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Preparation method of norfloxacin, ciprofloxacin and enrofloxacin

A technology of norfloxacin and ciprofloxacin is applied in the field of drug synthesis, and can solve the problems of high cost, increased consumption of N-methylpiperazine, low efficiency and the like

Active Publication Date: 2015-01-21
ZHEJIANG BENLI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The last two steps in the synthesis of norfloxacin, ciprofloxacin and enrofloxacin, that is, the hydrolysis of cyclized esters and the substitution of piperazine, there are three common methods: 1. Using hydrochloric acid, glacial acetic acid, sulfuric acid, etc. Acid to hydrolyze the cyclic ester to obtain carboxylic acid, and then replace it with piperazine to obtain the target product. The disadvantage is that a large amount of glacial acetic acid and sulfuric acid are needed as solvents and reagents. This method is costly and polluting
The adjusted process uses N-methylpiperazine to increase the alkalinity of the system, reducing the amount of alkali, but increasing the consumption of N-methylpiperazine
3. Using complex enzymes to hydrolyze cyclic esters into carboxylic acids and then shrink pipettes to obtain target molecules, the conditions are mild and the discharge of three wastes is small, but there are disadvantages of low efficiency and low yield

Method used

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  • Preparation method of norfloxacin, ciprofloxacin and enrofloxacin
  • Preparation method of norfloxacin, ciprofloxacin and enrofloxacin
  • Preparation method of norfloxacin, ciprofloxacin and enrofloxacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Step (1) At room temperature, add 40g (0.176mol) of 2,4-dichloro-5-fluorobenzoyl chloride and 36g (0.195mol) of tri-n-butylamine into the reaction flask, and add N,N-dimethylamino under stirring 25.5g (0.178mol) of ethyl acrylate, the reaction is exothermic by itself, the temperature of the reaction is controlled by cooling with cold water to about 70°C, and after the temperature is stable, it is then kept and stirred for 1 hour, and the reaction is completed. Add 100ml of xylene and 50ml of distilled water to the reaction solution, add hydrochloric acid to adjust the pH to 1-2, separate the organic layer, wash with water until neutral, evaporate the remaining water, transfer to another reaction bottle, and add ring Propylamine 11g (0.194mol), and pass into CO 2 gas, control the reaction pressure to 2 atm, and track it by HPLC. After the reaction is complete, the N,N-dimethylamine complex is recovered by distillation to obtain the mother liquor for future use.

[0063]...

Embodiment 2

[0066] Step (1) At room temperature, add 40g (0.176mol) of 2,4-dichloro-5-fluorobenzoyl chloride and 36g (0.195mol) of tri-n-butylamine into the reaction flask, and add N,N-dimethylamino under stirring 25.5g (0.178mol) of ethyl acrylate, the reaction is exothermic by itself, the temperature of the reaction is controlled by cooling with cold water to about 70°C, and after the temperature is stable, it is then kept and stirred for 1 hour, and the reaction is completed. Add 100ml of xylene and 50ml of distilled water to the reaction solution, add hydrochloric acid to adjust the pH to 1-2, separate the organic layer, wash with water until neutral, evaporate the remaining water, transfer to another reaction bottle, and add ring Propylamine 11g (0.194mol), and pass into CO 2 gas, control the reaction pressure to 2 atm, and track it by HPLC. After the reaction is complete, the N,N-dimethylamine complex is recovered by distillation to obtain the mother liquor for future use.

[0067]...

Embodiment 3

[0070] Step (1) At room temperature, add 40g (0.176mol) of 2,4-dichloro-5-fluorobenzoyl chloride and 32.7g (0.176mol) of tri-n-butylamine into the reaction flask, and add N,N-dimethyl 25.2 g (0.176 mol) of ethyl aminoacrylate, the reaction is exothermic by itself, cooled with cold water to control the reaction temperature to about 40°C, after the temperature stabilizes, keep stirring for 1 hour, and the reaction ends. Add 80ml of xylene and 40ml of distilled water to the reaction solution, add hydrochloric acid to adjust the pH to 1-2, separate the organic layer, wash with water until neutral, evaporate the remaining water, transfer to another reaction bottle, and add ring Propylamine 8g (0.141mol), and pass into CO 2 Gas, the reaction pressure is controlled to 1 atm, followed by HPLC, after the reaction is complete, the N,N-dimethylamine complex is recovered by distillation, and the mother liquor is obtained for future use.

[0071] Step (2) Add 80ml of xylene and 14.8g (0.2...

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Abstract

The invention discloses a preparation method of norfloxacin, ciprofloxacin and enrofloxacin. The preparation method comprises the following steps: directly reacting 1-ethyl-6-fluoro-7-chlo-4-oxo-1,4-dihydro-quinoline-3-carboxylate or 1-cyclopropyl-6-fluoro-7-chlo-4-oxo-1,4-dihydro-quinoline-3-carboxylate with piperazine (or N-ethyl piperazine); and then, performing after-treatment to prepare a corresponding target product norfloxacin (or ciprofloxacin or enrofloxacin). The preparation method disclosed by the invention is short in reaction step, convenient to operate, less investment and beneficial to industrial production; consumption of piperazine (or N-ethyl piperazine) can be reduced by more than half; under the catalytic action, the reaction temperature is low, the byproducts are less, the yield is high and the cost is low; heavy use of inorganic acid and inorganic alkaline is avoided, so that the pollution is reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a synthesis method of fluoroquinolones, in particular to a preparation method of norfloxacin, ciprofloxacin and enrofloxacin. technical background [0002] Quinolones are a class of chemically synthesized antibacterial drugs that have developed rapidly since their inception. Due to their advantages such as broad antibacterial spectrum, strong antibacterial activity, convenient administration, small adverse reactions, and no cross-resistance with other antibiotics, they have become clinical combination drugs. first choice. Quinolones have become a hot spot that people are competing to research and develop. Many literatures have reported the synthesis methods of such drugs, but there are generally disadvantages such as long steps, low yield, and large amount of three wastes. Therefore, people He has been making unremitting efforts to find a synthetic method with simpler o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56
CPCC07D215/56
Inventor 吴政杰
Owner ZHEJIANG BENLI TECH CO LTD
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