Novel method for preparing marbofloxacin

A technology of marbofloxacin and enamine, which is applied in the chemical field, can solve the problems of high price, no industrial value, and harsh reaction conditions of tetrabutyl fluoride ammonium, which is conducive to large-scale preparation and increases the electron cloud density , less side effects

Active Publication Date: 2010-01-06
ZHEJIANG GUOBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, because the tetrabutylammonium fluoride used is expensive, and the reaction needs to be carried out under strict anhydrous conditions, there is no industrial value
[0025] In summary, there are various deficiencies in the existing synthetic route of marbofloxacin, such as harsh reaction conditions, expensive chemical reagents, too long reaction route, more impurities in individual reaction steps, etc.

Method used

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  • Novel method for preparing marbofloxacin
  • Novel method for preparing marbofloxacin
  • Novel method for preparing marbofloxacin

Examples

Experimental program
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Embodiment 1

[0053] The synthesis of embodiment 1,3-(dimethylamino)-2-(2,3,4,5-tetrafluorobenzoyl) ethyl acetate

[0054] Drop into 4g sodium hydride (60%, 0.10mol) and 200ml toluene in the 500ml four-necked flask that is full of nitrogen, drop the toluene solution of 2,3,4,5-tetrafluorobenzoyl ethyl acetate ( 26.42g dissolved in 60ml toluene). After about 2-3 hours, the dripping is completed, and it is kept at 0° C. for 8 hours. Another 39.85 g of 1,1-dimethyl-2-methoxyimine methanesulfonate (0.20 mol) was added dropwise to the above solution at 0°C, and the reaction was incubated at 0-5°C for 15 hours. After the reaction is complete, filter under reduced pressure and bleach the filter cake with an appropriate amount of toluene. Combine the filtrates, wash twice with deionized water, each time with 40ml of deionized water, then dry with anhydrous sodium sulfate, and filter off the desiccant to obtain 3-(dimethylamino)-2-(2,3,4 , 5-tetrafluorobenzoyl) ethyl acetate toluene feed solution...

Embodiment 2

[0055] Embodiment 2, the synthesis of 3-(2-formyl-2-methylhydrazino)-2-(2,3,4,5-tetrafluorobenzoyl ethyl acrylate

[0056] 8.6 ml of glacial acetic acid (0.15 mol) was added to the feed solution obtained in the upward step, stirred for 10 minutes, and 8.81 g of N-amino-N-methylformamide (0.10 mol) was added dropwise at 5°C. After dropping, react at 5-10°C for 6 hours. After the reaction, the pH value was adjusted to 6 with an appropriate amount of sodium hydroxide solution. Then wash with ice water three times, 40ml of ice water each time. The organic layer was dried over anhydrous sodium sulfate, and the desiccant was filtered off to obtain ethyl 3-(2-formyl-2-methylhydrazino)-2-(2,3,4,5-tetrafluorobenzoylacrylate The toluene feed solution was directly used in the next step reaction without purification.

Embodiment 3、6

[0057] Embodiment 3,6,7, the synthesis of 8-trifluoro-1-(N-methylformylamino)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid ethyl ester

[0058] Add 6.36g of sodium carbonate (0.06mol) to the feed liquid obtained in the upward step, heat up to reflux, and react under reflux for 4 hours. During the reaction, the product gradually precipitated out. After the reaction, filter with suction. The filter cake was rinsed with deionized water until it became neutral, and then dried under vacuum at 60° C. to obtain 29.54 g (yield 90.0%) of light yellow to yellow powder with a melting point of 188-191° C.

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Abstract

The invention mainly discloses a novel method for preparing marbofloxacin, which comprises the following steps: under the protection of inert gases, 2,3,4,5-phenyl tetrafluoride formoxyl alkyl ester forms negative ions with alkali in an inert organic solvent, is condensed with imidic salt to obtain N-dimethyl substitutive enamine derivative, and reacts with N - methyl hydrazide in organic acid to obtain N-methyl-N-acyl substitutive enamine derivative; under the reflux state, the N-methyl-N-acyl substitutive enamine derivative is catalyzed by alkali to obtain quinoline carboxylic ether; the quinoline carboxylic ether takes water as a solvent, is catalyzed with alkali at proper temperature and is neutralized to obtain quinoline carboxylic acid; under the action of an acid-binding agent, the quinoline carboxylic acid is condensed with N-methyl piperazine to obtain a condensed piperazine substance; the condensed piperazine substance is heated to proper temperature in an alkalis hydroxid water solution, is kept at the temperature and is neutralized to obtain hydrolysate; and the hydrolysate takes water as a solvent and is reacted with dialkoxy methane or methylene halide to obtain the marbofloxacin under the catalysis of the catalyzer. The invention has high yield, thereby facilitating industrialized production at large scale.

Description

technical field [0001] The invention belongs to the field of chemistry, and specifically provides a new method for preparing marbofloxacin, which uses 2,3,4,5-tetrafluorobenzoyl ester as a raw material to obtain a target compound through a series of chemical reactions. Background technique [0002] Marbofloxacin (hereinafter referred to as compound I) is a new type of fluoroquinolone antibacterial drug for animals. It was first developed by Roche Company, and then further developed by Ve'toquinol Company. It was listed in Britain and France successively in 1995. Its structural formula is: [0003] [0004] Mabaofloxacin has the advantages of broad antibacterial spectrum, strong bactericidal power, fast absorption, wide distribution in the body, no cross-resistance with other antibacterial agents, convenient use, and small adverse reactions. Pharmacokinetic studies have shown that marbofloxacin has a long elimination half-life in animals, its bioavailability is close to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/06A61P31/04
Inventor 杨训谢伟灵侯仲轲刘聪李睿婷田利焕邱家军
Owner ZHEJIANG GUOBANG PHARMA
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