A preparation method of methyl 2-methoxy-4-aminobenzoate

Abstract

The invention belongs to the technical field of organic synthesis, and is particularly related to a method for preparing methyl 2-methoxy-4-aminobenzoate, which specifically comprises the following steps: step one: 2-methoxytoluene reacts with chromium oxide to synthesize 2-methoxybenzoic acid; step two: 2-methoxybenzoic acid and methanol prepared in step one are catalyzed by concentrated sulfuric acid to synthesize methyl 2-methoxybenzoate; step three: methyl 2-methoxybenzoate prepared in step two reacts with hydroxylamine sulfate to synthesize methyl 2-methoxy-4-aminobenzoate. The invention has the beneficial effects that the total reaction yield of the method for preparing methyl 2-methoxy-4-aminobenzoate is high, the obtained methyl 2-methoxy-4-aminobenzoate has high purity, is simple to operate, does not require dimethyl sulfate to participate in the reaction, and has mild reaction conditions, thereby reducing production costs, and large-scale production will not affect reaction performance, and the safety and controllability of the production process are higher.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing methyl 2-methoxy-4-aminobenzoate. Background Art

[0002] Lenvatinib was developed by Japan's Eisai Co., Ltd. and can be used to treat solid tumors such as thyroid cancer, kidney cancer, glioma, liver cancer, and ovarian cancer. Lenvatinib is particularly effective in treating liver cancer induced by hepatitis B, and is more suitable for Chinese liver cancer patients, providing a new treatment for Chinese patients with advanced liver cancer. Methyl 2-methoxy-4-aminobenzoate, as an important intermediate of Lenvatinib, has a good market prospect.

[0003] Patent CN107629001 introduces a method for preparing methyl 2-methoxy-4-aminobenzoate, which uses dimethyl sulfate in the synthesis. Dimethyl sulfate is a highly toxic methylating agent, and the production operation risk is high, which is not suitable for safe production. At the same time, patent US20170239249 discloses a method for preparing methyl 2-methoxy-4-aminobenzoate, which uses hydrogen and Pd / C catalysts, has a large safety hazard, and the cost is expensive, so it is difficult to use for large-scale industrial production. Therefore, how to develop a method for preparing methyl 2-methoxy-4-aminobenzoate without dimethyl sulfate, which is safe and controllable during large-scale production, and has high reaction yield and product purity, has become a problem to be solved. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for preparing methyl 2-methoxy-4-aminobenzoate.

[0005] The present invention relates to a method for preparing methyl 2-methoxy-4-aminobenzoate, which specifically comprises the following steps:

[0006] Step 1: Synthesis of 2-methoxybenzoic acid:

[0007] Dissolve 2-methoxytoluene in a reaction solvent, start stirring, first increase the temperature, then slowly drop an aqueous solution of chromium oxide into the reaction system, and then keep the temperature for reaction. After the reaction is completed by HPLC detection, cool the reaction solution, then add water for crystallization, then cool it twice and filter, wash the filter cake with water, and dry the filter cake to obtain 2-methoxybenzoic acid;

[0008] Step 2: Synthesis of methyl 2-methoxybenzoate:

[0009] The 2-methoxybenzoic acid prepared in step 1 is dissolved in methanol, stirred, and then concentrated sulfuric acid is added, the temperature is raised to reflux, and then the temperature is kept for reaction. After the reaction is completed by HPLC detection, the reaction solution is concentrated under reduced pressure until no fraction is produced, and after cooling, a saturated potassium carbonate aqueous solution is added to adjust the pH value of the reaction solution to neutral, and then dichloromethane is added for extraction 3 times, the dichloromethane phases are combined, and the dichloromethane phases are concentrated until no fraction is produced to obtain methyl 2-methoxybenzoate;

[0010] Step 3: Synthesis of methyl 2-methoxy-4-aminobenzoate:

[0011] The methyl 2-methoxybenzoate and potassium tert-butoxide prepared in step 2 are dissolved in a reaction solvent, stirred and heated, and then a methanol solution of hydroxylamine sulfate is added dropwise to the reaction system. After the addition is complete, the reaction is kept warm for reaction. After the reaction is completed by HPLC detection, the reaction solution is concentrated under reduced pressure until no fraction is produced, cooled first, and then water is added for pulping, cooled twice and filtered, the filter cake is washed with water to obtain a primary filter cake, methanol is added to the primary filter cake, the temperature is first raised to completely dissolved, then cooled and crystallized and filtered, the filter cake is washed with methanol to obtain a secondary filter cake, and the secondary filter cake is dried to obtain methyl 2-methoxy-4-aminobenzoate.

[0012] Preferably, the synthetic route is as follows:

[0013] .

[0014] Preferably, in step 1, the molar ratio of 2-methoxytoluene to chromium oxide is 1:2-5; the mass concentration of the aqueous solution of chromium oxide is 0.9-1.0 g / ml; the reaction solvent is concentrated sulfuric acid, or the reaction solvent is a mixed solution of concentrated sulfuric acid and acetic acid.

[0015] Preferably, in the step 1, the temperature is raised to 80-95°C; the reaction is kept warm for 2-5h; the temperature is lowered to 40-50°C; the volume of the water is measured in milliliters, the mass of the 2-methoxytoluene is measured in grams, and the volume of the water added during crystallization is 5-10 times the mass of the 2-methoxytoluene; the temperature is lowered to 0-5°C for the second time; and the temperature of the water used for washing the filter cake is controlled at 0-5°C.

[0016] Preferably, in step 2, the mass ratio of the 2-methoxybenzoic acid to concentrated sulfuric acid is 1:0.1-0.5; the volume of the methanol is measured in milliliters, the mass of the 2-methoxybenzoic acid is measured in grams, and the volume of the methanol is 9-10 times the mass of the 2-methoxybenzoic acid.

[0017] Preferably, in step 2, the temperature is raised to 65-75° C. and the reaction is kept warm for 8-12 hours.

[0018] Preferably, in step three, the molar ratio of methyl 2-methoxybenzoate, potassium tert-butoxide and hydroxylamine sulfate is 1:2-3:2.5-3.5; the mass concentration of the methanol solution of hydroxylamine sulfate is 0.4-0.5 g / ml; and the reaction solvent is methanol, toluene or ethanol.

[0019] Preferably, in the step three, the temperature is raised to 35-50° C. and the reaction is kept warm for 2-6 hours; the temperature is lowered to 25-30° C.; the volume of the water is measured in milliliters, the mass of the methyl 2-methoxybenzoate is measured in grams, and the volume of the water added during pulping is 5-10 times the mass of the methyl 2-methoxybenzoate.

[0020] Preferably, in the step three, the temperature is lowered to 0-10°C for the second time; the temperature of the water used for washing the filter cake is controlled at 0-10°C; the volume of the methanol is measured in milliliters, the mass of the methyl 2-methoxybenzoate is measured in grams, and the volume of the methanol added to the filter cake once is 3-5 times the mass of the methyl 2-methoxybenzoate; the temperature of the cooling and crystallization is 0-5°C, and the temperature of the methanol used for washing the filter cake is controlled at 0-5°C.

[0021] Preferably, the total yield of the three-step reaction is greater than 80%, and the purity of the methyl 2-methoxy-4-aminobenzoate is greater than 99.0%.

[0022] Compared with the prior art, the advantages and positive effects of the present invention are:

[0023] (1) The method for preparing methyl 2-methoxy-4-aminobenzoate has a high total reaction yield, reduces production costs, improves the utilization efficiency of raw materials, and thus improves economic benefits. The obtained methyl 2-methoxy-4-aminobenzoate has high purity, which improves market competitiveness. No complicated subsequent purification process is required, thereby reducing costs and time consumption.

[0024] (2) The preparation method of methyl 2-methoxy-4-aminobenzoate does not require dimethyl sulfate to participate in the reaction, thereby avoiding the danger of dimethyl sulfate to the safety of workers during the production process and reducing the harm to the environment;

[0025] (3) The preparation method of methyl 2-methoxy-4-aminobenzoate has mild reaction conditions, so that the reaction process is more stable, making the production process safer and easier to control, and the reaction performance will not be affected when it is scaled up to industrial production scale;

[0026] (4) The preparation method of methyl 2-methoxy-4-aminobenzoate is simple to operate, reduces labor costs, and improves the stability and reliability of large-scale production. DETAILED DESCRIPTION

[0027] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments.

[0028] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0029] Example 1

[0030] A method for preparing methyl 2-methoxy-4-aminobenzoate, comprising the following steps:

[0031] Step 1: Synthesis of 2-methoxybenzoic acid:

[0032] Dissolve 50g of 2-methoxytoluene in 250g of concentrated sulfuric acid, start stirring, heat to 85°C, dissolve 186.6g of chromium oxide in 200ml of water, and then slowly add dropwise to the reaction system. Keep warm for 5h. After the reaction is completed by HPLC detection, cool the reaction solution to 50°C, add 500ml of water for crystallization, cool it to 5°C for the second time, filter it, wash the filter cake with 100ml of 5°C water, and dry the filter cake at 50°C to obtain 57.9g of 2-methoxybenzoic acid with a purity of 98.6% and a reaction yield of 93%.

[0033] Step 2: Synthesis of methyl 2-methoxybenzoate:

[0034] Dissolve 57.9 g of 2-methoxybenzoic acid obtained in step 1 in 580 ml of methanol, start stirring, add 23 g of concentrated sulfuric acid, raise the temperature to 70°C, and keep the temperature for reaction for 10 hours. After the reaction is completed by HPLC detection, the reaction solution is concentrated under reduced pressure until no fraction is produced, add saturated potassium carbonate aqueous solution to adjust the pH value of the reaction solution to neutral, add 230 ml of dichloromethane for extraction, repeat the extraction 3 times, combine the dichloromethane phases, and concentrate the dichloromethane phases until no fraction is produced to obtain 60 g of methyl 2-methoxybenzoate with a purity of 98.2% and a reaction yield of 94.9%.

[0035] Step 3: Synthesis of methyl 2-methoxy-4-aminobenzoate:

[0036] 60g of methyl 2-methoxybenzoate obtained in step 2 and 103.2g of potassium tert-butoxide were dissolved in 180ml of methanol, and the temperature was raised to 40°C after stirring. 148.2g of hydroxylamine sulfate was dissolved in 360ml of methanol and added dropwise to the reaction system. The reaction was kept warm for 4h. After the reaction was completed by HPLC, the reaction solution was concentrated under reduced pressure until no fraction was produced, cooled to 30°C, and then 360ml of water was added for pulping. The mixture was cooled to 10°C for the second time and filtered. The filter cake was washed with 60ml of 10°C water to obtain a primary filter cake. 180ml of methanol was added to the primary filter cake, and the temperature was raised to completely dissolved, then cooled to 5°C for crystallization, and stirred at 5°C for 0.5h. The mixture was filtered again, and the filter cake was washed with 25ml of 5°C methanol to obtain a secondary filter cake. The secondary filter cake was dried at 40°C to obtain 61.8g of methyl 2-methoxy-4-aminobenzoate with a purity of 99.2% and a reaction yield of 94.5%.

[0037] Example 2

[0038] A method for preparing methyl 2-methoxy-4-aminobenzoate, comprising the following steps:

[0039] Step 1: Synthesis of 2-methoxybenzoic acid:

[0040] 100 g of 2-methoxytoluene was dissolved in a mixed solution of 300 g of concentrated sulfuric acid and 200 g of acetic acid. After stirring, the temperature was raised to 95°C. 248.8 g of chromium oxide was dissolved in 250 ml of water and then slowly added dropwise to the reaction system. The temperature was kept for 4 hours. After the reaction was completed by HPLC detection, the reaction solution was cooled to 45°C, 1000 ml of water was added for crystallization, and then the temperature was lowered to 3°C for the second time and filtered. The filter cake was washed with 200 ml of 3°C water and dried at 50°C to obtain 118.6 g of 2-methoxybenzoic acid with a purity of 98.7% and a reaction yield of 95.2%.

[0041] Step 2: Synthesis of methyl 2-methoxybenzoate:

[0042] Dissolve 118.6 g of 2-methoxybenzoic acid obtained in step 1 in 1100 ml of methanol, start stirring, add 35 g of concentrated sulfuric acid, raise the temperature to 75°C, and keep the temperature for reaction for 8 hours. After the reaction is completed by HPLC, the reaction solution is concentrated under reduced pressure until no fraction is produced, add saturated potassium carbonate aqueous solution to adjust the pH value of the reaction solution to neutral, add 450 ml of dichloromethane for extraction, repeat the extraction 3 times, combine the dichloromethane phases, and concentrate the dichloromethane phases until no fraction is produced to obtain 121.8 g of methyl 2-methoxybenzoate with a purity of 98.5% and a reaction yield of 94.0%.

[0043] Step 3: Synthesis of methyl 2-methoxy-4-aminobenzoate:

[0044] 121.8g of methyl 2-methoxybenzoate obtained in step 2 and 245.5g of potassium tert-butoxide were dissolved in 500ml of ethanol, stirred and heated to 35°C, 360g of hydroxylamine sulfate was dissolved in 720ml of methanol and added dropwise to the reaction system, and the reaction was kept warm for 6h. After the reaction was completed by HPLC, the reaction solution was concentrated under reduced pressure until no fraction was produced, cooled to 25°C, and then 800ml of water was added for pulping. The mixture was cooled to 5°C for the second time and filtered. The filter cake was washed with 150ml of 5°C water to obtain a primary filter cake. 400ml of methanol was added to the primary filter cake, the temperature was first raised to completely dissolved, then cooled to 2°C for crystallization, and stirred at 2°C for 1h, filtered again, and the filter cake was washed with 50ml of 2°C methanol to obtain a secondary filter cake. The secondary filter cake was dried at 40°C to obtain 123.1g of methyl 2-methoxy-4-aminobenzoate with a purity of 99.0% and a reaction yield of 92.7%.

[0045] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing methyl 2-methoxy-4-aminobenzoate, characterized in that: The specific steps include: Step 1: Synthesis of 2-methoxybenzoic acid: Dissolve 2-methoxytoluene in a reaction solvent, start stirring, first increase the temperature, then slowly drop an aqueous solution of chromium oxide into the reaction system, and then carry out a heat preservation reaction. After the reaction is completed by HPLC detection, the reaction solution is first cooled, and then water is added for crystallization, and then the temperature is reduced for a second time and then filtered, the filter cake is washed with water, and the filter cake is dried to obtain 2-methoxybenzoic acid; the reaction solvent is concentrated sulfuric acid, or the reaction solvent is a mixed solution of concentrated sulfuric acid and acetic acid; Step 2: Synthesis of methyl 2-methoxybenzoate: The 2-methoxybenzoic acid prepared in step 1 is dissolved in methanol, stirred, and then concentrated sulfuric acid is added, the temperature is raised to reflux, and then the temperature is kept for reaction. After the reaction is completed by HPLC detection, the reaction solution is concentrated under reduced pressure until no fraction is produced, and after cooling, a saturated potassium carbonate aqueous solution is added to adjust the pH value of the reaction solution to neutral, and then dichloromethane is added for extraction 3 times, the dichloromethane phases are combined, and the dichloromethane phases are concentrated until no fraction is produced to obtain methyl 2-methoxybenzoate; Step 3: Synthesis of methyl 2-methoxy-4-aminobenzoate: The methyl 2-methoxybenzoate and potassium tert-butoxide prepared in step 2 are dissolved in a reaction solvent, stirred and heated, and then a methanol solution of hydroxylamine sulfate is added dropwise to the reaction system. After the addition is complete, the reaction is kept warm for reaction. After the reaction is completed by HPLC detection, the reaction solution is concentrated under reduced pressure until no fraction is produced, cooled first, and then water is added for pulping, cooled twice and filtered, the filter cake is washed with water to obtain a primary filter cake, methanol is added to the primary filter cake, the temperature is first raised to completely dissolved, then cooled and crystallized and filtered, the filter cake is washed with methanol to obtain a secondary filter cake, and the secondary filter cake is dried to obtain methyl 2-methoxy-4-aminobenzoate.

2. The method for preparing methyl 2-methoxy-4-aminobenzoate according to claim 1, wherein The synthetic route is as follows: 。 3. The preparation method of methyl 2-methoxy-4-aminobenzoate according to claim 2, characterized in that, In the step 1, the molar ratio of the 2-methoxytoluene to the chromium oxide is 1:2-5; and the mass concentration of the aqueous solution of the chromium oxide is 0.9-1.0 g / ml.

4. The method for preparing methyl 2-methoxy-4-aminobenzoate according to claim 3, characterized in that: In the step 1, the temperature is raised to 80-95° C.; the temperature is kept for reaction for 2-5 hours; the temperature is lowered to 40-50° C.; the volume of the water is measured in milliliters, the mass of the 2-methoxytoluene is measured in grams, and the volume of the water added during crystallization is 5-10 times the mass of the 2-methoxytoluene; the temperature is lowered to 0-5° C. for the second time; and the temperature of the water used for washing the filter cake is controlled at 0-5° C.

5. The method for preparing methyl 2-methoxy-4-aminobenzoate according to claim 4, characterized in that: In the step 2, the mass ratio of the 2-methoxybenzoic acid to the concentrated sulfuric acid is 1:0.1-0.5; the volume of the methanol is measured in milliliters, the mass of the 2-methoxybenzoic acid is measured in grams, and the volume of the methanol is 9-10 times the mass of the 2-methoxybenzoic acid.

6. The method for preparing methyl 2-methoxy-4-aminobenzoate according to claim 5, characterized in that: In the step 2, the temperature is raised to 65-75° C. and the reaction is kept at this temperature for 8-12 hours.

7. The method for preparing methyl 2-methoxy-4-aminobenzoate according to claim 6, characterized in that: In the step 3, the molar ratio of methyl 2-methoxybenzoate, potassium tert-butoxide and hydroxylamine sulfate is 1:2-3:2.5-3.5; the mass concentration of the methanol solution of hydroxylamine sulfate is 0.4-0.5 g / ml; and the reaction solvent is methanol, toluene or ethanol.

8. The method for preparing methyl 2-methoxy-4-aminobenzoate according to claim 7, characterized in that: In the step three, the temperature is raised to 35-50° C. and the reaction is kept warm for 2-6 hours; the temperature is lowered to 25-30° C.; the volume of the water is measured in milliliters, the mass of the methyl 2-methoxybenzoate is measured in grams, and the volume of the water added during pulping is 5-10 times the mass of the methyl 2-methoxybenzoate.

9. The method for preparing methyl 2-methoxy-4-aminobenzoate according to claim 8, characterized in that: In the step three, the temperature is lowered to 0-10°C for the second time; the temperature of the water used for washing the filter cake is controlled at 0-10°C; the volume of the methanol is measured in milliliters, the mass of the methyl 2-methoxybenzoate is measured in grams, and the volume of the methanol added to the filter cake once is 3-5 times the mass of the methyl 2-methoxybenzoate; the temperature of the cooling and crystallization is 0-5°C, and the temperature of the methanol used for washing the filter cake is controlled at 0-5°C.

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