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A kind of synthetic method of cefoxizone sodium

A technology of cefoxidone sodium and a synthesis method, which is applied in the field of drug synthesis, can solve the problems of high reaction activity of active ester and difficult to control, and achieves the effects of ensuring stability and improving product purity

Active Publication Date: 2020-06-09
SHANDONG LUOXIN PHARMA GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Active esters have high reactivity, but this route simultaneously reacts at multiple sites and is difficult to control

Method used

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  • A kind of synthetic method of cefoxizone sodium
  • A kind of synthetic method of cefoxizone sodium
  • A kind of synthetic method of cefoxizone sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (1) Add 60mL of dimethyl carbonate and 7.06g of citric acid to a 500mL three-necked flask. While stirring, add 4.85g of MMTD, 10.00g of 7-ACA, and slowly add 34.82 of boron trifluoride-dimethyl carbonate complex. g. Control the temperature at 20~30℃ to react. After 1h, the reaction is monitored by HPLC. Add 1.28g of sodium dithionite, stir for 10min and transfer to water, add 80mL of isopropanol, slowly add concentrated ammonia water to adjust the pH to 3.0, and control the dropping time 30~60min, cooling down to 0~10℃ to crystallize for 1h. The wet product of 7-TDA was obtained by suction filtration. 12.74g, the purity was 99.4% by HPLC, and the maximum single impurities was 0.10%.

[0036] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of 3,5-dichloropyridone acetic acid, cool to 0~10℃, slowly add 5.85g of N,N-diisopropylethylamine dropwise, and stir After 15 minutes, warm to room temperature, add 33.06g of dithiodibenzothiazole, and slowly a...

Embodiment 2

[0039] (1) Add 60mL of dimethyl carbonate and 11.03g of tartaric acid to a 500mL three-necked flask. While stirring, add 4.85g of MMTD, 10.00g of 7-ACA, and slowly add 40.62g of boron trifluoride-dimethyl carbonate complex. Control the temperature at 20~30℃ to react. After 1h, the reaction is monitored by HPLC. Add 1.28g of sodium dithionite, stir for 10min and transfer to water, add 80mL of isopropanol, slowly add dropwise concentrated ammonia water to adjust the pH to 4.5, control the dropping time 30~ 60min, cooling to 0~10℃ and crystallization for 1h. Suction filtration yielded 12.88 g of 7-TDA wet product, with a purity of 99.3% as determined by HPLC and a maximum single impurity of 0.09%.

[0040] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of 3,5-dichloropyridone acetic acid, cool to 0~10℃, slowly add 3.31g of N,N-dimethylformamide dropwise, and stir for 15min , Rise to room temperature, add 33.06g of dithiodibenzothiazole, and slowly add 30...

Embodiment 3

[0043] (1) Add 60mL of dimethyl carbonate and 6.62g of acetic acid to a 500mL three-necked flask. While stirring, add 4.85g of MMTD, 10.00g of 7-ACA, and slowly add 46.42g of boron trifluoride-dimethyl carbonate complex. The temperature was controlled at 20~30℃, and the reaction was monitored by HPLC after 1h. Add 1.28g of sodium dithionite, stir for 10min and transfer to water, add 80mL of isopropanol, slowly add concentrated ammonia water to adjust the pH to 4.0, control the dropping time 30~ 60min, cooling to 0~10℃ and crystallization for 1h. Suction filtration obtains 12.80 g of 7-TDA wet product, with a purity of 99.3% as determined by HPLC and a maximum single impurity of 0.08%.

[0044] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of 3,5-dichloropyridone acetic acid, cool to 0~10℃, slowly add 3.94g of N,N-dimethylacetamide dropwise, and stir for 15min , Rise to room temperature, add 33.06g of dithiodibenzothiazole, and slowly add 26.92g of tr...

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PUM

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Abstract

The invention belongs to the technical field of medicines, and discloses a synthetic method of cefazedone sodium. Active ester is synthesized by taking 3,5-dichloro-4-pyridone-1-acetic acid and 2,2'-dithiobis(benzothiazole) as raw materials, then the active ester reacts with an intermediate generated from 7-aminocephalosporanic acid and mercaptoterazole, and the cefazedone sodium is obtained through salifying. According to the invention, a mixed solvent is used in 3-position substitution, so that the reaction is more stable and soft, and generation of by-products is reduced; the active ester is used in an acylation reaction, so that activity is high, and a 7-position acylation reaction is facilitated; and the yield and purity of the cefazedone sodium are relatively high.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for synthesizing cefazidone. Background technique [0002] Cefazerone was developed by EMerck, Darmstadt laboratory in the late 1970s and is the first-generation cephalosporin antibiotic. The chemical name of cefazidone sodium is: (6R, 7R)-3-(5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl)-7(3,5-dichloro- 4-pyridone-1-acetylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, its structural formula is as follows: [0003] [0004] The main synthetic methods of cefazerone sodium are as follows [0005] (1) Direct synthesis method. Patent CN101584671B takes 7-aminocephalosporanic acid (7-ACA) as raw material, reacts with 3,5-dichloropyridone acetic acid for amidation, and then reacts with 2-mercapto-5-methyl-1,3,4-thiol The reaction of diazole (MMTD) to synthesize cefazidone sodium. The synthetic route is shown in the following formula: [0006]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36C07D501/06
CPCC07D501/06C07D501/36
Inventor 高红军郑建伟王连慧
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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