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Synthesis for producing levo phosphomycin by dextro phosphomycin

A technology for levofosfomycin and dextrofosfomycin, which is applied in the synthesis field of preparing levofosfomycin from dextrofosfomycin, can solve the problems of danger, inability to use in industrial production, difficulty in detection and the like

Inactive Publication Date: 2006-11-01
BEIJING COLLAB PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Diazomethane is an explosive reagent, and a large amount of nitrogen gas is released during the reaction. This method is extremely dangerous and cannot be used in industrial production
[0013] 2) The detection of each step reaction using dimethyl phosphate derivatives as raw materials is difficult, requiring specific color reagents and color development conditions
[0014] In addition, it is worth noting that the method of preparing its benzyl ester derivatives from dexfosfomycin ((+)-[1S,2R]-cis-glycidyl phosphate) has not been reported yet. method (including using benzyl diazo compound) to prepare dexfosfomycin benzyl ester derivatives, all failed, so according to the EP0299484 method, it is impossible to start with (+)-[1S, 2R]-cis-epoxypropyl Phosphoric acid (dexfosfomycin) to obtain dexfofomycin benzyl ester and then perform configuration transformation on the derivatives of dexfofomycin benzyl ester

Method used

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  • Synthesis for producing levo phosphomycin by dextro phosphomycin
  • Synthesis for producing levo phosphomycin by dextro phosphomycin
  • Synthesis for producing levo phosphomycin by dextro phosphomycin

Examples

Experimental program
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Effect test

Embodiment 1

[0061] Preparation of levorotatory from (-) levorotatory α-methylbenzylamine salt ((+)-[1S,2R]-cis-glycidyl phosphate · (-) levorotatory α-phenylethylamine salt) Fosfomycin sodium ((-)-[1R,2S]-cis-glycidyl phosphate sodium)

[0062] Step 1: Preparation of [1S,2S]-dihydroxypropyl phosphate from (-)L-α-methylbenzylamine salt of D-fosfomycin

[0063](-) L-alpha-methylbenzylamine salt (25.9g, 0.10mol) of dexfosfomycin was dissolved in 80ml of water, under stirring at room temperature, 20ml of aqueous solution of sodium hydroxide (8.0g, 0.20mol) was added, separated, and water The phase was extracted with 40 ml of dichloromethane. Take the water phase, add 98% concentrated sulfuric acid (10 g, 0.10 mol), stir, and heat to reflux for 4 h. Concentrate under reduced pressure to remove most of the water, add 70ml of methanol and 30ml of ethanol, stir for 5min, let stand for 0.5h, filter, concentrate the filtrate, and dry in vacuo to obtain 15.5g of [1S,2S]-dihydroxypropylphosphoric a...

Embodiment 2

[0080] Preparation of Levofosfomycin Sodium ((-)-[1R,2S]-cis-Glycidyl Phosphate from Defosfomycin Sodium ((+)-[1S,2R]-cis-Glycidyl Phosphate) calcium phosphate)

[0081] Step 1: Preparation of [1S,2S]-dihydroxypropyl phosphate from dexfosfomycin sodium ((+)-[1S,2R]-cis-glycidyl phosphate sodium)

[0082] Defosfomycin sodium (24g, 0.13mol) was dissolved in 100ml of water, under stirring at room temperature, was added 70% perchloric acid aqueous solution (37.3g, 0.26mol), stirred, and heated to reflux for 4h. Concentrate under reduced pressure to remove most of the water, add 80ml of methanol, 50ml of isopropanol, stir for 5min, let stand for 0.5h, filter, concentrate the filtrate, and dry in vacuo to obtain 19.8g of [1S, 2S]-dihydroxypropyl phosphoric acid, the yield 96%.

[0083] Note: the NMR data is consistent with the data in Example 1.

[0084] Step 2: Preparation of [1S,2S]-Dibenzyl Dihydroxypropyl Phosphate from [1S,2S]-Dihydroxypropyl Phosphate

[0085] N,N'-diisopr...

Embodiment 3

[0100] Preparation of Levofosfomycin Sodium ((-)-[1R,2S]-cis-Glycidyl Phosphate from Defosfomycin Calcium ((+)-[1S,2R]-cis-Glycidyl Calcium Phosphate) Sodium Phosphate)

[0101] Step 1: Preparation of [1S,2S]-dihydroxypropyl phosphate from the calcium salt of dexfosfomycin

[0102] Add the calcium salt of dexfosfomycin (17.6g, 0.10mol) in 70ml of water, under stirring at 40°C, add 5mol / L sulfuric acid aqueous solution (20ml) dropwise, after the addition is complete, let stand at 40°C for 4h, filter, and Heated to reflux for 4h. Concentrate under reduced pressure to remove most of the water, add 50ml of methanol, stir for 5min, let stand for 0.5h, filter, concentrate the filtrate, and dry in vacuo to obtain 14.9g of [1S,2S]-dihydroxypropylphosphoric acid with a yield of 96%.

[0103] Note: the NMR data is consistent with the data in Example 1.

[0104] Step 2: Preparation of [1S,2S]-dihydroxypropylphosphate di-o-chlorobenzyl ester from [1S,2S]-dihydroxypropylphosphate

[01...

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Abstract

Synthesis of levo-phosphonomycin from dextro-phosphonomycin is carried out by taking dextro-phosphonomycin((+)-(1S,2R)-cis-epoxy propyl phosphoric acid) or dextro-phosphonomycin salt as raw materials and converting into levo-phosphonomycin((-)-(1R, 2S)-cis- epoxy propyl phosphoric acid) or levo-phosphonomycin salt.

Description

technical field [0001] The present invention relates to a kind of levofosfomycin ((-)-[1R, 2S]-cis - new synthetic method of glycidyl phosphate) and its salts. Background technique [0002] Levofosfomycin is a broad-spectrum antibiotic discovered in 1969 by Merck of the United States and CEPA of Spain from Streptomyces in Spanish soil. Its molecular weight is very small and it is a structure different from any other antibiotic. A new antibiotic; at an international symposium held in Madrid in 1975, experts agreed that levofosfomycin is a valuable new antibiotic. Then Spain, Italy, West Germany, China and Japan officially put into industrialized production; levofosfomycin series products are characterized by wide antibacterial spectrum, low toxicity and side effects, and no cross-drug resistance, and the market demand is increasing day by day. However, the current fosfomycin production process mainly uses chiral resolution technology to prepare levofosfomycin, which produce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6536
Inventor 张猛李继军余錚尹大力
Owner BEIJING COLLAB PHARMA
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