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Method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate

A technology of ceftazidime side chain acid and synthesis method, applied in the direction of organic chemistry and the like, can solve the problems of high price of triphenylphosphine, high production cost, influence on yield and the like, achieve easy mass production, avoid product stickiness, reduce The effect of production costs

Inactive Publication Date: 2017-05-24
淄博鑫泉医药技术服务有限公司
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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 a solvent, the color of the product is poor, and the purity of the product is low; Wang Qingquan of Harbin Pharmaceutical Group and others use dichloromethane as a solvent, triethylamine as a catalyst, and triphenylphosphine as a phosphating agent with a content of 97-97%. 98%
The disadvantage of this process is that dichloromethane is used as a solvent, and some products are dissolved in it, which affects the yield, and the price of triphenylphosphine is expensive, which makes the production cost higher

Method used

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  • Method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate
  • Method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate

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Experimental program
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Effect test

Embodiment 1

[0029] At 20°C, 34g ceftazidime side chain acid and 44gDM were added to the mixed solution of dichloride and acetonitrile (the quality of the mixed solution was 260g, and the density was 0.95g / cm 3 ), after stirring for 10 minutes, add 0.8 mL of pyridine, and dropwise add 7.7 mL of triethylamine at 20°C. The addition process took 1.5 hours. After the dropwise addition was completed, it was incubated at 21±1°C for 4 hours, then cooled to 5°C for 30 minutes, filtered with suction, and dried at 60°C to obtain the active ester of ceftazidime side chain acid, with a yield of 92.3 %, the content is 99.1%.

Embodiment 2

[0031] At 21°C, 35g of ceftazidime side chain acid and 48gDM were added to the mixed solution of dichloride and acetonitrile (the quality of the mixed solution was 250g, and the density was 1.0g / cm 3 ), after stirring for 10 minutes, add 1.0 mL of pyridine, dropwise add 8.0 mL of triethylamine at 22 ° C, after the dropwise addition, raise the temperature to 30 ° C and keep it warm for 50 min, cool down, add 28 mL of triethyl phosphite dropwise at 21 ° C, drop The addition process took 2.5 hours. After the dropwise addition was completed, it was incubated at 21±1°C for 3.0 hours, then cooled to 3°C for 30 minutes, filtered with suction, and dried at 60°C to obtain the active ester of ceftazidime side chain acid. The yield was 92.6%, the content is 99.3%.

Embodiment 3

[0033] At 23°C, 36g of ceftazidime side chain acid and 45gDM were added to the mixed solution of dichloride and acetonitrile (the quality of the mixed solution was 298g, and the density was 1.05g / cm 3 ), after stirring for 10 minutes, add 1.3 mL of pyridine, dropwise add 8.4 mL of triethylamine at 30°C, heat up to 30°C for 50 minutes after the dropwise addition, cool down, add 30mL of triethyl phosphite dropwise at 22°C, drop The addition process took 3.0 hours. After the dropwise addition was completed, it was incubated at 21±1°C for 5.0 hours, then cooled to 0°C and incubated for 30 minutes, filtered with suction, and dried at 60°C to obtain the active ester of ceftazidime side chain acid. The yield was 92.1%, the content is 99.1%.

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Abstract

The invention relates to a method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate and belongs to the technical field of preparation of ceftazidime intermediates. 2-(2-aminothiazole-4-yl)-2-acetic acid and dibenzothiazyl disulfide (DM) are used as raw materials, a dichloromethane and acetonitrile mixed solution serves as a solvent, catalysts pyridine and triethylamine are sequentially added, triethyl phosphite is used as a condensation agent to perform reaction, and suction filtration and drying are performed after reaction is completed to obtain the 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate. The process is simple, mild in condition, low in cost and high in reaction yield, and the prepared target product is high in quality and purity and suitable for mass production.

Description

technical field [0001] The invention relates to a synthesis method of ceftazidime side chain acid active ester, belonging to the technical field of preparation of ceftazidime intermediates. Background technique [0002] Ceftazidime is the third-generation cephalosporin antibiotic, which has the strongest killing effect on Pseudomonas aeruginosa. It is the drug of choice for the treatment of Gram-negative bacterial infections and has broad market prospects. [0003] The side-chain acid active ester of ceftazidime is an important intermediate of ceftazidime, and its quality and cost have an important impact on the raw material drug. Therefore, it is of great significance for the industrial production of ceftazidime to explore a synthesis process of ceftazidime side chain acid active ester with good quality, low cost, low toxicity and simple operation. [0004] The chemical name of the active ester of ceftazidime side chain acid is: 2-(2-amino-4-thiazolyl)-2-(tert-butoxycarbon...

Claims

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Application Information

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IPC IPC(8): C07D277/74
CPCC07D277/74
Inventor 张艳红刘成学张立明
Owner 淄博鑫泉医药技术服务有限公司
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