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Method for preparing faropenem

A technology for faropenem sodium and sodium isooctanoate is applied in the field of preparing antibiotic drug faropenem sodium, and can solve the problems of long operation steps, high price, unsuitability for industrialized production and the like

Active Publication Date: 2009-08-05
SHENYANG NO 1 PHARMA FACTORY DONGBEI PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above synthesis method has long operation steps, and uses silver salt with higher price, which is not suitable for industrial production

Method used

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  • Method for preparing faropenem
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  • Method for preparing faropenem

Examples

Experimental program
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Effect test

Embodiment 1

[0020] (3R,4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-[(R)-tetrahydrofuran-2-formylthio]azetidin-2- Preparation of ketone (I)

[0021] Method A:

[0022] Dissolve 184g (1.394mol) of R-(+)-thiotetrahydrofuran-2-carboxylic acid in 200ml of dry 1,4-dioxane, and dissolve 193ml (1.394mol) of triethylamine in 1,4-dioxane Oxycycline 50ml was added dropwise to the above solution under cooling, the pH value was 9 after dropping, and the stirring was continued for 0.5 hour, and set aside.

[0023] (3R, 4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-[(R)-acetoxy]azetidin-2-one (4- AA) 200g (0.697mol) was dissolved in 800ml of dry 1,4-dioxane, 142g (1.045mol) of dry zinc chloride was added at 20°C, and after stirring for 15 minutes, the R-( +)-Triethylamine salt of thiotetrahydrofuran-2-carboxylic acid, the rate of addition is controlled so that the temperature of the internal bath is not higher than 35°C. After dropping, the reaction was continued at 35°C for 8 hours. Stop the rea...

Embodiment 2

[0027] (3R,4R)-1-allyloxyoxalyl chloride-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-[(R)-tetrahydrofuran-2-formyl Preparation of Sulfuryl]azetidin-2-one (II)

[0028] Method A:

[0029] Dissolve 220 g (0.613 mol) of intermediate I in 1000 ml of dry dichloromethane, cool to -10°C, add 145.6 g (0.980 mol) of monoallyloxyoxalyl chloride dropwise, and after the drop is complete, dissolve 145 ml of triethylamine ( 1.04mol) was dissolved in 200ml of dichloromethane and added dropwise to the above reaction solution, the rate of addition was controlled so that the temperature of the internal bath was not higher than -10°C. After dripping, keep the reaction for 1.5 hours, stop the reaction, wash the organic phase with water 200ml×1, wash the organic phase with 5% sodium bicarbonate solution to be neutral, wash with 10% sodium chloride solution 200ml×1, dry over anhydrous sodium sulfate, concentrate, 260 g of light yellow oily substance II was obtained.

[0030] Method B:

[0031] Di...

Embodiment 3

[0033] (5R,6S)-6-[(R)-1-tert-butyldimethylsiloxyethyl]-2-[(R)-tetrahydrofuran-2-formylthio]penem-3-carboxylate Preparation of Acryl Acrylate (III)

[0034]Dissolve 260g (0.552mol) of intermediate II in 400ml of xylene, add 229g (1.380mol) of triethyl phosphite, add 1g of hydroquinone, reflux for 1.5 hours, wash the reaction solution with water 100ml×3, anhydrous sodium sulfate Drying and concentration gave a residue of 184 g. After column chromatography (silica gel column, petroleum ether / ethyl acetate 15:1), 150 g of a light yellow solid was obtained, with a yield of 49% (based on 4-AA), mp63-65 ℃.

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Abstract

A preparation method of faropenem sodium taken (3R, 4R)-4-acetoxy-3-((R) (t-butyldimethylsilyloxy) ethyl) 2-azetidinone as primary material is characterized by being prepared by five steps: an intermediate compound I is obtained through salt condensation of R-sulfo-tetrahydrofuran-2-formic acid under the catalysis of zinc halide; an intermediate compound II is gained through acidylation reaction of the intermediate compound I catalyzed by alkali and mono-oxyprophl group oxalyl chloride or allyloxy formoyl formaldehyde; the intermediate compound II is dissolved in triethyl phosphate solvent to obtain an intermediate III through cyclization; the intermediate III is added in the solvent and hydroxyl protecting group is divested through the action of ammonium bifluoride, thus obtaining an intermediate compound IV; the intermediate compound IV is dissolved in the solvent and the protecting group thereof is divested through the action of 4 (triphenylphosphine) palladuium and triphenyl phasphine, thereby getting the faropenem sodium by the effect of sodium iso-octoate. The method has less operation steps, high yield rate, low cost, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing antibiotic drug faropenem sodium in the field of chemical synthesis. Background technique [0002] Penem and carbapenem antibiotics are a group of new broad-spectrum β-lactam antibiotics that were developed only in the 1980s. It plays an extremely important role in the treatment of infections and infections in immunocompromised patients. Faropenem sodium, see structural formula 1, as a representative of penem antibiotics, is the only drug that can be used for oral administration that is the most fully researched and has been applied clinically. This product is not only relatively stable in chemical properties, but also due to its C 5 and C 6 The trans structure of the position and the unique tetrahydrofuran side chain of the 2 position make faropenem sodium also have the following characteristics: 1) broad antibacterial spectrum, strong antibacterial activity, good antibacterial effect on aerobic bacter...

Claims

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Application Information

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IPC IPC(8): C07D499/893
CPCY02P20/55
Inventor 郑白水李显林李娟苏显英
Owner SHENYANG NO 1 PHARMA FACTORY DONGBEI PHARMA GRP
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