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Ceftezole sodium compound and preparation thereof

A technology of ceftezole sodium and its compound, which is applied in the field of ceftezole sodium compound and its preparation, and can solve the problems of β-lactam ring opening, dark color, and low yield

Inactive Publication Date: 2018-06-08
宁夏天心医药有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The route is simple, but the yield is low, the total yield is only 18%
(3) Synthesize the 7-position acylation intermediate with the mixed acid anhydride method, the penicillin acylase method, etc. These methods also have the disadvantages of low yield and high cost; in addition, the 3-position nucleophilic substitution reaction system is an aqueous phase, which is easy to cause β-lactam ring opening, more side reactions, lower product purity, darker color, difficult to purify
Using Lewis acid such as boron trifluoride ether as a catalyst can complete the 3-position substitution reaction without aqueous medium, but the catalyst is expensive and has little application value (4) 1H-tetrazolium acetic acid and 2-mercapto-1,3 ,4 Thiadiazole undergoes dehydration condensation to generate 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester, 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2- Thioester directly reacts with 7-ACA to directly obtain ceftezole acid, but this method also has the disadvantages of low yield, many by-products, and difficult purification
[0004] Ceftezole sodium has poor stability, is unstable to temperature and light, has low purity, high content of polymers and other impurities, and darker color. The reason may be that some by-products and residual solvents are included in the final product. and other reasons

Method used

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  • Ceftezole sodium compound and preparation thereof
  • Ceftezole sodium compound and preparation thereof
  • Ceftezole sodium compound and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1: the preparation of ceftezole sodium compound

[0025] (1) Dissolve 2.56kg tetrazoleacetic acid and 2.43kg 2-mercapto-1,3,4-thiadiazole in tetrahydrofuran, slowly add 5.04kg N,N'-dicyclohexylcarbodiimide, ice React in the bath for 2 hours, remove 1,3-dicycloethylurea by filtration, concentrate the filtrate under reduced pressure, add 25L of chloroform, stir, filter and dry to obtain 4.1Kg of active ester as a yellow powder;

[0026] (2) Add 4.44Kg 7-ACA to 60L of chloroform and triethylamine with a volume ratio of 2:1, add the above-mentioned active ester to react for 5h under ice-bath conditions, add 400L of water, separate the water layer, and use 2mol / L of glacial acetic acid solution to adjust the pH to 2.0, stir in an ice bath for 1 h, filter, wash with purified water, and dry in vacuo to obtain 6.23 Kg of 7-(1H-tetrazolium acetamido) cephalosporanic acid;

[0027] (3) Add 50L acetic acid to 7-(1H-tetrazolium acetylamino) cephalosporanic acid and 2.0...

Embodiment 2

[0036] Embodiment 2: the preparation of ceftezole sodium compound

[0037] (1) Dissolve 30.33g of tetrazoleacetic acid and 31.11g of 2-mercapto-1,3,4-thiadiazole in tetrahydrofuran, slowly add 61.77g of N,N'-dicyclohexylcarbodiimide, ice React in the bath for 2 hours, remove 1,3-dicycloethylurea by filtration, concentrate the filtrate under reduced pressure, add 700ml of tetrahydrofuran, stir, filter and dry to obtain 59.24g of active ester as a yellow powder;

[0038](2) Add 58.34g of 7-ACA into 1400ml of chloroform and triethylamine with a volume ratio of 15:2, add the above-mentioned active ester to react for 4h under ice-bath conditions, add 600ml of water, separate the water layer, and use 1mol / L of hydrochloric acid solution to adjust the pH to 2.5, stir in an ice bath for 1 h, filter, wash with purified water, and dry in vacuo to obtain 94.79 g of 7-(1H-tetrazolium acetamido) cephalosporanic acid;

[0039] (3) Add 1500ml of acetic acid to 7-(1H-tetrazolium acetylamino...

Embodiment 3

[0042] Embodiment 3: the preparation of ceftezole sodium compound

[0043] (1) Dissolve 32.06g of tetrazoleacetic acid and 30.79g of 2-mercapto-1,3,4-thiadiazole in tetrahydrofuran, slowly add 60.42g of N,N'-dicyclohexylcarbodiimide, ice React in the bath for 2 hours, remove 1,3-dicycloethylurea by filtration, concentrate the filtrate under reduced pressure, add 700ml of absolute ethanol, stir, filter and dry to obtain 60.33g of active ester as a yellow powder;

[0044] (2) Add 60.12g of 7-ACA to 1500ml of chloroform and triethylamine with a volume ratio of 5:1, add the above-mentioned active ester to react for 4h under ice-bath conditions, add 600ml of water, separate the water layer, and use 1mol / L of nitric acid solution to adjust the pH to 3.0, stir in an ice bath for 1 h, filter, wash with purified water, and dry in vacuo to obtain 94.23 g of 7-(1H-tetrazolium acetamido) cephalosporanic acid;

[0045] (3) Add 1500ml of acetic acid to 7-(1H-tetrazolium acetylamino) cepha...

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Abstract

The invention discloses a ceftezole sodium compound. The ceftezole sodium compound is prepared by a molecular assembly and morphology optimization technology of a particle process crystal product. Theceftezole sodium compound has the characteristics of high purity, good color grade and good stability. The invention further discloses a preparation prepared by using the ceftezole sodium, namely ceftezole sodium for injection.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a ceftezole sodium compound and a preparation thereof prepared by adopting particle process crystal product molecular assembly and shape optimization technology. Background technique [0002] Ceftezole sodium is a semi-synthetic cephalosporin antibiotic synthesized and developed by Fujisawa Pharmaceutical Company in Japan, which was launched in April 1978 under the trade name of Ceolslin. It is mainly used to treat infections caused by Staphylococcus aureus, Streptococcus pyogenes, Pneumococcus, Escherichia coli, Klebsiella pneumoniae, etc., such as chronic respiratory system infections caused by sepsis, pneumonia, bronchitis, and bronchiectasis infection, and pulmonary abscess. Syndrome, peritonitis, pyelonephritis, cystitis, etc. The application of this drug in my country is relatively late. In 2002, Harbin Pharmaceutical and Tianjin Xinfeng produced raw materials...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/12A61K31/546A61P31/04A61K9/14
CPCA61K9/0019A61K9/14A61K31/546C07B2200/13C07D501/12C07D501/36
Inventor 张辉
Owner 宁夏天心医药有限责任公司
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