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Process for purifying Tazobactam

A process and selected technology, applied in the direction of organic chemistry, can solve the problems of difficult purification, difficult to remove impurities, difficult to dissolve in conventional organic solvents, etc., to achieve the effect of simple process and improved purification effect

Active Publication Date: 2012-02-08
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] It is very difficult to remove these impurities by existing technology, especially impurity (III) and impurity (V). Their physical and chemical properties are very similar to tazobactam, and tazobactam is especially in polar protic solvents at 40-100 ° C. It is very unstable, it is easy to decompose into impurity (I) and tazobactam is difficult to dissolve in conventional organic solvents, so it is difficult to purify, and impurity (III) and impurity (V) are existing preparation tazobactam process Substances that must be produced in
In US2005 / 0228176, a process for purifying tazobactam is disclosed, but it can only purify the impurity (II), and it is difficult to purify the other three impurities, and it has no effect at all, especially it is also mentioned in example 4 Adding methyl ethyl ketone to the water phase to purify impurities, the inventor's experiment proved that methyl ethyl ketone can react with tazobactam, resulting in very low yield

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  • Process for purifying Tazobactam
  • Process for purifying Tazobactam
  • Process for purifying Tazobactam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1, using propyl acetate to purify tazobactam crude product

[0026] 1. Add 200 g of the crude product of tazobactam [HPLC: 97.5%, impurity (II) 0.7%, impurity (III) 0.5%, impurity (V) 0.5%, impurity (IV) 0.3%], add 1600ml of pure water and cool to 0~15℃, add 8% NaHCO dropwise 3 The aqueous solution makes it clear. Then add 5.0 g of activated carbon for decolorization for 0.5 h, filter, wash with a small amount of water, and filter.

[0027] 2. Add 1000ml of propyl acetate to the filtrate, cool to 0-10°C, add hydrochloric acid dropwise to adjust the pH to 1.0-1.5, and keep warm at 0-10°C for 2.0-3.0h.

[0028] 3. Filter, wash with 100ml of water, filter, then wash with 50ml of ethanol, and filter.

[0029] 4. Dig out the filter cake, and vacuum bake the material at 35-40°C for 5.0-6.0h. Obtained 182g, HPLC99.5%, impurity (II), impurity (III), impurity (V), impurity (IV) all≤0.1%.

[0030] The above percentages are percentages by mass.

Embodiment 2

[0031] Embodiment 2, purifying the crude product of tazobactam with methyl ethyl ketone

[0032] 1. Tazobactam crude product [HPLC: 97.8%, impurity (II) 0.65%, impurity (III) 0.6%, impurity (V) 0.4%, impurity (IV) 0.4%] 200g, add 1600ml of pure water and cool to 0 -15℃, add 8% KHCO dropwise 3 The aqueous solution makes it clear. Then add 5.0 g of activated carbon for decolorization for 0.5 h, filter, wash with a small amount of water, and filter.

[0033] 2. Add 1200ml of methyl ethyl ketone to the filtrate, cool to 0-10°C, add nitric acid dropwise to adjust the pH to 1.5-2.5, and keep warm at 0-10°C for 2.0-3.0h.

[0034] 3. Filter, wash with 100ml of water, filter, then wash with 50ml of ethanol, and filter.

[0035] 4. Dig out the filter cake, and vacuum bake the material at 35-40°C for 5.0-6.0h. Obtained 186g, HPLC99.4%, impurity (II), impurity (III), impurity (V), impurity (IV) all≤0.1%.

[0036] The above percentages are percentages by mass.

Embodiment 3

[0037] Embodiment 3, using ethyl acetate to purify the crude product of tazobactam

[0038] 1. Add 200 g of the crude product of tazobactam [HPLC: 97.1%, impurity (II) 0.8%, impurity (III) 0.6%, impurity (V) 0.5%, impurity (IV) 0.3%], add 1600ml of pure water and cool to 0-10 ° C, add dropwise 8% NaHCO3 aqueous solution to make it clear. Then add 5.0 g of activated carbon for decolorization for 0.5 h, filter, wash with a small amount of water, and filter.

[0039] 2. Add 1000ml of ethyl acetate to the filtrate, cool to 0-10°C, add nitric acid dropwise to adjust the pH to 1.0-1.5, and keep warm at 0-10°C for 2.0-3.0h.

[0040] 3. Filter, wash with 100ml of water, filter, then wash with 50ml of ethanol, and filter.

[0041] 4. Dig out the filter cake, and vacuum bake the material at 35-40°C for 5.0-6.0h. The obtained material was 193g, HPLC: 99.7%, impurity (II), impurity (III), impurity (V), impurity (IV) were all ≤0.05%.

[0042] The above percentages are percentages by ma...

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Abstract

The invention provides a process for purifying Tazobactam, which comprises the following steps: (1) dissolving Tazobactam in aqueous solution of an inorganic alkali; (2) adding active carbon into feed liquid, decolorizing and filtering; (3) adding filtrate into an organic solvent; and (4) rising, filtering and drying filter cake under vacuum. In the invention, the process is simple, impurities are dissolved in the organic solvent in a separation process by selecting the solvent and slowly regulating the pH value with a corresponding acid, the selected solvent does not react with Tazobactam but can dissolve the impurities, and thus, high-yield and high-quality purification is realized, and the mass percentage content of the impurities produced in a Tazobactam preparation process is lowered to below 0.1 percent. Particularly, when ethyl acetate or methyl isobutyl ketone is used as the solvent and nitric acid is adopted, the purification effect is improved obviously and the mass percentage content of the Tazobactam can be reduced to a lower level, basically below 0.05 percent.

Description

technical field [0001] The invention relates to a process for purifying tazobactam. Background technique [0002] The chemical name of tazobactam (I) is 3a-methyl-7-oxidation-3B-(1H-1.2.3-triazole-1-methyl)-4-thia-1-azabicyclo[3.2. 0]-2a-carboxylic acid 4.4-dioxide: [0003] [0004] wherein H represents hydrogen. [0005] Tazobactam belongs to the β-lactamase inhibitor of penicillane sulfonic acids. The drug has the characteristics of low toxicity, good stability, strong enzyme inhibitory activity, and strong activity. Its preparation route is disclosed in U.S. Patent US4562073: [0006] [0007] It is reported in Japanese Patent JP63033187 that there is isomer impurity (II) in tazobactam: [0008] [0009] There is also a ring-expanding impurity (V): [0010] [0011] And its molecular structure mentioned in United States Pharmacopoeia USP32 is impurity (IV). In addition, the inventors have found that there is an impurity (III) in tazobactam. [0012] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/87C07D499/18
Inventor 包建华刘雨林马俊赵小平彭孙兵
Owner JIANGXI FUSHINE PHARMA CO LTD