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Process for synthesizing norfloxacin

A norfloxacin and synthesis method technology, applied in organic chemistry, antibacterial drugs, etc., can solve the problems of long steps, affecting the reaction yield, and difficulty in obtaining it, and achieve mild reaction conditions, simple process methods, and high product purity Effect

Active Publication Date: 2009-07-15
ZHEJIANG LEPU PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

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 reaction with piperazine, this route has simple raw materials, but the reaction of 3-chloro-4-fluoroaniline and diethyl ethoxymethylene malonate is easy to form an isomer, which affects the reaction yield
In 1985, Chu et al. (J Med Chem, 1985, 28: 1558) used ethyl α-(2,4-dichloro-5-fluorobenzoyl) acetate as raw material, reacted with triethyl orthoformate, and then reacted with ethyl Amine reaction, cyclization, hydrolysis, and reaction with piperazine, the raw materials of this route are not easy to obtain
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

[0016] 1) Add 43.2g of sodium methoxide into a 1L four-neck flask, add 90.0g of dimethyl carbonate, and then add 400ml of toluene. Stir and heat up to 70°C, add dropwise 41.4g of 2,4-dichloro-5-fluoroacetophenone toluene solution (toluene is 100ml), dropwise time is 5 hours, after dropping, raise the temperature to 80°C, and keep it warm for 2 hours After the reaction was completed, 300ml of water was added to adjust the pH to 5. The toluene layer was separated and concentrated to dryness to obtain 47.8g of methyl 2,4-dichloro-5-fluorobenzoylacetate, with a yield of 90.3%.

[0017] 2) Add 64.3g N, N'-dimethylformamide dimethyl acetal, 170ml toluene to 47.8g 2,4-dichloro-5-fluorobenzoic acid methyl ester, reflux for 2 hours, concentrate and reclaim toluene and N,N'-Dimethylformamide dimethyl acetal. At room temperature, 34.2 g of ethylamine-toluene solution (containing 80 ml of toluene) was added dropwise, and the temperature was raised to 40° C. for 2 hours for reaction after...

Embodiment 2

[0022] 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. Stir and heat up to 90°C, add dropwise 41.4g of 2,4-dichloro-5-fluoroacetophenone toluene solution (toluene is 100ml), dropwise time is 5 hours, after dropping, raise the temperature to 70°C, and keep warm for 2 hours After the reaction was completed, 300ml of water was added to adjust the pH to 6. The toluene layer was separated and concentrated to dryness to obtain 39.6g of methyl 2,4-dichloro-5-fluorobenzoylacetate, with a yield of 75.1%.

[0023] 2) Add 17.9g N, N'-dimethylformamide dimethyl acetal, 170ml toluene to 39.6g 2,4-dichloro-5-fluorobenzoic acid methyl ester, reflux for 3 hours, concentrate and reclaim toluene. At room temperature, 34.2 g of ethylamine-toluene solution (containing 80 ml of toluene) was added dropwise, and the temperature was raised to 50° C. for 2 hours for reaction after dropping. Concentrate under reduced pressure...

Embodiment 3

[0028] 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. Stir and heat up to 80°C, add dropwise 41.4g of 2,4-dichloro-5-fluoroacetophenone toluene solution (100ml of toluene), dropwise for 5 hours, raise the temperature to 90°C after dropping, and keep warm for 2 hours After the reaction was completed, 300ml of water was added to adjust the pH to 5. The toluene layer was separated and concentrated to dryness to obtain 47.3g of methyl 2,4-dichloro-5-fluorobenzoylacetate, with a yield of 90.0%.

[0029] 2) Add 47.6g N, N'-dimethylformamide dimethyl acetal, 170ml toluene to 47.3g 2,4-dichloro-5-fluorobenzoic acid methyl ester, reflux for 3 hours, concentrate and reclaim toluene and N,N'-Dimethylformamide dimethyl acetal. At room temperature, 34.2 g of ethylamine-toluene solution (containing 80 ml of toluene) was added dropwise, and the temperature was raised to 40° C. for 2 hours for reaction ...

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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 Applications(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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