Preparation method of prulifloxacin

A compound and ionic liquid technology, applied in the field of synthesizing pululifloxacin, can solve the problems of difficulty in obtaining high-purity products, unstable pululifloxacin, not suitable for industrialization, etc., achieving easy recovery and application, shortening production Effects of cycles, simplified post-processing

Inactive Publication Date: 2011-06-29
CHONGQING KERUI PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] 2. Prulifloxacin is unstable under acidic conditions. The crude product of prulifloxacin synthesized according to the above method is complicated after crystallization, and it is difficult to obtain high-purity products, which is not suitable for industrialization.

Method used

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  • Preparation method of prulifloxacin
  • Preparation method of prulifloxacin
  • Preparation method of prulifloxacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Step 1: Preparation of ethyl 6,7-difluoro-4-oxo-2-(ethylthio)quinoline-3-carboxylate:

[0043] Add [(3,4-difluorophenyl) amino] (ethylthio) methylene malonate 359.40 g (1.00 mol) and ionic liquid [bmim] BF successively into a 2000 ml four-neck flask 4 1000ml, 1.36g (0.01mol) of zinc chloride, feed nitrogen, keep the oil bath at 100°C to distill off the alcohol for 0.7h, almost no ethanol is distilled out, after cooling to room temperature, add 500ml of water, filter, and water the filter cake After washing, 302.54 g of ethyl 6,7-difluoro-4-oxo-2-(ethylthio)quinoline-3-carboxylate was obtained as yellowish white crystals, with a yield of 96.56% and a melting point of 128.2-129.6°C.

[0044] Step 2: Preparation of 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazetidino[3,2-a]quinoline-3-carboxy Ethyl acetate:

[0045] Add 302.50 g (0.97 mol) of ethyl 6,7-difluoro-4-oxo-2-(ethylthio)quinoline-3-carboxylate and ionic liquid [bmim]BF to a 3000ml three-neck flask successively ...

Embodiment 2

[0050] Embodiment 2: A kind of preparation method of prulifloxacin, different from Example 1 is the preparation of 6,7-difluoro-4-oxo-2-(ethylthio)quinoline-3-formic acid ethyl ester The method is:

[0051] Add [(3,4-difluorophenyl)amino](ethylthio)methylene malonate 359.40g (1.00mol), xylene 1000ml, zinc chloride 1.36 g (0.01mol), keep the oil bath temperature at 140°C for fractional distillation to remove alcohol for 1.0h, almost no ethanol will be distilled out, and the oil bath will be heated to 155°C to distill about 650ml of xylene (about 0.8h) and cooled to 0°C After filtering, the filter cake was washed with ice xylene to obtain 285.73 g of pale yellow-white crystal 6,7-difluoro-4-oxo-2-(ethylthio)quinoline-3-carboxylic acid ethyl ester, yield 91.24 %, melting point 128.1 ~ 129.8 ℃.

Embodiment 3

[0052] Embodiment 3: the preparation method of prulifloxacin, comprises the following steps:

[0053] Step 1: Synthesis of compound 6, ethyl 7-difluoro-4-oxo-2-(ethylthio)quinoline-3-carboxylate:

[0054] Method 1: Add [(3,4-difluorophenyl) amino] (ethylthio) methylene malonate, xylene and indium chloride in sequence in a three-necked flask, wherein the raw material ratio is expressed in molar Count, [(3,4-difluorophenyl) amino] (ethylthio) methylene malonate diethyl ester: xylene: indium chloride=1: 8: 0.005; keep the oil bath temperature at 140°C Fractional distillation to remove alcohol until no more ethanol is distilled out, heat the oil bath to 155°C to evaporate part of the xylene, cool to 0°C, filter, and wash the filter cake with ice xylene to obtain the compound 6,7-di Ethyl fluoro-4-oxo-2-(ethylthio)quinoline-3-carboxylate, the melting point is controlled at 127.5-130.5°C.

[0055] Method 2 Add [(3,4-difluorophenyl) amino] (ethylthio) methylene malonate, ionic liqu...

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Abstract

The invention provides a preparation method of prulifloxacin using [(3,4-difluorophenyl)amido](ethylthio) methylene malonic ester as starting material, xylene or ion liquid as reaction medium, Lewis acid as catalyst to synthesize 6,7-difluoro-4-hydroxy-2-(ethylthio) quinoline-3-ethyl formate of formula (IV), synthesizing compound of formula (II) by reacting compound of formula (IV) with acetic anhydride, chlorosulfonic acid, sodium carbonate by way of multi-charging 'one-pot'; performing displacement reaction of the compound of formula (II) and piperazine of formula (V) in ion liquid to generate the corresponding compound of formula (VI); obtaining the compound of formula (VII) by hydrolyzing the compound of formula (VI), reacting the compound of formula (VII) with the compound of formula(IX) to obtain prulifloxacin of formula (I). The preparation method has features of high yield, high product purity, and simple technique, suitable for industrialization.

Description

technical field [0001] The invention relates to a preparation method of quinolone anti-infection drugs, more specifically, the invention relates to a preparation method of synthesizing prulifloxacin. Background technique [0002] As one of the most common clinical diseases, infectious diseases involve almost all clinical specialties; at the same time, infectious diseases are also one of the most common causes of patient death. [0003] Quinolones originated in the 1980s. Their mechanism of action is to target bacterial DNA. By hindering bacterial DNA topoisomerase, bacterial DNA cannot form supercoils, resulting in irreversible damage to chromosomes, and eventually bacteria Unable to divide and reproduce, thus serving the purpose of anti-infection. Quinolones have become one of the hot spots in the development of anti-infective drugs. [0004] Prulifloxacin is a fourth-generation quinolone anti-infective drug jointly developed by Nippon Shinyaku and Meiji Jika, and was app...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04B01J27/10A61P31/04
Inventor 刘睿斌刘俊敏苏其果李强李荣陈立虹罗川萍
Owner CHONGQING KERUI PHARMA GRP
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