CN106188011B - The ultrasound synthesis and application of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton - Google Patents
The ultrasound synthesis and application of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton Download PDFInfo
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Abstract
The invention belongs to technical field of organic synthesis, disclose a kind of application of the ultrasonic synthetic method and the analog derivative of the quaternary ring-type beta-lactam derivative based on arylpyrazole skeleton.By introducing quaternary ring-type beta-lactam structure in a series of arylpyrazole skeleton of ethiprole into fipronil schiff base compounds, realize the combination of arylpyrazoles compound and beta-lactam class compound, ultrasonic irradiation is used in the synthesis process, using acyl chlorides as ketenes precursor, the high ketenes of in-situ preparation activity under alkali effect, this ketenes is directly used in the reaction of next step and fipronil imines without isolation, one-pot synthesis goes out a series of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, reducing influences caused by intermediate steps, improve yield.The quaternary ring-type beta-lactam derivative based on arylpyrazole skeleton of the present invention has good application prospect in insecticide and antibacterials, with obvious effects to be better than existing compound.
Description
Technical field
The present invention relates to technical field of organic synthesis more particularly to a kind of quaternary ring-type β based on arylpyrazole skeleton-interior
The ultrasonic synthetic method of amide derivatives further relates to the application of such compound.
Background technology
Arylpyrazoles compound occupies critical positions in current Agrochemicals, and ethiprole (fipronil) is for disease
The great representative arylpyrazoles pesticide of pest control, it can act on GABA receptors and then block chloride channel,
Research in recent years shows that glutamic acid gates the potential insect specificity target spot that chloride channel (GluCls) is also ethiprole.
But honeybee and very big, unfriendly to the environment medicine that constrains of aquatic toxicity is widely used in ethiprole, in order to develop
There is the highly selective novel fipronil insecticide of high-efficiency low-toxicity to target spot biology, structure of modification is carried out to ethiprole in recent years
Research topic by the extensive concern of domestic and foreign scholars, various fipronil derivatives are synthesized.
Beta-lactam compound refers to a kind of compound of the beta-lactam ring-type structure containing quaternary in molecule, this kind of
Compound can not only be used for organic synthesis intermediate, while be also a kind of important bioactive substance, such as penicillin, cephalosporin
It is used etc. antibiotics is clinically used as, research shows that beta-lactam nucleus, which is beta-lactam antibiotic, keeps biology
The crucial essential group of activity, the bactericidal effect mechanism of beta-lactam antibiotic is considered as that beta-lactam antibiotic can
Inhibit bacteria the synthesis of cell wall：Its chemical constitution and the end of substrate specificity D- alanyls-D-alanine of mucopeptide transpeptidase
There is similar space structure, so as to the competitively covalent bond of the enzyme active center with transpeptidase, generate irreversible inhibition
It acts on and inactivates mucopeptide transpeptidase, prevent the transpeptidation reaction that it is catalyzed from carrying out, so as to hinder the normal occlusion of bacteria cell wall
Into and lead to bacterial death.
The twenties in last century, it is chemical anti-that American scientist Richard and Loomis have found that ultrasonic wave can accelerate first
Should, but fail the attention for causing chemists for a long time, until the universal of the mid-80 large power supersonic equipment and develop,
Application of the ultrasonic wave in chemical industry rapidly develops, and produce new cross discipline --- phonochemistry.In recent years, both at home and abroad
Related acoustochemical research and academic exchange Showed Very Brisk, with acoustochemical development, ultrasonic wave has been widely used in oxygen
Change reaction, reduction reaction, addition reaction, substitution reaction, condensation reaction, hydrolysis etc., be almost related to each of organic chemistry
Field.
Based on considerations above, it is a series of that structural modification synthesis is carried out to 5 bit aminos of ethiprole by active structure splicing
Fipronil schiff base compound, and then quaternary ring-type beta-lactam structure is introduced in the arylpyrazole skeleton of ethiprole, it closes
Into a series of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, being cut out by active structure realizes aryl
The combination of pyrazole compound and beta-lactam compound, the quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton
In lactam structure there is substrate similar effect, pyrazole ring and quaternary beta-lactam nucleus have pi-pi accumulation effect, these have
The synergistic effect of the structure of bioactivity causes the quaternary ring-type beta-lactam based on arylpyrazole skeleton synthesized by the present invention
Derivative has excellent insecticidal effect and antibacterial preventive effect；In synthetic method, the main of quaternary beta-lactam nucleus is synthesized at present
Method is that staudinger reactions occur by ketenes and imines to synthesize, but since the chemical property of ketenes is very active,
Especially mono-substituted ketenes, difficulty is larger in preparation, and which limits the application range of this method, the present invention is made with acyl chlorides
For ketenes precursor, the high ketenes of in-situ preparation reactivity, this ketenes are directly used in without distillation separation in the presence of alkali
In next step and the reaction of fipronil imines, a series of quaternary ring-type beta-lactams based on arylpyrazole skeleton of one-pot synthesis
Derivative, reducing influences caused by intermediate steps, increases to total yield, is in addition applied to ultrasonic irradiation
In the synthesis of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, the cavitation of ultrasonic wave causes the spies such as C-X
The chemical bond for determining vibration frequency is more easily broken off, so that reaction yield further improves.
Invention content
The present invention is designed by active structure splicing principle and provides the compound of a kind of structure novel --- based on virtue
The quaternary ring-type beta-lactam derivatives of base pyrazol framework carry out structural modification by 5 bit aminos to ethiprole and synthesize a system
Row fipronil schiff base compound, and then quaternary ring-type beta-lactam structure is introduced in the arylpyrazole skeleton of ethiprole,
So as to fulfill the combination of arylpyrazoles compound and beta-lactam compound, in the synthesis process by ultrasonic irradiation
It is applied in the synthesis of the quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, using acyl chlorides as ketenes precursor,
The high ketenes of in-situ preparation reactivity under the action of alkali, this ketenes are directly used in next step and ethiprole without distillation separation
A series of reaction of class imines, quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton of one-pot synthesis, reduces
It is influenced caused by intermediate steps, to improve yield.
Based on considerations above, of the invention three goals of the invention are：
First purpose：A kind of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, structural formula are provided
As shown in general formula (A)：
In the general structure (A)：R1X is one of following three kinds of situations：
(1)H；
(2) halogen；
(3)R1X in X is SO or S, R1For-CN, C1~C4Alkyl or C1~C4Halogenated alkyl；Shown in specific as follows：
R2For substituted or unsubstituted phenyl, naphthalene, anthryl, phenanthryl, furyl, pyrrole radicals, thienyl, pyridyl group, quinoline
Quinoline base, indyl, it can be phenyl ring ortho position, meta position, contraposition that the substitution, which can be monosubstituted or polysubstituted, substituted position,
Substituted group includes alkyl, alkoxy, hydroxyl, halogen, nitro.
R3、R4It is each independently selected from H, halogen, phenyl, C1~C4Alkyl, cycloalkyl, C1~C4Halogenated alkyl, phenyl
Substituted C1~C4Alkyl, R3And R4It can be identical or differs；
Preferably, the R1Any one of X in following group：H、—SOCF3And-SOC2H5；
Preferably, the R2For compound R2Group R in-CHO2, the compound R2- CHO is in following compound
Any one：R2- CHO is benzaldehyde, 4-methoxybenzaldehyde, 2,3 dichloro benzaldehyde, the fluoro- 4- bromobenzaldehydes of 2-, 2,5-
The bromo- 4- hydroxy benzaldehydes of difluorobenzaldehyde, 2,6- dimethylbenzaldehydes, 3-, 4- fluorobenzaldehydes, 4- chlorobenzaldehydes, 3,5- bis- (three
Methyl fluoride) benzaldehyde；2,4,6- trifluro benzaldehydes, 1- methoxy-2-naphthaldehydes, 1- naphthaldehydes, 2- hydroxyl-1-naphthalene Formaldehydes；9-
Anthraldehyde；9- formaldehydes；2 furan carboxyaldehyde, 5- methyl -2 furan carboxyaldehyde；2- pyrrole aldehydes, 3- pyrrole aldehydes；2- thiophene first
Aldehyde；The bromo- 3- pyridine carboxaldehydes of 2- pyridine carboxaldehydes, 2-, bis- chloro- 3- pyridine carboxaldehydes of 2,6-；3- quinoline aldehydes and 3- indolecarboxaldehydes；
Best, the compound R2Any one of-CHO in following compound：Benzaldehyde, cinnamic acid, 4- fluorine
Benzaldehyde, 4-methoxybenzaldehyde and 4- hydroxy benzaldehydes；
Preferably, R3、R4It is each independently selected from any one in following group：-H、CH3-、Cl、 And
Substituted or unsubstituted phenyl；
Best, R3、R4It is each independently selected from any one in following group：-H、CH3-、And benzene
Base；
Second purpose：It is relatively low based on aryl pyrrole to provide a kind of efficient preparation, energy conservation and environmental protection, production cost of being easy to
The synthetic method of the quaternary ring-type beta-lactam derivatives (A) of azoles skeleton.
A kind of synthetic method of structural formula compound as shown in general formula (A)：Structure is carried out by 5 bit aminos to ethiprole
Modification synthesizes a series of fipronil schiff base compounds (prior art), and then under nitrogen protection by fipronil schiff basesAcyl chloridesIt is reacted under conditions of Ultrasonic Radiation with alkali solubilizer and general formula is prepared
(A) compound shown in.
More specifically, structural formula synthetic method of compound as shown in general formula (A) is：It will be under nitrogen protection to anti-
Answer addition fipronil schiff bases in containerThen it is anti-to be placed in ultrasonic wave by alkali and solvent for reaction vessel
It answers in device sink, acyl chlorides is added dropwise into reaction vessel under ultrasound conditionSolution after being diluted with solvent, half is small
When drip off, then proceed to ultrasonic reaction 3 hours, after isolating and purifying product.
Reaction unit is quickly weighed certain as shown in figure 4, wherein ultrasound reactor can adjust frequency, ultrasonic time
It measures the fipronil schiff bases that were dried in vacuo and is transferred in round-bottomed flask that (this round-bottomed flask is cleaned, dried and in advance in 105
Preserved in DEG C oven drying 2h postposition driers to room temperature), bottle mouth position connection constant pressure funnel among round-bottomed flask, side bottle
Mouth and constant pressure funnel upper end are clogged with turned welt rubber stopper, are replaced as reaction system by syringe needle and biexhaust pipe
Then nitrogen atmosphere is inserted into the nitrogen ball for being connected with plastic injector on turned welt rubber stopper, will be dissolved in without water-soluble by syringe
Anhydrous alkali in agent is added in reaction system, and finally acyl chlorides is diluted in solvent and is slowly dropped to reaction system, separation
Purifying uses silica gel column chromatography, and synthetic route is as follows：
The synthesis of the fipronil schiff bases is shown in：Chen Lianqing；Zhou Quan；The .1- such as Wan Zilu (bis- chloro- 4- fluoroforms of 2,6-
Base) phenyl -3- cyano -5- methylenes amino-pyrazol type compound and its micro-wave digestion synthetic method with using .201610015077.5,
Publication number：CN105503731A.
R1、R2、R3、R4As previously described；The alkali is selected from triethylamine, tri-n-butylamine, pyridine, DMAC N,N' dimethyl acetamide, triphen
Any one in base phosphine, potassium carbonate and sodium hydride；
It is sub- that the solvent is selected from benzene,toluene,xylene, chlorobenzene, nitrobenzene, ether, dichloromethane, chloroform, diformazan
Any one in sulfone, tetrahydrofuran, ethylene glycol diethyl ether and n-cyclohexyl-2-pyrrolidone；
Preferably, the alkali is triethylamine, pyridine or tri-n-butylamine.
Preferably, the organic solvent is appointing in benzene, toluene, ether, dichloromethane, chloroform and tetrahydrofuran
Meaning is a kind of, most preferably benzene；
Preferably, the Ultrasonic Radiation power is 100~150W, and the reaction time is 2~4h.
Preferably, the molar ratio of the fipronil schiff bases, acyl chlorides and alkali is 1：2.2：2.5.
Third purpose：A kind of above-mentioned quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton are provided in desinsection
Application in agent and antibacterials.
Third purpose to realize the present invention, the four-membered ring based on arylpyrazole skeleton that the present invention will be prepared
Shape beta-lactam derivatives are respectively used to prevention Orthoptera, Thysanoptera, Homoptera, Heteroptera, Lepidoptera, coleoptera, Hymenoptera
With Diptera class pest and anti-Staphylococcus aureus, escherichia coli and proteus vulgaris experiment, achieve good
Insecticidal effect and antibacterial effect.
Compared with prior art, the advantages of the present invention are as follows：
The present invention carries out structural modification in 5 bit aminos to ethiprole and synthesizes a series of fipronil schiff base compounds
On the basis of, and then quaternary ring-type beta-lactam structure is introduced in the arylpyrazole skeleton of ethiprole, synthesize a series of be based on
The quaternary ring-type beta-lactam derivatives of arylpyrazole skeleton, realize arylpyrazoles compound and beta-lactam compound
Combination, provide the compound of a kind of structure novel；
In synthetic method, the main method for synthesizing quaternary beta-lactam nucleus at present is occurred by ketenes and imines
Staudinger reacts to synthesize, but since the chemical property of ketenes is very active, prepared by especially mono-substituted ketenes
Upper difficulty is larger, and which limits the application range of this method, the present invention gives birth in the presence of alkali using acyl chlorides as ketenes precursor
Into the high ketenes of reactivity (I), this ketenes is directly used in the reaction of next step and fipronil imines without distillation separation,
A series of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton of one-pot synthesis, reduce intermediate steps and are brought
Influence, increase to total yield, in addition the present invention ultrasonic irradiation is applied to based on arylpyrazole skeleton four
In the synthesis of first ring-type beta-lactam derivatives, there is further raising to reaction yield.
Lactam structure in quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton has substrate is similar to make
With pyrazole ring and quaternary beta-lactam nucleus have pi-pi accumulation effect, and the synergistic effect of these biologically active structures causes
The quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton synthesized by the present invention have excellent bioactivity, especially
It is to show greater activity in desinsection and antibiosis, therefore with very big development and application values.
Description of the drawings
Fig. 1 is compound A2Total ion current figure (TIC figures)；
Fig. 2 is compound A2Extraction ion flow graph (EIC figures)；
Fig. 3 is compound A2Mass spectrogram；
Fig. 4 is reaction unit figure.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail, but these specific embodiments are not with any
Mode limits the scope of the invention.
Raw material used in following embodiment is known compound, is commercially available or can be with this field
The method synthesis known.
The synthesis of fipronil schiff bases is shown in：Chen Lianqing；Zhou Quan；The .1- such as Wan Zilu (2,6- dichlor-4-trifluoromethyls) benzene
Base -3- cyano -5- methylenes amino-pyrazol type compound and its micro-wave digestion synthetic method are open with applying .201610015077.5
Number：CN105503731A.
The synthetic method of fipronil schiff bases is shown in more than patent application publication text in embodiment 1,3,5,7,9 and 10
0041-0043 sections；
The synthetic method reference more than patent application publication text 0051-0053 of fipronil schiff bases in embodiment 2
The synthetic method of section；
The synthetic method of fipronil schiff bases is similar to the synthesis of fipronil schiff bases in embodiment 1 in embodiment 4
Method can refer to it, wherein reactant benzaldehyde will change and make cinnamic acid, other conditions such as solvent, temperature, feeds intake and rubs at catalyst
You are more constant than with isolation and purification method, you can obtains 1- (2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyls Asia
Sulfonyl -5- (3- phenyl allyls) imino group -1H- pyrazoles；
The synthetic method of fipronil schiff bases is shown in 0053-0055 sections of more than patent application publication text in embodiment 6；
The synthetic method of fipronil schiff bases is shown in more than patent application publication text 0047-0049 in embodiment 8
Section.
Embodiment 1, compound A1Synthesis
Dry reaction glass apparatus and magneton are taken out from baking oven, nitrogen protection is lower to add in 0.525g (1mmol) 1-
(2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl base -5- phenyl methylidene amino -1H- pyrazoles, and
0.253g (2.5mmol, about 0.25mL) anhydrous triethylamines are drawn with syringe and 4mL anhydrous benzenes are added in reaction bulb, by single port
Bottle, which is put into KQ3200E types (power 150W) ultrasonic sink, to react, then the 4mL benzene of 0.34g (2.2mmol) phenyllacetyl chloride is molten
Liquid is slowly dropped in reaction system, and about half an hour drips off, and continues ultrasonic reaction 3h after dripping off, and after reaction, is filtered and is removed
Triethylamine hydrochloride adds in 20mL ethyl acetate after being spin-dried for filtrate, is washed twice with 15mL saturated aqueous sodium carbonates, then use 15mL
Saturated sodium-chloride water solution is washed once, collected organic layer, is added in anhydrous magnesium sulfate and is dried overnight, and next day, which filters, removes anhydrous slufuric acid
Magnesium adds in 2g silica whites into filtrate and is spin-dried for into powdered, silica gel column chromatography separation (dry method loading, VEthyl acetate：Petroleum ether=1:20)
Obtain yellow oily compound A1, yield：86.3%.1H-NMR(400MHz,DMSO-d6)7.4-7.65(m,5H,Ar-H),7.22-
7.25(m,4H,Ar-H),7.15(d,1H,Ar-H),6.99(m,1H,Ar-H),6.94(m,1H,Ar-H),3.80(s,1H,
COCH)；3.62(s,1H,NCH)；IRν(cm-1):3083,2258(νC≡N),1724(νC=O),1575,1497,1312(νC-F),
761,685.
Embodiment 2, compound A2Synthesis
Dry reaction glass apparatus and magneton are being taken out from baking oven, nitrogen protection is lower to add in 0.541g (1mmol)
Compound 1- (2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl bases -5- (4- hydroxy phenyls) methylene
Amino -1H- pyrazoles, and draw 0.253g (2.5mmol, about 0.25mL) anhydrous triethylamines and the addition of 4mL anhydrous benzenes with syringe
In reaction bulb, single port bottle is put into KQ3200E types (power 150W) ultrasonic sink and is reacted, then by 0.34g (2.2mmol) benzene
The 4mL benzole solns of chloroacetic chloride are slowly dropped in reaction system, and about half an hour drips off, and continue ultrasonic reaction 3h, reaction after dripping off
After, it filters and removes triethylamine hydrochloride, 20mL ethyl acetate is added in after being spin-dried for filtrate, with 15mL saturated aqueous sodium carbonates
It washes twice, then is washed once with 15mL saturated sodium-chloride water solutions, collected organic layer, add in anhydrous magnesium sulfate and be dried overnight, next day
It filters and removes anhydrous magnesium sulfate, into filtrate, addition 2g silica whites are spin-dried for into powdered, silica gel column chromatography separation (dry method loading,
VEthyl acetate:Petroleum ether=1:20) faint yellow solid A is obtained2, yield：76%.1H-NMR(400MHz,DMSO-d6)10.02(s,1H,OH),
7.13-7.48(m,10H,Ar-H),6.61(d,1H,Ar-H),3.75(s,1H,COCH),3.21(s,1H,NCH).IRν(cm-1):3084,2252(νC≡N),1744(νC=O),1571,1498,1322(νC-F),762,681.
Embodiment 3, compound A3Synthesis
Dry reaction glass apparatus and magneton are taken out from baking oven, nitrogen protection is lower to add in 0.525g (1mmol) 1-
(2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl base -5- phenyl methylidene amino -1H- pyrazoles, and
0.253g (2.5mmol, about 0.25mL) anhydrous triethylamines are drawn with syringe and 4mL anhydrous benzenes are added in reaction bulb, by single port
Bottle, which is put into KQ3200E types (power 150W) ultrasonic sink, to react, then the 4mL by 0.4g (2.2mmol) 2- phenylbutyryl chlorides
Benzole soln is slowly dropped in reaction system, and about half an hour drips off, and continues ultrasonic reaction 3h after dripping off, and after reaction, is filtered
Triethylamine hydrochloride is removed, 20mL ethyl acetate is added in after being spin-dried for filtrate, is washed twice with 15mL saturated aqueous sodium carbonates, then use
15mL saturated sodium-chloride water solutions are washed once, collected organic layer, are added in anhydrous magnesium sulfate and are dried overnight, it is anhydrous that next day filters removing
Magnesium sulfate adds in 2g silica whites into filtrate and is spin-dried for into powdered, silica gel column chromatography separation (dry method loading, VEthyl acetate：Petroleum ether=1:
20) yellow oily compound A is obtained3, yield：91%.1H-NMR(400MHz,DMSO-d6)7.51-6.88(m,12H,Ar-H),
3.61(t,1H,NCH),1.95(q,2H,CH3CH2),1.05(t,3H,CH2CH3).IRν(cm-1):3091,2254(νC≡N),
1727(νC=O),1574,1496,1312(νC-F),762,683.
Embodiment 4, compound A4Synthesis
Dry reaction glass apparatus and magneton are taken out from baking oven, nitrogen protection is lower to add in 0.551g (1mmol) changes
Close object 1- (2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl bases -5- (3- phenyl allyls) imido
Base -1H- pyrazoles, and draw 0.253g (2.5mmol, about 0.25mL) anhydrous triethylamines and the addition of 4mL anhydrous benzenes instead with syringe
It answers in bottle, single port bottle is put into KQ3200E types (power 150W) ultrasonic sink and is reacted, then by 0.34g (2.2mmol) benzene second
The 4mL benzole solns of acyl chlorides are slowly dropped in reaction system, and about half an hour drips off, and continue ultrasonic reaction 3h, reaction knot after dripping off
Shu Hou is filtered and is removed triethylamine hydrochloride, is added in 20mL ethyl acetate after being spin-dried for filtrate, is washed with 15mL saturated aqueous sodium carbonates
Twice, then with 15mL saturated sodium-chloride water solutions it washes once, collected organic layer, adds in anhydrous magnesium sulfate and be dried overnight, next day takes out
Anhydrous magnesium sulfate is filtered out, into filtrate, addition 2g silica whites are spin-dried for into powdered, silica gel column chromatography separation (dry method loading,
VEthyl acetate:Petroleum ether=1:25) yellowish-brown oily compound A is obtained4, yield：82%.1H-NMR(400MHz,(CD3)2CO)7.18-7.50
(m, 13H, Ar-H and C=C-H), 6.71 (m, 1H, Ar-H), 3.79 (s, 1H, COCH), 3.21 (s, 1H, NCH) .IR ν
(cm-1):3083,2259(νC≡N),1734(νC=O),1575,1496,1311(νC-F), 765,686.HPLC-MS is shown in Fig. 1,2 and
3。
Embodiment 5, compound A5Synthesis
Dry reaction glass apparatus and magneton are taken out from baking oven, nitrogen protection is lower to add in 0.525g (1mmol) 1-
(2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl base -5- phenyl methylidene amino -1H- pyrazoles, and
0.198g (2.5mmol, about 0.2mL) anhydrous pyridines are drawn with syringe and 4mL anhydrous benzenes are added in reaction bulb, and single port bottle is put
Enter and reacted in KQ3200E types (power 150W) ultrasonic sink, then the 4mL benzole solns of 0.204g (2.2mmol) propionyl chloride are delayed
Slowly it is added drop-wise in reaction system, about half an hour drips off, and continues ultrasonic reaction 3h after dripping off, and after reaction, filters and removes pyridine
Hydrochloride is spin-dried for adding in 20mL ethyl acetate after filtrate, be washed twice with 15mL saturated aqueous sodium carbonates, then with 15mL saturation chlorine
To change sodium water solution to wash once, collected organic layer, add in anhydrous magnesium sulfate and be dried overnight, next day, which filters, removes anhydrous magnesium sulfate, to
2g silica whites are added in filtrate and are spin-dried for into powdered, silica gel column chromatography separation (dry method loading, VEthyl acetate：Petroleum ether=1:20) yellow is obtained
Oily compound A5, yield：85%.1H-NMR(400MHz,DMSO-d6)7.33-6.97(m,7H,Ar-H),3.76(s,1H,
COCH)；3.60(s,1H,NCH),1.23(d,3H,CHCH3).IRν(cm-1):3087,2258(νC≡N),1725(νC=O),
1575,1497,1312(νC-F),763,687.
Embodiment 6, compound A6Synthesis
Dry reaction glass apparatus and magneton are being taken out from baking oven, nitrogen protection is lower to add in 0.525g (1mmol)
Compound 1- (2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl bases -5- (4- fluorophenyls) methylene ammonia
Base -1H- pyrazoles, and draw 0.253g (2.5mmol, about 0.25mL) anhydrous triethylamines and the addition of 4mL anhydrous benzenes instead with syringe
It answers in bottle, single port bottle is put into KQ3200E types (power 150W) ultrasonic sink and is reacted, then by 0.34g (2.2mmol) benzene second
The 4mL benzole solns of acyl chlorides are slowly dropped in reaction system, and about half an hour drips off, and continue ultrasonic reaction 3h, reaction knot after dripping off
Shu Hou is filtered and is removed triethylamine hydrochloride, is added in 20mL ethyl acetate after being spin-dried for filtrate, is washed with 15mL saturated aqueous sodium carbonates
Twice, then with 15mL saturated sodium-chloride water solutions it washes once, collected organic layer, adds in anhydrous magnesium sulfate and be dried overnight, next day takes out
Anhydrous magnesium sulfate is filtered out, into filtrate, addition 2g silica whites are spin-dried for into powdered, silica gel column chromatography separation (dry method loading,
VEthyl acetate:Petroleum ether=1:20) faint yellow solid A is obtained6, yield：85%.1H-NMR(400MHz,DMSO-d6)7.13-7.48(m,
10H,Ar-H),6.61(d,1H,Ar-H),3.75(s,1H,COCH),3.21(s,1H,NCH).IRν(cm-1):3084,2253
(νC≡N),1754(νC=O),1575,1498,1312(νC-F),762,685.
Embodiment 7, compound A7Synthesis
Dry reaction glass apparatus and magneton are taken out from baking oven, nitrogen protection is lower to add in 0.525g (1mmol) 1-
(2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl base -5- phenyl methylidene amino -1H- pyrazoles, and
0.198g (2.5mmol, about 0.2mL) anhydrous pyridines are drawn with syringe and 4mL anhydrous benzenes are added in reaction bulb, and single port bottle is put
Enter and reacted in KQ3200E types (power 150W) ultrasonic sink, then the 4mL benzole solns by 0.233g (2.2mmol) isobutyryl chloride
It is slowly dropped in reaction system, about half an hour drips off, and continues ultrasonic reaction 3h after dripping off, and after reaction, filters and removes pyrrole
Thiamine hydrochloride is spin-dried for adding in 20mL ethyl acetate after filtrate, be washed twice with 15mL saturated aqueous sodium carbonates, then with 15mL saturations
Sodium-chloride water solution is washed once, collected organic layer, is added in anhydrous magnesium sulfate and is dried overnight, and next day, which filters, removes anhydrous magnesium sulfate,
2g silica whites are added in into filtrate and are spin-dried for into powdered, silica gel column chromatography separation (dry method loading, VEthyl acetate：Petroleum ether=1:20) it obtains yellow
Color oily compound A7, yield：88%.1H-NMR(400MHz,DMSO-d6)7.36-6.96(m,7H,Ar-H),3.62(s,1H,
NCH),1.23(s,3H,CHCH3),1.29(s,3H,CHCH3).IRν(cm-1):3089,2251(νC≡N),1725(νC=O),
1573,1497,1313(νC-F),761,681.
Embodiment 8, compound A8Synthesis
Dry reaction glass apparatus and magneton are being taken out from baking oven, nitrogen protection is lower to add in 0.555g (1mmol)
Compound 1- (2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl bases -5- (4- methoxyphenyls) are sub-
Methylamino -1H- pyrazoles, and added with syringe absorption 0.253g (2.5mmol, about 0.25mL) anhydrous triethylamines and 4mL anhydrous benzenes
Enter in reaction bulb, single port bottle is put into KQ3200E types (power 150W) ultrasonic sink and is reacted, then by 0.34g (2.2mmol)
The 4mL benzole solns of phenyllacetyl chloride are slowly dropped in reaction system, and about half an hour drips off, and continue ultrasonic reaction 3h after dripping off, instead
It after answering, filters and removes triethylamine hydrochloride, 20mL ethyl acetate is added in after being spin-dried for filtrate, it is water-soluble with 15mL saturated sodium carbonates
Liquid is washed twice, then is washed once with 15mL saturated sodium-chloride water solutions, collected organic layer, is added in anhydrous magnesium sulfate and is dried overnight, secondary
It filters day and removes anhydrous magnesium sulfate, addition 2g silica whites are spin-dried for into powdered into filtrate, and silica gel column chromatography is detached (in dry method
Sample, VEthyl acetate:Petroleum ether=1:20) faint yellow solid A is obtained8, yield：78%.1H-NMR(400MHz,DMSO-d6)7.12-7.49
(m,10H,Ar-H),6.62(d,1H,Ar-H),3.72(s,1H,COCH),3.58(m,3H,OCH3),3.22(s,1H,NCH)
.IRν(cm-1):3086,2254(νC≡N),1749(νC=O),1571,1492,1311(νC-F),762,681.
Embodiment 9, compound A9Synthesis
Dry reaction glass apparatus and magneton are taken out from baking oven, nitrogen protection is lower to add in 0.525g (1mmol) 1-
(2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl base -5- phenyl methylidene amino -1H- pyrazoles, and
0.198g (2.5mmol, about 0.2mL) anhydrous pyridines are drawn with syringe and 4mL anhydrous benzenes are added in reaction bulb, and single port bottle is put
Enter and reacted in KQ3200E types (power 150W) ultrasonic sink, then the 4mL benzene by 0.506g (2.2mmol) diphenyl-acetyl chloride
Solution is slowly dropped in reaction system, and about half an hour drips off, and continues ultrasonic reaction 3h after dripping off, after reaction, suction filtration removes
Pyridine hydrochloride is removed, 20mL ethyl acetate is added in after being spin-dried for filtrate, is washed twice with 15mL saturated aqueous sodium carbonates, then use 15mL
Saturated sodium-chloride water solution is washed once, collected organic layer, is added in anhydrous magnesium sulfate and is dried overnight, and next day, which filters, removes anhydrous slufuric acid
Magnesium adds in 2g silica whites into filtrate and is spin-dried for into powdered, silica gel column chromatography separation (dry method loading, VEthyl acetate：Petroleum ether=1:20)
Obtain yellow oily compound A9, yield：93%.1H-NMR(400MHz,DMSO-d6)7.56-6.96(m,17H,Ar-H),3.61
(s,1H,NCH),.IRν(cm-1):3081,2252(νC≡N),1735(νC=O),1573,1498,1312(νC-F),762,683.
Embodiment 10, compound A10Synthesis
Dry reaction glass apparatus and magneton are taken out from baking oven, nitrogen protection is lower to add in 0.525g (1mmol) 1-
(2,6 dichlor-4-trifluoromethyl) phenyl -3- cyano -4- trifluoromethyl sulphinyl base -5- phenyl methylidene amino -1H- pyrazoles, and
The anhydrous tri-n-butylamines of 0.462g (2.5mmol, about 0.46mL) are drawn with syringe and 4mL anhydrous benzenes are added in reaction bulb, by single port
Bottle is put into KQ3200E types (power 150W) ultrasonic sink and reacts, then by 0.323g (2.2mmol) cyclohexyl formyl chloride
4mL benzole solns are slowly dropped in reaction system, and about half an hour drips off, and continue ultrasonic reaction 3h after dripping off, and after reaction, are taken out
Tri-n-butylamine hydrochloride is filtered out, 20mL ethyl acetate is added in after being spin-dried for filtrate, is washed twice with 15mL saturated aqueous sodium carbonates, then
It is washed once with 15mL saturated sodium-chloride water solutions, collected organic layer, adds in anhydrous magnesium sulfate and be dried overnight, next day, which filters, removes nothing
Water magnesium sulfate adds in 2g silica whites into filtrate and is spin-dried for into powdered, silica gel column chromatography separation (dry method loading, VEthyl acetate：Petroleum ether=
1:20) yellow oily compound A is obtained10, yield：79%.1H-NMR(400MHz,DMSO-d6)7.37-6.98(m,1H,Ar-H),
3.80(s,1H,NCH)；1.62(m,4H,CCH2).1.44(m,6H,C CH2CH2).IRν(cm-1):3081,2251(νC≡N),
1721(νC=O),1575,1494,1312(νC-F),761,689.
Comparative example, compound A1Synthesis
Separately or concurrently change the reactive mode of embodiment 1, prepare compound A at ambient temperature1, prepare result and reality
The result for applying example 1 is listed in the table below in 1 simultaneously：
A under the conditions of 1 differential responses of table1Synthesis and its yield
Note：Two-step method first separates ketenes in comparative example 3, and olefinic recycle ketone generates target product with imine reaction.
From comparative example as can be seen that the reaction time and ultrasound whether have an impact to reaction yield, use Ultrasonic Radiation
Method yield compared with magnetic agitation is obviously improved, and the ketenes in one-step method is directly used in reaction institute in next step without isolation
Obtained yield is higher than two-step method.
The preparation of embodiment 11, quaternary ring-type beta-lactam derivatives solution based on arylpyrazole skeleton
Antiseptic dosage form prepared by the present embodiment is solution, by test compound A1—A10It is dissolved in DMSO respectively,
The pre- concentration for being made into 0.1% (m/v), is then diluted to 10,1,0.1mg/L 3 kind of concentration with 1% (m/v) acetic acid distilled water solution
As test sample, positive control drug Norfloxacin (NF) is directly configured to 10,1,0.1mg/ with 1% (m/v) acetic acid distilled water
3 kinds of concentration of L, blank control group are 1% (m/v) acetum.
Prepared dilute solution agent is ready for use on following embodiment.
Embodiment 12 evaluates the antibacterial activity of staphylococcus aureus
Plate test method determination is used to the antibacterial activity evaluation of staphylococcus aureus, is prepared using embodiment 11 each
The dilute solution agent of compound, using beef extract-peptone as culture medium, be inoculated with after 37 DEG C culture for 24 hours, observe, record it is antibacterial
Size is enclosed, and compared with positive control drug Norfloxacin (NF), evaluates the bacteriostatic activity height of test compound according to this, ++ it represents
High activity ,+represent medium activity ,-represent that activity is weaker.Result of the test is shown in Table 2.
2 compound A of table1~A10Anti-Staphylococcus aureus activity
Embodiment 13 evaluates the antibacterial activity of escherichia coli
Plate test method determination, eachization prepared using embodiment 11 are used to the antibacterial activity evaluation of escherichia coli
The dilute solution agent of object is closed, using beef extract-peptone as culture medium, is inoculated with after 37 DEG C of cultures for 24 hours, observation, record inhibition zone
Size, and compared with positive control drug Norfloxacin (NF), the bacteriostatic activity height of test compound is evaluated according to this, ++ represent high
Activity ,+represent medium activity ,-represent that activity is weaker.Result of the test is shown in Table 3.
3 compound A of table1~A10Anti- escherichia coli activity
Embodiment 14 evaluates the antibacterial activity of proteus vulgaris
Plate test method determination, eachization prepared using embodiment 11 are used to the antibacterial activity evaluation of proteus vulgaris
The dilute solution agent of object is closed, using beef extract-peptone as culture medium, is inoculated with after 37 DEG C of cultures for 24 hours, observation, record inhibition zone
Size, and compared with positive control drug Norfloxacin (NF), the bacteriostatic activity height of test compound is evaluated according to this, ++ represent high
Activity ,+represent medium activity ,-represent that activity is weaker.Result of the test is shown in Table 4.
4 compound A of table1~A10Anti- proteus vulgaris activity
Embodiment 15, compound A1-A10The preparation of suspending agent
The formulations of pesticide prepared by the present embodiment are suspending agent, and alleged below " gross mass " refers to " prepared suspending agent
Gross mass ".
The surfactant naphthalenesulfonic acid-formaldehyde condensate for first accounting for gross mass 5% by 10 parts is diluted in 10 parts and accounts for total matter respectively
It measures in 5% suitable antifreeze glycol, and is slowly added into the water for accounting for gross mass 25% into the solution respectively, quickly stirring
Lower sequentially added respectively into 10 groups of solution accounts for compound A prepared by the embodiment 1-10 of gross mass 25%1~A10And account for total matter
The suitable auxiliaries (preservative benzoic acid, antifoaming agent organosilicon and thickener xanthans) of amount 5%, are ground it after adding,
It is eventually adding the water for accounting for gross mass 35%.The suspending agent being prepared is added water into dilution and prepares compound A respectively1~A10Institute
Need concentration.Prepared dilute suspension agent is ready for use on following embodiment.
Embodiment 16, the biological evaluation to mythimna separata
By embodiment 15 prepare the quaternary ring-type β based on arylpyrazole skeleton provided by the invention with insecticidal activity-
The pesticide solution for being made into concentration 100mg/L is diluted with water in the suspending agent of lactam derivatives, chooses 20 3 age mythimna separatas and 10
One cun of long maize leaf, which is put in culture dish, carries out quantitative sprinkling, moves into greenhouse after drying and normally raises, 24~72 hours
Wait statistics survival and death toll.Experiment is repeated 3 times, and results are averaged.Activity in percentage, is divided into relative to blank control
A, B, C, D level Four, the death rate 100%~90% are A grades, and 90%~70~% of the death rate is B grades, the death rate 70%~50%
It it is C grades, the death rate 0%~50% is D grades.Test result is shown in Table 5.
5 A of table1~A10When test concentrations are 100mg/L to the activity of mythimna separata
| Compound | A1 | A2 | A3 | A4 | A5 | A6 | A7 | A8 | A9 | A10 |
| Active rank | A | A | A | A | A | A | B | A | B | A |
Embodiment 17, the biological evaluation to rice green leafhopper
By embodiment 15 prepare the quaternary ring-type β based on arylpyrazole skeleton provided by the invention with insecticidal activity-
The pesticide solution for being made into a concentration of 160mg/L is diluted with water in the suspending agent of lactam derivatives, chooses two core rice seedlings and immerses liquid
In, it takes out and dries after 5 seconds, be placed in Boiling tube, often 20 plants of pipe, then introduce the rice green leafhopper 5 age nymph of 20 or more, pipe
The wrapping of mouth white yarn cloth is placed under room temperature, and survival and dead borer population are checked after 24 hours.Experiment is repeated 3 times.As a result
It is averaged.Activity in percentage, is divided into A, B, C, D level Four relative to blank control, and the death rate 100%~90% is A grades,
The death rate 90%~70% is B grades, and the death rate 70%~50% is C grades, and the death rate 0%~50% is D grades.Test result is shown in Table
6。
6 A of table1~A10When test concentrations are 160mg/L to the activity of rice green leafhopper
| Compound | A1 | A2 | A3 | A4 | A5 | A6 | A7 | A8 | A9 | A10 |
| Active rank | A | B | A | A | A | A | B | A | A | A |
Embodiment 18：To the biological evaluation of northern house larva
By embodiment 15 prepare the quaternary ring-type β based on arylpyrazole skeleton provided by the invention with insecticidal activity-
The pesticide solution for being made into a concentration of 80mg/L is diluted with water in the suspending agent of lactam derivatives, adds 10mL and contains 10 4 ages
The raising water of mosquito larvae.A little feed is added daily, until mosquito larvae is all pupated or dead.The pupa of change is siphoned away at any time.It is real
It tests and is repeated 3 times.Results are averaged.Activity in percentage, is divided into A, B, C, D level Four, the death rate relative to blank control
100%~90% is A grades, and the death rate 90%~70% is B grades, and the death rate 70%~50% is C grades, the death rate 0%~50%
It is D grades.Test result is shown in Table 7.
7 compound A of table1~A10When test concentrations are 80mg/L to the activity of northern house larva
Embodiment 19, the biological evaluation to diamondback moth
Respectively using embodiment 15 prepare the 40 of 10 groups of compounds, the water dilute suspension agent of 80mg/L concentration, in order to test
It demonstrate,proves whether its safety to diamondback moth improves, using diamondback moth as test worm, each compound is determined to diamondback moth using spray-on process
Comprehensive toxicity (contact toxicity and Oral toxicity), correlated results is shown in Table 7.
7 compound A of table1-A10To the 48h Toxicity test results of diamondback moth
As can be known from Table 5：Ethiprole is higher to diamondback moth toxicity, and there is 4% poisoning rate in when 40mg/L, and in 80mg/
Rate of being poisoned to death during L reaches 46% close to half；It is mainly shown as the weak and limp landing of body or death.Compound A1~A10Then
It is relatively low to the comprehensive toxicity of diamondback moth, without poisoning manifestations when 40mg/L is handled, when 80mg/L is handled also without diamondback moth table
Reveal the symptom of poisoning.If processing mass concentration of the definition poisoning rate not higher than 3% is safe quality concentration, compound A1~
A1080mg/L is at least to the safe quality concentration of diamondback moth, than ethiprole (<40mg/L) at least improve 1 times.
Claims (12)
1. a kind of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, shown in structural formula such as general formula (A)：
In the general structure (A)：R1X is one of following three kinds of situations：
(1)H；
(2) halogen；
(3)R1X in X is SO or S, R1For-CN, C1~C4Alkyl or C1~C4Halogenated alkyl；
R2For substituted or unsubstituted phenyl, naphthalene, anthryl, phenanthryl, furyl, pyrrole radicals, thienyl, pyridyl group, quinolyl,
Indyl, it is phenyl ring ortho position, meta position and/or contraposition that the substitution, which is monosubstituted or polysubstituted, substituted position, substituted group
For alkyl, alkoxy, hydroxyl, halogen or nitro；
R3、R4It is each independently selected from H, halogen, phenyl, C1~C4Alkyl, cycloalkyl, C1~C4Halogenated alkyl, phenyl substitution
C1~C4Alkyl, R3And R4It is identical or differ.
2. the quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton according to claim 1, it is characterised in that：
The R1Any one of X in following group：H、—SOCF3And-SOC2H5；
The R2For compound R2Group R in-CHO2, the compound R2Any one of-CHO in following compound：
The fluoro- 4- bromobenzaldehydes of benzaldehyde, 4-methoxybenzaldehyde, 2,3 dichloro benzaldehyde, 2-, 2,5- difluorobenzaldehydes, 2,6- diformazans
The bromo- 4- hydroxy benzaldehydes of benzaldehyde, 3-, 4- fluorobenzaldehydes, 4- chlorobenzaldehydes；2,4,6- trifluro benzaldehydes, 1- methoxyl groups -2-
Naphthaldehyde, 1- naphthaldehydes, 2- hydroxyl-1-naphthalene Formaldehydes；9- anthraldehydes；9- formaldehydes；2 furan carboxyaldehyde, 5- methyl -2- furans first
Aldehyde；2- pyrrole aldehydes, 3- pyrrole aldehydes；2 thiophene carboxaldehyde；The bromo- 3- pyridine carboxaldehydes of 2- pyridine carboxaldehydes, 2-, bis- chloro- 3- pyrroles of 2,6-
Pyridine formaldehyde；3- quinoline aldehydes, 4- hydroxy benzaldehydes and 3- indolecarboxaldehydes；
The R3、R4It is each independently selected from any one in following group：-H、CH3-、Cl、And phenyl.
3. the quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton according to claim 2, it is characterised in that：
The compound R2Any one of-CHO in following compound：Benzaldehyde, 4- fluorobenzaldehydes, 4- methoxybenzene first
Aldehyde and 4- hydroxy benzaldehydes；
The R3、R4It is each independently selected from any one in following group：-H、CH3-、And phenyl.
4. a kind of any quaternary ring-type beta-lactam derivatives (A) based on arylpyrazole skeleton in claim 1-3
Synthetic method, step are as follows：
Under nitrogen protection by fipronil schiff basesAcyl chloridesWith alkali solubilizer in ultrasound
Compound shown in general formula (A) is prepared in reaction under conditions of wave radiation.
5. a kind of any quaternary ring-type beta-lactam derivatives (A) based on arylpyrazole skeleton in claim 1-3
Synthetic method, step are as follows：
Fipronil schiff bases are added in into reaction vessel under nitrogen protectionThen alkali and solvent will
Reaction vessel is placed in ultrasound reactor sink, and acyl chlorides is added dropwise into reaction vessel under ultrasound conditionWith molten
Solution after dilution agent, half an hour drip off, and then proceed to ultrasonic reaction 3 hours, and product is obtained after isolating and purifying.
6. synthetic method according to claim 4 or 5, it is characterised in that：The alkali be selected from triethylamine, tri-n-butylamine, pyridine,
Any one in DMAC N,N' dimethyl acetamide, triphenylphosphine, potassium carbonate and sodium hydride；
The solvent is selected from benzene,toluene,xylene, chlorobenzene, nitrobenzene, ether, dichloromethane, chloroform, dimethyl sulfoxide, four
Any one in hydrogen furans, ethylene glycol diethyl ether and n-cyclohexyl-2-pyrrolidone.
7. synthetic method according to claim 6, it is characterised in that：The alkali is triethylamine, tri-n-butylamine or pyridine；
The organic solvent is any one in benzene, toluene, ether, dichloromethane, chloroform and tetrahydrofuran.
8. synthetic method according to claim 4 or 5, it is characterised in that：The Ultrasonic Radiation power for 100~
150W, reaction time are 2~4h；The molar ratio of the fipronil schiff bases, acyl chlorides and alkali is 1：2.2：2.5.
9. any quaternary ring-type beta-lactam derivatives (A) based on arylpyrazole skeleton exist in a kind of claim 1-3
Prepare the application in insecticide and antibacterials.
10. application according to claim 9, it is characterised in that：The insecticide is for preventing Orthoptera, Thysanoptera, same
Wing mesh, Heteroptera, Lepidoptera, coleoptera, Hymenoptera and/or Diptera class pest；
The antibacterials are used for anti-Staphylococcus aureus, escherichia coli and/or proteus vulgaris.
11. a kind of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, structural formula is as shown in general formula A4：
12. a kind of quaternary ring-type beta-lactam derivatives based on arylpyrazole skeleton, structural formula is as shown in general formula A10：
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| US4629495A (en) * | 1982-07-15 | 1986-12-16 | May & Baker Limited | Herbicidal 5-amino-4-cyano-1-phenylpyrazoles |
| EP0282811A1 (en) * | 1987-03-11 | 1988-09-21 | Bayer Ag | 4-Cyano-1-aryl-pyrazoles |
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| US4629495A (en) * | 1982-07-15 | 1986-12-16 | May & Baker Limited | Herbicidal 5-amino-4-cyano-1-phenylpyrazoles |
| EP0282811A1 (en) * | 1987-03-11 | 1988-09-21 | Bayer Ag | 4-Cyano-1-aryl-pyrazoles |
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