CN108658942B - Oxoazetidine pyrazole carboxylate compound and microwave hydrothermal method synthesis method and application thereof - Google Patents
Oxoazetidine pyrazole carboxylate compound and microwave hydrothermal method synthesis method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis, in particular to an oxoazetidine pyrazole carboxylate compound and a microwave hydrothermal synthesis method and application thereof. On the basis of synthesizing the oxo-azetidine pyrazole derivative, an ester group is introduced on a pyrazole ring to synthesize an oxo-azetidine pyrazole carboxylic ester compound, so that the combination of the oxo-azetidine structure and the ester group structure of the pyrazole compound is realized, and a compound with a novel structure is provided; the invention uses Lewis acid as a catalyst to provide acidic conditions, and utilizes a microwave hydrothermal method to synthesize the oxoazetidine pyrazole carboxylate compound. The prepared compound has good application prospect in preventing and controlling harmful insects, mite pests, staphylococcus aureus and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to an oxoazetidine pyrazole carboxylate compound and a microwave hydrothermal synthesis method thereof, and also relates to application of the compound.
Background
The pyrethroid insecticides are applied to the prevention and treatment of agricultural pests in large quantity by destroying axon ion channels, and are an indispensable insecticide, and are characterized by high activity, low toxicity, low residue and easy degradation, because the combination of the ester pesticides and cholinesterase is reversible and is quickly hydrolyzed in a body, and the activity of the cholinesterase is easy to recover, the toxic action is light, namely, ester prodrugs have the advantages of high stability, long action time, good solubility, low toxic and side effects and the like, the oxoazetidine belongs to β -lactam compounds, the structure widely exists in sterilizing and anti-inflammatory drugs, is an important component for treating various infections such as septicemia, and for example, aztreonam resisting gram-negative bacteria is a drug containing an oxoazetidine structure, because the two structures have good biological activity, the common activity can be used in the field of synthesis for modifying the splicing technology, and the parent compound contains an oxoazetidine structure, and the pyrazoles are introduced into a new azacyclic structure.
For derivatization of an organic functional group cyano, a nitrogen atom on the cyano group is generally protonated, a lone pair electron of an oxygen atom on an alcohol and the protonated cyano group undergo a nucleophilic addition reaction, and finally the lone pair electron is converted into an ester group or an amide functional group in an acidic environment. Because the cyano group at the 3-position on the pyrazole ring and the pyrazole ring form a conjugated structure, the nucleophilic reaction activity is greatly reduced, the derivatization difficulty is greatly enhanced, and no report about direct esterification of the cyano group on the pyrazole ring exists at present.
Microwave technology has been developed in the 30 s of the 20 th century and is gradually applied to various fields along with development. The application of microwave radiation to organic synthesis is in the 60 s of the 20 th century, and the promotion of organic chemical reactions by microwave radiation has become a research hotspot and a new research field in the decades. The organic reaction efficiency under microwave radiation is greatly improved, some reactions which are difficult to realize by conventional heating reflux can also be realized under the action of microwaves, and the method has the advantages of simple operation, high yield, short time, easy recovery and the like. The hydrothermal method was studied beginning in the 19 th century. After 1900 years, scientists built the theory of hydrothermal synthesis and started to turn to the research of functional materials. Under hydrothermal conditions, the solvent may act as a chemical component and participate in the reaction. The existing hydrothermal method adopts a high-pressure reaction kettle as a container, and the conditions of high temperature and high pressure are achieved in a closed environment, so that the reaction is promoted. The microwave hydrothermal method integrates the advantages of the two methods, namely, microwave is used as a heating tool to realize stirring on a molecular level, the defect of uneven heating of a hydrothermal container is overcome, the reaction time is shortened, the working efficiency is improved, and the method has the advantages of high heating speed, uniform heating, no temperature gradient, no hysteresis effect and the like, and is a very effective novel organic synthesis method.
Disclosure of Invention
The main common method for derivatization of cyano groups is to provide acidic conditions by HCl gas, so that the cyano groups and alcohol are subjected to hydrolysis reaction to generate carboxylic ester or amide compounds, the selectivity is poor, and the reaction conditions need to be controlled more rigorously to generate esterification products. Meanwhile, the used HCl gas needs hydrogen and chlorine to be prepared at a high temperature of 250 ℃ in real time, the conditions are harsh, the operation is inconvenient, the post-treatment of the strong acid waste liquid is complicated, and the large-scale industrial production is difficult to carry out.
Based on the consideration, the invention designs and provides a compound with a novel structure, namely the oxoazetidine pyrazole carboxylate compound, by an active structure splicing principle, and provides two synthetic schemes. Scheme 1: reacting pyrazole derivative of oxo-azetidine with alcohol, and using Lewis acid as catalyst, preferably ferric trichloride or CuCl2And (3) as an acid catalyst, protonating the nitrogen atom on the cyano group at the 3-position on the pyrazole ring, carrying out nucleophilic addition reaction on the lone pair electron of the oxygen atom on the alcohol and the protonated cyano group, and converting into an ester group in an acid environment by a one-step method to generate the oxo-azetidine pyrazole carboxylate compound. Scheme 2: reacting pyrazole derivative as precursor with alcohol in the presence of Lewis acid as catalyst, preferably ferric trichloride or CuCl2Preparing an acid catalyst to generate a pyrazole carboxylic ester compound; then reacting with aldehyde and acyl chloride in alkaline environment to obtain the oxoazetidine pyrazole carboxylate compound.
The microwave technology is applied to organic synthesis reaction, the reaction speed is increased by dozens of even thousands of times compared with the conventional method, and the microwave technology is more and more widely applied to materials, pharmacy, chemical industry and other related fields. The hydrothermal method can provide a high-temperature and high-pressure closed environment, and can accelerate the dissolution of raw materials and the precipitation of products when applied to organic synthesis. The microwave hydrothermal method combining the advantages of the microwave hydrothermal method and the hydrothermal container can utilize the microwave as a heating tool, realize stirring on a molecular level, overcome the defect of uneven heating of the hydrothermal container, shorten reaction time, improve working efficiency, and have the advantages of high heating speed, even heating, no temperature gradient, no hysteresis effect and the like. In recent years, inorganic functional materials are prepared by a microwave hydrothermal method, and the application of the inorganic functional materials to organic synthesis is rare.
Based on the consideration, the method selectively converts the cyano into the ester group by the microwave hydrothermal method, and the preferable Lewis acid catalyst is convenient and easy to obtain, simple and convenient to operate, simple in post-treatment, greatly reduced in toxicity, more environment-friendly and safer, higher in yield and convenient for actual production.
The carbamate compound as pesticide has the advantages of fast acting, high selectivity, biodegradation, etc. the oxoazetidine belongs to β -lactam compound, and the structure is widely present in sterilizing, inflammation diminishing and virus resisting medicine and is an important component for treating various infections, such as septicemia, etc.
Based on the consideration, a series of compounds based on oxoazetidine pyrazole carboxylate are synthesized by introducing oxoazetidine pyrazole carboxylate onto amino at 5-position and introducing ester group onto cyano at 3-position of a pyrazole ring through active structure splicing. Through the splicing of the active structure, the combination of the pyrazole compound containing the oxo-azetidine and the ester compound is realized, so that the pyrazole compound has the biological active structure of both the oxo-azetidine and the ester compound.
Based on the above considerations, the three inventive objects of the present invention are respectively:
1. provided is an oxoazetidine pyrazole carboxylate compound having a structural formula shown in general formula (IV):
in the structural general formula (IV): r1One of saturated chain alkyl, cycloalkyl, alkoxy, furyl, pyrrolyl, thienyl, pyridyl, quinolyl, indolyl and substituted or unsubstituted phenyl, and the substitution is one or more ofThe position of (A) is ortho, meta or para of the benzene ring, and the substituted group is halogen, alkyl, alkoxy, hydroxyl, halogen, nitro or trifluoromethyl;
R2is phenyl, substituted phenyl, furyl, substituted furyl, pyrrolyl, thienyl, pyridyl, quinolyl or indolyl, the substitution is mono-substitution or poly-substitution, the substitution position is ortho-position, meta-position or para-position of a benzene ring, and the substituted group is alkyl, alkoxy, hydroxyl, halogen or nitro;
R3selected from H, halogen, cycloalkyl, haloalkyl, substituted phenyl, furyl, pyrrolyl, thienyl, pyridyl, quinolyl or indolyl, wherein the substitution is mono-substitution or multi-substitution, the substitution position is ortho, meta or para position of a benzene ring, and the substitution group is alkyl, alkoxy, hydroxyl, carbonyl, haloalkyl, halogen or nitro;
R4is R4R in-OH4I.e. R4-OH-free of hydroxyl groups, R4-OH is one of saturated alkyl alcohol, cycloalkyl alcohol, phenol, substituted or unsubstituted benzyl alcohol, the substitution is mono-or poly-substituted, the substitution position is ortho, meta or para to the phenyl ring, and the substituted group is alkyl, alkoxy, hydroxyl or halogen;
preferably, said R is1is-CH3、-CH2CH3、-CH2CH2CH3、
-(CH2)3CH3、
-(CH2)4CH3、-OCH3、
Wherein X is halogenA peptide;
R2is R2-CHO-deprived-CHO group, preferably, said R2-CHO is selected from any one of: benzaldehyde, 4-methoxybenzaldehyde, 2, 3-dichlorobenzaldehyde, 2-fluoro-4-bromobenzaldehyde, 2, 5-difluorobenzaldehyde, 2, 6-dimethylbenzaldehyde, 3-bromo-4-hydroxybenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 3, 5-bis (trifluoromethyl) benzaldehyde, 2-furaldehyde, 5-methyl-2-furaldehyde, 2-pyrrolecarbaldehyde, 3-pyrrolecarbaldehyde, 2-thiophenecarbaldehyde, 2-pyridinecarboxaldehyde;
preferably, R3Independently selected from any one of the following groups: -H, CH3-、Cl、
And substituted or unsubstituted phenyl;
preferably, R4Independently selected from any one of the following groups: -CH3、-CH2CH3、-CH2CH2CH3、
-(CH2)3CH3、
-(CH2)4CH3、-(CH2)5CH3、
2. The second purpose of the invention is to provide two methods for synthesizing the compound with the structural formula shown as the general formula (IV), and the method is simple, convenient, efficient, environment-friendly, low in toxicity and high in yield.
The method for synthesizing the compound represented by the general formula (iv) of the present invention can be prepared by the following scheme 1 or scheme 2:
scheme 1: a synthetic route to compounds of formula (IV):
(1) pyrazole derivatives
Adding into a microwave hydrothermal instrument, adding aldehyde, a molecular sieve and a solvent toluene, using strong acid toluenesulfonic acid as a catalyst to react, and synthesizing the methyleneamino pyrazole derivative with a carbon-nitrogen double bond structure
(2) Adding anhydrous pyridine and anhydrous benzene as solvent into methyleneamino pyrazole derivative in nitrogen environment, stirring for 30min, and dropwise adding acyl chloride
After the dropwise addition, stirring for 3 hours, and separating and purifying after the reaction is finished to obtain the oxo-azetidine pyrazole derivative
(3) Adding oxo-azetidine pyrazole derivative, catalyst and solvent R into a polytetrafluoroethylene liner of a microwave hydrothermal reaction kettle4OH, sealing the reaction kettle, putting the reaction kettle into a microwave hydrothermal instrument, heating the reaction kettle to 5-10 ℃ higher than the boiling point of the solvent with the microwave power of 500W, reacting for 10-60min, cooling to room temperature after the reaction is finished, removing the redundant solvent, and extracting and purifying to obtain the oxoazetidine pyrazole carboxylate compound;
R1、R2、R3as described above;
in the step (1), the reaction temperature is 120 ℃, the microwave power is 300-;
in the step (1), the aldehyde is furan-2-formaldehyde, 4-methyl-furan-2-formaldehyde, 3-hydroxy-4-methyl-benzaldehyde or pent-3-enal;
the catalyst in the step (3) is selected from Lewis acid;
in the step (3)Solvent R4OH is one of saturated alkyl alcohol, cycloalkyl alcohol, phenol, substituted benzyl alcohol and unsubstituted benzyl alcohol, the substitution is mono-substitution or poly-substitution, the substitution position is ortho-position, meta-position or para-position of a benzene ring, and the substituted group is alkyl, alkoxy, hydroxyl or halogen.
Further, the catalyst is selected from FeCl3、AlCl3、ZnCl2、CoCl2、CuCl2And SnCl4Any one of the above; preferably, the catalyst is FeCl3Or CuCl2；
Preferably, the solvent R is4OH is saturated alkyl alcohol;
preferably, the reaction time in the steps (1) and (3) is 20-30 min;
preferably, the microwave power in the steps (1) and (3) is 300W-350W;
further, the volume ratio of the oxoazetidine pyrazole derivative and the catalyst to the polytetrafluoroethylene inner container in the step (3) is 1mmol (2-6) mmol to 50mL, preferably 1mmol to 2mmol to 50 mL;
further, in the step (3), the oxoazetidine pyrazole derivative, the catalyst and the solvent R4The dosage ratio of OH is 1mmol (2-6) mmol (10-20) mL, preferably 1mmol:2mmol:15 mL;
further, pyrazole derivatives in the step (1)
The ratio of the aldehyde to the strong acid is 5mmol: (0.1-0.3) g, preferably 5mmol:5mmol:0.1 g.
Further, in the step (2), the acyl chloride is a benzene solution of cyclopropyl-acetyl chloride;
furthermore, the dosage ratio of the methylamino pyrazole derivative, the base and the acyl chloride in the step (2) is 1mol (2-3) mol, preferably 1mol:2.5mol:2.2 mol.
Scheme 2:
the method comprises the following steps in sequence:
(1) adding pyrazole derivative into microwave hydrothermal polytetrafluoroethylene liner
Catalyst and solvent R4OH, sealing the reaction kettle, putting the reaction kettle into a microwave hydrothermal instrument, heating the reaction kettle to 5-10 ℃ higher than the boiling point of the solvent by using the microwave power of 300-500W, reacting for 10-60min, cooling to room temperature after the reaction is finished, removing the redundant solvent, and extracting and purifying to obtain a carboxylate compound;
(2) adding a carboxylate compound into a microwave hydrothermal instrument, adding aldehyde, a molecular sieve and a solvent toluene, and reacting by using strong acid as a catalyst to synthesize an intermediate product, namely an imino pyrazole carboxylate compound;
(3) then adding alkali anhydrous pyridine and solvent anhydrous benzene into the intermediate product imino pyrazole carboxylic ester compound in nitrogen environment, stirring for 30min, and dropwise adding acyl chloride
After the dropwise addition is finished, stirring for 3 hours, and after the reaction is finished, separating and purifying to obtain the oxoazetidine pyrazole carboxylate-based compound;
further, the catalyst in step (1), the aldehyde, the strong acid, the base, and the acid chloride in step (2) are the catalyst, the aldehyde, the strong acid, the base, and the acid chloride in scheme 1;
further, the solvent R in the step (1)4OH is one of saturated alkyl alcohol, cycloalkyl alcohol, phenol and substituted or unsubstituted benzyl alcohol, the substitution is mono-substitution or poly-substitution, the substitution position is ortho-position, meta-position or para-position of a benzene ring, and the substituted group is alkyl, alkoxy, hydroxyl or halogen;
further, in the step (2), the reaction temperature is 120 ℃, the microwave power is 300-500W, and the reaction time is 10-60 min; preferably, the reaction time in the steps (1) and (2) is 20-30 min; preferably, the microwave power in the steps (1) and (2) is 300W-350W;
further, the using amount ratio of the carboxylate compound, the aldehyde and the strong acid in the step (2) is 5mmol to 5mmol (0.1-0.3) g;
furthermore, the volume ratio of the pyrazole derivative and the catalyst to the polytetrafluoroethylene inner container in the step (1) is 1mmol (5-15) mmol, and 50mL, preferably 1mmol (10 mmol) and 50 mL.
Further, the using amount ratio of the intermediate product imino pyrazole carboxylic ester compound in the step (3), the base and the acyl chloride is 1mol (2-3).
Pyrazole derivatives of the compound (I)
Reference documents: zhang Chang Jun, Cheng Zheng, Cao Xiao qun, et al, study on the Synthesis of fipronil [ J]The Shandong university of agriculture, 2009,40(1):145-147.
3. The third purpose of the invention is to provide the application of the compound with the structural formula shown as the general formula (IV) in the aspect of the test of controlling harmful insects (including orthoptera, thysanoptera, homoptera, heteroptera, lepidoptera, coleoptera and diptera), mite pests, staphylococcus aureus resistance, sensitive aerobic gram negative bacteria and common proteus, and the compound has good insecticidal effect and antibacterial effect.
Compared with the prior art, the invention has the following advantages and beneficial effects:
according to the invention, the 5-amino of the pyrazole ring is structurally modified to introduce oxoazetidine, and an ester group is introduced into the pyrazole ring, so that a series of oxoazetidine pyrazole carboxylate-based compounds are synthesized, the combination of the oxoazetidine structure and the ester group structure of the pyrazole compounds is realized, and a compound with a novel structure is provided;
in the synthesis method, the esterification of the general cyano mainly adopts HCl gas to provide acidic conditions, the reaction conditions are harsh, the post-treatment of the strongly acidic waste liquid is complicated, and the application of the reaction is greatly limited3And the 3-cyano group conjugated with the pyrazole ring is subjected to alcoholysis for the first time by serving as a catalyst to synthesize a series of compounds (IV) based on oxoazetidine pyrazole carboxylate
The method is stable and nontoxic, is convenient for post treatment, provides two synthesis schemes, can introduce the ester group and then introduce the oxoazetidine, also can introduce the oxoazetidine and then introduce the ester group, and can adjust the synthesis sequence in the process according to the requirements.
In addition, the microwave hydrothermal method is used in the reaction process, the microwave hydrothermal method and the hydrothermal method are combined, the advantages of uniformity of microwave heating, high temperature and high pressure generated by sealing of the hydrothermal method and the like are fully utilized, the two methods generate a synergistic effect, the advantages of the two methods are combined, and the method is applied to synthesis based on the oxoazetidine pyrazole carboxylate compound, so that the reaction yield is further improved.
Drawings
Fig. 1 is a schematic diagram of the control effect and normalized cocooning rate of the compound of different concentrations on the fly larvae in example 6.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.
The 5-amino-1H-pyrazole-3-carbonitriles of the following examples 1 to 4 are references described by the Applicant in the summary of the invention: zhang Changjun, Chengzhou, Cao Xiao qun, et al, the study on the synthesis of fipronil [ J ], academic journal of Shandong university of agriculture, 2009,40(1):145-147.
The volume of the polytetrafluoroethylene liner used in the following examples was 100 mL.
Example 1.1 Synthesis of propyl- (3-chloro-phenyl) -5- (3-cyclopropylmethyl-2-furan-4-oxo-azetidine) -1H-pyrazole-3-carboxylate (A1)
Scheme 1:
the compound 5-amino-1- (3-chloro-phenyl) -1H-pyrazole-3-carbonitrile is prepared from ethyl 2-amino-4-cyano-butyrate and 3-chloro-aniline reference: zhang Changjun, Chengzhou, Cao Xiaoqu, et al, the study on the synthesis of fipronil [ J ], academic journal of Shandong university of agriculture, 2009,40(1):145-147.
Adding 5mmol of prepared 5-amino-1- (3-chloro-phenyl) -1H-pyrazole-3-carbonitrile, 5mmol of furan-2-formaldehyde, 0.1g of p-toluenesulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene into a special polytetrafluoroethylene liner for a microwave hydrothermal instrument, sealing a reaction kettle, placing into the microwave hydrothermal instrument with the microwave power of 300W, heating to 120 ℃, and reacting for 20 min. After the reaction, the mixture is filtered, the filtrate is collected, 3g of silica gel powder is added into the filtrate, the mixture is dried into powder, and the powder is separated by silica gel column chromatography (dry loading, V)Ethyl acetate：VPetroleum ether1:10) to give 1- (3-chloro-phenyl) -5- [ (furan-2-methylene) -amino]-1H-pyrazole-3-carbonitrile.
The dried reaction glass apparatus and magneton were removed from the oven and the following reaction was carried out under nitrogen protection: to the reaction apparatus was added 1mmol of 1- (3-chloro-phenyl) -5- [ (furan-2-methylene) -amino ] -ethyl acetate]-1H-pyrazole-3-carbonitrile, adding 2.5mmol of anhydrous pyridine and 4mL of anhydrous benzene into a reaction instrument by sucking with a syringe, slowly dropwise adding 4mL of benzene solution containing 2.2mmol of cyclopropyl-acetyl chloride into the reaction system for about half an hour, and stirring for 3H after dropwise adding. After the reaction, the pyridine hydrochloride was removed by suction filtration, the filtrate was spin-dried, 20mL of ethyl acetate was added, then washed twice with 15mL of saturated aqueous sodium carbonate solution, then washed once with 15mL of saturated aqueous sodium chloride solution, the organic layer was collected, anhydrous magnesium sulfate was added to the obtained organic layer, dried overnight, the magnesium sulfate was removed by suction filtration the next day, 2g of silica gel powder was added to the filtrate, spin-dried to a powder, and separated by silica gel column chromatography (dry sampling, V)Ethyl acetate：VPetroleum ether1:8) to give 1- (3-chloro-phenyl) -5- (2-furan-4-oxo-3-propyl-azetidin-1-yl) -1H-pyrazole-3-carbonitrile.
Adding 2mmol1- (3-chloro-benzene) into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrumentYl) -5- (2-furan-4-oxo-3-propyl-azetidin-1-yl) -1H-pyrazole-3-carbonitrile, 4mmol FeCl3And 30mL of propanol, sealing the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 105 ℃ at the microwave power of 300W, and keeping the temperature for 30 min. After the reaction is finished, cooling to room temperature, transferring the reaction liquid into a rotary evaporation bottle to remove excessive solvent to obtain a thick substance, extracting the thick substance in a separating funnel by using 30mL ethyl acetate and 70mL water, collecting an organic phase, removing the excessive solvent, adding anhydrous magnesium sulfate into the organic phase, drying overnight, performing suction filtration on the next day to remove the magnesium sulfate, adding 3g silica gel powder into the filtrate, performing rotary drying, and performing silica gel column chromatography separation (dry loading, V)Ethyl acetate：VPetroleum ether1:4) to give the final product, propyl 1- (3-chloro-phenyl) -5- (3-cyclopropylmethyl-2-furan-4-oxo-azetidine) -1H-pyrazole-3-carboxylate (a)1)。
Scheme 2:
the synthesis of compound 5-amino-1- (3-chloro-phenyl) -1H-pyrazole-3-carbonitrile is the same as in scheme 1.
Adding 2mmol 5-amino-1- (3-chloro-phenyl) -1H-pyrazole-3-carbonitrile and 4mmol FeCl into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument3And 30mL of propanol, sealing the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 105 ℃ at the microwave power of 300W, and keeping the temperature for 30 min. After the reaction is finished, cooling to room temperature, transferring the reaction liquid into a rotary evaporation bottle to remove excessive solvent to obtain a thick substance, extracting the thick substance in a separating funnel by using 30mL ethyl acetate and 70mL water, collecting an organic phase, removing the excessive solvent, adding anhydrous magnesium sulfate, drying overnight, filtering the mixture for the next day to remove the anhydrous magnesium sulfate, adding 3g silica gel powder into the filtrate, carrying out rotary drying, and carrying out silica gel column chromatography separation (dry loading, V)Ethyl acetate：VPetroleum ether1:4) to give 5-amino-1- (3-chloro-phenyl) -1H-pyrazole-3-carboxylic acid propyl ester.
Adding 5mmol of collected 5-amino-1- (3-chloro-phenyl) -1H-pyrazole-3-propyl carboxylate, 5mmol of furan-2-formaldehyde and 0.1g of p-methyl in a special polytetrafluoroethylene inner container for a microwave hydrothermal instrumentBenzene sulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene, sealing the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating the reaction kettle to 120 ℃ with the microwave power of 300W, and reacting for 20 min. After the reaction, the mixture is filtered, the filtrate is collected, 3g of silica gel powder is added into the filtrate, the mixture is dried into powder, and the powder is separated by silica gel column chromatography (dry loading, V)Ethyl acetate：VPetroleum ether1:10) to give 1- (3-chloro-phenyl) -5- [ (furan-2-methylene) -amino]-1H-pyrazole-3-carboxylic acid propyl ester.
The dried reaction glass apparatus and magnetons were removed from the oven and the following reactions were carried out under nitrogen protection: to the reaction apparatus was added 1mmol of 1- (3-chloro-phenyl) -5- [ (furan-2-methylene) -amino ] -ethyl acetate]-1H-pyrazole-3-carboxylic acid propyl ester, sucking 2.5mmol of anhydrous pyridine and 4mL of anhydrous benzene by using a syringe, adding the anhydrous pyridine and the anhydrous benzene into a reaction instrument, slowly dropwise adding 4mL of benzene solution containing 2.2mmol of cyclopropyl-acetyl chloride into the reaction system for about half an hour, and continuing stirring for 3 hours after dropwise adding. After the reaction, the pyridine hydrochloride is removed by suction filtration, the filtrate is spin-dried, 20mL of ethyl acetate is added, then the filtrate is washed twice with 15mL of saturated sodium carbonate aqueous solution and once with 15mL of saturated sodium chloride aqueous solution, the organic layer is collected, anhydrous magnesium sulfate is added into the organic layer for drying overnight, the magnesium sulfate is removed by suction filtration, 2g of silica gel powder is added into the filtrate for spin-drying into powder, and the powder is separated by silica gel column chromatography (dry loading, V)Ethyl acetate：VPetroleum ether1:8) to give 1- (3-chloro-phenyl) -5- (3-cyclopropylmethyl-2-furan-4-oxo-azetidine) -1H-pyrazole-3-carboxylic acid propyl ester (a)1)。
Example 2.5 Synthesis of- [ 3-cyclopentylmethyl-2- (4-methyl-furan) -4-oxo-azetidine ] -1- (3-hydroxy-phenyl) -1H-pyrazole-3-carboxylic acid butyl ester (A2)
Scheme 1:
the compound 5-amino-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carbonitrile was prepared from ethyl 2-amino-4-cyano-butyrate and 3-chloro-aniline, the synthesis was performed according to example 1.
Special poly-tetra for microwave water heaterAdding 5mmol of collected 5-amino-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carbonitrile, 5mmol of 4-methyl-furan-2-formaldehyde, 0.1g of p-toluenesulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene into a vinyl fluoride inner container, sealing a reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 120 ℃ with the microwave power of 300W, and reacting for 20 min. After the reaction, the mixture is filtered, the filtrate is collected, 3g of silica gel powder is added into the filtrate, the mixture is dried into powder, and the powder is separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:10) to give 1- (3-hydroxy-phenyl) -5- [ (4-methylfuran-2-methylene) -amino]-1H-pyrazole-3-carbonitrile.
The dried reaction glass apparatus and magnetons were removed from the oven and the following reactions were carried out under nitrogen protection: to the reaction apparatus was added 1mmol of 1- (3-hydroxy-phenyl) -5- [ (4-methylfuran-2-methylene) -amino]-1H-pyrazole-3-carbonitrile, and adding 2.5mmol of anhydrous pyridine and 4mL of anhydrous benzene into a reaction instrument by sucking with a syringe, slowly dropwise adding 4mL of benzene solution containing 2.2mmol of cyclopentyl-acetyl chloride into the reaction system for about half an hour, and stirring for 3H after dropwise adding. After the reaction, the pyridine hydrochloride was removed by suction filtration, the filtrate was spin-dried, 20mL of ethyl acetate was added, then washed twice with 15mL of saturated aqueous sodium carbonate solution, then washed once with 15mL of saturated aqueous sodium chloride solution, the organic layer was collected, anhydrous magnesium sulfate was added to the organic layer, dried overnight, the magnesium sulfate was removed by suction filtration the next day, 2g of silica gel powder was added to the filtrate, spin-dried to a powder, and separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:8) to give 1- (3-hydroxy-phenyl) -5- (4-methyl-furan-4-oxo-3-propyl-azetidine) -1H-pyrazole-3-carbonitrile.
Adding 2mmol1- (3-hydroxy-phenyl) -5- (4-methyl-furan-4-oxo-3-propyl-azetidine) -1H-pyrazole-3-carbonitrile and 4mmol FeCl into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument3And 30mL of propanol, sealing the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 105 ℃ at the microwave power of 300W, and keeping the temperature for 30 min. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred to a rotary evaporation flask to remove excess solvent to obtain a thick substance, and then extracted with 30mL of ethyl acetate and 70mL of water in a separatory funnel, and the organic phase was collectedRemoving excessive solvent, adding anhydrous magnesium sulfate into the organic phase, drying overnight, vacuum filtering to remove magnesium sulfate the next day, adding 3g silica gel powder into the filtrate, spin drying, and separating with silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:4) to give the final product 5- [ 3-cyclopentylmethyl-2- (4-methyl-furan) -4-oxo-azetidine]-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carboxylic acid butyl ester (A)2)。
Scheme 2:
the synthesis of the compound 5-amino-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carbonitrile from ethyl 2-amino-4-cyano-butyrate and 3-hydroxy-aniline is the same as in scheme 1 of this example.
Adding 2mmol 5-amino-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carbonitrile and 4mmol FeCl into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument3And 30mL of n-butanol, sealing the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 120 ℃ at the microwave power of 300W, and keeping the temperature for 30 min. After the reaction is finished, cooling to room temperature, transferring the reaction liquid into a rotary evaporation bottle to remove excessive solvent to obtain a thick substance, extracting the thick substance in a separating funnel by using 30mL ethyl acetate and 70mL water, collecting an organic phase, removing the excessive solvent, adding anhydrous magnesium sulfate into the organic phase, drying overnight, performing suction filtration on the next day to remove the magnesium sulfate, adding 3g silica gel powder into the filtrate, performing rotary drying, and performing silica gel column chromatography separation (dry loading, V)Ethyl acetate:VPetroleum ether1:4) to give 5-amino-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carboxylic acid butyl ester.
Adding 5mmol of collected 5-amino-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carboxylic acid butyl ester, 5mmol of 4-methyl-furan-2-formaldehyde, 0.1g of p-toluenesulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument, sealing an outer tank of a reaction kettle, putting the outer tank into the microwave hydrothermal instrument, heating to 120 ℃ at the microwave power of 300W, and reacting for 20 min. After the reaction, the mixture is filtered, the filtrate is collected, 3g of silica gel powder is added into the filtrate, the mixture is dried into powder, and the powder is separated by silica gel column chromatography (dry loading, V)Acetic acidEthyl ester:VPetroleum ether1:8) to give 1- (3-hydroxy-phenyl) -5- [ (4-methyl-furan-2-methylene) -amino]-1H-pyrazole-3-carboxylic acid butyl ester.
The dried reaction glass apparatus and magnetons were removed from the oven and the following reactions were carried out under nitrogen protection: to the reaction apparatus was added 1mmol of 1- (3-hydroxy-phenyl) -5- [ (4-methyl-furan-2-methylene) -amino]-1H-pyrazole-3-carboxylic acid butyl ester, sucking 2.5mmol of anhydrous pyridine and 4mL of anhydrous benzene by using a syringe, adding the anhydrous pyridine and the anhydrous benzene into the reaction instrument, slowly dropwise adding 4mL of benzene solution containing 2.2mmol of cyclopentyl-acetyl chloride into the reaction system for about half an hour, and continuously stirring for 3 hours after dropwise adding. After the reaction, the pyridine hydrochloride was removed by suction filtration, the filtrate was spin-dried, 20mL of ethyl acetate was added, then washed twice with 15mL of saturated aqueous sodium carbonate solution, then washed once with 15mL of saturated aqueous sodium chloride solution, the organic layer was collected, anhydrous magnesium sulfate was added to the organic layer, dried overnight, the magnesium sulfate was removed by suction filtration the next day, 2g of silica gel powder was added to the filtrate, spin-dried to a powder, and separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:10) to yield 5- [ 3-cyclopentylmethyl-2- (4-methyl-furan) -4-oxo-azetidine]-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carboxylic acid butyl ester (A)2)。
Example 3.1-Cyclopenta-1, 3-dienyl-5- [2- (3-hydroxy-4-methyl-phenyl) -3- (2-methyl-cyclobutylmethyl) -4-oxo-azetidine]-pyrazole-3-carboxylic acid ethyl ester (A)3) Synthesis of (2)
Scheme 1:
the compound 5-amino-1-cyclopentyl-1, 3-dienyl-1H-pyrazole-3-carbonitrile was prepared from ethyl 2-amino-4-cyano-butyrate and cyclopentadienyl-1, 3-dimethylamine, the synthesis procedure being as in example 1.
Adding 5mmol of collected 5-amino-1- (3-hydroxy-phenyl) -1H-pyrazole-3-carbonitrile, 5mmol of 3-hydroxy-4-methyl-benzaldehyde, 0.1g of p-toluenesulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument, sealing, and reactingAnd (3) putting the kettle outside a tank into a microwave hydrothermal method instrument, heating to 120 ℃ under the microwave power of 300W, and reacting for 20 min. After the reaction, the mixture is filtered, the filtrate is collected, 3g of silica gel powder is added into the filtrate, the mixture is dried into powder, and the powder is separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:10) to give 1-cyclopenta-1, 3-dienyl-5- [ (3-hydroxy-4-methyl-benzylidene) -amino]-pyrazole-3-carbonitrile.
The dried reaction glass apparatus and magnetons were removed from the oven and the following reactions were carried out under nitrogen protection: 1mmol of 1-cyclopenta-1, 3-dienyl-5- [ (3-hydroxy-4-methyl-benzylidene) -amino ] s are introduced into the reaction apparatus]-pyrazole-3-carbonitrile, and adding 2.5mmol of anhydrous pyridine and 4mL of anhydrous benzene into a reaction instrument by sucking with a syringe, slowly dropwise adding 4mL of a benzene solution containing 2.2mmol of (2-methyl-cyclobutyl) -acetyl chloride into the reaction system for about half an hour, and stirring for 3 h. After the reaction, the pyridine hydrochloride was removed by suction filtration, the filtrate was spin-dried, 20mL of ethyl acetate was added, then washed twice with 15mL of saturated aqueous sodium carbonate solution, then washed once with 15mL of saturated aqueous sodium chloride solution, the organic layer was collected, anhydrous magnesium sulfate was added to the organic layer, dried overnight, the magnesium sulfate was removed by suction filtration the next day, 2g of silica gel powder was added to the filtrate, spin-dried to a powder, and separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:8) to give 1-cyclopenta-1, 3-dienyl-5- [2- (3-hydroxy-4-methyl-phenyl) -3- (2-methyl-cyclobutylmethyl) -4-oxo-azetidine]-pyrazole-3-carbonitrile.
Adding 2mmol 1-cyclopentyl-1, 3-dienyl-5- [2- (3-hydroxy-4-methyl-phenyl) -3- (2-methyl-cyclobutylmethyl) -4-oxo-azetidine into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument]-pyrazole-3-carbonitrile, 4mmol CuCl2And 30mL of ethanol, sealing the outer tank of the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 100 ℃ at the microwave power of 300W, and keeping the temperature for 30 min. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was transferred to a rotary evaporation flask to remove excess solvent to obtain a thick substance, and then extracted with 30mL of ethyl acetate and 70mL of water in a separatory funnel, the organic phase was collected to remove excess solvent, anhydrous magnesium sulfate was added to dry overnight, the magnesium sulfate was removed by suction filtration the next day, and the filtrate was addedAdding 3g of silica gel powder, spin-drying, and separating by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:4) to give the final product 1-cyclopenta-1, 3-dienyl-5- [2- (3-hydroxy-4-methyl-phenyl) -3- (2-methyl-cyclobutylmethyl) -4-oxo-azetidine]-pyrazole-3-carboxylic acid ethyl ester (A)3)。
Scheme 2:
the synthesis of the compound 5-amino-1-cyclopentyl-1, 3-dienyl-1H-pyrazole-3-carbonitrile from ethyl 2-amino-4-cyano-butyrate and cyclopentadienyl-1, 3-dimethylamine is as in scheme 1 of this example.
Adding 2mmol of 5-amino-1-cyclopentyl-1, 3-dienyl-1H-pyrazole-3-carbonitrile and 4mmol of CuCl into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument2And 30mL of absolute ethyl alcohol, sealing the outer tank of the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 120 ℃ at the microwave power of 300W, and keeping the temperature for 30 min. After the reaction, the reaction solution is cooled to room temperature, the reaction solution is transferred to a rotary evaporation bottle to remove excessive solvent to obtain a thick substance, then the thick substance is extracted by 30mL ethyl acetate and 70mL water in a separating funnel, the organic phase is collected to remove the excessive solvent, anhydrous magnesium sulfate is added to the mixture to be dried overnight, the magnesium sulfate is removed by suction filtration the next day, 3g silica gel powder is added to the filtrate to be dried by rotation, and the mixture is separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:4) to give 5-amino-1-cyclopentyl-1, 3-dienyl-1H-pyrazole-3-carboxylic acid ethyl ester.
Adding 5mmol of collected 5-amino-1-cyclopentyl-1, 3-dienyl-1H-pyrazole-3-carboxylic acid ethyl ester, 5mmol of collected 3-hydroxy-4-methyl-benzaldehyde, 0.1g of p-toluenesulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument, sealing an outer tank of a reaction kettle, putting the outer tank into the microwave hydrothermal instrument with the microwave power of 300W, and heating to 120 ℃ for reaction for 20 min. Suction filtering after reaction, collecting filtrate, adding 3g silica gel powder into the filtrate, spin drying to obtain powder, and separating by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:8) to give 1-cyclopenta-1, 3-dienyl-5- [ (3)-hydroxy-4-methyl-benzylidene) -amino]-1H-pyrazole-3-carboxylic acid ethyl ester.
The dried reaction glass apparatus and magnetons were removed from the oven and the following reactions were carried out under nitrogen protection: 1mmol of 1-cyclopenta-1, 3-dienyl-5- [ (3-hydroxy-4-methyl-benzylidene) -amino ] s are introduced into the reaction apparatus]-1H-pyrazole-3-carboxylic acid ethyl ester, and adding 2.5mmol of anhydrous pyridine and 4mL of anhydrous benzene into a reaction instrument by sucking with a syringe, slowly dropwise adding 4mL of benzene solution containing 2.2mmol of (2-methyl-cyclobutyl) -acetyl chloride into the reaction system for about half an hour, and continuing stirring for 3 hours after completing dropwise addition. After the reaction, the pyridine hydrochloride was removed by suction filtration, the filtrate was spin-dried, 20mL of ethyl acetate was added, then washed twice with 15mL of saturated aqueous sodium carbonate solution, then washed once with 15mL of saturated aqueous sodium chloride solution, the organic layer was collected, anhydrous magnesium sulfate was added to the organic layer, dried overnight, the magnesium sulfate was removed by suction filtration the next day, 2g of silica gel powder was added to the filtrate, spin-dried to a powder, and separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:10) to yield 1-cyclopenta-1, 3-dienyl-5- [2- (3-hydroxy-4-methyl-phenyl) -3- (2-methyl-cyclobutylmethyl) -4-oxo-azetidine]-pyrazole-3-carboxylic acid ethyl ester (A)3)。
Example 4.1-Epoxyethyl-5- (3-oxiranylmethyl-2-oxo-4-pent-3-enyl-azetidine) -1-pyrazole-3-carboxylic acid isopropyl ester
Scheme 1:
the compound 5-amino-1-oxiranylmethyl-1H-pyrazole-3-carbonitrile was prepared from ethyl 2-amino-4-cyano-butyrate and oxiran-2-amine, the synthesis method being according to the procedure of example 1.
Adding 5mmol of collected 5-amino-1-oxiranylmethyl-1H-pyrazole-3-carbonitrile and 5mmol of pentan-3-enal into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument, 0.1g of p-toluenesulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene, sealing an outer tank of a reaction kettle, performing microwave treatment at 300W, heating to 120 ℃, and reacting for 20 min. After the reaction is finished, carrying out suction filtration, collecting filtrate, and adding the filtrateAdding 3g silica gel powder, spin-drying to obtain powder, and separating with silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:10) to give 5-hex-4-enylidene amino-1-oxiranyl-1H-pyrazole-3-carbonitrile.
The dried reaction glass apparatus and magnetons were removed from the oven and the following reactions were carried out under nitrogen protection: adding 1mmol of 5-hex-4-enylidene amino-1-ethylene oxide-1H-pyrazole-3-carbonitrile into a reaction instrument, sucking 2.5mmol of anhydrous pyridine and 4mL of anhydrous benzene by using an injector, adding into the reaction instrument, slowly dropwise adding 4mL of benzene solution of 2.2mmol of oxirane-acetyl chloride into the reaction system for about half an hour, and continuing stirring for 3 hours after dropwise adding. After the reaction, the pyridine hydrochloride was removed by suction filtration, the filtrate was spin-dried, 20mL of ethyl acetate was added, then washed twice with 15mL of saturated aqueous sodium carbonate solution, then washed once with 15mL of saturated aqueous sodium chloride solution, the organic layer was collected, anhydrous magnesium sulfate was added, dried overnight, the magnesium sulfate was removed by suction filtration the next day, 2g of silica gel powder was added to the filtrate and spin-dried to a powder, and the powder was separated by silica gel column chromatography (dry loading, V. silica gel column chromatography)Ethyl acetate:VPetroleum ether1:8) to give 1-oxiranyl-5- (3-oxiranylmethyl-2-oxo-4-pent-3-enyl-azetidine) -1H-pyrazole-3-carbonitrile.
Adding 2mmol 1-ethylene oxide-5- (3-ethylene oxide methyl-2-oxo-4-pent-3-alkenyl-azetidine) -1H-pyrazole-3-carbonitrile and 4mmol CuCl into a special polytetrafluoroethylene liner for a microwave hydrothermal instrument2And 30mL of isopropanol, sealing the outer tank of the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 100 ℃ at the power of 300W, and keeping the temperature for 30 min. After the reaction, the reaction solution is cooled to room temperature, the reaction solution is transferred to a rotary evaporation bottle to remove excessive solvent to obtain a thick substance, then the thick substance is extracted by 30mL ethyl acetate and 70mL water in a separating funnel, the organic phase is collected to remove the excessive solvent, anhydrous magnesium sulfate is added to the mixture to be dried overnight, the magnesium sulfate is removed by suction filtration the next day, 3g silica gel powder is added to the filtrate to be dried by rotation, and the mixture is separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:4) to give the final product isopropyl 1-oxiranyl-5- (3-oxiranylmethyl-2-oxo-4-pent-3-enyl-azetidine) -1-pyrazole-3-carboxylate (a)4)。
Scheme 2:
the synthesis of the compound 5-amino-1-oxiranylmethyl-1H-pyrazole-3-carbonitrile from ethyl 2-amino-4-cyano-butyrate and oxiran-2-amine is as in scheme 1.
Adding 2mmol of 5-amino-1-oxiranylmethyl-1H-pyrazole-3-carbonitrile and 4mmol of CuCl into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument2And 30mL of isopropanol, sealing the outer tank of the reaction kettle, putting the reaction kettle into a microwave hydrothermal method instrument, heating to 120 ℃ with the microwave power of 300W, and keeping the temperature for 30 min. After the reaction, the reaction solution is cooled to room temperature, the reaction solution is transferred to a rotary evaporation bottle to remove excessive solvent to obtain a thick substance, then the thick substance is extracted by 30mL ethyl acetate and 70mL water in a separating funnel, the organic phase is collected to remove the excessive solvent, anhydrous magnesium sulfate is added to the mixture to be dried overnight, the magnesium sulfate is removed by suction filtration the next day, 3g silica gel powder is added to the filtrate to be dried by rotation, and the mixture is separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:4) to give 5-amino-1-oxiranyl-1-pyrazole-3-carboxylic acid isopropyl ester.
Adding 5mmol of collected 5-amino-1-ethylene oxide-1H-pyrazole-3-carboxylic acid isopropyl ester, 5mmol of pentan-3-enal, 0.1g of p-toluenesulfonic acid, 1g of 4A molecular sieve and 30mL of solvent toluene into a special polytetrafluoroethylene inner container for a microwave hydrothermal instrument, sealing an outer tank of a reaction kettle, putting the outer tank into the microwave hydrothermal instrument, heating to 120 ℃ under the microwave power of 300W, and reacting for 20 min. After the reaction, the mixture is filtered, the filtrate is collected, 3g of silica gel powder is added into the filtrate, the mixture is dried into powder, and the powder is separated by silica gel column chromatography (dry loading, V)Ethyl acetate:VPetroleum ether1:8) to give 5-hex-4-enylidene amino-1-oxiranyl-1H-pyrazole-3-carboxylic acid isopropyl ester.
The dried reaction glass apparatus and magneton were removed from the oven and the following reaction was carried out under nitrogen protection: 1mmol of 5-hex-4-enylidene amino-1-oxiranyl-1H-pyrazole-3-carboxylic acid isopropyl ester is added into a glass instrument, and 2.5mmol of anhydrous pyridine is sucked by a syringePyridine and 4mL anhydrous benzene are added into a glass instrument, then 2.2mmol of oxirane-acetyl chloride in 4mL benzene solution is slowly dripped into the reaction system, dripping is finished for about half an hour, and stirring is continued for 3h after dripping is finished. After the reaction, the pyridine hydrochloride was removed by suction filtration, the filtrate was spin-dried, 20mL of ethyl acetate was added, then washed twice with 15mL of saturated aqueous sodium carbonate solution, then washed once with 15mL of saturated aqueous sodium chloride solution, the organic layer was collected, anhydrous magnesium sulfate was added, dried overnight, the magnesium sulfate was removed by suction filtration the next day, 2g of silica gel powder was added to the filtrate and spin-dried to a powder, and the powder was separated by silica gel column chromatography (dry loading, V. silica gel column chromatography)Ethyl acetate:VPetroleum ether1:10) to give 1-epoxyethyl-5- (3-oxiranylmethyl-2-oxo-4-pent-3-enyl-azetidine) -1-pyrazole-3-carboxylic acid isopropyl ester (a)4)。
Example 5
The reaction time and the synthesis mode for synthesizing the final product from the oxoazetidine pyrazole in scheme 1 of example 1 were changed separately or simultaneously, the microwave power of the microwave hydrothermal method was 300W, and the other operations were exactly the same as in example 1 to prepare compounds, and the preparation results are shown in table 1 below together with the results of example 1.
TABLE 1 Synthesis and yield of Compound 1 under different conditions
From the three groups of comparative examples 1-3, the microwave hydrothermal method can achieve high yield in a short time, and the synthesis efficiency of the independent hydrothermal method and the microwave hydrothermal method is not high. The microwave hydrothermal method is proved to be applied to the synthesis process of the oxoazetidine pyrazole, the microwave method and the hydrothermal method are really and effectively combined together, the advantages of the uniformity of microwave heating, the high temperature and the high pressure generated by the sealing of the hydrothermal method and the like are fully utilized, the two methods generate a synergistic effect, the advantages of the two methods are fused, and a very positive experimental result is generated. The application also innovatively advances the technology for the synthesis of pyrazole carboxylic acid esters.
Example 6 control Effect on fly larvae of Bombyx mori
Selecting Compound A prepared in scheme 1 of examples 1-41～A4To prepare the emulsifiable concentrate dispersant. Respectively weighing 1.01g of compound (purity is 99%), dissolving in 8.49g of ethylene glycol monomethyl ether, weighing 0.50g of agricultural bag-B3-composite emulsifier, mixing well and stirring for 30min to respectively obtain compound A1～A4The uniform missible oil with the mass percentage concentration of 10% is reserved, and water is added to dilute the uniform missible oil to the required concentration in actual use.
The method comprises the steps of carrying out silkworm parasitism fly prevention tests by using silkworm variety Sanmianbai as a test insect, treating 500 silkworms with age of 4-6 days in five days in each experimental group, diluting the missible oil to 500mg/L, 200mg/L, 100mg/L and 50mg/L respectively by using distilled water, uniformly spraying the missible oil on mulberry leaves as liquid medicine until the mulberry leaves are fully covered with the liquid medicine, feeding the corresponding silkworms with the liquid medicine, numbering and marking the silkworms with the processed numbers, ensuring that the silkworms absorb the liquid medicine, making tracking marks, feeding the silkworms for 15 days, collecting cocoons, and investigating. Meanwhile, setting a blank control group without pesticide application and the other conditions as the same as those of the experimental group, after 15 days of feeding, silkworm cocoons are picked, cocoon picking investigation is carried out, and the cocoons-picking rate is calculated.
The parasitic rate of the parasitic flies of the silkworms in the blank control group was 20.63%, and the rate of the commercial cocoons in the blank control group was 69.8%.
The percentage of the control effect on the fly larvae at the concentrations of 500, 200, 100, 50mg/L and the normalized cocooning rate of the compounds are shown in FIGS. 1a-d, respectively.
For screening the agents for preventing and controlling the parasitic flies, the prevention effect is not lower than 80% in one of the screening indexes, and the normalized cocooning rate is not lower than 90% in the other screening index. As can be seen from FIG. 1a, 500mg/L of Compound A4The control effect on the houseflies is lower than 80 percent (the control effect is not shown in the low-gradient comparison), and the control effect is higher than 80 percent when the concentration of the rest compounds is 500 mg/L. As can be seen from FIG. 1b, the compound satisfying both the campon rate screening index and the preventive effect screening index at a concentration of 200mg/L is A1、A2And A3(ii) a As can be seen from FIG. 1c, the compound satisfying both the cocoon formation rate screening index and the preventive effect screening index at the compound concentration of 100mg/L was Compound A1，A2And A3(ii) a As can be seen from FIG. 1d, the compound satisfying both the campon rate screening index and the preventive effect screening index at a compound concentration of 50mg/L was Compound A3。
Calculating the formula:
cocooning rate = (cocooning number/500) × 100%; the parasitism rate is (maggot cocoon number/camptosoma number) × 100; the control effect% ((blank control group parasitic rate-treatment group parasitic rate)/blank control group parasitic rate) × 100%, and the normalized cocooning rate% (% cocooning rate of compound treatment group/cocooning rate of blank control group) × 100%.
Example 7 Activity against Staphylococcus aureus
The compounds A prepared in schemes 1 of examples 1 to 41-A4Respectively dissolving in DMSO to obtain 0.1% (m/v) concentration, diluting each compound with 1% (m/v) acetic acid distilled water solution to obtain 0.5, 0.25, and 0.125 mg/L3 concentrations as test sample, preparing positive control drug ciprofloxacin with 1% (m/v) acetic acid distilled water to obtain 0.5, 0.25, and 0.125 mg/L3 concentrations, and preparing negative control group with 1% (m/v) acetic acid solution. Circular sterilized filter paper sheets with the diameter of 6mm are respectively placed into the prepared solutions with different concentrations by using tweezers, and the negative control and the positive control are performed in the same way. These sheets were attached to agar solid medium coated with Staphylococcus aureus. Then placing the culture medium in a constant temperature incubator, culturing for 24h at 37 ℃, accurately measuring the diameters of all inhibition zones by using a vernier caliper after removing, and evaluating the inhibition activity of the tested compound, wherein, + represents high activity, and, + represents medium activity, and-represents weak activity. The test results are shown in Table 2. It can be seen that Compound A1The bacteriostatic effect is best when the concentration is 0.5mg/L, the bacteriostatic effect of the compound A3 is good when the concentrations are 0.5mg/L and 0.25mg/L, and the bacteriostatic effect of a low-concentration compound solution is not good at a high concentration.
TABLE 2 anti-Staphylococcus aureus Activity of Compounds A1-A4
Claims (4)
1. An oxoazetidine pyrazole carboxylate-based compound having the structural formula (IV):
in the structural general formula (IV): r1Is substituted phenyl, the substitution is mono-substitution or multi-substitution, the substituted position is ortho-position, meta-position or para-position of a benzene ring, and the substituted group is halogen, hydroxyl, nitro or trifluoromethyl;
R2is 3-hydroxy-4-methylphenyl, 3-pentenyl, furan-2-yl, 4-methyl-furan-2-yl;
R3is selected from-H, CH3-、Cl、
R4Independently selected from any one of the following groups: -CH3、-CH2CH3、-CH2CH2CH3、
-(CH2)4CH3、-(CH2)5CH3、
2. Use of the oxoazetidine pyrazole carboxylate-based compound according to claim 1 for the preparation of a medicament for controlling harmful insect and/or acarine pests.
3. Use according to claim 2, characterized in that: the harmful insects include orthoptera, Thysanoptera, Homoptera, Heteroptera, Lepidoptera, Coleoptera and/or Diptera harmful insects.
4. Use of the oxoazetidine pyrazole carboxylate-based compound according to claim 1 for the preparation of a medicament against staphylococcus aureus.
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| GB1368235A (en) * | 1970-11-03 | 1974-09-25 | Glaxo Lab Ltd | Azetidinone disulphides and their preparation |
| HRP980026A2 (en) * | 1998-01-20 | 1999-10-31 | Pliva Pharm & Chem Works | 1-izothiazolydinone derivatives of azetidine-2-ones, processes for the preparation and use thereof |
| JP4880348B2 (en) * | 2006-04-25 | 2012-02-22 | 壽製薬株式会社 | Azulene derivatives and serum cholesterol lowering agents containing the same |
| CA2925595A1 (en) * | 2013-10-17 | 2015-04-23 | Dow Agrosciences Llc | Processes for the preparation of pesticidal compounds |
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