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Method for preparing high-purity cefpodoxime proxetil

A technology of cefpodoxime axetil and cefpodoxime acid, which is applied in the field of preparing high-purity cefpodoxime axetil, can solve the problems of low yield and expensive quaternary ammonium salt, and achieve high yield, easy operation and good product stability Effect

Active Publication Date: 2019-01-18
ZHEJIANG APELOA TOSPO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method also requires the use of expensive quaternary ammonium salts and causes low yields due to the long reaction process of about 3 days

Method used

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  • Method for preparing high-purity cefpodoxime proxetil
  • Method for preparing high-purity cefpodoxime proxetil
  • Method for preparing high-purity cefpodoxime proxetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] In a 250ml reaction flask, put 10g (0.0234moL) of cefpodoxime acid B into 50ml of DMAc (N,N-dimethylacetamide) under nitrogen protection, stir and cool down to -20°C to dissolve, add [bmlm] OH0.05g, potassium carbonate 3.5g, stirred for 20 minutes. Add 6.5 g (0.0253 mol) of α-iodoethyl isopropyloxycarbonate dropwise, and control the temperature at -18°C to -19°C. After 30 minutes of reaction, the raw material cefpodoxamic acid B≤0.5% is controlled by HPLC, and the esterification reaction At the end, add 1g of medicinal activated carbon for decolorization. After decolorization, slowly press the esterification reaction product into 400ml of 1% methanol / purified aqueous solution that has been pre-cooled to 5°C. The product was washed with 50 mL of water and dried in vacuum to obtain 10.5 g of white powder solid (80.6% molar yield).

[0030] Product (R+S)HPLC=99.2%, R / (R+S)=0.51, Δ 3 = 0.35%.

Embodiment 2

[0032] In a 250ml reaction flask, put 10g (0.0234moL) of cefpodoxamic acid B into 50ml of DMAc under nitrogen protection, stir and cool down to -20°C to dissolve, add [bmlm]OH0.1g, sodium carbonate 3.1g and stir for 20 minutes . Add 6.5 g (0.0253 mol) of α-iodoethyloxyisopropyl carbonate dropwise, control the temperature at -18°C to -19°C, and react for 30 minutes.

[0033] HPLC control raw material cefpodoxamic acid B ≤ 0.5%, after the esterification reaction is completed, add 1g of medicinal activated carbon for decolorization, after the decolorization is completed, slowly press the esterification reactant into the pre-cooled to 5°C containing 1% methanol / purified aqueous solution In 400ml, after press filtration, continue to stir for 30 minutes, shake off the filter, wash the product with 50mL of purified water, and vacuum dry to obtain 10.2g of white powder solid (molar yield=78.3%).

[0034] Product (R+S)HPLC=99.1%, R / (R+S)=0.53, Δ3=0.36%.

Embodiment 3

[0036] Put 20g (0.0468moL) of cefpodoxamic acid B into 100ml of DMF in a 250ml four-necked flask under the protection of nitrogen, stir and cool down to -15℃~-18℃ to dissolve, add [bmlm]OH0.2g, potassium carbonate 6.3 g, stirred for 20 minutes. Add 13 g (0.0505 mol) of α-iodoethyl isopropyloxycarbonate dropwise, and keep the reaction for 30 minutes. After the HPLC control raw material cefpodoxamic acid B≤0.5%, the esterification reaction is completed, add 2 g of medicinal active carbon for decolorization, decolorization Slowly press the esterification reactant into 800 ml of 2% ethanol / purified aqueous solution pre-cooled to 5° C., press filter and precipitate solid, and continue to stir for 30 minutes. It was filtered by rejection, washed with 50 mL of purified water, and dried in vacuum to obtain 18.9 g of white powder solid (weight yield=94.5%).

[0037] Product (R+S)HPLC=99.2%, R / (R+S)=0.51, Δ 3 = 0.37%.

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Abstract

The invention discloses a method for preparing high-purity cefpodoxime proxetil. The method comprises the following steps: reacting cefpodoxime proxetil with iodo ester in an organic solvent in the presence of carbonate and basic ionic liquid; and performing post-treatment to obtain the cefpodoxime proxetil after reaction is completed. The cefpodoxime proxetil product prepared by the method has total impurities of less than 3 percent, and delta 3 isomer of 1.5 percent or less (EP7.0 specified total impurities are less than 4 percent, and USP35 specified total impurities are less than 6 percent), has good stability, molar ratio of 78.3-83.7 percent and high yield, is simple and convenient to operate, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing high-purity cefpodoxime axetil by using cefpodoxime acid as a raw material in one step. Background technique [0002] Cefpodoxime Proxetil Cefpodoxime Proxetil, CPDX-PR, (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(z)-(methoxyimino)-acetamido] -3-Methoxymethyl-8-oxo-5-thio-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid isopropoxycarbonyloxyethyl ester, the structure is as follows: Shown in I) is a cephalosporin ester prodrug, which, when administered orally, is converted into cefpodoxime, which is an antibacterial agent, by being rapidly hydrolyzed by esterases present on the intestinal wall. Cefpodoxime exhibits a broad range of antibacterial activity against Gram-positive and negative bacteria, such as Staphylococcus aureus, Streptococcus aureus, Escherichia coli, Klebsiella pneumoniae and Proteus vulgaris, and also has antibacterial activit...

Claims

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Application Information

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IPC IPC(8): C07D501/34C07D501/04
CPCC07D501/04C07D501/34
Inventor 祝占根厉昆李如宏厉梦琳陈亮杨彩霞金龙胡京晗
Owner ZHEJIANG APELOA TOSPO PHARMA
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