Preparation method of methyl 4-acetamido-5-chloro-2-methoxybenzoate

Abstract

The invention relates to a preparation method of methyl 4-acetamido-5-chloro-2-methoxybenzoate. The preparation method comprises the following steps: S1, reacting m-aminophenol with acetic anhydride to generate m-acetaminophenol; s2, enabling the m-acetaminophen to react with carbon dioxide to generate 4-acetamidosalicylic acid; s3, the 4-acetamido salicylic acid and dimethyl sulfate are subjected to a reaction, and 2-methoxy-4-acetamido methyl benzoate is generated; and S4, carrying out a reaction on the methyl 2-methoxy-4-acetamidobenzoate and hydrochloric acid, so as to generate the methyl 4-acetamido-5-chloro-2-methoxybenzoate. According to the preparation method, the product quality and the production efficiency are improved, the cost is reduced, the operation is simplified, and the preparation method is environmentally friendly and has remarkable industrial application prospects and market competitiveness.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate. Background Art

[0002] Metoclopramide, also known as metoclopramide, is a dopamine D2 receptor antagonist with 5-hydroxytryptamine 4 (5-HT4) receptor agonist effect and mild inhibitory effect on 5-HT3 receptor. The drug is widely used to treat vomiting caused by brain tumor surgery, tumor radiotherapy and chemotherapy, sequelae of brain trauma, acute craniocerebral injury and drugs. In addition, metoclopramide also has a good effect on digestive system symptoms such as bloating indigestion, loss of appetite, belching, nausea, vomiting, etc. It is also used for vomiting and motion sickness (ship) caused by sea and air operations, as well as to reduce nausea and vomiting reactions during barium meal examination and promote the passage of barium.

[0003] In the synthesis process of metoclopramide, 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester is a key intermediate. The quality of its 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 publicly reported documents 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 invention aims to provide a method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate, so as to solve the problems existing in the prior art, improve the synthesis efficiency, reduce the production cost, and reduce the impact on the environment. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate in view of the deficiencies in the prior art.

[0006] To achieve the above object, the technical solution adopted by the present invention is:

[0007] Provided is a method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate, the steps comprising:

[0008] S1, adding acetic anhydride dropwise to a solution of m-aminophenol and a solvent at 5°C±5°C, raising the temperature to 25°C±5°C and keeping the temperature for 2h-4h, so that the m-aminophenol reacts with the acetic anhydride to generate m-acetaminophenol;

[0009] Then, the first solvent is removed by vacuum concentration, methanol is added, the mixture is cooled, filtered, and dried to obtain meta-acetaminophen;

[0010] S2, passing carbon dioxide into the alkaline aqueous solution of meta-acetaminophen, raising the temperature to 100° C.±10° C. and keeping the temperature for 2 h-6 h, so that the meta-acetaminophen reacts with the carbon dioxide to generate 4-acetylaminosalicylic acid;

[0011] Then cool and filter, and the obtained liquid hydrochloric acid is precipitated to pH 2-3, and dried to obtain 4-acetylaminosalicylic acid;

[0012] S3, adding dimethyl sulfate dropwise to the alkaline solution of 4-acetylaminosalicylic acid and the first organic solvent, heating to 30° C.-40° C. and stirring for 11 h-13 h, so that the 4-acetylaminosalicylic acid and the dimethyl sulfate react to generate methyl 2-methoxy-4-acetylaminobenzoate;

[0013] Then transfer to cold water, stir and crystallize, filter, and dry to obtain methyl 2-methoxy-4-acetylaminobenzoate;

[0014] S4, adding hydrogen peroxide dropwise to the solution of methyl 2-methoxy-4-acetamidobenzoate, hydrochloric acid, a catalyst, and a second organic solvent at 10°C-20°C, raising the temperature to 25°C±5°C and keeping the temperature for 2h-4h, so that the methyl 2-methoxy-4-acetamidobenzoate reacts with the hydrochloric acid to generate methyl 4-acetamido-5-chloro-2-methoxybenzoate;

[0015] Then, the product is neutralized with a third alkaline substance to neutrality, transferred to cold water, stirred for crystallization, filtered and dried to obtain the product.

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

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

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

[0019] Preferably, in S2, the solid obtained by cooling and filtering is applied to the preparation of another batch.

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

[0021] The second alkaline 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, and tetrahydrofuran.

[0023] Preferably, in S3, after filtering and drying, recrystallization from ethyl acetate is also 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 alkaline substance is selected from: baking soda.

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

[0028] The present invention adopts the above technical solution, 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 invention has significant technical advantages and effects. First, by first acetylation protection of m-aminophenol, we significantly improve the stability of the intermediate, which not only ensures the smooth progress of subsequent reactions, 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 terms of operation, we replaced the chlorination reagent with hydrochloric acid and hydrogen peroxide to prepare chlorine in situ. This improvement makes the operation simpler, lower cost, and easier to industrialize. 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 emission of harmful chemicals, is more environmentally friendly, and is in line with the development trend of modern green chemistry.

[0031] In general, the preparation method of the present invention not only improves product quality and production efficiency, but also reduces costs, simplifies operations, is environmentally friendly, and has significant industrial application prospects and market competitiveness. DETAILED DESCRIPTION

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

[0033] Unless otherwise defined, technical or scientific terms used in the claims and the specification shall have the common meanings understood by persons having ordinary skills in the technical field to which the present invention belongs.

[0034] The words "include" or similar words used in the patent application specification and claims of the present invention mean that the items appearing before "include" include the items listed after "include" or their equivalents, and do not exclude other items.

[0035] The numerical values ​​mentioned in the present invention include all numerical values ​​that increase from low to high by one unit, assuming that there are at least two units between any lower value and the higher value. For example, if a component or a physical quantity is said to be from 1 to 100, 10 to 90 is more preferred, and 20 to 80 is the most preferred, it is intended to express that values ​​such as 5 to 95, 14 to 76, 23 to 67, 32 to 58, 41 to 49 are clearly listed in this specification; for values ​​less than 1, 0.0001, 0.001, 0.01 or 0.1 are considered to be more suitable as a unit. The above examples are for illustrative purposes only. In fact, all numerical combinations between the lowest value and the highest value listed are deemed to be clearly listed in this specification in a similar manner.

[0036] Example 1

[0037] This embodiment provides a method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate, the steps comprising:

[0038]

[0039] S1. Add 200.0 g of m-aminophenol and 1000 mL of acetone (solvent) into a reaction flask, and cool to 0°C-5°C; add 255.0 g of acetic anhydride dropwise into the reaction flask, and control the temperature at 5°C±5°C; after the addition, heat to 25°C±5°C and keep warm for 3 hours, so that the m-aminophenol reacts with the acetic anhydride to generate m-acetaminophenol;

[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 paracetamol, with a yield of 95.0%, HPLC purity of 99.92%, MP: 146°C-149°C, 1 H-NHR (DMSO-d6, 400MHz) δ: 5.22 (S, 2H), 6.20-6.93 (dd, 4H), 9.60 (S, 1H).

[0041] S2, adding 50.0g of the meta-acetaminophen, 30.6g of baking soda (the first alkaline substance), and 150mL of water into an autoclave; after introducing CO2 to 1.5MPa, heating to 90°C and keeping warm for 6h, so that the meta-acetaminophen reacts with the carbon dioxide to generate 4-acetylaminosalicylic acid;

[0042] Then cool to room temperature and release the pressure, continue to cool to 0℃-5℃, filter, and apply the obtained solid to the preparation of another batch. The obtained liquid hydrochloric acid is acidified to pH 2-3, filtered, and dried in a vacuum oven at 45℃ to obtain 29.0g of 4-acetylaminosalicylic acid, with HPLC purity of 99.41%, a primary conversion rate of 45.0%, and a molar yield of 95.0% after application, MP: 221℃-223℃, 1 H-NHR (DMSO-d6, 400MHz) δ: 3.710 (S, 3H), 6.155 (S, 2H), 6.530 (S, 1H), 7.652 (S, 1H).

[0043] S3, adding 100g of the 4-acetylaminosalicylic acid, 240g of potassium carbonate (the second alkaline substance), and 500mL of acetone (the first organic solvent) into a reaction flask; adding 250g of dimethyl sulfate dropwise under stirring; after the addition, heating to 35°C±5°C and stirring for 12h, so that the 4-acetylaminosalicylic acid reacts with the dimethyl sulfate to generate 2-methoxy-4-acetylaminobenzoic acid methyl ester;

[0044] The reaction solution was then transferred to cold water, stirred for crystallization and filtered, and dried at 50°C to obtain 102.5 g of methyl 2-methoxy-4-acetylaminobenzoate with a yield of 89.9% and an HPLC purity of 98.72%. After recrystallization with 300 mL of ethyl acetate, 93.6 g of a fine product was obtained with an HPLC purity of 99.78%, MP: 126°C-128°C. 1 H-NHR (DMSO-d6, 400MHz) 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, add 20g of the 2-methoxy-4-acetylaminobenzoic acid methyl ester, 13.6g of 36% hydrochloric acid, 0.1g of sodium tungstate (catalyst), and 120mL of acetone (second organic solvent) to the reaction bottle; control the temperature at 15°C ± 5°C and slowly drip 20.3g of 30% hydrogen peroxide, after about 3 hours of dripping, raise the temperature to 25°C and keep warm for 3h, so that the 2-methoxy-4-acetylaminobenzoic acid methyl ester reacts with the hydrochloric acid to generate 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester;

[0046] Then, the mixture was neutralized with baking soda (the third alkaline substance) to neutrality, transferred to cold water, stirred and crystallized, filtered, and dried at 50°C to obtain 22.2 g of methyl 4-acetamido-5-chloro-2-methoxybenzoate with a yield of 96%. After recrystallization with 100 mL of methanol, 20.5 g of fine product was obtained, with a HPLC purity of 99.99%, MP: 151°C-152°C, 1 H-NHR (DMSO-d6, 400MHz) 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 embodiment provides a method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate, the steps comprising:

[0049] S1. Add 200.0 g of m-aminophenol and 1000 mL of water (solvent) to a reaction flask, and cool to 0°C-5°C; add 255.0 g of acetic anhydride dropwise to the reaction flask, and control the temperature at 5°C±5°C; after the addition, heat to 25°C±5°C and keep warm for 3 hours, so that the m-aminophenol reacts with the acetic anhydride to generate m-acetaminophenol;

[0050] 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 meta-acetaminophen;

[0051] S2, adding 50.0g of the meta-acetaminophen, 30.6g of potassium carbonate (the first alkaline substance), and 150mL of water into an autoclave; after introducing CO2 to 1.5MPa, heating to 110°C and keeping warm for 2h, so that the meta-acetaminophen reacts with the carbon dioxide to generate 4-acetylaminosalicylic acid;

[0052] Then cool to room temperature and release the pressure, continue to cool to 0°C-5°C, filter, and apply the obtained solid to the preparation of another batch. The obtained liquid is acidified with hydrochloric acid to a pH of 2-3, filtered, and dried in a vacuum oven at 45°C to obtain 4-acetylaminosalicylic acid;

[0053] S3, add 100g of the 4-acetylaminosalicylic acid, 240g of potassium hydroxide (second alkaline substance), and 500mL of acetonitrile (first organic solvent) into a reaction flask; add 250g of dimethyl sulfate dropwise under stirring; after the addition, heat to 35°C±5°C and stir for 12h, so that the 4-acetylaminosalicylic acid reacts with the dimethyl sulfate to generate 2-methoxy-4-acetylaminobenzoic acid methyl ester;

[0054] The reaction solution was then transferred to cold water, stirred for crystallization, filtered, and dried at 50°C to obtain methyl 2-methoxy-4-acetylaminobenzoate;

[0055] S4, add 20g of the 2-methoxy-4-acetylaminobenzoic acid methyl ester, 13.6g of 36% hydrochloric acid, 0.1g of sodium tungstate (catalyst), and 120mL of toluene (second organic solvent) into the reaction bottle; control the temperature at 15°C ± 5°C and slowly drop 20.3g of 30% hydrogen peroxide, after about 3 hours of dripping, raise the temperature to 25°C and keep warm for 3h, so that the 2-methoxy-4-acetylaminobenzoic acid methyl ester reacts with the hydrochloric acid to generate 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester;

[0056] Then, the mixture was neutralized with baking soda (the third alkaline substance) to neutrality, transferred to cold water, stirred for crystallization, filtered, and dried at 50° C. to obtain methyl 4-acetamido-5-chloro-2-methoxybenzoate.

[0057] Comparative Example

[0058] This comparative example provides another method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate, the steps comprising:

[0059]

[0060] S1. According to the technical solution disclosed in patent US00427564 or document JACS1948,70(4),P1665-1666, m-aminophenol is reacted with carbon dioxide to generate p-aminosalicylic acid, with a conversion rate of 22%;

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

[0062] S2, reacting p-aminosalicylic acid with acetic anhydride to generate 4-acetylaminosalicylic acid;

[0063] S3, reacting 4-acetylaminosalicylic acid with dimethyl sulfate to generate methyl 2-methoxy-4-acetylaminobenzoate;

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

[0065] According to the technical solution 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 for transportation, storage, production equipment, etc., and acetic acid as a solvent has a strong smell. A large amount of industrial waste acid will be generated during the post-processing process, which will cause great pollution to the environment and is not conducive to industrial production.

[0067] Among them, the market price of reactant NCS is relatively high, and the product cost response is increased.

[0068] In summary, the preparation method of the present invention not only improves product quality and production efficiency, but also reduces costs, simplifies operations, is environmentally friendly, and has significant industrial application prospects and market competitiveness.

[0069] The above description is only a preferred embodiment of the present invention, and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the contents of the specification of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing methyl 4-acetamido-5-chloro-2-methoxybenzoate, characterized in that the steps include: S1, adding acetic anhydride dropwise to a solution of m-aminophenol and a solvent at 5°C±5°C, raising the temperature to 25°C±5°C and keeping the temperature for 2h-4h, so that the m-aminophenol reacts with the acetic anhydride to generate m-acetaminophenol; Then, the first solvent is removed by vacuum concentration, methanol is added, the mixture is cooled, filtered, and dried to obtain meta-acetaminophen; S2, passing carbon dioxide into the alkaline aqueous solution of meta-acetaminophen, raising the temperature to 100° C.±10° C. and keeping the temperature for 2 h-6 h, so that the meta-acetaminophen reacts with the carbon dioxide to generate 4-acetylaminosalicylic acid; Then cool and filter, and the resulting liquid is acidified with hydrochloric acid to a pH of 2-3, and dried to obtain 4-acetylaminosalicylic acid; S3, adding dimethyl sulfate dropwise to the alkaline solution of 4-acetylaminosalicylic acid and the first organic solvent, heating to 30° C.-40° C. and stirring for 11 h-13 h, so that the 4-acetylaminosalicylic acid and the dimethyl sulfate react to generate methyl 2-methoxy-4-acetylaminobenzoate; Then transfer to cold water, stir and crystallize, filter, and dry to obtain methyl 2-methoxy-4-acetylaminobenzoate; S4, adding hydrogen peroxide dropwise to the solution of methyl 2-methoxy-4-acetamidobenzoate, hydrochloric acid, a catalyst, and a second organic solvent at 10°C-20°C, raising the temperature to 25°C±5°C and keeping the temperature for 2h-4h, so that the methyl 2-methoxy-4-acetamidobenzoate reacts with the hydrochloric acid to generate methyl 4-acetamido-5-chloro-2-methoxybenzoate; Then, the product is neutralized with a third alkaline substance to neutrality, transferred to cold water, stirred for crystallization, filtered and dried to obtain the 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, and tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that: The alkaline aqueous solution of meta-acetaminophen comprises: the meta-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 S2, the solid obtained by cooling and filtering is applied to the preparation of another batch.

5. The preparation method according to claim 1, characterized in that: The alkaline solution of 4-acetylaminosalicylic acid and a first organic solvent comprises: the 4-acetylaminosalicylic acid, a second alkaline substance, and a 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, and tetrahydrofuran.

6. The preparation method according to claim 1, characterized in that: In S3, after filtering and drying, recrystallization from ethyl acetate is also performed.

7. The preparation method according to claim 1, characterized in that: The catalyst is selected from: sodium tungstate.

8. The preparation method according to claim 1, characterized in that: The second organic solvent is selected from at least one of toluene, acetonitrile, acetone, dichloromethane, and tetrahydrofuran.

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

10. The preparation method according to claim 1, characterized in that: In S4, after filtering and drying, methanol recrystallization is also performed.

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