CN112142595B - Preparation method and purification method of ethyl 2,4, 5-trifluoro-benzoylacetate - Google Patents

Preparation method and purification method of ethyl 2,4, 5-trifluoro-benzoylacetate Download PDF

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CN112142595B
CN112142595B CN202011081643.5A CN202011081643A CN112142595B CN 112142595 B CN112142595 B CN 112142595B CN 202011081643 A CN202011081643 A CN 202011081643A CN 112142595 B CN112142595 B CN 112142595B
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陈林瑞
胡振宇
马难难
黄钰
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Jiangsu Hansyn Pharmaceutical Co ltd
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Abstract

The invention relates to the field of organic synthesis, and in particular relates to a preparation method and a purification method of 2,4,5 trifluoro-benzoyl ethyl acetate. The invention adopts 2,4,5 trifluoro-benzoic acid to perform acyl chlorination reaction with acyl chloride, then continuously reacts with ethyl acetoacetate in alkalescent solution to obtain an intermediate product, and the intermediate product is heated to remove acetyl, thus obtaining the 2,4,5 trifluoro-benzoyl ethyl acetate. The invention adopts a one-pot method, is easy to operate, only generates a small amount of waste residues in the reaction process, and effectively avoids intramolecular hydrogen bonds and chelate structures. The solvent can be recycled, the method is economical and environment-friendly, the conversion rate is high, and the industrial production is facilitated, and the invention also provides a purification method, so that impurities in the reaction process are effectively removed, and the product with the purity of more than 99.5% is prepared.

Description

Preparation method and purification method of ethyl 2,4, 5-trifluoro-benzoylacetate
Technical Field
The invention relates to the field of organic synthesis, and in particular relates to a preparation method and a purification method of 2,4,5 trifluoro-benzoyl ethyl acetate.
Background
Delafloxacin is a novel fluoroquinolone antibacterial drug special for animals, and the synthetic route of delafloxacin has been reported in documents, but the synthetic report of the intermediate, namely ethyl 2,4,5 trifluorobenzoylacetate, is less. However, the synthesis methods reported in the prior documents and patents require addition of a large amount of acid, generate a large amount of acidic wastewater, and the reaction solution forms hydrogen bonds under certain acidic conditions to undergo room temperature self-crosslinking, which makes separation and purification difficult. Is not suitable for large-scale industrial production.
As shown in the following formula, WO2006/113509, 2006, A2 patent discloses preparation of 2,4,5 ethyl trifluorobenzoylacetate (a method of a compound 1, the solvent dosage is large, hydrochloric acid needs to be added in the reaction process to adjust PH-2-3, a large amount of acid-containing wastewater is generated, a product is easy to form a hydrogen bond under a certain acidic condition to generate room-temperature self-crosslinking, a chelate is easy to form in a reaction system, separation and purification are difficult to perform, the post-treatment cost is high, and the environmental pressure is large, which is not favorable for scale-up production.
Figure BDA0002720013650000011
Figure BDA0002720013650000021
Disclosure of Invention
The invention aims to provide a preparation method and a purification method of 2,4,5 trifluoro-benzoyl ethyl acetate, which have the advantages of simple operation, high selectivity, economy, environmental protection and high conversion rate and are beneficial to industrial production.
In order to achieve the purpose, the invention specifically adopts the following technical scheme:
a preparation method of 2,4,5 trifluoro-benzoyl acetic ether comprises the following steps:
Figure BDA0002720013650000022
step (1): reacting 2,4,5 trifluorobenzoic acid shown in the formula 2 with acyl chloride under the action of a catalyst at the temperature of between 5 and 80 ℃ to obtain 2,4,5 trifluorobenzoyl chloride shown in the formula 3;
step (2): reacting 2,4,5 trifluorobenzoyl chloride shown in formula 3 with ethyl acetoacetate in a weak alkaline solution at the temperature of 0-5 ℃ to obtain an intermediate product shown in formula 4;
and (3): heating the intermediate product shown in the formula 4 obtained in the step (2) to 50-80 ℃ to remove acetyl, and recovering the solvent to obtain the 2,4,5 trifluoro-benzoyl ethyl acetate shown in the formula 1.
Preferably, the acid chloride in the step (1) is oxalyl chloride, and the step (1) is carried out under the condition of an organic solvent; or the acyl chloride is selected from thionyl chloride, and no solvent is added in the step (1) reaction.
Preferably, the base in step (2) is selected from one or more of calcium oxide, potassium carbonate, sodium hydroxide, potassium bicarbonate or sodium bicarbonate. The base described herein, i.e., the desired base in a weakly alkaline solution.
Preferably, the molar ratio of 2,4,5 trifluorobenzoyl chloride to base in step (2) is 1:0.1-0.25.
Preferably, the molar ratio of the 2,4,5 trifluorobenzoyl chloride to the weak base in step (2) is 1:0.1-0.2.
Preferably, the solvent of the weak alkaline solution in the step (2) is one or more selected from 1,2 dichloroethane, tetrahydrofuran and acetonitrile.
Preferably, the mass-to-volume ratio of the 2,4,5 trifluorobenzoyl chloride to the solvent in step (2) is 1:10. The mass-to-volume ratio is g/ml.
A method for purifying ethyl 2,4, 5-trifluorobenzoylacetate prepared by the above preparation method comprises the following steps: 2,4,5, decolorizing the crude product of the trifluoro-benzoyl ethyl acetate by activated carbon, and recrystallizing in an alcohol-water system to obtain a high-purity product, wherein the mass fraction of the alcohol in the alcohol-water system is 15-30%. The mass fraction of alcohol as used herein refers to the mass of alcohol/(mass of alcohol + water).
Preferably, the alcohol in the alcohol-water system is selected from methanol, ethanol or isopropanol.
Preferably, the specific steps of the purification are as follows:
a: dissolving crude ethyl 2,4, 5-trifluorobenzoylacetate in a soluble solvent, decolorizing with active carbon, filtering, and evaporating to remove the solvent;
b: b, dissolving the product obtained in the step B in an alcohol-water system, and heating to 50-80 ℃ to dissolve the product;
c: and C, cooling the solution obtained in the step C to room temperature, and then placing the solution in an ice bath for crystallization at 0-10 ℃ to obtain a pure product.
Advantageous effects
The invention has simple synthetic route and convenient post-treatment.
A small amount of hydrochloric acid gas is generated in the process of generating the compound shown in the formula 3 through the reaction, which is inevitable in other inventions, and the hydrochloric acid gas is treated by a tail gas absorption device. The subsequent two-step reaction is carried out under the alkalescent condition, a one-pot method is adopted, the operation is easy, only a small amount of waste residues are generated in the reaction process, intramolecular hydrogen bonds and chelate structures are effectively avoided, and the solvent can be recycled.
The crude product is refined by using a mixed system of alcohol and water in a certain proportion for recrystallization, and the fact that the compound 1 almost in a ketone structure can be prepared by using the mixed system of alcohol and water in a certain proportion for recrystallization is unexpectedly found, so that the method is economical, environment-friendly, high in conversion rate and beneficial to industrial production.
Drawings
FIG. 1 is a nuclear magnetic spectrum of mixtures 1 and 5 of example 3 of the present invention.
FIG. 2 is a liquid phase diagram of mixtures 1 and 5 of example 3 of the present invention.
FIG. 3 is a liquid phase diagram of mixtures 1 and 5 of example 4 of the present invention.
FIG. 4 is a liquid phase diagram of mixtures 1 and 5 of example 5 of the present invention.
FIG. 5 is a liquid phase diagram of mixtures 1 and 5 of example 6 of the present invention.
FIGS. 6A and 6B are liquid phase diagrams of mixtures 1 and 5 of example 7 of the present invention.
FIG. 7 is a liquid phase diagram of mixtures 1 and 5 of example 8 of the present invention.
FIG. 8 is a liquid phase diagram of mixtures 1 and 5 of example 9 of the present invention.
FIG. 9 is a liquid phase diagram of Compound 1 of example 10 of the present invention.
FIG. 10 is a liquid phase diagram of Compound 1 of example 11 of the present invention.
FIG. 11 is a liquid phase diagram of Compound 1 of example 12 of the present invention.
FIG. 12 is a liquid phase diagram of Compound 1 of example 13 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The relative arrangement of the components and steps, the numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless it is specifically stated otherwise. Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.
Summary of the invention 1 H-NMR spectrum Bruker-400 NMR spectrometer with chemical shifts in parts per million and internal standard tetramethylsilane. The coupling constant (J) is close to 0.1Hz. The abbreviations used are as follows: s, single peak; d, doublet peak; t, triplet; q, quartet; qu, quintet; m, multiplet; br, broad peak.
The liquid chromatograph adopts an Agilent 1220InfinityII liquid chromatographic system, and the specific analysis method is as follows:
taking a proper amount of sample, adding diluent (ACN: H) 2 O = 8: 2) to prepare a solution containing about 1.0mg of the test solution per 1 ml; performing high performance liquid chromatography (China pharmacopoeia 2015 edition general rules 0512) with Welch xtime C18.6 × 150mm,3.5 μm or other equivalent chromatographic columns; at 10mM K 2 HPO 4 (pH = 6.8) aqueous solution as mobile phase a and acetonitrile as mobile phase B; the column temperature was 35 ℃; flow rate 1.0ml per minute; the detection wavelength is 240nm; gradient elution was performed as follows:
Figure BDA0002720013650000051
Figure BDA0002720013650000061
precisely measuring 20 mu l of test solution, injecting into a liquid chromatograph, and recording chromatogram; the single and total impurity contents were calculated and reported according to peak area normalization.
The present invention is described in detail below with reference to the attached drawings to facilitate the understanding of the present invention by those skilled in the art.
Figure BDA0002720013650000062
EXAMPLE 1 preparation of Compound 3
Figure BDA0002720013650000063
2, synthesis of 4,5 trifluorobenzoyl chloride (3): in a three-neck flask with a reflux condenser pipe and magnetic stirring, a drying pipe is arranged at the top of the condenser pipe, a tail gas absorption device is connected, 5% sodium hydroxide is used for absorbing tail gas, then 100g (0.57 mol) of 2,4,5, trifluorobenzoic acid and 80mL of dichloromethane are sequentially added, 1-2 drops of DMF (dimethyl formamide) are added as a catalyst, stirring is started, 79.31g (0.63 mol) of oxalyl chloride is added dropwise for about 30min, after the dropwise addition is finished, the solution is stirred for 3h at room temperature and becomes clear and transparent, a small amount of reaction liquid is taken and added with methanol for quenching, and Thin Layer Chromatography (TLC) monitoring is carried out (a developing agent system EtO-Ac/PE/HOAc (volume ratio) = 20/10/1). After the reaction is finished, the reaction liquid is cooled to room temperature, then the solvent and low-boiling-point impurities are evaporated in a rotary manner under the conditions of 40 ℃ and 0.1MPa, and the solvent is directly recovered and reused, so that 110.4g of light yellow liquid is obtained, and the molar yield is 100%.
EXAMPLE 2 preparation of Compound 3
Figure BDA0002720013650000071
2,4,5 Synthesis of trifluorobenzoyl chloride 3: in a three-neck flask with a reflux condenser pipe and magnetic stirring, a drying pipe is arranged at the top of the condenser pipe, a tail gas absorption device is connected, 5% sodium hydroxide is used for absorbing tail gas, then 100g (0.57 mol) of 2,4,5, trifluorobenzoic acid are sequentially added, then 101.5g (0.85m01) of thionyl chloride is added as a solvent, 1-2 drops of DMF are added as a catalyst, reflux stirring is carried out for 3 hours, the solution becomes clear and transparent, a small amount of reaction liquid is taken and added with methanol for quenching, and Thin Layer Chromatography (TLC) monitoring is carried out (a developing agent system EtO-Ac/PE/HOAc (volume ratio) = 20/10/1). After the reaction is finished, the reaction liquid is cooled to room temperature, and then thionyl chloride is evaporated in a rotary manner under the conditions of 40 ℃ and 0.1MPa to obtain 109g of light yellow liquid with the yield of 98.6 percent
EXAMPLE 3 preparation of mixtures of Compounds 1 and 5
Figure BDA0002720013650000072
A1000 ml three-neck flask was charged with 500ml acetonitrile, 7.8g (0.057 mol) potassium carbonate in sequence, cooled in ice bath at a temperature of 0 to 5 ℃ to add 81.25g (0.625 mol) ethyl acetoacetate, stirred for 1h, and 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 was added dropwise at a temperature of 0 ℃ to 5 ℃ over 30 min. And (2) keeping the temperature at about 5 ℃ for 2h, then raising the temperature to room temperature to obtain the compound shown in the formula 4, continuously heating to 70 ℃ without any post-treatment, reacting for 5h, cooling to room temperature after sampling TLC (thin layer chromatography) intermediate control, filtering to remove residues, recovering the solvent to obtain 136.6g of crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 97.3%, and HPLC (high performance liquid chromatography) detection shows that the compound 5: the ratio of compound 1 was 75: 24. The NMR spectrum of the crude product is shown in FIG. 1, and the liquid chromatogram of the crude product is shown in FIG. 2. Nuclear magnetic data:
1 H-NMR(400MHz，CDCl 3 )，δ1.25-1.32(3H，m)，3.92-3.93(1H，d，4.0Hz)，4.17-4.28(2H，m)，6.98-7.04(1H，m)，7.68-7.82(1H，m)。
EXAMPLE 4 preparation of mixtures of Compounds 1 and 5
Figure BDA0002720013650000081
500ml of acetonitrile and 15.6g (0.114 mol) of potassium carbonate are sequentially added into a 1000ml three-neck flask, the temperature of an ice bath is controlled to be 0-5 ℃, 81.25g (0.625 mol) of ethyl acetoacetate is added, the mixture is stirred for 1h, 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 is added dropwise, the temperature of the dropwise adding process is controlled to be 0-5 ℃, and the adding process is finished for 30 min. Keeping the temperature at about 5 ℃ for 2h, then raising the temperature to room temperature to obtain a compound 4, heating the compound 4 to 70 ℃ without any post-treatment, reacting for 5h, cooling the compound to room temperature after sampling TLC (thin layer chromatography) control, filtering to remove residues, recovering the solvent to obtain 134.0g of a crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 92.6%, and HPLC (high performance liquid chromatography) detects the compound 5: the ratio of compound 1 was 79: 19. The liquid chromatogram of the crude product is shown in FIG. 3.
EXAMPLE 5 preparation of Compound 1 and Compound 5 mixtures
Figure BDA0002720013650000082
A1000 ml three-neck flask was charged with 500ml dichloroethane, 7.8g (0.057 mol) potassium carbonate in that order, cooled in ice bath at a temperature of 0 ℃ to 5 ℃, 81.25g (0.625 mol) ethyl acetoacetate was added, stirred for 1 hour, 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 was added dropwise, and the addition was programmed to 0 to 5 ℃ for 30 min. Keeping the temperature at about 5 ℃ for 2h, and then heating to room temperature to obtain a compound 4. Then heating to 70 ℃ without any post-treatment, reacting for 5h, sampling, carrying out TLC (thin layer chromatography), cooling to room temperature, filtering to remove residues, recovering the solvent to obtain 135.8g of a crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 96.7 percent, HPLC (high performance liquid chromatography) shows that the compound is almost the compound 5, the purity is more than 95 percent, and a liquid chromatogram of a crude product is shown in figure 4.
EXAMPLE 6 preparation of a mixture of Compound 1 and Compound 5
Figure BDA0002720013650000091
500ml of dichloroethane and 15.6g (0.114 mol) of potassium carbonate are sequentially added into a 1000ml three-neck flask, the temperature of ice bath is controlled to be 0-5 ℃, 81.25g (0.625 mol) of ethyl acetoacetate is added, stirring is carried out for 1h, 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 is added dropwise, the temperature of the dropwise adding process is controlled to be 0-5 ℃, and the addition is finished for 30 min. Keeping the temperature at about 5 ℃ for 2h, and then heating to room temperature to obtain a compound 4. Heating to 70 ℃ without any post-treatment, reacting for 5h, cooling to room temperature after sampling TLC (thin layer chromatography), filtering to remove residues, recovering the solvent to obtain 134.9g of a crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 96.1 percent, and HPLC (high performance liquid chromatography) detects the compound 5: the ratio of compound 1 was 79: 17. The liquid chromatogram of the product is shown in FIG. 5.
EXAMPLE 7 preparation of a mixture of Compound 1 and Compound 5
Figure BDA0002720013650000092
500ml of acetonitrile and 6.1g (0.057 mol) of sodium carbonate are sequentially added into a 1000ml three-neck flask, the temperature is controlled at 0-5 ℃ in an ice bath, 81.25g (0.625 mol) of ethyl acetoacetate is added, the mixture is stirred for 1h, 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 is added dropwise, the temperature is controlled at 0-5 ℃ in the dropwise adding process, and the adding process is finished for 30 min. Keeping the temperature at about 5 ℃ for 2h, and then heating to room temperature to obtain a compound 4. Heating at 70 ℃ without any post-treatment, reacting for 5h, sampling, performing TLC (thin layer chromatography) for central control, cooling to room temperature, filtering to remove residues, recovering the solvent to obtain 136.8g of crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 98.2%, and detecting the compound 5 by HPLC: liquid chromatograms of crude product at 54: 44 ratio of compound 1 are shown in fig. 6A and 6B.
EXAMPLE 8 preparation of a mixture of Compound 1 and Compound 5
Figure BDA0002720013650000093
500ml of acetonitrile and 12.2g (0.114 mol) of sodium carbonate are sequentially added into a 1000ml three-neck flask, the temperature of an ice bath is controlled to be 0-5 ℃, 81.25g (0.625 mol) of ethyl acetoacetate is added, the mixture is stirred for 1h, 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 is added dropwise, the temperature of the dropwise adding process is controlled to be 0-5 ℃, and the adding process is finished for 30 min. Keeping the temperature at about 5 ℃ for 2h, then heating to room temperature, keeping the temperature for 5h to obtain a compound 4. The reaction system is heated to 70 ℃ without any post-treatment, reacting for 5h, cooling to room temperature after sampling TLC (thin layer chromatography) central control, filtering to remove residues, recovering the solvent to obtain 138.6g of a crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 98.4%, and the HPLC (high performance liquid chromatography) detects the compound 5: the compound 1 ratio was 24: 75. The liquid chromatogram of the crude product is shown in FIG. 7.
EXAMPLE 9 preparation of a mixture of Compound 1 and Compound 5
Figure BDA0002720013650000101
500ml of tetrahydrofuran and 15.3g (0.143 mol) of sodium carbonate are sequentially added into a 1000ml three-neck flask, the temperature is controlled at 0-5 ℃ in an ice bath, 81.25g (0.625 mol) of ethyl acetoacetate is added, the mixture is stirred for 1h, 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 is added dropwise, the temperature is controlled at 0-5 ℃ in the dropwise adding process, and the adding process is finished for 30 min. Keeping the temperature at about 5 ℃ for 2h, then heating to room temperature, and keeping the temperature for 5h to obtain a compound 4. And (2) heating the reaction system to 70 ℃ without any post-treatment, reacting for 5h, performing sampling TLC (thin layer chromatography) for central control, cooling to room temperature, filtering to remove residues, recovering the solvent to obtain 130.9g of a crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 93.3%, and HPLC (high performance liquid chromatography) detection shows that the compound 5: the liquid chromatogram of the crude product with compound 1 ratio of 69: 20 is shown in FIG. 8.
EXAMPLE 10 preparation of a mixture of Compound 1 and Compound 5
Figure BDA0002720013650000102
500ml of acetonitrile and 2.28g (0.057 mol) of sodium hydroxide are sequentially added into a 1000ml three-neck flask, 81.25g (0.625 mol) of ethyl acetoacetate are added into the three-neck flask under the ice bath temperature controlled at 0-5 ℃, the mixture is stirred for 1h, 110.4g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method of example 1 is added dropwise, and the temperature of the dropwise adding process is controlled at 0-5 ℃ for 30 min. Keeping the temperature at about 5 ℃ for 2h, then heating to room temperature, keeping the temperature for 5h to obtain a compound 4, heating the reaction system at 70 ℃ without any post-treatment, reacting for 5h, and obtaining a complex system after sample TLC (thin layer chromatography) central control. Cooling to room temperature, filtering to remove residues, recovering the solvent to obtain 100.0g of crude enol isomeric mixture of the compound 1 and the compound 5, wherein the yield is 71.3 percent, and HPLC detection shows that the compound 5: compound 1 ratio 77: 12. The liquid chromatogram of the crude product is shown in FIG. 9.
Example 11
Refining of the product
50g of the crude enol isomers of the compound 1 and the compound 5 prepared in example 3 and 100ml of toluene are dissolved, 5g of activated carbon is added for decolorization, the activated carbon is removed by filtration, the filtrate is dried by spinning, 350ml of 20% ethanol is added and heated to about 70 ℃ for clearing, the temperature is naturally reduced under stirring, crystals are separated out at about 45 ℃, the crystals are naturally cooled to room temperature and then placed in an ice bath for crystallization at 0-10 ℃ for 1h, the white crystals are obtained by filtration for 48.2g, the yield is 96.4%, the HPLC purity is more than 99.5%, and the liquid chromatogram of the refined product is shown in FIG. 10.
Example 12
Refining of the product
50g of enol isomeric crude products of the compound 1 and the compound 5 in the embodiment 3 and 100ml of toluene are dissolved, 5g of activated carbon is added for decolorization, the activated carbon is removed by filtration, the filtrate is dried by spinning, 350ml of 20 percent methanol is added for heating and clearing at about 70 ℃, the temperature is naturally reduced under stirring, crystals are separated out at about 48 ℃, the crystals are naturally cooled to room temperature and placed in an ice bath for crystallization for 1h at 0-10 ℃, 48.6g of white crystals are obtained by filtration, the yield is 97.2 percent, the HPLC purity is more than 99.5 percent, and the liquid chromatogram of the refined product is shown in figure 11.
Example 13
Refining of the product
50g of enol isomeric crude products of the compound 1 and the compound 5 in the embodiment 4 and 100ml of ethyl acetate are dissolved, 5g of activated carbon is added for decoloration, the activated carbon is removed by filtration, the filtrate is dried by spinning, 350ml of 30 percent isopropanol is added, the solution is heated to about 70 ℃ for clearing, the temperature is naturally reduced under stirring, crystals are separated out at about 40 ℃, the crystals are naturally cooled to the room temperature, the crystals are placed in an ice bath for crystallization for 1h at 0-10 ℃, 47.9g of white crystals are obtained by filtration, the yield is 95.8 percent, the HPLC purity is more than 99.5 percent, and the liquid chromatogram of the refined product is shown in figure 12.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the present invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention.

Claims (7)

1. A preparation method of ethyl 2,4, 5-trifluorobenzoylacetate is characterized by comprising the following steps:
Figure FDA0003844045080000011
step (1): reacting 2,4,5 trifluorobenzoic acid shown in the formula 2 with acyl chloride under the action of a catalyst at the temperature of between 5 and 80 ℃ to obtain 2,4,5 trifluorobenzoyl chloride shown in the formula 3;
step (2): reacting 2,4,5 trifluorobenzoyl chloride shown in the formula 3 with ethyl acetoacetate in a weak alkaline solution at the temperature of 0-5 ℃ to obtain an intermediate product shown in the formula 4; wherein, the alkali of the alkalescent solution is selected from one or more of calcium oxide, potassium carbonate, sodium hydroxide, potassium bicarbonate or sodium bicarbonate, and the solvent of the alkalescent solution is selected from one or more of 1,2 dichloroethane, tetrahydrofuran and acetonitrile;
and (3): heating the intermediate product shown in the formula 4 obtained in the step (2) to 50-80 ℃ to remove acetyl, and recovering the solvent to obtain the 2,4,5 trifluoro-benzoyl ethyl acetate shown in the formula 1.
2. The preparation method according to claim 1, wherein the acid chloride in step (1) is oxalyl chloride, and step (1) is carried out under organic solvent conditions; or the acyl chloride is selected from thionyl chloride, and no solvent is added in the step (1) reaction.
3. The method according to claim 1, wherein the molar ratio of 2,4,5 trifluorobenzoyl chloride to base in step (2) is 1:0.1-0.25.
4. The method according to claim 3, wherein the molar ratio of 2,4,5 trifluorobenzoyl chloride to weak base in step (2) is 1:0.1-0.2.
5. The method according to claim 1, wherein the mass-to-volume ratio of the 2,4,5 trifluorobenzoyl chloride to the solvent in step (2) is 1:10.
6. a process for purifying ethyl 2,4, 5-trifluorobenzoylacetate prepared according to any of claims 1 to 5, comprising the steps of: decolorizing the crude product of 2,4,5 trifluoro-benzoyl ethyl acetate by activated carbon, and recrystallizing in an alcohol-water system to obtain a high-purity product, wherein the mass fraction of alcohol in the alcohol-water system is 15-30%, and the alcohol in the alcohol-water system is selected from methanol, ethanol or isopropanol.
7. The purification method according to claim 6, wherein the specific steps of the purification are as follows:
a: dissolving crude ethyl 2,4, 5-trifluorobenzoylacetate in a soluble solvent, decolorizing with active carbon, filtering, and evaporating to remove the solvent;
b: b, dissolving the product obtained in the step B in an alcohol-water system, and heating to 50-80 ℃ for dissolving;
c: and D, cooling the solution obtained in the step C to room temperature, and then placing the solution in an ice bath for crystallization at 0-10 ℃ to obtain a pure product.
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