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Synthetic method of 2-mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate

The technology of a ceftazidime side chain acid and a synthesis method, which is applied in the field of medicine, can solve the problems of low product purity, strong irritation, strong volatility and the like, and achieve the effects of simple preparation process, good safety performance and high purity

Active Publication Date: 2015-04-08
SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage is that acetonitrile is used as the solvent, the color of the product is poor, and the purity of the product is low
[0008] Use triethylamine and pyridine as catalysts, the ratio of triethylamine and pyridine should be adjusted at any time as the reaction solvent system changes, the use conditions are very harsh, excessive pyridine will cause the product to become viscous, and excessive triethylamine will cause the yield to decrease Reduced, insufficient addition of triethylamine and pyridine will lead to slow reaction and low product purity
Use triethyl phosphite as dehydrating agent, triethyl phosphite has low flash point, strong volatility and strong irritation, which is not conducive to industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 33.1g of ceftazidime side chain acid and 33.1g of DM to a mixture of 119g of benzene and 99g of acetonitrile at 21°C, add 8.9g of aniline and 0.4g of 2-picoline in turn, cool down to 15°C, and dropwise add 9.9g of triphosphite Phenyl ester, after 1.3 hours, the reaction was continued for 0.5 hours after the addition, the temperature was lowered to 5°C, and the crude product was obtained by suction filtration. The crude product was added into 150 mL of methanol for 1 h at 22° C., filtered with suction to obtain a refined active ester with a yield of 95.2% and a purity of 99.1%.

Embodiment 2

[0031] Add 33.1g of ceftazidime side chain acid and 43.1g of DM to a mixture of 215g of benzene and 166g of acetonitrile at 22°C, add 9.5g of aniline and 0.4g of 2-picoline in turn, cool down to 17°C, and dropwise add 17.5g of triphosphite Phenyl ester, after 1.5 hours of dripping, the reaction was continued for 0.5 hours after the addition was completed, the temperature was lowered to 7°C, and the crude product was obtained by suction filtration. Add the crude product into 150mL of methanol at 23°C, soak for 1 hour, and filter with suction to obtain a refined active ester with a yield of 94.3% and a purity of 99%.

Embodiment 3

[0033] At 23°C, add 33.1g of ceftazidime side chain acid and 49.6g of DM to a mixture of 318g of benzene and 227g of acetonitrile, then add 10.1g of aniline and 0.5g of 2-picoline in turn, cool down to 18°C, and dropwise add 24.8g of triphosphite Phenyl ester, after 1.5 hours of dripping, the reaction was continued for 0.5 hours after the addition was completed, the temperature was lowered to 3°C, and the crude product was obtained by suction filtration. Add the crude product into 150mL methanol for 1h at 24°C, and filter with suction to obtain a refined active ester with a yield of 94.7% and a purity of 99.1%.

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PUM

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Abstract

The invention belongs to the field of a medical technology and specifically relates to a synthetic method of 2-mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate. The synthetic method comprises the following steps: ethyl 2-(2-aminothiazole-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetate and 2,2'-dibenzothiazole disulfide are added into a mixed liquor of benzene and acetonitrile; aniline and 2-methylpyridine are successively added; triphenyl phosphite is added dropwise to carry out a reaction; and after the reaction, a crude product is obtained, and the crude product is refined with methanol so as to obtain refined active ester. The synthetic method provided by the invention has simple process and is easy to implement. By the synthetic method, purity of the product reaches more than 99%, and yield reaches more than 94%.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a synthesis method of ceftazidime side chain acid active ester. Background technique [0002] Ceftazidime is an antibiotic with outstanding efficacy against Pseudomonas aeruginosa. It is one of the important third-generation semi-synthetic cephalosporin antibiotics. It has the characteristics of strong bactericidal power and wide antibacterial spectrum. It is widely used clinically. One of the newest and best-selling cephalosporins on the market. [0003] The side-chain acid active ester of ceftazidime is an important intermediate for the synthesis of ceftazime, and its quality and yield directly affect the quality and cost of the synthesized drug ceftazime. Therefore, it is of great significance to the development of my country's pharmaceutical industry to develop a low-cost, high-yield, and simple-to-operate synthesis process for ceftazidime side chain acid active...

Claims

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Application Information

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IPC IPC(8): C07D277/74
CPCC07D277/74
Inventor 房正薇张文国蔡会敏钱长健马永祥
Owner SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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