CN108658942A - One kind is based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds and its microwave-hydrothermal method synthetic method and application - Google Patents
One kind is based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds and its microwave-hydrothermal method synthetic method and application Download PDFInfo
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
The present invention relates to technical field of organic synthesis, more particularly to one kind is based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds and its microwave-hydrothermal method synthetic method and application.The present invention is on the basis of synthesizing oxo azetidine pyrazole derivatives, ester group is introduced on pyrazole ring, it has synthesized and has been based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds, the combination for realizing pyrazole compound aza-oxo-cyclobutane structure and ester group structure provides the compound of a kind of structure novel；The present invention uses lewis acid to provide acid condition as catalyst, using microwave-hydrothermal method synthesizing oxo azetidine pyrazole carboxylic acid ester compounds, this method stablizes nontoxic, convenient post-treatment, and two kinds of synthetic schemes are provided, the synthesis sequence during this can be adjusted as needed.The compound of preparation has good application prospect in prevention harmful insect, mite pest and anti-Staphylococcus aureus etc..
Description
Technical field
The present invention relates to technical field of organic synthesis, more particularly to a kind of aza-oxo-cyclobutane pyrazole carboxylic acid that is based on to be esterified
Object and its microwave-hydrothermal method synthetic method are closed, the application of such compound is further related to.
Background technology
Ester type compound tool is of great significance in medicinal chemistry art, they have very strong bioactivity.Such as ammonia
Carbamate class compound has many advantages, such as rapid effect, high selectivity, biodegradation, pyrethroid desinsection as pesticide
It also all include ester group in the active group of agent.Pyrethroid insecticides are widely used in agricultural insect management, by broken
Bad aixs cylinder ion channel kills pest, is a kind of indispensable insecticide, its main feature is that：High activity, toxicity is low, low-residual
Be easy to degrade.It is reversible since ester pesticides are combined with cholinesterase, and is hydrolyzed quickly in body, cholinester enzyme activity
Property is easier to restore, therefore its toxic effect is lighter.That is, ester prodrug have stability height, long action time, dissolubility good and
Less toxic side effect and other advantages.Aza-oxo-cyclobutane belongs to beta-lactam compound, which is widely present in bactericidal antiphlogistic
It is the important component for treating the various infection such as septicemia in antiviral drugs.Such as the aztreonam of anti-Gram-negative bacteria is exactly
Drug containing oxo heterocycle butane structure.It, can in synthesis field exactly because two kinds of structures all have good bioactivity
It is transformed with common active splicing.Using the pyrazole ring containing aza-oxo-cyclobutane as precursor structure, introduce
Ester group obtains the noval chemical compound there are two types of active structure.
For the derivatization of organo-functional group cyano, generally the nitrogen-atoms on cyano can be made to protonate, oxygen is former on alcohol
Nucleophilic addition occurs for the lone pair electrons of son and the cyano after protonation, is finally converted into ester group or amide in acidic environment
Functional group generally provides acid condition using strong acid such as HCl gases, strictly to be controlled in reaction process in existing report
Reaction condition processed is to reduce the generation of by-product amide, and the selectivity of reaction is not fine, and strong acid reaction liquid post-processes also very
It is complicated.Since 3 cyano forms conjugated structure with pyrazole ring on pyrazole ring ring, necleophilic reaction activity substantially reduces, derivative
Change difficulty to greatly enhance, there is presently no the reports about the cyano direct esterification on pyrazole ring ring.
Microwave technology is risen in the 1930s, as development is gradually applied to multiple fields.Applied to organic synthesis
It is in the 1960s, since then in decades, microwave radiation promotes being reacted to research hotspot and becoming one for organic chemistry
A new research field.Organic reaction efficiency under microwave radiation greatly improves, some are conventional to be heated to reflux and be difficult to realize
Reaction can also reach under microwave action, and easy to operate, and yield is high, and the time is short, easily recycling etc..Hydro-thermal method was 19th century
It begins one's study.Post-science men in 1900 establish hydrothermal synthesis theory, start the research of turning function material again later.
Under hydrothermal condition, solvent can work as a kind of chemical constituent and participate in reaction.Present hydro-thermal method multipurpose high-pressure reaction kettle
Container is made, the condition for the high pressure that reaches a high temperature in closed environment promotes the generation of reaction.Microwave-hydrothermal method set both
The advantages of method, realizes the stirring on molecular level that is, using microwave as heating tool, overcomes the heating of hydro-thermal container uneven
The shortcomings that, shorten the reaction time, improves working efficiency, there is that heating speed is fast, homogeneous heating, no temperature gradient, no hysteresis effect
The advantages that, it is a kind of very effective novel methodology of organic synthesis.
Invention content
The main method of common cyano group derivatization is to provide acid condition by HCl gases, and cyano is made to be sent out with alcohol
Raw hydrolysis generates carboxylate or amide compound, and selectivity is poor, to generate esterification products and need harsher control
Reaction condition processed.HCl gases used need hydrogen to be prepared immediately under 250 DEG C of high temperature with chlorine simultaneously, and condition is harsh, operation
Inconvenience, the post-processing of highly acid waste liquid are relatively complicated, it is difficult to carry out large-scale industrial production.
Based on considerations above, the present invention is designed by active structure splicing principle and provides the chemical combination of a kind of structure novel
Object --- aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds, and provide two kinds of synthetic schemes.Scheme 1：With oxo aza ring
The pyrazole derivatives of butane are that precursor and alcohol react, and catalyst, preferably ferric trichloride or CuCl are done with lewis acid2Acidity is done to urge
Agent makes the nitrogen-atoms on pyrazole ring on 3 cyano protonate, the lone pair electrons of oxygen atom and the cyanogen after protonation on alcohol
Nucleophilic addition occurs for base, is ester group in acidic environment one-step conversion, generates the esterification of aza-oxo-cyclobutane pyrazole carboxylic acid
Close object.Scheme 2：It is reacted by precursor and alcohol of pyrazole derivatives, catalyst, preferably ferric trichloride or CuCl is done with lewis acid2
Acidic catalyst is done, pyrazole carboxylic acid ester compounds are generated；It is reacted in alkaline environment with aldehyde and acyl chlorides again, finally obtains oxo
Azetidine pyrazole carboxylic acid ester compounds.
Microwave technology is applied to organic synthesis, reaction speed accelerate than conventional method it is tens of or even thousands of times, just
It is applied to material, pharmacy, chemical industry and other related fields more and more widely.Hydro-thermal method can provide the closed loop of high temperature and pressure
Border, the dissolving of raw material and the precipitation of product can be accelerated by applying to organic synthesis.The microwave-hydrothermal method that the two advantage is combined
Using microwave as heating tool, the stirring on molecular level is realized, hydro-thermal container is overcome to heat non-uniform disadvantage, shorten
Reaction time improves working efficiency, have the advantages that heating speed fast, homogeneous heating, without temperature gradient, without hysteresis effect.In recent years
Inorganic functional material mostly is prepared using microwave-hydrothermal method, it is more rare for organic synthesis.
Cyano is selectively converted to by ester group, preferred lewis acid by microwave-hydrothermal method based on the considerations above present invention
Convenient catalyst is easy to get, easy to operate, and post-processing is simple, and toxicity substantially reduces, more environment-friendly and safer, and yield is higher, convenient for real
Border produces.
Ester prodrug has stability height, long action time, dissolubility good and less toxic side effect and other advantages.Carbamates
Compound has many advantages, such as rapid effect, high selectivity, with biodegradation as pesticide.Aza-oxo-cyclobutane belongs to the interior acyls of β-
Aminated compounds, the structure are widely present in bactericidal antiphlogistic antiviral drugs, are the important of the various infection such as treatment septicemia
Ingredient.
Based on considerations above, oxo nitrogen heterocyclic ring butane and 3 are introduced in 5 bit amino of pyrazole ring by active structure splicing
Ester group is introduced on cyano, has been synthesized a series of based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds.Pass through active structure
Splicing, realizes the combination of the pyrazole compound containing aza-oxo-cyclobutane and ester type compound, it is made both to have oxo
Azetidine has the biologically active structure of ester type compound again.
Based on considerations above, of the invention three goals of the invention are respectively：
1, a kind of aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds are provided, shown in structural formula such as general formula (IV)：
In the general structure (IV)：R1Selected from saturation alkyl group, naphthenic base, alkoxy, furyl, pyrrole radicals, thiophene
One kind in base, pyridyl group, quinolyl, indyl, substituted or unsubstituted phenyl, it is described substitution be it is monosubstituted or polysubstituted,
Substituted position is phenyl ring ortho position, meta or para position, substituted group be halogen, alkyl, alkoxy, hydroxyl, halogen, nitro or
Trifluoromethyl；
R2It is for phenyl, substituted phenyl, furyl, substituted furyl, pyrrole radicals, thienyl, pyridyl group, quinolyl
Or indyl, it is phenyl ring ortho position, meta or para position, substituted group that the substitution, which is monosubstituted or polysubstituted, substituted position,
For alkyl, alkoxy, hydroxyl, halogen or nitro；
R3Selected from H, halogen, naphthenic base, halogenated alkyl, substituted phenyl, phenyl, furyl, pyrrole radicals, thienyl, pyrrole
Piperidinyl, quinolyl or indyl, it is phenyl ring ortho position, meta or para position that the substitution, which is monosubstituted or polysubstituted, substituted position,
Substituted group is alkyl, alkoxy, hydroxyl, carbonyl, halogenated alkyl, halogen or nitro；
R4For R4R in-OH4, i.e. R4- OH takes off the group after hydroxyl, R4- OH is saturated alkyl alcohol, cycloalkyl alcohol, benzene
One kind in phenol, substituted or unsubstituted benzyl alcohol, the substitution are that monosubstituted or polysubstituted, substituted position is phenyl ring neighbour
Position, meta or para position, substituted group are alkyl, alkoxy, hydroxyl or halogen；
Preferably, the R1For-CH3、-CH2CH3、-CH2CH2CH3、-(CH2)3CH3、-
(CH2)4CH3、-OCH3、 X therein is halogen；
R2For R2- CHO takes off the group after-CHO, it is preferred that the R2- CHO be selected from it is following any one：Benzaldehyde, 4-
The fluoro- 4- bromobenzaldehydes of methoxybenzaldehyde, 2,3 dichloro benzaldehyde, 2-, 2,5- difluorobenzaldehydes, 2,6- dimethylbenzaldehydes,
The bromo- 4- hydroxy benzaldehydes of 3-, 4- fluorobenzaldehydes, 4- chlorobenzaldehydes, 3,5- bis- (trifluoromethyl) benzaldehyde, 2 furan carboxyaldehyde, 5-
Methyl -2 furan carboxyaldehyde, 2- pyrrole aldehydes, 3- pyrrole aldehydes, 2 thiophene carboxaldehyde, 2- pyridine carboxaldehydes；
Preferably, R3It is independently selected from any one in following group：-H、CH3-、Cl、And substitution or
Unsubstituted phenyl；
Preferably, R4It is independently selected from any one in following group：-CH3、-CH2CH3、-CH2CH2CH3、-
(CH2)3CH3、-(CH2)4CH3、-(CH2)5CH3、
2, second object of the present invention is the method for providing two kinds of composite structure formulas compound as shown in general formula (IV),
The method simple and effective, environment-friendly and low-toxicity, yield is high.
Compound synthesis method shown in formula of (IV) of the present invention can lead to following scheme 1 or prepared by scheme 2：
Scheme 1：A kind of synthetic route of structural formula compound as shown in general formula (IV)：
(1) by pyrazole derivativesIt is added in microwave hydrothermal instrument, aldehyde, molecular sieve and solvent toluene is added, with strong
Sour toluenesulfonic acid is reacted as catalyst, synthesizes the methylene amino-pyrazol analog derivative with carbon-to-nitrogen double bon structure
(2) in nitrogen environment, alkali anhydrous pyridine, solvent anhydrous benzene is added into methylene amino-pyrazol analog derivative, stirs
30min is mixed, acyl chlorides is added dropwise dropwiseIt after dripping, stirs 3 hours, isolates and purifies to obtain oxo azepine after the completion of reaction
Cyclobutane pyrazole derivatives
(3) aza-oxo-cyclobutane pyrazole derivatives are added into the polytetrafluoroethylliner liner of microwave hydrothermal reaction kettle, urge
Agent and solvent R4OH is put into after sealing reaction kettle in microwave hydrothermal instrument, and microwave power 300-500W is warming up to higher than molten
5-10 DEG C of agent boiling point, reaction 10-60min are cooled to room temperature after reaction, remove excess of solvent, and extraction, purification obtain base
In aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds；
R1、R2、R3As previously described；
Reaction temperature described in step (1) is 120 DEG C, microwave power 300-500W, reaction time 10-60min；
Aldehyde is furans -2- formaldehyde, 4- methyl-ribofuranosyl -2- formaldehyde, 3- hydroxy-4-methyls-benzaldehyde in the step (1)
Or amyl- 3- olefine aldehydrs；
Catalyst is selected from lewis acid in the step (3)；
Solvent R in the step (3)4OH is saturated alkyl alcohol, cycloalkyl alcohol, phenol, substituted benzyl alcohol, unsubstituted
One kind in benzyl alcohol, the substitution are that monosubstituted or polysubstituted, substituted position is phenyl ring ortho position, meta or para position, substitution
Group be alkyl, alkoxy, hydroxyl or halogen.
Further, the catalyst is selected from FeCl3、AlCl3、ZnCl2、CoCl2、CuCl2And SnCl4In it is any one
Kind；Preferably, the catalyst is FeCl3Or CuCl2；
Preferably, the solvent R4OH is saturated alkyl alcohol；
Preferably, the reaction time is 20-30min in the step (1) and (3)；
Preferably, microwave power is 300W-350W in the step (1) and (3)；
Further, aza-oxo-cyclobutane pyrazole derivatives, catalyst amount and polytetrafluoroethyl-ne in the step (3)
The volumetric ratio of alkene liner is 1mmol:(2-6)mmol:50mL, preferably 1mmol:2mmol:50mL；
Further, aza-oxo-cyclobutane pyrazole derivatives and catalyst, solvent R in the step (3)4The use of OH
Amount is than being 1mmol:(2-6)mmol:(10-20) mL, preferably 1mmol:2mmol:15mL；
Further, pyrazole derivatives in the step (1)Aldehyde is 5mmol with strong acid amount ratio:
5mmol:(0.1-0.3) g, preferably 5mmol:5mmol:0.1g.
Further, in the step (2) acyl chlorides be cyclopropyl-chloroacetic chloride benzole soln；
Further, the amount ratio of step (2) Central Asia methylamino pyrazole derivatives, alkali and acyl chlorides is 1mol:(2-
3)mol:(2-3) mol, preferably 1mol:2.5mol:2.2mol.
Scheme 2：
Specifically include the following steps successively：
(1) pyrazole derivatives are added into microwave hydrothermal polytetrafluoroethylliner linerCatalysts and solvents
R4OH is put into after sealing reaction kettle in microwave hydrothermal instrument, and microwave power 300-500W is warming up to higher than solvent boiling point 5-10
DEG C, reaction 10-60min is cooled to room temperature after reaction, removes excess of solvent, and extraction, purification obtain carboxylate compound；
(2) carboxylate compound is added in microwave hydrothermal instrument, aldehyde, molecular sieve and solvent toluene is added, is urged with strong acid
Agent is reacted, and intermediate product iminopyrazoles carboxylate compound is synthesized；
(3) and then in nitrogen environment, be added into intermediate product iminopyrazoles carboxylate compound alkali anhydrous pyridine,
Solvent anhydrous benzene stirs 30min, acyl chlorides is added dropwise dropwiseIt after dripping, stirs 3 hours, is isolated and purified after the completion of reaction
It obtains being based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds；
Further, catalyst described in step (1), in step (2) aldehyde, strong acid, alkali, acyl chlorides as described in scheme 1
Catalyst, aldehyde, strong acid, alkali, acyl chlorides；
Further, step (1) the solvent R4OH is saturated alkyl alcohol, cycloalkyl alcohol, phenol, substituted or unsubstituted
One kind in benzyl alcohol, the substitution are that monosubstituted or polysubstituted, substituted position is phenyl ring ortho position, meta or para position, substitution
Group be alkyl, alkoxy, hydroxyl or halogen；
Further, reaction temperature described in step (2) is 120 DEG C, microwave power 300-500W, reaction time 10-
60min；Preferably, the reaction time is 20-30min in the step (1) and (2)；Preferably, micro- in the step (1) and (2)
Wave power is 300W-350W；
Further, carboxylate compound, aldehyde and strong acid amount ratio are 5mmol in the step (2):5mmol:(0.1-
0.3)g；
Further, the volumetric ratio of pyrazole derivatives, catalyst amount and polytetrafluoroethylliner liner described in step (1) is
1mmol:(5-15)mmol:50mL, preferably 1mmol:10mmol:50mL.
Further, the dosage of the intermediate product iminopyrazoles carboxylate compound in the step (3), alkali and acyl chlorides
Than for 1mol:(2-3)mol:(2-3)mol.
Compound (I) pyrazole derivativesBibliography：Zhang Changjun, Chen Zhen, Cao Xiaoqun wait fluorine worms
The study on the synthesis [J] of nitrile, Journal of Shandong agri.Univ, 2009,40 (1):145-147. methods synthesize.
3, third object of the present invention is that provide structural formula compound as shown in general formula (IV) is being harmful to elder brother to preventing
Worm (including Orthoptera, Thysanoptera, Homoptera, Heteroptera, Lepidoptera, coleoptera and Diptera), mite pest and anti-golden yellow
Application in terms of staphylococcus, sensitive aerobic gram-negative bacteria and proteus vulgaris experiment, achieves 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 pyrazole ring and introduces aza-oxo-cyclobutane, and in pyrazole ring
Introduce ester group, synthesized it is a series of be based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds, realize pyrazole compound oxygen
For the combination of azetidin alkyl structure and ester group structure, the compound of a kind of structure novel is provided；
In synthetic method, the esterification of general cyano mainly provides acid condition using HCl gases, and reaction condition is severe
It carves, the post-processing of highly acid waste liquid is cumbersome, strongly limits the application of the reaction, present invention FeCl3It is provided Deng as catalyst
Acid condition, the 3 cyano alcoholysis that will be conjugated for the first time with pyrazole ring, synthesis is a series of to be based on aza-oxo-cyclobutane pyrazoles
Carboxylate compound (IV)This method stablizes nontoxic, convenient post-treatment, and provides two kinds of synthesis
Scheme can first introduce ester group and be re-introduced into aza-oxo-cyclobutane, can also first introduce aza-oxo-cyclobutane and be re-introduced into ester group, can
To adjust the synthesis sequence during this as needed.
In addition the present invention has used microwave-hydrothermal method during the reaction, and microwave method and hydro-thermal method are combined, fully profit
The advantages that with the high temperature and pressure of the closed generation of uniformity and hydro-thermal method of microwave heating, allows both methods to generate synergistic effect,
It is applied in the synthesis based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds the advantages of having gathered two methods so that anti-
Product yield has further raising.
Description of the drawings
Fig. 1 is the control effect and normalization cocooning rate schematic diagram that various concentration compound posts silkworm fly in embodiment 6.
Specific implementation mode
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.
5- amino-1H- pyrazoles-3- first nitrile compounds in following example 1-4 are applicant according in invention content
The bibliography of description：Zhang Changjun, Chen Zhen, Cao Xiaoqun, wait the study on the synthesis [J] of ethiproles, Journal of Shandong agri.Univ,
2009,40(1):The method of 145-147 makes by oneself to obtain.
The volume of polytetrafluoroethylliner liner used is 100mL in following embodiment.
Embodiment 1.1- (the chloro- phenyl of 3-) -5- (3- Cvclopropvlmethvl -2- furans -4- oxo-azetidins) -1H- pyrroles
The synthesis of azoles -3- propyl carboxylates (A1)
Scheme 1：
Compound 5- amino -1- (the chloro- phenyl of 3-) -1H- pyrazoles -3- formonitrile HCNs are by 2- amino -4- cyano-ethyl butyrate and 3-
Chloro- aniline is with reference to bibliography：Zhang Changjun, Chen Zhen, Cao Xiaoqun wait the study on the synthesis [J] of ethiproles, Shandong Agricultural University to learn
Report, 2009,40 (1):145-147. method synthesis.
5- amino-the 1- (the chloro- phenyl of 3-)-being prepared into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
1H- pyrazoles -3- formonitrile HCN 5mmol and 5mmol furans -2- formaldehyde, 0.1g p-methyl benzenesulfonic acid, 4A molecular sieves 1g and solvent toluene
30mL seals reaction kettle, is put into microwave-hydrothermal method instrument, microwave power 300W, is heated to 120 DEG C, reacts 20min.Reaction
After filtered, collect filtrate, into filtrate be added 3g silica whites be spin-dried for into it is powdered, silica gel column chromatography detach (dry method
Loading, VEthyl acetate：VPetroleum ether=1:10) 1- (the chloro- phenyl of 3-) -5- [(furans -2- methylene)-amino] -1H- pyrazoles -3- first is obtained
Nitrile.
Dry reaction glass apparatus and magneton are taken out from baking oven, are reacted as follows under nitrogen protection：To anti-
1- (the chloro- phenyl of 3-) -5- [(furans -2- methylene)-amino] -1H- pyrazoles -3- formonitrile HCNs that 1mmol is added in instrument are answered, are used in combination
Syringe is drawn 2.5mmol anhydrous pyridines and 4mL anhydrous benzenes and is added in reaction kit, then by 4mL cyclopropyl containing 2.2mmol-second
The benzole soln of acyl chlorides is slowly dropped in reaction system, and about half an hour drips off, and continues to stir 3h after dripping off.After reaction, it takes out
Pyridine hydrochloride is filtered out, 20mL ethyl acetate is added after being spin-dried for filtrate, is then washed twice with 15mL saturated aqueous sodium carbonates,
It is washed once with 15mL saturated sodium-chloride water solutions again, collected organic layer, it is dried that anhydrous magnesium sulfate is added into gained organic layer
At night, next day, which filters, removes magnesium sulfate, after 2g silica whites are added into filtrate, is spin-dried for into powdered, silica gel column chromatography separation (dry method
Loading, VEthyl acetate：VPetroleum ether=1:8) 1- (the chloro- phenyl of 3-) -5- (2- furans -4- oxos -3- propyl-azetidine -1- is obtained
Base) -1H- pyrazoles -3- formonitrile HCNs.
2mmol1- (the chloro- phenyl of 3-) -5- (2- furans -4- are added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
Oxo -3- propyl-azetidine -1- bases) -1H- pyrazoles -3- formonitrile HCNs, 4mmol FeCl3With 30mL propyl alcohol, reaction kettle is sealed,
It is put into microwave-hydrothermal method instrument, microwave power 300W keeps 30min after being warming up to 105 DEG C.After reaction, it is cooled to room temperature,
Reaction solution is transferred in revolving bottle and removes excess of solvent and obtains thick liquid, then in separatory funnel with 30mL ethyl acetate and
70mL water is extracted, and is collected organic phase and is removed excess of solvent, and anhydrous magnesium sulfate is added into organic phase and is dried overnight, next day takes out
Magnesium sulfate is filtered out, 3g silica whites are added into filtrate and are spin-dried for, silica gel column chromatography detaches (dry method loading, VEthyl acetate：VPetroleum ether=1:
4) final product 1- (the chloro- phenyl of 3-) -5- (3- Cvclopropvlmethvl -2- furans -4- oxo-azetidins) -1H- pyrroles are obtained
Azoles -3- propyl carboxylates (A1)。
Scheme 2：
The synthetic method of compound 5- amino -1- (the chloro- phenyl of 3-) -1H- pyrazoles -3- formonitrile HCNs is the same as scheme 1.
2mmol5- amino -1- (the chloro- phenyl of 3-) -1H- pyrroles are added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
Azoles -3- formonitrile HCNs, 4mmol FeCl3With 30mL propyl alcohol, reaction kettle is sealed, is put into microwave-hydrothermal method instrument, microwave power 300W rises
Temperature is to keeping 30min after 105 DEG C.After reaction, it is cooled to room temperature, reaction solution is transferred in revolving bottle and removes excess of solvent
Thick liquid is obtained, is then extracted with 30mL ethyl acetate and 70mL water in separatory funnel, it is extra to collect organic phase removing
Solvent is added anhydrous magnesium sulfate and is dried overnight, and next day, which filters, removes anhydrous magnesium sulfate, and 3g silica whites are added into filtrate and are spin-dried for,
Silica gel column chromatography detaches (dry method loading, VEthyl acetate：VPetroleum ether=1:4) 5- amino -1- (the chloro- phenyl of 3-) -1H- pyrazoles -3- carboxylics are obtained
Propyl propionate.
5- amino-the 1- (the chloro- phenyl of 3-)-being collected into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
1H- pyrazoles -3- propyl carboxylate 5mmol and 5mmol furans -2- formaldehyde, 0.1g p-methyl benzenesulfonic acid, 4A molecular sieves 1g and solvent toluene
30mL seals reaction kettle, is put into microwave-hydrothermal method instrument, microwave power 300W, is heated to 120 DEG C, reacts 20min.Reaction knot
It is filtered after beam, collects filtrate, addition 3g silica whites are spin-dried for into powdered into filtrate, and silica gel column chromatography detaches (in dry method
Sample, VEthyl acetate：VPetroleum ether=1:10) 1- (the chloro- phenyl of 3-) -5- [(furans -2- methylene)-amino] -1H- pyrazoles -3- carboxylic acids are obtained
Propyl ester.
Dry reaction glass apparatus and magneton are taken out from baking oven, carry out following reaction under nitrogen protection：To anti-
1- (the chloro- phenyl of 3-) -5- [(furans -2- methylene)-amino] -1H- pyrazoles -3- propyl carboxylates that 1mmol is added in instrument are answered,
It is used in combination syringe to draw 2.5mmol anhydrous pyridines and 4mL anhydrous benzenes to be added in reaction kit, then by 4mL rings containing 2.2mmol third
The benzole soln of base-chloroacetic chloride is slowly dropped in reaction system, and about half an hour drips off, and continues to stir 3h after dripping off.Reaction terminates
Afterwards, it filters and removes pyridine hydrochloride, 20mL ethyl acetate is added after being spin-dried for filtrate, is then washed with 15mL saturated aqueous sodium carbonates
Twice, then with 15mL saturated sodium-chloride water solutions it washes once, collected organic layer, it is dried that anhydrous magnesium sulfate is added into organic layer
Night filters and removes magnesium sulfate, and into filtrate, addition 2g silica whites are spin-dried for into powdered, silica gel column chromatography separation (dry method loading,
VEthyl acetate：VPetroleum ether=1:8) 1- (the chloro- phenyl of 3-) -5- (3- Cvclopropvlmethvl -2- furans -4- oxo-azetidins) -1H- is obtained
Pyrazoles -3- propyl carboxylates (A1)。
Embodiment 2.5- [3- cyclopentyl-methyls -2- (4- methyl-ribofuranosyls) -4- oxo-azetidins] -1- (3- hydroxyls -
Phenyl) -1H- pyrazoles -3- butyls esters (A2) synthesis
Scheme 1：
Compound 5- amino -1- (3- hydroxy-phenies) -1H- pyrazoles -3- formonitrile HCNs by 2- amino -4- cyano-ethyl butyrate and
The chloro- aniline of 3- is made, and synthetic method is operated with reference to embodiment 1.
5- amino-the 1- (3- hydroxy-phenies)-being collected into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
1H- pyrazoles -3- formonitrile HCN 5mmol and 5mmol 4- methyl-ribofuranosyl -2- formaldehyde, 0.1g p-methyl benzenesulfonic acid, 4A molecular sieves 1g and solvent
Toluene 30mL, seals reaction kettle, is put into microwave-hydrothermal method instrument, microwave power 300W, is heated to 120 DEG C, reacts 20min.
It is filtered after reaction, collects filtrate, 3g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column chromatography separation
(dry method loading, VEthyl acetate:VPetroleum ether=1:10) 1- (3- hydroxy-phenies) -5- [(4- methylfuran -2- methylene)-ammonia is obtained
Base] -1H- pyrazoles -3- formonitrile HCNs.
Dry reaction glass apparatus and magneton are taken out from baking oven, carry out following reaction under nitrogen protection：To anti-
Answer 1- (3- hydroxy-phenies) -5- [(4- methylfuran -2- methylene)-amino] -1H- pyrazoles -3- that 1mmol is added in instrument
Formonitrile HCN is used in combination syringe to draw in 2.5mmol anhydrous pyridines and 4mL anhydrous benzenes addition reaction kit, then 4mL is contained 2.2mmol
The benzole soln of cyclopentyl-acetyl chlorine is slowly dropped in reaction system, and about half an hour drips off, and continues to stir 3h after dripping off.Reaction
After, it filters and removes pyridine hydrochloride, 20mL ethyl acetate is added after being spin-dried for filtrate, then uses 15mL saturated sodium carbonates water-soluble
Liquid is washed twice, then is washed once with 15mL saturated sodium-chloride water solutions, collected organic layer, and it is dry that anhydrous magnesium sulfate is added into organic layer
Dry overnight, next day, which filters, removes magnesium sulfate, and into filtrate, addition 2g silica whites are spin-dried for into powdered, and silica gel column chromatography separation is (dry
Method loading, VEthyl acetate:VPetroleum ether=1:8) 1- (3- hydroxy-phenies) -5- (4- methyl-ribofuranosyl -4- oxos -3- propyl-azacyclo- is obtained
Butane) -1H- pyrazoles -3- formonitrile HCNs.
2mmol1- (3- hydroxy-phenies) -5- (4- methyl-is added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
Furans -4- oxos -3- propyl-azetidine) -1H- pyrazoles -3- formonitrile HCNs, 4mmolFeCl3With 30mL propyl alcohol, reaction is sealed
Kettle is put into microwave-hydrothermal method instrument, and microwave power 300W keeps 30min after being warming up to 105 DEG C.After reaction, it is cooled to room
Reaction solution is transferred to removing excess of solvent in revolving bottle and obtains thick liquid, 30mL acetic acid second is then used in separatory funnel by temperature
Ester and 70mL water are extracted, and are collected organic phase and are removed excess of solvent, and anhydrous magnesium sulfate is added into organic phase and is dried overnight, secondary
It filters day and removes magnesium sulfate, 3g silica whites are added into filtrate and are spin-dried for, silica gel column chromatography detaches (dry method loading, VEthyl acetate:VPetroleum ether
=1:4) final product 5- [3- cyclopentyl-methyls -2- (4- methyl-ribofuranosyls) -4- oxo-azetidins] -1- (3- hydroxyls are obtained
Base-phenyl) -1H- pyrazoles -3- butyl's esters (A2)。
Scheme 2：
Compound 5- amino -1- (3- hydroxy-phenies) -1H- pyrazoles -3- formonitrile HCNs by 2- amino -4- cyano-ethyl butyrate and
The synthesis of 3- hydroxyls-aniline is the same as this embodiment scheme 1.
2mmol5- amino -1- (3- hydroxy-phenies) -1H- is added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
Pyrazoles -3- formonitrile HCNs, 4mmol FeCl3With 30mL n-butanols, reaction kettle is sealed, is put into microwave-hydrothermal method instrument, microwave power is
300W keeps 30min after being warming up to 120 DEG C.After reaction, it is cooled to room temperature, reaction solution is transferred in revolving bottle and is removed
Excess of solvent obtains thick liquid, is then extracted with 30mL ethyl acetate and 70mL water in separatory funnel, and organic phase is collected
Excess of solvent is removed, anhydrous magnesium sulfate is added into organic phase and is dried overnight, next day, which filters, removes magnesium sulfate, is added into filtrate
3g silica whites are spin-dried for, and silica gel column chromatography detaches (dry method loading, VEthyl acetate:VPetroleum ether=1:4) 5- amino -1- (3- hydroxyls-benzene are obtained
Base) -1H- pyrazoles -3- butyl carboxylates.
5- amino-the 1- (3- hydroxy-phenies)-being collected into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
1H- pyrazoles -3- butyl carboxylate 5mmol and 5mmol 4- methyl-ribofuranosyl -2- formaldehyde, 0.1g p-methyl benzenesulfonic acid, 4A molecular sieves 1g and
Solvent toluene 30mL seals reaction kettle outer tank, is put into microwave-hydrothermal method instrument, and microwave power 300W is heated to 120 DEG C, instead
Answer 20min.It is filtered after reaction, collects filtrate, 3g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column layer
Analysis separation (dry method loading, VEthyl acetate:VPetroleum ether=1:8) 1- (3- hydroxy-phenies) -5- [(4- methyl-ribofuranosyl -2- methylenes are obtained
Base)-amino] -1H- pyrazoles -3- butyl carboxylates.
Dry reaction glass apparatus and magneton are taken out from baking oven, carry out following reaction under nitrogen protection：To anti-
Answer 1- (3- hydroxy-phenies) -5- [(4- methyl-ribofuranosyl -2- methylene)-amino] -1H- pyrazoles -3- that 1mmol is added in instrument
Butyl carboxylate is used in combination syringe to draw in 2.5mmol anhydrous pyridines and 4mL anhydrous benzenes addition reaction kit, then 4mL is contained
The benzole soln of 2.2mmol cyclopentyl-acetyl chlorine is slowly dropped in reaction system, and about half an hour drips off, and continues to stir after dripping off
3h.After reaction, it filters and removes pyridine hydrochloride, 20mL ethyl acetate is added after being spin-dried for filtrate, then uses 15mL saturated carbons
Acid sodium aqueous solution is washed twice, then is washed once with 15mL saturated sodium-chloride water solutions, and collected organic layer is added anhydrous into organic layer
Magnesium sulfate is dried overnight, and next day, which filters, removes magnesium sulfate, and 2g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column chromatography
Detach (dry method loading, VEthyl acetate:VPetroleum ether=1:10) 5- [3- cyclopentyl-methyls -2- (4- methyl-ribofuranosyls) -4- oxos-azepine are obtained
Cyclobutane] -1- (3- hydroxy-phenies) -1H- pyrazoles -3- butyl's esters (A2)。
The amyl- 1,3- dialkylenes -5- of embodiment 3.1- rings [2- (3- hydroxy-4-methyls-phenyl) -3- (2- methyl-cyclobutyls
Methyl) -4- oxo-azetidins]-pyrazoles -3- Ethyl formates (A3) synthesis
Scheme 1：
The compound amyl- 1,3- dialkylenes -1H- pyrazoles -3- formonitrile HCNs of 5- amino -1- rings are by 2- amino -4- cyano-ethyl butyrate
It is made with cyclopentadienyl group -1,3- dimethyl amine, synthetic method is operated with reference to embodiment 1.
5- amino-the 1- (3- hydroxy-phenies)-being collected into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
1H- pyrazoles -3- formonitrile HCN 5mmol and 5mmol 3- hydroxy-4-methyls-benzaldehyde, 0.1g p-methyl benzenesulfonic acid, 4A molecular sieves 1g and molten
Agent toluene 30mL, seals reaction kettle outer tank, is put into microwave-hydrothermal method instrument, microwave power 300W, is heated to 120 DEG C, reaction
20min.It is filtered after reaction, collects filtrate, 3g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column chromatography
Detach (dry method loading, VEthyl acetate:VPetroleum ether=1:10) 1- rings amyl- 1,3- dialkylenes -5- [(3- hydroxy-4-methyls-benzal are obtained
Base)-amino]-pyrazoles -3- formonitrile HCNs.
Dry reaction glass apparatus and magneton are taken out from baking oven, carry out following reaction under nitrogen protection：To anti-
Answer the amyl- 1,3- dialkylenes -5- of 1- rings [(3- hydroxy-4-methyls-benzal)-amino]-pyrazoles -3- that 1mmol is added in instrument
Formonitrile HCN is used in combination syringe to draw in 2.5mmol anhydrous pyridines and 4mL anhydrous benzenes addition reaction kit, then 4mL is contained 2.2mmol
The benzole soln of (2- methyl-cyclobutyls)-chloroacetic chloride is slowly dropped in reaction system, and about half an hour drips off, and continues to stir after dripping off
Mix 3h.After reaction, it filters and removes pyridine hydrochloride, 20mL ethyl acetate is added after being spin-dried for filtrate, is then saturated with 15mL
Aqueous sodium carbonate is washed twice, then is washed once with 15mL saturated sodium-chloride water solutions, and nothing is added into organic layer for collected organic layer
Water magnesium sulfate is dried overnight, and next day, which filters, removes magnesium sulfate, and 2g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column layer
Analysis separation (dry method loading, VEthyl acetate:VPetroleum ether=1:8) the amyl- 1,3- dialkylenes -5- of 1- rings [2- (3- hydroxy-4-methyls-benzene are obtained
Base) -3- (2- methyl-cyclobutyls methyl) -4- oxo-azetidins]-pyrazoles -3- formonitrile HCNs.
The amyl- 1,3- dialkylenes -5- [2- (3- of 2mmol1- rings are added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
Hydroxy-4-methyl-phenyl) -3- (2- methyl-cyclobutyls methyl) -4- oxo-azetidins]-pyrazoles -3- formonitrile HCNs, 4mmol
CuCl2With 30mL ethyl alcohol, reaction kettle outer tank is sealed, is put into microwave-hydrothermal method instrument, microwave power 300W is warming up to 100 DEG C
After keep 30min.After reaction, it is cooled to room temperature, reaction solution, which is transferred to removing excess of solvent in revolving bottle, obtains thick shape
Object is then extracted in separatory funnel with 30mL ethyl acetate and 70mL water, is collected organic phase and is removed excess of solvent, is added
Anhydrous magnesium sulfate is dried overnight, and next day, which filters, removes magnesium sulfate, and 3g silica whites are added into filtrate and are spin-dried for, silica gel column chromatography separation
(dry method loading, VEthyl acetate:VPetroleum ether=1:4) final product 1- rings amyl- 1,3- dialkylenes -5- [2- (3- hydroxy-4-methyls-are obtained
Phenyl) -3- (2- methyl-cyclobutyls methyl) -4- oxo-azetidins]-pyrazoles -3- Ethyl formates (A3)。
Scheme 2：
The compound amyl- 1,3- dialkylenes -1H- pyrazoles -3- formonitrile HCNs of 5- amino -1- rings are by 2- amino -4- cyano-ethyl butyrate
Synthesis with cyclopentadienyl group -1,3- dimethyl amines is the same as this embodiment scheme 1.
The amyl- 1,3- dialkylenes-of 2mmol5- amino -1- rings are added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
1H- pyrazoles -3- formonitrile HCNs, 4mmol CuCl2With 30mL absolute ethyl alcohols, reaction kettle outer tank is sealed, is put into microwave-hydrothermal method instrument, it is micro-
Wave power is 300W, and 30min is kept after being warming up to 120 DEG C.After reaction, it is cooled to room temperature, reaction solution is transferred to revolving
Excess of solvent is removed in bottle and obtains thick liquid, is then extracted, is received with 30mL ethyl acetate and 70mL water in separatory funnel
Collect organic phase and remove excess of solvent, anhydrous magnesium sulfate is added and is dried overnight, next day, which filters, removes magnesium sulfate, and 3g is added into filtrate
Silica white is spin-dried for, and silica gel column chromatography detaches (dry method loading, VEthyl acetate:VPetroleum ether=1:4) the amyl- 1,3- diene of 5- amino -1- rings is obtained
Base -1H- pyrazoles -3- carboxylic acid, ethyl esters.
The amyl- 1,3- diene of 5- amino -1- rings being collected into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
Base -1H- pyrazoles -3- carboxylic acid, ethyl ester 5mmol and 5mmol 3- hydroxy-4-methyls-benzaldehyde, 0.1g p-methyl benzenesulfonic acid, 4A molecules
1g and solvent toluene 30mL is sieved, reaction kettle outer tank is sealed, is put into microwave-hydrothermal method instrument, microwave power 300W is heated to 120
DEG C, react 20min.It is filtered after reaction, collects filtrate, 3g silica whites are added into filtrate and are spin-dried for into powdered, silicagel column
Chromatography (dry method loading, VEthyl acetate:VPetroleum ether=1:8) 1- rings amyl- 1,3- dialkylenes -5- [(3- hydroxy-4-methyls-Asia are obtained
Benzyl)-amino] -1H- pyrazoles -3- carboxylic acid, ethyl esters.
Dry reaction glass apparatus and magneton are taken out from baking oven, carry out following reaction under nitrogen protection：To anti-
Answer the amyl- 1,3- dialkylenes -5- of 1- rings [(3- hydroxy-4-methyls-benzal)-amino] -1H- pyrazoles-that 1mmol is added in instrument
3- carboxylic acid, ethyl esters are used in combination syringe to draw in 2.5mmol anhydrous pyridines and 4mL anhydrous benzenes addition reaction kit, then 4mL are contained
The benzole soln of 2.2mmol (2- methyl-cyclobutyls)-chloroacetic chloride is slowly dropped in reaction system, and about half an hour drips off, after dripping off
Continue to stir 3h.After reaction, it filters and removes pyridine hydrochloride, 20mL ethyl acetate is added after being spin-dried for filtrate, then uses
15mL saturated aqueous sodium carbonates are washed twice, then are washed once with 15mL saturated sodium-chloride water solutions, collected organic layer, to organic layer
Middle addition anhydrous magnesium sulfate is dried overnight, and next day, which filters, removes magnesium sulfate, and into filtrate, addition 2g silica whites are spin-dried for into powdered,
Silica gel column chromatography detaches (dry method loading, VEthyl acetate:VPetroleum ether=1:10) the amyl- 1,3- dialkylenes -5- of 1- rings [2- (3- hydroxyls -4- are obtained
Methylphenyl) -3- (2- methyl-cyclobutyls methyl) -4- oxo-azetidins]-pyrazoles -3- Ethyl formates (A3)。
Embodiment 4.1- epoxy ethyls -5- (the amyl- 3- alkenyls-azetidins of 3- oxiranylmethyl radical -2- oxos -4-
Alkane) -1- pyrazoles -3- carboxylic acid isopropyls
Scheme 1：
Compound 5- amino -1- oxiranylmethyl radical -1H- pyrazoles -3- formonitrile HCNs are by 2- amino -4- cyano-ethyl butyrate
It is made with ethylene oxide -2- amine, operation of the synthetic method with reference to embodiment 1.
5- amino -1- Oxyranyle the first being collected into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
The amyl- 3- olefine aldehydrs of base -1H- pyrazoles -3- formonitrile HCNs 5mmol and 5mmol, 0.1g p-methyl benzenesulfonic acid, 4A molecular sieves 1g and solvent toluene
30mL seals reaction kettle outer tank, and microwave 300W is heated to 120 DEG C, reacts 20min.It is filtered after reaction, collects filter
3g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column chromatography separation (dry method loading, V for liquidEthyl acetate:VPetroleum ether=1:10)
Obtain 5- hex- 4- alkene yldeneamino -1- Oxyranyle -1H- pyrazoles -3- formonitrile HCNs.
Dry reaction glass apparatus and magneton are taken out from baking oven, carry out following reaction under nitrogen protection：To anti-
The 5- hex- 4- alkene yldeneamino -1- Oxyranyle -1H- pyrazoles -3- formonitrile HCNs that 1mmol is added in instrument are answered, syringe is used in combination to inhale
2.5mmol anhydrous pyridines and 4mL anhydrous benzenes is taken to be added in reaction kit, then by the 4mL of 2.2mmol oxa-s cyclohexane-chloroacetic chloride
Benzole soln is slowly dropped in reaction system, and about half an hour drips off, and continues to stir 3h after dripping off.After reaction, it filters and removes
Pyridine hydrochloride is added 20mL ethyl acetate after being spin-dried for filtrate, is then washed twice with 15mL saturated aqueous sodium carbonates, then use
15mL saturated sodium-chloride water solutions are washed once, collected organic layer, and anhydrous magnesium sulfate is added and is dried overnight, and next day, which filters, removes sulfuric acid
2g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column chromatography separation (dry method loading, V for magnesiumEthyl acetate:VPetroleum ether=1:8)
Obtain 1- Oxyranyles -5- (the amyl- 3- alkenyls-azetidines of 3- oxiranylmethyl radical -2- oxos -4-) -1H- pyrazoles -3-
Formonitrile HCN.
2mmol1- Oxyranyles -5- (3- epoxy second will be added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
The amyl- 3- alkenyls-azetidines of alkyl methyl -2- oxos -4-) -1H- pyrazoles -3- formonitrile HCNs, 4mmol CuCl2With 30mL isopropyls
Alcohol seals reaction kettle outer tank, is put into microwave-hydrothermal method instrument, power 300W, is warming up to 100 DEG C, keeps 30min.Reaction terminates
Afterwards, it is cooled to room temperature, reaction solution, which is transferred to removing excess of solvent in revolving bottle, obtains thick liquid, is then used in separatory funnel
30mL ethyl acetate and 70mL water are extracted, and are collected organic phase and are removed excess of solvent, and anhydrous magnesium sulfate is added and is dried overnight, secondary
It filters day and removes magnesium sulfate, 3g silica whites are added into filtrate and are spin-dried for, silica gel column chromatography detaches (dry method loading, VEthyl acetate:VPetroleum ether
=1:4) final product 1- epoxy ethyls -5- (the amyl- 3- alkenyls-azetidins of 3- oxiranylmethyl radical -2- oxos -4- are obtained
Alkane) -1- pyrazoles -3- carboxylic acid isopropyls (A4)。
Scheme 2：
Compound 5- amino -1- oxiranylmethyl radical -1H- pyrazoles -3- formonitrile HCNs are by 2- amino -4- cyano-ethyl butyrate
Synthesis with ethylene oxide -2- amine is the same as scheme 1.
2mmol5- amino -1- oxiranylmethyl radicals-will be added into the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
1H- pyrazoles -3- formonitrile HCNs, 4mmol CuCl2With 30mL isopropanols, reaction kettle outer tank is sealed, is put into microwave-hydrothermal method instrument, microwave
Power 300W is warming up to 120 DEG C, keeps 30min.After reaction, it is cooled to room temperature, reaction solution is transferred in revolving bottle and is removed
It goes excess of solvent to obtain thick liquid, is then extracted with 30mL ethyl acetate and 70mL water in separatory funnel, collected organic
Excess of solvent is mutually removed, anhydrous magnesium sulfate is added and is dried overnight, next day, which filters, removes magnesium sulfate, and 3g silica whites are added into filtrate
It is spin-dried for, silica gel column chromatography detaches (dry method loading, VEthyl acetate:VPetroleum ether=1:4) 5- amino -1- Oxyranyle -1- pyrazoles-is obtained
3- carboxylic acid isopropyls.
5- amino -1- Oxyranyles-the 1H- being collected into is added in the dedicated polytetrafluoroethylliner liner of microwave hydrothermal instrument
The amyl- 3- olefine aldehydrs of pyrazoles -3- carboxylic acid isopropyls 5mmol and 5mmol, 0.1g p-methyl benzenesulfonic acid, 4A molecular sieves 1g and solvent toluene
30mL seals reaction kettle outer tank, is put into microwave-hydrothermal method instrument, microwave power 300W, is heated to 120 DEG C, reacts 20min.Instead
It is filtered after answering, collects filtrate, addition 3g silica whites are spin-dried for into powdered into filtrate, and silica gel column chromatography separation is (dry
Method loading, VEthyl acetate:VPetroleum ether=1:8) 5- hex- 4- alkene yldeneamino -1- Oxyranyle -1H- pyrazoles -3- carboxylic acid isopropyls are obtained
Ester.
Dry reaction glass apparatus and magneton are taken out from baking oven, are reacted as follows under nitrogen protection：To glass
The 5- hex- 4- alkene yldeneamino -1- Oxyranyle -1H- pyrazoles -3- carboxylic acid isopropyls of 1mmol are added in glass instrument, note is used in combination
Emitter is drawn 2.5mmol anhydrous pyridines and 4mL anhydrous benzenes and is added in glass apparatus, then by 2.2mmol oxa-s cyclohexane-chloroacetic chloride
4mL benzole solns be slowly dropped in reaction system, about half an hour drips off, continue after dripping off stir 3h.After reaction, it filters
Pyridine hydrochloride is removed, 20mL ethyl acetate is added after being spin-dried for filtrate, is then washed twice with 15mL saturated aqueous sodium carbonates, then
It is washed once with 15mL saturated sodium-chloride water solutions, collected organic layer, anhydrous magnesium sulfate is added and is dried overnight, next day, which filters, removes desulfuration
2g silica whites are added into filtrate and are spin-dried for into powdered, silica gel column chromatography separation (dry method loading, V for sour magnesiumEthyl acetate:VPetroleum ether=1:
10) 1- epoxy ethyls -5- (the amyl- 3- alkenyls-azetidines of 3- oxiranylmethyl radical -2- oxos -4-) -1- pyrazoles -3- is obtained
Carboxylic acid isopropyl (A4)。
Embodiment 5
Separately or concurrently change the aza-oxo-cyclobutane pyrazoles in embodiment 1 in scheme 1 and synthesizes the anti-of final product
Between seasonable and synthesis mode, the microwave power 300W of microwave-hydrothermal method, other operations are identical with embodiment 1, prepare chemical combination
Object, the result for preparing result and embodiment 1 are listed in the table below in 1 simultaneously.
The synthesis of compound 1 and yield under 1. different condition of table
From comparative example 1~3 three group, comparative example can be seen that microwave-hydrothermal method and can within a short period of time reach compared with high yield
Rate, and individually hydro-thermal method and microwave method combined coefficient are all without microwave-hydrothermal method height.Prove that microwave-hydrothermal method applies to oxo
In azetidine pyrazoles building-up process, effectively microwave method and hydro-thermal method are combined together really, microwave is made full use of to add
The advantages that high temperature and pressure of the closed generation of uniformity and hydro-thermal method of heat, allows both methods to generate synergistic effect, has merged this
The advantages of two methods, produces very positive experimental result.Also the release of the novelty technology is used for pyrazoles carboxylic to the application
The synthesis of acid esters.
Embodiment 6, the control effect for posting silkworm fly
Choose compound A prepared by the scheme 1 of embodiment 1-41~A4To prepare missible oil dispersant.1.01g is first weighed respectively
Compound (purity is 99%), be dissolved in the glycol monoethyl ether of 8.49g, then to weigh the agricultural packet-B3- of 0.50g compound
Emulsifier is mixed uniformly and stirs 30min, respectively obtains compound A1~A4Mass percent concentration be 10% it is equal
Even missible oil is spare, is diluted with water to required concentration in actual use.
It is that test worm progress silkworm posts fly efficiency test to be slept white with cultivated silkworm breed variety three, and each experimental group handles 500 five ages 4
~6 age in days silkworms, use distilled water that above-mentioned missible oil is diluted to 500 respectively, 200,100,50mg/L is uniformly sprayed on as liquid
On mulberry leaf, until it is degree that mulberry leaf, which are covered with liquid, it is fed to corresponding silkworm, processing number and label is carried out, ensures that family nibbles drug containing
Mulberry leaf 3 days or more ensure that its absorbs liquid, and carry out trace labelling, and silkworm cocooning after raising 15 days plucks cocoon investigation.It sets simultaneously
Fixed not dispenser is blank control group, and other conditions are identical as experimental group, silkworm cocooning after raising 15 days, plucks cocoon investigation, and calculate
Cocooning rate.
It is 20.63% that the silkworm of blank control group, which posts fly parasitic rate, and the cocooning rate of blank control group is 69.8%.
Each compound a concentration of 500,200,100,50mg/L when post silkworm the control effect percentage and normalizing of fly
Change cocooning rate and is respectively placed in Fig. 1 a-d.
For post fly pesticide control screening, one of screening index be preventive effect be not less than 80%, screening index second is that normalizing
Change cocooning rate and is not less than 90%.By Fig. 1 a as it can be seen that the compound A of 500mg/L4Preventive effect to posting fly is less than 80% (low gradient ratio
No longer listed in relatively), preventive effect when remaining compound concentration is 500mg/L is above 80%.By Fig. 1 b it is found that compound concentration
For 200mg/L when, while the compound for meeting cocooning rate screening index and preventive effect screening index is A1、A2And A3；It can by Fig. 1 c
Know, when compound concentration is 100mg/L, while the compound for meeting Cocooning rate screening index and preventive effect screening index is compound
A1, A2And A3；By Fig. 1 d it is found that when compound concentration is 50mg/L, while meeting cocooning rate screening index and preventive effect screening index
Compound be compound A3。
Calculation formula：
Cocooning rate %=(number/500 of cocooing) * 100%；Parasitic rate %=(maggot cocoon number/cocooning number) * 100；Control effect %
=((blank control group parasitic rate-processing group parasitic rate)/blank control group parasitic rate) * 100% normalizes cocooning rate %=ization
Close the cocooning rate * 100% of cocooning rate/blank control group of object processing group.
Embodiment 7, the activity to staphylococcus aureus
By the compound A that embodiment 1-4 schemes 1 are made1-A4It is dissolved in DMSO respectively, is made into the dense of 0.1% (m/v) in advance
Degree, each compound is then diluted to 0.5 respectively with 1% (m/v) acetic acid distilled water solution, 0.25,3 kinds of 0.125mg/L it is dense
Degree is used as test sample, and positive control drug is Ciprofloxacin, be directly configured to 0.5 with 1% (m/v) acetic acid distilled water, 0.25,
3 kinds of concentration of 0.125mg/L, negative control group are 1% (m/v) acetum.With tweezers by the circular sterilization filter paper of diameter 6mm
Piece is respectively put into prepared various concentration solution, and negative and positive control equally operates.These scraps of paper are attached to and are coated with gold
On the Solid agar culture of staphylococcus aureus.Then culture medium is placed in constant incubator, cultivates for 24 hours, goes at 37 DEG C
All antibacterial circle diameters are accurately measured after removing with vernier caliper, evaluate the bacteriostatic activity height of test compound, ++ indicate high living
Property ,+indicate medium activity ,-indicate that activity is weaker.Test result is shown in Table 2.It can be seen that compound A1When a concentration of 0.5mg/L
Fungistatic effect is best, and fungistatic effect of the compound A-13 in a concentration of 0.5mg/L and 0.25mg/L is all fine, and the change of low concentration
Polymer solution does not have the good of high concentration to fungistatic effect.
The anti-Staphylococcus aureus activity of 2 compound A1~A4 of table
Claims (10)
1. one kind being based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds, shown in structural formula such as general formula (IV)：
In the general structure (IV)：R1Selected from saturation alkyl group, naphthenic base, alkoxy, furyl, pyrrole radicals, thienyl, pyrrole
One kind in piperidinyl, quinolyl, indyl, substituted phenyl, unsubstituted phenyl, it is described substitution be it is monosubstituted or polysubstituted,
Substituted position is phenyl ring ortho position, meta or para position, substituted group be halogen, alkyl, alkoxy, hydroxyl, halogen, nitro or
Trifluoromethyl；
R2For substituted phenyl, unsubstituted phenyl, furyl, substituted furyl, pyrrole radicals, thienyl, pyridyl group, quinoline
Base or indyl, it is phenyl ring ortho position, meta or para position, substituted base that the substitution, which is monosubstituted or polysubstituted, substituted position,
Group is alkyl, alkoxy, hydroxyl, halogen or nitro；
R3Selected from H, halogen, naphthenic base, halogenated alkyl, substituted phenyl, unsubstituted phenyl, furyl, pyrrole radicals, thienyl, pyrrole
Piperidinyl, quinolyl or indyl, it is phenyl ring ortho position, meta or para position that the substitution, which is monosubstituted or polysubstituted, substituted position,
Substituted group is alkyl, alkoxy, hydroxyl, carbonyl, halogenated alkyl, halogen or nitro；
R4For R4- OH takes off the group after-OH, R4- OH is saturated alkyl alcohol, cycloalkyl alcohol, phenol, substituted benzyl alcohol, does not take
One kind in the benzyl alcohol in generation, it is phenyl ring ortho position, meta or para position that the substitution, which is monosubstituted or polysubstituted, substituted position,
Substituted group is alkyl, alkoxy, hydroxyl or halogen.
2. according to claim 1 be based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds, it is characterised in that：The R1
For-CH3、-CH2CH3、-CH2CH2CH3、-(CH2)4CH3、-OCH3、X therein is halogen；
The R2For R2- CHO takes off the group after-CHO, R2- CHO be selected from it is following any one：Benzaldehyde, 4- methoxybenzene first
The fluoro- 4- bromobenzaldehydes of aldehyde, 2,3 dichloro benzaldehyde, 2-, 2,5- difluorobenzaldehydes, 2,6- dimethylbenzaldehydes, the bromo- 4- hydroxyls of 3-
Benzaldehyde, 4- fluorobenzaldehydes, 4- chlorobenzaldehydes, 3,5- bis- (trifluoromethyl) benzaldehyde, 2 furan carboxyaldehyde, 5- methyl -2- furans
Formaldehyde, 2- pyrrole aldehydes, 3- pyrrole aldehydes, 2 thiophene carboxaldehyde, 2- pyridine carboxaldehydes；
R3Any one in following group：-H、CH3-、Cl、Substituted phenyl and unsubstituted benzene
Base；
R4Any one in following group：-CH3、-CH2CH3、-CH2CH2CH3 -(CH2)3CH3、-(CH2)4CH3、-(CH2)5CH3、
3. a kind of synthesis method as claimed in claim 1 or 2 based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds：
Its synthetic route is as follows：
(1) by pyrazole derivativesIt is added in microwave hydrothermal instrument, aldehyde, molecular sieve and solvent toluene is added, with strong acid first
Benzene sulfonic acid is reacted as catalyst, synthesizes the methylene amino-pyrazol analog derivative with carbon-to-nitrogen double bon structure
(2) in nitrogen environment, alkali anhydrous pyridine, solvent anhydrous benzene, stirring are added into methylene amino-pyrazol analog derivative
Acyl chlorides is added dropwise in 30min dropwiseIt after dripping, stirs 3 hours, isolates and purifies to obtain oxo aza ring after the completion of reaction
Butane pyrazole derivatives
(3) aza-oxo-cyclobutane pyrazole derivatives, catalyst are added into the polytetrafluoroethylliner liner of microwave hydrothermal reaction kettle
With solvent R4OH is put into after sealing reaction kettle in microwave hydrothermal instrument, microwave power 300-500W, is warming up to and is boiled higher than solvent
5-10 DEG C of point, reaction 10-60min are cooled to room temperature after reaction, remove excess of solvent, and extraction, purification obtain being based on oxygen
For azetidine pyrazole carboxylic acid ester compounds；
Reaction temperature described in step (1) is 120 DEG C, microwave power 300-500W, reaction time 10-60min；
Aldehyde is furans -2- formaldehyde, 4- methyl-ribofuranosyl -2- formaldehyde, 3- hydroxy-4-methyls-benzaldehyde or amyl- in the step (1)
3- olefine aldehydrs；
Catalyst is selected from lewis acid in the step (3)；
Solvent R in the step (3)4OH is saturated alkyl alcohol, cycloalkyl alcohol, phenol, substituted benzyl alcohol, unsubstituted benzyl
One kind in alcohol, it is phenyl ring ortho position, meta or para position, substituted base that the substitution, which is monosubstituted or polysubstituted, substituted position,
Group is alkyl, alkoxy, hydroxyl or halogen.
4. according to the method described in claim 3, it is characterized in that：The catalyst is selected from FeCl3、AlCl3、ZnCl2、CoCl2、
CuCl2And SnCl4In any one.
5. according to the method described in claim 3, it is characterized in that：Aza-oxo-cyclobutane pyrazoles spread out in the step (3)
The volumetric ratio of biology, the dosage of catalyst and polytetrafluoroethylliner liner is 1mmol:(2-6)mmol:50mL.
6. according to the method described in claim 3, it is characterized in that：Pyrazole derivatives, aldehyde and strong acid dosage in the step (1)
Than for 5mmol:5mmol:(0.1-0.3)g；
The amount ratio of step (2) Central Asia methylamino pyrazole derivatives, alkali and acyl chlorides is 1mol:(2-3)mol:(2-3)
mol。
7. a kind of synthesis method as claimed in claim 1 or 2 based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds：
Its synthetic route is as follows：
Include the following steps successively：
(1) pyrazole derivatives are added into the polytetrafluoroethylliner liner of microwave hydrothermal reaction kettleCatalyst and molten
Agent R4OH is put into after sealing reaction kettle in microwave hydrothermal instrument, microwave power 300-500W, is warming up to the boiling point 5- higher than solvent
10 DEG C, reaction 10-60min is cooled to room temperature after reaction, removes excess of solvent, and extraction, purification obtain carboxylate chemical combination
Object；
(2) carboxylate compound is added in microwave hydrothermal instrument, aldehyde, molecular sieve and solvent toluene is added, with strong acid to toluene sulphur
Acid as catalyst reacts, and synthesizes intermediate product iminopyrazoles carboxylate compound；
(3) and then in nitrogen environment, alkali anhydrous pyridine, solvent are added into intermediate product iminopyrazoles carboxylate compound
Anhydrous benzene stirs 30min, acyl chlorides is added dropwise dropwiseIt after dripping, stirs 3 hours, isolates and purifies to obtain after the completion of reaction
Based on aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds；
Catalyst described in step (1) is selected from lewis acid；
Solvent R described in step (1)4OH is one in saturated alkyl alcohol, cycloalkyl alcohol, phenol, substituted or unsubstituted benzyl alcohol
Kind, it is phenyl ring ortho position, meta or para position that the substitution, which is monosubstituted or polysubstituted, substituted position, substituted group be alkyl,
Alkoxy, hydroxyl or halogen；
Reaction temperature described in step (2) is 120 DEG C, microwave power 300-500W, reaction time 10-60min；
Aldehyde is furans -2- formaldehyde, 4- methyl-ribofuranosyl -2- formaldehyde, 3- hydroxy-4-methyls-benzaldehyde or amyl- in the step (2)
3- olefine aldehydrs.
8. according to the method described in claim 7, it is characterized in that：Catalyst is selected from FeCl in the step (1)3、AlCl3、
ZnCl2、CoCl2、CuCl2And SnCl4In any one.
9. according to the method described in claim 8, it is characterized in that：Carboxylate compound, aldehyde and strong acid are used in the step (2)
Amount is than being 5mmol:5mmol:(0.1-0.3)g；Intermediate product iminopyrazoles carboxylate compound in the step (3), alkali with
The amount ratio of acyl chlorides is 1mol:(2-3)mol:(2-3)mol.
10. a kind of aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds object as claimed in claim 1 or 2 that is based on is harmful to elder brother in prevention
Application in worm and/or mite pest；
Application according to claim 10, it is characterised in that：The harmful insect include Orthoptera, Thysanoptera, Homoptera,
Heteroptera, Lepidoptera, coleoptera and/or Diptera harmful insect；
One kind aza-oxo-cyclobutane pyrazole carboxylic acid ester compounds as claimed in claim 1 or 2 that are based on are in anti-Staphylococcus aureus
Application in bacterium, sensitive aerobic gram-negative bacteria and/or proteus vulgaris.
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| CN109020930A (en) * | 2013-03-14 | 2018-12-18 | 微麦德斯公司 | The method of purification of 5- (halogenated methyl) furfural |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3872086A (en) * | 1970-11-03 | 1975-03-18 | Glaxo Lab Ltd | Certain disulfide derivatives of 2-azetidinones |
| CN1228430A (en) * | 1998-01-20 | 1999-09-15 | 普利瓦药物，化学，食品，化妆品工业公司 | 1-isothiazolidinone derivatives of azetidine-2-one, processes for preparation thereof and use thereof |
| JP2007291004A (en) * | 2006-04-25 | 2007-11-08 | Kotobuki Seiyaku Kk | Azulene derivative and serum cholesterol-reducing agent containing the same as active substance |
| CN105636441A (en) * | 2013-10-17 | 2016-06-01 | 美国陶氏益农公司 | Processes for the preparation of pesticidal compounds |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3872086A (en) * | 1970-11-03 | 1975-03-18 | Glaxo Lab Ltd | Certain disulfide derivatives of 2-azetidinones |
| CN1228430A (en) * | 1998-01-20 | 1999-09-15 | 普利瓦药物，化学，食品，化妆品工业公司 | 1-isothiazolidinone derivatives of azetidine-2-one, processes for preparation thereof and use thereof |
| JP2007291004A (en) * | 2006-04-25 | 2007-11-08 | Kotobuki Seiyaku Kk | Azulene derivative and serum cholesterol-reducing agent containing the same as active substance |
| CN105636441A (en) * | 2013-10-17 | 2016-06-01 | 美国陶氏益农公司 | Processes for the preparation of pesticidal compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109020930A (en) * | 2013-03-14 | 2018-12-18 | 微麦德斯公司 | The method of purification of 5- (halogenated methyl) furfural |
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