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Refinement method of ceforanide

A technology of cephreide and its refining method, which is applied in the field of cefereide refining, can solve the problems of cumbersome preparation process, difficult to obtain, and carry-in, and achieve the effects of good yield, high purity, and low price

Inactive Publication Date: 2013-01-30
ZHONGSHUAI PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After the production, the unreacted part of the ACATAA intermediate becomes the main impurity in the crude product of cefrelide. The drug N, N-dicyclohexylethylenediamine (DCEDA) is used in the purification process. The drug is not easy to obtain, and the preparation process is cumbersome and easy. Introduce new impurities during the preparation process

Method used

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  • Refinement method of ceforanide
  • Refinement method of ceforanide
  • Refinement method of ceforanide

Examples

Experimental program
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Effect test

Embodiment 1

[0033] The refinement of cefretex in this embodiment comprises the following steps:

[0034] (1) 20.0 g of the crude product of cefrelide prepared according to the patent WO2008010043 (HPLC purity is 73.5%, see figure 1 ), suspended in a mixed solution of 80mL acetone and 80mL water, added dropwise 6.5ml of dicyclohexylamine, and continued to stir for 30min to obtain a clear and transparent solution;

[0035] (2) Add dropwise 300mL of acetone to precipitate a precipitate, stir and crystallize in an ice bath for 30 min, then filter with suction, wash the filter cake with 30mL of acetone, and dry in vacuo to obtain cefrelide dicyclohexylamine salt;

[0036] (3) Suspend the above dicyclohexylamine salt of cefretex in 200mL of water and 200mL of methanol, adjust the pH value of the system to 7.5 with dilute sodium hydroxide solution, add 4g of activated carbon, stir for 15 minutes to decolorize, then suction filter and collect the filtrate The pH of the system was adjusted to 2....

Embodiment 2

[0038] The refinement of cefretex in this embodiment comprises the following steps:

[0039] (1) 20.0 g of the crude product of cefrelide prepared according to the patent WO2008010043 (HPLC purity is 73.5%, see figure 1 ), suspended in a mixed solution of 75 mL tetrahydrofuran and 75 mL water, added dropwise 6 ml of dicyclohexylamine, and continued to stir for 20 min to obtain a clear and transparent solution;

[0040] (2) Add 250 mL of tetrahydrofuran dropwise to precipitate a precipitate, stir and crystallize in an ice bath for 30 min, then filter with suction, wash the filter cake with 30 mL of tetrahydrofuran, and dry in vacuo to obtain the dicyclohexylamine salt of cefuroxime;

[0041] (3) Suspend the above dicyclohexylamine salt of cefretex in 150 mL of water and 150 mL of ethanol, adjust the pH value of the system to 7.5 with dilute sodium hydroxide solution, add 4 g of activated carbon, stir for 15 min to decolorize, and then filter with suction , collect the filtrat...

Embodiment 3

[0043] The refinement of cefretex in this embodiment comprises the following steps:

[0044] (1) 20.0 g of the crude product of cefrelide prepared according to the patent WO2008010043 (HPLC purity is 73.5%, see figure 1 ), suspended in a mixed solution of 100 mL acetonitrile and 100 mL water, added dropwise 10 ml of dicyclohexylamine, and continued to stir for 40 min to obtain a clear and transparent solution;

[0045] (2) Add 400 mL of acetonitrile dropwise, precipitate out, stir and crystallize in an ice bath for 60 min, then filter with suction, wash the filter cake with 30 mL of acetonitrile, and dry in vacuo to obtain the dicyclohexylamine salt of cefrelide;

[0046] (3) Suspend the above-mentioned cefretex dicyclohexylamine salt in 250 mL of water and 250 mL of isopropanol, adjust the pH value of the system to 8.5 with dilute sodium hydroxide solution, add 10 g of activated carbon, and stir for 30 min to decolorize Suction filtration, collect the filtrate and adjust th...

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Abstract

The invention provides a refinement method capable of obtaining high-purity ceforanide. The ceforanide crude product reacts with bicyclohexylamine; and since the impurity 3-[(1-carboxymethyl)tetrazolyl-5-sulfhydryl]methyl-7-amino-4-cephalosporanic acid (ceforanide intermediate ACATAA) bicyclohexylamine salt in the crude product and ceforanide bicyclohexylamine salt have different solubilities in an organic solvent-water solution, the ceforanide crude product can be refined. The method provided by the invention avoids using the high-toxicity strong-carcinogenicity arylamine substance N,N-dimethylaniline, and enhances the ceforanide purity from 70-85% of the crude product to 99.5% above of the refined product; and thus, the invention has the advantages of greatly higher purity, high yield and accessible raw materials, and is convenient for implementing industrial production of ceforanide.

Description

technical field [0001] The invention relates to a method for refining crude drug products, in particular to a method for refining cefrelide. Background technique [0002] Ceforanide is a second-generation semi-synthetic cephalosporin broad-spectrum antibiotic for parenteral use. It is suitable for various infections caused by sensitive bacteria. In recent years, its clinical application prospects are very promising. Ceforanide system Named as 3-[(1-carboxymethyl)tetrazolium-5-mercapto]methyl-7-[2-(2-carbamic acid)phenyl]acetamido-4-cephalosporanic acid, the structural formula is as follows: Ⅰ) as shown. [0003] [0004] (I) [0005] There are a lot of documents reporting the preparation method of cefereide, among which, as far back as the U.S. Patent No. 4,100,346 in 1978, it has been disclosed to use the following formula 3-[(1-carboxymethyl)tetrazolium-5-mercapto]methyl-7- Amino-4-cephalosporanic acid (ACATAA) is the method for preparing cefereide as the key interme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/12
Inventor 李锐孙卫东张胜华
Owner ZHONGSHUAI PHARMA SCI & TECH CO LTD
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