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Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material

A technology of cis-propenylphosphonic acid and fosfomycin, which is applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., can solve the problems of high price of catalysts and oxidants, inconvenient use, etc.

Inactive Publication Date: 2002-12-18
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are also other catalysts used for this epoxidation reaction, such as the use of titanium tetraisopropoxy complex (iso-PrO) 4 Ti is used as a catalyst, and metal peroxides (such as BaO 2 ) and per(di)ammonium sulfate ((NH 4 ) 2 S 2 o 8 ) is an oxidizing agent (see: JP 78 05, 120, 1978; JP 78 05, 121, 1978), due to the high price of the catalyst and oxidizing agent, the use is inconvenient, so it has not been applied in industry

Method used

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  • Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material
  • Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material

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Experimental program
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Embodiment 1

[0020] 1. Dissolve 10 g of cis-acrylphosphonic acid (content 83%, industrial product) in 30 ml of ethanol, and slowly add about 9 ml (+)-α-phenylethylamine dropwise at 25 ° C with stirring to make the mixture PH value is 5.5-6.0;

[0021] 2. Dissolve 0.4g of sodium molybdate in 2.0ml of water, and add it to the above solution while stirring;

[0022] 3. After heating up to 40°C, slowly add 3.5ml of 30% hydrogen peroxide (H 2 o 2 ), the dropwise addition was completed in 0.5 hours, and the reaction temperature should not exceed 60°C. The reaction was continued at this temperature for 2 hours.

[0023] 4. Put the above reaction solution in the refrigerator at -5°C overnight, filter it with suction, rinse the filter cake with ethanol, and dry it. 7.3 g of (-)-fosfomycin-(+)-α-phenethylamine salt was obtained, with a yield of 75%.

[0024] Elemental analysis (C 11 h 18 NO 4 P·3 / 2H 2 O) C, H, and the deviation between the measured value and the theoretical value of N are w...

Embodiment 2

[0030] 1. Dissolve 10g of cis-acrylphosphoric acid (content 83%, industrial product) in 30ml of deionized water, and slowly add 9ml of (+)-α-phenylethylamine dropwise under stirring at 25°C, so that the pH of the mixture is 5.5-6.0.

[0031] 2. Add 0.4 g of sodium molybdate into the above solution under stirring, and stir for 10 minutes.

[0032] 3. Raise the temperature to 40-45°C and slowly add 3.5ml of 30% H 2 o 2 , After 0.5 hours, the dropwise addition is completed, and the reaction temperature should not exceed 65°C. Thereafter the reaction was continued at 60°C for 1.5 hours.

[0033] 4. Vacuum remove 70% of the water from the above reaction solution, add 30ml of 95% ethanol, dissolve, stir evenly, and place in the refrigerator at -5°C overnight. Suction filtration, the filter cake was rinsed with ethanol and dried. 7.4 g of (-)-fosfomycin-(+)-α-phenethylamine salt was obtained, with a yield of 76%.

[0034] Elemental analysis (C 11 h 18 NO 4 P·3 / 2H 2 O) C, H,...

Embodiment 3

[0039] The sodium molybdate of 0.4g in embodiment 1 is changed into 0.4g ammonium molybdate, and other processing conditions are all identical with embodiment 1, and the yield and quality of gained product are also identical.

[0040] Molybdenum content of (-)-fosfomycin disodium salt measured by atomic absorption spectrophotometer: 13ppm

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Abstract

The method for synthesizing phosphonomycin by using cis-propene phosphonic acid as raw material relates to an epoxidation eraction of cis-propene phosphonic acid by using molybdate which is sodium salt or ammonium salt generally as catalyst in the course of synthesizing phosphonomycin. According to identical process sand invention can prepare phosphonomycin disodium salt, in terminal phosphonomycin product the molbdenum content only is 1 / 10 (10-15 ppm) of tungsteon content, so that the use of molbdate as catalyst can reduce residual of heavy metal and can reduce toxic side effect of medicine.

Description

technical field [0001] The invention relates to a method for synthesizing fosfomycin by catalyzing epoxidation reaction with cis-propenylphosphonic acid as raw material. Background technique [0002] The epoxidation of cis-acrylphosphonic acid in the synthesis of fosfomycin is a key reaction. At present, tungstate is used as a catalyst both at home and abroad, usually using sodium tungstate (Na 2 WO 4 2H 2 O) (See: USP 4,222,970 1980; CN 1060470, 1991; Chinese Journal of Pharmaceutical Industry 22(9), 391-4, 1991, etc.). . The catalyst has high catalytic activity and can completely realize epoxidation of cis-acrylphosphonic acid at a relatively low temperature. However, this reaction is generally carried out in a solvent of ethanol and about 30% water, and sodium tungstate has low solubility in a solvent system containing a large amount of ethanol, so it will crystallize out with the product, making the tungsten in the final fosfomycin product The content greatly exceeds...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
Inventor 石鸿昌王歆燕樊新印
Owner TSINGHUA UNIV
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