phenyl Urethylane, N-methoxyl group-N-{2-[2-replacement-4-chloro-3 (2) pyridazinones-5-sulphur methylene radical] phenyl Urethylane to the bacteriostatic activity of wheat scab (F.gyaminearum) greater than 90%, N-methoxyl group-N-{2-[2-(3-methyl)-4-chloro-3 (2) pyridazinones-5-oxygen methylene radical] phenyl Urethylane reaches 95% to the bacteriostatic activity of rice blast (P.grisea).Majority of compounds is lower to the bacteriostatic activity of Phytophthora capsici disease (P.rainfestans).
The gloomy grade of Li Hong (Li Hongsen in 2005; reach the clouds; Guo Yu comes; Yang Xin's tinkling of pieces of jade; Chen Fuheng. the synthetic and bioactivity research [J] of pyridazinone derivative. organic chemistry .2005; 25 (2), 204-207) benzoyl by bridge carbon link to each other with pyridazinone the design synthesized 16 novel pyridazine ketone compounds, in the hope of finding new sterilant.Give birth to survey the result and show, most compounds to two age Musca domestica larva show pesticidal preferably, and to three age nymph of a locust insecticidal activity not obvious.Under test concentrations, part of compounds to two age Musca domestica larva insecticidal activity all be better than contrast medicament hooligan and ABG-6215.In addition, compare with blank Musca domestica larva with the Musca domestica larva that part of compounds is handled with the contrast chemicals treatment, on form, obviously show individual little, grow and be subjected to remarkable inhibition, death time is 72 ~ 96h after dispenser mainly, and the contrast chemicals treatment Musca domestica larva death time then concentrates on 24 ~ 48h, and this demonstrates these compounds have insect growth regulator(IGR) to the effect of Musca domestica larva characteristics.
Medium (the Hu Fangzhong in Hu side in 2007, Zhang Min, Zhu Youquan, Zou Xiaomao, Liu Bin, synthetic and the weeding activity [J] of the polished .3-substituted benzyloxy of Yang Hua-6-substituted-amino pyridazine derivatives. organic chemistry .2007,27 (12), 1530-1536) the absolute ethanol solution tube sealing reaction by 3-substituted benzyloxy-6-fluorine pyridazine and dimethylamine, perhaps under refluxad react with morphine quinoline or piperidines respectively, synthesized 36 novel 3-substituted benzyloxy-6-substituted-amino pyridazine compounds, preliminary weeding activity test shows, this compounds has certain weeding activity, and their structure and the relation of weeding activity have been discussed.
Reached the clouds in 2008 etc. and (to reach the clouds; Zhu Weiwen; Shi Wangpeng; Li Xichen; Qiu Lihong; Sun Yufeng; synthetic and the insect growth regulator activity [J] of Yang Xin's tinkling of pieces of jade .5-substituted benzoyl urea-3 (2H)-pyridazinone derivative. Pesticide Science journal .2008; 10 (2); 141-146) for further finding to have the novel cpd of insect growth regulator activity; according to the early-stage Study achievement; go up introducing benzoylureas active group for 5 at 3 (2H)-pyridazinones; 17 5-substituted benzoyl ureas-3 (2H)-pyridazinone derivative has been synthesized in design; preliminary bioactivity research result shows; part of compounds has biological activity preferably to 3 nymph of a locust Locusta migretoria manilensis Linne in age (M eyen) when 200mg/L, make the nymph of a locust because of normally molt metamorphosis is dead, shows the function Characteristics of tangible insect growth regulator(IGR) (IGRs) compounds.
1,2, the 4-triazole class compounds also is found has wide biological activity, as sterilization, and desinsection, antiviral, the weeding isoreactivity, and this compounds toxicity is low, residual weak point, many commercialization pesticide species are as sterilant triazolone (Triadimefon), alkene azoles alcohol (Diniconazole), nitrile bacterium azoles (Myclobutanil), imibenconazole (Imibenconazole) etc.; Weedicide amicarbazone (Amicarbazone), azafenidin (Azafenidin) etc.; Sterilant triazophos (Triazophos), triaxamate (Triazamate), isazofos (Isazofos) etc. all contain 1,2, the 4-triazole structure.
Calendar year 2001 (Song Baoan, Hu Deyu, Ceng Song such as Song Bao'an, Huang Rongmao, Yang Song, Huang Jian. contain 1,2, the synthetic and bioactivity research [J] of 4-triazolyl phosphorodithioate new compound. organic chemistry, 2001,21 (7), 524-529) report is a lead compound with the triaxamate, the design and synthesized 12 S-(the 3-tertiary butyl-1-dimethylamino formyl-1H-1,2 of deriving, 4-triazole-5-yl)-and O, O-dialkyl dithiophosphate compound.Known that by bioassay results to the cigarette aphid, medicine chaste tree concentration is 500 * 10-6, the synthesising target compound majority all has insecticidal activity.
Zhang Xin etc. (Zhang Xin, Qin Zhanglan, Xiao Meng. contain the synthetic and bacteriostatic activity [J] of triazole ring and thiphene ring schiff bases. Pesticide Science journal, 2005,7 (4), 353-356) the synthetic schiff bases compounds that contains triazole ring and thiphene ring.Giving birth to the survey result and show, is under the 50 μ g/mL in concentration, and all compounds all have significant inhibition effect to rice seedling blight bacterium (R.solani), and inhibiting rate is greater than 85.0%; To the inhibiting rate of ring rot of apple bacterium (B.berengriana) up to 98.6%.
2008, (Chung, D.H. such as Chung; Kumarapperumab, S.C.; Suna, Y.; Li, Q.-J.; Chua, Y.K.; Arterburnb, J.B.; Parkera, W.B.; Smithc, J.; Spikc, K.; Ramanathand, H.N.; Schmaljohnc, C.S.; Jonssona, C.B. Synthesis of 1-β-d-ribofuranosyl-3-ethynyl[1,2,4] triazoleand its in vitro efficacy against Hantavirus[J] .AntiviralResearch, 2008,79 (1): 19-27.) synthesized compound 1-uracil nucleosides-3-acetylene-1,2, the 4-triazole, this compound has antiviral activity, to the EC of Hantaan virus (HTNV) and Andean virus (Andes virus)
50Value is respectively 10 and 4.4mol/L.
2007, (Liu Changling, Chi Huiwei such as Liu Changling, Cui Dongliang, Li Zhinian. the oxadiazole of replacement or triazole thioketone compounds and preparation thereof and application [P] .CN 1927859,2007[Chem.Abstr.2007,146,401977]) the synthetic and biological activity of report triazole thioketone active compound.Adopt spray method (Air Brush) to carry out insecticidal activity assay, find that part of compounds is 95% to the prevention effect of carmine spider mite when liquor strength is 600 μ g/mL.
2006, (Francis, B.J. such as Francis; Louise, S.P.; Bharat, S.R.Preparation of fungicidal pyrazine derivatiyes[P] .WO2006089060. 2006[Chem.Abstr.2006,145,271812]) reported and contained 1,2, the 4-triazole compounds is 100% to the inhibiting rate of wheat rust bacterium (P.recondite), the withered spot rhizoctonia of rice (R.oryzae) when spraying medicine concentration is 250 μ g/mL, inhibiting rate to cucumber sclerotiorum (S.sclerotiorum) is 98%, is 99% to the inhibiting rate of wheat glume blight bacterium (S.nodorum).
(Hamdy, N.A. such as Hamdy; Abdel-Aziz, H.A.; Farag, A.M.Synthesis of some 1,3-thiazole, 1,3,4-thiadiazole, pyrazolo[5,1-c]-1,2,4-triazine, and, 2,4-triazolo[5,1-c]-1,2,4-triazine derivatives based on the thiazolo[3,2-a] benzimidazolemoiety[J] .Monatsheftefur Chemie, 2007,138 (10), 1001-1010.) reported a series of pyrazoles [5,1-c]-1,2,4-triazine and 1,2,4-triazole [5,1-c]-1,2, the synthetic and bacteriostatic activity of 4-pyrrolotriazine derivatives.Some compound has medium restraining effect to bacterium and fungi, and most of test compounds demonstrate slight bacteriostatic activity to Candida albicans.
2008, (Havaldar, F. such as Havaldar; Patil, A.R.Syntheses of1,2,4triazole derivatives and their biological activity[J] .E-Journal of Chemis try, 2008,5 (2), be raw material 347-354) with N-(4-hydroxy phenyl) ethanamide, synthesized through six-step process and to have contained 1,2, the 4-triazole compounds has also carried out the bacteriostatic activity test.Give birth to survey the result and show that part of compounds has active preferably, Cryptococcus neoformans (C.neoformans) to streptococcus aureus (S.aureu), Bacillus subtilus (B.subtilis), Aspergillus flavus (A.niger) higher inhibitions activity is arranged.
(Carling, R.W. such as Carling; Madin, A.; Guiblin, A.; Russell, M.G.N.; Moore, K.W.; Mitchinson, A.; Sohal, B.; Pike, A.; Cook, S.M.; Ragan, I.C.; McKernan, R.M.; Quirk, K.; Ferris, P.; Marshall, G.; Thompson, S.A.; Wafford, K.A.; Dawson, G.R.; Atack, J.R.; Harrison Castro, J.L.; Street, L.J.7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluor-ophenyl)-1,2,4-triazolo[4,3-b] pyridazine:afunctionally selective γ-aminobutyric acid a (GABAA) r2/r3-subtype selective agonist that exhibits potent anxiolyticactivity but is not sedating in animal models [J] .J.Med. Chem.2005,48 (23), 7089-7092) reported that the compound of pyridazine and triazole is when consumption is 1-3mg/kg, have angst resistance effect preferably, can act on the GABA acceptor well.(Karnik, A.V. such as Karnik; Etal, 2006) report contains 1,2, and the 4-triazole compounds is to subtilis (B.subtilis), and the MIC value of intestinal bacteria (E.coli) is 50mg/L, is 100mg/L to the MIC value of Pseudomonas aeruginosa (P.aeruginosa).
(Ding Mingwu such as Ding Mingwu, Xiao Wenjing, Fu Baiqiao. have the 2-replacement-6H-imidazo [1,2-b]-1,2 of bacteriostatic activity, 4-triazole-6-ketone and preparation method thereof [P] .CN 1727342,2006[Chem. Abstr.2006,145,83343]) reported and contained 1,2, the synthetic and biological activity of 4-triazole compounds.Test-results shows: when 50mg/L concentration, part of compounds reaches 100% to rice blast (P.oryzae), wheat scab (F.graminearum), cotton wilt (F.oxysporum), Sclerotinia sclerotiorum (S.sclerotiorum), gray mold of cucumber (B.cinerea), beet cercospora leaf spot (C.beticola) inhibiting rate.
2008, (Sztanke, K. such as Sztanke; Tuzimski, T.; Rzymowska, J.; Pasternak, K.; Martyna, K.S.Synthesis, determination of thelipophilicity, anticancer and antimicrobial properties of somefused 1,2,4-triazo1e derivatives[J] .Eur.J.Med.Chem.2008,43 (2), 404-419) report contains 1,2, the 4-triazole compounds has well anticancer and bacteriostatic activity, and wherein the bacteriostatic activity of part of compounds is better than contrast medicament penbritin (Ampicillin) and paraxin (Chloramphenicol), and anti-mycotic activity is better than miconazole (Miconazole).
(Zafer, A.K. such as Zafer; Gulhan, Z.; Ahmet, O.; Gilbert, R.Newtriazole and triazolothiadiazine derivatives as possibleantimicrobial agents[J] .Eur.J.Med.Chem.2008,43 (1), 155-159) with the indolylacetic acid be raw material, with the thiocarbohydrazide closed loop obtain the triazole intermediate, then with under the different condition obtain containing 1 with substituted benzaldehyde and bromoacetophenone reaction respectively, 2,4-triazole compounds target product.Adopt micrococcus luteus (M.luteus), bacillus cereus (B.cereus), Bacillus proteus (P.vulgaris), Salmonella typhimurium (S.typhimurium), streptococcus aureus (S.aureus), intestinal bacteria (E.coli), Candida albicans (C.albicans), Candida glabrata (C.glabrata) is for supplying the examination bacterial classification, give birth to and survey result's demonstration, the majority of compounds bacterium is to having demonstrated certain activity for the examination bacterial classification, the MIC value is between 25-250mg/L, and is active in contrast medicament paraxin (Chloramphenico) and chaff ketone azoles (Ketoconazole).
(Karegoudar, P. such as Karegoudar; Prasad, D.J.; Ashok, M.; Mahalinga, M.; Poojary, B.; Holla, B.S.Synthesis, antimicrobialand anti-inflammatory activities of some 1,2,4-triazolo[3,4-b] [1,3,4] thiadiazolesand, 2,4-triazolo[3,4-b] [1,3,4] thiadiazinesbearing trichlorophenyl moiety[J] .Eur.J.Med.Chem.2008,43,808-815) with 1,2, the 4-tri chlorobenzaldehyde is a raw material, it is oxidized to acid after, through esterification, hydrazinolysis, the salify closed loop obtains corresponding triazole, obtains containing 1 with different raw material closed loop again, 2,4-triazole compounds compound.Compound shows the biological activity test of intestinal bacteria (E.coli), klebsiella (K.pneumoniae), Pseudomonas aeruginosa (P.aeruginosa), streptococcus aureus (S.Aureus) etc., majority of compounds is active all suitable with contrast medicine Ciprofloxacin (Ciprofloxacin) to their inhibition, and minimum inhibitory concentration is 6.25mg/L.Simultaneously, these compounds also have the effect of anti-anti-inflammatory.
Yin Kai (Yin Kai, Jiang Lihui, Zhou Houxiang, Huang Yong is to building 2 of southern .2-Polyfluoroalkyl replacement and glucosyl group replacement, 4-dihydro-1,2, the synthetic and insecticidal activity [J] of 4-triazole-3-thioketones class Schiff's base. organic chemistry .2008,28 (6), 1016-1023) wait report with 5-phenyl-4-amino-1,2,4-triazole-3-thioketones is a raw material, synthesized series 2,4-dihydro-1,2, the Polyfluoroalkyl substituent of 4-triazole-3-thioketones class Schiff's base.With mythimna separata, black bean aphid is the test worm, and wherein part target compound lethality rate to two-spotted spider mite and green rice leafhopper when concentration is 500mg/L reaches 94.2% and 93.3% respectively.
That the Schiff bases compound has is antibacterial, sterilization, biological activity such as antitumor, antiviral, the object that the person that all the time is the chemical research pays close attention to.Discover, 4-amino-1,2, the Schiff's base that 4-triazole and aldehyde condensation form has wide biological activity.(Holla, B.S. such as Holla in 2003; Veerendra, B.; Shivananda, M.K.; Poojary, B.Synthesischaracterization and anticancer activity studies on some Mannichbases derived from 1,2,4-triazoles[J] .Eur.J.Med. Chem.2003,38 (7-8), 759-767) synthetic triazole Schiff's base has the good restraining effect to the test cancer cells.(Sun Xiaohong such as Sun Xiaohong in 2008, Tao Yan, Liu Yuanfa, Jia Yingqi, the old .3-of nation methyl-4-amino-1,2, synthetic and the bioactivity research [J] of 4-triazole-5-thioketones Schiff's base. chemical journal, 2008,66 (2), 2234-2238) reported the synthetic and biological activity of the triazolinthione Schiff's base that 7 alkyl replace, one of them compound to the EC50 of dry rot of potato (Pythium solani) less than contrast medicament triazolone.(Hu Guoqiang such as Hu Guoqiang in 2006, Xie Songqiang, Du Gangjun, Huang Wenlong, Zhang Huibin, Huang Shengtang. two aminotriazole thioethers and with the synthetic and bacteriostatic activity [J] of piperonylaldehyde Schiff's base. applied chemistry, 2006,23 (3), 173-277) with piperonylaldehyde and 4-amino-1,2, the condensation of 4-triazole derivative, the Schiff bases compound of generation shows stronger inhibition activity to intestinal bacteria.
Summary of the invention: the object of the invention is to design has synthesized 1,2 of a series of novel structures, and 4-triazole Schiff's base pyridazinone derivative had both contained 1,2, and the 4-triazole structure also contains the pyridazinone composition, and schiff base structure is arranged; And this series compound carried out the sick novel pesticide initiative research of synthetic method and cucumber-mosaic-virus resistant (CMV).(I) is as follows for its general structure:
R wherein
1For:
R
3, R
4Be one of following each component; (1) hydrogen; (2) adjacent,, contraposition is single replaces or polysubstituted halogen atom; (3) adjacent,, contraposition is single replaces or polysubstituted itrile group; (4) adjacent,, contraposition is single replaces or polysubstituted nitro; (5) adjacent,, contraposition is single replaces or polysubstituted hydroxyl; (6) adjacent,, contraposition is single replaces or polysubstituted trifluoromethyl; (8) C1-6 alkyl; (9) C1-6 alkoxyl group; (10) C1-6 alkylthio; (11) adjacent,, contraposition is single replaces or polysubstituted dimethylamino;
R
2Be one of following each component; (1) hydrogen; (2) phenyl; (3) adjacent,, contraposition is single replaces or polysubstituted halogen atom phenyl; (4) tertiary butyl; (5) C1-6 alkyl; (6)
Wherein, R
5Be one of following each component; Hydrogen, neighbour,, contraposition is single replaces or polysubstituted halogen atom.
Above-mentioned C1-6 alkyl is one of methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, uncle's hexyl, new hexyl; Halogen atom is fluorine, chlorine, bromine or iodine.
The compound or the compound compositions that comprise effective formula (I) in the content of the present invention, its purposes are as the medicine of Antiphytoviral or medicament.
Described pharmaceutical composition contains the mixture as formula at least (I) compound of activeconstituents itself or itself and one or more pharmaceutically useful inert non-toxic vehicle or carrier.
Acceptable salt also can be used for preventing and treating plant virus, weeds, the animal pest that appears on husbandry, the forest aspect as activeconstituents in The compounds of this invention or its plant protection, and stores the animal pest on product, material protection, the health aspect.The compounds of this invention also can be used as defoliating agent, weedicide, anti-plant virus agent as activeconstituents.Particularly as anti-plant virus agent the time The compounds of this invention to cucumber mosaic virus (CMV) is had good active.
The preparation method of general formula of the present invention (I) compound is with gallic acid, mucochloric acid, 1, and 3-diamino thiocarbamide, substituted benzaldehyde, phenylhydrazine etc. are that raw material synthesized through etherificate, triazole closed loop, imidization, pyridazine closed loop, five steps of thioetherification, and synthetic route is as follows:
The first step: 3,4, the preparation of 5-trimethoxybenzoic acid
Take by weighing 20g (0.106mol) gallic acid and place 500mL four neck round-bottomed flasks, add 120mL water, logical nitrogen protection adds the solution that 32g (0.800mol) sodium hydroxide and 80mL water are made into; Under ice-water bath, add 35.6g (0.282mol) methyl-sulfate for the first time then, reaction 20min adds 35.6g (0.282mol) methyl-sulfate for the second time again, removes ice-water bath, and temperature is risen to 40～45 ℃, continues reaction 30min; At last with reaction system reflux 2h, add the solution that 8g (0.200mol) sodium hydroxide and 12mL water are made into once more, reheat reaction 2h is after the thing cooling to be mixed, use hcl acidifying, the trimethoxybenzoic acid precipitation suction filtration of separating out is also used the cold water thorough washing.Used water adds gac and carries out recrystallization, gets white needle-like crystals, 158～160 ℃ of product fusing points (166～167 ℃ of literature values), yield 57.4%;
Second step: the preparation of 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones
In the 250mL there-necked flask, add 3,4,5-trimethoxybenzoic acid (2.1g, 10mmol) and 1,3-diamino thiocarbamide (1.1g, 10mmol). treat oil bath temperature be stabilized in～165 ℃, insert the there-necked flask that reactant is housed, the reaction mixture fusion keeps 3h under this temperature.Be chilled to room temperature, 50mL hot-water cure after drying gets product with the dehydrated alcohol recrystallization, yield 61.5%, mp.228～230 ℃;
The 3rd step: 1,2, the preparation of 4-triazole Schiff's base thioketones
With 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones (2.8g, 10mmol) be dissolved in the 30mL dehydrated alcohol with replacement aldehyde (10mmol), add several Glacial acetic acid and make catalyzer, reflux, TLC follows the tracks of, 3～4h finishes reaction, be cooled to room temperature, separate out solid, suction filtration, solid gets compound with dehydrated alcohol or dehydrated alcohol/DMF recrystallization;
The 4th step: 4, the preparation of 5-two chloro-2-phenyl-pyridazinones
In the 100mL there-necked flask, add mucochloric acid 3.20g (18.9mmol), methyl alcohol 20mL, phenylhydrazine 2mL (20mmol), 10% hydrochloric acid 1.5mL, reflux, TLC follows the tracks of reaction, and raw material disappears behind the 4h, finishes reaction, naturally cooling is separated out yellow solid, suction filtration, infrared drying is used the dehydrated alcohol recrystallization, gets white cotton-shaped shinny crystal 2 .3g, mp:162-164 ℃ (163～165 ℃ of literature values), yield: 50.7%;
The 5th step: the preparation of target compound
With compound 1,2,4-triazole Schiff's base thioketones (1mmol), salt of wormwood (2.5mmol) and acetonitrile (40mL) place the 100mL reaction flask, under reflux behind the induction stirring 5min, slowly add 2-phenyl-4,5-dichloro pyridazinone (1mmol), TLC are followed the trail of stopped reaction to the completely dissolve of raw material point, in the reaction solution impouring cold water, separate out solid.The solid crude product that obtains after the filtration is by recrystallization or silica gel column chromatography separating purification.
In each step of above-mentioned preparation method, if the consumption of raw material changes, other reagent respective change in proportion then.
This step is applicable to all above-mentioned target compounds 1,2, the pyridazinone derivative that 4-triazole heterocycle is modified synthetic.
Embodiment
Embodiment one, compound 4-chloro-2-phenyl-5-{4-[(E)-(E)-vinylbenzene methyne amine]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is a) synthetic:
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Take by weighing 20g (0.106mol) gallic acid and place 500mL four neck round-bottomed flasks, add 120mL water, logical nitrogen protection adds the solution that 32g (0.800mol) sodium hydroxide and 80mL water are made into; Under ice-water bath, add 35.6g (0.282mol) methyl-sulfate for the first time then, reaction 20min adds 35.6g (0.282mol) methyl-sulfate for the second time again, removes ice-water bath, and temperature is risen to 40～45 ℃, continues reaction 30min; At last with reaction system reflux 2h, add the solution that 8g (0.200mol) sodium hydroxide and 12mL water are made into once more, reheat reaction 2h is after the thing cooling to be mixed, use hcl acidifying, the trimethoxybenzoic acid precipitation suction filtration of separating out is also used the cold water thorough washing.Used water adds gac and carries out recrystallization, gets white needle-like crystals, 158～160 ℃ of product fusing points, yield 57.4%;
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
In the 250mL there-necked flask, add 3,4,5-trimethoxybenzoic acid (2.1g, 10mmol) and 1,3-diamino thiocarbamide (1.1g, 10mmol). treat oil bath temperature be stabilized in～165 ℃, insert the there-necked flask that reactant is housed, the reaction mixture fusion keeps 3h under this temperature.Be chilled to room temperature, 50mL hot-water cure after drying gets product with the dehydrated alcohol recrystallization, yield 61.5%, mp.228～230 ℃;
(3) (E)-and 3-vinylbenzene time azomethine-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioketones synthetic:
With compound 1,2,4-triazole Schiff's base thioketones (2.8g, 10mmol) and phenylacrolein (1.32g 10mmol) is dissolved in the 30mL dehydrated alcohol, and adds 5 Glacial acetic acid, heating, backflow 3h is cooled to room temperature, suction filtration, solid is with dehydrated alcohol or dehydrated alcohol/DMF recrystallization, yellow crystals, yield 67.1%, mp:176～180 ℃;
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
In the 100mL there-necked flask, add mucochloric acid 3.20g (18.9mmol), methyl alcohol 20mL, phenylhydrazine 2mL (20mmol), 10% hydrochloric acid 1.5mL, reflux, TLC follows the tracks of reaction, and raw material disappears behind the 4h, finishes reaction, naturally cooling is separated out yellow solid, suction filtration, infrared drying is used the dehydrated alcohol recrystallization, gets white cotton-shaped shinny crystal 2 .3g, mp:162～164 ℃, yield: 50.7%;
(5) 4-chloro-2-phenyl-5-{4-[(E)-(E)-vinylbenzene methyne amine]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic:
With compound (E)-3-vinylbenzene time azomethine-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioketones (0.396g, 1mmol), salt of wormwood (2.5mmol) and acetonitrile (40mL) place the 100mL reaction flask, under reflux behind the induction stirring 5min, slowly add 2-phenyl-4, (0.24g 1mmol), continues reaction 3h stopped reaction to the 5-dichloro pyridazinone, in the reaction solution impouring cold water, separate out solid, the solid crude product that obtains after the filtration gets white crystal by silica gel column chromatography separating purification, yield 80%, mp:180～181 ℃.
Embodiment two, compound 4-chloro-2-phenyl-5-{[4-(E)-(2-chlorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is b) synthetic:
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(2-chlorobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,3-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment one (3) method and condition.Difference be to add o-chlorobenzaldehyde (1.40g, 10mmol), the reaction times is 3.5h, yield 63.8%, mp:194～197 ℃.
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(2-chlorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic:
Synthetic as embodiment one (5) method and condition.Difference is to add (E)-4-(2-chlorobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,3-triazole-3 (4H)-thioketones (0.40g, 1mmol), yield 80%, mp:179～180 ℃.
Embodiment three, compound 4-chloro-2-phenyl-5-{[4-(E)-(3,4,5-trimethoxy benzylidyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is c) synthetic:
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(3,4,5-trimethoxy-benzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,3-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment one (3) method and condition.Difference is to add 3,4, the 5-TMB (1.96g, 10mmol), the reaction times is 2.5h, yield 70.3%, mp:228～230 ℃.
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(3,4,5-trimethoxy benzylidyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic:
Synthetic as embodiment one (5) method and condition.Difference is to add (E)-4-(3,4,5-trimethoxy-benzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,3-triazole-3 (4H)-thioketones (0.46g, 1mmol), yield 80%, mp:159～160 ℃.
Embodiment four, compound 4-chloro-2-phenyl-5-{[4-(E)-(4-chlorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is d) synthetic:
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(4-chlorobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,4-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment one (3) method and condition.Difference be to add the 4-chlorobenzaldehyde (1.40g, 10mmol), the reaction times is 2.5h, yield 63.8%, mp:194～197 ℃.
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(4-chlorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic:
Synthetic as embodiment one (5) method and condition.Difference is to add (E)-4-(4-chlorobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,4-triazole-3 (4H)-thioketones (0.40g, 1mmol), yield 80%, mp:201～202 ℃.
Embodiment five, compound 4-chloro-2-phenyl-5-{[4-(E)-(E)-(2-fluorobenzene ethene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is e) synthetic
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(2-fluorobenzene ethene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,4-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment one (3) method and condition.Difference be to add 2-fluorine phenylacrolein (1.50g, 10mmol), the reaction times is 3.5h, yield 71.4%, mp:243～244 ℃;
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(E)-(2-fluorobenzene ethene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic
Synthetic as embodiment one (5) method and condition.Difference is to add (E)-4-(2-fluorobenzene ethene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,4-triazole-3 (4H)-thioketones (0.42g, 1mmol), yield 80%, mp:101～102 ℃.
Embodiment six, compound 4-chloro-2-phenyl-5-{[4-(E)-(E)-(4-fluorobenzene ethene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is f) synthetic
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(4-fluorobenzene ethene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,3-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment five (3) methods and condition.Difference be to add 4-fluorine phenylacrolein (1.50g, 10mmol), the reaction times is 1.5h, yield 72.5%, mp:199～201 ℃.
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(E)-(4-fluorobenzene ethene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic
Synthetic as embodiment five (5) methods and condition.Difference is to add (E)-4-(4-fluorobenzene ethene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,4-triazole-3 (4H)-thioketones (0.42g, 1mmol), the reaction times is 1.5h, yield 80%, mp:145～147 ℃.
Embodiment seven, compound 4-chloro-2-phenyl-5-{[4-(E)-(E)-(4-trifluoromethyl styrene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is g) synthetic
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(4-trifluoromethyl styrene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,4-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment one (3) method and condition.Difference be to add the 4-trifluoromethylated benzaldehyde (1.74g, 10mmol), the reaction times is 3.5h, yield 66.7%, mp:192～193 ℃.
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(E)-(4-trifluoromethyl styrene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic
Synthetic as embodiment one (5) method and condition.Difference is to add (E)-4-(4-trifluoromethyl styrene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,4-triazole-3 (4H)-thioketones (0.46g, 1mmol), the reaction times is 4.5h, yield 80%, mp:93～95 ℃.
Embodiment eight, compound 4-chloro-2-phenyl-5-{[4-(E)-(4-dimethylamino benzylidyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is h) synthetic
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(4-Dimethylaminobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,3-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment one (3) method and condition.Difference be to add 4-dimethylin phenyl aldehyde (1.49g, 10mmol), the reaction times is 3.5h, yield 70.3%, mp:228～230 ℃.
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(4-dimethylamino benzylidyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic
Synthetic as embodiment one (5) method and condition.Difference is to add (E)-4-(4-Dimethylaminobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,4-triazole-3 (4H)-thioketones (0.41g, 1mmol), the reaction times is 1.0h, yield 80%, mp:191～192 ℃.
Embodiment nine, compound 4-chloro-2-phenyl-5-{[4-(E)-(3-fluorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is i) synthetic
(1) 3,4,5-trimethoxybenzoic acid synthetic:
Synthetic as embodiment one (1) method and condition.
(2) 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones is synthetic:
Synthetic as embodiment one (2) method and condition.
(3) (E)-and 4-(3-fluorobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1,2,4-triazole-3 (4H)-thioketones synthetic:
Synthetic as embodiment one (3) method and condition.Difference be to add the 3-fluorobenzaldehyde (1.24g, 10mmol), reaction times 3.0h, yield 68.2%, mp:213～214 ℃.
Synthesizing of (4) 4,5-two chloro-2-phenyl-pyridazinones:
Synthetic as embodiment one (4) method and condition.
(5) 4-chloro-2-phenyl-5-{[4-(E)-(3-fluorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone synthetic
Synthetic as embodiment one (5) method and condition.Difference is to add (E)-4-(3-fluorobenzene time azomethine base)-5-(3,4, the 5-trimethoxyphenyl)-2H-1, and 2,4-triazole-3 (4H)-thioketones (0.38g, 1mmol), the reaction times is 1.0h, yield 80%, mp:192～193 ℃.
1,2 of partial synthesis, 4-triazole Schiff's base pyridazinone derivative proton nmr spectra (1HNMR) data are as shown in table 1, and physico-chemical property and ultimate analysis data are as shown in table 2, and infrared spectra (IR) data are as shown in table 3, carbon-13 nmr spectra (
13C NMR) data are as shown in table 4.
The proton nmr spectra data of table 1 compound
The physico-chemical property of table 2 compound and ultimate analysis
The IR data of table 3 compound
Table 4 compound
13The CNMR data
Embodiment ten, the compound a inhibition activity test test method sick to cucumber mosaic virus (CMV)
(1) test method
Chenopodium amaranticolor (Chenopodium amaranticolor) with the growing way unanimity is cooked withered spot host, with writing brush with the artificial frictional inoculation of virus on the of the right age blade that spreads silicon carbide, with clear water blade is cleaned up illumination cultivation 1.5h behind the 0.5h.Accurately take by weighing an amount of test compound in weighing bottle, add solvent DMF 30 μ L it is fully dissolved, if the insoluble 50 μ L that add to use the redistilled water that contains 1%Tween20 to be made into the compound solution of 500mg/L.Other gets 125 μ L2% Ningnanmycin aquas, adds solvent DMF 30 μ L, contains the redistilled water 5mL of 1%Tween20, is made into the Ningnanmycin solution of 500mg/L.Spread 500mg/L test compound and Ningnanmycin respectively at Zuo Banye, right half leaf is contrast with the solvent.Every chemicals treatment 3 strains, 6 leaves of every strain.The cultivation of in illumination box, preserving moisture subsequently, 28 ± 1 ℃ of controlled temperature, illumination 10000Lux observes behind 6 ~ 7d and record produces the number of withered spot.Withered spot inhibiting rate calculation formula:
X％＝(CK-T)/CK×100％
X: relative inhibition (%), CK: control group (right half leaf) withered spot number (individual)
T: compound treatment group (Zuo Banye) withered spot number (individual)
(2) test-results
Adopt aforesaid method, when drug concentration is 500 μ g/mL part of compounds having been carried out cucumber mosaic virus (CMV) live body therapeutic activity measures, the results are shown in Table 5. after tested, compound d, f, g, h are that 500 μ g/mL are respectively 45.8%, 46.7%, 45.1%, 48.2% to the live body treatment inhibiting rate that CMV infects in concentration, show certain anti-phytoviral activity.
Table 5 compound is to the result of treatment (%) of CMV
Table?5Curative?ffect?of?compounds?5?against?CMV?in?vivo?(％)
The embodiment of the invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited thereto.
Claims (6)
1. one kind contains 1,2,4-triazole Schiff's base pyridazinone derivative, and its feature structure general formula is as follows:
R wherein
1For:
Or
R
3, R
4Be one of following each component; (1) hydrogen; (2) adjacent,, contraposition is single replaces or polysubstituted halogen atom; (3) adjacent,, contraposition is single replaces or polysubstituted itrile group; (4) adjacent,, contraposition is single replaces or polysubstituted nitro; (5) adjacent,, contraposition is single replaces or polysubstituted hydroxyl; (6) adjacent,, contraposition is single replaces or polysubstituted trifluoromethyl; (8) C1-6 alkyl; (9) C1-6 alkoxyl group; (10) C1-6 alkylthio; (11) adjacent,, contraposition is single replaces or polysubstituted dimethylamino;
R
2For being one of following each component; (1) hydrogen; (2) phenyl; (3) adjacent,, contraposition is single replaces or polysubstituted halogen atom phenyl; (4) tertiary butyl; (5) C1-6 alkyl; (6)
Wherein, R
5Be one of following each component; Hydrogen, neighbour,, contraposition is single replaces or polysubstituted halogen atom.
2. according to claim 1ly a kind ofly contain 1,2,4-triazole Schiff's base pyridazinone derivative is characterized by: wherein component C1-6 alkyl is one of methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, uncle's hexyl, new hexyl; Halogen atom is fluorine, chlorine, bromine or iodine.
3. according to claim 1ly a kind ofly contain 1,2,4-triazole Schiff's base pyridazinone derivative is characterized in that the compound of partial synthesis is as follows:
1. 4-chloro-2-phenyl-5-{4-[(E)-(E)-vinylbenzene methyne amine]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is that a) structural formula is as follows:
2. 4-chloro-2-phenyl-5-{[4-(E)-(2-chlorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is b), structural formula is as follows:
3. 4-chloro-2-phenyl-5-{[4-(E)-(3,4,5-trimethoxy benzylidyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is c), structural formula is as follows:
4. 4-chloro-2-phenyl-5-{[4-(E)-(4-chlorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is d), structural formula is as follows:
5. 4-chloro-2-phenyl-5-{[4-(E)-(E)-(2-fluorobenzene ethene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is e), structural formula is as follows:
6. 4-chloro-2-phenyl-5-{[4-(E)-(E)-(4-fluorobenzene ethene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is f), structural formula is as follows:
7. 4-chloro-2-phenyl-5-{[4-(E)-(E)-(4-trifluoromethyl styrene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is g), structural formula is as follows:
8. 4-chloro-2-phenyl-5-{{4-(E)-(4-dimethylamino benzylidyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is h), structural formula is as follows:
9. 4-chloro-2-phenyl-5-{[4-(E)-(3-fluorobenzene methyne amine)]-5-(3,4, the 5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thioether } pyridazine-3 (2H)-ketone (compound number is i), structural formula is as follows:
4. a kind ofly contain 1 according to claim 1 is described, 2, the preparation method of 4-triazole Schiff's base pyridazinone derivative, the preparation method who it is characterized in that general formula (I) compound is with mucochloric acid, gallic acid, 1,3-diamino thiocarbamide, substituted benzaldehyde, phenylhydrazine etc. contain 1 for raw material synthesizes through the reaction of five steps, 2,4-triazole Schiff's base pyridazinone derivative:
The first step: 3,4, the preparation of 5-trimethoxybenzoic acid
Take by weighing 20g (0.106mol) gallic acid and place 500mL four neck round-bottomed flasks, add 120mL water, logical nitrogen protection adds the solution that 32g (0.800mol) sodium hydroxide and 80mL water are made into; Under ice-water bath, add 35.6g (0.282mol) methyl-sulfate for the first time then, reaction 20min adds 35.6g (0.282mol) methyl-sulfate for the second time again, removes ice-water bath, and temperature is risen to 40～45 ℃, continues reaction 30min; At last with reaction system reflux 2h, add the solution that 8g (0.200mol) sodium hydroxide and 12mL water are made into once more, reheat reaction 2h, after the thing cooling to be mixed, use hcl acidifying, also using cold water thorough washing, water to add gac the trimethoxybenzoic acid precipitation suction filtration of separating out carries out recrystallization, gets white needle-like crystals.158～160 ℃ of product fusing points (166～167 ℃ of literature values), yield 57.4%
Second step: the preparation of 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones
In the 250mL there-necked flask, add 3,4,5-trimethoxybenzoic acid (2.1g, 10mmol) with 1,3-diamino thiocarbamide (1.1g, 10mmol). treat oil bath temperature be stabilized in～165 ℃, insert the there-necked flask that reactant is housed, the reaction mixture fusion, keep 3h. to be chilled to room temperature under this temperature, 50mL hot-water cure after drying gets product with the dehydrated alcohol recrystallization, yield 61.5%, mp.228～230 ℃;
The 3rd step: 1,2, the preparation of 4-triazole Schiff's base thioketones
With 4-amino-5-(3,4, the 5-trimethoxyphenyl)-3-thioketones (2.8g, 10mmol) be dissolved in the 30mL dehydrated alcohol with replacement aldehyde (10mmol), add several Glacial acetic acid and make catalyzer, reflux, TLC follows the tracks of, 3～4h finishes reaction, be cooled to room temperature, separate out solid, suction filtration, solid gets compound with dehydrated alcohol or dehydrated alcohol/DMF recrystallization;
The 4th step: 4, the preparation of 5-two chloro-2-phenyl-pyridazinones
In the 100mL there-necked flask, add mucochloric acid 3.20g (18.9mmol), methyl alcohol 20mL, phenylhydrazine 2mL (20mmol), 10% hydrochloric acid 1.5mL, reflux, TLC follows the tracks of reaction, and raw material disappears behind the 4h, finishes reaction, naturally cooling is separated out yellow solid, suction filtration, infrared drying is used the dehydrated alcohol recrystallization, gets white cotton-shaped shinny crystal 2 .3g, mp:162-164 ℃ (163～165 ℃ of literature values), yield: 50.7%;
The 5th step: the preparation of target compound
With compound 1,2,4-triazole Schiff's base thioketones (1mmol), salt of wormwood (2.5mmol) and acetonitrile (40mL) place the 100mL reaction flask, under reflux behind the induction stirring 5min, slowly add 2-phenyl-4,5-dichloro pyridazinone (1mmol), TLC are followed the trail of stopped reaction to the completely dissolve of raw material point, in the reaction solution impouring cold water, separate out solid. the solid crude product that obtains after the filtration is by recrystallization or silica gel column chromatography separating purification.
5. according to claim 4ly a kind ofly contain 1,2, the preparation method of 4-triazole Schiff's base pyridazinone derivative, if it is characterized in that the raw material consumption changes in each step, other reagent respective change in proportion then.
According among the claim 1-3 any one described a kind of 1,2, the purposes of 4-triazole Schiff's base pyridazinone derivative is characterized in that each compound is used for medicine or the medicament as Antiphytoviral.
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| CN104086496A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | Antithrombotic compounds as well as preparation methods and applications of antithrombotic compounds |
| CN104098520A (en) * | 2014-07-23 | 2014-10-15 | 张远强 | Phenyl triazole schiff base compound as well as preparation method and application thereof |
| CN104086495A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | Compounds with terminally-disubstituted triazole Schiff base structure as well as preparation methods and applications of compounds |
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| CN104098520B (en) * | 2014-07-23 | 2016-01-20 | 张远强 | Phenyltriazole schiff base compounds, Preparation Method And The Use |
| CN105924432A (en) * | 2016-07-13 | 2016-09-07 | 青岛农业大学 | Pyridazinone derivative, and preparation method and application thereof |
| CN107216322A (en) * | 2017-07-28 | 2017-09-29 | 漳州卫生职业学院 | The synthetic method of triazole Liu isoxazoles |
| CN108409664A (en) * | 2018-02-14 | 2018-08-17 | 江苏医药职业学院 | A kind of organic synthesis of schiff base compounds and the method that crystal is prepared by the substance |
| CN112552241A (en) * | 2019-09-10 | 2021-03-26 | 中石化南京化工研究院有限公司 | Synthesis method of pyridazinone |
| CN112552241B (en) * | 2019-09-10 | 2022-07-08 | 中石化南京化工研究院有限公司 | Synthesis method of pyridazinone |
| CN113735842A (en) * | 2020-05-27 | 2021-12-03 | 河北农业大学 | 1,2, 4-triazole Schiff base thioether derivatives, and preparation method and application thereof |
| CN113735842B (en) * | 2020-05-27 | 2023-01-31 | 河北农业大学 | 1,2, 4-triazole Schiff base thioether derivatives, and preparation method and application thereof |
| CN116969955A (en) * | 2023-09-25 | 2023-10-31 | 中国药科大学 | [1,2,4] triazole [4,3-b ] pyridazine compound and preparation method and application thereof |
| CN116969955B (en) * | 2023-09-25 | 2023-12-19 | 中国药科大学 | [1,2,4] triazole [4,3-b ] pyridazine compound and preparation method and application thereof |
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