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Preparation method of besifloxacin hydrochloride

A technology of besifloxacin hydrochloride and quinoline carboxylic acid, which is applied in the field of compound preparation, can solve problems such as expensive, difficult to reproduce, and difficult to obtain, and achieve the effects of less impurities, easy operation, and less side reactions

Inactive Publication Date: 2015-05-06
广州仁恒医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Starting material 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid-O3,O4-diacetate Boroesters are very expensive, not readily available, and the method is difficult to reproduce

Method used

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  • Preparation method of besifloxacin hydrochloride
  • Preparation method of besifloxacin hydrochloride
  • Preparation method of besifloxacin hydrochloride

Examples

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preparation example Construction

[0041] See figure 1 , which is a synthetic route diagram of the preparation method of besifloxacin hydrochloride in the embodiment of the present invention, and the synthetic route diagram does not include the resin activation step of step (1).

[0042] The preparation method of besifloxacin hydrochloride provided by the present invention first connects 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid Activated 4-(bromomethyl)phenoxymethyl polystyrene resin with (R)-3-tritylaminohexahydroazepine The resin obtained by solid phase condensation is cracked under acidic conditions and the protective group trityl group is removed simultaneously to obtain (R)-7-(3-aminohexahydro-1H-aza -1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-carboxylic acid quinoline, and then chlorinated under the effect of thionyl chloride to form (R )-7-(3-Aminohexahydro-1H-aza -1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-carboxylic acid quinoline hydrochloride...

Embodiment 1

[0044] The preparation method of the besifloxacin hydrochloride that the embodiment of the present invention provides, comprises the following steps:

[0045] (1) Resin activation: take 13 g of 4-(bromomethyl) phenoxymethyl polystyrene resin, place it in anhydrous DMF to expand for 1.5 h, and then wash it twice with anhydrous DMF;

[0046] 4-(bromomethyl) phenoxymethyl polystyrene resin is from Novabiovchem company #01-64-0186, 150 mesh, 1.2meq / gram;

[0047] (2), preparation of quinoline carboxylic acid resin: add 180mL DMF to the activated resin in step (1), then add 4g 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydro-4 - Oxygen-3-quinoline carboxylic acid, treated with cesium carbonate, stirred at room temperature for 2 h, filtered with 50% DMF / water mixture, DMF, methanol and DCM, washed 3 times in turn, and filtered the obtained quinoline carboxylic acid resin ;

[0048] (3) Solid phase condensation: Add quinoline carboxylic acid resin to 200mL DCM / DMF mixture, add 20g (...

Embodiment 2

[0054] The preparation method of the besifloxacin hydrochloride that the embodiment of the present invention provides, comprises the following steps:

[0055] (1) Resin activation: take 10 g of 4-(bromomethyl) phenoxymethyl polystyrene resin, place it in anhydrous DMF to expand for 1 hour, and then wash it with anhydrous DMF for 4 times;

[0056] 4-(bromomethyl) phenoxymethyl polystyrene resin is from Novabiovchem company #01-64-0186, 100 mesh, 1.2meq / gram;

[0057] (2), preparation of quinoline carboxylic acid resin: add 200mLDMF to the activated resin in step (1), then add 5g 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydro-4 - Oxygen-3-quinoline carboxylic acid, treated with cesium carbonate, stirred at room temperature for 2 hours, filtered with 50% DMF / water mixture, DMF, methanol and DCM, washed twice and then filtered to obtain quinoline carboxylic acid resin;

[0058] (3) Solid phase condensation: Add quinoline carboxylic acid resin to 250mL DCM / DMF mixture, add 30g (R...

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Abstract

The invention discloses a preparation method of besifloxacin hydrochloride. The preparation method comprises the following steps: firstly connecting 1-cyclopropyl-6, 7-difluoro-8-chloro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid on activated 4-(bromomethyl) phenoxymethyl polystyrene resin, further performing solid-phase condensation with (R)-3-triphenylmethyl aminohexahydroazepine to obtain resin, then performing pyrolysis under acidic conditions, simultaneously removing a protective group, namely triphenylmethyl to obtain (R)-7-(3-aminohexahydro-1H-azepine)-1-yl)-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, further performing chlorination under the action of thionyl chloride, and forming a hydrochloride. Compared with the prior art, according to the preparation method of besifloxacin hydrochloride, raw materials are relatively easy to obtain, the side reactions in solid-phase synthesis are relatively few, the separation difficulty is greatly reduced, solid-phase resin can be further reused, the cost is low and the product yield is high.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to a preparation method of besifloxacin hydrochloride. Background technique [0002] The chemical name of besifloxacin hydrochloride is (R)-7-(3-aminohexahydro-1H-aza -1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dichloro-4-oxo-3-carboxylic acid quinoline hydrochloride, was produced by Bausch & Lomb in 2009 ( Bausch & Lomb) is listed in the United States under the trade name Besivance, which interferes with the synthesis of bacterial DNA by acting on the gyrase and topoisomerase IV of the DNA of Gram-negative and positive bacteria, thereby achieving the sterilization effect. The U.S. Food and Drug Administration has approved besifloxacin 0.6% ophthalmic suspension for the treatment of bacterial conjunctivitis; besifloxacin has a different mechanism of action than aminoglycosides, macrolides, and β- Lactam antibiotics are active against pathogens resistant to these antibiotics and...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCY02P20/55C07D401/04
Inventor 田元
Owner 广州仁恒医药科技股份有限公司
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