CN108084093A - The method of one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids - Google Patents
The method of one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids Download PDFInfo
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Abstract
The invention discloses a kind of methods of 3 difluoromethyl of one pot process, 1 methyl 1H pyrazoles, 4 carboxylic acid, comprise the following steps：In dimethylbenzene, 4,4 difluoro ethyl acetoacetates and triethyl orthoformate carry out condensation reaction under heating and metal carboxylate catalysis, methyl hydrazine aqueous solution is added dropwise after cooling, it heats up again and carries out ring closure reaction, gained ring closure reaction liquid obtains 3 difluoromethyl, 1 methyl 1H pyrazoles, 4 carboxylic acid through saponification, acidifying.This method technological design is rationally, high income, technological operation is simple, cost is relatively low, is suitble to industrialized production.
Description
Technical field
The invention belongs to compound intermediate synthesis technical field more particularly to a kind of one pot process 3- difluoromethyls-
The method of 1- methyl-1 H- pyrazoles -4- carboxylic acids.
Background technology
Pyrazol acid amide was developed, has structure novel, high activity and the wide succinate dehydrogenase suppression of insecticidal spectrum in recent years
Preparation（SDHI）Series bactericidal agent plays an important role of to improve crop quality and yield.
The molecular formula of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids：C6H6F2N2O2, molecular weight：176.12 it is to close
Using it is the pyrazole amide series bactericidal agent kind of Material synthesis up to 9 into the important intermediate of pyrazole amide series bactericidal agent, it is main
There are fluxapyroxad, biphenyl pyrrole bacterium amine, fluorine azoles ring bacterium amine, isopyrazam and benzo alkene fluorine bacterium azoles, therefore synthesize 3- difluoros
Methyl-1-methyl-1 H- pyrazoles-4- carboxylic acids are the important prerequisites for intervening pyrazole amide series bactericidal agent.
There are more patent and document to carry out research report to its synthesis technology at present, using more wherein in current industrial
Process route be to synthesize 2- ethoxymeyhylene -4 using 4,4- difluoros ethyl acetoacetate as raw material with orthoformic acid trimethylsilyl ethyl ester,
4- difluoro ethyl acetoacetates, then cyclization is reacted in water phase or water and organic solvent mixed phase with methyl hydrazine, obtain 3- difluoros
Methyl-1-methyl-1 H- pyrazoles-4- carboxylates, then target product is obtained through saponification and acidifying, as patent US5093347,
The reports such as EP1997808, WO2010009990, CN101959840.
Synthesis for 2- ethoxymeyhylene -4,4- difluoro ethyl acetoacetates, patent WO/2012/161965A1,
WO/2012/025469A1, WO/2009/012482A2 etc. have report, with 4,4- difluoros ethyl acetoacetate, primitive nail triethylenetetraminehexaacetic acid
Ester is raw material, the high―temperature nuclei under the action of acetic anhydride, post-treated after reaction to obtain 2- ethoxymeyhylenes -4,4- bis-
Acetyl fluoride ethyl acetate.This is also the generalized synthesis of this kind of reaction, but step reaction must post-treated removing system
By-product acetic acid and excess acetic acid acid anhydride etc. could preferably carry out next step reaction.
With 2- ethoxymeyhylene -4,4- difluoros ethyl acetoacetate synthesis 3- difluoromethyl -1- methyl-1 H- pyrazoles -4-
The method report of carboxylic acid is more.China Patent Publication No. CN1968934A it be by methyl hydrazine be added to 2- ethoxymeyhylenes-
It in the ethanol solution of 4,4- difluoro ethyl acetoacetates, at -40 DEG C, is reacted, after reaction, decompression, concentration are tied again
Crystalline substance obtains 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylates.Shortcoming is that this method needs to carry out at low temperature, is adopted
It is raw material with anhydrous methyl hydrazine, has the shortcomings that operational hazards are big, severe reaction conditions.United States Patent (USP) US20080154045A1
Reporting 2- methylamino ethoxies subunit difluoro acetoacetic ester and methyl hydrazine with European patent EP 1854788A1, cyclization is anti-at low temperature
Should, if ice-water bath cools down, 3- difluoromethyls-1- methyl-1-hydrogen-pyrazoles-4- formic acid esters is obtained more with high selectivity, but in product
- 1 methyl-1 of isomers 5- difluoromethyls-hydrogen -4- formic acid esters is still mixed with, the molar ratio of the two is equal to 94 ︰ 6, content of isomer
Still higher, product purity is relatively low.World patent WO2010009990A1 report synthesis high-purity 3- difluoromethyl -1- methyl -
The method of 1H- pyrazoles -4- carboxylic acids, GC purity reach 99.6%, but two fluoro acetyl second of raw material 2- ethoxies methine in the technique
The ring closure reaction of acid esters and methyl hydrazine will carry out under the conditions of -60 DEG C to -50 DEG C extremely low temperature.The process conditions are harsh, and industry is put
Big production difficulty is big, of high cost.Except above-mentioned problem, these patents are all reacted using substep batch process, and step is long, after
Processing is complicated, of high cost, is not comparatively ideal industrial process.
The content of the invention
The present invention be directed to problems of the prior art, it is therefore an objective to provide a kind of technological design rationally, high income, technique
It is easy to operate, cost is relatively low, be suitble to industrialized one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids side
Method.
In order to solve the above technical problems, the present invention uses following technical scheme：
A kind of method of one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids, comprises the following steps：
In dimethylbenzene, 4,4- difluoro ethyl acetoacetates and triethyl orthoformate carry out under heating and metal carboxylate catalysis
Condensation reaction, after cooling be added dropwise methyl hydrazine aqueous solution, then heat up carry out ring closure reaction, gained ring closure reaction liquid through saponification, acidifying,
Obtain 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that the gold
It is calcium acetate or calcium propionate to belong to carboxylate.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that described 4,
The molar ratio of 4- difluoros ethyl acetoacetate, triethyl orthoformate and methyl hydrazine is 1.0 ︰, 1.05~1.5 ︰ 0.9~1.3.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that described 4,
The molar ratio of 4- difluoros ethyl acetoacetate and metal carboxylate is 1.0 ︰ 0.01~0.5.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that described 4,
The amount ratio of 4- difluoros ethyl acetoacetate and dimethylbenzene is 500~1500mL of 1.0mol ︰.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that the contracting
The temperature of reaction is closed as 90~130 DEG C, the time is 2~5h.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that methyl hydrazine
The dropping temperature of aqueous solution is -10~20 DEG C；The temperature of the ring closure reaction is 0~30 DEG C, and the time is 0.5~2h.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that after cooling
Inorganic alkali solution is first added in, then methyl hydrazine aqueous solution is added dropwise.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that the nothing
Inorganic base in machine aqueous slkali includes sodium hydroxide, potassium hydroxide or potassium carbonate.
The method of above-mentioned one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, it is preferred that the nothing
The molar ratio of inorganic base in machine aqueous slkali and the methyl hydrazine in methyl hydrazine aqueous solution is 0.2~0.5 ︰ 0.9~1.0.
The present invention invention course be：
With 4,4- difluoros ethyl acetoacetate to synthesis 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids, currently used side
Fado uses batch process, and first step reaction generally adds in excessive acetic anhydride with triethyl orthoformate and reacted, and reaction is laggard
Row purification, second step batch process rejoins another solvent, then methyl hydrazine is added dropwise and is reacted, and with respect to one kettle way, there are steps
The shortcomings that length, post processing is more complicated, high expensive.And one kettle way prepares target product that often yield is low, therefore, there is presently no
The relevant report of one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids.
Applicant has found during one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids are attempted, by
In acetic anhydride and byproduct of reaction ethyl alcohol effect generate acetic acid, since ring closure reaction carries out generally in alkaline environment, acetic acid and
The presence of acetic anhydride can have an impact ring closure reaction, cause target product yield low.Therefore, need to increase in the prior art and remove
The impurity acetic acid of system generation and recycling acetic anhydride add the intermediate steps of novel solvent and methyl hydrazine reaction.So as to bring step
Rapid the shortcomings of time-consuming, and post processing is more complicated, high expensive.
Applicant passes through a large number of experiments, reaction condition is optimized, using catalysis of the calcium carboxylates as condensation reaction
Agent, for dimethylbenzene as condensation reaction and the solvent of ring closure reaction, the coproduct ethanol of condensation reaction generation will not be anti-with calcium carboxylates
Should, follow-up ring closure reaction will not be had an impact, thus eliminate the impurity that must first remove system generation in the prior art
Acetic acid and recycling acetic anhydride add the intermediate steps of novel solvent and methyl hydrazine reaction.Also, the influence of free from admixture acetic acid, adds
Calcium carboxylates excellent catalytic effect, the yield and purity of products obtained therefrom all greatly improve；In addition, the presence of calcium carboxylates is to subsequent reactions
It does not influence, can be removed in saponification is post-processed with acidifying.Therefore, operation of the present invention significantly simplifies, and is industrializing
Reduce a set of consersion unit and solvent reclaimer during production；Reaction time significantly shortens, and reaction efficiency greatly improves, and closes
It declines to a great extent into cost, and improves reaction yield and product purity.
Compared with prior art, the advantage of the invention is that：
The present invention is anti-as condensation using calcium carboxylates using one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids
The catalyst answered, dimethylbenzene is as condensation reaction and the solvent of ring closure reaction, and the generation of condensation reaction free from admixture, there is no to cyclization
The phenomenon that reaction has an impact, thus the yield of product greatly improves；In addition calcium carboxylates excellent catalytic effect, the yield of products obtained therefrom
It is further improved with purity, solves the technical issues of one kettle way yield is not high.In addition, for compared to batch process, this
Invention one pot process shortens the reaction time, simplifies operating procedure, and a set of consersion unit is reduced in industrialized production
And solvent reclaimer, production efficiency is improved, has saved cost, there are very high industrial applications to be worth.
Specific embodiment
Below in conjunction with specific preferred embodiment, the invention will be further described, but not thereby limiting the invention
Protection domain.
Embodiment 1
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml four-hole bottles in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 157.0（99%, 1.05mol）, dimethylbenzene 1000mL, calcium acetate
1.58g（0.01mol）, stirring is opened, reacts 2h in 90~100 DEG C；Then 10 DEG C are cooled to, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（Containing methyl hydrazine
0.9mol）It is warming up to 20 DEG C, when progress annulation 0.5 is small.Reaction finishes reaction solution and obtains target product through saponification, acidifying,
It filters, dry to obtain faint yellow solid product 134.1g, yield 75.1%, chromatogram quantitative analysis of the liquid phase content 98.5%.
Embodiment 2
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml four-hole bottles in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
1.58g（0.01mol）, stirring is opened, 2h is reacted in 90~100 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（Containing methyl hydrazine
0.9mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 136.1g, yield 76.2%, chromatogram quantitative analysis of the liquid phase content 98.6%.
Embodiment 3
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 194.3（99%, 1.3mol）, dimethylbenzene 1000mL, calcium acetate
1.58g（0.01mol）, stirring is opened, 2h is reacted in 90~100 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（Containing methyl hydrazine
0.9mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 136.4g, yield 76.3%, chromatogram quantitative analysis of the liquid phase content 98.4%.
Embodiment 4
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
7.9g（0.05mol）, stirring is opened, 2h is reacted in 90~100 DEG C, is then cooled to 10 DEG C, adds in the hydrogen that mass fraction is 30%
Aqueous solution of sodium oxide 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（Containing methyl hydrazine
0.9mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 140.5g, yield 78.7%, chromatogram quantitative analysis of the liquid phase content 98.5%.
Embodiment 5
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
15.8g（0.1mol）, stirring is opened, 2h is reacted in 90~100 DEG C, is then cooled to 10 DEG C, adds in the hydrogen that mass fraction is 30%
Aqueous solution of sodium oxide 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（Containing methyl hydrazine
0.9mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 143.9g, yield 80.7%, chromatogram quantitative analysis of the liquid phase content 98.7%.
Embodiment 6
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
79g（0.5mol）, stirring is opened, 2h is reacted in 90~100 DEG C, is then cooled to 10 DEG C, adds in the hydrogen-oxygen that mass fraction is 30%
Change sodium water solution 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（0.9mol containing methyl hydrazine）
Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product through saponification, acidifying, filters, dries faint yellow
Solid product 138.8g, yield 80.1%, chromatogram quantitative analysis of the liquid phase content 98.5%.
Embodiment 7
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
15.8g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（Containing methyl hydrazine
0.9mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 144.4g, yield 81.0%, chromatogram quantitative analysis of the liquid phase content 98.7%.
Embodiment 8
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
15.8g（0.1mol）, stirring is opened, 2h is reacted in 120~130 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 103.5g be added dropwise（Containing methyl hydrazine
0.9mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 141.8g, yield 79.2%, chromatogram quantitative analysis of the liquid phase content 98.3%.
Embodiment 9
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
15.8g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 26.6g（0.2mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（Containing methyl hydrazine
1.0mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 147.1g, yield 82.5%, chromatogram quantitative analysis of the liquid phase content 98.7%.
Embodiment 9
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
15.8g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 40.0g（0.3mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（Containing methyl hydrazine
1.0mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 148.6g, yield 83.3%, chromatogram quantitative analysis of the liquid phase content 98.6%.
Embodiment 10
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium acetate
15.8g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 66.6g（0.5mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（Containing methyl hydrazine
1.0mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 146.8g, yield 82.1%, chromatogram quantitative analysis of the liquid phase content 98.4%.
Embodiment 11
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium propionate
18.6g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 66.6g（0.5mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（Containing methyl hydrazine
1.0mol）Be warming up to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product, filtering, drying through saponification, acidifying
Obtain faint yellow solid product 144.3g, yield 80.8%, chromatogram quantitative analysis of the liquid phase content 98.5%.
Embodiment 12
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium propionate
18.6g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Potassium hydroxide aqueous solution 56.1g（0.3mol）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（1.0mol containing methyl hydrazine）It rises
Temperature to 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product through saponification, acidifying, filters, dries to obtain pale yellow colored solid
Body product 146.1g, yield 81.9%, chromatogram quantitative analysis of the liquid phase content 98.7%.
Embodiment 13
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium propionate
18.6g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Potassium hydroxide aqueous solution 138g（0.3mol）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（1.0mol containing methyl hydrazine）Heating
To 20 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product through saponification, acidifying, filters, dries to obtain faint yellow solid
Product 143.1g, yield 79.9%, chromatogram quantitative analysis of the liquid phase content 98.3%.
Embodiment 14
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 2000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1000mL, calcium propionate
18.6g（0.1mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 20 DEG C, it is 30% to add in mass fraction
Potassium hydroxide aqueous solution 138g（0.3mol）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（1.0mol containing methyl hydrazine）Heating
To 30 DEG C reaction 0.5 it is small when.Reaction finishes reaction solution and obtains target product through saponification, acidifying, filters, dries to obtain faint yellow solid
Product 139.9g, yield 78.1%, chromatogram quantitative analysis of the liquid phase content 98.2%.
Embodiment 15
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 3000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1500mL, calcium propionate
55.8g（0.3mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Sodium hydrate aqueous solution 66.6g（0.5mol containing NaOH）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（Containing methyl hydrazine
1.0mol）Be warming up to 20 DEG C reaction 1 it is small when.Reaction finishes reaction solution and obtains target product through saponification, acidifying, filters, dries
Faint yellow solid product 145.8g, yield 81.8%, chromatogram quantitative analysis of the liquid phase content 98.7%.
Embodiment 16
Equipped with mechanical agitation, condenser pipe, constant pressure funnel, thermometer 3000ml there-necked flasks in add in bis- acetyl fluorides of 4,4-
Ethyl acetate 169.4g（98%, 1.0mol）, triethyl orthoformate 171.9（99%, 1.15mol）, dimethylbenzene 1500mL, calcium propionate
55.8g（0.3mol）, stirring is opened, 2h is reacted in 100~110 DEG C, is then cooled to 10 DEG C, it is 30% to add in mass fraction
Wet chemical 230g（0.5mol containing potassium carbonate）, finish, 40% methyl hydrazine aqueous solution 115.0g be added dropwise（Containing methyl hydrazine
1.0mol）Be warming up to 20 DEG C reaction 1 it is small when.Reaction finishes reaction solution and obtains target product through saponification, acidifying, filters, dries
Faint yellow solid product 143.3g, yield 79.1%, chromatogram quantitative analysis of the liquid phase content 97.1%.
The above is only the preferred embodiment of the present invention, and protection scope of the present invention is not limited merely to above-mentioned implementation
Example.All technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It is noted that for the art
Those of ordinary skill for, improvements and modifications without departing from the principle of the present invention, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of method of one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids, comprises the following steps：
In dimethylbenzene, 4,4- difluoro ethyl acetoacetates and triethyl orthoformate carry out under heating and metal carboxylate catalysis
Condensation reaction, after cooling be added dropwise methyl hydrazine aqueous solution, then heat up carry out ring closure reaction, gained ring closure reaction liquid through saponification, acidifying,
Obtain 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids.
2. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 1,
It is characterized in that, the metal carboxylate is calcium acetate or calcium propionate.
3. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 2,
Be characterized in that, the molar ratio of 4, the 4- difluoros ethyl acetoacetate, triethyl orthoformate and methyl hydrazine for 1.0 ︰ 1.05~
1.5 ︰ 0.9~1.3.
4. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 3,
It is characterized in that, the molar ratio of 4, the 4- difluoros ethyl acetoacetate and metal carboxylate is 1.0 ︰ 0.01~0.5.
5. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 4,
It is characterized in that, the amount ratio of 4, the 4- difluoros ethyl acetoacetate and dimethylbenzene is 500~1500mL of 1.0mol ︰.
6. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 5,
It is characterized in that, the temperature of the condensation reaction is 90~130 DEG C, and the time is 2~5h.
7. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 6,
It is characterized in that, the dropping temperature of methyl hydrazine aqueous solution is -10~20 DEG C；The temperature of the ring closure reaction is 0~30 DEG C, and the time is
0.5~2h.
8. according to claim 1~7 any one of them one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids
Method, which is characterized in that inorganic alkali solution is first added in after cooling, then methyl hydrazine aqueous solution is added dropwise.
9. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 8,
It is characterized in that, the inorganic base in the inorganic alkali solution includes sodium hydroxide, potassium hydroxide or potassium carbonate.
10. the method for one pot process 3- difluoromethyls -1- methyl-1s H- pyrazoles -4- carboxylic acids according to claim 9,
It is characterized in that, the molar ratio of the inorganic base in the inorganic alkali solution and the methyl hydrazine in methyl hydrazine aqueous solution is 0.2~0.5 ︰
0.9~1.0.
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| CN115385792A (en) * | 2021-05-21 | 2022-11-25 | 帕潘纳(北京)科技有限公司 | Preparation method of pyrazole herbicide intermediate |
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Cited By (2)
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| CN115385792A (en) * | 2021-05-21 | 2022-11-25 | 帕潘纳(北京)科技有限公司 | Preparation method of pyrazole herbicide intermediate |
| CN115385792B (en) * | 2021-05-21 | 2024-02-02 | 帕潘纳(北京)科技有限公司 | Process for the preparation of pyrazole herbicide intermediates |
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