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Benzenesulfonamido methylene substituted mercapto pyrrolidine carbapenem derivatives

A technology of substituents and aminosulfonyl groups is applied in the field of mercaptopyrrolidine carbapenem derivatives substituted by benzenesulfonamide methylene, which can solve the problem of low clinical availability, inability to meet clinical needs, and increased bacterial resistance. And other issues

Active Publication Date: 2010-05-19
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 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
In addition, the half-life of meropenem and doripenem is relatively short, and the half-life in the human body is about 1 hour, which can no longer meet the clinical needs

Method used

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  • Benzenesulfonamido methylene substituted mercapto pyrrolidine carbapenem derivatives
  • Benzenesulfonamido methylene substituted mercapto pyrrolidine carbapenem derivatives
  • Benzenesulfonamido methylene substituted mercapto pyrrolidine carbapenem derivatives

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preparation example Construction

[0097] The present invention also provides the preparation method of above-mentioned compound, described method is but not limited to following method, and this method has following reaction equation:

[0098]

[0099] Reaction steps:

[0100] The preparation of compound shown in step 1 formula (a)

[0101] Add raw material 1 and methanol to the dry reaction bottle, mix uniformly, then add thionyl chloride solution dropwise therein, stir the obtained mixture for a period of time, then cool it, and precipitate crystals from the mixture. The obtained crystals are filtered, and the obtained filter cake is dried to obtain the compound represented by formula (a).

[0102] Preparation of compound shown in step 2 formula (b)

[0103] In a dry reaction flask, add the triethylamine solution to the dichloromethane solution of the compound represented by the formula (a) obtained in the previous step, stir the resulting mixture, and then add triethylamine and methanesulfonyl chlor...

Embodiment 1

[0134] Example 1 (4R, 5S, 6S)-3-[(2S, 4S)-2-[4-methyl-benzenesulfonamido]methylene- Pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0] Preparation of hept-2-ene-2-carboxylic acid (i.e. compound 1 of the present invention)

[0135]

[0136] Step 1 Preparation of (2S, 4R)-4-hydroxyl-2-methoxycarbonylpyrrolidine hydrochloride

[0137] In a dry reaction flask, 13.1 g (100 mmol) of trans-4-hydroxy-L-proline (commercially available from Shanghai Qiude Biochemical Co., Ltd.) and 50 ml of methanol were added and mixed uniformly. To the resulting mixture was added dropwise 8 ml of thionyl chloride at 0°C. After the dropwise addition, the resultant was warmed up to room temperature and stirred for 20 min, then warmed up to 40° C. and stirred for 14 h. The resultant was cooled, from which white crystals were precipitated, and a filter cake was obtained by filtration. The resulting filter cake was dried to obtain 13.9 g of the product, with a yiel...

Embodiment 2

[0156] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-[3-methyl-benzenesulfonamido]methylene- Pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0] Preparation of hept-2-ene-2-carboxylic acid (i.e. compound 2 of the present invention)

[0157]

[0158] Step 1 (2S,4S)-4-Mercapto-2-[N-(tert-butoxycarbonyl)-3-methyl-benzenesulfonamido] Preparation of methylene-1-(tert-butoxycarbonyl)pyrrolidine

[0159] With reference to the preparation method of step 5 in Example 1, 5.5 g (20mmol ) and N-(tert-butoxycarbonyl)-3-methyl-benzenesulfonamide (commercially available from Hengzhou Ruier Chemical Co., Ltd.) 9.0g (33mmol) to get (2S, 4S)-4-mercapto-2- [N-(tert-butoxycarbonyl)-3-carboxy-benzenesulfonamido]methylene-1-(tert-butoxycarbonyl)pyrrolidine 5.3 g, yield: 54.6%.

[0160] Step 2 (4R,5S,6S)-3-[(2S,4S)-2-[N-(tert-butoxycarbonyl)-3-methyl-benzenesulfonyl Amino]methylene-1-(tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4- Preparati...

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Abstract

The present invention relates to the field of pharmacy technology, concretely speaking, it relates to the compounds shown by formula (I), their pharmaceutically acceptable salts, their easily hydrolysable esters, their isomers, their hydrates, the hydrates of the above-said esters or salts, and the intermediates shown by formula (II), wherein R1, R2, R3, R4 and R5 are defined as that in the description. The present invention also relates to the preparation methods for these compounds and intermediates, the pharmaceutical compositions comprising these compounds and the use of these compounds in preparing the medicaments for treating and / or preventing infective diseases.

Description

technical field [0001] The present invention relates to benzenesulfonamide methylene substituted mercaptopyrrolidine carbapenem derivatives, their pharmaceutically acceptable salts, their easily hydrolyzed esters, their isomers, their hydrates, and the hydration of the above-mentioned esters or salts Compounds and intermediates thereof, preparation methods of these compounds and intermediates, pharmaceutical compositions containing these compounds, and uses of these compounds in the preparation of medicines for treating and / or preventing infectious diseases. Background technique [0002] Carbapenem antibiotics have attracted much attention because of their broad antibacterial spectrum, strong antibacterial activity and stability to β-lactamase. Carbapenem antibiotics that have been used clinically include imipenem, panipenem, meropenem, biapenem, and doripenem. Donipenem is a carbapenem antibiotic developed by Shionogi Co., Ltd. of Japan, and its structural formula is as fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20A61K31/40A61P31/00
CPCC07D477/20A61P31/00A61P31/04
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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