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Method for synthesizing levofosfomycin dextrophenethylamine salt from dextrofosfomysin levophenethylamine salt

A technology of fosfomycin and fosfomycin, which is applied in the field of synthesizing fosfomycin salts, can solve the problem of not finding di-tertiary alcohol ester of fosfomycin, unavoidable ring-opening of epoxy ring reduction, and not finding di-tertiary alcohol esters. Methods and examples of removing tertiary alcohol groups from tertiary alcohol esters, achieving the effect of cheap raw materials, low cost, and low toxicity

Inactive Publication Date: 2011-08-31
HUBEI XUNDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] 2. No literature was found to describe the method and examples for preparing fosfomycin di-tert-alcohol ester (1,2-epoxypropylphosphonic acid di-tert-alcohol ester) from fosfomycin;
[0010] 3. There are documents describing the method of hydrolysis and ring opening of fosfomycin dimethyl ester (1,2-epoxypropyl phosphonic acid dimethyl ester). (US4937367 example 31), but no fosfomycin di-tertiary alcohol ester (1 , 2-epoxypropylphosphonic acid di-tert-alcohol ester) hydrolysis ring-opening method and examples;
[0011] 4. No literature was found to describe the method and examples of 1-hydrocarbylsulfonyloxy-2-hydroxypropylphosphonic acid di-tertiary alcohol ester for removing tertiary alcohol groups
However, there are two defects in this method: the one is to use dicyclohexylcarbodiamide (DCC) which has a strong lachrymatory property and high toxicity, and the other is that it may be difficult to avoid the reduction ring opening problem of the epoxy ring when the protecting group is removed by hydrogenation

Method used

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  • Method for synthesizing levofosfomycin dextrophenethylamine salt from dextrofosfomysin levophenethylamine salt
  • Method for synthesizing levofosfomycin dextrophenethylamine salt from dextrofosfomysin levophenethylamine salt

Examples

Experimental program
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Embodiment approach

[0044] Reaction of dexfosfomycin levophenethylamine salt with alkali metal hydroxide to prepare dexfosfomycin dialkali metal salt; reaction of dexfosfomycin dialkali metal salt with acyl chloride reagent to prepare dexfosfomycin Acyl chloride; Defosfomycin acid chloride reacts with tertiary alcohol to prepare dexfosfomycin di-tert-alcohol ester; Tertiary alcohol ester; (1S, 2S)-1,2-dihydroxy propionate di-tert-alcohol ester reacts with alkylsulfonyl chloride to prepare (1S, 2S)-1-hydrocarbylsulfonyloxy-2-hydroxypropionate di-tert-alcohol Ester; (1S, 2S)-1-hydrocarbylsulfonyloxy-2-hydroxypropionate di-tert-alcohol ester removes tertiary alcohol group to prepare (1S, 2S)-1-sulfonyloxy-2-hydroxypropionate; Cyclization of (1S, 2S)-1-hydrocarbylsulfonyloxy-2-hydroxypropionate to prepare levofosfomycin dialkali metal salt; levofosfomycin dialkali metal salt and D-phenylethylamine acid inorganic salt Carrying out salt exchange reaction to prepare levofosfomycin dexphenethylamine sal...

Embodiment 1

[0047] (1) Preparation of Defosfomycin Disodium Salt

[0048] Add 27g of 30% sodium hydroxide, 50ml of water and 100ml of toluene into the reaction bottle, stir and cool down to 5°C, add 27.7g of D-fosfomycin L-phenethylamine salt, wait for all the solids to disappear, and then separate into layers. Take the water layer, concentrate it to dryness under reduced pressure, add 100ml of methanol to dissolve the material in the bottle, then add the methanol solution dropwise to 300ml of tert-butanol, precipitate out, filter it quickly, and dry it in vacuum at 50°C for 3 hours, then dry it at 100°C for 3 hours. Hours, anhydrous 17g dexfosfomycin disodium salt was obtained with a yield of 93%.

[0049] (2) Preparation of dexfosfomycin acid chloride

[0050] Mix 17g of dexfosfomycin disodium salt and 300ml of pyridine, add 25g of thionyl chloride dropwise at 0-5°C, react at 20-25°C for 2 hours, and transfer to the next step.

[0051] (3) Preparation of dexfosfomycin di-tert-butyl es...

Embodiment 2

[0064] (1) Preparation of dexfosfomycin dipotassium salt

[0065] Add 11.3g of potassium hydroxide, 50ml of water and 100ml of toluene into the reaction flask, stir and cool down to 0°C, add 27.7g of D-fosfomycin L-phenethylamine salt, wait until all the solids disappear, and then separate into layers. Take the water layer, concentrate it to dryness under reduced pressure, add 150ml of methanol to dissolve the material in the bottle, then add the methanol solution dropwise to 300ml of DMF, precipitate out, filter it quickly, dry it in vacuum at 50°C for 3 hours, and then dry it at 100°C for 3 hours to obtain 19.5 g of anhydrous dexfosfomycin dipotassium salt, yield 91%.

[0066] (2) Preparation of dexfosfomycin acid chloride

[0067] Mix 19.5g of dexfosfomycin dipotassium salt with 350ml of pyridine, add 25g of thionyl chloride dropwise at 0-5°C, react at 20-25°C for 5 hours, and transfer to the next reaction.

[0068] (3) Preparation of dexfosfomycin di-tertiary alcohol est...

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Abstract

The invention relates to a method for synthesizing a levofosfomycin dextrophenethylamine salt from a dextrofosfomysin levophenethylamine salt, comprising the steps of: taking the dextrofosfomysin levophenethylamine salt as a raw material, firstly preparing a dextrofosfomysin di-alkali metal salt, generating dextrofosfomysin acyl chloride via acyl chloridization and reacting with tertiary alcohol to generate dextrofosfomysin di-tert- alcohol ester, hydrolyzing to open an epoxy ring so as to generate (1S, 2S)-1,2-dihydroxy propionic phosphoric acid di-tert- alcohol ester and reacting with alkylsulfonyl chloride to generate (1S, 2S)-1-alkyl sulfonyloxy-2-dihydroxy propionic phosphoric acid di-tert- alcohol ester, performing acidolysis to deprive the alkyl sulfonyloxy, completing the inversion of configuration to generate the levofosfomycin alkali metal salt, and preparing the levofosfomycin dextrophenethylamine salt from the alkali metal salt.

Description

technical field [0001] The invention relates to a method for synthesizing levofosfomycin salt by using dexfosfomycin as a raw material through configuration transformation. Background technique [0002] Fosfomycin is a broad-spectrum antibiotic and a fungicide during the breeding period. It has inhibitory effects on most Streptococcus, Pseudomonas aeruginosa, Proteus mirabilis, and some Pneumococcus pneumoniae and indole-negative Proteus. Fosfomycin is suitable for infection and sepsis in urinary tract, respiratory tract, digestive tract, gynecology, skin soft tissue and other parts. Oral administration can treat intestinal infection, urinary tract infection, Serratia infection, Helicobacter pylori infection, blepharitis, hordeolum, otitis media, paranasal sinusitis, dacryocystitis, etc.; intravenous injection can treat respiratory tract infection, urinary tract infection Infection, sepsis, pelvic inflammatory disease, adnexitis, intrauterine infection and other gynecologic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/655
Inventor 易章国
Owner HUBEI XUNDA PHARMA