CN103214466A - Methyl arylpyrazole fluorouracil compounds, and preparation method and application thereof - Google Patents
Methyl arylpyrazole fluorouracil compounds, and preparation method and application thereof Download PDFInfo
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- CN103214466A CN103214466A CN201310098957XA CN201310098957A CN103214466A CN 103214466 A CN103214466 A CN 103214466A CN 201310098957X A CN201310098957X A CN 201310098957XA CN 201310098957 A CN201310098957 A CN 201310098957A CN 103214466 A CN103214466 A CN 103214466A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 100
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 59
- 239000002904 solvent Substances 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- -1 nitro, methoxyl group Chemical group 0.000 claims description 15
- 150000001298 alcohols Chemical class 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000003586 protic polar solvent Substances 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
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Abstract
The invention discloses methyl arylpyrazole fluorouracil compounds, and a preparation method and an application thereof. The compounds are compounds represented by the structural general formula (I) and pharmaceutically acceptable salts thereof. The compounds provided by the invention have the advantages of low dose, good insecticidal effect, simple process method, low cost, and wide market prospect.
Description
Technical field
The invention belongs to pesticide field, be specifically related to a kind of methyl aryl pyrazoles Fluracil compounds, preparation method and as the application of sterilant.
Background technology
Along with the continuous growth of whole world population, cultivated area reduces relatively, and food problem more and more is subjected to people's attention.Disease, worm, harmful every year all can bring serious loss to agriculture production, and its average loss that causes during plant-growth is about 10～20%, will cause tremendous loss to grain-production, and agricultural chemicals becomes indispensable guarantee in agriculture production.
The focus sterilant of existing market has fluorine worm nitrile, chlorine insect amide etc.But external monitoring for resistance finds, Homoptera insect Bemisia tabaci, Bemisia argentifolii, etc. the field population main flow sterilants such as Provado have been produced resistance or resistance in various degree, beaten drug-fast alarm bell for the agricultural insect of control.In addition, because the reach of science and to the development of the understanding and the pest management theory of agricultural chemicals, national governments at aspects such as legislations the various agricultural chemicals of strict control to the harm of non-target organism with to the potential impact of environment, so the exploitation of the pesticide new variety of environmental friendliness or environmental safety has wide space and rich profit.
Pyrazole compound is because of advantages such as it has efficiently, low toxicity and structure diversities, and its research and development is the new approach of novel pesticide initiative having increased.On the pyrazoles ring, the four big sites that replace of " reserving a seat for sb. " make the scientific research personnel have enough ample scopes for abilities.Along with pyrazoles substitution in ring site with substituent different, given pyrazole compound different biological activitys.From the pyrazoles agricultural chemicals of present listing, its range of application is extremely extensive, and involved weeding, desinsection/kill a plurality of fields such as mite, sterilization and plant growth regulating have boundless research and development prospect.
Summary of the invention
The purpose of this invention is to provide a kind of methyl aryl pyrazoles Fluracil compounds with insecticidal action.
Another object of the present invention provides the preparation method of above-claimed cpd.
A further object of the invention provides the application of above-claimed cpd aspect the preparation sterilant.
Purpose of the present invention can reach by following measure:
The compound of a kind of general structure (I) or its pharmacy acceptable salt,
Wherein,
R is
Heteroaryl or substituted heteroaryl,
R
1, R
2And R
3Be hydrogen, nitro, C independently of one another
1～6Alkoxyl group, C
1～6Alkyl or C
1～6Substituted alkyl;
Described substituted heteroaryl or C
1～6Substituting group in the substituted alkyl is selected from halogen, nitro, C
1～6Alkoxyl group or C
1～6In the alkyl one or more.
Preferably, R is
Pyridine or haloperidid.
Further preferred, R is
Pyridine or chloro-pyridine.
Preferably, R
1, R
2And R
3Be hydrogen, nitro, C independently of one another
1～4Alkoxyl group, C
1～4Alkyl or C
1～4Haloalkyl.
Further preferred, R
1, R
2And R
3Be hydrogen, nitro, methoxyl group, methyl or trifluoromethyl independently of one another.
Most preferred, R
1Be hydrogen, nitro, methoxyl group, methyl or trifluoromethyl; R
2Be hydrogen or methyl; R
3Be hydrogen.
Compound among the present invention or its pharmacy acceptable salt, wherein compound is preferably selected from
" pharmacy acceptable salt " expression among the present invention keeps the biological effectiveness of parent compound and those salt of character.This class salt comprises:
(1) with sour salify, free alkali by parent compound and mineral acid or organic acid reaction get, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprises acetate, trifluoroacetic acid, propionic acid, vinylformic acid, caproic acid, the pentamethylene propionic acid, hydroxyethanoic acid, pyruvic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, phenylformic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, styracin, dodecyl sulphate, glyconic acid, L-glutamic acid, aspartic acid, stearic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
(2) salt that is present in that acid proton in the parent compound is replaced by metal ion or is generated with the organic bases ligand compound, the metal example is alkalimetal ion, alkaline-earth metal ions or aluminum ion for example, and organic bases is thanomin, diethanolamine, trolamine, Trometamol, N-methylglucosamine etc. for example.
Heteroaryl among the present invention refers to the heterogeneous ring compound (fragrant heterocycle) with aromaticity, and modal is five-ring and six-ring, or condenses and encircle the compound that forms by them.Five yuan of main fragrant heterocycles have furans, thiophene, pyrroles, pyrazoles etc., and hexa-atomic fragrant heterocycle has pyridine, pyrimidine etc.
The preparation method of compound of the present invention, its reaction process is as follows:
Wherein, the definition of R as mentioned above.
In the preparation method, adopt protic solvents such as alcohols, acids or water among the reaction A, be preferably water or ethanol, temperature of reaction is 0 ℃～150 ℃, preferred 75 ℃～90 ℃;
Adopt non-proton dipole solvents such as ketone, dimethyl formamide among the reaction B, be preferably dimethyl formamide (DMF); Temperature of reaction is 0 ℃～120 ℃, preferred 15 ℃～30 ℃;
Adopt protic solvents such as alcohols, water among the reaction C, be preferably water, ethanol; Temperature of reaction among the reaction C is-20 ℃～40 ℃, preferred-10 ℃～15 ℃;
Adopt protic solvents such as alcohols, water among the reaction D, be preferably water, ethanol; Temperature of reaction among the reaction D is 20 ℃～120 ℃, preferred 85 ℃～100 ℃
Adopt protic solvents such as alcohols, water among the reaction E, be preferably water, ethanol; Temperature of reaction among the reaction E is 20 ℃～120 ℃, preferred 85 ℃～100 ℃;
Adopt non-proton dipole solvents such as ketone, dimethyl formamide among the reaction F, preferred dimethyl formamide (DMF); Temperature of reaction is 0 ℃～120 ℃, preferred 15 ℃～30 ℃.
Compound of the present invention or its pharmacy acceptable salt can be applicable to prepare the sterilant aspect, and further, (I) of the present invention formula compound can be used alone as sterilant, or make formulation as sterilant with auxiliary, render a service so that promote its desinsection.
The invention also discloses a kind of insect-killing composition, it is an activeconstituents with compound of the present invention or its pharmacy acceptable salt, is aided with acceptable accessories and forms.The compound of general formula (I) can be made into granule, wettable powder, and flowable liquid, formulations such as emulsifiable concentrates or insect aerosol are used.
In the practical application, can directly use the product of above-mentioned formulation, also dilutable water obtains expecting after the concentration, uses again.
Auxiliary used herein comprises carrier (thinner) and other auxiliarys such as spreading agent, wetting agent, emulsifying agent, dispersion agent etc.Carrier is divided into solid carrier and liquid vehicle.Liquid vehicle comprises: aromatic hydrocarbon is toluene and dimethylbenzene for example; Alcohols is butanols for example, octanol and ethylene glycol; Ketone is acetone and pimelinketone for example; Animal oil and vegetables oil; Fatty acid ester; Petroleum fractions is kerosene and gasoline for example.Solid carrier comprises: clay, kaolin, attapulgite, diatomite, polynite, wilkinite etc.
Emulsifying agent and dispersion agent are generally made by tensio-active agent.Tensio-active agent comprises anion surfactant, cats product, nonionogenic tenside and amphoterics.The sodium sulfate of higher alcohols for example, dodecyl benzyl dimethyl ammonium chloride, alkylphenol polyoxyethylene, tween series, sapn series etc.
The application example of spreading agent has polyoxyethylene nonylphenol ether, lauryl phenol Soxylat A 25-7.The application example of wetting agent has Aerosol OT.The application example of fixing agent has carboxymethyl cellulose, polyvinyl alcohol etc.
Agricultural chemicals of the present invention can use separately or with more than one sterilant, sterilant, miticide, weedicide, plant-growth regulator, soil sterilant and chemical fertilizer or other pesticide combination are used.
In the present composition, the form of agricultural chemicals is depended in the variation of its active ingredient concentration, use-pattern and other condition.Though active ingredient can be used separately, be benchmark with the composition, its amount of application is generally 0.04%～95% (weight), is preferably 0.04%～1% (weight).
(I) of the present invention formula compound can also be made aerosol bomb.Except (I) of the present invention formula compound, also contain the solvent of 0.1%～70% weight and the propelling agent of 28%～99.88% weight in the insect aerosol.Solvent is the D60 of C10～18, D80, D110 solvent wet goods alkane solvents; Water; One or more mixture such as the small molecular alcohol kind solvent of C2～C8.
In view of the 5 FU 5 fluorouracil pair cell has the strongly inhibited effect, has the synthetic and repair ability of extremely strong destruction cell DNA, the present invention introduces pyrazoles pesticide molecule structure with its active group, utilizes its effect of blocking various biological insect dna replication dnas, thereby produces insecticidal effect.And the metabolism of Fluracil is fast, and is residual few in the body of insect, can reduce agricultural chemicals to second environmental pollution.Thereby the present invention transforms by chemical process existing Insecticidal pyrazolines and obtains the wider novel pesticide of the higher range of application of the better security of effect to its local structure.The The compounds of this invention consumption is few, good disinsection effect, and synthetic process is simple, and with low cost, have vast market prospect.
Carry out following representational testing sequence with embodiment of the invention gained compound, to measure the insecticidal activity of The compounds of this invention.
Method A (to the culex insecticidal effect):
Each the compound 1-11 that respectively embodiment is obtained is made into aerosol according to the method for embodiment 26.
Adopt the standard testing cylinder, aerosol is tested according to regulation among the GB13917.2-2009.To be placed in the cylinder unit for the examination insect; after waiting to try worm recovery normal activity; metered injection 1g medicament from insect aerosol; extract baffle plate behind the 1min out, make medicament contact timing immediately with the examination worm; write down the insect quantity of going down; behind the 20min, will be transferred in the dependent insect cage of cleaning, check dead borer population behind the 24h for the examination worm.
According to enquiry data, calculate the 24h mortality ratio.Stipulate active grade scale: the A level: 90%≤24h mortality ratio＜100; B level: 75%≤24h mortality ratio＜90%; C level: 50%≤24h mortality ratio＜75%; D level: 25%≤24h mortality ratio＜50%; E level: 0%≤24h mortality ratio＜25%.
Test-results shows: in 11 compounds of the present invention culex is had significant insecticidal effect, A level activity has 7, is respectively compound 1, compound 2, compound 3, compound 4, compound 5, compound 6 and compound 11; The D level has 4, is respectively compound 7, compound 8, compound 9, compound 10.
Method B (to the housefly insecticidal effect):
Each the compound 1-11 that respectively embodiment is obtained is made into aerosol according to the method for embodiment 26.
Adopt the standard testing cylinder, aerosol is tested according to regulation among the GB13917.2-2009.To be placed in the cylinder unit for the examination insect; after waiting to try worm recovery normal activity; metered injection 1g medicament from insect aerosol; extract baffle plate behind the 1min out, make medicament contact timing immediately with the examination worm; write down the insect quantity of going down; behind the 20min, will be transferred in the dependent insect cage of cleaning, check dead borer population behind the 24h for the examination worm.
According to enquiry data, calculate the 24h mortality ratio.Stipulate active grade scale: the A level: 90%≤24h mortality ratio＜100; B level: 75%≤24h mortality ratio＜90%; C level: 50%≤24h mortality ratio＜75%; D level: 25%≤24h mortality ratio＜50%; E level: 0%≤24h mortality ratio＜25%.
Test-results shows: The compounds of this invention has significant insecticidal effect to housefly, particularly has A level activity in 11 compounds and has 4, is respectively compound 1, compound 5, compound 6, compound 11; 1 of B level is compound 3; 4 of C levels are respectively compound 2, compound 4, compound 7, compound 9; The D level has 2, is respectively compound 8, compound 10.
Embodiment
Embodiment 1
Synthesizing of this example explanation 5 FU 5 fluorouracil acetate
In four-hole boiling flask, add KOH1.12g(20mmol), H
2O15mL, dissolving back adds 5 FU 5 fluorouracil 2.6g(20mmol) and Mono Chloro Acetic Acid 1.82g(22mmol) the 10mL aqueous solution, 6h is continued to react in the back that finishes.After reaction finishes, regulate pH to 2, have a large amount of white solids to separate out, filter with concentrated hydrochloric acid, washing, the water recrystallization gets product 3.0g, and yield is 80%.Product fusing point: 289-291 ℃.
Embodiment 2
Synthesizing of this example explanation 5 FU 5 fluorouracil acid amides alcohol
In there-necked flask, add 5 FU 5 fluorouracil acetate 3.76g (20mmol),, stir 1h with the 50mLDMF dissolving.Slowly drip thanomin 1.6g (24mmol), back flow reaction 24h under the room temperature.Reaction adds water 100mL after finishing behind the concentrated solvent, have a large amount of solids to separate out, and filters, and ethyl alcohol recrystallization is used in washing, gets product 3.18g, yield 69%.Product fusing point: 253-256 ℃.
Embodiment 3
Methyl isophthalic acid-phenyl-1H-pyrazoles-5-carboxylic acid is synthetic for this example explanation 3-
In four-hole boiling flask, add phenylhydrazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), and room temperature reaction 2h filters, and ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-phenyl-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 2h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 2h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 58.2%, fusing point 192-194 ℃.
Embodiment 4
Synthetic (compound 1) of this example explanation 3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 24h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 68.4%, fusing point: 176-178 ℃.
1H?NMR：2.28(3H,s),3.36(2H,t),4.15(2H,t),4.29(2H,s),6.92(1H,s),7.42～7.49(5H,m),7.97(1H,d),8.30(1H,t),11.82(1H,s)
Embodiment 5
Synthesizing of this example explanation 3-methyl isophthalic acid-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 4-methoxyl group phenylhydrazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 2h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(4-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 3h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 4h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 60.2%, fusing point 164-168 ℃.
Embodiment 6
Synthetic (compound 2) of this example explanation 3-methyl isophthalic acid-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 24h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 71.1%.Fusing point: 202-203 ℃.
1H?NMR：2.26(3H,s),3.35(2H,t),3.81(3H,s),4.13(2H,t),4.29(2H,s),6.88(1H,s),6.98～7.34(4H,m),7.96～7.98(1H,d),8.30(1H,s),11.82(1H,s)
Embodiment 7
Synthesizing of this example explanation 3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 4-procarbazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 2h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(4-aminomethyl phenyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 2h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 3h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 59.4%, fusing point 203-206 ℃.
Embodiment 8
Synthetic (compound 3) of this example explanation 3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(4-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 20h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 65.9%.Fusing point: 198-201 ℃.
1H?NMR：2.27(3H,s),2.49～2.51(3H,m),3.35(2H,d),4.13～4.15(2H,t),4.28(2H,s),6.89(1H,s),7.25～7.30(4H,m),7.96(1H,d),8.29(1H,s),11.80(1H,d)
Embodiment 9
Synthesizing of this example explanation 3-methyl isophthalic acid-(4-nitrophenyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 4-nitrophenyl hydrazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 2h, filter, ethyl alcohol recrystallization gets product 5-hydroxy-3-methyl-1-(4-nitrophenyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 4h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(4-nitrophenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 2h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets yellow solid.Yield 58.4%, fusing point 231-233 ℃.
Embodiment 10
Synthetic (compound 4) of this example explanation 3-methyl isophthalic acid-(4-nitrophenyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(4-nitrophenyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 26h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 62.1%.Fusing point: 289-292 ℃.
1H?NMR：2.27(3H,s),3.35(2H,d),4.15(2H,s),4.28(2H,s),6.92(1H,s),7.93(1H,d),8.05～8.40(4H,m)8.30(1H,s),11.81(1H,s)
Embodiment 11
Synthesizing of this example explanation 3-methyl isophthalic acid-(3-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 3-procarbazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 3h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(3-aminomethyl phenyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 2h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 3h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 56.3%, fusing point 158-160 ℃.
Embodiment 12
Synthetic (compound 5) of this example explanation 3-methyl isophthalic acid-(3-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(3-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 18h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 64.2%.Fusing point: 184-187 ℃.
1H?NMR：2.26(3H,s),2.35(3H,s),3.34(2H,d),4.16～4.18(2H,t),4.28(2H,s),6.90(1H,s),7.18～7.24(3H,t),7.33(1H,t),7.9(1H,d)，8.30(1H,s),11.81(1H,s)
Embodiment 13
Synthesizing of this example explanation 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 2-procarbazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 2h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(2-aminomethyl phenyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 3h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product III and 20ml50%NaOH, reflux 2h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 63.5%, fusing point 164-166 ℃.
Embodiment 14
Synthetic (compound 6) of this example explanation 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 24h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 75.3%.Fusing point: 187-189 ℃.
1H?NMR：1.96(3H,s),2.08(3H,s),3.43～3.44(2H,m),4.23～4.25(2H,t),4.29(2H,s),6.78(1H,s),7.31～7.49(4H,m),7.99(1H,d),8.39(1H,t),11.80(1H,s)
Embodiment 15
Synthesizing of this example explanation 3-methyl isophthalic acid-(3, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 3,5-dimethyl hydrazinobenzene 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), and room temperature reaction 4h filters, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(3, the 5-3,5-dimethylphenyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 2h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(3, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 3h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 54.3%, fusing point 162-164 ℃.
Embodiment 16
Synthetic (compound 7) of this example explanation 3-methyl isophthalic acid-(3, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(3, the 5-3,5-dimethylphenyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 18h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 65.9%.Fusing point: 223-226 ℃.
1H?NMR：2.26(3H,s),2.35(3H,s),3.43～3.45(2H,t),4.23～4.26(2H,t),4.28(2H,d)6.82(1H,d),7.08(3H,m)，8.10(1H,s),8.30(1H,t),11.80(1H,s)。
Embodiment 17
Synthesizing of this example explanation 3-methyl isophthalic acid-(4-Trifluoromethoxyphen-l)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 4-trifluoromethoxy phenylhydrazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 2h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(4-Trifluoromethoxyphen-l)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 3h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(4-Trifluoromethoxyphen-l)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 2h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 65.2%, fusing point 169-173 ℃.
Embodiment 18
Synthetic (compound 8) of this example explanation 3-methyl isophthalic acid-(4-Trifluoromethoxyphen-l)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(4-Trifluoromethoxyphen-l)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 20h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 71.5%.Fusing point: 172-175 ℃.
1H?NMR：2.32(3H,s),3.41～3.45(2H,t),4.24～4.29(4H,m),6.80(1H,s),7.56～7.59(2H,d),7.72～7.75(2H,m)，7.99(1H,d),8.39(1H,t),11.81(1H,s)。
Embodiment 19
Synthesizing of this example explanation 3-methyl isophthalic acid-(4-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 4-trifluoromethyl phenyl hydrazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 3h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(4-trifluoromethyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 2h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(4-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 3h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 60.2%, fusing point 145-148 ℃.
Embodiment 20
Synthetic (compound 9) of this example explanation 3-methyl isophthalic acid-(4-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(4-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 16h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 58.1%.Fusing point 205-207 ℃.
1H?NMR：2.39(3H,s),3.43～3.45(2H,m),4.26～4.29(4H,m),6.83(1H,s),7.35～7.38(1H,d),7.39～7.43(1H,d)，7.45～7.50(1H,t),7.59～7.63(1H,m),7.98～8.00(1H,d),8.39(1H,s),11.85(1H,s)
Embodiment 21
Synthesizing of this example explanation 3-methyl isophthalic acid-(3-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 3-trifluoromethyl phenyl hydrazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 3h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(3-trifluoromethyl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 5h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(3-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 4h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 56.9%, fusing point 183-187 ℃.
Embodiment 22
Synthetic (compound 10) of this example explanation 3-methyl isophthalic acid-(3-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(3-trifluoromethyl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 28h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 73.5%, fusing point: 226-228 ℃.
1H?NMR：2.36(3H,s),3.41～3.45(2H,t),4.25～3.31(2H,m),4.33～4.36(2H,m),6.82(1H,s),7.80～7.83(1H,t),7.87～7.95(3H,m)，8.00～8.03(1H,d),8.42～8.49(1H,t),10.29(1H,s)
Embodiment 23
Synthesizing of this example explanation 3-methyl isophthalic acid-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid
In four-hole boiling flask, add 3-chloro-2-pyridine hydrazine 10mmol, ethanol 15ml, the dissolving back adds ethyl acetopyruvate 1.58g (10mmol), room temperature reaction 3h, filter, ethyl alcohol recrystallization gets 5-hydroxy-3-methyl-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and concentrated hydrochloric acid 8ml, reflux 3h.Reaction is spin-dried for solvent after finishing, and gets 3-methyl isophthalic acid-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid, ethyl ester.
In four-hole boiling flask, add above-mentioned product and 20ml50%NaOH, reflux 3h.Reaction finishes postcooling to room temperature, and concentrated hydrochloric acid transfers pH to 2-3, use ethyl acetate extraction, gets organic phase, drying, revolves steaming, recrystallization, gets white solid.Yield 55.3%, fusing point 171-174 ℃.
Embodiment 24
Synthetic (compound 11) of this example explanation 3-methyl isophthalic acid-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid-2-(2-(5 FU 5 fluorouracil-1-yl) ethanoyl) ethyl ester
In the single port flask, add 3-methyl isophthalic acid-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid 5mmol,, add Fluracil acid amides alcohol 5mmol, treat to dissolve fully back backflow stirring reaction 16h with the DMF dissolving.Reaction is spin-dried for solvent after finishing, and the ethyl acetate column chromatography gets white solid.Yield 70.2%.Fusing point: 158～160 ℃.
1H?NMR：2.31（3H，s），3.29（2H，d），4.10-4.13（2H，t），4.28-4.30（2H，t），6.81（1H，s），7.98（1H，d），7.63-8.54（3H，m），8.30（1H，m），11.81（1H，s）
Embodiment 25 10% emulsifiable concentratess:
With 80 parts of N, dinethylformamide and 10 parts of dodecyl phenol polyethenoxy ethers join in 10 parts of right 1 described each compounds of the present invention, make emulsifiable concentrates.During actual the use, add water and dilute 250～25000 times successively and promptly get each soup.
Embodiment 26 0.1% insect aerosols
Be warming up to 40 ℃, take by weighing right 1 described each compound 0.1 weight part of the present invention, and D80 solvent oil 39.9 weight parts, two materials are mixed with the preparation pesticide preparation.The gained preparation is put into the aerosol jar, inject third butane, 60.0 weight parts adding to depress, to obtain insect aerosol by valve.
Embodiment 27 20% wettable powder:
With 55 parts of kaolin, 20 parts of diatomite, 2 parts of calcium lignin sulphonates and 3 parts of Sodium dodecylbenzene sulfonatees join in 20 parts of right 1 described each compounds of the present invention, are mixed with wettable powder.During actual the use, this wettable powder is added water, dilute 500～50000 times successively and promptly get each soup.
Claims (10)
1. the compound of a general structure (I) or its pharmacy acceptable salt,
Wherein,
R is
Heteroaryl or substituted heteroaryl,
R
1, R
2And R
3Be hydrogen, nitro, C independently of one another
1～6Alkoxyl group, C
1～6Alkyl or C
1～6Substituted alkyl;
Described substituted heteroaryl or C
1～6Substituting group in the substituted alkyl is selected from halogen, nitro, C
1～6Alkoxyl group or C
1～6In the alkyl one or more.
2. compound according to claim 1 or its pharmacy acceptable salt, wherein
R is
Pyridine or chloro-pyridine.
3. compound according to claim 1 or its pharmacy acceptable salt, wherein
R
1, R
2And R
3Be hydrogen, nitro, C independently of one another
1～4Alkoxyl group, C
1～4Alkyl or C
1～4Haloalkyl.
4. compound according to claim 3 or its pharmacy acceptable salt, wherein
R
1, R
2And R
3Be hydrogen, nitro, methoxyl group, methyl or trifluoromethyl independently of one another.
5. according to each described compound or its pharmacy acceptable salt in the claim 1～4, wherein compound is selected from
6. the preparation method of the described compound of claim 1, its reaction process is as follows:
Wherein, R is
Heteroaryl or substituted heteroaryl, R
1, R
2And R
3Be hydrogen, nitro, C independently of one another
1～6Alkoxyl group, C
1～6Alkyl or C
1～6Substituted alkyl; Described substituted heteroaryl or C
1～6Substituting group in the substituted alkyl is selected from halogen, nitro, C
1～6Alkoxyl group or C
1～6In the alkyl one or more.
7. preparation method according to claim 6, wherein
Adopt water, alcohols or acids protic solvent among the reaction A; Temperature of reaction is 0 ℃～150 ℃;
Adopt non-proton dipole solvents such as ketone, dimethyl formamide among the reaction B; Temperature of reaction is 0 ℃～120 ℃;
Adopt water or alcohols protic solvent among the reaction C; Temperature of reaction is-20 ℃～40 ℃;
Adopt water or alcohols protic solvent among the reaction D; Temperature of reaction is 20 ℃～120 ℃;
Adopt water or alcohols protic solvent among the reaction E; Temperature of reaction is 20 ℃～120 ℃;
Adopt non-proton dipole solvents such as ketone, dimethyl formamide among the reaction F; Temperature of reaction is 0 ℃～120 ℃.
8. preparation method according to claim 7, wherein
The solvent that reaction A adopts is water or ethanol, and temperature of reaction is 75 ℃～90 ℃;
The solvent that reaction B adopts is a dimethyl formamide, and temperature of reaction is 15 ℃～30 ℃;
The solvent that reaction C adopts is water or ethanol; Temperature of reaction is-10 ℃～15 ℃;
The solvent that reaction D adopts is water or ethanol; Temperature of reaction is 85 ℃～100 ℃;
The solvent that reaction E adopts is water or ethanol; Temperature of reaction is 85 ℃～100 ℃;
Reaction F adopts dimethyl formamide to make solvent, 15 ℃～30 ℃ of temperature of reaction.
9. each described compound or its pharmacy acceptable salt application in the preparation sterilant in the claim 1～4.
10. insect-killing composition, it is an activeconstituents with each described compound or its pharmacy acceptable salt in the claim 1～4, is aided with acceptable accessories and forms.
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|---|---|---|---|---|
| CN101723943A (en) * | 2009-11-24 | 2010-06-09 | 南京工业大学 | 1,3,4-thiadiazole fluorouracil compound as well as preparation method and application thereof |
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| RONG WAN, ET AL: "SYNTHESIS AND INSECTICIDAL ACTIVITIES OF NOVEL 1,3,4-THIADIAZOLE 5-FLUOROURACIL ACETAMIDES DERIVATIVES:AN RNA INTERFERENCE INSECTICIDE", 《NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS》 * |
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| CN104672208A (en) * | 2013-11-27 | 2015-06-03 | 中国科学院大连化学物理研究所 | Synthesis method of (3,5-bistrifluoromethylpyrazolyl)pyridine derivatives |
| CN104672208B (en) * | 2013-11-27 | 2017-01-04 | 中国科学院大连化学物理研究所 | A kind of synthetic method of (3,5-bis trifluoromethyl pyrazolyl) pyridine derivate |
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