CN105418503A - Synthesis method for 3-difluromethylation-1-methyl-1H-pyrazol-4-carboxylic acid ethyl ester - Google Patents
Synthesis method for 3-difluromethylation-1-methyl-1H-pyrazol-4-carboxylic acid ethyl ester Download PDFInfo
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- CN105418503A CN105418503A CN201510920669.7A CN201510920669A CN105418503A CN 105418503 A CN105418503 A CN 105418503A CN 201510920669 A CN201510920669 A CN 201510920669A CN 105418503 A CN105418503 A CN 105418503A
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- ethyl ester
- carboxylic acid
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- pyrazoles
- difluoromethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 relates to a synthesis method for a compound, in particular to a synthesis method for 3-difluromethylation-1-methyl-1H-pyrazol-4-carboxylic acid ethyl ester. The method comprises the steps that a water bath reaction is performed by taking 2-ethyoxyl methylene-4,4-difluoro acetoacetic ether and hydrazine hydrate as raw materials to prepare 3-difluromethylation-1H-pyrazol-4-carboxylic acid ethyl ester, the 3-difluromethylation-1H-pyrrole-4-carboxylic acid ethyl ester and dimethyl carbonate are subjected to an oil bath reaction, extraction is performed through methylbenzene, and then the 3-difluromethylation-1-methyl-1H-pyrazol-4-carboxylic acid ethyl ester is prepared. The method is mild in reaction condition and high in yield.
Description
Technical field
The present invention relates to a kind of synthetic method of compound, a kind of synthetic method of 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester.
Background technology
3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester is organic chemical industry's intermediate, be widely used in synthesis medicine and agricultural chemicals, purposes is very extensive, dozens of kind is had with the agricultural chemicals of its synthesis, the new type bactericide manufactured has unique function, a kind of rising sterilization, pesticide intermediate, but 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester never comparatively ideal industrial process.Technique backwardness, the long flow path of traditional mode of production 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester, yield is low, quantity of three wastes is large, is difficult to administer.
Summary of the invention
The invention provides the synthetic method of the 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester that a kind of reaction conditions is gentle, yield is high.
For achieving the above object, the synthetic route of 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester of the present invention:
In order to solve the problems of the technologies described above, the technical solution adopted in the present invention is:
(1) hydrazine hydrate taking 15 ~ 20g (0.28 ~ 0.30mol) 60% puts into the 1L there-necked flask with agitator, adds 300 ~ 400mL distilled water, starts agitator, stirs 10 ~ 20min with the rotating speed of 300 ~ 400r/min;
(2) after having stirred, there-necked flask is moved into ice bath device, control temperature, at 0 ~ 5 DEG C, divides and adds 45 ~ 60g2-ethoxymeyhylene-4,4-difluoro methyl aceto acetate altogether for 3 ~ 5 times wherein, continues shaking table oscillatory reaction 2 ~ 3h;
(3) reaction terminates to add 50 ~ 60mL toluene in backward there-necked flask, separating funnel is poured into after mixing, leave standstill extracting and demixing, separation is extracted phase, put into water distilling apparatus and be warming up to 120 ~ 125 DEG C, toluene is removed in distillation, obtains brown oil liquid 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester;
(4) the above-mentioned obtained 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester of 35 ~ 45g is taken and 20 ~ 25g methylcarbonate is poured in the 1L there-necked flask with agitator, add 250 ~ 300mL toluene again, start agitator, stir 5 ~ 10min with the rotating speed of 200 ~ 300r/min;
(5) after being uniformly mixed, there-necked flask is moved in oil bath pan, be heated to 85 ~ 95 DEG C of insulation reaction 4 ~ 6h, regulate pH to 7 ~ 8 with the sodium hydroxide solution that mass concentration is 5% afterwards;
(6) making its layering by regulating the standing 12 ~ 15h of the liquid after pH value, getting upper oil phase, putting into water distilling apparatus, be heated to after toluene are removed in 115 ~ 120 DEG C of distillations and namely obtain 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester.
Specific embodiments
The hydrazine hydrate taking 15 ~ 20g (0.28 ~ 0.30mol) 60% puts into the 1L there-necked flask with agitator, adds 300 ~ 400mL distilled water, starts agitator, stirs 10 ~ 20min with the rotating speed of 300 ~ 400r/min; After stirring completes, there-necked flask is moved into ice bath device, control temperature, at 0 ~ 5 DEG C, divides and adds 45 ~ 60g2-ethoxymeyhylene-4,4-difluoro methyl aceto acetate altogether for 3 ~ 5 times wherein, continues shaking table oscillatory reaction 2 ~ 3h; Reaction terminates to add 50 ~ 60mL toluene in backward there-necked flask, pours separating funnel into, leave standstill extracting and demixing after mixing, separation is extracted phase, put into water distilling apparatus and be warming up to 120 ~ 125 DEG C, toluene is removed in distillation, obtains brown oil liquid 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester; Take the above-mentioned obtained 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester of 35 ~ 45g and 20 ~ 25g methylcarbonate is poured in the 1L there-necked flask with agitator, add 250 ~ 300mL toluene again, start agitator, stir 5 ~ 10min with the rotating speed of 200 ~ 300r/min; After being uniformly mixed, there-necked flask is moved in oil bath pan, be heated to 85 ~ 95 DEG C of insulation reaction 4 ~ 6h, regulate pH to 7 ~ 8 with the sodium hydroxide solution that mass concentration is 5% afterwards; Making its layering by regulating the standing 12 ~ 15h of the liquid after pH value, getting upper oil phase, putting into water distilling apparatus, be heated to after toluene are removed in 115 ~ 120 DEG C of distillations and namely obtain 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester.
Example 1
The hydrazine hydrate taking 15g (0.28mol) 60% puts into the 1L there-necked flask with agitator, adds 300mL distilled water, starts agitator, stirs 10min with the rotating speed of 300r/min; After stirring completes, there-necked flask is moved into ice bath device, control temperature, at 0 DEG C, divides and adds 45g2-ethoxymeyhylene-4,4-difluoro methyl aceto acetate altogether for 3 times wherein, continues shaking table oscillatory reaction 2h; Reaction terminates to add 50mL toluene in backward there-necked flask, pours separating funnel into, leave standstill extracting and demixing after mixing, separation is extracted phase, put into water distilling apparatus and be warming up to 120 DEG C, toluene is removed in distillation, obtains brown oil liquid 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester; Take the above-mentioned obtained 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester of 35g and 20g methylcarbonate is poured in the 1L there-necked flask with agitator, then add 250mL toluene, start agitator, stir 5min with the rotating speed of 200r/min; After being uniformly mixed, there-necked flask is moved in oil bath pan, be heated to 85 DEG C of insulation reaction 4h, regulate pH to 7 with the sodium hydroxide solution that mass concentration is 5% afterwards; Leave standstill 12h make its layering by regulating the liquid after pH value, get upper oil phase, put into water distilling apparatus, be heated to after toluene are removed in 115 DEG C of distillations and namely obtain 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester.
Example 2
The hydrazine hydrate taking 18g (0.29mol) 60% puts into the 1L there-necked flask with agitator, adds 350mL distilled water, starts agitator, stirs 15min with the rotating speed of 350r/min; After stirring completes, there-necked flask is moved into ice bath device, control temperature, at 3 DEG C, divides and adds 50g2-ethoxymeyhylene-4,4-difluoro methyl aceto acetate altogether for 4 times wherein, continues shaking table oscillatory reaction 2h; Reaction terminates to add 55mL toluene in backward there-necked flask, pours separating funnel into, leave standstill extracting and demixing after mixing, separation is extracted phase, put into water distilling apparatus and be warming up to 123 DEG C, toluene is removed in distillation, obtains brown oil liquid 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester; Take the above-mentioned obtained 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester of 40g and 23g methylcarbonate is poured in the 1L there-necked flask with agitator, then add 280mL toluene, start agitator, stir 8min with the rotating speed of 250r/min; After being uniformly mixed, there-necked flask is moved in oil bath pan, be heated to 90 DEG C of insulation reaction 5h, regulate pH to 7 with the sodium hydroxide solution that mass concentration is 5% afterwards; Leave standstill 13h make its layering by regulating the liquid after pH value, get upper oil phase, put into water distilling apparatus, be heated to after toluene are removed in 118 DEG C of distillations and namely obtain 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester.
Example 3
The hydrazine hydrate taking 20g (0.30mol) 60% puts into the 1L there-necked flask with agitator, adds 400mL distilled water, starts agitator, stirs 20min with the rotating speed of 400r/min; After stirring completes, there-necked flask is moved into ice bath device, control temperature, at 5 DEG C, divides and adds 60g2-ethoxymeyhylene-4,4-difluoro methyl aceto acetate altogether for 5 times wherein, continues shaking table oscillatory reaction 3h; Reaction terminates to add 60mL toluene in backward there-necked flask, pours separating funnel into, leave standstill extracting and demixing after mixing, separation is extracted phase, put into water distilling apparatus and be warming up to 125 DEG C, toluene is removed in distillation, obtains brown oil liquid 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester; Take the above-mentioned obtained 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester of 45g and 25g methylcarbonate is poured in the 1L there-necked flask with agitator, then add 300mL toluene, start agitator, stir 10min with the rotating speed of 300r/min; After being uniformly mixed, there-necked flask is moved in oil bath pan, be heated to 95 DEG C of insulation reaction 6h, regulate pH to 8 with the sodium hydroxide solution that mass concentration is 5% afterwards; Leave standstill 15h make its layering by regulating the liquid after pH value, get upper oil phase, put into water distilling apparatus, be heated to after toluene are removed in 120 DEG C of distillations and namely obtain 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester.
Claims (1)
1. a synthetic method for 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester, is characterized in that concrete synthesis step is:
(1) hydrazine hydrate taking 15 ~ 20g (0.28 ~ 0.30mol) 60% puts into the 1L there-necked flask with agitator, adds 300 ~ 400mL distilled water, starts agitator, stirs 10 ~ 20min with the rotating speed of 300 ~ 400r/min;
(2) after having stirred, there-necked flask is moved into ice bath device, control temperature, at 0 ~ 5 DEG C, divides and adds 45 ~ 60g2-ethoxymeyhylene-4,4-difluoro methyl aceto acetate altogether for 3 ~ 5 times wherein, continues shaking table oscillatory reaction 2 ~ 3h;
(3) reaction terminates to add 50 ~ 60mL toluene in backward there-necked flask, separating funnel is poured into after mixing, leave standstill extracting and demixing, separation is extracted phase, put into water distilling apparatus and be warming up to 120 ~ 125 DEG C, toluene is removed in distillation, obtains brown oil liquid 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester;
(4) the above-mentioned obtained 3-difluoromethyl-1H-pyrazoles-4-carboxylic acid, ethyl ester of 35 ~ 45g is taken and 20 ~ 25g methylcarbonate is poured in the 1L there-necked flask with agitator, add 250 ~ 300mL toluene again, start agitator, stir 5 ~ 10min with the rotating speed of 200 ~ 300r/min;
(5) after being uniformly mixed, there-necked flask is moved in oil bath pan, be heated to 85 ~ 95 DEG C of insulation reaction 4 ~ 6h, regulate pH to 7 ~ 8 with the sodium hydroxide solution that mass concentration is 5% afterwards;
(6) making its layering by regulating the standing 12 ~ 15h of the liquid after pH value, getting upper oil phase, putting into water distilling apparatus, be heated to after toluene are removed in 115 ~ 120 DEG C of distillations and namely obtain 3-difluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233768A (en) * | 2020-03-18 | 2020-06-05 | 徐州圣元化工有限公司 | Preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000044541A (en) * | 1998-08-03 | 2000-02-15 | Mitsui Chemicals Inc | Production of 1,3-dialkylpyrazole-4-carboxylic acid ester |
| EP2151434A1 (en) * | 2008-08-05 | 2010-02-10 | Institut Pasteur | Alkoxypyrazoles and the process for their preparation |
| CN103570623A (en) * | 2013-11-12 | 2014-02-12 | 湖南化工研究院 | Preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid |
| CN103842345A (en) * | 2012-09-05 | 2014-06-04 | 撻马化学工业株式会社 | Method for producing 1-substituted-3- fluoroalkylpyrazole-4-carboxylic acid ester |
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- 2015-12-12 CN CN201510920669.7A patent/CN105418503A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000044541A (en) * | 1998-08-03 | 2000-02-15 | Mitsui Chemicals Inc | Production of 1,3-dialkylpyrazole-4-carboxylic acid ester |
| EP2151434A1 (en) * | 2008-08-05 | 2010-02-10 | Institut Pasteur | Alkoxypyrazoles and the process for their preparation |
| CN103842345A (en) * | 2012-09-05 | 2014-06-04 | 撻马化学工业株式会社 | Method for producing 1-substituted-3- fluoroalkylpyrazole-4-carboxylic acid ester |
| CN103570623A (en) * | 2013-11-12 | 2014-02-12 | 湖南化工研究院 | Preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233768A (en) * | 2020-03-18 | 2020-06-05 | 徐州圣元化工有限公司 | Preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester |
| CN111233768B (en) * | 2020-03-18 | 2021-08-03 | 徐州圣元化工有限公司 | Preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester |
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Application publication date: 20160323 |