CN106380447B - The preparation method and intermediate of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formic acid and its intermediate - Google Patents
The preparation method and intermediate of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formic acid and its intermediate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention discloses the preparation methods and intermediate of a kind of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formic acid and its intermediate, the preparation method of intermediate includes the following steps: solvent-free or under conditions of have solvent, compound 1 and KF are subjected to fluorination reaction under the effect of the catalyst, obtain compound 2；Preparation method of the present invention further includes that reaction is hydrolyzed in the compound 2 in the presence of alkali, obtains the compound 3, and the preparation method raw material is cheap and easily-available, easy to operate, and security risk is low, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formic acid and its intermediate and
Intermediate.
Background technique
3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acid, is synthesizing new high-efficiency low-toxicity sterilised products isopyrazam
(Bixafen), an important intermediate of fluxapyroxad (Fluxapyroxad), biphenyl pyrrole bacterium amine (Isopyrazam) etc.,
There is suitable vast market prospect in future, synthetic method has also obtained the great interest and research extensively of chemist.
Report that more is using 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formic acid esters as raw material, by being fluorinated again at present
It hydrolyzes and 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acid is made, as shown above.Chinese patent literature CN101558044A,
CN105218448A, CN1875006A, US2006276656A1, CN200480032248, CN102718712A,
CN102731402A etc. is reported using 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formic acid esters as raw material, with hydrogen fluoride or fluorine
Change hydrogen and catalytic amount or equivalent amine blends are fluorinated as fluorination reagent, using acidity or hydrolyzed under basic conditions, from
And the method that 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formic acid is prepared；Chinese patent literature CN1875006A,
CN105218448A, which also reported, uses potassium fluoride to carry out fluorinated method as fluorination reagent, but the former does not refer to yield, after
Person's yield is relatively low；Chinese patent literature CN103582631A is reported with 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formic acid esters
Or the reaction that 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formic acid carries out in potassium fluoride aqueous solution, although operation and reaction item
Part is more mild, but since dichloromethyl is very active, is easy to hydrolyze in the presence of water, it is more difficult to obtain very high yield.On
State has one common to be unfavorable for commercially producing by the method for raw material of 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formic acid esters
Method be exactly the raw material be usually to pass through methyl hydrazine cyclization, the bad control of isomers, cause yield losses and raw material at
This is higher.
There are also it is a kind of be exactly Chinese patent literature CN102718712B report with 3- dichloromethyl -1- methyl-1 H- pyrrole
Azoles -4- formonitrile HCN is raw material, hydrolyzes the method for preparing 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acid again by fluorination.The fluorine
Chemical industry skill is carried out using hydrogen fluoride or under conditions of amines catalyst, and yield is very high.The raw materials used 3- dichloromethyl-of this method
Isomers generates seldom in 1- methyl-1 H- pyrazoles -4- formonitrile HCN synthesis process, improves yield, reduces unnecessary isomers
Purification step reduces the cost of the raw material.But the technique uses anhydrous hydrogen fluoride as fluorination reagent, and hydrogen fluoride has height
Poison and strong corrosive, harm to the human body is very big, consersion unit require it is also more harsh, therefore produce when implementing security risk compared with
Height, operation are also more difficult.
Therefore it is cheap and easily-available, easy to operate to find raw material, the low 3- difluoro first for being suitable for industrialized production of security risk
The preparation method of base -1- methyl-1 H- pyrazoles -4- formic acid is current technical problem urgently to be solved.
Summary of the invention
Technical problem to be solved by the present invention lies in order to overcome existing 3- difluoromethyl -1- methyl-1 H- pyrazoles -
In the preparation method of 4- carboxylic acid and its intermediate, the harm of reaction raw materials cost hydrogen fluoride costly and in reaction process compared with
Greatly, be unfavorable for the defect of industrialized production, thus provide a kind of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acid and its
The preparation method and intermediate of intermediate, this method had both avoided expensive raw material 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- first
The use of acid esters also avoids the use of high risk hydrogen fluoride, and easy to operate, is 3- difluoromethyl -1- methyl-1 H- pyrrole
The synthesis of azoles -4- formic acid and its intermediate provides a kind of method of new suitable industrialized production.
The present invention mainly solves above-mentioned technical problem by the following technical programs.
The present invention provides a kind of preparations of the intermediate of the methyl-1 H- pyrazoles -4- formic acid of 3- difluoromethyl -1- shown in formula 2
Method comprising the following steps: solvent-free or under conditions of have solvent, by compound 1 and KF under the effect of the catalyst into
Row fluorination reaction；
R is CN or CONR in the compound 11R2, R1And R2Independent is C1-C4Alkyl；Or NR1R2For C2-C5
3-6 member C-N heterocycle, wherein in the C-N heterocycle only include 1 N atom；
The catalyst is tetraphenylphosphonibromide bromide, quaternary ammonium salt-type phase transfer catalyst, ionic liquid class phase transfer catalysis (PTC)
One of agent and crown ether-like phase transfer catalysts are a variety of.
Wherein, the R1And R2It is preferred that being each independently methyl or ethyl, it is further preferably each independently first
Base.
Wherein, the preferred tetramethyl ammonium chloride of the quaternary ammonium salt-type phase transfer catalyst, tetrabutylammonium chloride, tetrabutyl bromine
Change ammonium, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, tetraethylammonium bromide, benzyl triethyl ammonium bromide, tetramethyl bromide
Change one of ammonium and tetrabutyl ammonium fluoride or a variety of, more preferable tetramethyl ammonium chloride, tetrabutylammonium chloride, tetrabutyl phosphonium bromide
One of ammonium, 4 bromide and tetrabutyl ammonium fluoride are a variety of；
Wherein, the ionic liquid class phase transfer catalyst preferred cationic be N- alkyl pyridine or N- alkyl imidazole,
And anion is one of chloride ion, bromide ion, fluorine ion, trifluoracetic acid root, tetrafluoroborate and hexafluoro-phosphate radical or more
Kind；More preferable 1- butyl -3- methyl imidazolium tetrafluoroborate and/or 1- butyl -3- methylimidazole hexafluorophosphate；The N- alkane
Alkyl in base is C1-C6Alkyl, preferably butyl.
Wherein, the preferred 18- crown- 6 of the crown ether-like phase transfer catalysts；
It is described have solvent under conditions of, the solvent is in amide solvent, sulfone class solvent and polyalcohols solvent
It is one or more；
Wherein, the preferred n,N-Dimethylformamide of the amide solvent, n,N-dimethylacetamide and N- methylpyrrole
One of alkanone is a variety of；And/or the preferred dimethyl sulfoxide of the sulfone class solvent and/or sulfolane, more preferable sulfolane；With/
Or, the preferred polyethylene glycols solvent of the polyalcohols compound, the preferably poly- tetraethylene glycol two of the polyethylene glycols solvent
Methyl ether.
The molar ratio of heretofore described fluorination reaction, the KF and compound 1 is referred to this field, and such is anti-
Answer conventional ratio, 2:1-6:1 specifically preferred according to the invention, more preferable 3:1-5:1.
Heretofore described fluorination reaction, the dosage of the catalyst are referred to the conventional of such reaction of this field and use
Amount, the 0.1%-5%, more preferable 1%-2% of 1 mass of compound specifically preferred according to the invention.
Heretofore described fluorination reaction temperature is referred to such reaction ordinary temperature of this field, and the present invention is especially excellent
Select 100-200 DEG C, further preferred 130-180 DEG C, more preferable 150 DEG C.
The time of heretofore described fluorination reaction can monitor whether reaction ties using this field conventional detection mode
Whether beam, HPLC detection reaction specifically preferred according to the invention terminate.
Heretofore described fluorination reaction is preferably carried out in the case where there is solvent condition.
Wherein, the dosage of the solvent is referred to such reaction conventional amount used of this field, specifically preferred according to the invention for change
1-5 times, more preferable 1.6-2 times for closing 1 mass of object.
Heretofore described fluorination reaction, the reaction generally further include post-processing stages, and the post-processing can be with
With reference to this field routine post processing mode, following post processing mode specifically preferred according to the invention: filtering, rectifying obtain the compound
2.
Wherein, in the post-processing of the fluorination reaction, filtering, distillation operation can refer to this field routine operation.
The present invention also provides a kind of preparation method of the methyl-1 H- pyrazoles -4- formic acid of 3- difluoromethyl -1- shown in formula 3,
It comprises the steps of:
(1) according to the preparation method of the compound 2, the compound 2 is prepared；
(2) have solvent or it is solvent-free under the conditions of, gained compound 2 in step (1) is subjected to water in the presence of alkali
Solution reaction, obtains the compound 3,
In preparation method of the present invention, the method and condition of hydrolysis described in step (2) can be ability
The conventional method and condition of the such hydrolysis in domain, following methods and condition specifically preferred according to the invention:
In preparation method of the present invention, the aqueous solution of the preferred inorganic base compound of alkali described in step (2), into
One of aqueous solution of the preferred sodium hydroxide of one step, potassium hydroxide and lithium hydroxide is a variety of, and more preferable sodium hydroxide is water-soluble
Liquid.
Wherein, the concentration of the aqueous solution of the alkaloid compound be preferred 10-50%, more preferable 10-30%, it is described dense
Degree refers to mass fraction of the alkaloid compound in its aqueous solution.
In preparation method of the present invention, preferably, the hydrolysis carries out under solvent-free conditions.
In preparation method of the present invention, it is described after reaction, can also include post-processing, the post-processing can
For this field routine post processing mode, preferably stratification, acidification, cooling, filtering and washing, drying obtains the compound 3, i.e.,
It can.
Wherein, it is preferable to use hydrochloric acid, the preferred 3%- of the concentration of hydrochloric acid in the described hydrolysis post-processing, when the acidification
8%, further preferred 5%；Subject to when the dosage of hydrochloric acid is preferably by pH value adjustment to 1-5, further preferably by pH value adjustment to 3
Subject to；The hydrochloric acid, which is preferably added dropwise, is added water phase；And/or the cooling is preferably dropped to room temperature (20-25 DEG C)；And/or institute
The filtering and washing stated preferably uses water washing；And/or the drying preferable temperature is 80-100 DEG C, vacuum degree is preferably greater than
10-100mbar。
The present invention also provides a kind of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acid intermediates as follows, structures
Are as follows:
Wherein, R CONR1R2, R1And R2It is independently C1-C4Alkyl；Or NR1R2For C2-C53-6 member C-N heterocycle,
It wherein only include 1 N atom in the C-N heterocycle；The R1And R2Preferred methyl or ethyl, further preferred methyl.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that:
1, in the present invention, the use of expensive raw material 3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formic acid esters is avoided, and
The dosage of KF is less, substantially reduces the synthesis cost of 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formic acid.
2, in the present invention, the use of high risk hydrogen fluoride is avoided, and easy to operate, is 3- difluoromethyl -1- methyl -
The synthesis of 1H- pyrazoles -4- formic acid and its intermediate provides a kind of method of new suitable industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1
95.0g (0.5mol) 1- methyl-1 H- pyrazoles -4- formonitrile HCN, 88.0g (1.5mol) are added in four round flask
The KF of spray drying, 0.95g tetrabutylammonium chloride are warming up to 150 DEG C, and raw material to be detected after completion of the reaction, filters, filtrate rectifying
3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN 67.5g, purity 99.0% are obtained, yield 85% can be directly used in next step
Reaction.
Embodiment 2
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 88.0g is done by spraying
Dry KF, 0.95g tetrabutylammonium bromide, 190.0g sulfolane are warming up to 150 DEG C, and raw material to be detected after completion of the reaction, filters,
Filtrate rectifying obtains 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN 72.1g, purity 99.2%, and yield 91% can be used directly
It is reacted in next step.
Embodiment 3
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 88.0g is done by spraying
Dry KF, 1.9g tetrabutylammonium bromide, 190.0g sulfolane are warming up to 150 DEG C, and raw material to be detected after completion of the reaction, filters, filter
Liquid rectifying obtains 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN 74.4g, purity 99.3%, and yield 94% can be directly used for
It reacts in next step.
Embodiment 4
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetrabutyl ammonium fluoride, 190.0g sulfolane are warming up to 150 DEG C, raw material to be detected after completion of the reaction, mistake
Filter, filtrate rectifying obtain 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN 75.3g, and purity 99.1%, yield 95% can be direct
For reacting in next step.
Embodiment 5
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g 4 bromide, 190.0g sulfolane are warming up to 130 DEG C, raw material to be detected after completion of the reaction, mistake
Filter, filtrate rectifying obtain 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN 57.0g, and purity 98.6%, yield 72% can be direct
For reacting in next step.
Embodiment 6
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 88.0g is done by spraying
Dry KF, 0.95g1- butyl -3- methyl imidazolium tetrafluoroborate, 190.0g sulfolane are warming up to 150 DEG C, and raw material to be detected is anti-
After answering, filtering, filtrate rectifying obtains 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN 62.2g, purity 98.5%, yield
78%, it can be directly used for reacting in next step.
Embodiment 7
119.2g (0.5mol) N, N- dimethyl -3- dichloromethyl -1- methyl-1 H- pyrrole is added in four round flask
Azoles -4- formamide, the KF of 88.0g spray drying, 0.95g tetrabutylammonium bromide, 190.0g sulfolane is warming up to 150 DEG C, to be checked
Survey raw material after completion of the reaction, filtering, filtrate rectifying obtains N, N- dimethyl -3- difluoromethyl -1- methyl-1 H- pyrazole-4-carboxamide
75.8g, purity 97.6%, yield 73% can be directly used for reacting in next step.
Embodiment 8
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetraphenylphosphonibromide bromide, 190.0g sulfolane are warming up to 150 DEG C, react 20h, liquid phase detection is calculated theoretical
Yield 12%.
Embodiment 9
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 88.0g is done by spraying
Dry KF, 0.95g1- butyl -3- methylimidazole hexafluorophosphate, 190.0g sulfolane are warming up to 150 DEG C, react 20h, liquid phase
Theoretical yield 6% is calculated to obtain in detection.
Embodiment 10
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetrabutylammonium bromide, 190.0gN, dinethylformamide are warming up to 150 DEG C, react 20h, liquid phase inspection
Calculate to obtain theoretical yield 43%.
Embodiment 11
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetrabutylammonium bromide, 190.0gDMSO are warming up to 150 DEG C, react 20h, and theoretical receipts are calculated to obtain in liquid phase detection
Rate 15%.
Embodiment 12
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95gN- butyl-pyridinium tetrafluoroborate, 190.0g sulfolane are warming up to 150 DEG C, react 20h, liquid phase detection
Calculate to obtain theoretical yield 67%.
Embodiment 13
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetrabutylammonium bromide, 190.0gPEG400 are warming up to 150 DEG C, react 22h, liquid phase detection is calculated theoretical
Yield 26%.
Embodiment 14
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetrabutylammonium bromide, 190.0g sulfolane, 5.0g18- crown- 6 are warming up to 150 DEG C, react 22h, liquid phase
Theoretical yield 62% is calculated to obtain in detection.
Embodiment 15
31.4g3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN, 80.0g15% hydrogen are added in four round flask
Aqueous solution of sodium oxide is warming up to 90-100 DEG C, and after completion of the reaction, 233.6g5% is slowly added dropwise at 90-100 DEG C in raw material to be detected
Hydrochloric acid, until pH is less than 3, after dirty solution temperature is slowly down to room temperature, filtering and washing, 3- difluoromethyl -1- methyl-obtained by drying
1H- pyrazoles -4- formic acid finished product 33.8g, purity 99.0%, yield 95%.
Embodiment 16
31.4g3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN, 80.0g15% hydrogen are added in four round flask
Aqueous solution of sodium oxide, 62.8g toluene are warming up to 90-100 DEG C, raw material to be detected after completion of the reaction, stratification, water phase 90-
233.6g5% hydrochloric acid is slowly added dropwise at 100 DEG C, until pH is less than 3, after dirty solution temperature is slowly down to room temperature, filtering and washing is dried
Dry 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formic acid finished product 33.0g to obtain the final product, purity 99.2%, yield 93%.
Embodiment 17
20.5gN, N- dimethyl -3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formyl are added in four round flask
Amine, 80.0g15% sodium hydrate aqueous solution, 62.8g toluene are warming up to 90-100 DEG C, and raw material to be detected after completion of the reaction, is stood
233.6g5% hydrochloric acid is slowly added dropwise at 90-100 DEG C of water phase in layering, until pH is less than 3, after dirty solution temperature is slowly down to room
Temperature, filtering and washing, 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formic acid finished product 16.8g obtained by drying, purity 99.6%, yield
95%.
Embodiment 18
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 1.9g18- crown- 6,285.0g polyethylene glycol dimethyl ether are warming up to 150 DEG C, raw material to be detected after completion of the reaction, mistake
Filter, filtrate rectifying obtain 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN 53.2g, and purity 99.3%, yield 67.2% can be straight
It connects for reacting in next step.
Comparative example 1
95.0g (0.5mol) 1- methyl-1 H- pyrazoles -4- formonitrile HCN, 88.0g (1.5mol) are added in four round flask
The KF of spray drying is warming up to 150 DEG C, reacts 20h, and liquid phase detection is generated without product.
Comparative example 2
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetrabutylammonium chloride, 190.0g o-dichlorohenzene are warming up to 150 DEG C, react 20h, and liquid phase is detected without product
It generates.
Comparative example 3
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 146.7g is spraying
Dry KF, 0.95g tetrabutyl phosphonium bromide phosphine, 190.0g sulfolane are warming up to 150 DEG C, react 20h, and liquid phase detection is raw without product
At.
Comparative example 4
95.0g3- dichloromethyl -1- methyl-1 H- pyrazoles -4- formonitrile HCN is added in four round flask, 106.1g is spraying
Dry NaF, 0.95g tetrabutylammonium bromide, 190.0g sulfolane are warming up to 150 DEG C, react 20h, and liquid phase detection is raw without product
At.
Reference implementation example
It (is prepared to 22.5g3- (dichloromethyl) -1- methyl-1 H- pyrazoles -4- phosgene according to document CN103396363A)
In, the dissolution of 110.0g methylene chloride is added, is cooled to 0-5 DEG C, slowly instills the dimethylamine agueous solution of 32.4g40%, drips
Bi Hou allows reaction solution to be back to room temperature naturally and continues to stir, and after completion of the reaction to liquid phase detection raw material, ice water is added and is quenched, is layered,
Organic phase is washed twice (pH is less than 3) with 5% dilute hydrochloric acid respectively, then is washed twice with 5% NaOH aqueous solution, rear to be layered,
Precipitation is up to 3- (dichloromethyl)-N, N, 1- trimethyl -1H- pyrazole-4-carboxamide, yield 89%, purity 98.5%.3- (two
Chloromethyl)-N, N, 1- trimethyl -1H- pyrazole-4-carboxamide: LC-MS (ESI) calcd for C8H11Cl2N3O [M+H+]:
236.0357, found:236.0319.
Claims (10)
1. a kind of preparation method of the intermediate of the methyl-1 H- pyrazoles -4- formic acid of 3- difluoromethyl -1- shown in formula 2, feature exist
In, including the following steps: solvent-free or under conditions of have solvent, compound 1 and KF are subjected to fluorine under the effect of the catalyst
Change reaction；
R is CN in the compound 1；The catalyst is tetrabutyl ammonium fluoride；It is described have solvent under conditions of, it is described molten
Agent is sulfolane；The molar ratio of the KF and compound 1 are 2:1-6:1；Temperature with, the fluorination reaction is 100-200
℃。
2. preparation method as described in claim 1, which is characterized in that the molar ratio of the KF and compound 1 are 3:1-5:
1。
3. preparation method as described in claim 1, which is characterized in that the dosage of the catalyst is 1 mass of compound
0.1%-5%.
4. preparation method as claimed in claim 3, which is characterized in that the dosage of the catalyst is 1 mass of compound
1%-2%.
5. preparation method as described in claim 1, which is characterized in that the temperature of the fluorination reaction is 130-180 DEG C.
6. preparation method as claimed in claim 5, which is characterized in that the temperature of the fluorination reaction is 150 DEG C.
7. preparation method as described in claim 1, which is characterized in that the time of the fluorination reaction is reacted with HPLC detection is
No end.
8. preparation method as described in claim 1, which is characterized in that when carrying out fluorination reaction under conditions of having solvent, institute
The dosage for stating solvent in fluorination reaction is 1-5 times of quality of compound 1.
9. preparation method as claimed in claim 8, which is characterized in that when carrying out fluorination reaction under conditions of having solvent, institute
The dosage for stating solvent in fluorination reaction is 1.6-2 times of quality of compound 1.
10. a kind of preparation method of the methyl-1 H- pyrazoles -4- formic acid of 3- difluoromethyl -1- shown in formula 3 comprising the steps of:
(1) according to preparation method of any of claims 1-9, prepare compound 2；
(2) have solvent or it is solvent-free under the conditions of, gained compound 2 in step (1) is hydrolyzed instead in the presence of alkali
It answers,
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| CN108314694A (en) * | 2018-02-02 | 2018-07-24 | 苏州贺康新材料科技有限公司 | A kind of preparation method of lithium battery electrolytes fire retardant |
| CN114790173B (en) * | 2022-04-29 | 2023-08-01 | 浙江南郊化学有限公司 | Green synthesis process of 1-methyl-3-difluoromethyl pyrazole-4-formic acid |
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