Improved synthesis process of methyl 2-chloro-4-fluoro-5-aminobenzoate

Abstract

The invention discloses an improved synthesis process of methyl 2-chloro-4-fluoro-5-aminobenzoate, and belongs to the field of fine chemical engineering. According to the method, 2-chloro-4-fluoro-5-nitryl trichloromethyl benzene is taken as a raw material, and three-step reaction of hydrolysis, esterification and reduction is carried out. In the first-step hydrolysis reaction, due to the existence of metal iron ions, Friedel-Crafts acylation reaction is catalyzed and initiated, and a product part is self-polymerized to generate tar, so that the yield is reduced. In order to avoid the situation, a chelating agent is introduced to be complexed with metal ions, the catalytic ability of the metal ions is shielded, and the yield is greatly improved. The chelating agent has the advantages that the chelating agent is common in market, chelating conditions are easy to achieve, practicability is high, tar can be greatly reduced after chelating, reaction operation is simple and convenient, reaction yield and product purity are high and the like, and the chelating agent is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of fine chemicals, and particularly relates to an improved synthesis process of methyl 2-chloro-4-fluoro-5-aminobenzoate. Background Art

[0002] Sulfentrazone is a protoporphyrinogen oxidase (PPO) inhibitor herbicide developed by BASF, which has excellent control effects against resistant broad-leaved weeds and is applicable to a variety of crops. Its chemical structural formula is:

[0003]

[0004] Sulfentrazone can be used as a non-selective herbicide, which can effectively control a variety of broad-leaved weeds, including weeds resistant to glyphosate, ALS and triazines. It has many characteristics such as fast non-selective action, long residual period, low volatility, safe for crops and rapid degradation of soil residues, and is applicable to a variety of production systems and non-cultivated land. Its activity is very high, and excellent herbicidal effects can be achieved with very small doses, and the dosage of the active ingredient is 18 - 125 g / ha. It can be mixed with herbicides for gramineous weeds (such as glyphosate) with good effects, and can be applied in a variety of crop fields and non-cultivated land, with little rotation restriction.

[0005] As an important intermediate for the synthesis of sulfentrazone, methyl 2-chloro-4-fluoro-5-aminobenzoate currently has few domestic manufacturers, but the market demand for this product continues to increase, and the market prospect is good. There are two common processes for producing methyl 2-chloro-4-fluoro-5-aminobenzoate:

[0006] A. Using 2-chloro-4-fluoro-trichloromethylbenzene as the raw material, through nitration, hydrolysis, acyl chlorination with thionyl chloride, esterification and reduction reactions to obtain the target product; this process route is long, toxic, with low yield, and because thionyl chloride is used, a large amount of sulfur dioxide and hydrogen chloride gases are generated, which are not easy to absorb, and the three wastes are high, but off-white methyl 2-chloro-4-fluoro-5-aminobenzoate can be obtained;

[0007] B. Using 2-chloro-4-fluoro-5-nitro-trichloromethylbenzene as the raw material, through hydrolysis, esterification and reduction reactions to obtain the target product. Although this process has a short route and high yield, due to the incomplete removal of ferric trichloride added, the color of the obtained methyl 2-chloro-4-fluoro-5-aminobenzoate is gray-brown.

[0008] Therefore, it is necessary to develop a synthesis process of methyl 2-chloro-4-fluoro-5-aminobenzoate suitable for industrial production. Summary of the Invention

[0009] To solve the above technical problems, the present invention provides a method for removing iron ions from methyl 2-chloro-4-fluoro-5-aminobenzoate using a chelating agent. The method involves three steps of hydrolysis, esterification, and reduction starting from 2-chloro-4-fluoro-5-nitrobenzotrichloride. During the first hydrolysis reaction, since metal iron ions are added as a catalyst and it is inevitable to introduce metal ions due to factors such as equipment or raw material quality during the production process, and even after purification by methods such as washing with water, washing with alkali, or recrystallization, there will still be trace amounts of metal ions remaining, resulting in a dark-colored product. To avoid this situation, a chelating agent is introduced to complex with the metal ions to remove the metal ions and obtain methyl 2-chloro-4-fluoro-5-aminobenzoate with a lighter color.

[0010] An improved synthesis process of methyl 2-chloro-4-fluoro-5-aminobenzoate according to the present invention is completed through three steps of hydrolysis, esterification, and reduction using 2-chloro-4-fluoro-5-nitrobenzotrichloride as a raw material. The reaction equation is expressed as:

[0011]

[0012] This process is the main process for producing methyl 2-chloro-4-fluoro-5-aminobenzoate at present. However, the product obtained by this process has a relatively dark color, being gray-brown. Through in-depth comparative experimental studies, it is found that this is due to the presence of trace amounts of metal iron ions in the product.

[0013] As a catalyst for the reaction, metal iron ions must be added to the reaction system and cannot be avoided. And during the water washing and alkali washing processes after the esterification reaction, the iron ions still cannot be completely removed. Although it does not affect the normal progress of the reduction reaction, it will be reflected in the color of the final product.

[0014] The improved synthesis process of methyl 2-chloro-4-fluoro-5-aminobenzoate described in the present invention includes the following steps: using 2-chloro-4-fluoro-5-nitrobenzotrichloride as a raw material, after hydrolysis and esterification reactions, when the reactions are completed, a chelating agent is added for sufficient complexation, followed by water washing, alkali washing, and layering. After the oil layer is replaced with a solvent, a reduction reaction is carried out to obtain methyl 2-chloro-4-fluoro-5-aminobenzoate.

[0015] Further, in the above technical solution, the chelating agent is selected from one or more of ethylenediaminetetraacetic acid and its sodium salt (EDTA), diethylenetriaminepentaacetic acid and its sodium salt (DTPA), ethylenediaminetetramethylenephosphonic acid and its sodium salt (EDTMPA), 1,2-cyclohexanediaminetetraacetic acid and its sodium salt (DCTA), and ethylenediaminedi(o-phenylacetic acid) and its sodium salt (EDDHA).

[0016] Further, in the above technical solution, the metal chelating agent is preferably sodium ethylenediaminetetraacetate or sodium diethylenetriaminepentaacetate.

[0017] Further, in the above technical solution, the dosage of the chelating agent is 0.005-0.05% of the weight of 2-chloro-4-fluoro-5-nitrobenzotrichloride.

[0018] Further, in the above technical solution, the dosage of the chelating agent is preferably 0.01-0.02% of the weight of 2-chloro-4-fluoro-5-nitrobenzotrichloride.

[0019] Further, in the above technical solution, the method for detecting metal ions in the reaction solution is atomic absorption spectrometry, yellow prussiate of potash colorimetry or inductively coupled plasma-mass spectrometry.

[0020] Further, in the above technical solution, the reaction operation is as follows: Add 2-chloro-4-fluoro-5-nitrobenzotrichloride, ferric trichloride, and 1,2-dichloroethane to the reaction kettle, raise the temperature, then dropwise add water. After the addition is complete, keep the temperature constant and take samples for detection. After the reaction is completed, lower the temperature of the kettle, start to dropwise add methanol for the esterification reaction. After the addition is complete, keep the temperature constant and take samples for detection. After the reaction is completed, distill and recover the excess methanol. After distillation, add the chelating agent, stir well for complexation, then add water and sodium bicarbonate aqueous solution for washing and layering successively. Concentrate the oil layer to distill out dichloroethane, add methanol, raise the temperature and stir until completely dissolved and clear; Transfer the reaction solution while it is hot to an autoclave, add palladium-carbon catalyst; After purging with hydrogen, carry out the hydrogenation reduction reaction. After the reaction is completed, vent and filter while it is hot. Concentrate the mother liquor to remove the solvent, then add methanol aqueous solution for recrystallization, suction filtration, and drying to obtain white solid methyl 2-chloro-4-fluoro-5-aminobenzoate. Specific Embodiments

[0021] The following non-limiting examples can enable those of ordinary skill in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. The test methods described in the examples are all conventional methods unless otherwise specified; the reagents and materials are all commercially available unless otherwise specified.

[0022] Comparative Example 1 (This example is a traditional operation process without adding a chelating agent)

[0023] Add 150 g of 2-chloro-4-fluoro-5-nitrobenzotrichloride, 0.45 g of ferric trichloride, and 150 g of 1,2-dichloroethane to a 500 ml reaction kettle, raise the temperature to 90-100 °C for initiation. After successful initiation, slowly dropwise add water at this temperature. After the addition is complete, keep the temperature constant until no gas is released and take samples for detection. When the remaining raw materials are ≤ 0.5%, it is considered that the reaction is completed, and lower the temperature of the reaction kettle to 55-65 °C.

[0024] After the temperature reduction is completed, methanol is added dropwise for esterification. After the addition is complete, it is kept warm until no gas is evolved for detection. After the reaction ends, methanol is recovered by distillation, and the temperature is reduced to 25 - 35°C for water washing and alkali washing. The oil layer is concentrated to distill out dichloroethane, methanol is added and the temperature is raised to 40 - 60°C and stirred until completely dissolved. The reaction solution is all transferred to an autoclave, and 1.5 g of 10% Pd / C catalyst is added for hydrogenation reduction reaction (0.2 MPa). After the reaction shows no pressure drop, a sample is taken for analysis. When 10% of the intermediate remains, the catalyst is filtered off while it is hot. After the mother liquor is concentrated to remove methanol, 75% methanol aqueous solution is added for recrystallization. After the filter cake is dried, 87 g of methyl 2-chloro-4-fluoro-5-aminobenzoate is obtained, with a content of 99%. The total yield of the three steps is 85%, and the color of the product is grayish brown.

[0025] Example 1

[0026] 150 g of 2-chloro-4-fluoro-5-nitrobenzotrichloride, 0.45 g of ferric trichloride, and 150 g of 1,2-dichloroethane are added to a 500 ml reaction kettle, and the temperature is raised to 90 - 100°C for initiation. After successful initiation, water is slowly added dropwise at this temperature. After the addition is complete, it is kept warm until no gas is evolved for sampling and detection. When the remaining raw material is ≤0.5%, the reaction is considered to have ended. The temperature of the reaction kettle is reduced to 55 - 65°C, and methanol is added dropwise for esterification. After the addition is complete, it is kept warm until no gas is evolved for detection. After the reaction ends, methanol is recovered by distillation, 0.03 g of chelating agent sodium ethylenediaminetetraacetate is added, and it is stirred at 55 - 65°C for 2 h for full complexation;

[0027] After the complexation is completed, the temperature is reduced to 25 - 35°C for water washing and alkali washing. The oil layer is concentrated to distill out dichloroethane, methanol is added and the temperature is raised to 40 - 60°C and stirred until completely dissolved. The reaction solution is all transferred to an autoclave, and 1.5 g of 10% Pd / C catalyst is added for hydrogenation reduction reaction (0.2 MPa). After the reaction shows no pressure drop, a sample is taken for analysis and no raw material or intermediate remains. The catalyst is filtered off while it is hot. After the mother liquor is concentrated to remove methanol, 75% methanol aqueous solution is added for recrystallization. After the filter cake is dried, 86.7 g of methyl 2-chloro-4-fluoro-5-aminobenzoate is obtained, with a content of 99%. The total yield of the three steps is 84.7%, and the color of the product is white.

[0028] Example 2

[0029] Add 150 g of 2-chloro-4-fluoro-5-nitrobenzotrichloride, 0.45 g of ferric chloride, and 150 g of 1,2-dichloroethane into a 500 ml reaction kettle. Heat up to 90 - 100 °C for initiation. After successful initiation, slowly add water dropwise at this temperature. After the addition is complete, keep warm until no gas is evolved and then take a sample for detection. When the remaining raw materials ≤ 0.5% is regarded as the end of the reaction. Cool the reaction kettle to 55 - 65 °C, and start to add methanol dropwise for esterification. After the addition is complete, keep warm until no gas is evolved and then detect. After the reaction is over, distill and recover methanol. Add 0.15 g of chelating agent diethylenetriamine pentaacetic acid sodium, and stir at 55 - 65 °C for 2 h for full complexation;

[0030] After the complexation is complete, cool down to 25 - 35 °C for water washing and alkali washing. Concentrate the oil layer to distill out dichloroethane, add methanol and heat up to 40 - 60 °C and stir until completely dissolved. Transfer all the reaction solution into an autoclave, add 1.5 g of 10% Pd / C catalyst for hydrogenation reduction reaction (0.2 MPa). After the reaction has no pressure drop, take a sample for analysis and there is no remaining raw material and intermediate. Filter out the catalyst while it is hot. After the mother liquor is concentrated to remove methanol, then add 75% methanol aqueous solution for recrystallization. After the filter cake is dried, 87.6 g of methyl 2-chloro-4-fluoro-5-aminobenzoate is obtained, with a content of 99%. The total yield of the three steps is 85.6%. The color of the product is white.

[0031] The above examples describe the main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above examples. What is described in the above examples and the specification only illustrates the principle of the present invention. Without departing from the principle of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. An improved synthesis process of methyl 2-chloro-4-fluoro-5-aminobenzoate, characterized in that: The following steps are involved: 2-Chloro-4-fluoro-5-nitrotrichloromethylbenzene is used as a raw material, and after hydrolysis and esterification reactions, a chelating agent is added for full complexation, and the product is washed with water and alkali to separate the layers. After the oil layer replaces the solvent, a reduction reaction is performed to obtain methyl 2-chloro-4-fluoro-5-aminobenzoate.

2. The improved synthesis process of 2-chloro-4-fluoro-5-aminobenzoic acid methyl ester according to claim 1, characterized in that: The chelating agent is selected from one or more of ethylenediaminetetraacetic acid and its sodium salt, diethylenetriaminepentaacetic acid and its sodium salt, ethylenediaminetetramethylenephosphonic acid and its sodium salt, 1,2-cyclohexanediaminetetraacetic acid and its sodium salt, and ethylenediaminedi-o-phenylacetic acid and its sodium salt.

3. The improved synthesis process of 2-chloro-4-fluoro-5-aminobenzoic acid methyl ester according to claim 2, characterized in that: The chelating agent is selected from sodium ethylenediaminetetraacetate or sodium diethylenetriaminepentaacetate.

4. The improved synthesis process of 2-chloro-4-fluoro-5-aminobenzoic acid methyl ester according to claim 1, characterized in that: The amount of the chelating agent is 0.005-0.05% of the weight of 2-chloro-4-fluoro-5-aminobenzoic acid methyl ester.

5. The improved synthesis process of 2-chloro-4-fluoro-5-aminobenzoic acid methyl ester according to claim 4, characterized in that: The amount of the chelating agent is preferably 0.01-0.02% by weight of 2-chloro-4-fluoro-5-nitrotrichloromethylbenzene.

6. The method for removing iron ions from methyl 2-chloro-4-fluoro-5-aminobenzoate by using a chelating agent according to claim 1, characterized in that: The metal ions in the reaction solution are detected by atomic absorption spectrometry, hematoxylin colorimetry or inductively coupled plasma-mass spectrometry.

7. The method for removing iron ions from methyl 2-chloro-4-fluoro-5-aminobenzoate by using a chelating agent according to claim 1, characterized in that: The reaction operation is as follows: 2-chloro-4-fluoro-5-nitrotrichloromethylbenzene, ferric chloride and 1,2-dichloroethane are added to the reaction kettle, water is added dropwise after the temperature is raised, and sampling is performed at the temperature after the addition is completed. After the reaction is completed, the kettle temperature is lowered, and methanol is added dropwise for esterification reaction. After the addition is completed, sampling is performed at the temperature after the addition is completed. After the reaction is completed, the excess methanol is distilled and recovered, and a chelating agent is added after the distillation, and the complexation is fully stirred. Water and sodium bicarbonate aqueous solution are added successively for washing and stratification, and the oil layer is concentrated to evaporate the dichloroethane, and methanol is added to heat and stir until all the solvents are dissolved. The reaction solution is transferred into an autoclave while hot, and a palladium carbon catalyst is added. After hydrogen replacement, a hydrogenation reduction reaction is performed, and after the reaction is completed, the solution is vented while hot. The mixture was filtered, the mother liquor was concentrated to remove the solvent, and then methanol aqueous solution was added for recrystallization, suction filtration and drying to obtain methyl 2-chloro-4-fluoro-5-aminobenzoate as a white solid.

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