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Method for preparing ceftazidime by one-pot process

A technology of ceftazidime and aminocephalosporanic acid, which is applied in the field of drug synthesis, can solve problems such as product loss, waste of excipients, and impact on the overall yield of ceftazidime, and achieve the effects of increased product yield, high safety, and easy operation

Active Publication Date: 2015-09-09
QILU ANTIBIOTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of preparing ceftazime, the method needs to separately crystallize and separate three parts of 7-amino-3-(1-pyridylmethyl) cephalosporin (7-APCA) hydrochloride, ceftazidime tert-butyl ester and ceftazime dihydrochloride For intermediates, a large amount of excipients need to be wasted during the separation of each step of the intermediate, and part of the product is lost during the separation process, which ultimately affects the overall yield of ceftazidime

Method used

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  • Method for preparing ceftazidime by one-pot process
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  • Method for preparing ceftazidime by one-pot process

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Embodiment 1, the preparation of ceftazidime:

[0049] 30 g (0.11 mol) of 7-aminocephalosporanic acid, 300 mL of dichloromethane, and 35 mL (0.16 mol) of hexamethyldisilazane were placed in a reaction flask, heated to reflux for 8 hours, and N,N-diethyl ether was added under ice bath 29mL (0.18mol) of base aniline, 32g (0.16mol) of trimethylsilyl iodide, react at room temperature for 3hr, add pyridine 18mL (0.22mol) under ice bath, continue to react for 1hr;

[0050] The above feed liquid was cooled to -25°C, 39 g (0.12 mol) of ceftazidime side chain acid chloride hydrochloride (compound of formula 5) was added in batches, and the reaction was incubated for 2 h after the addition;

[0051] The temperature is controlled at 0±5°C, the above-mentioned reaction feed liquid is slowly transferred into the mixed solution of 50mL concentrated hydrochloric acid / 50mL water (the solution is pre-cooled to 0°C in advance), the temperature is kept and stirred until it is completely d...

Embodiment 2

[0052] Embodiment 2, the synthesis of ceftazidime:

[0053] 40 g of 7-aminocephalosporanic acid, 300 mL of dichloromethane, and 95.5 mL (0.39 mol) of N,O-bistrimethylsilylacetamide were placed in a reaction flask, heated to reflux for 8 hours, and N,N-dimethylacetal was added under ice bath. 40 mL (0.24 mol) of phenylaniline, 43 g of trimethylsilyl iodide, react at room temperature for 3 h, add 24 ml (0.29 mol) of pyridine under ice bath, and continue to react for 1 h;

[0054] The above-mentioned feed liquid was cooled to -25°C, 72 g (0.28 mol) of ceftazidime side chain acid chloride hydrochloride (compound of formula 5) was added in batches, and the reaction was incubated for 2 h after the addition;

[0055] The temperature is controlled at 0±5°C, the above-mentioned reaction feed liquid is slowly transferred into the mixed solution of 70mL concentrated hydrochloric acid / 70mL water (the solution is pre-cooled to 0°C in advance), the temperature is kept and stirred until it i...

Embodiment 3

[0056] Embodiment 3, the synthesis of ceftazidime:

[0057] As described in Example 1, the difference is that the silanizing agent is 39.2 mL (0.31 mol) of trimethylchlorosilane, the acid scavenging agent is 12.3 mL (0.09 mol) of triethylamine, and the pH value of the aqueous phase after extraction is adjusted with 10 % (mass percent) sodium hydroxide.

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Abstract

The invention relates to a method for preparing ceftazidime by a one-pot process. The method comprises the following steps: by using 7-aminocephalosporanic acid as the raw material, carrying out silanization reaction and iodination reaction, reacting with pyridine, directly adding the liquid into ceftazidime side chain acyl chloride hydrochloride to perform acylation reaction without separation to obtain ceftazidime iodate, adding the liquid into a concentrated hydrochloric acid-water mixed solution to perform deprotection, extracting to stratify, and regulating the pH value of the water phase with an alkaline solution to obtain ceftazidime (6R,7R)-7-[[(2-amino-4-thiazolyl)-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]octyl-2-ene-3-methylpyridine pentahydrate. The method has the advantages of high yield, low cost, mild technological conditions, controllable technical process, high safety and low energy consumption, and is simple to operate.

Description

technical field [0001] The invention relates to a new one-pot method for synthesizing ceftazidime, and belongs to the technical field of drug synthesis. Background technique [0002] Ceftazidime is a third-generation broad-spectrum antibiotic developed by GlaxoSmithKline, UK. It is used for sepsis, lower respiratory tract infections, abdominal and biliary tract infections, complicated urinary tract infections, and severe skin and soft tissue infections caused by sensitive gram-negative bacilli. It is especially suitable for infections in immunocompromised persons caused by multi-drug resistant Gram-negative bacilli, nosocomial infections, and central nervous system infections caused by Gram-negative bacilli or Pseudomonas aeruginosa. This product was listed in the UK for the first time in 1983, and is now listed in Category B of the National Basic Medical Insurance and Work Injury Insurance Catalogue. The clinical application effect is unmatched by other new and old cephalo...

Claims

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Application Information

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IPC IPC(8): C07D501/46C07D501/04
CPCC07D501/04C07D501/46
Inventor 王晓艳王欣付景龙侯传山王勇进李凤侠康宏元范美菊
Owner QILU ANTIBIOTICS PHARMA
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