Method for preparing cefuroxime acid

A technology of cefuroxime acid and furoxine, which is applied in the field of drug synthesis, can solve the problems of large equipment damage, high recovery cost, harsh reaction conditions, etc., and achieve the effect of low cost and high yield

Inactive Publication Date: 2017-02-22
珠海保税区丽珠合成制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The step of generating cefuroxime acid from the DCCF reaction, the synthetic route reported by the patent process of the prior art is basically similar, and mainly has the following two shortcomings: 1, the solvent used is such as: tetrahydrofuran, dichloromethane, acetonitrile are more toxic; 2 1. A binary or even quaternary mixed solvent system is used, and the mixed solvent system is soluble in each other. High technology is required for recovery and separation, and the recovery cost is high; 3. The reaction conditions are harsh and need to be maintained at -40°C, which will not only damage the equipment large and energy-intensive

Method used

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  • Method for preparing cefuroxime acid

Examples

Experimental program
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Effect test

Embodiment 1

[0043] Example 1 Preparation of decarbamoylcefuroxine (DCCF)

[0044] Experiment (1): The method of the present invention prepares decarbamylated cefuroxime (DCCF)

[0045] (a) Dissolve triphosgene (24.4g) in carbon dichloride (350ml), stir and cool down to -21°C, add DMAC (75ml), SMIA (41g,), and control the temperature to -10°C and stir to react;

[0046] (b) After the reaction is completed, control the temperature to about 0°C and add purified water, stir and stand still to separate the layers, remove the water layer, and store the organic layer at low temperature for later use.

[0047] (c) Add purified water (230ml) to D-7-ACA (42.3g), cool down to about 0°C, add 15% NaOH dropwise to control pH=8.0, and stir until completely dissolved.

[0048](d) Drop the organic layer solution prepared in step (b) into the D-7-ACA solution prepared in step (c), and simultaneously add 15% NaOH dropwise to control pH6.0. After the dropwise addition was completed, let stand to separate t...

Embodiment 2

[0055] The preparation of embodiment 2 cefuroxime acid

[0056] Experiment (3): the method of the present invention prepares cefuroxime acid

[0057] (1) Dissolve DCCF (40.0g) in methyl acetate (360ml), cool down to -39°C, add CSI (23.1g), and react at -25°C.

[0058] (2) After the reaction is completed, add purified water and heat up to 20°C for hydrolysis.

[0059] (3) After the hydrolysis is complete, adjust the pH to 4.5 with sodium bicarbonate (48.0g), add methyl acetate (240ml), adjust the pH to 2.0 with 30% hydrochloric acid, let stand to separate the organic layer, and concentrate at temperature T=40°C to Viscous concentrated organic layer.

[0060] (4) Add purified water to the concentrated organic layer, lower the temperature to 10° C., filter after crystallization, wash the filter cake with purified water, and dry to obtain 41.2 g of cefuroxime acid with a molar yield of 92.6% and an HPLC purity of 99.5%.

[0061] Experiment (4): Prepare cefuroxime acid according...

Embodiment 3

[0067] (1) Dissolve DCCF (40.0g) in ethyl acetate (360ml), the feed ratio of DCCF and ethyl acetate is 1:9 (w / v), cool down to -35°C, add CSI (23.1g), control Reaction at -20°C.

[0068] (2) After the reaction is completed, add purified water and heat up to 25°C for hydrolysis.

[0069] (3) After the hydrolysis is complete, adjust the pH to 4.9 with sodium bicarbonate (48.0 g), add ethyl acetate (240 ml), adjust the pH to 2.0 with 30% hydrochloric acid, let stand to separate the organic layer, and concentrate at temperature T=40°C to Viscous concentrated organic layer.

[0070] (4) Add purified water to the concentrated organic layer, lower the temperature to 5° C., filter after crystallization, wash the filter cake with purified water, and dry to obtain 41.1 g of cefuroxime acid with a molar yield of 92.3% and an HPLC purity of 99.3%.

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Abstract

The invention provides a method for preparing cefuroxime acid. The method is characterized by comprising the following steps: (1) mixing deammonized formyl cefuroxime in liquid ester, adding a strong amino carbamylation reagent sulfonylisocynate, and performing a temperature-controlled reaction; (2) adding purified water after the reaction is completed, and performing hydrolysis; (3) adding the liquid ester after hydrolysis is completed, adjusting the pH value to be 1.9-2.0 by using hydrochloric acid, standing for layering, and performing vacuum concentration on an organic layer so as to obtain an organic layer concentrated solution; (4) adding purified water into the organic layer concentrated solution, performing crystallization, and filtering so as to obtain cefuroxime acid, wherein the liquid ester used in the step (1) and the step (3) is selected from methyl acetate, acetic ether, n-butyl acetate, methyl formate, ethyl formate and propyl formate. The method for preparing cefuroxime acid, which is provided by the invention, is green and environmental-friendly, low in cost, high in yield and good in quality.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of a cephalosporin antibiotic intermediate, in particular to a preparation method of cefuroxime acid. Background technique [0002] Cefuroxime acid (Cefuroxime acid, structural formula 1), the chemical name is (6R, 7R)-7-[2-furyl (methoxyimino) acetamido]-3-carbamoyloxymethyl-8-oxo - 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. [0003] [0004] Cefuroxime acid is a key intermediate in the synthesis of the second-generation cephalosporin antibiotics cefuroxime axetil and cefuroxime sodium. Cefuroxime is quite stable against the β-lactamase produced by Gluconococcus and Gram-negative bacilli, and has a broad-spectrum antibacterial effect. It is mainly used clinically in the lower respiratory tract, urinary system, Infections in skin and soft tissues, bones and joints, female genitalia, etc. are also effective for sepsis and meningitis. Cef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/04C07D501/06C07D501/34
CPCC07D501/04C07D501/06C07D501/34
Inventor 张鹏肖鸿邱琪李罗浩邝毅斌戴奇志
Owner 珠海保税区丽珠合成制药有限公司
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