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Preparation method of cefroxadine parent nucleus

A technology of cefoxadine and parent nucleus, which is applied in the field of preparation of cefoxadine parent nucleus and can solve the problem of high total phosphorus content

Active Publication Date: 2021-02-05
湖北凌晟药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Aiming at the problem that the total phosphorus content in the waste water is relatively high in the process of synthesizing the cefoxadine mother nucleus, the invention provides a preparation method of the cefoxadine mother nucleus

Method used

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  • Preparation method of cefroxadine parent nucleus
  • Preparation method of cefroxadine parent nucleus
  • Preparation method of cefroxadine parent nucleus

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Embodiment 1

[0033] The present embodiment provides a kind of preparation method of cefoxadine nucleus, specifically comprises the following steps:

[0034] S1. At room temperature, add 46.9 g (0.1 mol) of p-nitrobenzyl 7-phenylacetamido-3-hydroxyl-3-cephem-4-carboxylate and one p-toluenesulfonic acid to a 500 ml reaction flask. Hydrate 1.0g (0.005mol) and chloroform 235ml, mixed, heated to reflux, slowly dropwise added trimethyl orthoformate 12.7g (0.12mol), after the drop, continue to reflux for 6h to carry out enol methylation reaction. The material was cooled to room temperature, 50ml of water was added, stirred for 10min, and then separated into layers, the organic layer was collected, the aqueous layer was extracted once with 10ml of chloroform, the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated to obtain white formazan 43.5 g (0.09 mol) of the base solid, the molar yield is 90.1%, and the purity is 99.1%;

[0035] S2. Add 68.6 g (0.18 mol) of tr...

Embodiment 2

[0038] The present embodiment provides a kind of preparation method of cefoxadine nucleus, specifically comprises the following steps:

[0039]S1. At room temperature, add 46.9 g (0.1 mol) of p-nitrobenzyl 7-phenylacetamido-3-hydroxyl-3-cephem-4-carboxylate and one p-toluenesulfonic acid to a 500 ml reaction flask. Hydrate 1.0g (0.005mol) and chloroform 235ml, mixed, heated to reflux, slowly dropwise added trimethyl orthoformate 13.8g (0.13mol), after the drop, continued to reflux for 6h to carry out enol methylation reaction. The material was cooled to room temperature, 50ml of water was added, stirred for 10min, and then separated into layers, the organic layer was collected, the aqueous layer was extracted once with 10ml of chloroform, the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated to obtain white formazan 44.0 g (0.091 mol) of the base solid, the molar yield is 91.1%, and the purity is 99.2%;

[0040] S2. Add 76.3 g (0.20 mol) of t...

Embodiment 3

[0043] The present embodiment provides a kind of preparation method of cefoxadine nucleus, specifically comprises the following steps:

[0044] S1. At room temperature, add 46.9 g (0.1 mol) of p-nitrobenzyl 7-phenylacetamido-3-hydroxyl-3-cephem-4-carboxylate and one p-toluenesulfonic acid to a 500 ml reaction flask. Hydrate 2.0g (0.010mol) and chloroform 235ml, mix, heat to reflux, slowly dropwise add trimethyl orthoformate 14.8g (0.14mol) to it, continue to reflux for 6h after dropping to carry out enol methylation reaction. The material was cooled to room temperature, 50ml of water was added, stirred for 10min, and then separated into layers, the organic layer was collected, the aqueous layer was extracted once with 10ml of chloroform, the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated to obtain white formazan 44.1 g (0.091 mol) of the base solid, the molar yield is 91.3%, and the purity is 99.3%;

[0045] S2. Add 80.1 g (0.21 mol) of tr...

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Abstract

The invention relates to the technical field of synthesis of medical intermediates, and in particular, relates to a preparation method of a cefroxadine parent nucleus. The preparation method comprisesthe steps: taking 7-phenylacetylamino-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester as an initial raw material, taking trimethyl orthoformate as a methylation reagent to carry out enol methylation reaction, and carrying out phenylacetamido removal reaction in a solvent containing triphenyl dichlorophosphate, isobutanol hydrochloride and an acid-binding agent; and carrying out a carboxylic acid protective group removal reaction on the obtained product to prepare the cefroxadine parent nucleus. According to the preparation method, no wastewater is generated in the reaction process ofremoving the 7-position protecting group, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a preparation method of cefoxadine nuclei. Background technique [0002] Cefoxadin is a common cephalosporin antibiotic, which has bactericidal effect on Staphylococcus, Escherichia coli, Influenza Bacillus, Klebsiella, etc. Infections in the respiratory tract, urinary tract, skin and soft tissues, reproductive organs (including the prostate) and other parts are also commonly used for otitis media. [0003] Cefoxadin core 7-AMOCA (7-amino-3-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid) is Synthesizing the key intermediate of cefoxadin is difficult to synthesize and requires high requirements on the actual production process and technical level. Most of the existing technologies use 3-OH cephem compounds as raw materials, remove the 7-position protection by triphenylphosphine, carbon tetrabromide, etc., remove ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/59C07D501/04
CPCC07D501/59C07D501/04Y02P20/55
Inventor 何健宋炳浩金联明金大俊门万辉邹菁
Owner 湖北凌晟药业股份有限公司