1beta-methyl carbapenem compound

A compound, methyl technology, applied in the field of medicine, can solve the problems of not meeting clinical needs, short half-life, and low clinical utilization

Active Publication Date: 2009-02-11
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to the continuous increase of bacterial resistance due to the abuse of antibiotics and the limitation of digestive tract absorption, the currently marketed carbapenems can only be administered as injections in clinical practice, and the clinical utilization is not high. The half-life of penem is relatively short, which can no longer meet the clinical needs

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] The preparation of embodiment 1 (2S, 4S)-4-mercapto-2-formyl [(benzoic acid-3-yl) amino]-1-methyl-pyrrolidine

[0086] 10.2 g (50 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-methyl-pyrrolidine and 100 ml of anhydrous tetrahydrofuran were added to the dry reaction flask. Under nitrogen protection, DCC (dicyclohexylcarboimide) 12.4g (60mmol) was added at room temperature, reacted for 0.5h, and 8.2g (60mmol) of 3-amino-benzoic acid in 100ml of tetrahydrofuran solution was added below 0°C, and continued Reaction 1h. Concentrate under reduced pressure, add 50 ml of 4 mol / L hydrochloric acid to the residue, stir for 2 hours, adjust to basicity with dilute alkali solution, and precipitate a solid, which is recrystallized from a mixed solution of acetonitrile and acetone to obtain 11.8 g of the product, yield: 84.1%.

Embodiment 2

[0087] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(benzoic acid-3-yl)amino]-1-methyl-pyrrolidin-4-yl]sulfanyl -6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester preparation

[0088] In a dry reaction flask, add (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1- Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 35.8g (60mmol) in 400ml of acetonitrile solution, cooled to below -20°C, add diisopropylethylamine 16ml and ( 2S,4S)-4-mercapto-2-formyl[(benzoic acid-3-yl)amino]-1-methyl-pyrrolidine 17.4g (62mmol) in 200ml acetonitrile, stirred at 0°C for 24h. After the reaction was completed, 600ml of ethyl acetate was added to dilute, washed with water and saturated brine successively, the organic layer was dried and concentrated to obtain 28.3g of solid, yield: 75.6%.

Embodiment 3

[0089] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(benzoic acid-3-yl)amino]-1-methyl-pyrrolidin-4-yl]sulfanyl - Preparation of 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

[0090] (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(benzoic acid-3-yl)amino]-1-methyl-pyrrolidin-4-yl]thio-6 -[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 12.5g ( 20mmol) was dissolved in a mixture of 600mlTHF and 50ml of water, 5g of 10% palladium-carbon was added, stirred at room temperature for 2h under hydrogen pressure of 5MPa, the palladium-carbon was filtered off, 150ml of THF was added to the filtrate, the layers were separated, and the water layer was collected. Add 20 ml of 10% magnesium chloride aqueous solution to THF, let it stand still, separate the water layer, and repeat the operation once. The water phases were combined, 50ml of methanol was slowly added dropwise at 0°C, stirred at -10°C for 1...

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Abstract

The invention pertains to the technical field of medicine and particularly relates to 1Beta-methyl carbon-substituted penem compound shown as general formula (I), and pharmaceutically acceptable salts, easily hydrolysable ester and isomers of the compound; wherein, R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are defined as the specification. The invention also relates to a preparation method of the compounds, medicine composition containing the compounds as well as application of the compounds to the preparation of medicines treating and/or preventing infectious diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to 1β-methylcarbapenem compounds, pharmaceutically acceptable salts thereof, easily hydrolyzed esters thereof, isomers thereof, preparation methods of these compounds, and medicines containing these compounds Compositions, and the use of these compounds in the preparation of medicines for treating and / or preventing infectious diseases. 2. Background technology [0002] Carbapenem antibiotics are a class of β-lactam antibiotics developed in the 1970s. It has attracted much attention because of its broad antibacterial spectrum, strong antibacterial activity, and stability to β-lactamase. Its structural feature is that the sulfur at the 1-position of the penicillane core is replaced by carbon, and the 2-position has a double bond, which combines the five-membered ring of penicillin and the conjugated double bond of cephalosporin to activate the β-lactam ring. [0003] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20A61K31/4439A61K31/407A61P31/00
CPCY02P20/55
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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