Method for synthesizing faropenem sodium

A technology of faropenem sodium and p-nitrobenzyl ester, applied in the field of medicinal chemistry, can solve the problems of difficult removal of triphenylphosphine, lower yield, expensive silver nitrate, etc., to facilitate industrial production and improve operability Effect

Active Publication Date: 2014-06-25
JIANGSU QINGJIANG PHARMA
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  • Abstract
  • Description
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Problems solved by technology

[0007] use 4-AA and trityl mercaptan to carry out acyl substitution reaction under alkaline conditions to obtain the azetidinone protected by thiotrityl group, and then When tetrahydrofuran-2-formyl chloride is connected with lactam, silver nitrate is used as a condensation agent, but silver nitrate is expensive and the cost is too high, and the silver chloride generated at the same time is not easy to filter and is not suitable for large-scale production
[0008]2. U.S. Patent US4997829 reports the classic preparation method: acyl substitution reaction with (R)-tetrahydrofuran-2-thiocarboxylic acid to generate thioester, and then condensation , chlorine substitution, intramolecular Witting cyclization reaction, removal of hydroxyl protecting group and carboxyl protecting group to

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  • Method for synthesizing faropenem sodium

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Embodiment 1

[0031] (R) -tetrahydrofuran-2-thiocarboxylic acid (198g, 1.5 mol) was placed in a 3L reaction flask, and 1 mol / L sodium hydroxide bath solution (1.5 L) was added to adjust the pH to 9-10, 0- At 5°C, add dropwise 4AA (287g, 1.0mol) in acetone (1 L) solution, after the drop is complete, adjust the pH to about 8 with 1 mol / L sodium oxide, and react at room temperature for 2 h. Add water (500 ml) Dilute, extract with ethyl acetate (600 ml x 3), combine organic layers, wash with 5% sodium bicarbonate solution (300 ml x 2) and water (300 ml x 2) successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate , to obtain a light yellow oil (about 360 g), which was directly put into the next reaction.

Embodiment 2

[0033] The concentrated solution obtained above, triethylamine (170g, 1.7 mol) and dichloromethane (1.5 L) were mixed, and p-nitrobenzyl chlorooxalate (414.1 g, 1.7 mol) was added dropwise at 0-5 ℃, and the dropwise , react at the same temperature for 2 h, dilute with water (1 L), extract with dichloromethane (500 ml x 4), combine the organic layers, and successively add water (300 ml x 2) and 5% sodium bicarbonate solution (300 ml x 2) Wash, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a light yellow oil (about 530 g), which is directly put into the next reaction.

Embodiment 3

[0035] Mix the oil obtained above, xylene (4L) and triethyl phosphite (500ml), heat to reflux for 5h, evaporate xylene and triethyl phosphite under reduced pressure, and wash the residue with ethyl acetate-n-hexane ( 1:5, 1 L) and recrystallized to obtain a light yellow solid (334.3g, 61%, based on 4AA).

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Abstract

The invention provides a method for synthesizing faropenem sodium. According to the method, oxalic acid chloride p-nitrobenzyl ester is used for replacing allyloxy oxalyl chloride in a conventional process, and thus the generation of polymer impurities is effectively prevented, and the raw material conversion rate and the product yield are increased; by adopting a method of catalytic hydrogenation under an acidic condition, silylation protection groups and p-nitrobenzyl ester protection groups are removed, organophosphorus impurities which are difficult to treat are effectively prevented, the separation and purification of products are facilitated, the maneuverability is improved, and the industrialized production is facilitated.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a preparation method of faropenem sodium. Background technique [0002] Faropenem sodium is the first penem antibiotic developed by Japan's Suntory Company and launched in 1997. It is similar to several carbapenem antibiotics that have been on the market. It has a broad antibacterial spectrum and strong antibacterial activity. β-lactamase is stable, and it also has good effects on extended-spectrum β-lactamase-producing bacteria, Citrobacter, enterococcus and anaerobic bacteria. It is the world's first orally effective penem antibiotic that is stable to β-lactamase so far. Its structural formula is as follows: [0003] [0004] There are many reports about the preparation method of faropenem sodium, mainly as follows: [0005] 1. The method reported in J. Antibiotics 1988,41,1685, see the following reaction formula: [0006] [0007] Use 4-AA and trityl mercaptan to perform acyl s...

Claims

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Application Information

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IPC IPC(8): C07D499/893C07D499/08
CPCY02P20/55C07D499/893C07D499/08
Inventor 汪武卫陈洁顾海成王伟
Owner JIANGSU QINGJIANG PHARMA
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