CN108218702B - Preparation method of 2-fluoro ethyl acetoacetate - Google Patents
Preparation method of 2-fluoro ethyl acetoacetate Download PDFInfo
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- CN108218702B CN108218702B CN201711455956.0A CN201711455956A CN108218702B CN 108218702 B CN108218702 B CN 108218702B CN 201711455956 A CN201711455956 A CN 201711455956A CN 108218702 B CN108218702 B CN 108218702B
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- fluoroacetoacetate
- chloroacetoacetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The invention discloses a preparation method of 2-fluoro ethyl acetoacetate, which comprises the following steps: taking 2-chloroacetoacetic acid ethyl ester and excessive mixed gas containing fluorine gas as raw materials, taking hydrofluoric acid as a solvent and a catalyst, adding a fluorine surfactant, and reacting at a low temperature to obtain the 2-fluoroacetoacetic acid ethyl ester. According to the technical scheme, the 2-chloroacetoacetic acid ethyl ester and the excessive mixed gas containing the fluorine gas are used as raw materials, so that the phenomenon that the purity of the product is influenced because the 2-chloroacetoacetic acid ethyl ester is not completely reacted is avoided; hydrofluoric acid is added as a solvent and a catalyst, so that the reaction rate can be accelerated, and the generated impurity gas can be prevented from being dissolved in the reaction mixed liquid again; the addition of the fluorine surfactant not only allows the ethyl 2-chloroacetoacetate, the hydrofluoric acid and the fluorine gas to be more uniformly mixed, but also suppresses side reactions. By adopting the technical scheme to prepare the 2-fluoro ethyl acetoacetate, the prepared product has high purity, the production cost is reduced, and the method is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of ethyl 2-fluoroacetoacetate.
Background
The pharmaceutical intermediate industry is a branch of the chemical industry, and after more than 30 years of development, chemical raw materials and intermediates required by the pharmaceutical production in China can be basically matched, but a small amount of pharmaceutical intermediates need to be imported.
2-Fluoroacetoacetic acid ethyl ester (molecular formula C)6H9FO3) Is an important fluorine-containing compound, has wide application and development prospect in the industrial fields of drug intermediates, catalysts for cyclization, oxidation and halogenation reactions and the like, and is particularly used in the fields of agricultural chemistry and pharmacy. The 2-fluoro ethyl acetoacetate is used as a raw material or a key intermediate, and can be used for producing various medicaments. 2-fluoro ethyl acetoacetate as an important pharmaceutical and chemical intermediate almost completely depends on import at present, the method for synthesizing 2-fluoro ethyl acetoacetate in China is less, and the currently known synthesis method needs a plurality of organic compounds as raw materials, so that the production cost is inevitably increased, and other substances are introduced into a reaction system, which brings inconvenience for subsequent purification and combines the advantages of low cost, high purity, and the likeThe purity of the obtained 2-fluoro ethyl acetoacetate is not ideal, and the method is not suitable for large-scale production.
Disclosure of Invention
The invention aims to overcome the technical defects, provides a preparation method of 2-fluoro ethyl acetoacetate and solves the technical problems of high preparation cost and low purity of 2-fluoro ethyl acetoacetate in the prior art.
In order to achieve the technical purpose, the technical scheme of the invention provides a preparation method of 2-fluoro ethyl acetoacetate, which comprises the following steps: taking 2-chloroacetoacetic acid ethyl ester and excessive mixed gas containing fluorine gas as raw materials, taking hydrofluoric acid as a solvent and a catalyst, adding a fluorine surfactant, and reacting at a low temperature to obtain the 2-fluoroacetoacetic acid ethyl ester.
Compared with the prior art, the invention has the beneficial effects that: according to the technical scheme, the 2-ethyl chloroacetoacetate and the excessive mixed gas containing the fluorine gas are used as raw materials, so that the 2-ethyl chloroacetoacetate and the fluorine gas can be fully reacted, and the influence on the purity of a product caused by the fact that part of the 2-ethyl chloroacetoacetate does not participate in the reaction is avoided; adding a proper amount of hydrofluoric acid as a solvent and a catalyst, so that the reaction rate can be accelerated, and the generated impurity gas can be prevented from being dissolved in the reaction mixed liquid again; the addition of a proper amount of fluorine surfactant not only can more uniformly mix the ethyl 2-chloroacetoacetate, the hydrofluoric acid and the fluorine gas, but also can comprehensively inhibit the occurrence of side reactions and avoid the generation of impurities such as the ethyl 2, 2-difluoroacetoacetate, the ethyl 4, 4-difluoroacetoacetate and the like. Because the fluorine gas is very active, if the fluorine gas is directly used for reacting with the ethyl 2-chloroacetoacetate, the reaction is very violent, and a large amount of heat is released, so that the ethyl 2-chloroacetoacetate is decomposed. The 2-fluoro ethyl acetoacetate prepared by the technical scheme has few raw material types, and the prepared product has high purity and the production cost is also reduced.
Detailed Description
The embodiment provides a preparation method of ethyl 2-fluoroacetoacetate, which specifically comprises the following steps:
(1) preparing materials according to the following mass ratio: respectively weighing 2-chloroacetoacetic acid ethyl ester and hydrofluoric acid according to the mass ratio of the 2-chloroacetoacetic acid ethyl ester to the hydrofluoric acid of 8-12: 1, and then according to the fluorine surfactant: weighing the fluorosurfactant at the mass ratio of the 2-ethyl chloroacetoacetate of 0.0005-0.0015: 1; the mass ratio of the 2-chloroacetoacetic acid ethyl ester to the hydrofluoric acid is 8-12: 1, if the addition amount of the hydrofluoric acid is too small, the catalytic effect of the hydrofluoric acid is not obvious, and if the addition amount of the hydrofluoric acid is too large, the reaction rate is low; the fluorine surfactant can be perfluorooctyl sulfonic acid triphenyl sulfonium salt or perfluorobutyl sulfonic acid, preferably, the fluorine surfactant is perfluorobutyl sulfonic acid, and the perfluorobutyl sulfonic acid has a more obvious inhibition effect on side reactions and is more environment-friendly; the addition amount of the fluorine surfactant is 0.05-0.15% of the mass of the 2-ethyl chloroacetoacetate, if the addition amount of the fluorine surfactant is less than 0.05%, the inhibition effect is not obvious, and if the addition amount of the fluorine surfactant is more than 0.15%, the purity of the finally prepared 2-ethyl fluoroacetoacetate is influenced.
(2) Adding hydrofluoric acid, 2-chloroacetoacetic acid ethyl ester and a fluorine surfactant into a reaction kettle, stirring and mixing uniformly, reducing the temperature in the reaction kettle until the temperature in the reaction kettle is reduced to-10-0 ℃, wherein if the reaction temperature is lower than-10 ℃, the yield of reaction products is low, and if the temperature is higher than 0 ℃, the reaction is severe, so that the 2-chloroacetoacetic acid ethyl ester is decomposed; introducing a fluorine-nitrogen mixed gas with the fluorine gas volume fraction of 35% into the reaction kettle at a rate of 1-3 m3The fluorine gas is a strong oxidant, can react with almost all substances and is very violent, so the concentration of the fluorine gas needs to be diluted by inert gas, the fluorination reaction is easy to control, the fluorination selectivity can also be improved, and the fluorine-nitrogen mixed gas with the fluorine gas volume fraction of 35 percent is selected because the reaction is easier to control, the reaction is milder and the fluorination selectivity is optimal; selecting the ventilation rate to be 1-3 m3The reaction is carried out for one hand to avoid the temperature rise in the reaction kettle caused by violent reaction and for the other hand to ensure that reactants are fully contacted to promote the reaction to be fully carried out; when fluorine is introduced into the mixed gasStopping ventilation and stopping reaction when the mass ratio of the gas to the 2-chloroacetoacetic acid ethyl ester is 0.25-0.5: 1; that is, the mass ratio of the fluorine gas and ethyl 2-chloroacetoacetate in the reaction is 0.25 to 0.5:1, the molar ratio of the fluorine gas and ethyl 2-chloroacetoacetate is 1.083 to 2.166:1 in terms of conversion, and the fluorine gas in the reaction is excessive, which is advantageous for the reaction to proceed more sufficiently. When the temperature of the mixed liquid in the reaction kettle is recovered to the room temperature, introducing nitrogen into the reaction kettle, and removing residual hydrogen fluoride and other impurity gases in the reaction kettle to obtain a crude product of the 2-fluoroacetoacetate;
(3) and (3) transferring the crude product of the ethyl 2-fluoroacetoacetate obtained in the step (2) into a rectifying tower, rectifying by adopting a vacuum rectification mode, and collecting liquid with the boiling point of 90.1-90.3 ℃ to obtain the ethyl 2-fluoroacetoacetate.
The above experimental methods are all conventional methods unless otherwise specified.
The preparation of ethyl 2-fluoroacetoacetate according to the present invention will be further described with reference to the following specific examples. The following examples are illustrative only and are not to be construed as limiting the invention.
Example 1:
this example provides a method for preparing ethyl 2-fluoroacetoacetate, wherein: the mass ratio of fluorine gas to ethyl 2-chloroacetoacetate was 0.326:1, the mass ratio of ethyl 2-chloroacetoacetate to hydrofluoric acid was 10:1, the fluorine surfactant was perfluorobutyl sulfonic acid, and the amount of perfluorobutyl sulfonic acid added was 0.1% by mass of ethyl 2-chloroacetoacetate.
The preparation method of ethyl 2-fluoroacetoacetate provided by the embodiment specifically comprises the following steps:
(1) weighing the following raw materials by mass: 300kg of 2-chloroacetoacetic acid ethyl ester, 30kg of hydrofluoric acid and 300g of perfluorobutyl sulfonic acid;
(2) adding hydrofluoric acid, 2-ethyl chloroacetoacetate and a fluorine surfactant into a reaction kettle, stirring and mixing uniformly, reducing the temperature in the reaction kettle until the temperature in the reaction kettle is reduced to-10 ℃, introducing a fluorine-nitrogen mixed gas with the fluorine gas volume fraction of 35% into the reaction kettle,the aeration rate was 2m3H, when 180m of gas is introduced3When the fluorine-nitrogen mixed gas is introduced, namely the mass of the introduced fluorine gas is 97.9kg, stopping introducing the fluorine gas and closing the reaction kettle; when the temperature of the mixed liquid in the reaction kettle is recovered to the room temperature, introducing nitrogen into the reaction kettle, and removing residual hydrogen fluoride and other impurity gases in the reaction kettle to obtain a crude product of the 2-fluoroacetoacetate;
(3) and (3) transferring the crude product of the ethyl 2-fluoroacetoacetate obtained in the step (2) into a rectifying tower, rectifying by adopting a vacuum rectification mode, and collecting liquid with the boiling point of 90.1-90.3 ℃ to obtain the ethyl 2-fluoroacetoacetate.
After the reaction was completed, the yield of ethyl 2-fluoroacetoacetate finally obtained was 68.51%, and the purity was 98.7%.
Example 2:
this example provides a method for preparing ethyl 2-fluoroacetoacetate, wherein: the mass ratio of fluorine gas to ethyl 2-chloroacetoacetate was 0.5:1, the mass ratio of ethyl 2-chloroacetoacetate to hydrofluoric acid was 8:1, the fluorine surfactant was perfluorobutyl sulfonic acid, and the amount of perfluorobutyl sulfonic acid added was 0.05% by mass of ethyl 2-chloroacetoacetate.
The preparation method of ethyl 2-fluoroacetoacetate provided by the embodiment specifically comprises the following steps:
(1) weighing the following raw materials by mass: 100kg of 2-chloroacetoacetic acid ethyl ester, 12.5kg of hydrofluoric acid and 50g of perfluorobutyl sulfonic acid;
(2) adding hydrofluoric acid, 2-ethyl chloroacetoacetate and a fluorine surfactant into a reaction kettle, stirring and mixing uniformly, reducing the temperature in the reaction kettle until the temperature in the reaction kettle is reduced to-5 ℃, introducing a fluorine-nitrogen mixed gas with the fluorine volume fraction of 35% into the reaction kettle, and introducing the fluorine-nitrogen mixed gas at the gas introduction rate of 1m3H, when 92m of gas is introduced3When the fluorine-nitrogen mixed gas is introduced, namely the mass of the introduced fluorine gas is 50kg, stopping introducing the fluorine gas and closing the reaction kettle; when the temperature of the mixed liquid in the reaction kettle is recovered to the room temperature, introducing nitrogen into the reaction kettle, and removing residual hydrogen fluoride and other impurity gases in the reaction kettle to obtain a crude product of the 2-fluoroacetoacetate;
(3) and (3) transferring the crude product of the ethyl 2-fluoroacetoacetate obtained in the step (2) into a rectifying tower, rectifying by adopting a vacuum rectification mode, and collecting liquid with the boiling point of 90.1-90.3 ℃ to obtain the ethyl 2-fluoroacetoacetate.
After the reaction was completed, the yield of ethyl 2-fluoroacetoacetate finally obtained was 67.32%, and the purity was 98.1%.
Example 3:
this example provides a method for preparing ethyl 2-fluoroacetoacetate, wherein: the mass ratio of fluorine gas to ethyl 2-chloroacetoacetate was 0.25:1, the mass ratio of ethyl 2-chloroacetoacetate to hydrofluoric acid was 12:1, the fluorine surfactant was perfluorobutyl sulfonic acid, and the amount of perfluorobutyl sulfonic acid added was 0.15% by mass of ethyl 2-chloroacetoacetate.
The preparation method of ethyl 2-fluoroacetoacetate provided by the embodiment specifically comprises the following steps:
(1) weighing the following raw materials by mass: 500kg of ethyl 2-chloroacetoacetate, 41.67kg of hydrofluoric acid and 75g of perfluorobutyl sulfonic acid;
(2) adding hydrofluoric acid, ethyl 2-chloroacetoacetate and a fluorine surfactant into a reaction kettle, stirring and mixing uniformly, reducing the temperature in the reaction kettle until the temperature in the reaction kettle is reduced to 0 ℃, introducing a fluorine-nitrogen mixed gas with the fluorine volume fraction of 35% into the reaction kettle at the gas introduction rate of 3m3H, when 230m is introduced3When the fluorine-nitrogen mixed gas is introduced, namely the mass of the introduced fluorine gas is 125kg, stopping introducing the fluorine gas and closing the reaction kettle; when the temperature of the mixed liquid in the reaction kettle is recovered to the room temperature, introducing nitrogen into the reaction kettle, and removing residual hydrogen fluoride and other impurity gases in the reaction kettle to obtain a crude product of the 2-fluoroacetoacetate;
(3) and (3) transferring the crude product of the ethyl 2-fluoroacetoacetate obtained in the step (2) into a rectifying tower, rectifying by adopting a vacuum rectification mode, and collecting liquid with the boiling point of 90.1-90.3 ℃ to obtain the ethyl 2-fluoroacetoacetate.
After the reaction was completed, the yield of ethyl 2-fluoroacetoacetate finally obtained was 68.44%, and the purity was 98.4%.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (7)
1. A preparation method of 2-fluoro ethyl acetoacetate is characterized by comprising the following steps: taking 2-ethyl chloroacetoacetate and excessive mixed gas containing fluorine gas as raw materials, taking hydrofluoric acid as a solvent and a catalyst, adding a fluorine surfactant, and reacting at a low temperature to obtain 2-ethyl fluoroacetoacetate; the fluorosurfactant is perfluorobutyl sulfonic acid.
2. The method for producing ethyl 2-fluoroacetoacetate of claim 1, wherein the reaction temperature is-10 to 0 ℃.
3. The method of producing ethyl 2-fluoroacetoacetate of claim 1, wherein the mass ratio of the fluorine gas to ethyl 2-chloroacetoacetate is 0.25 to 0.5: 1.
4. The method for preparing ethyl 2-fluoroacetoacetate of claim 1, wherein the mass ratio of ethyl 2-chloroacetoacetate to hydrofluoric acid is 8-12: 1.
5. The method for producing ethyl 2-fluoroacetoacetate of claim 1, wherein the amount of the fluorinated surfactant added is 0.05 to 0.15% by mass of ethyl 2-chloroacetoacetate.
6. The process according to claim 1, wherein the mixed gas containing fluorine gas is a mixed gas of fluorine and nitrogen, and the volume fraction of fluorine gas is 35%.
7. The method according to claim 6, wherein the mixed gas of fluorine and nitrogen is introduced into the reactor uniformly and then introduced into the reactorThe speed is 1-3 m3/h。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0891962A1 (en) * | 1996-03-26 | 1999-01-20 | F-Tech Inc. | Process for the preparation of fluorinated dicarbonyl compounds |
| US6951957B2 (en) * | 1999-03-23 | 2005-10-04 | Asahi Glass Company, Limited | Process for producing a fluorine-containing compound by liquid phase fluorination |
| CN103664584A (en) * | 2013-12-23 | 2014-03-26 | 湖南方盛制药股份有限公司 | Method for preparing a-fluoro-propionyl acetate |
| CN107382678A (en) * | 2017-07-11 | 2017-11-24 | 浙江巨圣氟化学有限公司 | A kind of preparation method of perfluoro butyl methyl ether |
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2017
- 2017-12-28 CN CN201711455956.0A patent/CN108218702B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0891962A1 (en) * | 1996-03-26 | 1999-01-20 | F-Tech Inc. | Process for the preparation of fluorinated dicarbonyl compounds |
| US6951957B2 (en) * | 1999-03-23 | 2005-10-04 | Asahi Glass Company, Limited | Process for producing a fluorine-containing compound by liquid phase fluorination |
| CN103664584A (en) * | 2013-12-23 | 2014-03-26 | 湖南方盛制药股份有限公司 | Method for preparing a-fluoro-propionyl acetate |
| CN107382678A (en) * | 2017-07-11 | 2017-11-24 | 浙江巨圣氟化学有限公司 | A kind of preparation method of perfluoro butyl methyl ether |
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