Preparation method of sitafloxacin intermediate

A technology of sitafloxacin and intermediates, which is applied in the field of preparation of intermediates, can solve the problems of low product yield, cumbersome post-processing, many side reactions, etc., and achieves high solvent recovery rate, simple post-processing and low price. Effect

Active Publication Date: 2019-02-01
JIANGXI FUSHINE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The synthetic route of the prior art has disadvantages such as relatively long steps, cumbersome post-treatment, many side reactions, low p...

Method used

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  • Preparation method of sitafloxacin intermediate
  • Preparation method of sitafloxacin intermediate
  • Preparation method of sitafloxacin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Add (21g, 0.10mol) 3-chloro-2,4,5-trifluorobenzoic acid, 210ml dichloromethane and 1ml DMF into a 500ml four-neck flask, stir until dissolved, cool down to 0-10°C, and slowly add (13.1g, 0.11mol) thionyl chloride, dropwise completed, transferred to room temperature for 3h reaction, dichloromethane was distilled off at 55-60°C under normal pressure, and excess thionyl chloride was distilled off under reduced pressure to obtain the intermediate Acyl chloride (IV), add 100ml of dichloromethane distilled out into the reaction bottle, stir, and make a solution for later use.

[0038] Add (23.4g, 0.105mol) ethyl 3-bromo-2-ethoxyacrylate (V) and 100ml dichloromethane into a 500ml reaction flask, stir evenly, cool down to 0-10°C, add (6.8g, 0.105mol ) zinc powder, stirred for 0.5h, slowly added dropwise the intermediate acid chloride (IV) solution, the dropwise addition was completed, transferred to react at room temperature for 2h, filtered, added 100ml of water in the filtrat...

Embodiment 2

[0041] Add (21g, 0.10mol) 3-chloro-2,4,5-trifluorobenzoic acid, 210ml dichloromethane and 1ml DMF into a 500ml four-neck flask, stir until dissolved, cool down to 0-10°C, and slowly add (13.1g, 0.11mol) thionyl chloride, after the dropwise addition was completed, it was transferred to room temperature to react for 4 hours to obtain the intermediate acid chloride (IV) solution, which was ready for use.

[0042] Add (23.4g, 0.105mol) ethyl 3-bromo-2-ethoxyacrylate (V) and 100ml dichloromethane into a 500ml reaction flask, stir evenly, cool down to 0-10°C, add (7.2g, 0.11mol ) zinc powder, stirred for 1h, slowly added dropwise the intermediate acid chloride (IV) solution, after the dropwise addition was completed, transferred to react at room temperature for 3h, filtered, added 150ml of water in the filtrate, stirred, left to stand, layered, separated the organic phase, added Dry over anhydrous sodium sulfate, filter, and recover dichloromethane from the filtrate under normal pre...

Embodiment 3

[0044] Add (21g, 0.10mol) 3-chloro-2,4,5-trifluorobenzoic acid, 210ml dichloromethane and 1ml DMF into a 500ml four-neck flask, stir until dissolved, cool down to 0-10°C, and slowly add (13.4g, 0.105mol) oxalyl chloride, after the dropwise addition was completed, it was transferred to room temperature and reacted for 3h to obtain the intermediate acid chloride (IV) solution, which was ready for use.

[0045] Add (23.4g, 0.105mol) ethyl 3-bromo-2-ethoxyacrylate (V) and 100ml dichloromethane into a 500ml reaction flask, stir evenly, cool down to 0-10°C, add (7.2g, 0.11mol ) iron powder, stirred for 1h, slowly added dropwise the intermediate acid chloride (IV) solution, after the dropwise addition was completed, transferred to react at room temperature for 2h, filtered, added 150ml of water in the filtrate, stirred, left to stand, layered, separated the organic phase, added Dry over anhydrous sodium sulfate, filter, first recover dichloromethane from the filtrate under normal press...

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Abstract

The invention discloses a preparation method of a sitafloxacin intermediate, wherein the preparation method includes the steps: in the presence of low-valence metals or transition metals, 3-chloro-2,4,5-trifluorobenzoyl chloride undergoes a reaction with ethyl 3-bromo-2-ethoxyacrylate to obtain the sitafloxacin intermediate. Compared with the prior art, the preparation method of the sitafloxacin intermediate II has the advantages of simple synthetic route, mild reaction conditions, simple post-treatment, low energy consumption, high solvent recovery rate, low cost and easy availability of adopted raw materials and reagents. The preparation method provided by the invention has the yield of 96% or more, has the purity of the obtained product 99% or more after simple conventional post-treatment, is suitable for industrialized mass production and has good market prospects.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of an intermediate of sitafloxacin. Background technique [0002] Sitafloxacin, the chemical name is (-)-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1 -[(1R,2S)-2-Fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, a broad-spectrum product developed by Daiichi Pharmaceutical Sankyo Co., Ltd. Quinolones antibacterial drugs, which were first launched in Japan in 2008. Its 3 / 2 hydrate is clinically used for the treatment of severe and refractory bacterial infections, recurrent infections and certain drug-resistant bacterial infections. Sitafloxacin can inhibit bacterial DNA gyrase and topoisoenzyme, and its inhibitory effect on these two enzymes is stronger than that of other quinolones. [0003] Because sitafloxacin contains a cis-fluorocyclopropylamine group in its structure, it has good pharmacokinetic ...

Claims

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Application Information

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IPC IPC(8): C07C69/738C07C67/343C07C63/70C07C51/60
CPCC07C51/60C07C67/343C07C63/70C07C69/738
Inventor 李振业谢永居余翔张红卫余明远龚杰张桂菊曹敏刘婕
Owner JIANGXI FUSHINE PHARMA CO LTD
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