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Crystallization refining method of Meropenem

A technology for meropenem and a purification method, which is applied in the direction of organic chemistry, etc., can solve the problems of difficult removal of residual solvents, inability to achieve industrial production, and increase in impurity content, and achieve the effects of increased production capacity, improved production capacity, and low solvent residues.

Active Publication Date: 2010-12-22
JIANGSU DESANO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the solubility of meropenem in water is very low. For example, a large amount of water is required to dissolve it at room temperature. In this way, a large amount of organic solvent is required when adding an organic solvent for crystallization in the next step, and industrial production cannot be realized.
Some people add alkaline substances to the water when dissolving, but it will damage the product and increase the impurity content; some people will increase the water temperature to dissolve it at high temperature, which will also cause damage to the product and increase the impurity content
[0004] The traditional drying method is vacuum drying, but the residual solvent is still difficult to remove completely

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 1. Add 40ml of anhydrous methanol to a 100ml three-necked flask, stir at a medium speed, cool down to 15±2°C, add 10g of crude meropenem to the three-necked flask, and stir to fully dissolve.

[0025] 2. Add 1.5g of activated carbon to the clarified feed liquid, stir at a medium speed, keep warm at 15±2°C, and decolorize for 20 minutes.

[0026] 3. After the decolorization is completed, filter the charcoal with filter paper, filter the filtrate twice with a 0.45 μm hydrophilic filter membrane, and pour the filtrate (37 ml) into a 500 ml four-necked bottle.

[0027] 4. Stir and cool down to 10±1°C, keep the temperature at 10±1°C, add 200ml of mixed solvent (1:4) of water and tetrahydrofuran at a uniform speed, control the dropping time at about 2 hours, stop stirring after the dropping, and let stand to analyze Crystal for 1 hour.

[0028] 5. Vacuum filter the crystalline suspension, soak and wash the filter cake with a mixed solution of water-ethanol-ethyl acetate (1:1...

Embodiment 2

[0036] 1. Add 40ml of anhydrous methanol to a 100ml three-necked flask, stir at a medium speed, cool down to 15±2°C, add 10g of crude meropenem to the three-necked flask, and stir to fully dissolve.

[0037] 2. Add 1.5g of activated carbon to the clarified feed liquid, stir at a medium speed, keep warm at 15±2°C, and decolorize for 20 minutes.

[0038] 3. After the decolorization is completed, filter the charcoal with filter paper, filter the filtrate twice with a 0.45 μm hydrophilic filter membrane, and pour the filtrate (37 ml) into a 500 ml four-necked bottle.

[0039] 4. Stir and cool down to 10±1°C, keep the temperature at 10±1°C, add 200ml of mixed solvent (1:4) of water and isopropanol at a constant speed, control the dropping time at about 2 hours, stop stirring at the end of the dropping, and let it stand Set crystallization for 1 hour.

[0040] 5. Vacuum filter the crystalline suspension, soak and wash the filter cake with a mixed solution of water-ethanol-ethyl ace...

Embodiment 3

[0048] 1. Add 40ml of anhydrous methanol to a 100ml three-necked flask, stir at a medium speed, cool down to 15±2°C, add 10g of crude meropenem to the three-necked flask, and stir to fully dissolve.

[0049] 2. Add 1.5g of activated carbon to the clarified feed liquid, stir at a medium speed, keep warm at 15±2°C, and decolorize for 20 minutes.

[0050] 3. After the decolorization is completed, filter the charcoal with filter paper, filter the filtrate twice with a 0.45 μm hydrophilic filter membrane, and pour the filtrate (36 ml) into a 500 ml four-necked bottle.

[0051] 4. Stir and cool down to 10±1°C, keep the temperature at 10±1°C, add 200ml of a mixed solvent (1:4) of water and sec-hexanol at a uniform speed, control the time of adding drops to about 2 hours, stop stirring after dropping, and let Set crystallization for 1 hour.

[0052] 5. Vacuum filter the crystalline suspension, soak and wash the filter cake with a mixed solution of water-ethanol-ethyl acetate (1:1:1) ...

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PUM

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Abstract

The invention relates to a crystallization refining method of Meropenem, which has low impurity content. The crystallization refining method of Meropenem comprises the following steps: a) dissolving Meropenem crude into methyl alcohol; b) decoloring, decarbonizing, degerming and filtering; c) adding the mixture of water and precipitator into filtrate, and precipitating, wherein the precipitator is the one or the mixture of two-four types of C2-C6 alcohol, C3-C8 ketone, C2-C8 ether or tetrahydrofuran at any ratio, and the volume ratio of water to precipitator is 1:3-1:5; d) filtering to obtain crystallization; e) washing the crystallization by mixed solvent of water and organic solvent of alcohol and esters; and f) drying to obtain the finished product. The invention utilizes the characteristic that Meropenem is easy to dissolve in methyl alcohol, and a small quantity of methyl alcohol can cause Meropenem to dissolve at normal temperature; same equipment can increase inventory for multiple times if being compared with the prior art, and production capability is obviously improved. Because a small quantity of methyl alcohol is used, a great quantity of crystallization solvent can be added, crystallization is complete, yield is high, and impurities can be thoroughly removed.

Description

technical field [0001] The invention relates to a method for crystallization and purification of meropenem. Background technique [0002] The crude product of meropenem is self-made in the company's laboratory. The crude product is obtained by docking the core MAP of meropenem with the side chain, and then hydrogenating the deprotection group to obtain the crude product (crude product quality standard: total impurity ≤ 1.0%, single impurity ≤ 0.5%) (MAP and The side chain was purchased from Taizhou Yiming Pharmaceutical Chemical Co., Ltd.). [0003] The crude product of meropenem (β-methyl carbapenem antibiotics) is refined to remove impurities, and then sterilized to obtain sterile meropenem, most of which are dissolved in water, decarbonized and filtered, sterilized and filtered, and analyzed by adding acetone or tetrahydrofuran, etc. Crystal, vacuum drying method, and finally get the finished product that meets the national pharmacopoeia standard (remarks: 2010 edition C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/02
Inventor 冯兰春周枫
Owner JIANGSU DESANO PHARMA
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