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Preparation method of fosfomycin amine salt

A technology of fosfomycin and ammonia salt, applied in the field of preparation of fosfomycin ammonia salt, can solve the problems of low yield, cumbersome reaction steps and the like, and achieve the effects of convenient operation, high yield and mild reaction conditions

Active Publication Date: 2012-12-05
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The technical problem to be solved by the present invention is to provide a preparation method of fosfomycin trometamol in order to overcome defects such as complicated reaction steps and low yield in the existing preparation method of fosfomycin trometamol

Method used

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  • Preparation method of fosfomycin amine salt
  • Preparation method of fosfomycin amine salt
  • Preparation method of fosfomycin amine salt

Examples

Experimental program
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Effect test

Embodiment 1

[0038] In a 500ml three-necked flask, put left phosphorus and right ammonium salt (23.35g, 84.2mmol), tromethamine (10.20g, 84.2mmol) and methanol 170g (215mL), stir at room temperature for 15 minutes, and start to add isomethamine dropwise. Methyl cyanate (4.80g, 84.2mmol) (CAS No. 624-83-9), the dropwise addition was completed in about five minutes, the temperature rose to 33°C, then stirred for 30 minutes, and the methanol was removed by rotary evaporation under reduced pressure, and 200g of ethanol was added. Cool to 0°C, filter, wash with 30g of ethanol, and vacuum dry at 45°C to obtain 18.73g of white solid with a yield of 85.8%. m.p.119~121°C, 1 H NMR (D 2 O): (ppm)=1.33(d,3H,CH 3 ),3.20-2.79(m,2H,CH),3.57(s,6H,CH 2 ).

Embodiment 2

[0040] In a 500ml three-neck flask, put fosfomycin bis tromethamine (32.03g, 84.2mmol) and methanol 170g, stir at room temperature for 15 minutes, start to drop methyl isocyanate (4.80g, 84.2mmol), The dropwise addition was completed in about five minutes, then stirred at room temperature for 30 minutes, and then the methanol was removed by rotary evaporation under reduced pressure, and 200g of ethanol was added, cooled to 0°C, filtered, washed with 30g of ethanol, and vacuum-dried at 45°C to obtain 19.65g of a white solid, with a yield of 90.0 %, m.p.119~121℃.

Embodiment 3

[0042] In a 500ml three-necked flask, put left phosphorus and right ammonium salt (23.35g, 84.2mmol), tromethamine (10.20g, 84.2mmol) and methanol 170g (215mL), stir at room temperature for 15 minutes, and start to drop benzene Ethyl isocyanate (12.39g, 84.2mmol), (CAS No. 1943-82-4) was added dropwise in about 8 minutes, the temperature rose to 33°C, then stirred for 30 minutes, and the methanol was removed by rotary evaporation under reduced pressure, and 200g of ethanol was added, cooled After reaching 0°C, filtered, washed with 30g of ethanol, and vacuum dried at 45°C, 18.32g of white solid was obtained, with a yield of 83.9%. m.p.119~121,

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Abstract

The invention discloses a preparation method of fosfomycin amine salt, which comprises the following steps of: in organic solvent, enabling fosfomycin phenylethylamine salt to react with isocyanate, isothiocyanate, ketene, dipolymer of isocyanate, dipolymer of isothiocyanate or dipolymer of ketene, and tromethamine; or in the organic solvent, enabling fosfomycin bistromethamine to react with isocyanate, isothiocyanate, ketene, dipolymer of isocyanate, dipolymer of isothiocyanate or dipolymer of ketene. The preparation method provided by the invention has the advantages that the fosfomycin amine salt can be prepared in one step only, a low-temperature ion exchange column is not required, the yield is high, the cost is low, the waste gas, waste water and waste residue are less, the reaction conditions are moderate, the energy consumption is low, the operation is convenient to conduct and the method is suitable for industrial production.

Description

technical field [0001] The present invention specifically relates to the preparation method of fosfomycin ammonium salt. Background technique [0002] Fosfomycin trometamol (Fosfomycin trometamol), the trade name is Monuril, the chemical name is (1R,2S)-(1,2-epoxypropylene)phosphate·2-amino-2-hydroxymethyl-1, 3 propylene glycol salt (1:1), molecular formula is C 4 h 11 NO 3 .C 3 h 7 o 4 P, the molecular weight is 259.19, and the structural formula is: [0003] [0004] It is a white crystalline powder. Fosfomycin trometamol is a drug that has been used for the treatment of genitourinary tract infection for a long time, and the drug was first disclosed in patent EP27957 (Zambon, 1981). [0005] Some processes using left phosphorus and right ammonium salt (CAS No. 25383-07-7, structural formula below) as reactants are well known. [0006] [0007] Patent EP27597 describes the reaction of fosfomycin bis tromethamine (structural formula as follows) with p-toluenes...

Claims

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Application Information

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IPC IPC(8): C07F9/655
CPCC07F9/65505
Inventor 陈发普
Owner NORTHEAST PHARMA GRP
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