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A carbapenem derivative

A drug and compound technology, applied in the field of medicine, can solve problems such as poor absorption

Inactive Publication Date: 2017-04-05
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Carbapenem antibiotics are generally poorly absorbed in the digestive tract, and most of them can only be used for injection

Method used

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  • A carbapenem derivative
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1, (+)-(4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidine]sulfur]-6 Preparation of -[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid (Compound A)

[0080] Refer to the methods described in EP0632039, J.Antibiot.2006, 59(4):241-247 for preparation, and the full text is incorporated by reference. 36.1 g of doripenem monohydrate (compound A) was obtained, with a yield of 40.3%.

Embodiment 2

[0081] Example 2, (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidine]sulfur]-6-[(1R )-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid-(2-methoxy)ethyl Synthesis of Esters (Compound 1)

[0082] Doripenem monohydrate 4.39g (10mmol), 2-chloroethyl methyl ether 0.91ml (20mmol) and benzyltriethylammonium chloride 2.27g (20mmol) plus DMF 9ml, add diisopropyl Ethylamine 4.4ml (20mmol), react at 45°C for 4 hours, TLC detects that the reaction is complete, cool to 5°C, add 20ml of ethyl acetate, 20ml of water, adjust the pH to 4 with 1M citric acid solution under stirring, separate liquid, water The phase was adjusted to pH 7.6 with saturated potassium bicarbonate solution, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, evaporated to dryness, and the residue was prepared for column separation (ethanol-dichloromethane-acetone, 1:20:40), Evaporation to dryness gave 1.26 g (26.3%) of a yellowish ...

Embodiment 3

[0084] Example 3, (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidine]sulfur]-6-[(1R )-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid-(5-methyl-1,3 Synthesis of -dioxol-2-one) methyl ester (compound 2)

[0085] Doripenem monohydrate 4.39g (10mmol), 4-chloromethyl-5-ethyl-1,3-dioxol-2-one 2.97g (20mmol) and benzyltriethyl chloride Add 2.27g (20mmol) of ammonium and 9ml of DMF, add 4.4ml (20mmol) of diisopropylethylamine under stirring, react at 45°C for 4 hours, TLC detects that the reaction is complete, cool to 5°C, add 20ml of ethyl acetate and 20ml of water , adjusted to pH 4 with 1M citric acid solution under stirring, separated, the aqueous phase was adjusted to pH 7.6 with saturated potassium bicarbonate solution, washed with water after extraction with ethyl acetate, dried with anhydrous magnesium sulfate, evaporated to dryness, and the residue prepared column Separation (ethanol-dichloromethane-acetone, 1:20:40) was evap...

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Abstract

Belonging to the technical field of medicine, the invention in particular relates to a carbapenem ester compound shown as general formula (I), its stereoisomer or solvate, wherein R is defined as the specification. The invention also relates to a preparation of the compounds, pharmaceutical compositions containing the compounds, and application of the compounds in preparation of drugs for treatment and / or prevention of infectious diseases. (formula (I)).

Description

[0001] 1. Technical field [0002] The invention belongs to the technical field of medicine, and in particular relates to a carbapenem ester derivative, its stereoisomer, its hydrate and a pharmaceutically acceptable salt thereof, a preparation method of these compounds, and a pharmaceutical composition containing these compounds And the use of the compound in the preparation of medicines for treating and / or preventing infectious diseases. [0003] 2. Background technology [0004] Doripenem (S-4661) is a broad-spectrum carbapenem antibiotic developed by Shionogi Company in Japan. -1 stability and other advantages. Its chemical name is (+)-(4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidine]sulfur]-6 -[(1R)-1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid monohydrate, the structural formula is as follows Formula compound A shown. [0005] [0006] Most carbapenem antibiotics can only be administered by injection due to thei...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/20C07D477/08A61K31/431A61P31/04
CPCC07D477/08C07D477/20
Inventor 毋立华郑德强王淑华刘文涛王长斌张利剑
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES