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A kind of synthetic method of ceftazidime

A technology of ceftazidime and a synthesis method, applied in the field of drug synthesis, can solve the problems of unstable ceftazidime crystal quality, by-product pollution, long reaction steps and the like, and achieve the effects of being beneficial to production control, easy to handle and low in cost

Active Publication Date: 2011-12-21
哈药集团股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At the problems referred to above, the object of the present invention is to provide a kind of preparation method of the ceftazidime that overcomes the long reaction step of the prior art, low yield, unstable quality of ceftazidime crystals, and larger shortcomings of by-product pollution after the reaction

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  • A kind of synthetic method of ceftazidime

Examples

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Embodiment 1

[0054] [Example 1] Synthesis of 7-APCA

[0055] Add 1.0 g of 7-ACA (7-aminocephalosporanic acid) to 5.0 g of dichloromethane, then add 1.0 g of hexamethyldisilazane, stir and heat under reflux for about 5 hours at 35-45°C. Under the catalysis of xylidine, 0.05 g of trimethylchlorosilane and 1.0 g of trimethyl iodosilane were added, the reaction was continued for 5 hours, 1 g of pyridine was added, and the reaction progress was detected by high performance liquid phase. When the 7-ACA residue is measured to be ≤0.5%, the reaction is over, add methanol and dilute hydrochloric acid, separate layers, add activated carbon to the water phase for decolorization for 20 minutes, and filter. Then add 0.5 to 2.0 grams of isopropanol to the filtrate as a dispersant, adjust the pH to 1.0 to 1.2 with triethylamine, stir until a large amount of crystals are precipitated, and continue to add dropwise until the final pH reaches 2.8 to 3.0. After suction filtration and washing with 0.5 g of is...

Embodiment 2

[0056] [embodiment 2] the synthesis of ceftazidime tert-butyl ester

[0057] Add 1.0 g of 7-APCA and 1.8 g of α-(2-aminothiazol-4-yl)-α-[(tert-butoxycarbonyl)isopropoxyimino]acetate to 5 g dichloromethane and 0.7 g methanol as a solvent, stirring and cooling down to 4°C. After maintaining the temperature for 5 minutes, 0.7 g of triethylamine was added, and the temperature was controlled at 0-10°C. After 10 hours, the 7-APCA residue was detected, and the reaction was considered to be over when the 7-APCA residue ≤ 2 mg / ml was monitored by high performance liquid chromatography. Lower the temperature to 0-3°C and grow the crystal for 3 hours. Filter, wash the filter cake with dichloromethane, filter dry and vacuum dry for 4 hours to obtain 1.482 g of ceftazidime tert-butyl ester. The mass yield is 148.2%. The purity of ceftazidime tert-butyl ester in the tested product was 98.1%.

Embodiment 3

[0058] [embodiment 3] the synthesis of ceftazidime dihydrochloride

[0059] Dissolve 1.0 g of ceftazidime tert-butyl ester in a mixed solution of 2 g of hydrochloric acid and formic acid (the weight ratio of hydrochloric acid: formic acid is 2:1 to 3:2), and react at room temperature until the residue of ceftazidime tert-butyl ester is ≤0.5%. The reaction is over. Slowly add acetone to the filtrate to carry out solvent crystallization. When the crystallization liquid appears slightly turbid, stop adding solvent, slowly stir and grow the crystal for 0.5 hours, continue to add the remaining solvent, and then stir and grow the crystal for 1 hour. After suction filtration and washing, the wet product is vacuum Dry to obtain 0.91 g of ceftazidime dihydrochloride. The mass yield is 91%, and the product purity of ceftazime dihydrochloride in the product is 98.3%.

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Abstract

The invention relates to a method for preparing ceftazidime. The synthesis method comprises the following steps: by taking 7-aminocephalosporanic acid (7-ACA) as a starting raw material, introducing a pyridine ion to 3-position methylene of 7-ACA so as to obtain 7-amino-3-(1-picolyl)-cephem acid (7-APCA) hydrochloride; then introducing a side chain with a thiazole ring on 7-position amino of the 7-APCA hydrochloride through acylation reaction; and carrying out hydrolyzing reaction, refining reaction and the like so as to obtain ceftazidime. The synthesis method for preparing the ceftazidime inthe invention is simple to operate and high in yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing cephalosporins, in particular to a method for synthesizing ceftazidime, and belongs to the technical field of drug synthesis. Background technique [0002] Ceftazidime is the antibiotic with the strongest anti-Pseudomonas aeruginosa among the third-generation cephalosporins created by GlaxoSmithKline. Road infections and severe skin and soft tissue infections. It is especially suitable for infection of immunocompromised persons caused by multiple drug-resistant Gram-negative bacilli, nosocomial infections, and central nervous system infections caused by Gram-negative bacilli or Pseudomonas aeruginosa. The usual production process is to first introduce pyridine to the C-3 position of 7-ACA, and then react the condensate with the active thioester at the 7β side chain of ceftazidime to generate ceftazidime (WO: 85 04659, 1985-10-24.). [0003] Ceftazidime, chemical name is (6R,7R)-7-[[(2-amino-4-thiazol...

Claims

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Application Information

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IPC IPC(8): C07D501/46C07D501/02
Inventor 吴志军刘煜婷
Owner 哈药集团股份有限公司
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