Preparation method of intermediate of antibacterial drug

A technology of antibacterial drug, fosfomycin, which is applied in the preparation of important antibacterial drug intermediate fosfomycin levophosphoryl ammonium salt and the field of preparation of antibacterial drug intermediates, which can solve the problem of high preparation cost of modified PW/C catalyst, Difficult to achieve industrialization, low catalytic activity and other problems, to achieve the effect of shortened reaction time, simple post-treatment, high catalytic activity

Active Publication Date: 2021-03-05
SINOPHARM ZHIJUN (SHENZHEN) PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, H 2 WO 4 The catalytic activity of the / C catalyst is low, and the yield of the vortex salt is only about 60%. The preparation cost of the modified PW / C catalyst is high, the process is complicated, and it is difficult to realize industrialization

Method used

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Examples

Experimental program
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Effect test

preparation example Construction

[0028] The invention provides a preparation method of fosfomycin left phosphorus and right ammonium salt. The preparation method comprises the following steps: at room temperature, dissolving cisacrylphosphonic acid in an alcoholic solvent, and then slowly adding (+)-α-phenylethyl ether Amine, after the dropwise addition, adjust the pH of the system to 5.5~6, continue to stir for 1~3min, then add the silver catalyst, and continue to slowly add hydrogen peroxide dropwise, after the completion, continue to stir for 10~30min, then quickly heat the system to 50~ At 55°C, filter while it is hot, then cool the filtrate, crystallize, and wash to obtain fosfomycin left phosphorus and right ammonium salt.

[0029] According to the preparation method of an antibacterial drug intermediate fosfomycin levophosphine salt of the present invention, the silver catalyst is preferably silver carbonate.

[0030] According to the preparation method of an antibacterial drug intermediate fosfomycin ...

Embodiment 1

[0043] At room temperature, dissolve 0.1mol cis-acrylphosphonic acid in absolute ethanol, then slowly add 0.11mol (+)-α-phenylethylamine dropwise, after the dropwise addition, adjust the pH of the system to 5.5, and continue stirring for 3 minutes. Then add 0.2g of silver carbonate powder, and slowly add 17g (0.15mol) of 30% hydrogen peroxide dropwise. After the dropwise addition, continue to stir for 30min. The filtrate was cooled to 0°C for crystallization, and then the crystals were washed with ice ethanol to obtain fosfomycin levophosphine salt with a yield of 94.6%.

Embodiment 2

[0045] At room temperature, dissolve 0.1mol cis-acrylphosphonic acid in absolute ethanol, then slowly add 0.15mol (+)-α-phenylethylamine dropwise, after the dropwise addition, adjust the pH value of the system to 6, and continue stirring for 3 minutes. Then add 0.5g of silver carbonate powder, and slowly add 17g (0.15mol) of 30% hydrogen peroxide dropwise. After the dropwise addition, continue to stir for 30min. The filtrate was cooled to 0°C for crystallization, and then the crystals were washed with ice ethanol to obtain fosfomycin levophosphine salt with a yield of 96.2%.

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Abstract

The invention provides a preparation method of phosphamycin levophosphorylamine. The preparation method comprises the following steps: dissolving cis-propenylphosphonic acid in an alcohol solvent at room temperature, slowly dropwise adding (+)-alpha-phenylethylamine, regulating the pH value of the formed system to 5.5-6, continuing stirring for 1-3 minutes, adding a silver catalyst, slowly and dropwise adding hydrogen peroxide, continuing stirring for 10-30 minutes, then rapidly heating the system to 50-55 DEG C, conducting filtering while the system is hot, and then cooling, crystallizing andwashing the filtrate successively to obtain the phosphamycin levophosphorylamine. According to the invention, silver carbonate is used as a catalyst, hydrogen peroxide is used as an oxidizing agent,heating is not needed in an oxidative cyclization process, and a reaction can be performed at normal temperature. The silver carbonate has very high catalytic activity in the invention, and compared with the prior art, the method has the advantages of small dosage, mild reactions, effective shortening of reaction time, simple post-treatment, and realization of separation of the catalyst from the system only through filtration of the system while the system is hot.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of an antibacterial drug intermediate, and more specifically to a preparation method of an important antibacterial drug intermediate fosfomycin levophosphine salt. Background technique [0002] Fosfomycin (phosphomyein, fosfomyein, FOM) chemical name: (1R,2S-(-)-cis-1,2-epoxypropylphosphonic acid, molecular formula: C 3 h 7 o 4 P, is an antibiotic with broad spectrum, low toxicity, less sensitization, less resistance, and synergistic effect with most antibiotics. Fosfomycin was discovered in Streptomyces in Spanish soil by Merck and CEPA in 1967. Fosfomycin has stable epoxy groups and phosphonic acid groups, and its efficacy is very stable, which is significantly different from most similar drugs. Synergistic effect, sensitive to Staphylococcus, Escherichia coli, Neisseria meningitidis, Neisseria gonorrhoeae, Salmonella typhi, Serratia, Proteus, Pseudomonas a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/655B01J27/232C07C211/27C07C209/00
CPCC07F9/65505B01J27/232C07C209/00C07B2200/07C07C211/27Y02A50/30
Inventor 李治泉
Owner SINOPHARM ZHIJUN (SHENZHEN) PHARMA CO LTD
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