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Synthetic method of cefazedone sodium

A technology of cefazedone sodium and its synthesis method, which is applied in the field of drug synthesis, can solve the problems of high reactivity of active esters and difficult control, and achieve the effects of ensuring stability and improving product purity

Active Publication Date: 2019-04-02
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK 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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  • Synthetic method of cefazedone sodium
  • Synthetic method of cefazedone sodium
  • Synthetic method of cefazedone sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (1) Add 60mL of dimethyl carbonate and 7.06g of citric acid into a 500mL three-necked flask, add 4.85g of MMTD while stirring, add 10.00g of 7-ACA, and slowly add boron trifluoride-dimethyl carbonate complex 34.82 g, control the temperature at 20-30°C, and monitor the reaction by HPLC after 1 hour, add 1.28g of sodium dithionite, stir for 10 minutes, transfer to water, add 80mL of isopropanol, slowly add concentrated ammonia water to adjust the pH to 3.0, and control the dropping time After 30-60 minutes, cool down to 0-10°C to crystallize for 1 hour. Suction filtration yielded 12.74 g of 7-TDA wet product, with a purity of 99.4% by HPLC and a maximum of 0.10% impurity.

[0036] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of 3,5-dichloropyridoneacetic acid, cool down to 0-10°C, slowly add 5.85g of N,N-diisopropylethylamine dropwise, and stir After 15 minutes, it was raised to room temperature, 33.06 g of dithiodibenzothiazole was added, a...

Embodiment 2

[0039] (1) Add 60mL of dimethyl carbonate and 11.03g of tartaric acid into a 500mL three-necked flask, add 4.85g of MMTD while stirring, add 10.00g of 7-ACA, and slowly add 40.62g of boron trifluoride-dimethyl carbonate complex, Control the temperature at 20-30°C and react. After 1 hour, HPLC monitors the end of the reaction. Add 1.28g of sodium dithionite, stir for 10 minutes, transfer to water, add 80mL of isopropanol, slowly add concentrated ammonia water to adjust the pH to 4.5, and control the dropping time for 30~ After 60 minutes, the temperature was lowered to 0-10°C for 1 hour of crystallization. Suction filtration yielded 12.88 g of 7-TDA wet product, with a purity of 99.3% detected by HPLC and a maximum of 0.09% impurity.

[0040] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of 3,5-dichloropyridoneacetic acid, cool down to 0-10°C, slowly add 3.31g of N,N-dimethylformamide dropwise, and stir for 15min , raised to room temperature, added...

Embodiment 3

[0043] (1) Add 60mL of dimethyl carbonate and 6.62g of acetic acid into a 500mL three-necked flask, add 4.85g of MMTD while stirring, add 10.00g of 7-ACA, and slowly add 46.42g of boron trifluoride-dimethyl carbonate complex, Control the temperature at 20-30°C and react. After 1 hour, HPLC monitors the end of the reaction. Add 1.28g of sodium dithionite, stir for 10 minutes, transfer to water, add 80mL of isopropanol, slowly add concentrated ammonia water to adjust the pH to 4.0, and control the dropping time for 30~ After 60 minutes, the temperature was lowered to 0-10°C for 1 hour of crystallization. Suction filtration yielded 12.80 g of 7-TDA wet product, with a purity of 99.3% by HPLC and a maximum of 0.08% impurity.

[0044] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of 3,5-dichloropyridoneacetic acid, cool down to 0-10°C, slowly add 3.94g of N,N-dimethylacetamide dropwise, and stir for 15min , raised to room temperature, added 33.06 g of ...

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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 in particular relates to a synthesis method of cefazedone. Background technique [0002] Cefoxizone was developed by EMerck, Darmstadt laboratory in the late 1970s and is the first generation of cephalosporin antibiotics. The chemical name of cefoxizone 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 synthetic method of cefoxizone sodium mainly contains following several [0005] (1) Direct synthesis method. Patent CN101584671B uses 7-aminocephalosporanic acid (7-ACA) as raw material, and 3,5-dichloropyridone acetic acid undergoes amidation reaction, and then reacts with 2-mercapto-5-methyl-1,3,4-thio Diazole (MMTD) reaction synthesis of cefazedone sodium. The synthetic route is shown in the fol...

Claims

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Application Information

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