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Class C β-lactamase inhibitors and their preparation methods and applications

A technology for lactamase and inhibitors, which is applied in the field of C-class β-lactamase inhibitors and their preparation, can solve the problems of the market demand for C-class β-lactamase inhibitors, and achieve high product purity and responsiveness. Moderate and controllable effect

Active Publication Date: 2020-08-28
THE HONG KONG POLYTECHNIC UNIV SHENZHEN RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a class C β-lactamase inhibitor and its preparation method, aiming to solve the problem of the existing market demand for class C β-lactamase inhibitors.

Method used

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  • Class C β-lactamase inhibitors and their preparation methods and applications
  • Class C β-lactamase inhibitors and their preparation methods and applications
  • Class C β-lactamase inhibitors and their preparation methods and applications

Examples

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preparation example Construction

[0028] Correspondingly, the embodiment of the present invention also provides a preparation method of a class C β-lactamase inhibitor, comprising the following steps:

[0029] Step (1). After cooling the first aprotic solvent, add liquid bromine, sulfuric acid, sodium nitrite or potassium nitrite under stirring conditions, and then add 6-aminopenicillinic acid. Perform constant temperature reaction to obtain 6,6-dibromopenicillinic acid;

[0030] Step (2). Dissolve the 6,6-dibromopenicillin in the second aprotic solvent, add diphenyldiazomethane at room temperature, and react to prepare benzhydryl 6,6-dibromopenicillin acid;

[0031] Step (3). Dissolve the benzhydryl 6,6-dibromopenicillin acid in tetrahydrofuran, add Grignard reagent and 3-(2-thienyl)propionaldehyde, and react to prepare benzhydryl-6α-bromo- 6β-(1R-hydroxy-3(2-thienyl)propyl)penicillinic acid;

[0032] Step (4). After dissolving the benzhydryl-6α-bromo-6β-(1R-hydroxy-3(2-thienyl)propyl) penicillin acid, coo...

Embodiment 1

[0056] A class C β-lactamase inhibitor, the class C β-lactamase inhibitor is 6α-(1R-hydroxyl-3(2-thiophene-yl)propyl) penicillin acid, which has the following formula 1 shows the structure,

[0057]

[0058] The preparation method of described C class β-lactamase inhibitor, comprises the following steps:

[0059] S11. Cool 60mL of dichloromethane to 5°C, add 14.4g (90mmol) of liquid bromine, 24mL of 2.5N (1.25mol / L) sulfuric acid and 4.14g (60mmol) of sodium nitrite under stirring conditions, and divide in about 5 minutes Add 6.5 g (30 mmol) of 6-aminopenicillinic acid in batches, keep the temperature at 4-10° C., and react at 5° C. for 30 minutes. Then, 50mL of 1M sodium bisulfite solution was added dropwise into the reaction solution, keeping the temperature at 5-15°C, the color of the liquid bromine gradually faded, and the reaction solution appeared light yellow. The organic phase was obtained by extraction and separation, the aqueous phase was extracted twice with di...

Embodiment 2

[0072] The 6α-(1R-hydroxy-3(2-thien-yl)propyl)penicillin acid provided in the example was tested in vitro for its inhibitory activity on class C β-lactamases.

[0073] (1) Insert the DNA sequences of P99 and PenP into a modified pET30a vector by molecular cloning method, which contains 6 histidine tags and restriction sites for HRV3C protease, and constructed by this method Plasmids containing P99 or PenP gene sequences, and then the two plasmids were respectively transformed into Escherichia coli BL21 (DE3). Next, regardless of whether it is PenP or P99, the same steps are used for protein expression and purification. After the bacteria were inoculated overnight, they were diluted 1:100 into 2.4L of LB nutrient medium, cultured at 37°C for 2.5 hours until the OD600 reached 0.6-0.8, and then added isopropylthio-β-D-galactoside ( IPTG) induced protein expression, and then cultured at 30°C for 5 hours, and then centrifuged to harvest the bacteria.

[0074] The fusion protein e...

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Abstract

The invention provides a C type beta-lactamase inhibitor. The C type beta-lactamase inhibitor is 6 alpha-(1R-hydroxy-3(2-thiophene-yl)propyl) penicillic acid, and the structure of the C type beta-lactamase inhibitor is represented by formula 1 in the invention.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a class C β-lactamase inhibitor and its preparation method and application. Background technique [0002] The production of β-lactamase is the most important way for bacteria to resist β-lactam antibiotics. β-lactamases can be divided into four types according to sequence homology: A, B, C, and D. Class A and C are the two most common types of β-lactamases in clinical practice. Amidases, especially extended-spectrum β-lactamases, can render most antibiotics ineffective, thus posing a huge threat to hospital and community health. For a long time, there are only three clinically available β-lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam, but these three are only suitable for class A β-lactamase. As for another class of β-lactamases with more broad-spectrum activity, only the newly listed avibactam has an inhibitory effect. Therefore, there is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/861C07D499/04C07D499/08A61K31/431A61P31/04A61K31/43A61K31/546
CPCA61K31/43A61K31/431A61K31/546C07D499/04C07D499/08C07D499/861A61K2300/00
Inventor 潘雪华贺云娇陈建辉赵燕湘
Owner THE HONG KONG POLYTECHNIC UNIV SHENZHEN RES INST
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