Purification method of crude mezlocillinic acid

Abstract

This invention discloses a purification method for crude meropenem acid. The method involves adding a solvent to a reaction vessel, cooling the mixture to 16-20°C, adding the crude meropenem acid and an antioxidant, controlling the temperature at 16-23°C, and starting to add an alkaline solution dropwise. The solution is dissolved for 30-40 minutes, with the pH of the dissolved solution controlled at 6-10. A decolorizing agent is added, and the mixture is stirred and filtered. An extractant is added for a first extraction, followed by a second extraction with the same extractant in the aqueous phase. Both aqueous phases are collected, and the temperature is controlled at 16-20°C. Dilute hydrochloric acid is added dropwise to the aqueous phase. If the mixture becomes turbid, seed crystals are added to promote crystal growth. Dilute hydrochloric acid is continued to be added until the pH reaches 1.6-2. The temperature is lowered to 0-5°C to promote crystal growth. The mixture is centrifuged, and the filter cake is washed with purified water until the filtrate is neutral. The filtrate is then rinsed with ethanol at -20 to -10°C, and finally vacuum dried at 40-50°C to obtain purified meropenem acid. This purification method significantly reduces the content of single impurities, total impurities, and polymers in the product, improving product quality and making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, and specifically to a method for purifying crude mezlocillinic acid. Background Technology

[0002] Meropenem is a third-generation semi-synthetic broad-spectrum antibiotic. It is resistant to acid, alkali, and enzymes, and has strong antibacterial activity against Gram-positive cocci and Gram-positive bacilli. It is effective against bacterial infections such as Rebola pneumoniae, Pseudomonas aeruginosa, and Streptococcus.

[0003] Meropenem sodium is one of China's essential medicines. It was first marketed in Germany in 1977 and subsequently approved for marketing by pharmaceutical authorities in the US, Japan, and Europe in the 1980s. Its antibacterial activity is similar to carbenicillin, but its spectrum of action is broader and its antibacterial activity is wider than that of natural penicillin. Its use as a single agent is gradually decreasing; it is now often used in combination with sulbactam in compound preparations. Chemical name: (2S,5R,6R)-3,3-dimethyl-6-[(R)-2[3-(methanesulfonyl)-2-oxo-1-imidazolidineformamide]-2-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-formate sodium salt, with the following structural formula:

[0004]

[0005] Meropenem sodium is a highly effective benzodiazepine penicillin antibiotic, but it is poorly absorbed from the gastrointestinal tract. Its sodium salt is commonly used for parenteral administration, but this often causes allergic reactions, threatening patient safety. Allergic reactions to β-lactam antibiotics are related to their high molecular weight polymers and impurities. For safe medication, controlling polymers and impurities must begin at the source. Meropenem acid, as a starting material for meropenem sodium, is crucial for improving the quality of the sodium salt by reducing its polymer and impurity content, thus controlling sensitizing substances. Currently, commercially available meropenem acid typically contains approximately 0.5% single impurities, 1% total impurities, and 0.1% polymers. Therefore, there is an urgent need to provide a purification method for crude meropenem acid to reduce its polymer and impurity content. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a purification method for crude mezlocillin acid, which greatly reduces the content of single impurities, total impurities and polymers in the product, improves the quality of the product, and is suitable for large-scale industrial production.

[0007] The technical solution of this invention is as follows:

[0008] The purification method for crude meropenem acid involves adding solvent to a reaction vessel, cooling to 16-20℃, adding crude meropenem acid and an antioxidant, stirring, controlling the temperature at 16-23℃, and starting to add alkaline solution dropwise. The solution is dissolved in 30-40 minutes, with the pH of the dissolved solution controlled at 6-10. A decolorizing agent is added, and the mixture is stirred and filtered. An extractant is added for a first extraction, and the aqueous phase is then subjected to a second extraction. Both aqueous phases are collected, and the temperature is controlled at 16-20℃. Dilute hydrochloric acid is added dropwise to the aqueous phase. If turbidity occurs, seed crystals are added to promote crystal growth. Dilute hydrochloric acid is continued to be added until the pH reaches 1.6-2. The temperature is lowered to 0-5℃ for crystal growth, centrifuged, and the filter cake is washed with purified water until the filtrate is neutral. The filtrate is then rinsed with ethanol at -20~-10℃, and finally vacuum dried at 40-50℃ to obtain purified meropenem acid.

[0009] Preferably, the solvent is one or more selected from purified water, ethyl acetate, tetrahydrofuran, and acetonitrile.

[0010] Preferably, the solvent is purified water.

[0011] Preferably, the antioxidant is one or more of EDTA-2Na, sodium bisulfite, and sodium metabisulfite.

[0012] Preferably, the antioxidant is EDTA-2Na.

[0013] Preferably, the alkaline solution is a sodium hydroxide solution, triethylamine, ammonia, sodium bicarbonate solution, or sodium carbonate solution.

[0014] Preferably, the alkaline solution is a sodium hydroxide solution.

[0015] Preferably, the mass ratio of crude mezlocillin acid, antioxidant, solvent and decolorizing agent is 1:0.01-0.005:8-12:0.08-0.12.

[0016] Preferably, the extractant is ethyl acetate or methyl acetate.

[0017] Preferably, the extractant is ethyl acetate.

[0018] Preferably, the mass ratio of the extractant in the primary extraction, the extractant in the secondary extraction, and the solvent is 1:1:2-5.

[0019] Preferably, the seed crystal is meropenemic acid, and the mass ratio of crude meropenem to seed crystal is 1:0.01-0.02.

[0020] Preferably, the decolorizing agent is activated carbon.

[0021] Preferably, the mass ratio of ethanol to solvent is 1:10.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] The purification method for crude mezlocillin acid of the present invention greatly reduces the content of single impurities, total impurities and polymers in the product, improves the product quality, and is suitable for large-scale industrial production; moreover, the method is simple, easy to operate, the raw materials are readily available, and the solvent can be recycled, which has high economic value and environmental benefits. Attached Figure Description

[0024] Figure 1 This is the polymer spectrum of crude mezlocillin acid.

[0025] Figure 2 This is the polymer spectrum of the refined meropenem acid from Example 1.

[0026] Figure 3 This is the polymer spectrum of the refined meropenem acid from Example 2.

[0027] Figure 4 This is the polymer spectrum of the refined meropenem acid from Example 3.

[0028] Figure 5 This is the polymer spectrum of the refined meropenem acid in Comparative Example 1. Detailed Implementation

[0029] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention.

[0030] Example 1

[0031] The purification method of crude mezlocillinic acid in this embodiment is as follows:

[0032] Under nitrogen protection, add 1000g of purified water to a 2L reaction flask, cool to 17℃, and then add 100g of crude meropenem and EDTA. 0.8g of melamine was added and stirred for 5 minutes. The temperature was controlled at 18℃, and 2.5% sodium hydroxide solution was added dropwise. The solution was dissolved in 2.5% sodium hydroxide solution for 40 minutes, and the pH of the dissolved solution was controlled at 8.2. 10g of activated carbon was added and stirred for 30 minutes. The mixture was filtered, and 350g of ethyl acetate was added for a first extraction. Another 350g of ethyl acetate was added to the aqueous phase for a second extraction. The organic phase was recycled. The two aqueous phases were collected, and the temperature was controlled at 18℃. 5% dilute hydrochloric acid was added dropwise to the aqueous phase to induce crystallization. The solution became turbid at approximately pH 4.5. 1g of seed crystals was added to promote crystal growth for 30 minutes. 5% dilute hydrochloric acid was added dropwise until the pH reached 2. The temperature was lowered to 5℃, and crystal growth continued for 30 minutes. The mixture was centrifuged, and the filter cake was washed with purified water until the filtrate was neutral. The filtrate was then washed with ethanol at -20℃, dried under vacuum, and the wet product was dried at 50℃ under vacuum to obtain 89.2g of purified melamine acid, with a yield of 89.2%. The single impurity content was 0.054%, the total impurity content was 0.196%, and the polymer content was 0.016%. Figure 1 This is the polymer spectrum of crude meropenem. Figure 2 This is the polymer spectrum of the refined meropenem acid in this embodiment.

[0033] Example 2

[0034] The purification method of crude mezlocillinic acid in this embodiment is as follows:

[0035] Under nitrogen protection, add 1000g of purified water to a 2L reaction flask, cool to 17℃, and then add 100g of crude meropenem and EDTA. 0.8g was added and stirred for 5 minutes; the temperature was controlled at 16℃, and 2.5% sodium hydroxide solution was added dropwise, and the solution was dissolved in 40 minutes, with the pH of the dissolved solution controlled at 6; 10g of activated carbon was added, and the mixture was stirred for 30 minutes, filtered, and 350g of methyl acetate was added for a first extraction. Another 350g of methyl acetate was added to the aqueous phase for a second extraction. The organic phase was recovered and reused. The two aqueous phases were collected, and the temperature was controlled at 16℃. 5% dilute hydrochloric acid was added dropwise to the aqueous phase to induce crystallization. The solution became turbid at approximately pH 4.5. 1g of seed crystals was added to promote crystal growth for 30 minutes, and 5% dilute hydrochloric acid was added dropwise until the pH reached 2. The temperature was lowered to 5℃, and crystal growth was continued for 30 minutes. The mixture was centrifuged, and the filter cake was washed with purified water until the filtrate was neutral. The mixture was then rinsed with -20℃ ethanol, dried under vacuum, and the wet product was dried at 50℃ under vacuum to obtain 89g of purified mezlocillin acid, with a yield of 89%, 0.1% single impurities, 0.286% total impurities, and 0.02% polymer. Figure 3 This is the polymer spectrum of the refined meropenem acid in this embodiment.

[0036] Example 3

[0037] The purification method of crude mezlocillinic acid in this embodiment is as follows:

[0038] Under nitrogen protection, 1000 g of tetrahydrofuran was added to a 2 L reaction flask, the temperature was lowered to 17 °C, 100 g of crude meropenemic acid and 0.8 g of sodium bisulfite were added, and the mixture was stirred for 5 min. The temperature was maintained at 23 °C, and 2.5% sodium hydroxide solution was added dropwise, and the mixture was allowed to dissolve completely within 40 min, maintaining the pH of the dissolved solution at 6. 10 g of activated carbon was added, and the mixture was stirred for 30 min. The mixture was filtered, and 350 g of ethyl acetate was added for a first extraction. The aqueous phase was then subjected to a second extraction with 350 g of ethyl acetate. The organic phase was recovered and reused. Two aqueous phases were prepared at 20°C. 5% dilute hydrochloric acid was added dropwise to the aqueous phase to induce crystallization. When the pH reached approximately 4.5 and the solution became turbid, 1g of seed crystals was added and allowed to grow for 30 minutes. 5% dilute hydrochloric acid was then added dropwise until the pH reached 2. The temperature was lowered to 5°C, and crystals were grown for another 30 minutes. The mixture was centrifuged, and the filter cake was washed with purified water until the filtrate was neutral. It was then rinsed with ethanol at -20°C, dried under vacuum, and the wet product was vacuum-dried at 50°C to obtain 85g of purified meropenem acid, with a yield of 85%. The impurities were: 0.084% single impurities, 0.311% total impurities, and 0.026% polymer. Figure 4 This is the polymer spectrum of the refined meropenem acid in this embodiment.

[0039] Comparative Example 1

[0040] The purification method for crude meropenem acid in Comparative Example 1 is as follows:

[0041] Under nitrogen protection, add 1000g of purified water to a 2L reaction flask, cool to 17℃, and then add 100g of crude meropenem and EDTA. 0.8g of melamine was added and stirred for 5 minutes. The temperature was controlled at 16℃, and 2.5% sodium hydroxide solution was added dropwise. The solution was dissolved in 2.5% sodium hydroxide solution for 40 minutes, and the pH of the dissolved solution was controlled at 12.5. 10g of activated carbon was added and stirred for 30 minutes. The mixture was filtered, and 350g of ethyl acetate was added for a first extraction. Another 350g of ethyl acetate was added to the aqueous phase for a second extraction. The organic phase was recycled. The two aqueous phases were collected, and the temperature was controlled at 20℃. 5% dilute hydrochloric acid was added dropwise to the aqueous phase to induce crystallization. The solution became turbid at approximately pH 4.5. 1g of seed crystals was added to promote crystal growth for 30 minutes. 5% dilute hydrochloric acid was added dropwise until the pH reached 2. The temperature was lowered to 5℃, and crystal growth continued for 30 minutes. The mixture was centrifuged, and the filter cake was washed with purified water until the filtrate was neutral. The filter cake was then rinsed with -20℃ ethanol, dried under vacuum, and the wet product was dried at 50℃ under vacuum to obtain 86g of purified melamine acid, with a yield of 86%. The single impurity content was 0.181%, the total impurity content was 0.413%, and the polymer content was 0.05%. Figure 5 This is the polymer spectrum of the refined meropenem acid in Comparative Example 1.

[0042] Comparative Example 2

[0043] The purification method for crude meropenem acid in Comparative Example 2 is as follows:

[0044] Under nitrogen protection, add 1000g of purified water to a 2L reaction flask, cool to 17℃, and then add 100g of crude meropenem and EDTA. 0.8g of methyl methacrylate was added and stirred for 5 minutes. The temperature was controlled at 18℃, and 2.5% sodium hydroxide solution was added dropwise. The solution was dissolved in 40 minutes, and the pH of the dissolved solution was controlled at 8.2. 10g of activated carbon was added and stirred for 30 minutes. The solution was filtered and 350g of ethyl acetate was added for a first extraction. 350g of ethyl acetate was added to the aqueous phase for a second extraction. The organic phase was recycled. The aqueous phases were collected from both extractions. The temperature was controlled at 18℃, and 5% dilute hydrochloric acid was added dropwise to the aqueous phase to induce crystallization. The solution was turbid at a pH of about 4.5. 0.5g of seed crystals was added and crystallized in 30 minutes. 5% dilute hydrochloric acid was added dropwise until the pH reached 2. The temperature was lowered to 5℃ and crystallized in 30 minutes. The solution was centrifuged and the filter cake was washed with purified water until the filtrate was neutral. The solution was then washed with ethanol at -20℃, dried under vacuum, and the wet product was dried at 50℃ under vacuum to obtain 84.3g of purified mezlocillin acid, with a yield of 84.3%. The single impurity was 0.451%, the total impurity was 0.846%, and the polymer was 0.05%.

[0045] Comparative Example 3

[0046] The purification method for crude meropenem acid in Comparative Example 3 is as follows:

[0047] Under nitrogen protection, add 1000g of purified water to a 2L reaction flask, cool to 17℃, and then add 100g of crude meropenem and EDTA. 0.8g of methyl methacrylate was added and stirred for 5 minutes. The temperature was controlled at 18℃, and 2.5% sodium hydroxide solution was added dropwise. The solution was dissolved in 40 minutes, and the pH of the dissolved solution was controlled at 8.2. 10g of activated carbon was added and stirred for 30 minutes. The solution was filtered and 350g of ethyl acetate was added for a first extraction. 350g of ethyl acetate was added to the aqueous phase for a second extraction. The organic phase was recycled. The aqueous phases were collected from both extractions. The temperature was controlled at 18℃, and 5% dilute hydrochloric acid was added dropwise to the aqueous phase to induce crystallization. The solution was turbid at a pH of about 4.5. 1g of seed crystals was added and crystallized in 30 minutes. 5% dilute hydrochloric acid was added dropwise until the pH reached 3.0. The temperature was lowered to 5℃ and crystallized in 30 minutes. The solution was centrifuged and the filter cake was washed with purified water until the filtrate was neutral. The solution was then washed with ethanol at -20℃, dried under vacuum, and the wet product was dried at 50℃ under vacuum to obtain 72.1g of purified mezlocillin acid, with a yield of 72.1%. The single impurity was 0.074%, the total impurity was 0.296%, and the polymer was 0.036%.

[0048] Comparative Example 4

[0049] The purification method for crude meropenem acid in Comparative Example 4 is as follows:

[0050] Under nitrogen protection, add 1000g of purified water to a 2L reaction flask, cool to 17℃, and then add 100g of crude meropenem and EDTA. 0.8g of melamine was added and stirred for 5 minutes. The temperature was controlled at 18℃, and 2.5% sodium hydroxide solution was added dropwise. The solution was dissolved in 40 minutes, and the pH of the dissolved solution was controlled at 8.2. 10g of activated carbon was added and stirred for 30 minutes. The solution was filtered, and 350g of ethyl acetate was added for a first extraction. 350g of ethyl acetate was added to the aqueous phase for a second extraction. The organic phase was recycled. The aqueous phases were collected twice. The temperature was controlled at 25℃, and 5% dilute hydrochloric acid was added dropwise to the aqueous phase to induce crystallization. The solution was turbid at a pH of about 4.5. 1g of seed crystals was added to grow crystals for 30 minutes. 5% dilute hydrochloric acid was added dropwise until the pH reached 2. The temperature was lowered to 5℃, and crystals were grown for 30 minutes. The solution was centrifuged, and the filter cake was washed with purified water until the filtrate was neutral. The solution was then washed with ethanol at -20℃, dried under vacuum, and the wet product was dried at 50℃ under vacuum to obtain 87.5g of pure mezlocillin acid, with a yield of 87.5%. The single impurity was 0.138%, the total impurity was 0.537%, and the polymer was 0.05%.

Claims

1. A method for purifying crude mezlocillin acid, characterized in that, Under the protection of nitrogen, 1000g of purified water was added into a 2L reaction flask, cooled to 17℃, 100g of crude mezlocillin acid and 0.8g of EDTA were added, and stirred for 5min; the temperature was controlled at 18℃, 2.5% sodium hydroxide solution was added dropwise, and the solution was clarified in 40min, and the pH of the clarified solution was controlled at 8.2; 10g of activated carbon was added, stirred for 30min, filtered, 350g of ethyl acetate was added for first extraction, and 350g of ethyl acetate was added for second extraction of the water phase, the organic phase was recovered and reused, the two water phases were collected, the temperature was controlled at 18℃, 5% dilute hydrochloric acid was added dropwise to the water phase to crystallize, the pH was 4.5, the solution was turbid, 1g of crystal seed was added to grow crystals for 30min, 5% dilute hydrochloric acid was continuously added until the pH was 2, the temperature was lowered to 5℃, and the crystals were grown for 30min, centrifuged, the filter cake was washed with purified water until the filtrate was neutral, then washed with -20℃ ethanol, dried, and the wet product was vacuum dried at 50℃ to obtain 89.2g of fine mezlocillin acid, the yield was 89.2%, the single impurity was 0.054%, the total impurity was 0.196%, and the polymer was 0.016%.

2. A process for the purification of crude mezocillin acid characterized in that, Under the protection of nitrogen, 1000g of purified water was added into a 2L reaction flask, cooled to 17℃, 100g of crude mezlocillin acid and 0.8g of EDTA were added, and stirred for 5min; the temperature was controlled at 18℃, 2.5% sodium hydroxide solution was added dropwise, and the solution was clarified in 40min, and the pH of the clarified solution was controlled at 8.2; 10g of activated carbon was added, stirred for 30min, filtered, 350g of ethyl acetate was added for first extraction, and 350g of ethyl acetate was added for second extraction of the water phase, the organic phase was recovered and reused, the two water phases were collected, the temperature was controlled at 18℃, 5% dilute hydrochloric acid was added dropwise to the water phase to crystallize, the pH was 4.5, the solution was turbid, 1g of crystal seed was added to grow crystals for 30min, 5% dilute hydrochloric acid was continuously added until the pH was 2, the temperature was lowered to 5℃, and the crystals were grown for 30min, centrifuged, the filter cake was washed with purified water until the filtrate was neutral, then washed with -20℃ ethanol, dried, and the wet product was vacuum dried at 50℃ to obtain 89.2g of fine mezlocillin acid, the yield was 89.2%, the single impurity was 0.054%, the total impurity was 0.196%, and the polymer was 0.016%.

3. A process for the purification of crude mezlocillin acid characterized in that, Under the protection of nitrogen, 1000g of purified water was added into a 2L reaction flask, cooled to 17℃, 100g of crude mezlocillin acid and 0.8g of EDTA were added, and stirred for 5min; the temperature was controlled at 18℃, 2.5% sodium hydroxide solution was added dropwise, and the solution was clarified in 40min, and the pH of the clarified solution was controlled at 8.2; 10g of activated carbon was added, stirred for 30min, filtered, 350g of ethyl acetate was added for first extraction, and 350g of ethyl acetate was added for second extraction of the water phase, the organic phase was recovered and reused, the two water phases were collected, the temperature was controlled at 18℃, 5% dilute hydrochloric acid was added dropwise to the water phase to crystallize, the pH was 4.5, the solution was turbid, 1g of crystal seed was added to grow crystals for 30min, 5% dilute hydrochloric acid was continuously added until the pH was 2, the temperature was lowered to 5℃, and the crystals were grown for 30min, centrifuged, the filter cake was washed with purified water until the filtrate was neutral, then washed with -20℃ ethanol, dried, and the wet product was vacuum dried at 50℃ to obtain 89.2g of fine mezlocillin acid, the yield was 89.2%, the single impurity was 0.054%, the total impurity was 0.196%, and the polymer was 0.016%.

Images