A process for the preparation of methyl 4-acetamido-5-chloro-2-methoxybenzoate

Abstract

The present application relates to a kind of preparation methods of 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester, steps include: S1, m-amino phenol is reacted with acetic anhydride to generate m-acetylamino phenol;S2, the m-acetylamino phenol is reacted with carbon dioxide to generate 4-acetylamino salicylic acid;S3, the 4-acetylamino salicylic acid is reacted with dimethyl sulfate to generate 2-methoxy-4-acetylamino benzoic acid methyl ester;S4, the 2-methoxy-4-acetylamino benzoic acid methyl ester is reacted with hydrochloric acid to generate 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester.The preparation method of the present application not only improves product quality and production efficiency, but also reduces cost, simplifies operation, and is friendly to environment, with significant industrial application prospect and market competitiveness.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, and particularly relates to a preparation method of 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester. BACKGROUND

[0002] Metoclopramide, also known as Reglan, is a dopamine D2 receptor antagonist, has 5-hydroxytryptamine 4 (5-HT4) receptor agonistic effect, and has a slight inhibitory effect on 5-HT3 receptors. The drug is widely used for the treatment of vomiting caused by brain tumor surgery, tumor radiotherapy and chemotherapy, sequelae of brain trauma, acute brain injury and drugs. In addition, metoclopramide also has good effect on digestive system symptoms such as bloating, anorexia, belching, nausea and vomiting. It is also used for vomiting caused by sea and air operations and motion sickness, and to reduce the nausea and vomiting reaction during barium meal examination, and to promote the passage of barium.

[0003] In the synthesis process of metoclopramide, 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester as a key intermediate, the synthesis method directly affects the quality of the drug synthesis product and the content of by-products, and has important economic significance. However, there are few literatures reported on the synthesis method of 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester in China, which limits the further development and optimization of metoclopramide production technology.

[0004] The present application aims to provide a preparation method of 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester to solve the problems in the prior art, improve the synthesis efficiency, reduce the production cost, and reduce the impact on the environment. SUMMARY

[0005] The present application aims to provide a preparation method of 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester to solve the problems in the prior art, improve the synthesis efficiency, reduce the production cost, and reduce the impact on the environment.

[0006] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is:

[0007] The present application provides a preparation method of 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester, comprising the following steps:

[0008] S1, acetic anhydride is added dropwise to a solution of m-amino phenol and a solvent at 5℃±5℃, and the temperature is raised to 25℃±5℃ and kept for 2h-4h, so that the m-amino phenol reacts with the acetic anhydride to generate m-acetamidophenol;

[0009] Then the first solvent is removed by negative pressure concentration, methanol is added and cooled and filtered, and the m-acetamidophenol is dried to obtain the m-acetamidophenol;

[0010] S2, carbon dioxide is introduced into the basic aqueous solution of the m-acetaminophen, heated to 100°C ± 10°C and kept for 2h-6h, so that the m-acetaminophen reacts with the carbon dioxide to generate 4-acetamino salicylic acid;

[0011] Then cool and filter, the resulting liquid hydrochloric acid to pH 2-3, drying to obtain 4-acetamino salicylic acid;

[0012] S3, dimethyl sulfate is added to the basic solution of the 4-acetamino salicylic acid and the first organic solvent, heated to 30°C-40°C and stirred for 11h-13h, so that the 4-acetamino salicylic acid reacts with the dimethyl sulfate to generate 2-methoxy-4-acetamino benzene acid methyl ester;

[0013] Then transfer to cold water, stirring and crystallization and filtration, drying to obtain 2-methoxy-4-acetamino benzene acid methyl ester;

[0014] S4, hydrogen peroxide is added to the solution of the 2-methoxy-4-acetamino benzene acid methyl ester, hydrochloric acid, catalyst, and the second organic solvent at 10°C-20°C, heated to 25°C ± 5°C and kept for 2h-4h, so that the 2-methoxy-4-acetamino benzene acid methyl ester reacts with the hydrochloric acid to generate 4-acetamino-5-chloro-2-methoxy benzene acid methyl ester;

[0015] Then neutralized to neutral with a third basic substance, and transfer to cold water, stirring and crystallization, filtration and drying to obtain.

[0016] Preferably, the solvent is selected from at least one of water, methanol, ethanol, acetone, or tetrahydrofuran.

[0017] Preferably, the basic aqueous solution of the m-acetaminophen comprises: the m-acetaminophen, a first basic substance, and water; wherein,

[0018] The first basic substance is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, or baking soda.

[0019] Preferably, in the S2, the resulting solid is used in the preparation of another batch.

[0020] Preferably, the basic solution of the 4-acetamino salicylic acid and the first organic solvent comprises: the 4-acetamino salicylic acid, a second basic substance, and the first organic solvent; wherein,

[0021] The second basic substance is selected from at least one of potassium hydroxide, potassium carbonate, or cesium carbonate;

[0022] The first organic solvent is selected from at least one of acetonitrile, acetone, dioxane, or tetrahydrofuran.

[0023] Preferably, in S3, after filtration and drying, ethyl acetate recrystallization is further performed.

[0024] Preferably, the catalyst is selected from sodium tungstate.

[0025] Preferably, the second organic solvent is selected from at least one of toluene, acetonitrile, acetone, dichloromethane, or tetrahydrofuran.

[0026] Preferably, the third basic substance is selected from baking soda.

[0027] Preferably, in S4, after filtration and drying, methanol recrystallization is further performed.

[0028] The present application adopts the above technical scheme, and has the following technical effects compared with the prior art:

[0029] The preparation method of 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester provided by the present application has significant technical advantages and effects. First, by acetylating the m-amino phenol first, we significantly improve the stability of the intermediate, which not only ensures the smooth progress of the subsequent reaction, but also ensures the high quality of the final product. In addition, our preparation method increases the carboxylation conversion rate from 22% to 45%, and the total yield reaches 95%, which means higher raw material utilization and lower production cost.

[0030] In operation, we change the chlorinating reagent to hydrochloric acid hydrogen peroxide to prepare chlorine in situ, which makes the operation more convenient, the cost lower, and the industrial production easier. This method reduces the dependence on complex equipment, making the entire synthesis process more efficient and economical. In addition, our preparation method reduces the use and discharge of harmful chemicals, is more environmentally friendly, and conforms to the development trend of modern green chemistry.

[0031] Overall, the preparation method of the present application not only improves product quality and production efficiency, but also reduces cost, simplifies operation, and is environmentally friendly, with significant industrial application prospects and market competitiveness. DETAILED DESCRIPTION

[0032] The specific embodiments of the present application will be described in detail below.

[0033] Unless otherwise defined, technical or scientific terms used in the claims and specification should be understood as having the ordinary meaning as understood by a person skilled in the art to which the present application belongs.

[0034] As used in the specification and claims of this patent application, the phrase "includes" and variations thereof, such as "including," means that the item or items named after the term is inclusive and does not exclude other items.

[0035] Numerical values referred to in the present invention include all values from the lower to the upper limit of the range in increments of one unit, unless otherwise indicated. In this respect, a value that is "approximately" a stated value means that the stated value and all values less than the stated value by less than the smallest unit of recitation, and all values greater than the stated value by less than the smallest unit of recitation. For example, a component or physical quantity is stated to be from 1 to 100, 10 to 90, and 20 to 80, it is intended that values such as 5 to 95, 14 to 76, 23 to 67, 32 to 58, 41 to 49, etc. are to be construed as being explicitly stated. For values which are less than one, 0.1, 0.01, or 0.001 are also intended to be explicitly stated. The foregoing examples are merely representative of the way in which the present invention can be claimed and are intended to be construed in a similar way to the examples given above.

[0036] Example 1

[0037] The present embodiment provides a method for preparing 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester, the steps comprising:

[0038]

[0039] S1, 200.0 g of m-aminophenol and 1000 mL of acetone (solvent) were added to a reaction bottle and cooled to 0-5°C; 255.0 g of acetic anhydride was added dropwise to the reaction bottle, and the temperature was controlled at 5°C±5°C; after the addition was completed, the temperature was raised to 25°C±5°C and incubated for 3 h, so that the m-aminophenol reacted with the acetic anhydride to form m-acetamidophenol;

[0040] Then the acetone was concentrated under negative pressure until no liquid was discharged, 600 g of methanol was added, stirred and cooled to below 10°C, filtered, and dried in a vacuum oven at 45°C, to obtain 149.4 g of m-acetamidophenol, with a yield of 95.0% and an HPLC purity of 99.92%, MP: 146-149°C, 1 H-NHR (DMSO-d6, 400 MHz) δ: 5.22 (S, 2H), 6.20-6.93 (dd, 4H), 9.60 (S, 1H).

[0041] S2, 50.0 g of the m-acetamidophenol, 30.6 g of baking soda (first basic substance), and 150 mL of water were added to an autoclave; after CO2 was introduced to 1.5 MPa, the temperature was raised to 90°C and incubated for 6 h, so that the m-acetamidophenol reacted with the carbon dioxide to form 4-acetamidosalicylic acid;

[0042] Then cool to room temperature and release pressure, continue to cool to 0-5°C, filter, the resulting solid to another batch of preparation, the resulting liquid hydrochloric acid to pH 2-3, filter, 45°C vacuum oven drying, 29.0g of 4-acetylamino salicylic acid, HPLC purity of 99.41%, one conversion rate of 45.0%, after the molar yield of 95.0%, MP: 221-223°C, 1 H-NHR (DMSO-d6, 400 MHz) δ: 3.710 (S, 3H), 6.155 (S, 2H), 6.530 (S, 1H), 7.652 (S, 1H).

[0043] S3, in the reaction bottle 100g of the 4-acetylamino salicylic acid, 240g of potassium carbonate (the second basic material), and 500mL of acetone (the first organic solvent); under stirring conditions, 250g of dimethyl sulfate is added dropwise; after the addition, the temperature is raised to 35°C±5°C and stirred for 12h, so that the 4-acetylamino salicylic acid reacts with the dimethyl sulfate to generate 2-methoxy-4-acetylamino benzene acid methyl ester;

[0044] Then the reaction liquid is transferred to cold water, stirred to crystallize and filtered, and dried at 50°C, to obtain 102.5g of 2-methoxy-4-acetylamino benzene acid methyl ester, with a yield of 89.9%, HPLC purity of 98.72%, and 93.6g of fine product after recrystallization with 300mL of ethyl acetate, with an HPLC purity of 99.78%, MP: 126-128°C, 1 H-NHR (DMSO-d6, 400 MHz) δ: 2.225 (S, 3H), 3.889 (S, 3H), 3.930 (S, 3H), 6.825-6.856 (dd, 1H), 7.420 (S, 1H), 7.650 (S, 1H), 7.817-7.842 (d, 1H).

[0045] S4, in the reaction bottle 20g of the 2-methoxy-4-acetylamino benzene acid methyl ester, 13.6g of 36% hydrochloric acid, 0.1g of sodium tungstate (catalyst), and 120mL of acetone (second organic solvent); control the temperature at 15°C±5°C, slowly add 20.3g of 30% hydrogen peroxide, about 3h for dropwise addition, then raise the temperature to 25°C and keep for 3h, so that the 2-methoxy-4-acetylamino benzene acid methyl ester reacts with the hydrochloric acid to generate 4-acetylamino-5-chloro-2-methoxy benzene acid methyl ester;

[0046] Then neutralized to neutral with sodium bicarbonate (third basic substance) and transferred to cold water for stirring and crystallization, filtered, and dried in a vacuum oven at 50°C to obtain 22.2 g of 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester with a yield of 96%, and 20.5 g of fine product after recrystallization from 100 mL of methanol, with a purity of 99.99% by HPLC and a MP of 151-152°C, 1 H-NHR (DMSO-d6, 400 MHz) δ: 2.370 (S, 3H), 3.964 (S, 3H), 3.930 (S, 3H), 7.765 (S, 1H), 7.874 (S, 1H), 8.310 (S, 1H).

[0047] Example 2

[0048] This example provides a method for preparing 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester, which comprises the following steps:

[0049] S1, 200.0 g of m-aminophenol and 1000 mL of water (solvent) were added to a reaction bottle and cooled to 0-5°C; 255.0 g of acetic anhydride was added dropwise to the reaction bottle while controlling the temperature at 5°C±5°C; after the addition was completed, the temperature was raised to 25°C±5°C and kept for 3 h to allow the m-aminophenol to react with the acetic anhydride to form m-acetylamino phenol;

[0050] Then the acetone was concentrated under negative pressure until no liquid was discharged, 600 g of methanol was added, and the mixture was stirred and cooled to below 10°C, filtered, and dried in a vacuum oven at 45°C to obtain m-acetylamino phenol;

[0051] S2, 50.0 g of the m-acetylamino phenol, 30.6 g of potassium carbonate (first basic substance), and 150 mL of water were added to an autoclave; after CO2 was introduced to 1.5 MPa, the temperature was raised to 110°C and kept for 2 h to allow the m-acetylamino phenol to react with the carbon dioxide to form 4-acetylamino salicylic acid;

[0052] Then cooled to room temperature and released the pressure, continued to cool to 0-5°C, filtered, the obtained solid was used in the preparation of another batch, the obtained liquid was acidified with hydrochloric acid to pH 2-3, filtered, and dried in a vacuum oven at 45°C to obtain 4-acetylamino salicylic acid;

[0053] S3, 100 g of the 4-acetylamino salicylic acid, 240 g of potassium hydroxide (second basic substance), and 500 mL of acetonitrile (first organic solvent) were added to a reaction bottle; 250 g of dimethyl sulfate was added dropwise under stirring; after the addition was completed, the temperature was raised to 35°C±5°C and stirred for 12 h to allow the 4-acetylamino salicylic acid to react with the dimethyl sulfate to form 2-methoxy-4-acetylamino benzoic acid methyl ester;

[0054] Then the reaction solution is transferred to cold water, stirred to crystallize, filtered, and dried at 50°C to obtain 2-methoxy-4-acetylamino benzoic acid methyl ester.

[0055] S4, 20 g of the 2-methoxy-4-acetylamino benzoic acid methyl ester, 13.6 g of 36% hydrochloric acid, 0.1 g of sodium tungstate (catalyst), and 120 mL of toluene (second organic solvent) are added to a reaction bottle; the temperature is controlled at 15°C±5°C, and 20.3 g of 30% hydrogen peroxide is slowly added dropwise, which takes about 3 hours; then the temperature is raised to 25°C and kept for 3 hours, so that the 2-methoxy-4-acetylamino benzoic acid methyl ester reacts with the hydrochloric acid to form 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester.

[0056] Then it is neutralized to neutral with baking soda (third basic substance), transferred to cold water, stirred to crystallize, filtered, and dried at 50°C to obtain 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester.

[0057] Comparative Example

[0058] This comparative example provides another method for preparing 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester, which comprises the following steps:

[0059]

[0060] S1, according to the technical solution disclosed in patent US00427564 or document JACS 1948, 70(4), P1665-1666, p-aminosalicylic acid is prepared by reacting m-amino phenol with carbon dioxide, and the conversion rate is 22%;

[0061] The product p-aminosalicylic acid is unstable and easily oxidized, the product color is deep, and the purification method is complex;

[0062] S2, 4-acetylamino salicylic acid is prepared by reacting p-aminosalicylic acid with acetic anhydride;

[0063] S3, 2-methoxy-4-acetylamino benzoic acid methyl ester is prepared by reacting 4-acetylamino salicylic acid with dimethyl sulfate;

[0064] S4、According to the technical scheme disclosed in document M Murakami, N Inukai, A Koda, K Nakano, "An Improved Synthesis of Metoclopramide", Chemical & Pharmaceutical Bulletin, 1971, 19(8): 1696-1699, document R. Pakula, K. Butkiewicz, Z. Trojanowska, J. Ruszczak, "New findings in the synthesis of metoclopramide, Archiv Der Pharmazie, 1980, 313(4): 297-300, methyl 2-methoxy-4-acetamidobenzoate is reacted with chlorine to generate methyl 4-acetamido-5-chloro-2-methoxybenzoate; or

[0065] According to the technical scheme disclosed in patent CN105523952, methyl 2-methoxy-4-acetamidobenzoate is reacted with NCS to generate methyl 4-acetamido-5-chloro-2-methoxybenzoate;

[0066] Among them, the reactant chlorine has high requirements on transportation, storage, production equipment and the like, and the acetic acid as a solvent has a heavy taste, a large amount of industrial waste acid will be generated in the post-processing process, which is large in environmental pollution and is not conducive to industrial production;

[0067] Among them, the reactant NCS has a high market price, and the product cost is increased in response.

[0068] In summary, the preparation method of the present application not only improves the product quality and production efficiency, but also reduces the cost, simplifies the operation, and is friendly to the environment, and has a significant industrial application prospect and market competitiveness.

[0069] The above only describes the preferred embodiments of the present application, and does not limit the embodiments and protection scope of the present application. For those skilled in the art, it should be realized that any equivalent replacement and obvious change made by applying the content of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate, characterized in that the step... include: S1. Acetic anhydride is added dropwise to a solution of m-aminophenol and solvent at 5℃±5℃, the temperature is raised to 25℃±5℃ and kept at this temperature for 2h-4h, so that the m-aminophenol reacts with the acetic anhydride to generate m-acetaminophenol. Then, the solvent is removed by negative pressure concentration, methanol is added, and the mixture is cooled, filtered, and dried to obtain m-acetaminophen. S2. Carbon dioxide is passed into the alkaline aqueous solution of m-acetaminophen, the temperature is raised to 100℃±10℃ and kept at this temperature for 2h-6h, so that the m-acetaminophen reacts with the carbon dioxide to generate 4-acetaminosalicylic acid. After cooling and filtration, the resulting liquid was acidified with hydrochloric acid until the pH reached 2-3, and then dried to obtain 4-acetamidosalicylic acid. S3. Dimethyl sulfate is added dropwise to the alkaline solution of 4-acetaminosalicylic acid and the first organic solvent, the temperature is raised to 30℃-40℃ and stirred for 11h-13h, so that the 4-acetaminosalicylic acid reacts with the dimethyl sulfate to generate methyl 2-methoxy-4-acetaminobenzoate. Then, the mixture was transferred to cold water, stirred to precipitate crystals, filtered, and dried to obtain methyl 2-methoxy-4-acetaminobenzoate. S4. Hydrogen peroxide is added dropwise to the solution of methyl 2-methoxy-4-acetaminobenzoate, hydrochloric acid, sodium tungstate, and acetone at 10℃-20℃. The temperature is then raised to 25℃±5℃ and maintained for 2h-4h, so that methyl 2-methoxy-4-acetaminobenzoate reacts with the hydrochloric acid to generate methyl 4-acetamido-5-chloro-2-methoxybenzoate. Then, it is neutralized to neutral with a third alkaline substance, transferred to cold water, stirred to precipitate crystals, filtered, and dried to obtain the final product.

2. The preparation method according to claim 1, characterized in that, The solvent is selected from at least one of water, methanol, ethanol, acetone, or tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that, The alkaline aqueous solution of m-acetaminophen comprises: m-acetaminophen, a first alkaline substance, and water; wherein, The first alkaline substance is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, or baking soda.

4. The preparation method according to claim 1, characterized in that, In step S2, the solid obtained from cooling and filtration is reused in the preparation of another batch.

5. The preparation method according to claim 1, characterized in that, The alkaline solution of 4-acetaminosalicylic acid and a first organic solvent comprises: 4-acetaminosalicylic acid, a second alkaline substance, and the first organic solvent; wherein, The second alkaline substance is selected from at least one of potassium hydroxide, potassium carbonate, or cesium carbonate; The first organic solvent is selected from at least one of acetonitrile, acetone, dioxane, or tetrahydrofuran.

6. The preparation method according to claim 1, characterized in that, In step S3, after filtration and drying, ethyl acetate is recrystallized.

7. The preparation method according to claim 1, characterized in that, The third alkaline substance is selected from: baking soda.

8. The preparation method according to claim 1, characterized in that, In step S4, after filtration and drying, methanol is recrystallized.

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