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A kind of synthetic method of prafloxacin

A synthetic method and compound technology, applied in the direction of organic chemistry, can solve the problems of pollution, seriousness, low purity, etc., and achieve the effect of high yield, less impurities, and simple operation

Active Publication Date: 2020-12-29
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Wherein, in the preparation method of prafloxacin fluoroquinolone quinoline core through β-substituted amino-α-substituted benzoyl acrylate, β-substituted amino-α-substituted benzoyl acrylate, and then 1 - The purity of aminocyclopropane is low after nucleophilic substitution reaction, and the cyclization is carried out with inorganic base as acid-binding agent in a high-boiling point protic solvent, and the pollution caused by post-treatment is very serious

Method used

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  • A kind of synthetic method of prafloxacin
  • A kind of synthetic method of prafloxacin
  • A kind of synthetic method of prafloxacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthetic method of present embodiment prafloxacin comprises the following steps:

[0045] (1) Preparation of ethyl 2-(2,4-dichloro-3-cyano-5-fluorobenzoyl)-3-cyclopropylaminoacrylate, the compound of formula 5

[0046]

[0047] Put 24g of 2,4-dichloro-3-cyano-5-fluorobenzoic acid into the reaction bottle, add 240mL of dichloromethane, dropwise add 28.8g of thionyl chloride; stir for 5 minutes after dropping, add 2mL of triethylamine , stirred slowly to 35-40°C, refluxed for 3-5 hours; after the reaction was completed, cooled to -5--10°C, and added dropwise a mixture of 15.2g of triethylamine and 21.5g of ethyl 3-dimethylaminoacrylate After the drop, the temperature was raised to room temperature and the reaction was continued for 12 hours. TLC detected that the reaction compound 7 was completely reacted; the temperature was lowered in an ice bath, and 24 mL of acetic acid was added below 10 ° C, stirred for 5 minutes, and then 9 g of 1-aminocyclopropane was adde...

Embodiment 2

[0058] The difference between this example and Example 1 is only that: step (3) uses propionic acid instead of acetic acid, and 9 mL of methanesulfonic acid instead of sulfuric acid, and finally obtained 7-chloro-8-cyano-1-cyclopropyl-6 - Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (compound of formula 3) 13.2 g, yield 96%.

Embodiment 3

[0060] The difference between this embodiment and Example 1 is only that: use pyridine as an acid-binding agent in step (4), finally obtain prafloxacin 11.9g, yield 90.3%, HPLC purity 99.33%, as image 3 shown.

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Abstract

The invention relates to a synthesis method of pradofloxacin. According to the method, a cheap and easy-to-obtain compound is taken as a raw material and subjected to chlorination, acylation, nucleophilic substitution, cyclization, hydrolysis and alkylation reactions, and the target product, namely, pradofloxacin, is obtained. The nucleophilic substitution target product beta-substituted amino-alpha-substituted benzoyl acrylate compound has good quality and has the purity of 98% or above and the yield of 80%-90%, and the yield is increased by 10% or above as compared with that in the prior art; the provided ester hydrolysis method and product quality are good, and the reaction yield reaches 93%-98%; organic base is used for replacing conventional inorganic base to serve as a cyclization reaction catalyst, the operation is simple, no pollution is caused, and the cost is substantially reduced; halogenated hydrocarbon is taken as an alkylation solvent, the reaction temperature is the roomtemperature, the reaction is mild and easy to operate, fewer impurities are produced in the alkylation reaction at the temperature of 20-40 DEG C as compared with those produced in the alkylation reaction at the high temperature in the prior art, the yield is high, halogenated hydrocarbon solvents are easy to recycle and reuse, pollution is greatly reduced, and the synthesis method is environmentally friendly.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a synthesis method of prafloxacin. Background technique [0002] Pradofloxacin is a third-generation enhanced-spectrum veterinary antibiotic of fluoroquinolones developed by Bayer. It is mainly used as a prescription drug for the treatment of bacterial infections in dogs and cats. Quinolones mainly inhibit the A subunit of DNA gyrase (also known as topoisomerase II), and only a few drugs also act on the B subunit, thereby destroying its activity and interfering with the synthesis of deoxyribonucleic acid, ribonucleic acid and protein. Make bacteria can no longer divide, and play a bactericidal effect. [0003] The chemical name of prafloxacin is 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo-(4.3.0)nonan-8-yl)-6 -Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, the molecular formula is C21H21FN4O3, the molecular weight is 396.41, and the structural formula i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘雄黄想亮姚成志陈为人马舟军
Owner ZHEJIANG MENOVO PHARMA