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Method for conveniently preparing fosfomycin trometamol

A technology for fosfomycin tromethamine and tromethamine, which is applied in the field of preparation of fosfomycin tromethamine, can solve the problems of no industrialized production value and high cost of chiral reagents, and achieves high purity and high yield. high rate effect

Active Publication Date: 2018-12-14
湖南华纳大药厂手性药物有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] (4), other methods: in CN102807586A, fosfomycin trometamol is obtained by reacting left phosphorus and right amine salt with thiocyanate or enone, and this method does not have practical industrial production value; cisacrylphosphoric acid is introduced in CN102659842A Asymmetric oxidation to fosfomycin acid under the chiral ligand, and then react with tromethamine to obtain fosfomycin tromethamine, the cost of chiral reagents is high
[0010] Among the above-mentioned numerous methods for synthesizing fosfomycin trometamol, there are not many simple and easy methods that can fully meet the Pharmacopoeia standard

Method used

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  • Method for conveniently preparing fosfomycin trometamol
  • Method for conveniently preparing fosfomycin trometamol
  • Method for conveniently preparing fosfomycin trometamol

Examples

Experimental program
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Effect test

Embodiment 1

[0039] 1. Preparation of fosfomycin trometamol crude product:

[0040] Take 25.7g of tromethamine and add it into 200g of absolute ethanol, heat up to 70-73°C to dissolve, and obtain solution A. Then take 57.2g left phosphorous right ammonium salt and add it into 343g absolute ethanol, heat up to 50-55°C to dissolve, and obtain solution B. Add the ethanol solution of left phosphorus and right amine salt (solution B) into the ethanol solution of tromethamine (solution A), and the intermediate fosfomycin bis(alpha-methylbenzylamine / tromethamine) salt is precipitated, suspended in ethanol In , this suspension is defined as reaction system C. Dissolve 39.2g of p-toluenesulfonic acid monohydrate in 50g of absolute ethanol, keep the temperature at 47-51°C, and slowly add it dropwise to reaction system C, and the dropwise addition is completed in 40 minutes. The reaction liquid dissolved clearly, indicating that the reaction was complete, and the temperature was gradually lowered t...

Embodiment 2

[0044] 1, the preparation of fosfomycin trometamol crude product:

[0045] Take 25.7g of tromethamine and add it into 200g of absolute ethanol, heat up to 70-73°C to dissolve, and obtain solution A. Then take 57.2g left phosphorous right ammonium salt and add it into 343g absolute ethanol, heat up to 50-55°C to dissolve, and obtain solution B. Add tromethamine ethanol solution (A solution) into the left phosphorus and right ammonium salt ethanol solution (B solution), and the intermediate fosfomycin bis(alpha-methylbenzylamine / tromethamine) salt is precipitated, and the suspension For the reaction system C. Dissolve 39.2g of p-toluenesulfonic acid monohydrate in 50g of absolute ethanol, keep the temperature at 47-51°C, and slowly add it dropwise to reaction system C, and the dropwise addition is completed in 40 minutes. The reaction liquid dissolved clearly, indicating that the reaction was complete, and the temperature was gradually lowered to 0°C, slowly stirred and crysta...

Embodiment 3

[0049] 1, the preparation of fosfomycin trometamol crude product:

[0050] Take 25.7g of tromethamine and add it into 200g of absolute ethanol, heat up to 70-73°C to dissolve, and obtain solution A. Then take 57.2g left phosphorous right ammonium salt and add it into 343g absolute ethanol, heat up to 50-55°C to dissolve, and obtain solution B. Add the ethanol solution of left phosphorus and right amine salt (solution B) into the ethanol solution of tromethamine (solution A), and the intermediate fosfomycin bis(alpha-methylbenzylamine / tromethamine) salt is precipitated, suspended in ethanol In , this suspension is defined as reaction system C. Dissolve 39.2g of p-toluenesulfonic acid monohydrate in 50g of absolute ethanol, keep the temperature at 47-51°C, and slowly add it dropwise to reaction system C, and the dropwise addition is completed in 40 minutes. The reaction liquid dissolved clearly, indicating that the reaction was complete. Gradually lower the temperature to 0-5°...

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Abstract

The invention discloses a synthesis method of fosfomycin trometamol. The method comprises the following steps: (1), taking fosfomycin phenylethylamine salt and tromethamine as raw material to preparefosfomycin bis (alpha-methylbenzylamine / tromethamine) salt, adding an alcoholic solution of methanesulfonic acid or para-toluenesulfonic acid in a stirring condition, stirring and performing cooling crystallization after dropwise adding is accomplished, and filtering to obtain a crude wet product; and (2), refining the crude product to obtain a refined product, and performing vacuum drying, so asto obtain a refined dried product. The method is simple to operate and mild in reaction condition, and ensures that both the product purity and the yield achieve high levels.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of fosfomycin trometamol. Background technique [0002] Fosfomycin trometamol, the chemical name is (1R,2S)-(1,2-epoxypropyl)phosphate.2-amino-2-hydroxymethyl-1,3-propanediol salt. It is the earliest water-soluble salt developed by Italian Zombon Company, and it is clinically used for urinary tract infection. Its synthetic method mainly concentrates on the following several kinds: [0003] (1), oxalic acid precipitation method. Tromethamine, oxalic acid are dissolved in water, add fosfomycin calcium subsequently, add oxalic acid aqueous solution under stirring, filter and remove oxalate solid, filtrate is concentrated under reduced pressure to dryness, and crystallization obtains fosfomycin tromethamine (Yin Dali, CN1060657A ); Fosfomycin sodium is suspended in methanol, heated to reflux, oxalic acid, trometamol heated and dissolved ...

Claims

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Application Information

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IPC IPC(8): C07F9/655C07C213/08C07C215/10
CPCC07C213/02C07C213/08C07F9/65505C07C215/10
Inventor 陆晓盛李乐欢皮士卿刘庆林徐燕黄本东
Owner 湖南华纳大药厂手性药物有限公司
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