Crystallization method of piperacillin

Abstract

The invention discloses a crystallization method of piperacillin, belonging to the technical field of medicine. In the method, sodium bicarbonate is used as the alkali, the piperacillin is prepared into piperacillin sodium aqueous solution with concentration of 10-50%, after absorption and removal of impurities, with absence of organic solvent, the solution is treated by pure aqueous phase fractional crystallization, thus, the piperacillin acid is obtained. In the method, the frequently-used ethyl acetate, acetone or alcohol and water mixed solvent crystallization method is replaced by the pure aqueous phase crystallization method, the phenomena, for example, the product is not easy to devitrify or is tacky in devitrification, caused by the existence of organic solvent, are avoided, and the quality and the yield of products both are improved greatly. The method has the advantages of obtaining the raw material easily, being low in cost, being less harmful for environment, being safe and reliable, and being excellent in product quality.

Description

technical field

[0001] The invention relates to a method for crystallizing piperacillin, which belongs to the technical field of medicine. Background technique

[0002] Piperacillin, chemical name (2S,5R,6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1 -piperazinecarboxamido)-2-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monohydrate, manufactured by Japan Toyama Chemical Industry Developed by Co., Ltd., it is a semi-synthetic penicillin antibiotic with broad-spectrum antibacterial effect. The structural formula of piperacillin is as follows:

[0003]

[0004] At present, the freeze-drying method is used in the use of piperacillin, and it is prepared into sodium salt form and used in combination with β-lactam inhibitors such as sulbactam sodium or tazobactam sodium to improve its antibacterial activity. However, since the freeze-drying process has no ability to remove impurities, the quality of piperacillin acid plays a key role in improving...

Examples

Embodiment 1

[0019] Put 200g of piperacillin and 600mL of purified water into a 1000mL three-necked bottle in turn, control the temperature at 5~10°C, slowly add 31.5g of solid sodium bicarbonate, and continue to stir for 60 minutes after the addition is complete until the system is dissolved and clarified. At this time, the pH of the system is 4.95 . Add 1.0g of EDTA-2Na and 10g of activated carbon, stir for 30min to decolorize, and then filter with suction. Transfer the filtrate to a clean three-necked flask, adjust the system temperature to 40~45°C, slowly add 2mol / L hydrochloric acid dropwise until the pH of the system is 4.0, stir and crystallize for 60min. Continue to slowly add hydrochloric acid dropwise until the pH value of the system is 1.0, and stir and crystallize for 60 minutes. Suction filter the reaction system, beat and wash the material with 100 mL of purified water. After drying, 196.5 g of finished white crystalline piperacillin was obtained, with a crystallization yie...

Embodiment 2

[0021] Put 200g of piperacillin and 1200mL of purified water into a 1000mL three-necked bottle in sequence, control the temperature at 5~10°C, slowly add 31.5g of solid sodium bicarbonate, and continue stirring for 60 minutes after the addition is complete until the system is dissolved and clarified. At this time, the pH of the system is 5.05 . Add 1.0g of EDTA-2Na and 10g of activated carbon, stir for 30min to decolorize, and then filter with suction. Transfer the filtrate to a clean three-necked flask, adjust the temperature of the system to 40-45°C, slowly add 2mol / L hydrochloric acid dropwise until the pH of the system is 4.15, stir and crystallize for 60min. Continue to slowly add hydrochloric acid dropwise until the pH value of the system is 1.05, and stir and crystallize for 60 minutes. Suction filter the reaction system, beat and wash the material with 100 mL of purified water. After drying, 192.3 g of finished white crystalline piperacillin was obtained, with a crys...

Embodiment 3

[0023] Put 200g of piperacillin and 1800mL of purified water into a 1000mL three-neck bottle in turn, control the temperature at 5~10°C, slowly add 31.5g of solid sodium bicarbonate, and continue stirring for 60 minutes after the addition is complete until the system is dissolved and clarified. At this time, the pH of the system is 5.10 . Add 1.0g of EDTA-2Na and 10g of activated carbon, stir for 30min to decolorize, and then filter with suction. Transfer the filtrate to a clean three-necked flask, adjust the temperature of the system to 40~45°C, slowly add 2mol / L hydrochloric acid dropwise until the pH of the system is 4.10, stir and crystallize for 60min. Continue to slowly add hydrochloric acid dropwise until the pH value of the system is 1.13, and stir and crystallize for 60 minutes. Suction filter the reaction system, beat and wash the material with 100 mL of purified water. After drying, 192.8 g of finished white crystalline piperacillin was obtained, with a crystalliz...

technical field

[0001] The invention relates to a method for crystallizing piperacillin, which belongs to the technical field of medicine. Background technique

[0002] Piperacillin, chemical name (2S,5R,6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1 -piperazinecarboxamido)-2-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monohydrate, manufactured by Japan Toyama Chemical Industry Developed by Co., Ltd., it is a semi-synthetic penicillin antibiotic with broad-spectrum antibacterial effect. The structural formula of piperacillin is as follows:

[0003]

[0004] At present, the freeze-drying method is used in the use of piperacillin, and it is prepared into sodium salt form and used in combination with β-lactam inhibitors such as sulbactam sodium or tazobactam sodium to improve its antibacterial activity. However, since the freeze-drying process has no ability to remove impurities, the quality of piperacillin acid plays a key role in improving...

Examples

Embodiment 1

[0019] Put 200g of piperacillin and 600mL of purified water into a 1000mL three-necked bottle in turn, control the temperature at 5~10°C, slowly add 31.5g of solid sodium bicarbonate, and continue to stir for 60 minutes after the addition is complete until the system is dissolved and clarified. At this time, the pH of the system is 4.95 . Add 1.0g of EDTA-2Na and 10g of activated carbon, stir for 30min to decolorize, and then filter with suction. Transfer the filtrate to a clean three-necked flask, adjust the system temperature to 40~45°C, slowly add 2mol / L hydrochloric acid dropwise until the pH of the system is 4.0, stir and crystallize for 60min. Continue to slowly add hydrochloric acid dropwise until the pH value of the system is 1.0, and stir and crystallize for 60 minutes. Suction filter the reaction system, beat and wash the material with 100 mL of purified water. After drying, 196.5 g of finished white crystalline piperacillin was obtained, with a crystallization yie...

Embodiment 2

[0021] Put 200g of piperacillin and 1200mL of purified water into a 1000mL three-necked bottle in sequence, control the temperature at 5~10°C, slowly add 31.5g of solid sodium bicarbonate, and continue stirring for 60 minutes after the addition is complete until the system is dissolved and clarified. At this time, the pH of the system is 5.05 . Add 1.0g of EDTA-2Na and 10g of activated carbon, stir for 30min to decolorize, and then filter with suction. Transfer the filtrate to a clean three-necked flask, adjust the temperature of the system to 40-45°C, slowly add 2mol / L hydrochloric acid dropwise until the pH of the system is 4.15, stir and crystallize for 60min. Continue to slowly add hydrochloric acid dropwise until the pH value of the system is 1.05, and stir and crystallize for 60 minutes. Suction filter the reaction system, beat and wash the material with 100 mL of purified water. After drying, 192.3 g of finished white crystalline piperacillin was obtained, with a crys...

Embodiment 3

[0023] Put 200g of piperacillin and 1800mL of purified water into a 1000mL three-neck bottle in turn, control the temperature at 5~10°C, slowly add 31.5g of solid sodium bicarbonate, and continue stirring for 60 minutes after the addition is complete until the system is dissolved and clarified. At this time, the pH of the system is 5.10 . Add 1.0g of EDTA-2Na and 10g of activated carbon, stir for 30min to decolorize, and then filter with suction. Transfer the filtrate to a clean three-necked flask, adjust the temperature of the system to 40~45°C, slowly add 2mol / L hydrochloric acid dropwise until the pH of the system is 4.10, stir and crystallize for 60min. Continue to slowly add hydrochloric acid dropwise until the pH value of the system is 1.13, and stir and crystallize for 60 minutes. Suction filter the reaction system, beat and wash the material with 100 mL of purified water. After drying, 192.8 g of finished white crystalline piperacillin was obtained, with a crystalliz...

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