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A kind of production method of cefotaxime sodium

A technology for cefotaxime sodium and a production method, which is applied to the production field of cefotaxime sodium and can solve the problems of reduced product stability, uneven reaction time, and unprominence.

Active Publication Date: 2021-04-20
广药白云山化学制药(珠海)有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, when sporozinidine sodium faces the scale of industrialized preparation, these problems will affect the preparation process as the amount of feed increases, resulting in product quality problems and even making the preparation impossible.
[0008] In the specific implementation process of industrialization, according to the methods provided by patents CN101434611B, CN105461739B, and US7700581B2, two problems are very prominent, resulting in no way to carry out industrialization:
[0009] (1) During the preparation process of the crude product of cefotaxime amidine sodium, when cefotaxime amidine meets water and ethanol mixed solution, part will form agglomerates and cannot be dissolved after long-term stirring, which not only causes a substantial reduction in yield, but also forms lye Excessive, resulting in unqualified product quality, this problem is not prominent in the small test and pilot test stage
For example: carry out the preparation of cefotazimid sodium according to the existing method, when small-scale experiment, if drop into 30g cefazime amidine raw material to prepare cefotazime amidine sodium, produce about 10% insoluble agglomeration solid in solution, after about Stir continuously for 2 hours, and it can be dissolved substantially; during pilot production, if 3 kg of cefotazimid raw material is put into cefotazime sodium to prepare cefotazime sodium, about 20% insoluble agglomerated solids will be produced in the solution, and the agglomerated solids are relatively large. After about 2 hours of continuous stirring, it is also difficult to continue to dissolve. It can only be dissolved by continuously fishing out the solid with a sieve and crushing it and putting it in again; in large-scale production, if 30kg of cefazimidine raw materials are put in to prepare cefotazime sodium. , it is estimated that about 30% insoluble lumpy solids will be produced in the solution, and the lumpy solids are larger, and it is impossible to carry out stable production at all.
At the same time, longer feeding reaction time and more uneven contact with lye will also cause the product to decompose, which will eventually affect the quality of the finished product
[0010] (2) When carrying out the refined preparation of cefotaxime sodium, it is easy to cause the product color to increase, and also cause the product stability to decrease. When the industrialization time is far longer than the pilot test time, qualified products cannot be prepared. This problem is also reflected in the stage of industrialization

Method used

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  • A kind of production method of cefotaxime sodium
  • A kind of production method of cefotaxime sodium
  • A kind of production method of cefotaxime sodium

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Embodiment approach

[0037] As an embodiment, the weight of cefotaxime in the S1: volume of organic solvent A = 1 g: (3-5) mL. The preparation method of the alkali solution is as follows: prepare an aqueous solution of sodium hydroxide or sodium carbonate, and then add the organic solvent A to dilute to form an alkali solution with a weight concentration of 5-10%. By adding the organic solvent A into the aqueous alkali solution, on the one hand, the concentration of the alkali is reduced, and on the other hand, too much water is added to prevent crystallization in the later stage. During the preparation of the alkaline solution, the ratio of the input amount of sodium hydroxide, water and organic solvent A satisfies: sodium hydroxide weight: water volume=1g: (2~3) mL, the volume of organic solvent A: sodium hydroxide aqueous solution Volume=(4~5):1.

[0038] As a preferred embodiment, when the crude product of cefotaxime sodium in S2 is refined, the crude product of cefotaxime sodium is dissolved...

Embodiment 1

[0043] The production method of the cefotaxime sodium of the present embodiment may further comprise the steps:

[0044] S1: Salt formation of cefotaxime:

[0045] S1.1: 40kg of cefotaxime and 160L of absolute ethanol were used to prepare a suspension of cefotaxime. Dissolve 2.8kg of NaOH solid in 6L of water, and then add 30L of absolute ethanol to dilute to prepare a sodium hydroxide alkali solution. Cool the solution made of 44L water and 0.1kg EDTA disodium to below 10°C, add the cefazime amidine turbid solution and sodium hydroxide alkali solution in small amounts, and keep the pH of the reaction system in the range of 5-7. , until the cefotazimemidine is completely added, continue to adjust the pH to 7.2 with sodium hydroxide solution;

[0046] S1.2: Add 4kg of activated carbon for decolorization for 15 minutes, filter, wash with 20L of 80% ethanol, and combine the washing liquid into the filtrate;

[0047] S1.3: Add 50 L of absolute ethanol dropwise. At this time, the...

Embodiment 2

[0053] The production method of the cefotaxime sodium of the present embodiment may further comprise the steps:

[0054] S1: Salt formation of cefotaxime:

[0055] S1.1: Mix 80kg of cefotaxime and 320L of absolute ethanol in batches in proportion to make a cloudy solution. Dissolve 5.6kg of NaOH solid into 12L of water and add 60L of absolute ethanol to dilute. Cool the solution made of 88L water and 200g disodium EDTA to below 10°C, add cefotaxime turbid solution and sodium hydroxide alkali solution in small amounts, and add in turns to keep the pH in the range of 5-7 until cefotaxime Add it completely, and continue to adjust the pH to 7.2 with sodium hydroxide solution;

[0056] S1.2: Add 8 kg of activated carbon to decolorize for 15 minutes, filter, wash with 30L of 80% ethanol, and combine the washing liquid into the filtrate;

[0057] S1.3: Add 100 L of absolute ethanol dropwise. At this time, the solution is slightly turbid. Add 200 g of cefotaxime sodium as a seed cr...

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Abstract

The present invention provides a kind of production method of cefotazime amidine sodium, comprising the following steps: S1: prepare the crude product of cefotazime amidine sodium: first make cefotazime amidine suspension with organic solvent A, and described organic solution A is Anhydrous alkyl alcohol or anhydrous alkyl ketone with 1-4 carbon atoms, add cefotazime amidine suspension and alkaline solution to the reaction vessel alternately and control the pH of the reaction system to be 5-7, continue to add The organic solvent A is used as a precipitant to precipitate solids, and the crude product of cefotaxime sodium is obtained after separation; S2: the crude product of cefotaxime sodium is refined to obtain the finished product of cefotazime sodium. The production method of the cefotaxime sodium of the present invention realizes the smooth progress of the industrialization of the cefotazime sodium and can ensure the stability of product quality.

Description

technical field [0001] The invention relates to the technical field of chemical industry and pharmacy, in particular to a production method of cefotaxime sodium. Background technique [0002] 7-[α-(N,N'-diisopropylamidinothio)acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1 ,2,4-triazin-3-yl)thio]methyl]-cephalosporanic acid, also known as cefotaximemidine, is the first cefathiamidine analogue created by Chinese invention patent application number CN200410050908, which is effective against some Gram-positive bacteria Has better activity. However, the aqueous solution of cefotaxime has a low pH and is acidic, has obvious irritation to muscles and blood vessels, and has poor stability, so it is not suitable for direct medicinal use. [0003] The alkali metal salt formed by cefazimid and equimolar base has obvious enhanced water solubility, and its pH is also close to that of human body fluid to avoid irritation, so it has great clinical application value and developmen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36C07D501/04C07D501/12
CPCC07D501/04C07D501/12C07D501/36
Inventor 林航万平刘红英
Owner 广药白云山化学制药(珠海)有限公司
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