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Preparation method of fosfomycin tromethamine

A technology for fosfomycin tromethamine and tromethamine, which is applied in the field of preparation of fosfomycin tromethamine, can solve the problems of high cost, unstable epoxy ring, high cost and the like, and achieves a high stability. Effect

Active Publication Date: 2014-10-08
桂林华信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses expensive chiral reagents, and the cost is high
[0006] At the same time, the epoxy ring in fosfomycin trometamol is very unstable, and it is easy to react with water, amine and hydroxyl to open the ring and form the corresponding impurities

Method used

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  • Preparation method of fosfomycin tromethamine
  • Preparation method of fosfomycin tromethamine
  • Preparation method of fosfomycin tromethamine

Examples

Experimental program
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Effect test

Embodiment 1

[0033] (1) Preparation of p-toluenesulfonic acid tromethamine salt: p-toluenesulfonic acid monohydrate and tromethamine are dissolved in dehydrated alcohol, and the mol ratio of p-toluenesulfonic acid monohydrate and tromethamine is 1.0:1.0, the mass of absolute ethanol is 5 times the mass of p-toluenesulfonic acid monohydrate; heat to 70°C, stir until clear and transparent, cool down to -10°C at a rate of 10°C / h, then keep warm for 1h, centrifuge The solid was separated, and the product was washed and filtered with absolute ethanol to obtain a wet product of tromethamine p-toluenesulfonate salt, and the wet product of tromethamine p-toluenesulfonate salt was vacuum-dried at 70°C to obtain a crystal-free Tromethamine p-toluenesulfonate salt of water;

[0034](2) prepare fosfomycin tromethamine crude product: dissolve tromethamine p-toluenesulfonate salt in dehydrated alcohol, and dehydrated alcohol quality is 9 times of tromethamine p-toluenesulfonate salt quality; Stir at 62...

Embodiment 2

[0038] (1) Preparation of p-toluenesulfonic acid tromethamine salt: p-toluenesulfonic acid monohydrate and tromethamine are dissolved in dehydrated alcohol, and the mol ratio of p-toluenesulfonic acid monohydrate and tromethamine is 1.0:1.1, the mass of absolute ethanol is 8 times the mass of p-toluenesulfonic acid monohydrate. Heat to 80°C, stir until clear and transparent, cool down to 0°C at a rate of 8°C / h, then keep warm for 1.5h, centrifuge to obtain the solid, and wash and filter the product with absolute ethanol to obtain tromethamine p-toluenesulfonate Alkoxide wet product, the p-toluenesulfonate tromethamine salt wet product is vacuum-dried at 80°C to obtain the p-toluenesulfonate tromethamine salt without crystal water;

[0039] (2) prepare fosfomycin tromethamine crude product: dissolve tromethamine p-toluenesulfonate in absolute ethanol, and the quality of dehydrated alcohol is 13 times of tromethamine p-toluenesulfonate quality; Stir at 42.5±2.5°C to obtain a cl...

Embodiment 3

[0043] (1) Preparation of p-toluenesulfonic acid tromethamine salt: p-toluenesulfonic acid monohydrate and tromethamine are dissolved in dehydrated alcohol, and the mol ratio of p-toluenesulfonic acid monohydrate and tromethamine is 1.0:1.3, the mass of absolute ethanol is 3 times that of p-toluenesulfonic acid monohydrate. Heat to 60°C, stir until clear and transparent, cool down to 10°C at a rate of 5°C / h, then keep warm for 1 hour, centrifuge to obtain the solid, and wash and filter the product with absolute ethanol to obtain tromethamine p-toluenesulfonate Salt wet product, the p-toluenesulfonate tromethamine salt wet product is vacuum-dried at 60°C to obtain the p-toluenesulfonate tromethamine salt without crystal water;

[0044] (2) Preparation of fosfomycin tromethamine crude product: dissolving p-toluenesulfonate tromethamine salt in dehydrated alcohol, the quality of dehydrated alcohol is 6 times of p-toluenesulfonate tromethamine salt quality; heating Stir at 67.5±2...

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Abstract

The invention provides a preparation method of fosfomycin tromethamine. The preparation method of fosfomycin tromethamine comprises the following steps: (1) preparing tromethamine p-toluenesulfonate, namely carrying out reaction on p-toluenesulfonic acid monohydrate and tromethamine in an anhydrous alcoholic solution A, then separating and drying, so that tromethamine p-toluenesulfonate containing no crystal water is obtained; (2) preparing a fosfomycin tromethamine crude product, namely carrying out reaction on tromethamine p-toluenesulfonate and fosfomycin phenylethylamine salt monohydrate in an anhydrous alcoholic solution B, so that the fosfomycin tromethamine crude product is obtained; (3) refining fosfomycin tromethamine, namely refining the fosfomycin tromethamine crude product in an anhydrous alcoholic solution C, so that fosfomycin tromethamine is obtained. The fosfomycin tromethamine product obtained by adopting the preparation method provided by the invention is high in purity and has a single crystal form, and stability of the fosfomycin tromethamine product is greatly improved.

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-epoxypropylene)phosphate·2-amino-2-hydroxymethyl-1,3 propanediol salt (1 :1). At present, the fosfomycin trometamol salt in the industry mainly has the following several preparation methods: [0003] 1. Through fosfomycin bis tromethamine (chemical name (1R, 2S)-(1,2-epoxypropylene) phosphate 2-amino-2-hydroxymethyl-1,3 propanediol salt (1 : 2)) prepare fosfomycin trometamol. Patent ES577527, EP27579 discloses the monohydrate of left phosphorus and right amine (chemical name is: (R)-alpha-methylbenzylamine (2R-cis)-(3-methyloxiranyl) phosphonic acid (1: 1) Monohydrate) prepares fosfomycin bis-tromethamine with bimolecular tromethamine in ethanol, and fosfomycin bis-tromethamine reacts with p-toluenesulfonic acid monohydra...

Claims

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Application Information

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IPC IPC(8): C07F9/655C07C213/08C07C215/10
Inventor 黄绍智陈亦文时孟军唐世锭
Owner 桂林华信制药有限公司
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