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A kind of preparation technology of cefoxizone sodium

A cefazedone sodium and preparation process technology, applied in the field of drug synthesis, can solve the problems of high reactivity of active esters, difficult industrial production operations, difficult storage, etc., and achieve product yield and purity improvement, side reaction suppression, and thorough reaction Effect

Active Publication Date: 2021-01-01
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 poor stability and are not easy to store. The reaction must be carried out continuously, and industrial production is difficult.

Method used

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  • A kind of preparation technology of cefoxizone sodium
  • A kind of preparation technology of cefoxizone sodium
  • A kind of preparation technology 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 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 1.28 g of sodium dithionite, stir for 10 minutes, transfer to water and add 80 mL of isopropanol, slowly add concentrated ammonia water dropwise 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 and vacuum drying yielded 11.60 g of 7-TDA, with a yield of 91.7%, a purity of 99.4% by HPLC, and a maximum of 0.08% simple impurities.

[0036] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 10.00g of 3,5-dichloropyridoneacetic acid, cool down to -10~0℃, slowly add 5.85g of N,N-diisopropylethylamine dropwise, 10.86 g of pivaloyl chloride was slowly added. Control the...

Embodiment 2

[0039] (1) Add 60mL of dimethyl carbonate and 9.86g of 2-hydroxysuccinic 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 Compound 40.62g, temperature control 20~30℃ for reaction, after 1h HPLC monitors the reaction is over, add 1.28g sodium dithionite, stir for 10min, transfer to water, add n-butanol 80mL, slowly add triethylamine dropwise to adjust the pH to 4.5, Control the dropping time for 30-60 minutes, cool down to 0-10°C and crystallize for 1 hour. Suction filtration and vacuum drying yielded 11.65 g of 7-TDA, with a yield of 92.1%, a purity of 99.2% by HPLC, and a maximum of 0.10% simple impurities.

[0040] (2) Add 150 mL of dichloromethane to a 500 mL three-necked flask, add 10.00 g of 3,5-dichloropyridone acetic acid, cool down to -10-0°C, slowly add 3.31 g of DMF dropwise, and slowly add 10.86 g of pivaloyl chloride. Control the temperature at -10-0°C and react...

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 that the reaction is over. Add 1.28g of sodium dithionite, stir for 10 minutes, transfer to water and add 80mL of isopropanol, slowly add sodium hydroxide 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 and vacuum drying gave 11.64 g of 7-TDA, with a yield of 92.0%, a purity of 99.3% by HPLC, and a maximum of 0.08%.

[0044] (2) Add 150 mL of dichloromethane to a 500 mL three-necked flask, add 10.00 g of 3,5-dichloropyridone acetic acid, cool down to -10-0°C, slowly add 3.94 g of DMAC dropwise, and slowly add 10.86 g of pivaloyl chloride. Control the temperature ...

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Abstract

The invention belongs to the technical field of medicine, and discloses a preparation technology of cefazedone sodium. 3,5-dichloropyridone acetic acid and pivaloyl chloride are taken as the raw materials to synthesize mixed acid anhydrides; and then cefazedone sodium is obtained after salt forming reactions between mixed acid anhydrides and an intermediate prepared from 7-aminocephalosporanic acid and thiol tetrazole. A mixed solvent is used in 3-substitution, the reaction becomes more stable and softer, the byproducts are reduced; in acylation reactions, mixed acid anhydrides are used, the activity is high, 7-acylation reactions are promoted, and thus the yield and purity of cefazedone sodium are high.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation process of cefazedone sodium. 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 a raw material, undergoes amidation reaction with 3,5-dichloropyridoneacetic acid, and then reacts with 2-mercapto-5-methyl-1,3,4-thia Diazole (MMTD) reaction synthesis of cefazedone sodium. The synthetic route is show...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/06
CPCC07D501/06C07D501/36
Inventor 李明杰孙聚李强
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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