CN104447328A - Method for preparing alkyl 4,4-difluoroacetylacetate - Google Patents
Method for preparing alkyl 4,4-difluoroacetylacetate Download PDFInfo
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- 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
- C07C67/313—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 doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention discloses a method for preparing alkyl 4,4-difluoroacetylacetate. The method has the advantages of easily available raw materials, simple process flow, safety in operation and high yield. The method comprises the following steps: (1) carrying out hydrolysis reaction on 1,1,2,2-tetrafluoroethyl ether used as a raw material and water in an acid and separating to obtain ethyl difluoroacetate and hydrogen fluoride; (2) reacting ethyl difluoroacetate obtained in the step (1) and alkyl acetate in the presence of an alkaline catalyst to obtain 1,1-difluoro-2-butenoic acid alkyl ester-2-hydroxy salt; and (3) neutralizing 1,1-difluoro-2-butenoic acid alkyl ester-2-hydroxy salt obtained in the step (2) and hydrogen fluoride to obtain alkyl 4,4-difluoroacetylacetate.
Description
Technical field
The present invention relates to the preparation method field of 4,4-difluoro-acetyl-acetic acid alkylesters, particularly relate to a kind of preparation method of 4,4-difluoro-acetyl-acetic acid alkylesters.
Background technology
4,4-difluoro-acetyl-acetic acid alkylesters is the intermediate of synthesizing new agricultural chemicals and medicine, has a wide range of applications at chemical industry and field of medicaments.The method that preparation 4,4-difluoro-acetyl-acetic acid alkylesters is conventional is Claisen condensation reaction.Claisen condensation reaction be ester class containing α-reactive hydrogen at catalyzer as under the effect of the basic catalysts such as sodium alkoxide, trityl sodium, there is the reaction that condensation reaction forms beta-ketoester compounds.At preparation 4,4-difluoro-acetyl-acetic acid alkylesters, conventional ethyl difluoro and alkyl acetate are obtained by reacting product under basic catalyst catalysis.
It is the Claisen condensation reaction that sodium hydride prepares 4,4-difluoro methyl aceto acetate that patent CN1968934A describes catalyzer.This reaction joins in tetrahydrofuran (THF) by sodium hydride, adds the mixture of ethyl difluoro and ethyl acetate, and react 7h at 35-40 DEG C at 40 DEG C.After reaction terminates, washing, water layer methyl tertiary butyl ether extracts, and organic layer is dry, distill to obtain 4,4-difluoro methyl aceto acetates, and yield is 71.2%.But adopt sodium hydride as catalyzer in this reaction, can produce a large amount of hydrogen in large-scale operation, have the danger of blast, safety coefficient is lower.
Patent CN101959840B relates to 4, a kind of preparation method of 4-difluoro-acetyl-acetic acid alkylesters, comprise and a) first make alkyl acetate, ROM alkoxide and difluoroacetic acid alkyl ester react when not having additional solvent, wherein M is sodium or potassium ion, forms enolate (V); B) corresponding 4 are discharged with acid from enolate (V), 4-difluoro-acetyl-acetic acid alkylesters (I), acid used can be hydrogenchloride, hydrogen bromide, hydrogen iodide, sulfuric acid, formic acid, acetic acid, oxalic acid, citric acid, methylsulfonic acid or tosic acid.Patent CN102791694A relates to the method preparing Acetacetic acid alkyl ester equally, and acid used in preparation is a kind of mineral acid (such as hydrogenchloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, nitric acid) or a kind of organic acid (such as formic acid, acetic acid, propionic acid, citric acid, oxalic acid, methylsulfonic acid or p-methyl benzenesulfonic acid).Above-mentioned two patents all relate to the method preparing Acetacetic acid alkyl ester, but all need extra one of adding sour to make reaction proceed in reaction process.
Patent EP0694523 adopts 1,1,2,2-tetra-fluoro ethyl methyl ether (or ether) cracking under activated alumina catalysis to generate difluoroacetic acid fluorine, and difluoroacetic acid fluorine obtains ethyl difluoro with ethyl esterification again.But this technical process is more complicated, need just can obtain ethyl difluoro through two steps.
Therefore, for overcoming above-mentioned defect in prior art, it is simple that the present invention proposes a kind of technical process, operational safety, without the need to introducing the method for preparation 4, the 4-difluoro-acetyl-acetic acid alkylesters of extraneous acid in reaction process.
Summary of the invention
First object of the present invention is to provide a kind of preparation method of 4,4-difluoro-acetyl-acetic acid alkylesters, and this preparation method's step is simple, and operational safety, solves the problem of the preparation flow complexity of intermediate ethyl difluoro.Making raw material hydrolysis can obtain ethyl difluoro by single step reaction by adding sulfuric acid in initial reaction raw material, simplifying existing preparation process.
A present invention also object solves in reaction process to need to introduce the extraneous sour problem that reaction just can be made to proceed.The present invention as the acid added in subsequent step by the by product HF that produces in reaction process, is not only made HF obtain recycle, and avoids environmental pollution.
Thus, the invention provides a kind of 4,4-difluoro-acetyl-acetic acid alkylesters preparation method, comprising: (1) is that raw material, in acid, hydrolysis reaction occurs with 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether, be separated and obtain ethyl difluoro and hydrogen fluoride; (2) under the effect of basic catalyst, 1,1-difluoro-2-butene acid alkyl ester-2-hydroxy salt is obtained by reacting by the ethyl difluoro obtained in (1) and alkyl acetate; (3) carry out neutralization by 1, the 1-difluoro-2-butene acid alkyl ester-2-hydroxy salt obtained in (2) and hydrogen fluoride and obtain 4,4-difluoro-acetyl-acetic acid alkylesters, wherein, 4,4-difluoro-acetyl-acetic acid alkylesters has following structural formula:
R is selected from C1-C6 straight or branched alkyl; Preferably, R is selected from the straight or branched alkyl of C1-C4, such as, be the straight chained alkyl of C1-C4, the branched-chain alkyl of C4; Preferred, R is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl or the tertiary butyl; Particularly preferred, R is methyl or ethyl.
Acid described in step of the present invention (1) can be nitric acid, hydrochloric acid, and sulfuric acid, is more preferably sulfuric acid, most preferably is sulfuric acid, oleum that massfraction is greater than 98%.
In hydrolysis reaction described in step of the present invention (1), 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether and water add-on press amount of substance than being 1:1-3, are more preferably 1:1.1-1.5.Add the water little over amount in hydrolysis reaction, 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether is hydrolyzed complete as far as possible.
In a concrete embodiment of the present invention, described step specifically comprises in (1): in reaction unit, add sulfuric acid, then adds water and 1 successively, 1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether, be hydrolyzed reaction, is separated and obtains ethyl difluoro and hydrogen fluoride.Wherein, after adding sulfuric acid, temperature of reaction is down to 5-35 DEG C, preferably, is down to 10-30 DEG C, more slowly adds water.Because add sulfuric acid in the process of water will discharge a large amount of heats in sulfuric acid, if do not lowered the temperature before, be easy to cause reaction vessel to explode.In a concrete embodiment, after adding water and 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether successively, temperature of reaction rises to 50-60 DEG C, and the reaction times is 0.5-2h, and preferably, temperature of reaction rises to 54-56 DEG C, and the reaction times is 1h.
In the present invention's embodiment, be separated in described step (1) and obtain after ethyl difluoro and hydrogen fluoride comprises and being first separated hydrogen fluoride, then ethyl difluoro is separated.Described is separated can collects acquisition after reaction after product is heated to 70-90 DEG C to hydrogen fluoride, or described is separated can be completed by rectification under vacuum hydrogen fluoride, and in rectifying, temperature controls as 0-30 DEG C, and preferably, temperature controls at 10-20 DEG C.The described separating step to ethyl difluoro can be completed by underpressure distillation, and the temperature of underpressure distillation controls at 30-80 DEG C.More preferred, describedly also to comprise ethyl difluoro purification step after the separation of ethyl difluoro.In an embodiment, described ethyl difluoro purification step comprises the ethyl difluoro after by separation and carries out alkali cleaning, washing and distillation; Preferably, described caustic scrubbing step is sodium hydrogen carbonate solution washing.In another embodiment, described ethyl difluoro refine comprise by be separated after ethyl difluoro pass into ammonia, regulate PH to 7, filter, filtrate adjusts PH=5 ~ 6 with the vitriol oil, then distills.
The reaction unit that step of the present invention (1) uses is preferably lining teflon reactor.Owing to having sulfuric acid in reaction raw materials, adopt the reactor of lining teflon material relative to other materials, erosion resistance is better.
In the preferred embodiment of the present invention, the hydrogen fluoride produced in step (1) can as the reactant of step (3).Thus, HF is applied further, and can not be discharged in air.
Ethyl difluoro in step of the present invention (2): alkyl acetate: basic catalyst add-on presses amount of substance ratio=1:1-3:1-2.Adding excessive alkyl acetate in this step is to make the ethyl difluoro obtained react completely, and increases the speed of reaction of positive reaction.In a preferred embodiment, ethyl difluoro: alkyl acetate: the amount of substance ratio=1:1.1-2:1-2 of basic catalyst.
Step of the present invention (2) neutral and alkali catalyzer is selected from trityl sodium, sodium nitride, sodium amide, lithium diisopropylamine (LDA), sodium methylate, sodium ethylate, potassium tert.-butoxide.In a preferred embodiment, described basic catalyst is selected from sodium ethylate.
In a concrete embodiment of the present invention, described step specifically comprises in (2): in reaction unit, add the ethyl difluoro that alkyl acetate and step (1) obtain, then add basic catalyst and react.Reaction environment in described step (2) is preferably nitrogen, and nitrogen can make the material of some easy oxidations by air in reactant just obtain the protection of nitrogen.The temperature that adds of described alkyl acetate and ethyl difluoro is 5-35 DEG C, is preferably 10-30 DEG C.The temperature that adds of described basic catalyst is-10-55 DEG C, is preferably-10-5 DEG C.In an embodiment, adding the temperature of reaction after basic catalyst is 55-70 DEG C, and the reaction times is 1-3h, and preferably, temperature of reaction is 60-65 DEG C, and the reaction times is 2h.
In step of the present invention (2), reaction unit is preferably glass reaction bottle.
In a concrete embodiment of the present invention, described step specifically comprises in (3): at temperature is 10-30 DEG C, pass into hydrogen fluoride gas, control pH=5-7, is separated and obtains product after reaction.Preferably, described temperature is 10-20 DEG C.In an embodiment of the invention, it is 40-60 DEG C of underpressure distillation separating alcohol, ethyl acetate that described separation is included in control temperature, and then control temperature obtains 4,4-difluoro methyl aceto acetate 60-90 DEG C of underpressure distillation.In another embodiment of the present invention, described be separated into reaction after add water filtration, rectifying obtains 4,4-difluoro methyl aceto acetate.
In a concrete embodiment, 4,4-difluoro-acetyl-acetic acid alkylesters preparation methods of the present invention comprise:
(1) in reaction unit, add acid, then add water and 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether successively, be hydrolyzed reaction, is separated and obtains ethyl difluoro and hydrogen fluoride;
(2) in reaction unit, add the ethyl difluoro that alkyl acetate and step (1) obtain, then add basic catalyst and react;
(3) at temperature is 10-30 DEG C, pass into hydrogen fluoride gas, control pH=5-7, be separated after reaction and obtain product.
Preferably, described method comprises:
(1) in reaction unit, add sulfuric acid, drip water when temperature 5-35 DEG C, then add 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether, 1,1, the amount of substance that 2,2-tetrafluoro ethyl diethyldithiocarbamate ether and water react, than being 1:1-1:3, dripping and terminates, be warming up to 50-60 DEG C of reaction 0.5-2h, be separated and obtain ethyl difluoro and hydrogen fluoride;
(2) under nitrogen protection, in reaction unit, temperature 5-35 DEG C adds alkyl acetate, ethyl difluoro, then, is cooled to-10-55 DEG C and adds basic catalyst, be warming up to 55-70 DEG C, insulation reaction 1-3h.Ethyl difluoro: alkyl acetate: the amount of substance ratio=1:2:1 of basic catalyst.
(3) be cooled to 5-20 DEG C, pass into the hydrogen fluoride gas that in (1), reaction produces, control pH=5-7, be separated after reaction and obtain product.
The reaction formula of 4,4-difluoro-acetyl-acetic acid alkylesters of the present invention is as follows:
Wherein, R is C1-C6 straight or branched alkyl.
The method that the present invention proposes has following outstanding technical superiority:
1. prepare 4,4-difluoro-acetyl-acetic acid alkylesters by the method, as long as required intermediate ethyl difluoro just can be obtained by a step, which simplify reaction process, improve preparation efficiency.
2. method of the present invention can greatly improve the yield of product 4,4-difluoro-acetyl-acetic acid alkylesters; Use sodium ethylate as catalyzer in reaction process, improve safety coefficient; The by product hydrogen fluoride produced in reaction process can be applied in subsequent reactions further, is beneficial to environmental protection.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated.Embodiment is that to prepare 4,4-difluoro methyl aceto acetate be the reaction process that product illustrates.
Embodiment 1
In the reactor of the lining teflon of a 1000mL, add 98% sulfuric acid 243g (2.4mol), water-bath is lowered the temperature, control temperature 10-30 DEG C, slow dropping water 57g (3.2mol), then slowly adds 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether 438g (3.0mol).Drip and terminate, be warming up to 54-56 DEG C of reaction 1 hour.Now, almost there is no gas overflowing, be slowly warming up to 80 DEG C, have hydrogen fluoride gas to overflow (being passed into by spilling gas in next step reaction).System is lowered the temperature, to 10 ~ 20 DEG C, temperature control T < 30 DEG C, by system rectification under vacuum separating fluorine hydride (separating hydrogen fluoride to pass in next step reaction), after cut, temperature control T < 80 DEG C, decompression steams ethyl difluoro crude product, and crude product is through washing, and sodium hydrogen carbonate solution washs, washing and rectifying obtain ethyl difluoro 316.0g, yield 85%.
In the glass reaction bottle of a 1000mL; under nitrogen protection; 10-30 DEG C adds ethyl acetate 352g (4.0mol); ethyl difluoro 248g (2.0mol); then, be cooled to-10-5 DEG C and add solid sodium ethanol 143g (2.1mol), warming-in-water in batches; be warming up to 60-65 DEG C, insulation reaction 2h.Be cooled to 10-20 DEG C, pass into the hydrogen fluoride gas that previous step reaction produces, control pH=7.Reaction solution is proceeded to water distilling apparatus, carries out underpressure distillation, steam ethanol, ethyl acetate and 4,4-difluoro methyl aceto acetate crude product, this mixture is carried out rectifying, and control still temperature T < 60 DEG C, P=-0.08MPa steams ethanol, ethyl acetate, then still temperature T≤90 DEG C are controlled, P≤-0.095MPa, it is 4,4-difluoro methyl aceto acetate 241g that rectification under vacuum obtains colourless transparent liquid, content 96.0%, yield 72.5%.
Embodiment 2:
At the reactor of the lining teflon of a 1000ml, add 98% sulfuric acid 243g (2.4mol), water-bath is lowered the temperature, control temperature 10-30 DEG C, slow dropping water 57g (3.2mol), then slowly adds 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether 438g (3.0mol).Drip and terminate, be warming up to 54-56 DEG C of reaction 1 hour.Now, almost there is no gas overflowing, be slowly warming up to 80 DEG C, have hydrogen fluoride gas to overflow (being passed into by spilling gas in next step reaction).System is lowered the temperature, to 10 ~ 20 DEG C, temperature control T < 30 DEG C, by system rectification under vacuum separating fluorine hydride (separating hydrogen fluoride to pass in next step reaction), after cut, temperature control T < 80 DEG C, decompression steams ethyl difluoro crude product, crude product temperature control T < 10 DEG C, pass into ammonia, regulate pH=7, filter, filter cake 200g ethyl acetate drip washing, the mother liquor vitriol oil adjusts pH=5 ~ 6, carry out the mixed solution 491g that air distillation obtains ethyl difluoro and ethyl acetate again, conversion ethyl difluoro 334.6g, yield 90%.
In the glass reaction bottle of a 1000mL; under nitrogen protection; 10-30 DEG C adds ethyl acetate 352g (4.0mol); ethyl difluoro 248g (2.0mol); then, be cooled to-10-5 DEG C and add solid sodium ethanol 143g (2.1mol), warming-in-water in batches; be warming up to 60-65 DEG C, insulation reaction 2h.Be cooled to 10-20 DEG C, pass into the hydrogen fluoride gas that previous step reaction produces, control pH=5 ~ 6.Reaction solution is proceeded to water distilling apparatus, carry out underpressure distillation, control still temperature T < 60 DEG C, P=-0.08MPa steams ethanol, ethyl acetate, obtain ethanol and ethyl acetate and a small amount of 4,4-difluoro methyl aceto acetate mixing solutions 350g, then still temperature T≤90 DEG C are controlled, P≤-0.095MPa, underpressure distillation obtains 4, the 4-difluoro methyl aceto acetate solution 273.4g of content > 90%, content 92%, conversion contains 4,4-difluoro methyl aceto acetate 251.5g, yield 75.7%.
Embodiment 3:
At the reactor of the lining teflon of a 1000ml, add 98% sulfuric acid 243g (2.4mol), water-bath is lowered the temperature, control temperature 10-30 DEG C, slow dropping water 57g (3.2mol), then slowly adds 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether 438g (3.0mol).Drip and terminate, be warming up to 54-56 DEG C of reaction 1 hour.Now, almost there is no gas overflowing, be slowly warming up to 80 DEG C, have hydrogen fluoride gas to overflow (being passed into by spilling gas in next step reaction).System is lowered the temperature, to 10 ~ 20 DEG C, temperature control T < 30 DEG C, by system rectification under vacuum separating fluorine hydride (separating hydrogen fluoride to pass in next step reaction), after cut, temperature control T < 80 DEG C, decompression steams ethyl difluoro crude product, crude product temperature control T < 10 DEG C, pass into ammonia, regulate pH=7, filter, filter cake 200g ethyl acetate drip washing, the mother liquor vitriol oil adjusts pH=5 ~ 6, carry out the mixed solution 491g that air distillation obtains ethyl difluoro and ethyl acetate again, conversion ethyl difluoro 334.6g, yield 90%.
In the glass reaction bottle of a 1000mL; under nitrogen protection; 10-30 DEG C adds ethyl acetate 352g (4.0mol); ethyl difluoro 248g (2.0mol); then, temperature control T≤55 DEG C add solid sodium ethanol 143g (2.1mol) in batches, warming-in-water; be warming up to 60-65 DEG C, insulation reaction 2h.Be cooled to 10-20 DEG C, pass into the hydrogen fluoride gas that previous step reaction produces, control pH=5 ~ 6.Reaction solution is proceeded to water distilling apparatus, carry out underpressure distillation, control still temperature T < 60 DEG C, P=-0.08MPa steams ethanol, ethyl acetate, obtain ethanol and ethyl acetate and a small amount of 4,4-difluoro methyl aceto acetate mixing solutions 345g, then still temperature T≤90 DEG C are controlled, P≤-0.095MPa, underpressure distillation obtains 4, the 4-difluoro methyl aceto acetate solution 280g of content > 90%, content 91.5%, conversion contains 4,4-difluoro methyl aceto acetate 256.2g, yield 77.1%.
Embodiment 4:
At the reactor of the lining teflon of a 1000ml, add 98% sulfuric acid 243g (2.4mol), water-bath is lowered the temperature, control temperature 10-30 DEG C, slow dropping water 57g (3.2mol), then slowly adds 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether 438g (3.0mol).Drip and terminate, be warming up to 54-56 DEG C of reaction 1 hour.Now, almost there is no gas overflowing, be slowly warming up to 80 DEG C, have hydrogen fluoride gas to overflow (being passed into by spilling gas in next step reaction).System is lowered the temperature, to 10 ~ 20 DEG C, temperature control T < 30 DEG C, by system rectification under vacuum separating fluorine hydride (separating hydrogen fluoride to pass in next step reaction), after cut, temperature control T < 80 DEG C, decompression steams ethyl difluoro crude product, crude product temperature control T < 10 DEG C, pass into ammonia, regulate pH=7, filter, filter cake 200g ethyl acetate drip washing, the mother liquor vitriol oil adjusts pH=5 ~ 6, carry out the mixed solution 491g that air distillation obtains ethyl difluoro and ethyl acetate again, conversion ethyl difluoro 334.6g, yield 90%.
In the glass reaction bottle of a 1000mL; under nitrogen protection; 10-30 DEG C adds ethyl acetate 352g (4.0mol); ethyl difluoro 248g (2.0mol); then, temperature control T≤55 DEG C add solid sodium ethanol 143g (2.1mol) in batches, warming-in-water; be warming up to 60-65 DEG C, insulation reaction 2h.Be cooled to 10-20 DEG C, pass into the hydrogen fluoride gas that previous step reaction produces, control pH=7.Reaction solution is proceeded to water distilling apparatus, carry out underpressure distillation, control still temperature T < 60 DEG C, P=-0.08MPa steams ethanol, ethyl acetate, obtain ethanol and ethyl acetate and a small amount of 4,4-difluoro methyl aceto acetate mixing solutions 346g, then still temperature T≤90 DEG C are controlled, P≤-0.095MPa, underpressure distillation obtains 4, the 4-difluoro methyl aceto acetate solution 282g of content > 90%, content 91.6%, conversion contains 4,4-difluoro methyl aceto acetate 258.3g, yield 77.7%.
Embodiment 5:
At the reactor of the lining teflon of a 1000ml, add 98% sulfuric acid 243g (2.4mol), water-bath is lowered the temperature, control temperature 10-30 DEG C, slow dropping water 57g (3.2mol), then slowly adds 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether 438g (3.0mol).Drip and terminate, be warming up to 54-56 DEG C of reaction 1 hour.Now, almost there is no gas overflowing, be slowly warming up to 80 DEG C, have hydrogen fluoride gas to overflow (being passed into by spilling gas in next step reaction).System is lowered the temperature, to 10 ~ 20 DEG C, temperature control T < 30 DEG C, by system rectification under vacuum separating fluorine hydride (separating hydrogen fluoride to pass in next step reaction), after cut, temperature control T < 80 DEG C, decompression steams ethyl difluoro crude product, crude product temperature control T < 10 DEG C, pass into ammonia, regulate pH=7, filter, filter cake 200g ethyl acetate drip washing, the mother liquor vitriol oil adjusts pH=5 ~ 6, carry out the mixed solution 491g that air distillation obtains ethyl difluoro and ethyl acetate again, conversion ethyl difluoro 334.6g, yield 90%.
In the glass reaction bottle of a 1000mL; under nitrogen protection; 10-30 DEG C adds ethyl acetate 352g (4.0mol); ethyl difluoro 248g (2.0mol); then, temperature control T≤55 DEG C add solid sodium ethanol 143g (2.1mol) in batches, warming-in-water; be warming up to 60-65 DEG C, insulation reaction 2h.Be cooled to 10-20 DEG C, pass into the hydrogen fluoride gas that previous step reaction produces, control pH=7.Drip water to system, after stirring 2h, filter, filter cake ethyl acetate is washed, and merge mother liquor, rectifying, obtains 4,4-difluoro methyl aceto acetate 240.7g, content 98%, conversion yield 71.0%.
Embodiment 6:
At the reactor of the lining teflon of a 1000ml, add 98% sulfuric acid 243g (2.4mol), water-bath is lowered the temperature, control temperature 10-30 DEG C, slow dropping water 57g (3.2mol), then slowly adds 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether 438g (3.0mol).Drip and terminate, be warming up to 54-56 DEG C of reaction 1 hour.Now, almost there is no gas overflowing, be slowly warming up to 80 DEG C, have hydrogen fluoride gas to overflow (being passed into by spilling gas in next step reaction).System is lowered the temperature, to 10 ~ 20 DEG C, temperature control T < 30 DEG C, by system rectification under vacuum separating fluorine hydride (separating hydrogen fluoride to pass in next step reaction), after cut, temperature control T < 80 DEG C, decompression steams ethyl difluoro crude product, crude product temperature control T < 10 DEG C, pass into ammonia, regulate pH=7, filter, filter cake 200g ethyl acetate drip washing, the mother liquor vitriol oil adjusts pH=5 ~ 6, carry out the mixed solution that air distillation obtains ethyl difluoro and ethyl acetate again, conversion ethyl difluoro 323.4g, yield 87%.
In the glass reaction bottle of a 1000mL; under nitrogen protection; 10-30 DEG C adds ethyl acetate 352g (4.0mol); ethyl difluoro 248g (2.0mol); then, temperature control T≤55 DEG C add solid sodium ethanol 144.5g (2.12mol) in batches, warming-in-water; be warming up to 60-65 DEG C, insulation reaction 2h.Be cooled to 10-20 DEG C, pass into the hydrogen fluoride gas that previous step reaction produces, control pH=7.Reaction solution is proceeded to water distilling apparatus, carry out underpressure distillation, control still temperature T < 60 DEG C, P=-0.08MPa steams ethanol, ethyl acetate, obtain ethanol and ethyl acetate and a small amount of 4,4-difluoro methyl aceto acetate mixing solutions 346g, then still temperature T≤90 DEG C are controlled, P≤-0.095MPa, underpressure distillation obtains 4, the 4-difluoro methyl aceto acetate solution 284g of content > 90%, content 91.5%, conversion contains 4,4-difluoro methyl aceto acetate 260.0g, yield 78.2%.
Known by above embodiment, regulate certain temperature or the isoparametric value of pH in reaction process, the ultimate yield of product is different, but in the method, the yield of ethyl difluoro is all more than 85%, and the yield of 4,4-difluoro methyl aceto acetate is all more than 71%, not only the method effect stability is described, and far away higher than additive method of the prior art.Illustrating that the method for the invention is very effective for preparing ethyl difluoro and 4,4-difluoro methyl aceto acetate, being applicable to large-scale production and application.
This specification sheets above in conjunction with embodiment to invention has been explaination, but should be understood that these describe and explaination just in order to understand the present invention better, and not form any restriction of the present invention.Those skilled in the art can carry out necessary change to the specific embodiment of the present invention and not depart from the spirit and scope of the present invention after having read present specification.Protection scope of the present invention is limited by the accompanying claims, and covers the equivalents of claim.
Claims (10)
1. a difluoro-acetyl-acetic acid alkylesters preparation method, comprising: (1) with 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether be raw material in acid with water generation hydrolysis reaction, be separated obtain ethyl difluoro and hydrogen fluoride; (2) under the effect of basic catalyst, 1,1-difluoro-2-butene acid alkyl ester-2-hydroxy salt is obtained by reacting by the ethyl difluoro obtained in (1) and alkyl acetate; (3) carry out neutralization by 1, the 1-difluoro-2-butene acid alkyl ester-2-hydroxy salt obtained in (2) and hydrogen fluoride and obtain 4,4-difluoro-acetyl-acetic acid alkylesters, wherein, 4,4-difluoro-acetyl-acetic acid alkylesters has following structural formula:
Wherein, R is selected from C1-C6 straight or branched alkyl.
2. method according to claim 1, is characterized in that, described R is selected from the straight chained alkyl of C1-C4 or the branched-chain alkyl of C4.
3. method according to claim 1, is characterized in that, the hydrogen fluoride produced in described step (1) is as the reactant of step (3).
4. the method according to claim 1-3 any one, is characterized in that, the acid described in step (1) is sulfuric acid.
5. the method according to claim 1-3 any one, is characterized in that, the add-on that in described step (1), 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether and water react presses amount of substance than being 1:1-3.
6. the method according to claim 1-3 any one, is characterized in that, ethyl difluoro in described step (2): alkyl acetate: the add-on of basic catalyst presses amount of substance ratio=1:1-3:1-2.
7. method according to claim 6, is characterized in that, described step (2) neutral and alkali catalyzer is selected from trityl sodium, sodium nitride, sodium amide, lithium diisopropylamine, sodium methylate, sodium ethylate and potassium tert.-butoxide.
8. the method according to claim 1-3 any one, it is characterized in that, described step specifically comprises in (1): in reaction unit, add sulfuric acid, then adds water and 1 successively, 1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether, be hydrolyzed reaction, is separated and obtains ethyl difluoro and hydrogen fluoride, wherein, after adding sulfuric acid, temperature of reaction is down to 5-35 DEG C; After adding water and 1,1,2,2-tetrafluoro ethyl diethyldithiocarbamate ether successively, temperature of reaction rises to 50-60 DEG C, and the reaction times is 0.5-2h.
9. the method according to claim 1-3 any one, it is characterized in that, described step (2) specifically comprises: in reaction unit, add the ethyl difluoro that alkyl acetate and step (1) obtain, then add basic catalyst to react, described step (2) reaction environment is nitrogen, the temperature that adds of described alkyl acetate and ethyl difluoro is 5-35 DEG C, the temperature that adds of described basic catalyst is-10-55 DEG C, adding the temperature of reaction after basic catalyst is 55-70 DEG C, and the reaction times is 1-3h.
10. the method according to claim 1-3 any one, is characterized in that, described step (3) specifically comprises: at temperature is 10-30 DEG C, pass into hydrogen fluoride gas, control pH=5-7, is separated and obtains product after reaction.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN102206155A (en) * | 2011-04-19 | 2011-10-05 | 巨化集团公司 | Method for synthesizing ethyl 4,4-difluoroacetoacetate |
| WO2014013076A1 (en) * | 2012-07-20 | 2014-01-23 | Eisai R&D Management Co., Ltd. | Hexahydropyrrolothiazine compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102206155A (en) * | 2011-04-19 | 2011-10-05 | 巨化集团公司 | Method for synthesizing ethyl 4,4-difluoroacetoacetate |
| WO2014013076A1 (en) * | 2012-07-20 | 2014-01-23 | Eisai R&D Management Co., Ltd. | Hexahydropyrrolothiazine compounds |
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| JANIS JAUNZEMS等: "An Atom-Efficient Route to Ethyl 3‑(difluoromethyl)-1-methyl‑1H‑pyrazole-4-carboxylate (DFMMP) A Key Building Block for a Novel Fungicide Family", 《ORG. PROCESS RES. DEV. 》 * |
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Address after: 123129 yimatou Fuxin fluorination Industrial Development Zone, Meng County, Fuxin City, Liaoning Province Patentee after: Jinkai (Liaoning) Life Technology Co.,Ltd. Address before: 123129 yimatou Fuxin fluorination Industrial Development Zone, Meng County, Fuxin City, Liaoning Province Patentee before: KINGCHEM LIAONING CHEMICAL Co.,Ltd. |