Process for producing o-aminobenzene methyl ester

Abstract

The invention discloses a process for producing o-aminobenzene methyl ester, and relates to the technical field of synthesis of medical organic matters. According to the process for producing the o-aminobenzene methyl ester, the o-aminobenzene methyl ester mainly comprises the following components in parts by weight: 66-70 parts of phthalic anhydride, 22-27 parts of ammonium nitrate, 36-42 parts of ammonia water, 27-30 parts of a copper hydroxide solution, 64-68 parts of a sodium hydroxide solution, 300 parts of methanol, 63-66 parts of a sodium hypochlorite solution and 4-6 parts of vitamin C. According to the invention, heat accumulation in the synthesis process can be inhibited, the risk of thermal runaway during batch production of o-aminobenzene methyl ester is prevented, heat in the synthesis process is reduced, an operator can conveniently control the temperature in the synthesis process, and the safety in the preparation process of o-aminobenzene methyl ester is improved. In addition, the content and yield of the obtained o-aminobenzene methyl ester can be further improved, and the yield is increased.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical organic compound synthesis, in particular to a process for producing o-aminobenzyl ester. Background Art

[0002] Methyl anthranilate, also known as methyl anthranilate, is an organic compound with the molecular formula C8H9NO2. It occurs as a colorless crystal or pale yellow liquid with a grape-like odor. It changes color with prolonged exposure to light and evaporates with water vapor. It is readily soluble in ethanol and ether. Methyl anthranilate has applications in biomedicine, including the production of the nonsteroidal anti-inflammatory analgesic mefenamic acid, the synthesis of vitamin L, the antiarrhythmic drug quinolones, and non-barbiturate hypnotics.

[0003] At present, there are two main synthetic routes for methyl anthranilate. One is to directly esterify anthranilic acid and methanol under the catalysis of concentrated sulfuric acid to obtain methyl anthranilate; the other is the phthalic anhydride method, that is, phthalic anhydride and ammonia water undergo amidation reaction and then esterify to obtain methyl anthranilate.

[0004] Among them, the first is a reversible reaction, which will lead to incomplete reaction and affect the yield and purity of the product; the second has problems such as difficult to control reaction conditions, many unstable factors, and the occurrence of side reactions, which will lead to reduced product yield and purity. In addition, the sodium carbonate produced after the reaction cannot be recovered and is discarded into the residual liquid, resulting in material waste, and the residual liquid will cause excessive salt content, polluting the environment.

[0005] However, the o-nitrobenzoic acid method produces a lot of wastewater, and the byproduct o-aminobenzoic acid intramolecular salt produced during the reaction consumes a large amount of acidic catalyst, and the yield is lower than that of the phthalic anhydride method. Therefore, the phthalic anhydride method is mostly used to prepare methyl o-aminobenzoate.

[0006] For example, Chinese patent publication number CN101948400B discloses a method for preparing methyl anthranilate. The method comprises the following steps: first, phthalic anhydride and ammonia water are used as raw materials, and an amidation reaction is performed to generate amine o-formamidobenzoate. Then, a sodium hydroxide solution is added to the mixture to generate sodium o-formamidobenzoate. The ammonia molecules in the reaction solution are removed. Then, a methanol solution and a sodium hypochlorite solution are added to the reaction solution to react and generate a paste of methyl anthranilate. The paste of methyl anthranilate is heated and dissolved in water. Finally, the mixture of methyl anthranilate and water is distilled to obtain methyl anthranilate.

[0007] The methyl anthranilate obtained by the invention has a high content of up to 98.4%; a good appearance, and a product light transmittance of 58.6%; and a high yield, which is 0.4%-0.5% higher than the original process.

[0008] However, the preparation of methyl anthranilate through the phthalic anhydride method has the characteristics of large reaction exotherm and high risk of thermal runaway during the reaction process. Especially in batch production, the accumulation of large amounts of heat is more likely to cause production risks. Summary of the Invention

[0009] The present invention aims to solve the above technical problems, overcome the shortcomings of the prior art and provide a process for producing o-aminobenzyl ester.

[0010] In order to solve the above technical problems, the present invention provides a process for producing o-aminobenzyl ester.

[0011] Technical Effect: The process can suppress heat accumulation during the synthesis process, preventing the risk of thermal runaway during the mass production of o-aminobenzyl ester. This reduces heat during the synthesis process, making it easier for operators to control the temperature during the synthesis process, and improving the safety of the o-aminobenzyl ester preparation process. Furthermore, the content and yield of o-aminobenzyl ester can be further increased, thereby improving production.

[0012] The technical solution further defined in the present invention is: a process for producing o-aminobenzyl ester, comprising the following components by weight:

[0013]

[0014] Furthermore, the temperature of the hot water is 60°C.

[0015] In the aforementioned process for producing o-aminobenzyl ester, the concentration of aqueous ammonia is 20-25%, preferably 22%.

[0016] In the aforementioned process for producing o-aminobenzyl ester, the concentration of the sodium hydroxide solution is 36-38%, preferably 38%.

[0017] In the aforementioned process for producing o-aminobenzyl ester, the concentration of the sodium hypochlorite solution is 13-16%, preferably 14%.

[0018] In the aforementioned process for producing o-aminobenzyl ester, the methanol concentration is 75%.

[0019] The aforementioned process for producing o-aminobenzyl ester comprises the following steps:

[0020] S1, taking a certain amount of ammonia water, placing it in a freezer, and lowering its temperature to 5-8°C; taking a certain amount of nitric acid and phthalic anhydride, slowly adding them to the ammonia water while stirring, and completing the reaction within 3 hours to obtain a mixed solution; during the reaction, the solution temperature is controlled below 30°C;

[0021] S2, adding a quantitative copper hydroxide solution to the mixed solution, filtering out the precipitate after sufficient reaction, and obtaining a filtrate;

[0022] S3, taking a quantitative sodium hydroxide solution, slowly adding it to the filtrate within 30 minutes to displace and generate a sodium o-formamidobenzoate solution;

[0023] S4, transferring the obtained sodium o-formamidobenzoate solution to an esterification kettle, maintaining the solution temperature below 10°C, adding a certain amount of methanol and sodium hypochlorite solution, mixing and reacting for 3 hours to obtain a paste of methyl o-aminobenzoate solution;

[0024] S5, adding vitamin C to the paste methyl anthranilate solution until the pH value of the solution reaches 7;

[0025] S6, raise the temperature to 50°C, dissolve the paste of methyl anthranilate, add hot water to promote stratification, and let it stand for 2 hours to separate; take the lower layer of solution, first raise the temperature to 70°C to remove methanol and residual vitamin C, then perform vacuum filtration and secondary stratification, and finally distill to obtain the finished product of methyl anthranilate.

[0026] In the aforementioned process for producing o-aminobenzyl ester, in step S1, when adding ammonium nitrate and phthalic anhydride, the addition of ammonium nitrate and phthalic anhydride is stopped after the solution temperature reaches 28°C, and the solution is cooled to 20°C and then the addition is continued dropwise until the reaction is completed.

[0027] In the aforementioned process for producing o-aminobenzyl ester, in step S4, the sodium hypochlorite solution is divided into 5 parts, which are added to the sodium o-formamidobenzoate solution in 5 times and at different positions to ensure that the solution temperature is always below 10°C.

[0028] In the aforementioned process for producing o-aminobenzyl ester, in step S6, the distillation conditions are 2.2 kPa and 138° C.; the purity of the obtained o-aminobenzyl ester product is 99.2%.

[0029] The beneficial effects of the present invention are:

[0030] (1) In the present invention, the added ammonium nitrate reacts with water to produce ammonia gas and nitric acid, and the ammonia gas dissolves in water to form ammonia water, which increases the concentration of the ammonia water while absorbing a large amount of heat, and at the same time provides acidic conditions for the entire reaction, accelerating the reaction of ammonia water and phthalic anhydride; and the reaction of phthalic anhydride and ammonia water generates a large amount of heat, part of which is absorbed, which greatly facilitates the control of the reaction temperature and reduces the risk of thermal runaway;

[0031] (2) In the present invention, during the reaction process of the entire step S1, the generated nitric acid reacts with the copper hydroxide solution to form copper nitrate crystals, thereby removing most of the nitric acid and ensuring the purity of the obtained filtrate; controlling the temperature within 30°C, preferably 25°C, can make the reaction most complete, so the reaction is stopped after 28°C, cooled to 20°C and then added, which can control the overall reaction temperature at about 25°C, achieving the optimal reaction temperature, and can also avoid heat concentration and the risk of thermal runaway caused by exceeding 30°C;

[0032] (3) In the present invention, a large amount of heat is generated when the sodium hypochlorite solution is added, so it needs to be added in multiple times to avoid heat concentration; in addition, adding it at different locations can also avoid heat accumulation and prevent insufficient purity caused by local overheating;

[0033] (4) In the present invention, after adding methanol and sodium hypochlorite, the entire solution is in an alkaline state. Therefore, the addition of vitamin C can destroy the oxidizing property of sodium hypochlorite and effectively remove the sodium hypochlorite in the solution. When the pH value of the solution reaches 7, it indicates that the sodium hypochlorite has been completely removed. Since the boiling point of methanol is 64.7°C and the decomposition temperature of vitamin C is 70°C, the methanol and the remaining vitamin C can be removed by heating the solution to 70°C, thereby improving the purity of the final product.

[0034] (5) In the present invention, since the boiling point of o-aminobenzyl ester is as high as 273°C, under this condition, the water in the lower solution can be quickly removed to obtain the o-aminobenzyl ester finished product; and the methanol, vitamin C and other substances remaining in the lower solution are quickly volatilized and decomposed under this condition, further improving the purity of the o-aminobenzyl ester finished product to more than 99.2%. DETAILED DESCRIPTION

[0035] To make the objectives, technical solutions, and advantages of the present invention more apparent, a detailed description is given below in conjunction with specific embodiments. The following description sets forth many specific details to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar modifications without departing from the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0037] The present embodiment provides a process for producing o-aminobenzyl ester, which mainly comprises, by weight, 66-70 parts of phthalic anhydride, 22-27 parts of ammonium nitrate, 36-42 parts of aqueous ammonia, 27-30 parts of copper hydroxide solution, 64-68 parts of sodium hydroxide solution, 300 parts of methanol, 63-66 parts of sodium hypochlorite solution, and 4-6 parts of vitamin C. In addition, 1000 parts of hot water at a temperature of 60°C is required.

[0038] In the present invention, the concentration of ammonia water is 20-25%, preferably 22%. When ammonium nitrate is added to ammonia water, it reacts with water to form ammonia gas, which then dissolves in water, increasing the concentration of ammonia water. Therefore, the concentration of ammonia water used can be appropriately reduced to reduce costs.

[0039] The concentration of the sodium hydroxide solution used in the present invention is 36-38%, preferably 38%. After the sodium hydroxide solution is added, it is used to replace and generate sodium o-formamidobenzoate. Therefore, a slightly higher concentration can ensure that the replacement reaction is complete and increase the concentration of the final product.

[0040] The concentration of the sodium hypochlorite solution used in the present invention is 13-16%, preferably 14%; the concentration of methanol is 75%.

[0041] The preparation and production of o-aminobenzyl ester comprises the following steps:

[0042] S1. Take a certain amount of ammonia water, place it in a freezer, and lower its temperature to 5-8°C; take a certain amount of nitric acid and phthalic anhydride, slowly add them into the ammonia water while stirring, and complete the reaction within 3 hours to obtain a mixed solution; during the reaction, control the solution temperature below 30°C.

[0043] In this step, ammonium nitrate reacts with water to produce ammonia gas and nitric acid, and the ammonia gas dissolves in water to form ammonia water, which increases the concentration of the ammonia water while absorbing a large amount of heat. At the same time, it provides acidic conditions for the entire reaction and accelerates the reaction of ammonia water and phthalic anhydride. The reaction of phthalic anhydride and ammonia water generates a large amount of heat, part of which is absorbed, which greatly facilitates the control of the reaction temperature and reduces the risk of thermal runaway.

[0044] During the entire reaction process, the temperature is controlled within 30°C, preferably at 25°C, which can make the reaction most complete. Therefore, it is stopped after 28°C, cooled to 20°C and then added. The overall reaction temperature can be controlled at around 25°C, achieving the optimal reaction temperature, and avoiding heat concentration and the risk of thermal runaway caused by exceeding 30°C.

[0045] S2, adding a quantitative copper hydroxide solution to the mixed solution, filtering out the precipitate after sufficient reaction, and obtaining a filtrate. In this step, the generated nitric acid reacts with the copper hydroxide solution to form copper nitrate crystals, thereby removing most of the nitric acid and ensuring the purity of the obtained filtrate.

[0046] S3, taking a quantitative sodium hydroxide solution, slowly adding it to the filtrate within 30 minutes to replace and generate a sodium o-formamidobenzoate solution.

[0047] S4, transferring the obtained sodium o-formamidobenzoate solution to an esterification kettle, maintaining the solution temperature below 10° C., adding a certain amount of methanol and sodium hypochlorite solution, mixing and reacting for 3 hours to obtain a paste-like methyl o-aminobenzoate solution.

[0048] In this step, a large amount of heat is generated when the sodium hypochlorite solution is added, so it needs to be added in multiple times to avoid heat concentration. In addition, adding it at different locations can also avoid heat accumulation and prevent insufficient purity caused by local overheating.

[0049] S5. Add vitamin C to the paste of methyl anthranilate solution until the pH value of the solution reaches 7.

[0050] In this step, after adding methanol and sodium hypochlorite, the entire solution is in an alkaline state. Therefore, adding vitamin C can destroy the oxidizing property of sodium hypochlorite and effectively remove the sodium hypochlorite in the solution. When the pH value of the solution reaches 7, it indicates that the sodium hypochlorite has been completely removed.

[0051] S6, raise the temperature to 50°C, dissolve the paste of methyl anthranilate, add hot water to promote stratification, and let it stand for 2 hours to separate; take the lower layer of solution, first raise the temperature to 70°C to remove methanol and residual vitamin C, then perform vacuum filtration and secondary stratification, and finally distill to obtain the finished product of methyl anthranilate.

[0052] In this step, since methanol has a boiling point of 64.7°C and vitamin C decomposes at 70°C, heating the solution to 70°C removes the methanol and remaining vitamin C, improving the purity of the final product. Furthermore, since o-aminobenzyl ester has a boiling point of 273°C, under these conditions, the water in the lower solution can be quickly removed, resulting in the o-aminobenzyl ester product. Furthermore, residual methanol, vitamin C, and other substances in the lower solution quickly evaporate and decompose under these conditions, further improving the purity of the o-aminobenzyl ester product to over 99.2%.

[0053] The present invention has designed several examples and used the conventional phthalic anhydride method as a comparative example to conduct a test comparison of the thermal runaway risk, reaction yield, and purity of the examples and the comparative example. The amount of each substance used in the examples and the comparative example is shown in Table 1:

[0054] Table 1: Parts of substances in each embodiment and comparative example

[0055]

[0056] When preparing o-aminobenzyl ester by the phthalic anhydride method, the risk assessment of thermal runaway mainly includes the assessment of three stages, including the Hofmann rearrangement reaction stage, the amidation stage, and the crystallization and post-processing stage.

[0057] The evaluation criteria are a comprehensive assessment of heat release ΔH and heating rate, as shown in Table 2.

[0058] Table 2 Heating rate and heat release in each stage of the embodiment and comparative example

[0059]

[0060]

[0061] As shown in Table 2, compared to the comparative example, the heating rate and heat release of each example decreased in all three stages, with Example 3 showing the largest decrease, followed by Example 1. This is because Example 3 contains the highest levels of ammonium nitrate and copper hydroxide, thus minimizing the risk of thermal runaway.

[0062] Table 3 Data and properties of o-aminobenzyl esters obtained in various embodiments and comparative examples

[0063]

[0064] As shown in Table 3, the yield of o-aminobenzyl ester prepared using Example 1 can reach 95.5%, the purity is above 99.8%, the purity of the o-aminobenzyl ester finished product is extremely high, the product is nearly colorless, the performance is excellent, and it is significantly enhanced compared with the comparative example. The yield and purity of Example 3 are close to those of the comparative example, and the o-aminobenzyl ester obtained is light yellow.

[0065] From the data in Table 2 and Table 3, it can be seen that Example 1 not only has good thermal risk control, but also can significantly improve the final yield and product purity, which is a great improvement compared to the existing phthalic anhydride method.

[0066] In addition to the above embodiments, the present invention may also have other implementations. Any technical solution formed by equivalent replacement or equivalent transformation falls within the scope of protection required by the present invention.

Claims

1. A process for producing o-aminobenzyl ester, characterized in that, Includes the following components by weight:

2. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: The temperature of the hot water is 60°C.

3. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: The concentration of the ammonia water is 20-25%, preferably 22%.

4. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: The concentration of the sodium hydroxide solution is 36-38%, preferably 38%.

5. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: The concentration of the sodium hypochlorite solution is 13-16%, preferably 14%.

6. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: The methanol concentration is 75%.

7. A process for producing o-aminobenzyl ester according to claim 1, characterized in that, The steps include: S1, taking a fixed amount of ammonia water, placing it in a freezer, and lowering its temperature to 5-8°C; taking a fixed amount of ammonium nitrate and phthalic anhydride, slowly adding them to the ammonia water while stirring, and completing the reaction within 3 hours to obtain a mixed solution; during the reaction, the solution temperature is controlled below 30°C; S2, adding a quantitative copper hydroxide solution to the mixed solution, filtering out the precipitate after sufficient reaction, and obtaining a filtrate; S3, taking a quantitative sodium hydroxide solution, slowly adding it to the filtrate within 30 minutes to displace and generate a sodium o-formamidobenzoate solution; S4, transferring the obtained sodium o-formamidobenzoate solution to an esterification kettle, maintaining the solution temperature below 10°C, adding a certain amount of methanol and sodium hypochlorite solution, mixing and reacting for 3 hours to obtain a paste of methyl o-aminobenzoate solution; S5, adding vitamin C to the paste methyl anthranilate solution until the pH value of the solution reaches 7; S6, raise the temperature to 50°C, dissolve the paste of methyl anthranilate, add hot water to promote stratification, and let it stand for 2 hours to separate; take the lower layer of solution, first raise the temperature to 70°C to remove methanol and residual vitamin C, then perform vacuum filtration and secondary stratification, and finally distill to obtain the finished product of methyl anthranilate.

8. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: In step S1, when adding ammonium nitrate and phthalic anhydride, the addition of ammonium nitrate and phthalic anhydride is stopped after the solution temperature reaches 28° C., and the temperature is lowered to 20° C. and then the addition is continued dropwise until the reaction is completed.

9. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: In step S4, the sodium hypochlorite solution is divided into 5 portions and added to the sodium o-formamidobenzoate solution at different positions in 5 times to ensure that the solution temperature is always below 10°C.

10. A process for producing o-aminobenzyl ester according to claim 1, characterized in that: In step S6, the distillation conditions are 2.2 kPa and 138° C.; the purity of the obtained o-aminobenzyl ester product is at least 99.2%.

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