KR900001075B1 - Preparation of alkyl trifluroaceto acetate - Google Patents

Abstract

A method of preparing a C1-5 alkyl trifluoroacetoacetate (I) comprises bringing an acetylating agent (II) selected from acetyl halides and acetic anhydride into reaction contact with a C1-5 alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluoro butanoate (III) under acetylating conditions of temp. and pressure effective to prepare (I), the temp. being from 10oC to reflux temp. of the mixt. of (II) and (III). The alkyl acetato also produced can be recycled for condensation with additional alkyl trifluoroacetate to produce (III). Condensation is pref. in the presence of a strong base such as sodium metal and the prod. is neutralised with a strong, anhydrous, mineral acid, pref. HCl.

Description

Method for preparing alkyl trifluoroaceto acetate

1 is a process schematic diagram of the present invention.

The present invention provides a novel process for the production of alkyltrifluoroaceto acetate by acetylating lower alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate.

Methods of combining halogenated esters with other esters are well known in the art.

For example, ethyl trifluoroacetoacetate was prepared by alkali condensation of ethyl acetate and ethyl trifluoroacetate.

Neutralization yields a reaction product consisting of a salt and ethanol hemiketal of ethyltrifluoroacetoacetate, which is chemically identical to ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate. . In order to convert this hemimetal into ethyltrifluoroacetoacetate, the hemimetal must be hydrolyzed and removed with ethanol, but unfortunately here the hydrate of ethyltrifluoroacetoacetate is obtained as well as the ethanol must be disposed of as a by-product. Therefore, such a process according to the prior art is not satisfactory industrially or economically.

Ethyltrifluoroacetoacetate is a useful intermediate in the manufacture of pesticides and pharmaceuticals. It is necessary to exclude the hydrate form in order to be most effective. Therefore, as in the prior art, in the case of the hydrate of ethyl trifluoroacetoacetate, there is a disadvantage that the operating cost is expensive because it has to go through additional dehydration process. For example, in the dehydration process, prior art uses cupric acetate to form a copper complex of trifluoroacetoacetate, and then the complex is reacted with nitrogen sulfite to free trifluoro. Acetoacetate and distillation to isolate. Another prior art method is a method of extracting trifluoroacetoacetate, which is solvent extracted and separated from an aqueous medium, with a dehydrating agent such as calcium chloride and magnesium sulfate, followed by distillation through molecular sieve to obtain the final product. have.

However, the present invention provides a method for preparing anhydrous lower alkyl trifluoroacetoacetate, which is convenient and economically unlike the prior art, and another feature is that alkanol is not produced as a by-product, instead. The resulting alkyl acetate is recycled and used as a reactant, thereby additionally producing alkyltrifluoroacetoacetate.

The present invention is to prepare alkyl trifluoroacetoacetate and alkyl acetate by reacting alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate with an acetylating agent such as acetyl halide or acetic acid. The products obtained are each separated from each other. The recovered alkyl acetate is easily recycled to the condensation reaction with the added alkyltrifluoroacetate to produce alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate.

Halides are fluorine, chlorine, bromine and iodine. More specifically, the present invention provides a method for preparing C ₁ -C ₅ alkyltrifluoroacetoacetate by condensing in the presence of a strong basic condensing agent, C ₁ -C ₅ alkyl acetate and C ₁ -C ₅ alkyltrifluoroacetate. The strong bases used in the preparation of the condensates are those comprising sodium metal, sodium ethoxide, sodium hydride and the like.

To neutralize the condensate, a strong mineral is used, including hydrochloric acid, phosphoric acid, sulfuric acid and the like as anhydride, but suitable hydrochloric acid is suitable. 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate (C ₁ -C ₅ alkyltrifluoroacetoacetate of C ₁ -C ₅ alkanol hemichemistry) ) Is reacted with acetyl halide or acetic anhydride to produce C ₁ -C ₅ alkyl trifluoroacetoacetate, C ₁ -C ₅ alkylacetate, hydrogen halide or salts and acids of acetic acid and base and finally to acetoacetate, The salt and acetate are separated from each other. Precipitated salts can be removed by filtration, centrifugation, solvent extraction and the like, and acetoacetate, hydrogen halide or acetic acid halide and acetate can be conveniently separated by fractional distillation or other suitable technique.

The invention will be described in more detail according to the accompanying drawings.

An appropriate amount of sodium hydride, preferably an oil emulsion form of strong base, is added to the base-directed condensation zone at ambient or suitable reaction temperature and ethyltrifluoroacetate and ethyl acetate Was injected into the condensation zone to stir the reaction mixture. By adding a suitable inert organic solvent thereto, the reaction can be further controlled, and of course, it may facilitate the separation of the final product. Suitable solvents include cyclohexane, dedecane ethyl ether, hexane, methylcyclohexane, 1,2-dimethoxyethane, tetrahydrofuran, benzene and the like.

The condensation reaction is initiated in a controlled manner to produce sodium salt and ethanol of ethyltrifluoroacetoacetate. Nitrogen gas or other inert gas can be used to remove the released hydrogen gas.

The resulting reaction mixture was transferred to a neutralization step to obtain 10 to 15% excess mole of strong anhydrous mine, preferably anhydrous hydrochloric acid, in order to neutralize the reaction mixture, to obtain ethanol hemichetal of salt and ethyltrifluoroacetoacetate and neutralized product. The gas was heated to remove excess hydrogen chloride in gas phase.

The obtained neutralization product was then transferred to an acetylation process and reacted with acetyl halides, preferably acetyl chloride, to obtain hydrochloric acid, ethyl acetate and ethyl trifluoroacetoacetate.

The product after the acetylation process was transferred to a product separation process to filter or separate salt precipitates. Ethyl acetate, ethyltrifluoroacetoacetate and hydrochloric acid were separated by distillation or other methods. In this way, the final product of ethyl trifluoroacetoacetate is prepared, and the obtained ethyl acetate is recycled to the condensation process again.

An important aspect of the present invention is the acetylation of the product obtained in the neutralization process, and the product obtained through the neutralization process is ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate (ethyltrifluor Distilled by ethanol hemi- etal of low acetoacetate) found that hemi- ketal decomposed into ethanol and ethyltrifluoroacetoacetate, but unfortunately these two compounds were azeotropically distilled into ethyltrifluor Obtained again with hemical of low acetoacetate. Therefore, the removal of all ethanol produced is useful for the preparation of agrochemicals such as the 2,4-substituted-5-thiazolecarboxylic acids and derivatives thereof mentioned in US Pat. No. 4,199,506 by chlorination of ethyltrifluoroacetoacetate. It is essential for preparing the intermediate ethyl 2-chlorotrifluoroacetoacetate.

Since 1 mole of ethyltrifluoroacetate produces 1 mole of ethanol in the salt-direct condensation process, acetyl chloride requires 1 mole per mole of ethyltrifluoroacetate during the acetylation process. However, it was found that when a little more than 1 equivalent of acetylchloride was used, an byproduct ethyl 3-acetoxy-4,4,4-trifluoro-2-butanoate was produced in an undesirable amount.

Therefore, if the hemiketal is contained in the product in an amount of 0.8 equivalent or less, this is an undesirable amount. Therefore, in the acetylation process, it is preferable to use about 0.8-1.0 equivalents of acetyl chloride per hemicantal equivalent.

Using about 0.95 equivalents of acetylchloride minimizes the production of ethyl 3-acetoxy-4,4,4-trifluoro-2-butenoate as well as unreacted in distilled ethyltrifluoroacetoacetate. The amount of hemical can also be minimized.

Salt-direct condensation is preferably carried out in an inert organic medium, and such a medium can be easily provided by using a selected alkylacetate and a selected alkyl trifluoroacetate with an inert organic solvent. Suitable solvents as described above are dodecane. Dodecane is characterized by a high enough boiling point to allow very good separation of the solvent from the acetoacetate final product during the distillation process.

The amount of the solvent used is not important because the use of the solvent may be excluded. Even so, it is advisable to use chemically inert organic solvents in the process to control the reaction and to facilitate the transfer of the material to other processes. The acetylation reaction is carried out under atmospheric pressure, but the pressure is not so important. Thus, if it is necessary to control the reaction or to keep the reactants and products in the desired phase, the pressure may be lower or higher than atmospheric pressure.

Although the temperature is not very important for the acetylation reaction, the temperature at which butanoate and acetylanilide are in contact with each other depending on the selected pressure of trifluorobutanoate is about 10 ° C to 115 ° C or more.

It is important to keep in mind that suitable reaction conditions for the acetylation process are that the reaction of acetyl chloride and ethanol is exothermic.

In general, the reaction mixture is preferably kept below 30 ° C in the initial stage of the reaction to add acetyl chloride. At this temperature the rate of reaction is relatively slow by the release of hydrogen chloride. As the reaction temperature is increased, the release rate of the hydrogen chloride is unnecessarily faster, and the volatiles are significantly increased because the hydrogen chloride is accompanied by volatiles as the temperature increases rapidly.

On the other hand, if the temperature of the reaction mixture is maintained at 30 ° C. or lower, the reaction rate is undesirably slow, so that the reaction mixture must be gradually heated to the reflux temperature in order to control the release of the hydrogen chloride at a suitable rate.

Lower alkyl and alkoxy are linear or branched alkyl moieties having 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and the like.

The following examples are intended to illustrate the present invention in detail, and the present invention is not limited thereto.

Example 1

[Condensation]

22.3 parts by weight of sodium hydride (60% mineral oil dispersion) was added to a dried reaction vessel equipped with a heat exchanger, a stirrer, a thermometer, a reflux condenser and a flow meter in the presence of sufficient nitrogen. Nitrogen gas minimizes the reduction of volatile components. 61.8 parts by weight of dry cyclohexane was added at room temperature with an inert organic solvent while stirring to obtain a sodium hydride oil dispersion. Then, 79.0 parts by weight of ethyltrifluoroacetate was continuously injected from the bottom for 15 minutes. The stirred slurry was then heated to reflux under reflux and refluxed. Next, the reaction rate was controlled by starting the plycene condensation reaction by slowly and continuously adding 53.9 parts by weight of ethyl acetate at a constant rate for 2 hours and maintaining the reaction temperature at 45-60 ° C. After completion of the reaction in which the release of hydrogen gas was stopped, sodium salts of ethanol and ethyltrifluoroacetoacetate were added to dilute the mixture, and 55.7 parts by weight of cyclohexane was further added to the reaction mixture.

[China]

The reaction mixture was transferred to a neutralization vessel equipped with a stirrer, a thermometer, and a reflux condenser. The reaction mixture was cooled to 25-30 ° C., and anhydrous HCl (22.3 parts by weight) was added to the bottom of the vessel for 1 hour.

While HCl was added, the temperature of the vessel was kept below 30 ° C. The resulting slurry was then heated to reflux under atmospheric pressure and blown away with excess HCl gas while refluxing and bent with a caustic scrubber.

[Acetylation]

The resulting slurry was cooled to 25-30 ° C. and 41.5 parts by weight of acetyl chloride was added slowly and continuously while maintaining the temperature of the mixture below 30 ° C. for about 35 minutes. Thereafter, about 20 parts by weight of HCl gas was released while gradually heating under atmospheric pressure and refluxing for 1 3/4 hours to reflux the mixture.

[Isolate product]

The slurry was kept at 30 ° C. and filtered to remove the precipitated sodium chloride. The resulting salt filtered cake was washed twice with a total of 86.6 parts by weight of cyclohexane and the washed filtrate was filtered off with the original ethyltrifluoroacetoacetate. After mixing the water it is transferred to a distillation vessel. A fractionation column, a cooling condenser and a product collector were attached to the distillation vessel. Cyclohexane and ethyl acetate were distilled off at a vapor temperature of 46-71 ° C. and a pressure of 325 mmHg.

This distillate is recycled to ethyl acetate and used in the next step. The distillation of the second fraction was carried out at a steam temperature of 71 ° C. and the original pressure of 325 mm Hg, and distillation was completed in a final vessel at a pressure of 20 mm Hg and a temperature of 150-160 ° C. As a result of analyzing the second fraction (about 82 parts by weight), it was found that 94.0 wt% of ethyltrifluoroacetoacetate was included, and the yield was about 75%.

Example 2

In this example, dodecane was used instead of cyclohexane as an inert organic solvent. In addition, the salt produced during the neutralization process is fractionated from ethyl acetate and ethyl trifluoroacetoacetate, and then removed from dodecane by aqueous extraction. 22 parts by weight of sodium hydride (60% mineral oil dispersion) was added to the reaction vessel mentioned in Example 1 under sufficient nitrogen conditions, followed by addition of 164 parts by weight of dry dodecane at room temperature with stirring to obtain a sodium hydride dispersion. . Next, 74 parts by weight of ethyltrifluoroacetate was continuously added from the bottom of the stirring solution for 15 minutes, and then the stirred slurry was heated to 70 DEG C, and 51 parts by weight of ethyl acetate were slowly and continuously added thereto at a constant rate for 2 hours. The Klysene condensation reaction was initiated.

After the condensation reaction was completed, anhydrous HCl (21.9 parts by weight) was added through the bottom for 1 hour. The temperature of the vessel was kept below 40 ° C. during the addition of HCl. The resulting slurry was heated to reflux under atmospheric pressure and excess HCl was blown off.

The slurry was cooled to 58-60 ° C. and 40 parts by weight of acetyl chloride was continuously added while maintaining the temperature of the vessel at 58-60 ° C. for 1 hour through the bottom of the container. Excess HCl was released while gradually heating under atmospheric pressure to reflux the mixture.

After the temperature of the vessel was 75-80 ° C., the mixture was transferred to a distillation vessel equipped with a fractionation column, a cooling condenser and a collector. Distillation was carried out under a pressure of 315-320 mmHg. Under this pressure the mixture is heated to reflux to equilibrate in the column. Ethyl acetate was then distilled and collected in a cooled collector. The temperature of the vessel gradually increased during the distillation. When the temperature of the steam reaches 75 ° C. (about 51 parts by weight of distillate is collected), the collector is removed and the ethyl acetate is collected in a container and recycled. The second fraction starts distillation under pressure of 315-320mmHg, and during fractional distillation the final pressure drops to 40mmHg. The last temperature of the vessel was 130 ° C.

The yield of ethyltrifluoroacetoacetate obtained from the second fraction was about 80%. The residue of the distillation vessel was washed with 209 parts by weight of water with stirring, the mixture was separated into an aqueous layer and an organic layer, the aqueous layer containing sodium chloride was extracted and transferred to a waste plant, and the second water extract was also removed in a similar manner. . The organic layer containing dodecane was purified by distillation for regeneration.

Example 3

This example specifically illustrates the preparation of ethyltrifluoroacetoacetate using a strong base as the sodium ethoxide to condense ethyl acetate and ethyltrifluoroacetate.

71.05 parts by weight of ethyltrifluoroacetate and 57.33 parts by weight of ethyl acetate were added to a flask of suitable capacity, and 34.04 parts by weight of sodium ethoxide was slowly added to induce the reaction to a temperature of 35 ° C or lower. The mixture was heated to reflux at atmospheric pressure for 2 hours and the reaction mixture was cooled to room temperature, then neutralized by addition of 21 parts by weight of hydrochloric anhydride while maintaining the temperature below 40 ° C. Sodium chloride precipitates during neutralization.

In order to remove unreacted hydrochloric acid, the pressure of the flask was reduced to 100 mmHg, and 78.5 parts by weight of acetyl chloride was added dropwise to the reaction mixture for 1 hour. The hydrochloric acid produced in the middle was removed. Fractional distillation and analysis of the resulting product under reduced pressure showed that ethyltrifluoroacetoacetate was obtained in a yield of 59%, and it was also found that no hemimetal was present in the distillation product by 19F NMR.

Example 4

This example illustrates the preparation of n-butyltrifluoroacetoacetate.

40 parts of n-butyltrifluoroacetate, 32 parts of n-butyl acetate, and 100 parts of dodecane were added to a three-necked flask having a suitable capacity, and 5.9 parts of sodium metal was added to the reaction mixture. The temperature of the mixture slowly increases for 20 minutes to 55 ° C. The temperature is maintained at 55 ° C. for 1 hour using a cold water bath, then the reaction is heated to 85-90 ° C. and held at this temperature for 75 minutes to complete the reaction.

23.5 parts by weight of sulfuric acid (95-98%) was then added dropwise to the reaction mixture. The temperature of the mixture was kept at 25-30 ° C. using a cold water bath.

After the addition of sulfuric acid was completed, 18 parts by weight of isetyl chloride was added dropwise to the reaction mixture for 5 minutes while maintaining the temperature at 25-30 ° C. The resulting mixture was a slurry containing sodium chloride. Volatile components were removed by vacuum distillation. Fractional distillation of the distillate yielded 10 parts by weight of n-butyltrifluoroacetoacetate, the chemical structure of which was confirmed by NMR and elemental analysis.

Claims (15)

C ₁ -C ₅ alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate is contacted with an acetylating agent selected from the group consisting of acetyl halide and acetic anhydride under acetylation pressure conditions, The reaction is carried out at a temperature of at least about 10 ° C. and at the reflux temperature of the reaction mixture containing noate from C ₁ -C ₅ alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluoro with the highest alkalizing agent. Method for producing a C ₁ -C ₅ alkyltrifluoroacetoacetate, characterized in that. The acetyl halide or acetic anhydride according to claim 1, wherein ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate is prepared under temperature and pressure conditions effective for preparing ethyltrifluoroacetoacetate. In a reaction mixture containing a maximum of acetyl halide or acetic anhydride and ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate Process for producing ethyl trifluoroacetoacetate, characterized in that carried out at reflux temperature of. C ₁ -C ₅ alkylacetate and C ₁ -C ₅ alkyltrifluoroacetate are condensed in the presence of a strong base condensing agent and neutralized with a strong mineral to give C ₁ -C ₅ alkyl 3-alkoxy-3-hydroxy-4, 4,4-trifluoro gained butanoate, the salts of this acetoacetate, C ₁ -C ₅ alkyl acetate, and the base in the temperature of the solution below at least about 10 ℃ by C ₁ -C ₅ alkyl and trifluoromethyl And reacting with the acetyl halide or acetic anhydride under sufficient pressure to produce an acid, and separating the acetoacetate, the salt and the acetate, respectively, into a C ₁ -C ₅ alkyltrifluoroacetoacetate. 4. The reaction mixture of ethyl acetate and ethyl trifluoroacetate in the presence of a strong base condensate is obtained by removing hydrogen gas, and then drying the mixture. Neutralization with mineral acid to obtain salts and bases of ethyl-3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate and acid, and the product obtained by neutralization were ethyl acetate and ethyltrifluoroacetoacetate. The reaction is carried out in contact with an acetyl halide under the temperature and pressure conditions effective to produce the reaction, the reaction is carried out at a temperature of at least about 10 ℃ or less and the reflux temperature of the reaction mixture containing the acetyl halide and the neutralizing product, salt and ethyl acetate and Ethyltrifluoroacetate, characterized in that each is separated by ethyltrifluoroacetoacetate The method of acetate. In a base direct condensation process, ethyl acetate and ethyltrifluoroacetate were contacted with each other in the presence of a strong base condensate to obtain a reaction mixture of a salt of ethyltrifluoroacetoacetate and ethanol, in which hydrogen gas was removed, and the reaction mixture in a neutralization process. Was neutralized with anhydrous hydrochloric acid to obtain a salt and a base of ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate and an acid. React with an acetyl halide under temperature and pressure conditions effective for the production of trifluoroacetoacetate and acid halides removed in the gas phase, the reaction being at a temperature of up to about 10 ° C. and refluxing the reaction mixture comprising the acetyl halide and the neutralization product. Temperature, and in the separation step, salt, ethyl acetate and ethyl triflu Remove the respective ROIs diacetoacetate and ethyl acetate The method of manufacturing an acetoacetate with ethyl trifluoroacetate, characterized by Sikkim recycled to the condensation step. The method of claim 5, wherein in the base direct condensation step, ethyl acetate and ethyl trifluoroacetate are contacted with each other in the presence of sodium hydride to remove the sodium salt of ethyltrifluoroacetoacetate, ethanol and an inert gas. After obtaining a reaction mixture of hydrogen gas, the reaction mixture was neutralized with anhydrous hydrochloric acid in a neutralization step to obtain ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate, The neutralization product is reacted with acetyl chloride under the temperature and pressure conditions effective for the preparation of ethyl acetate, ethyl trifluoroacetoacetate and HCl being removed, the reaction being carried out at a temperature of about 10 ° C. or less and the acetyl chloride and the neutralization product. At the reflux temperature of the reaction mixture, and in the separation process, filtration or Removed by removing the salt and separating the acetoacetate in a fractional distillation is ethyl acetate and ethyl trifluoroacetate and then, ethyl acetate The method of manufacturing an acetoacetate with ethyl trifluoroacetate, characterized by Sikkim recycled to the condensation step. 7. The method of claim 6, wherein the anhydrous hydrochloric acid is used in stoichiometric excess in excess of about 10-15%. 8. The method of claim 7, wherein the acetylchloride is used in stoichiometric amounts of about 1.0-0.8. The method of claim 3 wherein the strong base is selected from the group consisting of sodium metal, sodium ethoxide and sodium hydride. 10. The method of claim 9, wherein the strong mine is selected from the group consisting of hydrochloric acid, phosphoric acid and sulfuric acid. The method of claim 3 wherein the condensation occurs in an inert organic solvent. The method of claim 11, wherein the solvent is cyclohexane or dodecane. Acetylating agent and C ₁ -C ₅ alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate under non-refluxing conditions, acetyl halide and acetic anhydride and C ₁ -C ₅ alkyl A method for preparing C ₁ -C ₅ alkyltrifluoroacetoacetate, characterized by refluxing with an acetylating agent selected from the group consisting of 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate. The method of claim 13, wherein acetyl halide or acetic anhydride is mixed with ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate under non-reflux conditions and acetyl halide or acetic anhydride and ethyl 3 A method for producing ethyl trifluoroacetoacetate, characterized by reflux with ethoxy-3-hydroxy-4,4,4-trifluorobutanoate. The method of claim 13, wherein acetyl halide or acetic acid is mixed with N-butyl 3-butoxy-3-hydroxy-4,4,4-trifluorobutanoate and non-acetyl halide or acetic anhydride is used under non-reflux conditions. A method for producing n-butyltrifluoroacetoacetate, comprising refluxing with n-butyl 3-butoxy-3-hydroxy-4,4,4-trifluorobutanoate.

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