CN105330651B - 1 containing (miscellaneous) aryl and piperazine, 2,4- triazolinthione derivatives and preparation method and application - Google Patents

1 containing (miscellaneous) aryl and piperazine, 2,4- triazolinthione derivatives and preparation method and application Download PDF

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CN105330651B
CN105330651B CN201510603490.9A CN201510603490A CN105330651B CN 105330651 B CN105330651 B CN 105330651B CN 201510603490 A CN201510603490 A CN 201510603490A CN 105330651 B CN105330651 B CN 105330651B
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piperazine
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triazole
thioketones
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CN105330651A (en
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王宝雷
李正名
张丽媛
张燕
张晓�
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Nankai University
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    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings

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  • Agronomy & Crop Science (AREA)
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Abstract

The invention discloses 1 containing (miscellaneous) aryl and piperazine, 2,4 triazolinthione derivatives and preparation method and application.The synthetic method reactions steps are few, and condition is simply gentle, simple to operation, high income.The present invention has a structural formula as shown in general formula I and II, R in formula1、R2、R3Defined with claim 1.The compounds of this invention has the phytopathogens such as cucumber fusarium axysporum, peanut Cercospora bacteria, Botryosphaeria berengeriana f. sp, tomato early blight bacterium, fusarium graminearum, rhizoctonia cerealis certain in vitro inhibitory activity, especially there is higher in vitro inhibitory activity to cucumber fusarium axysporum, peanut Cercospora bacteria, Botryosphaeria berengeriana f. sp, rhizoctonia cerealis.The general formula I and Compounds of formula II of the present invention has the in vitro inhibitory activity of rice KARI enzymes at the same time.The present invention is suitable for the integrated control to fungus damage on various crops.

Description

1 containing (miscellaneous) aryl and piperazine, 2,4- triazolinthione derivatives and preparation method and Using
Technical field
The invention belongs to disinfectant use in agriculture field, is related to a kind of 1,2,4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine Preparation method and applications.
Background technology
Agriculture, woods, herd, the prevention during the realization of the every profession and trade such as secondary, fishing and public health for phytopathogen is One of important topic.With the intensification of people's environmental consciousness, some pollution environment, killing beneficial organism, develop immunity to drugs, difficult drop The old pesticide of solution is progressively eliminated, the direction of following New pesticides discovery will be the efficient environment friendly agricultural of research and development low toxicity and Environmentally friendly agricultural chemical.Wherein heterocyclic compound is due to its good drug efficacy, and dosage is few, degradable, to warm-blooded animal low toxicity, to bird The advantages of class, safe fish, become the hot spot of current pesticide developing.
KARI enzymes (ketol acid reductoisomerase, Ketol-acid Reductoisomerase) are primarily present in plant Play one of key enzyme of catalysis branched-chain amino acid biosynthesis in vivo with microorganism (such as bacterium, fungi), can be removed as design Careless agent or the target of fungicide.Triazole is a kind of important heterocyclic system, and triazole class compounds have broad-spectrum biological activity, such as disappear The features such as inflammation, weeding, antiviral, antitumor, coordinate plant growth isoreactivity, and toxicity are low, residual is short.Aminotriazole(ATA) and aldehyde The formed triazole Schiff of condensation has good coordination ability, and with antibacterial, antibacterial, antiviral activity etc. Feature.Importantly, as bioisostere, triazole ring can be used for the bases such as Ti Dai oxazoles, thiazole, pyrazoles, acid amides Roll into a ball to design new drug, it is currently the key areas of pesticide developing.
Important intermediate of the piperazine as medicine, pesticide, can be husky with synthesizing piperazine phosphate, orfloxacin, rifampin, oxygen fluorine Star, Enrofloxacin, Lomefloxacin etc., piperazine ring is a synergist groups to a certain extent, its small toxicity, and nitrogen-atoms can make it Multiple hydrogen bonds or ionic bond are formed, and then can effectively adjust the lipid and acid-base balance constant increase molecule of medicine It is alkaline and water-soluble, so as to increase the activity of molecule.To obtain the bioactive molecule of efficient, wide spectrum and good properties, It is one of common means of SARS drug design to carry out splicing to synthesize the novel compound of structure by various active fragment.To the greatest extent Pipe triazole Schiff carries out assembling by Mannich reactions from different aminated compounds and synthesizes triazolinthione analog derivative (ZL200510047151.3 has been documented；CN101519381A；CN1411450A；Organic chemistry, 2000,20 (5), 738-742).But in the prior art, 1,2, the 4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine as representative of the present invention Preparation and its sterilization, ARI enzyme inhibition activities it is not disclosed.
The content of the invention
It is an object of the invention to provide a kind of 1,2,4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine, it can be answered For the integrated control to fungus damage on various crops.
1,2, the 4- triazolinthione derivatives provided by the invention containing (miscellaneous) aryl and piperazine, have such as general formula I and II institutes The structural formula shown：
In formula：
R1Monosubstituted, polysubstituted, unsubstituted aryl or heteroaryl, the substituent be low alkyl group, lower alkoxy, Low-grade halogenated alkyl, halogen atom, nitro, cyano group；Heteroaryl is to contain heteroatomic 5 yuan of rings of one or more N, O, S or 6 yuan of rings, Including：Furans, thiophene, pyrazoles, imidazoles, triazole, pyridine, pyrimidine, pyrazine, pyridazine；Aryl is mainly phenyl；
R2The substituted functional groups of H or single or multiple, functional group therein include low alkyl group, low-grade halogenated alkyl, nitro, Cyano group, alkoxy, halogen atom；
R3It is low alkyl group, benzyl, substituted benzyl, phenyl, substituted-phenyl, pyrimidine radicals, substituted pyrimidyl, pyridine radicals, takes For pyridine radicals, the substituent on the substituted benzyl, substituted-phenyl, substituted pyrimidyl and substituted pyridinyl is low alkyl group, low Level haloalkyl or halogen atom, the substitution are monosubstituted or polysubstituted；
Term " low alkyl group " for methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
Term " lower alkoxy " for methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, Sec-butoxy, tert-butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy；
The carbon skeleton of term " low-grade halogenated alkyl " is identical in defined low alkyl group therewith, herein under the premise of it is rudimentary Haloalkyl is that the hydrogen atom on low alkyl group can partly or entirely be substituted by halogen atom；
The halogen atom is fluorine, chlorine, bromine or iodine.
The general formula compound I of the present invention can be prepared by following method, and substituent therein is outer as before unless specified otherwise Limited.
Formula III compound and formula IV compound ethanol or Isosorbide-5-Nitrae-dioxane are mixed, add 37% formaldehyde (HCHO) Aqueous solution, stirring reaction.Add water to filter out solid after filtering the solid being born or concentration, recrystallized with ethanol or alcohol-water, Or directly compound of formula I is washed to obtain with ethanol.Reaction temperature can be room temperature to solvent boiling point temperature, be usually 20 DEG C~110 ℃；When reaction time is usually 0.5~3 small；The compound shown in compound, formula IV shown in the formula III, mole of HCHO Than for 1: 1: 3.5~4.5.Its compound of formula IV (1- substituted-piperazinyls) also can use its hydrochloride form, then in the reaction system Add and reacted with the triethylamine of acid group (hydrochloric acid) equimolar amounts.
Compounds of formula III can according to document (J.Agric.Food Chem., 2000,48：5312-5315； J.Heterocyclic Chem.1976,13：925-926；J.Indian Chem.Soc., 2009,86：109-112) operate into It is prepared by row.
The part of compounds of general formula IV (1- substituted-piperazinyls) is commercially available.The preparation of the part of compounds of general formula IV may be referred to Document (J.Chem.Res., 2006, (12)：Method in 809-811) carries out.
General formula compound II can be prepared by following method, and substituent therein is outer unless specified otherwise to be limited as before.
Formula III compound and Piperazine anhydrous are mixed with 95% ethanol or Isosorbide-5-Nitrae-dioxane, add 37% formaldehyde (HCHO) aqueous solution, stirring reaction.Water is added to filter out solid after filtering the solid being born or concentration, with ethanol or alcohol-water Recrystallization, or directly Formula II compound is washed to obtain with ethanol.Reaction temperature can be room temperature to solvent boiling point temperature, be usually 20 DEG C~110 DEG C；When reaction time is usually 0.5~1.5 small；Compound, Piperazine anhydrous, HCHO shown in the formula III are rubbed You are than being 1: 0.49: 2.5~3.5.
The present invention general formula I and Compounds of formula II to cucumber fusarium axysporum, peanut Cercospora bacteria, Botryosphaeria berengeriana f. sp, The phytopathogens such as tomato early blight bacterium, fusarium graminearum, rhizoctonia cerealis have certain in vitro inhibitory activity, especially to Huang Cucurbit wilt bacterium, peanut Cercospora bacteria, Botryosphaeria berengeriana f. sp, rhizoctonia cerealis have higher in vitro inhibitory activity.The present invention General formula I and Compounds of formula II there is the in vitro inhibitory activity of rice KARI enzymes at the same time.Therefore, present invention additionally comprises general formula chemical combination Thing is used for the purposes for controlling plant fungus damage.
Present invention additionally comprises be used as the bactericidal composition of active component using general formula I and Compounds of formula II.The Bactericidal composite Agricultural, forestry, acceptable carrier in health are further included in thing.
The present invention provides a kind of 1,2,4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine, it can be applied to each The integrated control of fungus damage on kind crop.
The present invention once disclosed 1,2, the 4- triazoles containing substituted-piperazinyl relative to 104356123 A of Chinese invention patent CN Mannich base derivative and preparation method and application, 5- are methyl or trifluoromethyl in its 1,2,4- triazole ring, and 4- are miscellaneous Ring group methylene amino, from the point of view of compareing the compound in the present invention, 3- are aryl or heteroaryl in 1,2,4- triazole ring, and 4- are Aryl methylene amino, the compound preferably gone out in of the invention is to cucumber fusarium axysporum, Botryosphaeria berengeriana f. sp and rhizoctonia cerealis With prominent inhibitory activity, the aryl or heteroaryl in its structure on 1,2,4- triazole ring 3- positions are than patent Methyl or trifluoromethyl in CN201410668130.2 on relevant position, will play 1,2,4- triazole ring very big conjugation effect Should, while polycyclic connected skeleton causes compound structure to have stronger rigidity, or the difference of bactericidal activity can be produced.This Outside, compound has significant in vitro KARI enzyme inhibition activities in the present invention, it may be possible to by acting in plant epiphyte body KARI enzymes are suppressed the activity of its catalysis branched-chain amino acid biosynthesis, show bactericidal activity
Embodiment
Further illustrate the present invention with reference to embodiments, the purpose is to be better understood when that present disclosure is body The substantive distinguishing features of the existing present invention, therefore the cited case is not construed as limiting the scope of the invention.Here also refer in particular to Go out specific experiment method and apparatus involved in embodiment unless otherwise specified, be conventional method or said according to manufacturer The condition of bright book suggestion is implemented, and involved reagent is commercially available without specified otherwise.
Embodiment 1
The preparation method of compound 15
Step A：Prepare 5- (furans -2- bases) -1,3,4- oxadiazole -2- mercaptan
9.00g (71.4mmol) 2- furoyls hydrazine and 300mL absolute ethyl alcohols are added in 500mL round-bottomed flasks, in ice bath Under (0 DEG C) stirring condition, 21.66g (285.5mmol) CS is added2With 4.00g (71.4mmol) KOH, ice is removed after charging Bath, is heated to reflux 7h.It is cooled to room temperature rotation and removes solvent, residue is used salt acid for adjusting pH 2~3 after adding suitable quantity of water dissolving, stirred 2h, filters, ethyl alcohol recrystallization, dry 9.36g white solids, yield 78%.
Step B：Prepare 4- amino -5- (furans -2- bases) -4H-1,2,4- triazole -3- mercaptan
8.90g (52.9mmol) 5- (furans -2- bases) -1,3,4- oxadiazole -2- mercaptan is added in 100mL round-bottomed flasks, 17.00g (264.6mmol) hydrazine hydrate (80%) and 30mL absolute ethyl alcohols, agitating and heating reflux 7h.Rotation is cooled to room temperature except molten Agent, residue uses salt acid for adjusting pH 1~2 after adding suitable quantity of water dissolving, 30min is stirred at room temperature, filters, ethyl alcohol recrystallization, dry Obtain 5.68g white solids, yield 56%.
Step C：Prepare 5- (furans -2- bases) -4- ((4- trifluoromethyls) phenylmethylene) amino) -4H-1,2,4- tri- Azoles -3- mercaptan
Sequentially add 2.00g (11.0mmol) 4- amino -5- (furans -2- bases) -4H-1 in 50mL round-bottomed flasks, 2,4- tri- Azoles -3- mercaptan, 1.70g (12.1mmol) p-trifluoromethyl benzaldehyde, the glacial acetic acid of 15mL absolute ethyl alcohols and 5mL, mixture add Heat reflux 5h.It is cooled to room temperature, there is crystal precipitation, filters, the washing of a small amount of ethanol, dry 2.90g white solids, yield 78%.
Step D：Prepare 3- (furans -2- bases) -1- ((4- phenylpiperazine -1- bases) methyl) -4- ((4- trifluoromethyls Methylene) amino) -1H-1, -5 (4H)-thioketones of 2,4- triazole
0.30g (1.0mmol) 5- (furans -2- bases) -4- ((4- trifluoromethyls) phenyl methylidenes are added in 50mL round-bottomed flasks Base) amino) -4H-1,2,4- triazole -3- mercaptan, 0.21g (1.0mmol) 1-phps and 15mL absolute ethyl alcohols, with stirring The formalin of 0.30g (3.7mmol) 37% is added, 1h is reacted at room temperature, there is solid precipitation, is filtered, with a small amount of anhydrous second Alcohol washs, and obtains 0.45g white solids, yield 88%.
Embodiment 2
The preparation method of compound 23
Step A：Prepare 5- (pyridin-3-yl) -1,3,4- oxadiazole -2- mercaptan
17.00g (123.9mmol) 3- pyridinecarboxylics hydrazine and 100mL absolute ethyl alcohols are added in 250mL round-bottomed flasks, in ice Under (0 DEG C) stirring of bath, 37.83g (324.3mmol) CS is added2With 6.93g (123.9mmol) KOH, ice is removed after charging Bath, is heated to reflux 10h.It is cooled to room temperature rotation and removes solvent, residue uses salt acid for adjusting pH 2~3 after being dissolved with water, stir 2h, takes out Filter, ethyl alcohol recrystallization, dry 9.10g white solids, yield 41%.
Step B：Prepare 4- amino -5- (pyridin-3-yl) -4H-1,2,4- triazole -3- mercaptan
Addition 8.75g (55.8mmol) 5- (pyridin-3-yl) -1 in 250mL round-bottomed flasks, 3,4- oxadiazole -2- mercaptan, 20.95g (334.8mmol) hydrazine hydrate (80%) and 100mL absolute ethyl alcohols, are heated to reflux 12h.It is cooled to room temperature rotation and removes solvent, Residue uses salt acid for adjusting pH 1~2 after being dissolved with suitable quantity of water, and 30min is stirred at room temperature, and filters, ethyl alcohol recrystallization, dry 8.41g white solids, yield 78%.
Step C：Prepare 4- ((4- fluorobenzene methylene) amino) -5- (pyridin-3-yl) -4H-1,2,4- triazole -3- mercaptan
Sequentially add 1.00g (5.6mmol) 4- amino -5- (pyridin-3-yl) -4H-1 in 100mL round-bottomed flasks, 2,4- tri- Azoles -3- mercaptan, 0.78g (6.1mmol) 4-Fluorobenzaldehydes and 20mL glacial acetic acid, are heated to reflux 7h.It is cooled to room temperature, there is crystal analysis Go out, filter, the washing of a small amount of ethanol, dry 1.55g yellow solids, yield 93%.
Step D：Preparation 4- ((4- fluorobenzene methylene) amino) -1- ((4- (pyridine -2- bases) piperazine -1- bases) methyl) - 3- (pyridin-3-yl) -1H-1, -5 (4H)-thioketones of 2,4- triazole
In 50mL round-bottomed flasks, 0.30g (0.9mmol) 4- ((4- fluorobenzene methylene) amino) -5- (pyridine -3- are added Base) -4H-1,2,4- triazole -3- mercaptan, 0.15g (0.9mmol) 1- (pyridine -2- bases) piperazine, 15mL absolute ethyl alcohols, are finally stirred The formalin of 0.30g (3.7mmol) 37% is added under the conditions of mixing, 1h is reacted at room temperature, there is solid precipitation, is filtered, with a small amount of Absolute ethyl alcohol washs, and obtains 0.46g yellow solids, yield 74%.
Embodiment 3
The preparation method of compound 34.
Step A：Prepare 5- phenyl -1,3,4- oxadiazole -2- mercaptan
19.00g (139.6mmol) benzoyl hydrazines and 100mL absolute ethyl alcohols are added in 250mL round-bottomed flasks, in ice bath (0 DEG C) under stirring condition, add 42.43g (558.2mmol) CS2With 7.81g (139.6mmol) KOH, removed after charging Ice bath, is heated to reflux 7h.It is cooled to room temperature rotation and removes solvent, residue is used salt acid for adjusting pH 2~3 after adding suitable quantity of water dissolving, stirred 2h is mixed, is filtered, ethyl alcohol recrystallization, obtains 18.16g white solids, yield 73%.
Step B：Prepare 4- amino-5-phenyls -4H-1,2,4- triazole -3- mercaptan
30.00g (168.3mmol) 5- phenyl -1,3,4- oxadiazole -2- mercaptan, 80.00g are added in 250mL round-bottomed flasks (1.3mol) hydrazine hydrate (80%) and 100mL absolute ethyl alcohols, agitating and heating reflux 6h.It is cooled to room temperature rotation and removes solvent, residue Salt acid for adjusting pH 1~2 is used after adding suitable quantity of water dissolving, 30min is stirred at room temperature, is filtered, ethyl alcohol recrystallization, it is purplish red to obtain 17.81g Color crystal, yield 55%.
Step C：Prepare 4- ((4- fluorobenzene methylene) amino) -5- phenyl -4H-1,2,4- triazole -3- mercaptan
Addition 4.00g (20.8mmol) 4- amino-5-phenyls -4H-1 in 50mL round-bottomed flasks, 2,4- triazole -3- mercaptan, 3.01g (20.8mmol) 4-Fluorobenzaldehyde, 20mL absolute ethyl alcohols and 5mL glacial acetic acid, mixture are heated to reflux 6h.It is cooled to room Temperature, there is crystal precipitation, filters, the washing of a small amount of ethanol, dry 5.76g clear crystals, yield 93%.
Step D：4- ((4- fluorobenzene methylene) amino) -1- ((4- (4- methylpyrimidine -2- bases) piperazine -1- bases) first Base) -3- phenyl -1H-1, -5 (4H)-thioketones of 2,4- triazole
Addition 0.3g (1.0mmol) 4- (4- fluorobenzene methylene) amino-5-phenyls -4H-1 in 50mL round-bottomed flasks, 2, 4- triazole -3- mercaptan, 0.18g (1.0mmol) 1- (4- methylpyrimidine -2- bases) piperazines and 10mL absolute ethyl alcohols, add with stirring Enter 37% formalins of 0.30g (3.7mmol), react at room temperature 2h, there is solid precipitation, filter, solid ethyl alcohol recrystallization, obtains 0.47g white solids, yield 96%.
Embodiment 4
The preparation method of compound 47.
Step A：Prepare 5- (2- fluorophenyls) -1,3,4- oxadiazole -2- mercaptan
The adjacent fluorobenzoyl hydrazines of 5.00g (32.4mmol) and 50mL absolute ethyl alcohols are added in 100mL round-bottomed flasks, in ice bath (0 DEG C) under stirring condition, add 9.86g (129.8mmol) CS2With 1.82g (32.4mmol) KOH, ice is removed after charging Bath, is heated to reflux 7h.It is cooled to room temperature rotation and removes solvent, residue is used salt acid for adjusting pH 2~3 after adding suitable quantity of water dissolving, stirred 2h, filters, ethyl alcohol recrystallization, obtains 5.41g brown solids, yield 85%.
Step B：Prepare 4- amino -5- (2- fluorophenyls) -4H-1,2,4- triazole -3- mercaptan
In 50mL round-bottomed flasks add 5.88g (30.0mmol) 5- (2- fluorophenyls) -1,3,4- oxadiazole -2- mercaptan, 18.75g (300.0mmol) hydrazine hydrate (80%) and 20mL water, agitating and heating reflux 6h.It is dilute that the progress of 200mL water is added after cooling Release, with salt acid for adjusting pH 1~2, filter, ethyl alcohol recrystallization, obtains 3.59g brown solids, yield 57%.
Step C：Preparation 5- (2- fluorophenyls) -4- ((4- trifluoromethylbenzenes methylene) amino) -4H-1,2,4- triazoles - 3- mercaptan
Sequentially add 3.00g (14.3mmol) 4- amino -5- (2- fluorophenyls) -4H-1 in 50mL round-bottomed flasks, 2,4- tri- Azoles -3- mercaptan, 2.49g (14.3mmol) p-trifluoromethyl benzaldehyde, 20mL absolute ethyl alcohols and 5mL glacial acetic acid, mixture heating Flow back 6h.It is cooled to room temperature, there is crystal precipitation, filters, a small amount of ethanol and water washing, dry 4.26g white solids, yield 81%
Step D：1- ((4- (4,6- dimethyl pyrimidine -2- bases) piperazine -1- bases) methyl) -3- (2- fluorophenyls) -4- ((4- Trifluoromethylbenzene methylene) amino) -1H-1, -5 (4H)-thioketones of 2,4- triazole
In 50mL round-bottomed flasks, 0.3g (0.8mmol) 5- (2- fluorophenyls) -4- ((4- trifluoromethyl methylenes are added Base) amino) -4H-1,2,4- triazole -3- mercaptan, 0.16g (0.8mmol) 1- (4,6- dimethyl pyrimidine -2- bases) piperazines and 10mL Absolute ethyl alcohol, adds the formalin of 0.28g (3.5mmol) 37% with stirring, reacts at room temperature 2h, there is solid precipitation, takes out Filter, with ethyl alcohol recrystallization, obtains white solid 0.42g, yield 90%.
Embodiment 5
The preparation method of compound 48.
Step A：Prepare 5- (3,4,5- trimethoxy -2- nitrobenzophenones) -1,3,4- oxadiazole -2- mercaptan
Added in 50mL round-bottomed flasks 1.36g (5.0mmol) 3,4,5- trimethoxy -2- nitrobenzoyls hydrazides and 20mL without Water-ethanol, under ice bath (0 DEG C) stirring condition, adds 1.52g (20.0mmol) CS2With 0.28g (5.0mmol) KOH, charging After remove ice bath, be heated to reflux 7h.It is cooled to room temperature rotation and removes solvent, residue is adjusted after adding suitable quantity of water dissolving with hydrochloric acid PH 2~3, stirs 2h, filters, ethyl alcohol recrystallization, obtains 1.46g light yellow solids, yield 93%.
Step B：Prepare 4- amino -5- (3,4,5- trimethoxy -2- nitrobenzophenones) -4H-1,2,4- triazole -3- mercaptan
1.88g (6.0mmol) 5- (3,4,5- trimethoxy -2- nitrobenzophenones) -1,3,4- is added in 50mL round-bottomed flasks Oxadiazole -2- mercaptan, 3.75g (60.0mmol) hydrazine hydrate (80%) and 20mL absolute ethyl alcohols, agitating and heating reflux 6h.It is cooled to Room temperature rotation removes solvent, and residue uses salt acid for adjusting pH 1~2 after adding suitable quantity of water dissolving, 30min is stirred at room temperature, filters, ethanol Recrystallization, obtains 1.63g brown solids, yield 83%.
Step C：Prepare 4- ((4- chlorobenzenes methylene) amino) -5- (3,4,5- trimethoxy -2- nitrobenzophenones) -4H- 1,2,4- triazole -3- mercaptan
0.40g (1.2mmol) 4- amino -5- (3,4,5- trimethoxy -2- nitrobenzenes are sequentially added in 50mL round-bottomed flasks Base) -4H-1,2,4- triazole -3- mercaptan, 0.19g (1.4mmol) 4-chloro-benzaldehyde, 10mL absolute ethyl alcohols and 0.5mL glacial acetic acid, It is heated to reflux 6h.It is cooled to room temperature, there is crystal precipitation, filters, the washing of a small amount of ethanol, dry 0.32g light yellow solids, yield 58%.
Step D：Preparation 4- ((4- chlorobenzenes methylene) amino) -1- ((4- (pyrimidine -2-base) piperazine -1- bases) methyl) - 3- (3,4,5- trimethoxy -2- nitrobenzophenones) -1H-1, -5 (4H)-thioketones of 2,4- triazole
Sequentially added in 50mL round-bottomed flasks 0.20g (0.4mmol) 4- ((4- chlorobenzenes methylene) amino) -5- (3,4, 5- trimethoxy -2- nitrobenzophenones) -4H-1,2,4- triazole -3- mercaptan, 0.11g (0.4mmol) 1- (pyrimidine -2-base) piperazine two Hydrochloride, 10mL absolute ethyl alcohols and 0.09g (0.9mmol) triethylamine, add 0.15g (1.9mmol) 37% formaldehyde with stirring Aqueous solution, reacts at room temperature 2h, there is solid precipitation, filters, with ethyl alcohol recrystallization, obtains 0.22g white solids, yield 79%.
Embodiment 6
The preparation method of compound 54
Step A and step B are the same as embodiment 1
Step C：Prepare 4- ((4- chlorobenzenes methylene) amino) -5- (furans -2- bases) -4H-1,2,4- triazole -3- mercaptan
Addition 2.00g (11.0mmol) 4- amino -5- (furans -2- bases) -4H-1 in the round-bottomed flask of 50mL, 2,4- tri- Azoles -3- mercaptan, 1.70g (12.1mmol) 4-chloro-benzaldehyde, 15mL absolute ethyl alcohols and 5mL glacial acetic acid, are heated to reflux 5h.It is cooled to Room temperature, there is crystal precipitation, filters, the washing of a small amount of ethanol, dry 2.60g white solids, yield 78%.
Step D：Prepare double (4- ((4- chlorobenzenes methylene) the amino) -3- of 1,1 '-(piperazine-Isosorbide-5-Nitrae-diyl dimethylene) (furans -2- bases) -1H-1, -5 (4H)-thioketones of 2,4- triazole
In 50mL round-bottomed flasks, 0.60g (2.0mmol) 4- ((4- chlorobenzenes methylene) amino) -5- (furans -2- are added Base) -4H-1,2,4- triazole -3- mercaptan, 0.08g (0.97mmol) Piperazine anhydrous and 20mL absolute ethyl alcohols, add with stirring The formalin of 0.5g (6.2mmol) 37%, reacts at room temperature 1h, there is solid precipitation, filters, is washed with a small amount of absolute ethyl alcohol, Dry 0.69g white solids, yield 97%.
Table 1 lists the structure and physical property of partial Formula I and Compounds of formula II.
Table 1
Table 2 lists general formula I and Compounds of formula II1H NMR datas.
Table 2
Active testing example
Embodiment 7
The measure of in vitro Plating bactericidal activity
It will break into culture dish of the bacterium piece access containing 50 μ g/mL liquids, be put into black in 25 DEG C of biochemical cultivation cases for examination germ Light culture, fungistatic effect is investigated after 3 days.Often handle 3 repetitions.Using only plus sterile water not adding medicine person for compare.It the results are shown in Table 3.(%)
Inhibiting rate (%)=[(blank colony diameter-processing colony diameter) ÷ (blank colony diameter -4)] × 100%
The in vitro bactericidal activity (50 μ g/mL, inhibiting rate %) of 3. compound of table
No. Cucumber withers Peanut foxiness Apple wheel line Tomato early epidemic Gibberella saubinetii Wheat line is withered
01 90.0 31.0 60.9 29.4 9.1 90.1
02 57.5 37.9 75.0 29.4 27.3 95.1
03 32.5 27.6 26.6 35.3 27.3 81.5
04 40.0 20.7 57.8 23.5 9.1 67.9
05 60.0 27.6 79.7 29.4 22.7 84.0
06 32.5 31.0 43.8 29.4 22.7 82.7
07 17.5 31.0 34.4 23.5 9.1 80.2
08 20.0 20.7 46.9 23.5 13.6 53.1
09 32.5 41.4 75.0 29.4 13.6 96.3
10 15.0 27.6 67.2 35.3 27.3 76.5
11 32.5 41.4 57.8 17.6 18.2 93.8
12 35.0 27.6 75.0 35.3 18.2 88.9
13 22.5 34.5 95.3 35.3 36.4 95.1
14 17.5 37.9 65.6 29.4 18.2 84.0
15 10.0 17.2 75.0 23.5 27.3 93.8
16 40.0 31.0 75.0 23.5 18.2 95.1
17 32.5 31.0 89.1 29.4 13.6 95.1
18 27.5 34.5 92.2 23.5 9.1 97.5
19 12.5 10.3 53.1 17.6 18.2 18.5
20 5.0 0.0 37.5 17.6 18.2 29.6
21 10.0 13.8 28.1 23.5 9.1 30.9
22 10.0 24.1 50.0 17.6 27.3 43.2
23 2.5 13.8 20.3 23.5 9.1 24.7
24 10.0 10.3 51.6 29.4 18.2 45.7
25 10.0 10.3 25.0 11.8 9.1 35.8
26 15.0 6.9 28.1 17.6 4.5 39.5
27 10.0 6.9 25.0 23.5 27.3 32.1
28 10.0 10.3 35.9 23.5 27.3 43.2
29 7.5 3.4 3.1 17.6 9.1 34.6
30 0.0 13.3 14.3 47.5
31 13.2 36.7 61.9 78.8
32 5.3 13.3 26.2 48.8
33 34.4 36.4 65.2 23.1 27.6 91.9
34 40.6 45.5 78.3 30.8 44.8 85.1
35 25.0 27.3 67.4 30.8 10.3 75.7
36 18.8 4.5 43.5 38.5 34.5 71.6
37 18.8 18.2 69.6 23.1 20.7 81.1
38 18.8 31.8 80.4 38.5 37.9 87.8
39 25.0 22.7 54.3 30.8 20.7 71.6
40 25.0 27.3 76.1 30.8 20.7 87.8
41 21.9 4.5 43.5 15.4 13.8 56.8
42 43.8 13.6 76.1 38.5 20.7 45.9
43 25.0 18.2 80.4 30.8 17.2 71.6
44 18.8 13.6 69.6 23.1 27.6 51.4
45 15.6 9.1 39.1 30.8 17.2 64.9
46 15.6 18.2 543 15.4 10.3 78.4
47 18.8 27.3 58.7 23.1 10.3 83.8
48 5.3 20.0 26.2 73.8
49 15.8 23.3 42.9 56.3
50 7.9 13.3 21.4 42.5
51 23.7 33.3 38.1 76.3
52 7.9 70.0 14.3 71.3
53 7.9 30.0 19.0 71.3
54 10.0 13.8 35.9 17.6 13.6 60.5
55 7.5 13.8 39.1 35.3 27.3 48.1
56 10.0 10.3 54.7 17.6 13.6 53.1
57 12.5 17.2 12.5 29.4 27.3 24.7
58 0.0 10.3 7.8 11.8 9.1 29.6
59 2.6 13.3 14.3 80.0
60 12.5 4.5 26.1 23.1 3.4 44.6
61 12.5 13.6 41.3 30.8 34.5 67.6
62 3.1 4.5 15.2 23.1 10.3 41.9
63 18.8 9.1 15.2 23.1 24.1 63.5
64 12.5 13.6 43.5 15.4 3.4 52.7
65 5.3 10.0 4.8 23.8
66 2.6 10.0 38.1 25.0
Embodiment 8
The measure of in vitro KARI enzyme inhibition activities
Using the Bacillus coli cells of recombinant plasmid (containing rice KARI enzyme genes) conversion come high-volume expressing K ARI enzymes (Lee, Y.T.；Ta, H.T.；Duggleby, R.G.Plant Sci.2005,168,1035.), the researchization under conditions of in vitro The interaction of compound and KARI enzymes.Using dynamic-analysis method, appropriate compound solution, 0.1mol/L Tris-HCl are buffered Liquid (pH=8.0), 0.2mmol/L NADPH, 1mmol/L MgCl2And appropriate rice KARI zymoproteins mix in cuvette It is even, added after being kept the temperature at 30 DEG C and start enzyme reaction containing the acetolactic mixed liquors of 0.1mmol/L, it is linear with initial reaction stage The slope (Δ OD340/min) of changing unit represents initial enzyme activity, and the continuous absorbance for recording 340nm be (monitoring NADPH's Abatement), be absorbed curve, is compareed with blank test (being not added with compound) and calculates inhibiting rate.It the results are shown in Table 4.(%)
Inhibiting rate (%)=[(NADPH absorption curves are oblique in NADPH absorption curves slope-compound test in blank test Rate) NADPH absorption curves slope in ÷ blank tests] × 100%
The in vitro KARI enzyme inhibition activities (200 μ g/mL) of 4. compound of table
No. Inhibiting rate % No. Inhibiting rate % No. Inhibiting rate %
01 50.8 26 88.7 61 69.3
04 71.4 43 90.1 62 60.5
11 33.3 44 53.4 63 82.0
19 63.6 49 51.8 64 62.0
20 53.7 59 81.8 65 74.8
22 51.7 60 72.0 66 78.4

Claims (8)

1. 1,2,4- triazolinthione derivatives of the one kind containing (miscellaneous) aryl and piperazine, have the structural formula as shown in general formula I and II：
It is characterized in that：
R1It is phenyl, 2- fluorophenyls, 2- nitros -3,4,5- trimethoxyphenyls, furans -2- bases, pyridin-3-yl；
R2It is 4- fluorine, 4- chlorine, 4- trifluoromethyls；
R3It is 4- chlorobenzyls, 2,4- dichloro benzyls, phenyl, pyridine -2- bases, pyrimidine -2-base, 4- methylpyrimidine -2- bases, 4,6- bis- Methylpyrimidine -2- bases.
2. 1,2, the 4- triazolinthione derivatives according to claim 1 containing (miscellaneous) aryl and piperazine, it is characterised in that it It is following compounds：
1- ((4- (4- chlorobenzyls) piperazine -1- bases) methyl) -4- ((4- chlorobenzenes methylene) amino) -3- (furans -2- bases) - 1H-1, -5 (4H)-thioketones (01) of 2,4- triazole, 4- ((4- chlorobenzenes methylene) amino) -1- ((4- (2,4- dichloro benzyl) piperazines Piperazine -1- bases) methyl) -3- (furans -2- bases) -1H-1, -5 (4H)-thioketones (02) of 2,4- triazole, 4- ((4- chlorobenzenes methylene) Amino) -3- (furans -2- bases) -1- ((4- (4- methylpyrimidine -2- bases) piperazine -1- bases) methyl) -1H-1,2,4- triazoles -5 (4H)-thioketones (04), 4- ((4- fluorobenzene methylene) amino) -3- (furans -2- bases) -1- ((4- phenylpiperazine -1- bases) first Base) -1H-1, -5 (4H)-thioketones (09) of 2,4- triazole, 4- ((4- fluorobenzene methylene) amino) -3- (furans -2- bases) -1- ((4- (4- methylpyrimidine -2- bases) piperazine -1- bases) methyl) -1H-1, -5 (4H)-thioketones (10) of 2,4- triazole, 1- ((4- (4,6- Dimethyl pyrimidine -2- bases) piperazine -1- bases) methyl) -4- ((4- fluorobenzene methylene) amino) -3- (furans -2- bases) -1H-1, - 5 (4H)-thioketones (11) of 2,4- triazole, 4- ((4- fluorobenzene methylene) amino) -3- (furans -2- bases) -1- ((4- (pyridine -2- Base) piperazine -1- bases) methyl) -1H-1, -5 (4H)-thioketones (12) of 2,4- triazole, 1- ((4- (4- chlorobenzyls) piperazine -1- bases) first Base) -3- (furans -2- bases) -4- ((4- trifluoromethylbenzenes methylene) amino) -1H-1, -5 (4H)-thioketones of 2,4- triazole (13), 3- (furans -2- bases) -1- ((4- phenylpiperazine -1- bases) methyl) -4- ((4- trifluoromethylbenzenes methylene) amino) - 1H-1, -5 (4H)-thioketones (15) of 2,4- triazole, 3- (furans -2- bases) -1- ((4- (4- methylpyrimidine -2- bases) piperazine -1- bases) Methyl) -4- ((4- trifluoromethylbenzenes methylene) amino) -1H-1, -5 (4H)-thioketones (16) of 2,4- triazole, 1- ((4- (4,6- Dimethyl pyrimidine -2- bases) piperazine -1- bases) methyl) -3- (furans -2- bases) -4- ((4- trifluoromethylbenzenes methylene) amino) - 1H-1, -5 (4H)-thioketones (17) of 2,4- triazole, 3- (furans -2- bases) -1- ((4- (pyridine -2- bases) piperazine -1- bases) methyl) - 4- ((4- trifluoromethylbenzenes methylene) amino) -1H-1, -5 (4H)-thioketones (18) of 2,4- triazole, 4- ((4- fluorophenyl methylenes Base) amino) -3- phenyl -1- ((4- (pyrimidine -2-base) piperazine -1- bases) methyl) -1H-1, -5 (4H)-thioketones of 2,4- triazole (33), 4- ((4- fluorobenzene methylene) amino) -1- ((4- (4- methylpyrimidine -2- bases) piperazine -1- bases) methyl) -3- phenyl - 1H-1, -5 (4H)-thioketones (34) of 2,4- triazole, 1- ((4- (4,6- dimethyl pyrimidine -2- bases) piperazine -1- bases) methyl) -3- benzene Base -4- ((4- trifluoromethylbenzenes methylene) amino) -1H-1, ((4- chlorphenyls are sub- by -5 (4H)-thioketones (38) of 2,4- triazole, 4- Methyl) amino) -3- (2- fluorophenyls) -1- ((4- (4- methylpyrimidine -2- bases) piperazine -1- bases) methyl) -1H-1,2,4- triazoles - 5 (4H)-thioketones (40), 4- ((4- fluorobenzene methylene) amino) -3- (2- fluorophenyls) -1- ((4- (4- methylpyrimidine -2- bases) Piperazine -1- bases) methyl) -1H-1, -5 (4H)-thioketones (43) of 2,4- triazole, 1,1 '-(piperazine-Isosorbide-5-Nitrae-diyl dimethylene) are double (4- ((4- chlorobenzenes methylene) amino) -3- phenyl -1H-1, -5 (4H)-thioketones (59) of 2,4- triazole.
3. the preparation method of 1,2, the 4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine described in claim 1, its feature It is to mix the compound of formula III and formula IV compound ethanol or Isosorbide-5-Nitrae-dioxane, adds 37% formalin, stir Mix reaction；Reaction temperature be 20 DEG C~110 DEG C, the reaction time for 0.5~3 it is small when, reaction finishes, filter birth solid or After concentration plus water filters out solid, is recrystallized with ethanol or alcohol-water, or directly wash to obtain compound of formula I, reaction equation with ethanol It is as follows：
R in formula1、R2、R3Defined with claim 1；The compound shown in compound, formula IV, first shown in the formula III The molar ratio of aldehyde is 1: 1: 3.5~4.5.
4. the preparation method of 1,2, the 4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine described in claim 1, its feature It is to mix formula III compound and Piperazine anhydrous ethanol or Isosorbide-5-Nitrae-dioxane, adds 37% formalin, stirring is anti- Should, reaction temperature is 20 DEG C~110 DEG C, and when the reaction time is 0.5~1.5 small, reaction finishes, and filters the solid of birth, uses Ethanol or alcohol-water recrystallization, or directly with ethanol wash Formula II compound, reaction equation are as follows：
R in formula1、R2Defined with claim 1；Compound, Piperazine anhydrous, the molar ratio of formaldehyde shown in the formula III are 1: 0.49: 2.5~3.5.
5. preparation method according to claim 3, it is characterised in that its hydrochloride of formula IV compound (1- substituted-piperazinyls) Reacted, need to add in the reaction system and reacted with the triethylamine of hydrochloric acid equimolar amounts.
6. any 1,2, the 4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine of claim 1-2 are as active component Bactericidal composition；And agricultural, forestry, acceptable carrier in health are further included in the bactericidal composition.
7. any 1,2, the 4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine of claim 1-2 are used to manufacture KARI Enzyme inhibitor.
8. any 1,2, the 4- triazolinthione derivatives containing (miscellaneous) aryl and piperazine of claim 1-2 are used for various works The purposes of the prevention of fungus damage on thing.
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