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Preparation method of ertapenem sodium salt

A technology of ertapenem sodium salt and solvent, applied in the field of preparation of ertapenem sodium salt, can solve the problems of potential safety hazards and high cost

Inactive Publication Date: 2014-01-22
TIANJIN JIUHAI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, many companies in China are committed to the research and development of ertapenem, and most of them adopt Merck's patented route (patent number: US2004 / 0235817A1) to overcome the problems of high cost and potential safety hazards in this route

Method used

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  • Preparation method of ertapenem sodium salt

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] The preparation method of the ertapenem sodium salt of an embodiment comprises the following steps:

[0018] (1) Under the condition of -30°C, the penem core MAP with the protective group and the side chain of ertapenem undergo a docking reaction in the solvent tetrahydrofuran and triethylamine to generate an intermediate product; and

[0019] (2) The above intermediate product was deprotected by hydrogenation with palladium-charcoal as a catalyst and sodium bicarbonate as an alkalizing agent to obtain ertapenem sodium salt, namely [4R,5S,6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo- 1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt, the yield was 98%. Its synthetic route is shown in the following formula:

[0020]

Embodiment 2

[0022] The preparation method of the ertapenem sodium salt of an embodiment comprises the following steps:

[0023] (1) Under the condition of -0°C, the penem core MAP with a protective group of formula I and the side chain of ertapenem of formula II were docked in the solvent diisopropylamine and acetonitrile to generate an intermediate product ;and

[0024] (2) The above intermediate product was deprotected by hydrogenation with palladium-charcoal as a catalyst and sodium bicarbonate as an alkalizing agent to obtain ertapenem sodium salt, namely [4R,5S,6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo- 1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt, yield 98.5%.

[0025]

Embodiment 3

[0027] The preparation method of the ertapenem sodium salt of an embodiment comprises the following steps:

[0028] (1) Under the condition of 20°C, the penem mother nucleus MAP with a protective group of formula I and the side chain of ertapenem of formula II were docked in the solvent diisopropylethylamine and dichloromethane, generate intermediate products; and

[0029] (2) The above intermediate product was deprotected by hydrogenation with palladium-charcoal as a catalyst and sodium bicarbonate as an alkalizing agent to obtain ertapenem sodium salt, namely [4R,5S,6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo- 1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt, the yield is 98.8%.

[0030] By using the above preparation method to synthesize ertapenem sodium salt, the yield is greatly improved, and the cost is reduced, and the operation steps are simplified; the required reagents are cheap and environ...

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Abstract

The invention provides a preparation method of an ertapenem sodium salt. The preparation method comprises the following steps: (1) carrying out docking reaction on meropenem mother nucleus MAP (beta-methyl vinyl phosphate) with a protecting group and an ertapenem side chain in a solvent or alkali, so as to generate intermediate products; (2) carrying out hydrogenated deprotection on the intermediate products by taking palladium-carbon as a catalyst and sodium bicarbonate as an alkalizer to prepare the ertapenem sodium salt, namely [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-carboxy phenyl) amino]-3-pyrrolidyl] sulfenyl]-6-[(1R)-1-hydroxy ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0] hepta-2-alkene-2-carboxylic acid monosodium salt. The ertapenem sodium salt is synthetized by adopting the preparation method, so that the yield is greatly improved; meanwhile, the reduction cost is reduced; the operation steps are simplified; the required reagent is low in price, and friendly to environment.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of ertapenem sodium salt. Background technique [0002] Ertapenem (ertapenem) is a new type of broad-spectrum carbapenem antibiotics developed by Merck Pharmaceutical Company of the United States. It can be used to treat community-acquired mixed infections with stable penem antibiotics against DHP-Ⅰ. This product was launched in the United States and Europe in November 2001 and April 2002, respectively. The drug is currently all dependent on imports in the country, and there is no manufacturer to produce it. [0003] At present, many companies in China are committed to the research and development of ertapenem, and most of them adopt the patent route of Merck (patent number: US2004 / 0235817A1) to overcome the problems of high cost and potential safety hazards in this route. Contents of the invention [0004] The purpose of the present invention is to ove...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/06
CPCC07D477/06C07D477/20Y02P20/55
Inventor 尹新明
Owner TIANJIN JIUHAI MEDICAL TECH
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