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Process for synthesizing norfloxacin

A technology of norfloxacin and a synthetic method, which is applied in the directions of organic chemistry and antibacterial drugs, can solve problems such as difficulty in industrial production, influence on reaction yield, difficulty in obtaining raw materials, etc., and achieves simple methods, simple process methods, and improved The effect of utilization

Active Publication Date: 2010-12-08
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The patent (span 1986 547361) uses 7-ethanesulfonyl quinoline carboxylate as raw material, reacts with piperazine, and then hydrolyzes to obtain norfloxacin. The raw material of this route is also not easy to obtain
The patent (span 1986 540010) uses 2-chloro-4-amino-5-fluorobenzoic acid ethyl ester as raw material, reacts with N,N-diethanolamine to obtain 2-4-piperazinyl-5-fluorobenzoic acid ethyl ester, React with diethyl malonate to obtain ethyl α-(2-chloro-4-piperazinyl-5-fluorobenzoyl)acetate, then react with triethyl orthoformate and ethylamine, cyclize and hydrolyze to obtain Norfloxacin, this route has long steps and is not easy for industrial production
Patent (span 1985 540055) reacts 2-chloro-4-piperazinyl-5-fluorobenzoic acid ethyl ester with β-ethylaminoacrylonitrile, cyclization and hydrolysis to obtain norfloxacin. Raw materials are not easy to obtain

Method used

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  • Process for synthesizing norfloxacin

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Experimental program
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Effect test

Embodiment 1

[0017] 1) Add 43.2 g of sodium methoxide into a 1 L four-necked flask, add 90.0 g of dimethyl carbonate, and then add 400 ml of toluene. The temperature was raised to 70°C with stirring, and 41.4g of 2,4-dichloro-5-fluoroacetophenone toluene solution (wherein toluene was 100ml) was added dropwise. The addition time was 5 hours. After the reaction was completed, 300 ml of water was added to adjust pH=5, the toluene layer was separated, and concentrated to dryness to obtain 47.8 g of methyl 2,4-dichloro-5-fluorobenzoylacetate with a yield of 90.3%.

[0018] 2) 47.8g of methyl 2,4-dichloro-5-fluorobenzoylacetate was added with 64.3g of N,N'-dimethylformamide dimethylacetal, 170ml of toluene, refluxed for 2 hours, and concentrated to recover toluene and N , N'-dimethylformamide dimethyl acetal. 34.2 g of ethylamine toluene solution (containing 80 ml of toluene) was added dropwise at room temperature, and the temperature was raised to 40° C. for reaction for 2 hours after dropping...

Embodiment 2

[0023] 1) Add 43.2g of sodium ethoxide into a 1L four-necked flask, add 18.0g of dimethyl carbonate, and then add 400ml of toluene. The temperature was raised to 90°C with stirring, and 41.4g of 2,4-dichloro-5-fluoroacetophenone toluene solution (wherein toluene was 100ml) was added dropwise. The addition time was 5 hours. After the reaction, 300 ml of water was added to adjust pH=6, the toluene layer was separated, and concentrated to dryness to obtain 39.6 g of methyl 2,4-dichloro-5-fluorobenzoylacetate, with a yield of 75.1%.

[0024] 2) 17.9g of N,N'-dimethylformamide dimethylacetal and 170ml of toluene were added to 39.6g of methyl 2,4-dichloro-5-fluorobenzoylacetate, refluxed for 3 hours, and concentrated to recover toluene. 34.2 g of ethylamine toluene solution (containing 80 ml of toluene) was added dropwise at room temperature, and the temperature was raised to 50° C. for reaction for 2 hours after dropping. Concentrate to dryness under reduced pressure to obtain 45....

Embodiment 3

[0029] 1) Add 43.2 g of potassium tert-butoxide into a 1 L four-necked flask, add 54.0 g of dimethyl carbonate, and then add 400 ml of toluene. The temperature was raised to 80°C with stirring, and 41.4g of 2,4-dichloro-5-fluoroacetophenone toluene solution (wherein toluene was 100ml) was added dropwise, and the addition time was 5 hours. After the reaction was completed, 300 ml of water was added to adjust pH=5, the toluene layer was separated, and concentrated to dryness to obtain 47.3 g of methyl 2,4-dichloro-5-fluorobenzoylacetate with a yield of 90.0%.

[0030] 2) 47.3g of methyl 2,4-dichloro-5-fluorobenzoylacetate was added with 47.6g of N,N'-dimethylformamide dimethylacetal, 170ml of toluene, refluxed for 3 hours, and concentrated to recover toluene and N , N'-dimethylformamide dimethyl acetal. 34.2 g of ethylamine toluene solution (containing 80 ml of toluene) was added dropwise at room temperature, and the temperature was raised to 40° C. for reaction for 2 hours aft...

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Abstract

The invention discloses a synthetic method of norfloxacin. The method comprises the following steps: taking toluene as a solvent, causing methyl carbonate to react with 2,4-dichloroo-5-fluoroacetophenone in the presence of a catalyst at the temperature of 70-90 DEG C to obtain 2,4-dichloro-5-fluorobenzenepropionic acid methyl ester, reflux reacting with N,N-dimethylformamide dimethyl acetal in toluene solution for 2-3h to obtain 3-ethylamino-2-(2,4-dichloro-5-fluorobenzoyl) methyl acrylate, cyclizing to obtain 1-ethyl-7-chloro-6-fluo-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester, reacting with a chelating agent at the temperature of 80-110 DEG C for 2-3h to obtain 1-ethyl-7-chloro-6-fluo-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester trifluoracetic acid anhydride bononized chelate, reacting with piperazine at the temperature of 20-40 DEG C for 10-24h to obtain the norfloxacin. The method has the advantages of simple process and mild reaction condition, avoids production of reverse ring in the traditional process, provides high-purity product, and is applicable to industrialized production.

Description

technical field [0001] The invention relates to a compound synthesis process, in particular to a norfloxacin synthesis method. Background technique [0002] Norfloxacin, chemical name: 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. English name: 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazine)-3-quinolinecarboxylic acid, which is a quinolone antibacterial drug with strong antibacterial properties, broad antibacterial spectrum, and biological It has the advantages of high utilization, good tissue permeability, no cross-resistance with other antibiotics, and small side effects. According to the difference of starting materials, the synthetic methods of norfloxacin can be summarized into the following 6 kinds. In 1980, Koga et al. (J MedChem, 1980, 23: 1358) used 3-chloro-4-fluoroaniline as a raw material to react with diethyl ethoxymethylene malonate, through cyclization, N-ethylation, Hydrolysis, and then react with piperazine, this ro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/56A61P31/04
Inventor 蒋成君王敏孙科达
Owner ZHEJIANG LEPU PHARMA CO LTD
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