A kind of preparation process of metoclopramide

Abstract

This invention belongs to the field of pharmaceutical material synthesis technology, specifically relating to a preparation process of metoclopramide. The invention first hydrolyzes 4-acetamido-5-chloro-2-methoxybenzoate to obtain the hydrolysate 4-amino-5-chloro-2-methoxybenzoic acid. Then, dichloromethane, the hydrolysate, and N,N'-carbonyldiimidazole are added to a reaction vessel, and the mixture is heated to 40-50°C and maintained at this temperature. After the reaction, N,N-diethylethylenediamine is added dropwise to the reaction solution, controlling the temperature inside the reaction vessel to not exceed 43°C during the addition. After the addition is complete, the mixture is kept under reflux and the reaction is maintained at this temperature. Crude metoclopramide is obtained after the reaction, which is then purified to obtain metoclopramide. This invention achieves a high yield and improved purity of metoclopramide through the optimization of various conditions, such as screening and determining the raw material ratio and controlling the type and amount of solvent.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical material synthesis technology, specifically relating to the preparation process of metoclopramide. Background Technology

[0002] Metoclopramide, also known as clopramide, is a white to pale yellow crystalline powder with a strong central antiemetic effect. Metoclopramide is a potent centrally acting antiemetic; it is a dopamine D2 receptor antagonist and also has a 5-HT4 receptor agonist effect, while exhibiting a mild inhibitory effect on 5-HT3 receptors. It acts on dopamine receptors in the chemoreceptor trigger zone (CTZ) of the medulla oblongata, thereby increasing the CTZ threshold and exerting a strong central antiemetic effect. This drug primarily acts on the upper digestive tract, promoting the motility of the stomach and upper intestinal segment; increasing the tension of the gastrointestinal sphincter at rest, increasing the tension and amplitude of the lower esophageal sphincter, increasing the pressure at the lower end of the esophagus, blocking gastroesophageal reflux, strengthening gastric and esophageal peristalsis, enhancing the ability to clear esophageal contents, and promoting gastric emptying; promoting relaxation of the pylorus, duodenum, and upper jejunum, forming functional coordination between the gastric antrum, gastric body, and upper small intestine.

[0003] CN202111156605.6, a method for preparing a new impurity of metoclopramide diamine, involves the synthesis process of metoclopramide, namely...

[0004] This is a commonly used process route for metoclopramide. However, the yield of metoclopramide achieved under conventional process conditions is only about 90%. This process requires strict control over reagents and involves many uncontrollable factors that affect the yield and purity of metoclopramide. Furthermore, this existing technology does not involve research on the yield and purity of the target product, metoclopramide.

[0005] Therefore, the technical problem to be solved by this invention is to further explore a preparation process for metoclopramide and optimize the process conditions, which can not only significantly improve production efficiency and promote green and safe production, but also further improve the yield and purity of metoclopramide. Summary of the Invention

[0006] To address the problems in the background art, the present invention provides a synthesis process for metoclopramide that has low solvent requirements, mild preparation conditions, simple process, high production efficiency, and can produce metoclopramide with high yield and high purity.

[0007] To achieve the above objectives, the specific solution adopted by the present invention is as follows:

[0008] (1) Add anhydrous ethanol, deionized water and liquid alkali to the reaction vessel, start stirring, add 4-acetamido-5-chloro-2-methoxybenzoate, heat to reflux, there is almost no visible solid in the reaction vessel, keep the reaction vessel at 85-90℃ for 2-4 hours, TLC shows no raw material and single hydrolysis compound residue.

[0009] The liquid alkali is a 20-40% sodium hydroxide solution; the mass ratio of 4-acetamido-5-chloro-2-methoxybenzoate, anhydrous ethanol, deionized water, and liquid alkali is 1:0.6-1.0:3-5:1.2-1.5.

[0010] (2) After the reaction in step (1) is kept warm, stop heating and cool down to below 65°C. Then, start adding hydrochloric acid dropwise under stirring. During the process, the reaction solution is continuously cooled down and the pH is adjusted to 4-5. Stir and cool down to below 12°C. Stir and crystallize for 30-60 minutes. After crystallization, place it in a centrifuge and centrifuge to obtain wet product.

[0011] (3) Add anhydrous ethanol and wet product to the reactor, heat to reflux, and add deionized water dropwise to the reactor through a high-level tank. During the dropwise addition process, the temperature inside the reactor should not be lower than 74°C until the solution is clear. After turning off the heating, allow it to cool naturally. The solution will begin to become turbid at about 72°C. Cool it down to below 20°C, stir to precipitate crystals for 30-60 minutes, centrifuge to separate the crystals, wash the filter cake with 85% ethanol, and dry it at 70-80°C for 3-4 hours to obtain the hydrolysate.

[0012] The mass ratio of anhydrous ethanol, wet product and deionized water is 9-10:1:1.5-2.5.

[0013] (4) Add dichloromethane and the hydrolysate from step (3) to the reactor. After stirring and dispersing at room temperature, add N,N'-carbonyldiimidazole in two batches with an interval of 0.5 hours between additions. After the addition is complete, heat to 40-50°C and keep the temperature for 1-2 hours. After the reaction, add N,N-diethylethylenediamine dropwise to the reaction solution, controlling the temperature inside the reactor to not exceed 43°C during the dropwise addition. After the dropwise addition is complete, keep the reactor under reflux with a reflux temperature not lower than 45°C and keep the temperature for 1-2 hours. The molar ratio of the hydrolysate to N,N'-carbonyldiimidazole is 1:1-2; the molar ratio of the hydrolysate to N,N-diethylethylenediamine is 1:1.02-1.30.

[0014] Further preferred formulations include: a molar ratio of hydrolysate to N,N'-carbonyldiimidazole of 1:1.02–1.18; a molar ratio of hydrolysate to N,N-diethylethylenediamine of 1:1.03–1.20; and a mass ratio of hydrolysate to dichloromethane of 1:8–15. The choice of dichloromethane solvent and the molar ratios between the hydrolysate and N,N'-carbonyldiimidazole and N,N-diethylethylenediamine are key factors affecting the reactant yield; ratios below or above these values ​​decrease the yield.

[0015] (5) After the reaction is completed, dichloromethane is removed by vacuum distillation, deionized water is added, and the mixture is stirred at 20°C for 30-60 minutes to crystallize. After centrifugation, the filter cake is washed with deionized water and finally dried at 70-80°C to obtain crude metoclopramide. After refining, metoclopramide is obtained.

[0016] The mass ratio of hydrolysate to deionized water is 1:9 to 12.

[0017] The refining process is as follows: Isopropanol and crude metoclopramide are added to a reaction vessel, heated and refluxed until the solution is clear, activated carbon is added, and reflux is continued for 30-60 minutes; after reflux, the solution is filtered while hot, and the filtrate is filtered through a filter until clear, cooled to below 20°C, and stirred to crystallize for at least 1.5 hours. After crystallization, the solution is centrifuged, the filter cake is washed, and the filter cake is dried to obtain metoclopramide.

[0018] The mass ratio of crude metoclopramide to isopropanol is 1:7-8; the amount of activated carbon added is 1-5% of the mass of crude metoclopramide.

[0019] The reaction flow chart is as follows:

[0020]

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] In this invention, by optimizing various conditions, screening raw material ratios, and controlling the type and amount of solvent, the final synthesized metoclopramide has a high yield and can significantly improve the purity of metoclopramide at the same time. Detailed Implementation

[0023] The present invention will be described in detail below with reference to the embodiments, but the present invention is not limited to these embodiments.

[0024] Example 1

[0025] (1) Add 72 kg of anhydrous ethanol, 358 kg of deionized water, and 123.5 kg of 40% sodium hydroxide solution to the reactor. Start stirring and add 85 kg of 4-acetamido-5-chloro-2-methoxybenzoate. Heat to reflux. At this point, there is almost no visible solid in the reactor. Keep the reactor at 85°C for 3 hours. TLC indicates no residue of raw materials and single hydrolyzed compounds.

[0026] (2) After the reaction in step (1) is kept warm, stop heating and cool down to below 60°C. Then, start adding 1.2M hydrochloric acid dropwise under stirring. During the process, the reaction solution is continuously cooled down. After adjusting the pH to 4.3, continue stirring and cooling down to 10°C. Stir and crystallize for 40 minutes. After crystallization, place it in a centrifuge and centrifuge to obtain the wet product.

[0027] (3) Add 85 kg of anhydrous ethanol and 9.2 kg of wet product to the reactor, heat to reflux, and add 16 kg of deionized water dropwise to the reactor through a high-level tank. During the dropwise addition process, the temperature inside the reactor should not be lower than 80°C until the solution is clear. After turning off the heating, allow it to cool naturally. Turbidity will begin to appear. Cool to 10°C, stir to precipitate crystals for 30 minutes, centrifuge, wash the filter cake with 85% ethanol, and dry at 75°C for 3-4 hours to obtain the hydrolysate 4-amino-5-chloro-2-methoxybenzoic acid. Based on the theoretical yield of 4-acetamido-5-chloro-2-methoxybenzoic acid ester, the yield of the hydrolysate reaches 96.25%.

[0028] (4) Add 72 kg of dichloromethane and 5.2 kg of 4-amino-5-chloro-2-methoxybenzoic acid (relative molecular mass 201.61) hydrolysate from step (3) to the reactor. After stirring and dispersing at room temperature, add 4.5 kg of N,N'-carbonyldiimidazole in two batches with an interval of 0.5 hours between additions. After the addition is complete, heat to 45°C and keep the temperature for 2 hours. After the reaction, add 3.5 kg of N,N-diethylethylenediamine dropwise to the reaction solution. Control the temperature inside the reactor to not exceed 43°C during the dropwise addition. After the dropwise addition is complete, keep the reactor under reflux at 50°C and keep the temperature for 1 hour.

[0029] (5) After the reaction, dichloromethane was removed by vacuum distillation, 57 kg of deionized water was added, and the mixture was stirred at 10 °C for 30 minutes to crystallize. After centrifugation, the filter cake was washed with deionized water and finally dried at 70 °C to obtain crude metoclopramide. 65 kg of isopropanol and 8.3 kg of crude metoclopramide were added to a reaction vessel, and the mixture was heated to reflux until clear. 0.1 kg of activated carbon was added, and reflux was continued for 30 minutes. After reflux, the mixture was filtered while hot, and the filtrate was filtered through a filter until clear. The temperature was lowered to below 20 °C, and the mixture was stirred to crystallize for at least 1.5 hours. After crystallization, the mixture was centrifuged, and the filter cake was washed and dried to obtain metoclopramide. Based on the theoretical yield of 4-amino-5-chloro-2-methoxybenzoic acid, the yield of metoclopramide reached 95.1%, and the purity of metoclopramide reached 99.95%.

[0030] Example 2

[0031] (1) Add 80 kg of anhydrous ethanol, 372 kg of deionized water, and 129.2 kg of 40% sodium hydroxide solution to the reactor. Start stirring and add 92 kg of 4-acetamido-5-chloro-2-methoxybenzoate. Heat to reflux. At this point, there is almost no visible solid in the reactor. Keep the reactor at 90°C for 2 hours. TLC indicates no raw material or single hydrolysis compound residue.

[0032] (2) After the reaction in step (1) is kept warm, stop heating and cool down to below 60°C. Then, start adding 1.2M hydrochloric acid dropwise under stirring. During the process, the reaction solution is continuously cooled down. After adjusting the pH to 4.5, continue stirring and cooling down to 10°C. Stir and crystallize for 60 minutes. After crystallization, place it in a centrifuge and centrifuge to obtain the wet product.

[0033] (3) Add 92 kg of anhydrous ethanol and 10.3 kg of wet product to the reactor, heat to reflux, and add 18 kg of deionized water dropwise to the reactor through a high-level tank. The temperature inside the reactor is 85°C during the dropwise addition process, until the solution is clear. After turning off the heating, allow it to cool naturally. Turbidity will begin to appear. Cool to 10°C, stir to precipitate crystals for 50 minutes, centrifuge, wash the filter cake with 85% ethanol, and dry at 80°C for 4 hours to obtain the hydrolysate 4-amino-5-chloro-2-methoxybenzoic acid. Based on the theoretical yield of 4-acetamido-5-chloro-2-methoxybenzoic acid ester, the yield of the hydrolysate reaches 95.78%.

[0034] (4) Add 83 kg of dichloromethane and 6.4 kg of the hydrolysate from step (3), 4-amino-5-chloro-2-methoxybenzoic acid (relative molecular mass 201.61), to the reactor. After stirring and dispersing at room temperature, add 5.7 kg of N,N'-carbonyldiimidazole in two batches with an interval of 0.5 hours between additions. After the addition is completed, heat to 45°C and keep the temperature for 2 hours. After the reaction, add 4.0 kg of N,N-diethylethylenediamine dropwise to the reaction solution. Control the temperature inside the reactor to 40°C during the dropwise addition. After the dropwise addition is completed, keep the reactor under reflux at 50°C and keep the temperature for 2 hours.

[0035] (5) After the reaction, dichloromethane was removed by vacuum distillation, 65 kg of deionized water was added, and the mixture was stirred at 10 °C for 50 minutes to crystallize. After centrifugation, the filter cake was washed with deionized water and finally dried at 80 °C to obtain crude metoclopramide. 72 kg of isopropanol and 9.1 kg of crude metoclopramide were added to the reactor, and the mixture was heated to reflux until clear. 0.2 kg of activated carbon was added, and reflux was continued for 30 minutes. After reflux, the mixture was filtered while hot, and the filtrate was filtered through a filter until clear. The solution was cooled to 10 °C and stirred to crystallize for 2.0 hours. After crystallization, the mixture was centrifuged, and the filter cake was washed and dried to obtain metoclopramide. Based on the theoretical yield of 4-amino-5-chloro-2-methoxybenzoic acid, the yield of metoclopramide reached 94.6%, and the purity of metoclopramide reached 99.92%.

[0036] Comparative Example 1

[0037] Compared with Example 1, Comparative Example 1 differs in that the dichloromethane solvent in step (4) is replaced with ethyl acetate, while the other operations are the same as in Example 1, and metoclopramide is produced.

[0038] Based on the theoretical yield of 4-amino-5-chloro-2-methoxybenzoic acid, the yield of metoclopramide reached 87.3%, and the purity of metoclopramide reached 99.65%.

[0039] Comparative Example 2

[0040] The difference between Comparative Example 2 and Example 1 is that the amount of N,N'-carbonyldiimidazole added is 4.9 kg, while the other operations are the same as in Example 1, to produce metoclopramide.

[0041] Based on the theoretical yield of 4-amino-5-chloro-2-methoxybenzoic acid, the yield of metoclopramide reached 88.5%, and the purity of metoclopramide reached 99.73%.

[0042] Comparative Example 3

[0043] Compared with Example 1, Comparative Example 3 differs in that the amount of N,N-diethylethylenediamine added is 4.0 kg, while the other operations are the same as in Example 1, to produce metoclopramide.

[0044] Based on the theoretical yield of 4-amino-5-chloro-2-methoxybenzoic acid, the yield of metoclopramide reached 83.8%, and the purity of metoclopramide reached 99.57%.

[0045] Comparative Example 4

[0046] Compared with Example 1, Comparative Example 4 differs in that: after feeding the materials in step (4), the temperature is raised to 35°C and kept warm for 2 hours. Other operations are the same as in Example 1, and metoclopramide is produced.

[0047] Based on the theoretical yield of 4-amino-5-chloro-2-methoxybenzoic acid, the yield of metoclopramide reached 80.2%, and the purity of metoclopramide reached 99.28%.

Claims

1. A preparation process for metoclopramide, characterized in that: The preparation steps are as follows: (1) Add anhydrous ethanol, deionized water, and liquid alkali to the reaction vessel, start stirring, add 4-acetamido-5-chloro-2-methoxybenzoate, heat to reflux, and when there is no visible solid in the reaction vessel, keep the reaction vessel at 85~90℃ for 2~4h; the liquid alkali is a 20~40% sodium hydroxide solution by mass. (2) After the reaction in step (1) is kept warm, stop heating and cool down to below 65°C. Then, start adding hydrochloric acid dropwise under stirring. During the process, the reaction solution is continuously cooled down and the pH is adjusted to 4~5. Stir and cool down to below 12°C. Stir and crystallize for 30~60 minutes. After crystallization, place it in a centrifuge and centrifuge to obtain wet product. (3) Add anhydrous ethanol and wet product to the reactor, heat to reflux, and add deionized water dropwise to the reactor through a high-level tank. During the dropwise addition process, the temperature inside the reactor should not be lower than 74°C until the solution is clear. After turning off the heating, let it cool down naturally. The solution will start to become turbid. Cool down to below 20°C, stir to precipitate crystals for 30-60 minutes, centrifuge to separate, wash the filter cake, and dry at 70-80°C for 3-4 hours to obtain the hydrolysate. (4) Add dichloromethane and the hydrolysate from step (3) to the reactor. After stirring and dispersing at room temperature, add N,N'-carbonyldiimidazole in batches with an interval of 0.5 hours between additions. After the addition is completed, heat to 45~50℃ and keep the reaction temperature for 1~2 hours. After the reaction, add N,N-diethylethylenediamine dropwise to the reaction solution. Control the temperature inside the reactor to not exceed 43℃ during the dropwise addition. After the dropwise addition is completed, keep the reactor under reflux with a reflux temperature not lower than 45℃ and keep the reaction temperature for 1~2 hours. The molar ratio of the hydrolysate to N,N'-carbonyldiimidazole is 1:1.02~1.

18. The molar ratio of the hydrolysate to N,N-diethylethylenediamine is 1:1.03~1.

20. (5) After the reaction is completed, dichloromethane is removed by vacuum distillation, deionized water is added, and the mixture is stirred at 20°C for 30-60 minutes to crystallize. After centrifugation, the filter cake is washed with deionized water and finally dried at 70-80°C to obtain crude metoclopramide. After purification, metoclopramide is obtained. The refining process is as follows: Isopropanol and crude metoclopramide are added to a reaction vessel, heated and refluxed until the solution is clear, activated carbon is added, and reflux is continued for 30-60 minutes; after reflux, the solution is filtered while hot, and the filtrate is filtered through a filter until clear, cooled to below 20°C, and stirred to crystallize for more than 1.5 hours. After crystallization, the solution is centrifuged, and the filter cake is washed and dried to obtain metoclopramide; wherein, the mass ratio of crude metoclopramide to isopropanol is 1:7-8; the amount of activated carbon added is 1-5% of the mass of crude metoclopramide.

2. The preparation process of metoclopramide according to claim 1, characterized in that: In step (1), the mass ratio of 4-acetamido-5-chloro-2-methoxybenzoate, anhydrous ethanol, deionized water, and liquid alkali is 1:0.6~1.0:3~5:1.2~1.

5.

3. The preparation process of metoclopramide according to claim 1, characterized in that: In step (3), the mass ratio of anhydrous ethanol, wet product and deionized water is 9~10:1:1.5~2.

5.

4. The preparation process of metoclopramide according to claim 1, characterized in that: In step (4), the molar ratio of the hydrolysate to dichloromethane is 1:8~15.

5. The preparation process of metoclopramide according to claim 1, characterized in that: In step (5), the mass ratio of hydrolysate to deionized water is 1:9~12.

Images