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

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

CN101711250AActive Publication Date: 2010-05-19XUANZHU BIOPHARMACEUTICAL CO LTD
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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

Patent Timeline
19 May 2010
Publication
CN101711250A
IPC
C07D477/20; A61K31/40; A61P31/00
CPC
C07D477/20; A61P31/00; A61P31/04
Inventors
黄振华