Process for the preparation of ethyl 4,4,4-trifluoroacetoacetate
Ethyl tetrafluoroacetoacetate was prepared by condensation reaction of trifluoroacetyl chloride and base in an organic solvent, which solved the problems of multiple side reactions, low yield and high safety risks in the existing synthesis methods, and realized efficient and safe industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZIBO FEIYUAN CHEM CO LTD
- Filing Date
- 2023-09-28
- Publication Date
- 2026-07-24
AI Technical Summary
Existing methods for synthesizing ethyl trifluoroacetoacetate suffer from numerous side reactions, low yields, difficulty in separating the products, harsh reaction conditions, challenges in handling byproducts, and high safety risks.
Ethyl 4,4,4-trifluoroacetoacetate was prepared by reacting trifluoroacetyl chloride with a base in an organic solvent, followed by the addition of ethyl acetate, through a condensation reaction. Pyridine was used as the base, and chloroform was preferred as the organic solvent. Trifluoroacetyl chloride was added at a temperature below 0°C, and then the temperature was raised to 20-30°C for further reaction. Finally, the mixture was washed with water and dried with anhydrous sodium sulfate.
It achieves mild conditions, simple operation, fast reaction speed, easy product separation, is suitable for industrial production, has high yield and improved safety.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing ethyl 4,4,4-trifluoroacetoacetate. Background Technology
[0002] Ethyl 4,4,4-trifluoroacetoacetate, or simply ethyl trifluoroacetoacetate, has two configurations: enol and keto, which can usually be freely converted. The specific structure is shown below:
[0003] .
[0004] Ethyl trifluoroacetoacetate is an important fine intermediate used in the synthesis of some pesticides, pharmaceuticals, and organic intermediates. Its synthesis mainly involves the reaction of a base with trifluoroacetyl chloride to generate a trifluoroacetyl base intermediate, which is then condensed with ethyl acetate to form ethyl trifluoroacetoacetate. Currently, the main methods for synthesizing ethyl trifluoroacetoacetate both domestically and internationally include the following:
[0005] The Claisen condensation method uses ethyl trifluoroacetoacetate, ethyl acetate, and sodium ethoxide solution as raw materials to prepare ethyl trifluoroacetoacetate. This method is the most classic method for preparing ethyl trifluoroacetoacetate, but it has disadvantages such as many side reactions, low yield, and difficulty in separating the products. For example, the reaction involves the removal of ethanol, but the presence of ethanol in the reaction system inhibits the ethanol removal reaction; ethyl acetate is prone to self-condensation under the reaction conditions to form ethyl acetoacetate, and due to the presence of sodium ethoxide, the reaction system needs to be kept anhydrous. This method has been used to synthesize ethyl trifluoroacetoacetate in patents such as CN106565475A, WO2015085464, CN106188013A, CN106699506A, and CN115260174A.
[0006] Furthermore, patent CN113072449A reports a reaction using trifluoroacetone and methyl chloroformate as raw materials in a pipeline reactor catalyzed by hydrogen chloride gas. However, this method has drawbacks such as demanding reaction conditions, difficult byproduct handling, and safety concerns. For example, the method requires high reaction temperatures and pressures, increasing energy consumption and equipment requirements during production. In addition, the reaction generates large amounts of byproducts such as hydrogen chloride and formic acid, which require appropriate treatment and disposal, increasing production costs and operational complexity. Trifluoroacetone and hydrogen chloride are flammable, explosive, and toxic chemicals, potentially increasing the risk of accidents. Summary of the Invention
[0007] The purpose of this invention is to provide a method for preparing ethyl 4,4,4-trifluoroacetoacetate, which is characterized by mild conditions, simple operation, fast reaction rate, easy product separation, and suitability for industrial production.
[0008] The method for preparing ethyl 4,4,4-trifluoroacetoacetate according to the present invention involves first adding trifluoroacetyl chloride and a base to an organic solvent for reaction, and then adding ethyl acetate for further reaction to obtain ethyl 4,4,4-trifluoroacetoacetate.
[0009] In this invention, the organic solvent is at least one selected from dichloromethane, chloroform, tetrahydrofuran, toluene, and cyclohexane; preferably chloroform.
[0010] In this invention, the mass of the organic solvent is 3-5 times the mass of the alkali.
[0011] In this invention, the base is at least one selected from diethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydroxide, and dimethylaminopyridine; preferably pyridine.
[0012] In this invention, the molar ratio of trifluoroacetyl chloride to alkali is 1:(1-3).
[0013] In this invention, the molar ratio of trifluoroacetyl chloride to ethyl acetate is 1:(1-2).
[0014] In this invention, the alkali is first dissolved in an organic solvent, and then trifluoroacetyl chloride is added and reacted for 0.5-3 hours at a temperature not higher than 0°C.
[0015] In this invention, after adding ethyl acetate, the temperature is raised to 20-30℃ and the reaction is carried out for 2-6 hours.
[0016] In this invention, after the reaction is complete, the reactants are washed with water, the organic phase is dried with anhydrous sodium sulfate, and finally the organic solvent is evaporated to obtain ethyl 4,4,4-trifluoroacetoacetate.
[0017] Taking pyridine as a base as an example, the reaction mechanism for the preparation of ethyl 4,4,4-trifluoroacetoacetate is as follows:
[0018]
[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0020] This invention uses trifluoroacetyl chloride, alkali, and ethyl acetate as raw materials to prepare ethyl 4,4,4-trifluoroacetoacetate through a condensation reaction in an organic solvent. The conditions are mild, the operation is simple, the reaction rate is fast, and the product is easy to separate, making it suitable for industrial production. Detailed Implementation
[0021] The present invention will be further described below with reference to the embodiments. Unless otherwise specified, the raw materials used in the embodiments are all commercially available conventional raw materials; unless otherwise specified, the process methods used in the embodiments are all conventional methods in the art.
[0022] Example 1
[0023] Ethyl 4,4,4-trifluoroacetoacetate was prepared by the following method:
[0024] 1.5 mol of pyridine was dissolved in 360 g of chloroform. 1 mol of trifluoroacetyl chloride was added at a temperature not exceeding 0 °C, and the mixture was stirred for 0.5 h. Then, 1.5 mol of ethyl acetate was added, and the mixture was stirred at 25 °C for 3 h. The reactants were then washed with water, and the organic phase was dried over anhydrous sodium sulfate. Finally, chloroform was evaporated to obtain ethyl 4,4,4-trifluoroacetoacetate, weighing 173.5 g, with a yield of 94.3% (based on ethyl trifluoroacetate) and a GC purity of 98.2%.
[0025] Example 2
[0026] Ethyl 4,4,4-trifluoroacetoacetate was prepared by the following method:
[0027] 1.5 mol of pyridine was dissolved in 590 g of dichloromethane. 1 mol of trifluoroacetyl chloride was added at a temperature not exceeding 0 °C, and the mixture was stirred for 1 h. Then, 2 mol of ethyl acetate was added, and the mixture was stirred at 25 °C for 4 h. The reactants were then washed with water, and the organic phase was dried over anhydrous sodium sulfate. Finally, chloroform was evaporated to obtain ethyl 4,4,4-trifluoroacetoacetate, weighing 175.7 g, with a yield of 95.5% (based on ethyl trifluoroacetate) and a GC purity of 98.0%.
[0028] Example 3
[0029] Ethyl 4,4,4-trifluoroacetoacetate was prepared by the following method:
[0030] 3 mol of pyridine was dissolved in 800 g of tetrahydrofuran. 1 mol of trifluoroacetyl chloride was added at a temperature not exceeding 0 °C, and the mixture was stirred for 2 h. Then, 1.2 mol of ethyl acetate was added, and the mixture was stirred at 20 °C for 2 h. The reactants were then washed with water, and the organic phase was dried over anhydrous sodium sulfate. Finally, chloroform was evaporated to obtain ethyl 4,4,4-trifluoroacetoacetate, weighing 175.2 g, with a yield of 95.2% (based on ethyl trifluoroacetate) and a GC purity of 97.9%.
[0031] Example 4
[0032] Ethyl 4,4,4-trifluoroacetoacetate was prepared by the following method:
[0033] 1 mol of pyridine was dissolved in 300 g of cyclohexane. 1 mol of trifluoroacetyl chloride was added at a temperature not exceeding 0 °C, and the mixture was stirred for 3 h. Then, 1 mol of ethyl acetate was added, and the mixture was stirred at 30 °C for 6 h. The reactants were then washed with water, and the organic phase was dried over anhydrous sodium sulfate. Finally, chloroform was evaporated to obtain ethyl 4,4,4-trifluoroacetoacetate, weighing 172.2 g, with a yield of 93.6% (based on ethyl trifluoroacetate) and a GC purity of 97.4%.
[0034] Comparative Example 1
[0035] Compared with the synthesis method of ethyl 4,4,4-trifluoroacetoacetate disclosed in patent CN113072449A, Example 1 is as follows:
[0036] (1) Weigh 114.3g (1.0mol) of trifluoroacetone and 228.6g of toluene into a mixing bottle and stir well to make solution A; 110.2g (1.0mol) of ethyl chloroformate (content 98.5%) is used as solution B;
[0037] (2) Set the temperature of the pipeline reactor to 50℃ and the pressure to 0.5MPa. Set the flow rate of pump A to 8ml / min and the flow rate of pump B to 2ml / min. After the set temperature is reached, open the exhaust valve and the hydrogen chloride gas inlet valve to introduce hydrogen chloride gas. Open pump A to introduce a mixture of trifluoroacetone and toluene, and open pump B to introduce ethyl chloroformate.
[0038] (3) After 20 minutes, a sample was taken from the reactor outlet reaction liquid and the residual ethyl chloroformate was found to be 0.49%, indicating that the reaction was qualified;
[0039] (4) After the reaction was completed, the reaction solution was subjected to a first atmospheric distillation to recover toluene and a small amount of residual raw materials. The distillation endpoint temperature was 115℃. Then, a second vacuum distillation was performed to obtain 174g of ethyl 4,4,4-trifluoroacetoacetate with a GC purity of 97.2% and a pure yield of 92.0%.
[0040] Comparative Example 2
[0041] Compared with the preparation method of ethyl 4,4,4-trifluoroacetoacetate disclosed in patent CN103694119A, Example 1 is as follows:
[0042] At 25°C, 200 mL of anhydrous ethanol was added to the reactor, followed by 510 g (1.5 mol) of 20% sodium ethoxide ethanol solution, and then 105.6 g (1.2 mol) of ethyl acetate. The reaction solution was cooled to 5-10°C, and then 142 g (1.0 mol) of ethyl trifluoroacetate was added dropwise, controlling the temperature at 10-20°C. After the addition was complete, the temperature was raised to 60°C and reacted for 2 hours, then the reaction solution was cooled to 10-15°C. 166.6 g (1.7 mol) of concentrated sulfuric acid was added dropwise to the reaction solution, controlling the temperature at 20-30°C. After the addition was complete, the reaction was carried out at 30°C for 2.5 hours, yielding a turbid liquid containing sodium sulfate precipitate. The sodium sulfate precipitate was removed by filtration, the filter cake was washed with ethyl acetate, and the filtrate was subjected to vacuum distillation to obtain 157.0 g of ethyl trifluoroacetoacetate, with a yield of 85.3% (based on ethyl trifluoroacetate) and a purity of 95.2%.
Claims
1. A method for preparing ethyl 4,4,4-trifluoroacetoacetate, characterized in that: First, dissolve the alkali in an organic solvent, and add trifluoroacetyl chloride at a temperature not higher than 0°C for 0.5-3 hours; then add ethyl acetate and heat to 20-30°C for 2-6 hours to obtain ethyl 4,4,4-trifluoroacetoacetate. The molar ratio of trifluoroacetyl chloride to ethyl acetate is 1:(1-2). The base is pyridine, and the molar ratio of trifluoroacetyl chloride to the base is 1:(1-3).
2. The method for preparing ethyl 4,4,4-trifluoroacetoacetate according to claim 1, characterized in that: The organic solvent is at least one of dichloromethane, chloroform, tetrahydrofuran, toluene, and cyclohexane.
3. The method for preparing ethyl 4,4,4-trifluoroacetoacetate according to claim 2, characterized in that: The mass of the organic solvent is 3-5 times the mass of the alkali.
4. The method for preparing ethyl 4,4,4-trifluoroacetoacetate according to claim 1, characterized in that: After the reaction was complete, the reactants were washed with water, the organic phase was dried with anhydrous sodium sulfate, and finally the organic solvent was evaporated to obtain ethyl 4,4,4-trifluoroacetoacetate.