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Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds

A compound, methyl technology, applied in the direction of organic chemistry, bulk chemical production, medical preparations containing active ingredients, etc., can solve the problems of low clinical utilization, failure to meet clinical needs, and weak antibacterial activity of MRSA

Active Publication Date: 2009-02-18
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Due to the continuous increase of bacterial resistance and the limitation of digestive tract absorption due to the abuse of antibiotics, the carbapenems currently on the market can only be administered as injections in clinical practice, and the clinical utilization is not high, and the antibacterial activity against MRSA Weak, can no longer meet clinical needs

Method used

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  • Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds
  • Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds
  • Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1 (2S, 4S)-4-mercapto-2-formyl [4-(E)-(N, N-dimethylacrylamide-3-yl) phenylamino] -1-(tert-butyl oxygen Preparation of carbonyl)pyrrolidine

[0101] 14.5 g (50 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine and 200 ml of anhydrous tetrahydrofuran were added to the dry reaction flask. Under nitrogen protection, 9.8g (60mmol) of 1,1-carbonyldiimidazole was added at room temperature, reacted for 2h, and 9.9g (52mmol) of (E)-3-(4-aminophenyl)-N was added below 0°C, A solution of N-dimethylacrylamide in acetone continued to react for 1h. Then 100ml of 1mol / L hydrochloric acid was added dropwise, extracted with ethyl acetate (50ml×2), the organic phase was washed with water and saturated sodium chloride solution successively, concentrated under reduced pressure, the residue was added with 200ml of 5mol / L hydrochloric acid, stirred for 2h, and The dilute alkaline solution was adjusted to be alkaline, and a solid was precipitated, which...

Embodiment 2

[0102] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[4-(E)-(N,N-dimethylacrylamide-3-yl)phenylamine Base]-1-(tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[ 3,2,0]hept-2-ene - Preparation of p-nitrobenzyl 2-carboxylate

[0103]In the reaction flask, add (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-aza Bicyclo[3,2,0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 17.9g (30mmol) in 150ml of acetonitrile solution, cooled to below -10°C, added 8ml of diisopropylethylamine and ( 2S, 4S)-4-mercapto-2-formyl[4-(E)-(N,N-dimethylacrylamide-3-yl)phenylamino]-1-(tert-butoxycarbonyl)pyrrole Acetonitrile solution of 13.4g (32mmol) of alkanes in 100ml was stirred at 0°C for 15h. After the reaction was completed, it was diluted with 400 ml of ethyl acetate, washed with water and saturated brine successively, and the organic layer was dried and concentrated to obtain 17.1 g of solid, yield: 74.5%.

Embodiment 3

[0104] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[4-(E)-(N,N-dimethylacrylamide-3-yl)phenylamino group ]-pyridine Rolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene - Preparation of 2-carboxylic acid

[0105] (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[4-(E)-(N,N-dimethylacrylamide-3-yl)phenylamino]- 1-(tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2 , 0] 15.3g (20mmol) of p-nitrobenzyl hept-2-ene-2-carboxylate was dissolved in 100ml of dichloromethane, 20ml of anisole and 30ml of nitromethane were added, and 1mol was added dropwise at -50°C 150ml of nitromethane solution in / L aluminum trichloride, stirred at -40°C for 2h, added 200ml of water, precipitated solid, filtered, dissolved the filter cake in a mixture of 400mlTHF and 30ml of water, added 5g of 10% palladium-carbon, Stir the reaction at room temperature under 5MPa hydrogen pressure for 2h, filter off palladium carbon, add THF150ml to ...

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Abstract

The present invention relates to a formanilide substituted sulfhydryl pyrrolidine carbapenems compound as shown in Formula (I), easily hydrolyzed ester thereof, acceptable non-toxicity salt thereof in pharmacy, isomer thereof, hydrate thereof, and hydrate of ester or salt thereof. The present invention also relates to a preparation method of the compound as shown in Formula (I), application of the compounds as active substances for medicine, in particular to the application for preparing the medicine used for treating and / or preventing infectious diseases. The R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and X are defined in details in the specification.

Description

1. Technical field [0001] The present invention relates to mercaptopyrrolidine carbapenems substituted by formanilide, their easily hydrolyzed esters, their pharmaceutically acceptable non-toxic salts, their isomers, their hydrates, and the hydration of their esters or salts Compounds, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds for the preparation of drugs for treating and / or preventing infectious diseases belong to the field of medical technology. 2. Background technology [0002] Carbapenems are new broad-spectrum, enzyme-resistant and highly effective β-lactam antibiotics developed in the 1970s. In 1976, Thiamycin, the first carbapenem antibiotic, was discovered, but it was not used clinically due to its poor chemical stability. Later, the chemical structure modification of thiamycin produced a series of carbapenem derivatives. At present, such drugs that have been marketed include imipe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20A61K31/407A61P31/04
CPCY02P20/55
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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