DK169869B1 - Process for preparing ethyl trifluoroacetoacetate - Google Patents

Description

DK 169869 B1

The present invention relates to a process for the preparation of ethyl trifluoroacetoacetate, wherein ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate is acetylated with acetyl chloride.

5

It is well known to couple halogenated esters with other esters, which can be done by the so-called Claisen condensation, see L. Claisen and 0. Lowman, Ber. 20, 651 (1887). Using this reaction, e.g. ethyl trifluoroacetoacetate prepared by an alkaline condensation of ethyl acetate with ethyl trifluoroacetate. By neutralization, a reaction product is formed consisting of a salt and the ethanol hemiketal of ethyl trifluoroacetoacetate, which can be chemically identified as ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate. To convert this hemiketal to ethyl trifluoroacetate acetate, it is hydrolyzed while removing ethanol. Unfortunately, this results in the formation of the hydrate of ethyl trifluoroacetate acetate. Furthermore, ethanol is formed as a by-product that is discarded, so that the process known so far becomes environmentally questionable and economically disadvantageous.

Ethyl trifluoroacetate acetate is suitable as an intermediate in the preparation of agricultural chemicals and pharmaceuticals. In order to be used for these purposes, it is usually necessary to avoid the formation of the hydrate. Therefore, in the known process, the hydrate of ethyl trifluoroacetate acetate must be dehydrated, necessitating an additional and costly process step. To achieve the dehydration, e.g. by the known processes proposed to use cupri acetate to form a copper complex of the trifluoroacetoacetate. After filtration, the complex is then reacted with hydrogen sulfide to release trifluoroacetoacetate, which is then isolated by distillation. In another known process, the trifluoroacetoacetate is isolated from aqueous medium by solvent extraction and dehydration with dehydrating agents, e.g. calcium chloride, magnesium sulfate or a molecular sieve, distilling the final product. t

The present invention has for its object to provide a convenient and economically advantageous preparation of anhydrous alkyl trifluoroacetoacetate. Furthermore, ethanol is not produced as a by-product. Instead, ethyl acetate is formed which can be recycled and used as a reagent to form more alkyl trifluoroacetoacetate.

10

In the process of the invention, an alkyl 3-alkoxy-3-hydroxy-4,4,4-trifluorobutanoate is first formed, which is then reacted with acetyl halide or acetic anhydride to give ethyl trifluoroacetoacetate and ethyl acetate.

15 The resulting products are isolated from one another. Recycled ethyl acetate may conveniently be recycled for condensation with more ethyl trifluoroacetoacetate to give ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate. According to a preferred embodiment of the process according to the invention, the condensation is carried out in the presence of sodium hydride. Examples of other suitable strong bases are metallic sodium and sodium ethoxide. The condensation product is neutralized with a strong, generally anhydrous mineral acid such as hydrogen chloride, phosphoric acid or sulfuric acid. Anhydrous hydrogen chloride is preferred. The neutralization product, which is ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate (ethanol hemiketal of C ^-Cg-ethyl trifluoroacetate), is reacted with acetyl chloride or acetic anhydride to give ethyl trifluoroacetoacetate, 30 ethyl acetate, hydrogen halide or acetic acid and the salt of the base and acid. Finally, the acetoacetate, salt and acetate are separated from each other. The salt can be precipitated and removed by filtration, centrifugation, solvent extraction, etc. The acetoacetate, hydrogen halide or acetic acid halide and acetate are suitably separated by fractional distillation or by other appropriate means.

3 DK 169869 B1

In order to better illustrate a preferred embodiment of the invention, reference is made to the drawing which comprises a flow chart of the method according to the invention. At room temperature or other appropriate reaction temperature, an appropriate amount of a strong base such as sodium hydride, preferably as an oil emulsion, is added to a base-directed condensation zone. Ethyl trifluoroacetate and ethyl acetate are then dosed into the condensation zone and the reaction mixture is stirred. A suitable inert organic solvent can also be added so that the reaction can be better controlled and separation of the final product can be facilitated. Examples of suitable solvents are cyclohexane, dodecanethyl ether, hexane, methylcyclohexane, 1,2-dimethoxyethane, tetrahydrofuran, benzene and the like. The condensation reaction is started in a controlled manner to form the sodium salt of ethyl trifluoroacetoacetate and ethanol.

A nitrogen gas or other inert gas can be used to flush and remove developed hydrogen gas.

The resulting reaction mixture is transferred to the neutralization zone where a strong anhydrous mineral acid, preferably anhydrous hydrochloric acid, is added, preferably in a 10-15% molar excess, to neutralize the reaction mixture and to form the salt and ethanol hemiketal of ethyl trifluoroacetoacetate. The neutralization product is heated to remove excess hydrogen chloride as a gas.

Next, the neutralization product is introduced into the acetylation zone, whereby acetyl chloride is reacted to form hydrogen chloride, ethyl acetate and ethyl trifluoroacetoacetate.

The product for the acetylation step is transferred into the product separation zone. Salt is precipitated and filtered or otherwise separated. Ethyl acetate, ethyl trifluoroacetate and hydrogen chloride are separated by distillation or otherwise. Thereby, ethyl tri-fluoroacetoacetate is produced as the final product together with ethyl acetate, which can be recycled to the condensation zone. *

An important feature of the invention comprises the acetylation of the product from the neutralization step. This product may be ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate (ethanol hemiketal of ethyl trifluoroacetate). It has been found that, by conventional distillation of the product, the hemiketal decomposes to form ethanol and ethyl trifluoroacetate. Unfortunately, these two compounds will be able to distill and recombine in the distillation publisher to form the hemiketal of ethyl trifluoroacetoacetate.

Removal of substantially all ethanol is necessary to effectively chlorine ethyl trifluoroacetoacetate to form ethyl 2-chlorotrifluoroacetoacetate, which is a chemical compound suitable as an intermediate for the preparation of certain agricultural chemicals, namely 2,4-disubstituted-5- thiazole carboxylic acid and derivatives thereof, as disclosed in U.S. Patent No. 4,199,506.

In the base-directed condensation step, one mole of ethyl trifluoroacetate will result in the formation of one mole of ethanol.

Therefore, approx. 1 mole of acetyl chloride per mole of ethyl trifluoroacetate in the acetylation. However, it has been found that by using little more than one equivalent of acetyl chloride, an undesirable amount of the by-product, ethyl 3-acetoxy-4,4,4-trifluoro-2-butenoate, is obtained. With 0.80 equivalents or less, the amount of hemiketal in the product will be undesirably high. It is therefore preferred that 0.80 to 1.0 equivalent of acetyl chloride be used per day. equivalent of the hemiketal used in the acetylation. The use of about 0.95 equivalent of acetyl chloride decreases the formation of ethyl 3-acetoxy-4,4,4-trifluoro-2-butanoate while reducing unreacted hemiketal in the distilled ethyl trifluoroacetoacetate. * 5 DK 169869 B1

The base-directed condensation is preferably carried out in an inert organic medium. Such a medium is conveniently provided using an inert organic solvent such as alkyl acetate or alkyl trifluoroacetate. Among the aforementioned suitable solvents, dodecane is preferred. Dodecan has a sufficiently high boiling point to give excellent separation of the solvent from the final product acetoacetate in the distillation step. The amount of solvent used is not critical, as the use of solvent can be completely avoided. However, the reaction can be better controlled, and the transfer of material from one zone to another is facilitated by the use of an organic solvent which is chemically inert during the process.

15

The acetylation reaction can be carried out at atmospheric pressure, although pressure is not critical. The pressure may be lower or higher than the atmospheric pressure if required to control the reaction or to maintain the reagents and product in the desired phase. The temperature at which the acetylation reaction is carried out is not critical. Depending on the particular alkyl trifluorobutanoate and the selected pressure, the temperature at which the butanoate and acetyl chloride are reacted will vary from ca. 10 ° C to 115 ° C or higher.

As to the preferred reaction conditions during acetylation, it must be taken into account that the reaction of acetyl chloride with ethanol is exothermic. Usually, the reaction mixture is maintained below 30 ° C during the initial step of the reaction with the addition of acetyl chloride. At this temperature, the rate of reaction as indicated by the development of hydrogen chloride is relatively slow. At an increased reaction temperature, the development of hydrogen chloride 35 can occur at an undesirably high rate. In addition, considerable loss of volatile material may occur due to its entrapment in the hydrogen chloride by the rapid rise of the temperature 6 DK 169869 B1 tf trip. On the other hand, if the reaction mixture is maintained at or below 30 ° C, the reaction rate may be unacceptably slow. As a result, the mixture will gradually warm to the boiling point and release hydrogen chloride at a controlled and acceptable rate.

Examples of lower alkyl or alkoxy include an alkyl group which may be either straight or branched, with 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy. . . .

The process according to the invention will be illustrated in the following by means of some examples in which all parts are indicated by weight, unless otherwise stated.

EXAMPLE 1

15 CONDENSATION

A dry reactor equipped with a heat exchanger, stirrer, thermocouple, a reflux condenser and a flow meter was charged with 22.3 parts of sodium hydride (60¾ mineral oil dispersion) under a nitrogen atmosphere. Nitrogen-20 flow was kept low to reduce volatile losses.

With stirring, 61.8 parts of dry cyclohexane was added as an inert organic solvent at room temperature to obtain sodium hydride oil dispersion. The stirred mixture was then continuously fed under the surface with 79.0 parts of ethyl trifluoroacetate over 15 minutes. The slurry was stirred and then heated under reflux at an atmospheric pressure. A Claisen condensation reaction was initiated under the slow and continuous addition of 53.9 parts of ethyl acetate at a constant rate over 2 hours. The reaction rate was controlled by maintaining the reaction temperature between 45 and 60 ° C.

7 DK 169869 B1

After completion of the reaction as indicated by cessation of hydrogen evolution, an additional 55.7 parts of cyclohexane was added to the reaction mixture containing ethanol and the sodium salt of ethyl trifluoroacetoacetate to dilute the mixture.

NEUTRALIZATION

The reaction mixture was transferred to a neutralization vessel consisting of a reactor equipped with a stirrer, a thermocouple and a reflux condenser. After cooling the reaction mixture to 25-30 ° C, HCl (22.3 parts) was added under the surface over 1 hour. During HCl addition, the reactor temperature was maintained below 30 ° C. The resulting slurry was then heated under reflux at atmospheric pressure and thus maintained to evaporate excess HCl which was vented through a basic washing column.

ACETYLATION

The slurry was cooled to 25-30 ° C, and 41.5 parts of acetyl chloride was slowly and continuously added over 20 minutes while maintaining the temperature of the mixture below 30 ° C. The mixture was then gradually heated under reflux at atmospheric pressure and thus maintained at room temperature. 1 3/4 hour, during which about 20 parts of HCl developed.

25 PRODUCT SEPARATION

The slurry was maintained at 30 ° C and filtered to remove precipitated sodium chloride. The resulting salt filter cake was washed twice with a total of 86.6 parts of cyclohexane. The wash filtrates were combined with the original ethyl trifluoroacetoacetate containing filtrate and the mixture was transferred to a distillation apparatus.

8 DK 169869 B1 • Λ

The distillation apparatus included a fractionation column, a condenser and a product imprint. Cyclohexane and ethyl acetate were distilled at 325 mm Hg absolute pressure and a vapor temperature between 46 ° C and 71 ° C. The process 5 contained ethyl acetate which was recycled in a previous production. Distillation of the second fraction proceeded at initial pressure of 325 mm Hg absolute and a vapor temperature of 71 ° C and was completed at a final temperature of 150-160 ° C at 20 mm Hg absolute. This second fraction (about 82 parts) was analyzed for 94.0% by weight of ethyltrifluoroacetoacetate. The yield of ethyltrifluoroacetoacetate was about 75%.

EXAMPLE 2

This example describes the use of dodecane instead of cyclohexane as an inert organic solvent. Furthermore, the salt formed during neutralization is removed from the dodecane by aqueous extraction after fractional distillation of ethyl acetate and ethyl trifluoroacetoacetate.

The reactor described in Example 1 was charged with 22 parts of 20 sodium hydride (60% mineral oil dispersion) under a cover of nitrogen. With stirring, 164 parts of dry dodecane were added at room temperature to the sodium hydride oil dispersion. The stirred mixture was then continuously added under the surface 74 parts of ethyl trifluoroacetate over 15 minutes. The stirring was then stirred and heated to 70 ° C. A Claisen condensation was initiated by the slow and continuous addition of 51 parts of ethyl acetate at a constant rate over 2 hours.

After completion of the condensation, anhydrous HCl (21.9 parts) was added under the surface over 1 hour. During the "HCl addition, the boiler temperature was maintained below 40 ° C. The resulting slurry was then heated under heating. reflux at atmospheric pressure to remove excess HC1.

The slurry was cooled to 58-60 ° C and 40 parts of acetyl chloride was continuously added below the surface over 1 hour while maintaining a temperature of 58-60 ° C in the mixture. The mixture was gradually heated under reflux at atmospheric pressure and maintained under these conditions to evaporate excess HCl. The temperature was then reduced to 75-80 ° C and the mixture was transferred to a distillation vessel equipped with a fractionation column and a condenser as well as a pre-mixer. The distillation apparatus was gradually evacuated to 315-320 mm Hg absolute. At this pressure, the mixture was heated at reflux to achieve equilibrium in the column. The ethyl acetate feed was then distilled and collected in a chilled publisher. During the distillation, the boiler temperature was gradually increased.

After reaching the steam temperature of 75 ° C (approximately after collecting 51 parts of distillate), the distillate was isolated and transferred to a container. The resulting process was recycled. Distillation of the second fraction proceeded at an initial pressure of 315-320 mm Hg absolute, and the pressure was rapidly reduced during the distillation of this fraction to a final pressure of 40 mm Hg absolute. The final boiler temperature was 130 ° C. Yield of ethyl trifluoroacetoacetate at the second fraction was approx.

25 80%.

The distillation residue was washed with 209 parts of water with stirring. The mixture was allowed to separate into an aqueous layer and an organic layer. The aqueous layer containing sodium chloride was stripped and discarded.

Another aqueous extraction was carried out in a similar manner. The organic layer containing the dodecane was purified for recycling by distillation.

EXAMPLE 3

This example illustrates the preparation of ethyl trifluoroacetoacetate, where sodium ethoxide is the strong base used to condense ethyl acetate and ethyl trifluoroacetate.

Into a suitable flask were 71.05 parts of ethyl trifluoroacetate and 57.33 parts of ethyl acetate. With vigorous stirring, 34.04 parts of sodium methoxide was added slowly to keep the reaction mass below 35 ° C. The mixture was heated under reflux at atmospheric pressure for 2 hours. The reaction mixture was cooled to room temperature and neutralized with 21 parts by weight of anhydrous hydrochloric acid, maintaining the temperature below 40 ° C. Sodium chloride precipitated under neutralization. Next, the pressure in the flask was reduced to 100 mm Hg absolute to remove unreacted hydrochloric acid. Next, 78.5 parts of acetyl chloride were added over 1 hour to the reaction mixture. After the addition of the acetyl chloride was completed, the pressure was reduced to 100 mm 2Γ Hg absolute to remove hydrogen chloride formed during the acetylation. The resulting product was distilled by fractionation at reduced pressure. An analysis of the distillation product showed an ethyl trifluoroacetate acetate yield of 59%. No hemical number was present in the distillation product determined by F NMR.

EXAMPLE 4

This example illustrates the preparation of n-butyl trifluoroacetoacetate.

* Into a suitable three-neck flask were introduced 40 parts of n-butyl-50 trifluoroacetate, 32 parts of n-butyl acetate and 100 parts of dodecane.

With stirring, 5.9 parts of metallic sodium was added to the reaction mixture. The temperature of the mixture gradually increased to 55 ° C over 20 minutes. The temperature was controlled at 55 ° C for 1 hour using a cold water bath. Then, the reaction mixture was heated to 85-90 ° C and maintained at this temperature for 75 minutes to ensure the completion of the reaction. Next, 5 23.5 parts of sulfuric acid (95-98%) were added to the reaction mixture with stirring. The temperature of the mixture was adjusted to 25-30 ° C by a cold water bath.

After addition of sulfuric acid, 18 parts of acetyl chloride were added dropwise over 5 minutes to the reaction mixture while maintaining the temperature at 25-30 ° C. The resulting mixture was a slurry of sodium chloride. Volatiles were evaporated by simple vacuum distillation. The distillate was fractionated to obtain 10 parts of n-butyl trifluoroacetoacetate, whose chemical structure was confirmed by NMR technique and elemental analysis.

The above examples may be varied within the scope of the invention.

Claims (4)

12 DK 169869 B1> A process for the preparation of ethyl trifluoroacetoacetate, characterized by the following steps: a) reacting ethyl acetate and ethyl trifluoroacetate in the presence of a strong base to form a reaction mixture of a salt of ethyl trifluoroacetoacetate and ethanol while simultaneously removing the gaseous hydrogen developed during the reaction , b) neutralizing the reaction mixture with a strong mineral acid to give ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate and the salt of the acid and base; c) reacting the ethanol contained in the reaction mixture with acetyl chloride or acetic anhydride. under reaction conditions for temperature and pressure, thereby forming a reaction product of ethyl acetate and ethyl trifluoroacetoacetate substantially free of free ethanol, which temperature ranges from approx. And d) separating the resulting ethyl trifluoroacetoacetate from salt and ethyl acetate. Process according to claim 1, characterized in that the process is carried out in a reactor apparatus, wherein step a) is carried out in a base-directed condensation zone, step b) is carried out in a neutralization zone, step c) is carried out in an acetylation zone, the separation of salt, ethyl acetate and ethyl trifluoroaceto - λ acetate in step d) is carried out in a separation zone, and in the further step e) the ethyl acetate is recycled to the condensation zone. Process according to claim 1, characterized in that (a) the condensation of ethyl acetate and ethyl trifluoroacetate is carried out in the presence of sodium hydride, removing hydrogen gas from the condensation zone by rinsing with an inert gas, (b) neutralizing the is carried out with anhydrous hydrogen chloride gas to form ethyl 3-ethoxy-3-hydroxy-4,4,4-trifluorobutanoate, (c) separating or fracentrifuging salt in the separation zone and separating ethyl acetate and ethyl trifluoroacetoacetate by fractional distillation, and (d) the ethyl acetate is recycled to the condensation zone. Process according to claims 1-3, characterized in that anhydrous hydrogen chloride is used in an excess of 10-15% in relation to the stoichiometric amount, while the acetyl chloride is used in an amount of 1.0-0.8 in relation to the stoichiometric quantity.