Novel method for preparing cefroxadine parent nucleus 7-AMOCA

A technology of cefoxadin and a new method, which is applied in the field of preparation of cephalosporin intermediates, can solve the problems of easy explosion, strong stimulation, and dyspnea, and achieve the goals of improving production safety, mild process operating conditions, and reducing costs Effect

Inactive Publication Date: 2020-03-13
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Inhalation can lead to necrosis of tracheal and bronchial epithelial cells, puncture leading to mediastinal or subcutaneous emphysema; serious bodily harm to workshop workers
[0009] The diazomethane used in the above synthesis method of route 2 belongs to explosives, and it is very easy to explode when it is heated, exposed to open flame, or subjected to vibration and friction; and inhalation has a strong stimulating effect on the respiratory tract and inhibits the central nervous system. effect, can cause dyspnea, chest pain; therefore not suitable for industrial production

Method used

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  • Novel method for preparing cefroxadine parent nucleus 7-AMOCA
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  • Novel method for preparing cefroxadine parent nucleus 7-AMOCA

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Embodiment 1

[0029] The present invention proposes a kind of novel method for preparing cefoxadine mother nucleus 7-AMOCA, comprises the steps:

[0030] (1) Preparation of methides:

[0031] Take a 1000ml dry three-necked flask, add 50g (0.099mol) of 3-hydroxycephalosporin, 300ml of N, N-dimethylformamide, 22g (0.1584mol) of potassium carbonate under mechanical stirring; heat up to 60-65°C after stirring well ; then dropwise add 53.99g (0.594mol) of dimethyl carbonate, and stir for 3 hours after the dropwise addition is completed for 30 minutes; after the reaction is completed, cool down to 25°C; pour it into 500ml of water and 300ml of dichloromethane, stir well , standing and layering; the water phase was extracted with 130ml of dichloromethane, the dichloromethane layers were combined, dried over anhydrous magnesium sulfate for 2 hours, the desiccant was filtered off, and the dichloromethane was recovered to the end to obtain a white methylated solid 46.1 g (0.090 mol), yield 89.7%.

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Embodiment 2

[0035] The present invention proposes a kind of novel method for preparing cefoxadine mother nucleus 7-AMOCA, comprises the steps:

[0036] (1) Preparation of reduced product:

[0037] Take a 1000ml dry three-neck flask, add 62g (0.124mol) of 3-hydroxycephalosporin, 350ml of N, N-dimethylformamide, 27.35g (0.198mol) of potassium carbonate under mechanical stirring; heat up to 60-65 ℃; then dropwise add 111.58g (1.239mol) of dimethyl carbonate, and stir for 3 hours after the dropwise addition is completed for 30 minutes; after the reaction is completed, cool down to 25°C; pour it into 600ml of water and 320ml of dichloromethane, and stir evenly After standing, the layers were separated; the water phase was extracted with 150ml of dichloromethane, the dichloromethane layers were combined, dried over anhydrous magnesium sulfate for 2 hours, the desiccant was filtered off, and the dichloromethane was recovered to the end to obtain a white methylated solid 60.1 g (0.117 mol), yiel...

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Abstract

The invention discloses a novel method for preparing a cefroxadine parent nucleus 7-AMOCA. The method comprises the following steps: (1) preparing a methide: adding 3-hydroxycephalosporin, N,N-dimethylformamide and potassium carbonate in the stirring process, heating the obtained mixture, adding dimethyl carbonate, performing stirring until a reaction is finished, cooling the reacted mixture to room temperature, adding water and dichloromethane, performing stirring until uniformity, standing for layering, and drying and concentrating the obtained mixture to obtain the methide; and (2) preparing the cefroxadine parent nucleus: adding dichloromethane, dibromotriphenylphosphine and 2,6-dimethylpyridine in a nitrogen introducing state, cooling the obtained mixture, adding the methide and m-cresol, performing stirring until a reaction is finished, adding water, performing stirring until uniformity, standing for layering, adjusting the pH value of the obtained water layer to crystallize thewater layer, and drying obtained crystals to obtain the white cefroxadine parent nucleus 7-AMOCA. The method has the advantages of easily available raw materials, simplification of a three-step reaction into a two-step reaction, avoiding of the highly-toxic reagent dimethyl sulfate from being used in the preparation of the cefroxadine parent nucleus, simplicity in operation, and improved yield.

Description

technical field [0001] The invention relates to the technical field of preparation of cephalosporin intermediates, in particular to a new method for preparing cefoxadin core 7-AMOCA. Background technique [0002] As an oral cephalosporin, cefoxadin has broad-spectrum antibacterial activity and has bactericidal effects on Staphylococcus, Escherichia coli, Influenza Bacillus, Klebsiella, etc. Infections in organs and other parts are also commonly used for otitis media. 7-AMOCA is the key mother nucleus for the synthesis of cefoxadin, and its chemical name is (6R,7R)-7-amino-3-methoxy-8-oxo-5-thia-1-azabicyclo[4.2. 0] Oct-2-ene-2-carboxylic acid, molecular structural formula is: [0003] [0004] There are mainly 2 synthetic technical routes of the existing cefoxadin nucleus 7-AMOCA. Route 1 is obtained through methylation and deprotection reaction with 3-OH cephem compound as the starting reaction material. The reaction route is as follows : [0005] [0006] Route 2...

Claims

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Application Information

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IPC IPC(8): C07D501/59C07D501/04
CPCC07D501/04C07D501/59
Inventor 杨双兵刘玉亭付林魏旭力李桂莲鲁亮
Owner HUAZHONG PHARMA
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