CN106977457A - A kind of formic acid of 1 methylpyrazole of 3 difluoromethyl 4 and its synthetic method - Google Patents
A kind of formic acid of 1 methylpyrazole of 3 difluoromethyl 4 and its synthetic method Download PDFInfo
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- CN106977457A CN106977457A CN201611197338.6A CN201611197338A CN106977457A CN 106977457 A CN106977457 A CN 106977457A CN 201611197338 A CN201611197338 A CN 201611197338A CN 106977457 A CN106977457 A CN 106977457A
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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
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Abstract
The present invention relates to chemical field, in particular, it is related to a kind of formic acid of 3 difluoromethyl, 1 methylpyrazole 4 and its synthetic method, synthetic method includes step：DFKE synthesis；DFVKE synthesis；DFPE synthesis；DFPA synthesis.The raw material used in the synthetic method of the present invention is cheap and easy to get, environmental protection, and reaction condition of the present invention is simple, and impurity is few, high income, and the quality of the obtained formic acid of 3 difluoromethyl, 1 methylpyrazole 4 is high, and purity is high, and yield is more than 90%.
Description
Technical field
The present invention relates to chemical field, in particular, be related to a kind of 3- difluoromethyls -1- methyl pyrazole -4- formic acid and
Its synthetic method.
Background technology
3- difluoromethyl -1- methyl pyrazole -4- formic acid is abbreviated as DFPA, the master for the synthesis DFPA that appears in the newspapers both at home and abroad at present
It is respectively 1,1,2,2 to want initiation material ,-tetrafluoro dimethylamine, difluoroacetic acid chloride, 4,4- difluoro acetoacetyl ethyl acetate and
The formic acid esters of 3- dichloromethyl -1- methylpyrazoles -4, wherein being deposited with 4,4- difluoro acetoacetyl ethyl acetate for predominant starting material
It is easy to get relatively in raw material, the advantage of high income, with certain industrial prospect, but there is raw material seldom in several initiation materials,
And expensive, the not high defect of yield, and sodium hydride can be typically used in synthesis, there is safe hidden danger.
The content of the invention
For problem above, a kind of raw material of present invention offer is simple and easy to get, and security is good, the preparation method of high income.
The solution of the present invention is：3- difluoromethyl -1- methyl pyrazole -4- formic acid, the chemical shift of its proton nmr spectra
For：12.82 (s, 1H), 8.33 (s, 1H), 7.20 (t, J=53.8Hz, 1H), 3.91 (s, 3H).
A kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid, this method comprises the following steps：
A, DFKE synthesis：At a temperature of 0~5 DEG C, difluoro is added after organic base, stirring reaction are added into ethyl acetate
Ethyl acetate and 15~20min of stirring reaction at 0~10 DEG C of temperature, then heat to 20~25 DEG C and are incubated 3.5~4h；Protect
0~5 DEG C is cooled to after temperature and is passed through 15% ethanolic hydrogen chloride up to pH value to 2~3, is easy to accurate control to add the amount of hydrogen chloride,
Avoid acidifying insufficient or excessive, be acidified it is insufficient and it is excessive can all cause yield relatively low, and add into solution dichloromethane,
It is concentrated under reduced pressure to give concentrate 1 and filter cake；Filter cake is added after dichloromethane mashing, is concentrated under reduced pressure to give concentrate 2, mixing concentration
Liquid 1 and concentrate 2 obtain DFKE；
B, DFVKE synthesis：Acetic anhydride is added in the DFKE that step a is obtained, primitive nail triethylenetetraminehexaacetic acid is added dropwise at 95~100 DEG C
Ester is simultaneously incubated 0.5~1h；Then 40~60 DEG C are cooled to, DFVKE is obtained after being concentrated under reduced pressure；
C, DFPE synthesis：Dimethylbenzene and methyl hydrazine are first mixed and are cooled to 0~2 DEG C again, is then added dropwise in step b and obtains
DFVKE, 20-25 DEG C of temperature control is added dropwise, the relatively low reaction of temperature is incomplete, temperature drift, and product impurity is high, colour-difference, preferably 22
DEG C, after 30~40min of reaction, point liquid retains organic layer；
D, DFPA synthesis：Aqueous slkali is warming up to 55~65 DEG C, the organic layer obtained in step c is instilled, reaction 1~
1.5h；Then organic solvent is reclaimed, retains water layer, by the water layer in 80~85 DEG C of 20~30min of acidifying of temperature, Temperature fall
To 30~35 DEG C, then water cooling is to 10~15 DEG C, and suction filtration drying obtains finished product DFPA after 30~40min of insulation.
Further, alkali described in step a is one kind in organic base, and the organic base is caustic alcohol, potassium ethoxide, three second
One kind in amine, pyridine or diisopropyl ethylhexylamine.
Further, the mol ratio of ethyl acetate, organic base and ethyl difluoro is (2~3) in step a:(1~
1.1):1。
Further, pulping process is in step a：It is beaten 2~3 times using dichloromethane, merges 2~3 mashing filtrates,
Being beaten 2 times makes material (DFKE) of the double team in filter cake (salt) be substantially dissolved in chloroform, it is to avoid DFKE loss of material.
Further, triethyl orthoformate is added dropwise at 100 DEG C in step b.
Further, being concentrated under reduced pressure for step b is referred to as：It is concentrated under reduced pressure into 100~110 DEG C of temperature, vacuum -0.098
~-1, can remove the solvent of excessive raw material and side reaction generation.
Further, the concentration of methyl hydrazine is 35~40% in step c, and methyl hydrazine and DFVKE mol ratio are 1:1, one
Aspect is that, in order to save raw material, on the other hand raising yield is conducive to wastewater treatment.
The chemical equation of the synthetic method of the present invention is as follows：
Beneficial effects of the present invention are：The raw material used in the synthetic method of the present invention is cheap and easy to get, environmental protection, this hair
Bright reaction condition is simple, and impurity is few, high income, and the quality of obtained 3- difluoromethyls -1- methyl pyrazole -4- formic acid is high, purity
Height, yield is more than 90%.
Brief description of the drawings
Fig. 1 is the liquid chromatogram of 3- difluoromethyls -1- methyl pyrazole -4- formic acid of the present invention；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of 3- difluoromethyls -1- methyl pyrazole -4- formic acid of the present invention.
Embodiment
The following is specific embodiment of the invention and with reference to accompanying drawing, technical scheme is further described,
But the present invention is not limited to these embodiments.
Embodiment 1
A, DFKE synthesis：At a temperature of 0 DEG C, difluoroacetic acid is added after adding caustic alcohol stirring reaction into ethyl acetate
Ethyl ester, the mol ratio of ethyl acetate, organic base and ethyl difluoro is 2:1:1, the stirring reaction 15min at 3 DEG C of temperature, so
After be warming up to 20 DEG C and be incubated 3.5h；1 DEG C is cooled to after insulation and is passed through hydrogen chloride until pH value is to 2, and adds into solution two
Chloromethanes, is concentrated under reduced pressure to give concentrate 1 and filter cake；Filter cake adds dichloromethane and is beaten 2 times, merges 2 mashing filtrates, decompression
Concentrate 2 is concentrated to give, mixed concentrated liquid 1 and concentrate 2 obtain DFKE；
B, DFVKE synthesis：Acetic anhydride is added in the DFKE that step a is obtained, triethyl orthoformate is added dropwise simultaneously at 95 DEG C
It is incubated 1h；Then 60 DEG C are cooled to, 100 DEG C of temperature is concentrated under reduced pressure into, DFVKE is obtained after vacuum -1；
C, DFPE synthesis：Dimethylbenzene and methyl hydrazine are first mixed and are cooled to 0 DEG C again, the concentration of methyl hydrazine is 36%, first
Base hydrazine and DFVKE mol ratio are 1:1, the DFVKE obtained in step b is then added dropwise, is added dropwise after 22 DEG C of temperature control, reaction 30min,
Liquid is divided to retain organic layer；
D, DFPA synthesis：Aqueous slkali is warming up to 55 DEG C, the organic layer obtained in step c is instilled, 1h is reacted；Then return
Organic solvent is received, retains water layer, by the water layer in 80 DEG C of temperature acidifying 25min, 30 DEG C are naturally cooling to, then water cooling is to 15
DEG C, suction filtration drying obtains finished product DFPA after insulation 30min.
Embodiment 2
A, DFKE synthesis：At a temperature of 5 DEG C, the mixture of potassium ethoxide and pyridine is added into ethyl acetate, stirring is anti-
Should after add ethyl difluoro, the mol ratio of ethyl acetate, organic base and ethyl difluoro is 3:1.1:1, in temperature 10
Stirring reaction 20min at DEG C, then heats to 20 DEG C and is incubated 4h；0 DEG C is cooled to after insulation and is passed through hydrogen chloride until pH value is arrived
3, and dichloromethane is added into solution, it is concentrated under reduced pressure to give concentrate 1 and filter cake；Filter cake adds dichloromethane and is beaten 3 times, closes
And 3 mashing filtrates, concentrate 2 is concentrated under reduced pressure to give, mixed concentrated liquid 1 and concentrate 2 obtain DFKE；
B, DFVKE synthesis：Acetic anhydride is added in the DFKE that step a is obtained, triethyl orthoformate is added dropwise simultaneously at 100 DEG C
It is incubated 0.8h；Then 50 DEG C are cooled to, 110 DEG C of temperature is concentrated under reduced pressure into, DFVKE is obtained after vacuum -0.098；
C, DFPE synthesis：Dimethylbenzene and methyl hydrazine are first mixed and are cooled to 1 DEG C again, the concentration of methyl hydrazine is 36%, first
Base hydrazine and DFVKE mol ratio are 1:1, the DFVKE obtained in step b is then added dropwise, is added dropwise after 20 DEG C of temperature control, reaction 40min,
Liquid is divided to retain organic layer；
D, DFPA synthesis：Aqueous slkali is warming up to 65 DEG C, the organic layer obtained in step c is instilled, 1.5h is reacted；Then
Organic solvent is reclaimed, retains water layer, by the water layer in 85 DEG C of temperature acidifying 20min, 35 DEG C are naturally cooling to, then water cooling is extremely
10 DEG C, it is incubated suction filtration drying after 40min and obtains finished product DFPA.
Embodiment 3
A, DFKE synthesis：At a temperature of 5 DEG C, the mixed of triethylamine and diisopropyl ethylhexylamine is added into ethyl acetate
Ethyl difluoro is added after compound, stirring reaction, the mol ratio of ethyl acetate, organic base and ethyl difluoro is 2.3:1:
1, the stirring reaction 15min at 6 DEG C of temperature, then heat to 23 DEG C and are incubated 4h；0 DEG C is cooled to after insulation, and to be passed through hydrogen chloride straight
To pH value to 2.7, and dichloromethane is added into solution, be concentrated under reduced pressure to give concentrate 1 and filter cake；Filter cake adds dichloromethane
Mashing 2 times, merges 2 mashing filtrates, is concentrated under reduced pressure to give concentrate 2, mixed concentrated liquid 1 and concentrate 2 obtain DFKE；
B, DFVKE synthesis：Acetic anhydride is added in the DFKE that step a is obtained, triethyl orthoformate is added dropwise simultaneously at 100 DEG C
It is incubated 1h；Then 40 DEG C are cooled to, 110 DEG C of temperature is concentrated under reduced pressure into, DFVKE is obtained after vacuum -0.099；
C, DFPE synthesis：Dimethylbenzene and methyl hydrazine are first mixed and are cooled to 2 DEG C again, the concentration of methyl hydrazine is 35%, first
Base hydrazine and DFVKE mol ratio are 1:1, the DFVKE obtained in step b is then added dropwise, is added dropwise after 25 DEG C of temperature control, reaction 37min,
Liquid is divided to retain organic layer；
D, DFPA synthesis：Aqueous slkali is warming up to 55 DEG C, the organic layer obtained in step c is instilled, 1h is reacted；Then return
Organic solvent is received, retains water layer, by the water layer in 85 DEG C of temperature acidifying 20min, 30 DEG C are naturally cooling to, then water cooling is to 15
DEG C, suction filtration drying obtains finished product DFPA after insulation 30min.
Embodiment 4
A, DFKE synthesis：At a temperature of 4 DEG C, addition difluoro second after potassium ethoxide, stirring reaction is added into ethyl acetate
Acetoacetic ester, the mol ratio of ethyl acetate, organic base and ethyl difluoro is 2:1:1, the stirring reaction at 10 DEG C of temperature
20min, then heats to 20 DEG C and is incubated 3.5h；0 DEG C is cooled to after insulation and is passed through hydrogen chloride until pH value is to 3, and to solution
Middle addition dichloromethane, is concentrated under reduced pressure to give concentrate 1 and filter cake；Filter cake adds dichloromethane and is beaten 3 times, merges 3 mashing
Filtrate, is concentrated under reduced pressure to give concentrate 2, and mixed concentrated liquid 1 and concentrate 2 obtain DFKE；
B, DFVKE synthesis：Acetic anhydride is added in the DFKE that step a is obtained, triethyl orthoformate is added dropwise simultaneously at 95 DEG C
It is incubated 0.5h；Then 40 DEG C are cooled to, 100 DEG C of temperature is concentrated under reduced pressure into, DFVKE is obtained after vacuum -0.098；
C, DFPE synthesis：Dimethylbenzene and methyl hydrazine are first mixed and are cooled to 2 DEG C again, the concentration of methyl hydrazine is 37%, first
Base hydrazine and DFVKE mol ratio are 1:1, the DFVKE obtained in step b is then added dropwise, is added dropwise after 25 DEG C of temperature control, reaction 35min,
Liquid is divided to retain organic layer；
D, DFPA synthesis：Aqueous slkali is warming up to 55 DEG C, the organic layer obtained in step c is instilled, 1.5h is reacted；Then
Organic solvent is reclaimed, retains water layer, by the water layer in 80 DEG C of temperature acidifying 30min, 30 DEG C are naturally cooling to, then water cooling is extremely
15 DEG C, it is incubated suction filtration drying after 40min and obtains finished product DFPA.
3- difluoromethyl -1- methyl pyrazole -4- the formic acid synthesized using the present invention is randomly selected to carry out by liquid chromatogram
Detection.
The testing result of table 1
| Sequence number | Retention time | Concentration | Peak area |
| 1 | 6.548 | 2.821 | 635769 |
| 2 | 7.374 | 95.97 | 21628488 |
| 3 | 9.245 | 1.205 | 271460 |
It can be seen that from Fig. 1 and table 1：3- difluoromethyl -1- methyl pyrazole -4- formic acid the purity that the present invention is synthesized exists
More than 95%, and product quality is preferable.
3- difluoromethyl -1- methyl pyrazole -4- formic acid the sample that the present invention is synthesized carries out hydrogen nuclear magnetic resonance analysis of spectrum,
As a result see Fig. 2, the chemical shift of its proton nmr spectra for 12.82 (s, 1H), 8.33 (s, 1H), 7.20 (t, J=53.8Hz,
1H),3.91(s,3H)。
Specific embodiment described herein is only to spirit explanation for example of the invention.Technology neck belonging to of the invention
The technical staff in domain can be made various modifications or supplement to described specific embodiment or be substituted using similar mode, but simultaneously
Do not deviate by the spirit of the present invention or surmount scope defined in appended claims.
It is skilled to this area although having been made a detailed description to the present invention and being cited some specific embodiments
For technical staff, as long as it is obvious that can make various changes or correct without departing from the spirit and scope of the present invention.
Claims (8)
1.3- difluoromethyl -1- methyl pyrazole -4- formic acid, it is characterised in that the chemical shift of its proton nmr spectra is：
12.82 (s, 1H), 8.33 (s, 1H), 7.20 (t, J=53.8Hz, 1H), 3.91 (s, 3H).
2. a kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid as claimed in claim 1, this method includes
Following steps：
A, DFKE synthesis：At a temperature of 0~5 DEG C, difluoroacetic acid is added after organic base, stirring reaction are added into ethyl acetate
Ethyl ester and 15~20min of stirring reaction at 0~10 DEG C of temperature, then heat to 20~25 DEG C and are incubated 3.5~4h；After insulation
It is cooled to 0~5 DEG C and is passed through hydrogen chloride up to pH value adds dichloromethane to 2~3, and into solution, is concentrated under reduced pressure to give concentration
Liquid 1 and filter cake；Filter cake is added after dichloromethane mashing, is concentrated under reduced pressure to give concentrate 2, mixed concentrated liquid 1 and concentrate 2 are obtained
DFKE；
B, DFVKE synthesis：Acetic anhydride is added in the DFKE that step a is obtained, triethyl orthoformate is added dropwise simultaneously at 95~100 DEG C
It is incubated 0.5~1h；Then 40~60 DEG C are cooled to, DFVKE is obtained after being concentrated under reduced pressure；
C, DFPE synthesis：Dimethylbenzene and methyl hydrazine are first mixed and are cooled to 0~2 DEG C again, is then added dropwise what is obtained in step b
After DFVKE, 30~40min of reaction, point liquid retains organic layer；
D, DFPA synthesis：Aqueous slkali is warming up to 55~65 DEG C, the organic layer obtained in step c is instilled, 1~1.5h is reacted；
Then organic solvent is reclaimed, retains water layer, by the water layer in 80~85 DEG C of 20~30min of acidifying of temperature, 30 are naturally cooling to
~35 DEG C, then water cooling is to 10~15 DEG C, and suction filtration drying obtains finished product DFPA after 30~40min of insulation.
3. a kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid according to claim 2, its feature exists
In：Alkali described in step a is one kind in organic base, and the organic base is that caustic alcohol, potassium ethoxide, triethylamine, pyridine or two are different
One or more in ethyl hexylamine.
4. a kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid according to claim 2, its feature exists
In：The mol ratio of ethyl acetate, organic base and ethyl difluoro is (2~3) in step a:(1~1.1):1.
5. a kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid according to claim 2, its feature exists
In：Pulping process is in step a：It is beaten 2~3 times using dichloromethane, merges 2~3 mashing filtrates.
6. a kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid according to claim 2, its feature exists
In：Triethyl orthoformate is added dropwise at 100 DEG C in step b.
7. a kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid according to claim 2, its feature exists
In：Being concentrated under reduced pressure for step b is referred to as：It is concentrated under reduced pressure into 100~110 DEG C of temperature, vacuum -0.098~-1.
8. a kind of synthetic method of 3- difluoromethyls -1- methyl pyrazole -4- formic acid according to claim 2, its feature exists
In：The concentration of methyl hydrazine is 35~40% in step c, and methyl hydrazine and DFVKE mol ratio are 1:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084093A (en) * | 2017-12-21 | 2018-05-29 | 湖南海利化工股份有限公司 | The method of one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids |
| CN112480007A (en) * | 2020-12-08 | 2021-03-12 | 宿迁市科莱博生物化学有限公司 | Synthetic method of 1, 3-dimethyl-1H-pyrazole-4-carboxylic acid |
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| CN1812959A (en) * | 2003-07-01 | 2006-08-02 | 拜尔农作物科学股份公司 | Method for producing difluoro-acetyl-acetic acid alkylesters |
| CN1968934A (en) * | 2004-06-18 | 2007-05-23 | 巴斯福股份公司 | 1-methyl-3-difluoromethyl-pyrazol-4-carbonic acid-(ortho-phenyl)-anilides, and use thereof as a fungicide |
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| US5093347A (en) * | 1991-01-28 | 1992-03-03 | Monsanto Company | 3-difluoromethylpyrazolecarboxamide fungicides, compositions and use |
| CN1708496A (en) * | 2002-11-01 | 2005-12-14 | 辛根塔参与股份公司 | Cyclopropyl-thienyl-carboxamide as fungicides |
| CN1812959A (en) * | 2003-07-01 | 2006-08-02 | 拜尔农作物科学股份公司 | Method for producing difluoro-acetyl-acetic acid alkylesters |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108084093A (en) * | 2017-12-21 | 2018-05-29 | 湖南海利化工股份有限公司 | The method of one pot process 3- difluoromethyl -1- methyl-1 H- pyrazoles -4- carboxylic acids |
| CN108084093B (en) * | 2017-12-21 | 2020-03-27 | 湖南海利化工股份有限公司 | Method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by one-pot method |
| CN112480007A (en) * | 2020-12-08 | 2021-03-12 | 宿迁市科莱博生物化学有限公司 | Synthetic method of 1, 3-dimethyl-1H-pyrazole-4-carboxylic acid |
| CN112480007B (en) * | 2020-12-08 | 2022-11-18 | 宿迁市科莱博生物化学有限公司 | Synthetic method of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid |
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Application publication date: 20170725 |