New method for synthesizing besifloxacin

A technology of besifloxacin and synthetic method, applied in the field of preparation of besifloxacin, can solve the problems of difficult nucleophilic substitution, harsh reaction conditions, long reaction time, etc., and reduce the process and reaction conditions of chiral resolution Gentle, easy-to-go effect

Inactive Publication Date: 2013-04-17
FARMASINO PHARMA ANHUI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The key intermediate of this route is obtained from the starting material 5-chloro-2,4,-dimethylbenzoic acid as a raw material, because the reactivity of chlorine is low, and nucleophilic

Method used

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  • New method for synthesizing besifloxacin
  • New method for synthesizing besifloxacin
  • New method for synthesizing besifloxacin

Examples

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Effect test

Embodiment 1

[0017] Example 1 L-lysine methyl ester (VI).

[0018] Dissolve L-lysine (1.46g, 0.01mol) in methanol (20ml), add thionyl chloride dropwise to the reaction solution at room temperature, after the dropwise addition, react at room temperature for 2 hours, TLC detection After the reaction was completed, the reaction solution was concentrated to obtain the crude compound VI (1.5 g, yield 84.4%).

Embodiment 2

[0019] Example 2 L-type aminocaprolactam (VII).

[0020] Dissolve L-lysine methyl ester (1.6g, 0.01mol) in methanol (40ml), stir well so that the solid material is fully dissolved, then add (1.08g, 0.02mol) sodium methoxide to the reaction solution, at room temperature Stir evenly, react at room temperature for 5 hours, then raise the temperature to 80°C and react for 12 hours, then cool down to 0°C, a white solid precipitates, filters, and washes with a little methanol to obtain the crude product of compound VII (0.98g, yield 76.6%).

Embodiment 3

[0021] Example 3 (R)-7-(3-aminohexahydro-1H-azepine-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3quine Phinolic acid (III).

[0022] Dissolve intermediate II (2.83g, 0.01mol) in acetonitrile (30ml), stir until intermediate II is completely dissolved, then slowly add side chain L-type aminocaprolactam (2.58g, 0.02mol) dropwise to the reaction solution, After the dropwise addition is complete, add triethylamine (3.03g, 0.03mol) to the reaction solution, stir well, heat and reflux for 10 hours, after TLC detects that the reaction is complete, concentrate the reaction solution, add 80ml of dichloromethane, and saturate with NaCl Solution (50ml*3) washed the organic phase, dried the organic phase with anhydrous sodium sulfate, and concentrated the reaction solution to obtain the crude compound III (2.8 g, yield 77.9%).

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Abstract

The invention relates to a method for synthesizing an anti-infective drug, namely besifloxacin. The method comprises the steps of taking 2,4,5-trifluorobenzoic acid as a starting material, condensing L-amino caprolactam and 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinoline carboxylic acid to obtain (R)-7-(3-amino hexahydro-1H-azepine-1-yl)-1-cyclopropyl-6-fluorine-1,4-dihydro-4-oxygen-3-cinchoninic acid, and chloridizing with chlorosulfonic acid to obtain the final product besifloxacin. According to the new method for synthesizing the besifloxacin, the preparation method is simple, the reaction is easy to control, an intermediate is stable and easy to obtain, the yield is higher, and industrial production, storage and transportation are facilitated.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of besifloxacin. Background technique [0002] The chemical name of besifloxacin is (R)-7-(3-aminohexahydro-1H-azepan-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4 -Dihydro-4-oxo-quinoline-3-carboxylic acid, whose structural formula is: [0003] [0004] Besifloxacin is a broad-spectrum antibacterial agent for the treatment of bacterial conjunctivitis. Compared with other quinolones, it has equivalent or stronger antibacterial effect on G+ bacteria, G- bacteria and anaerobic bacteria that are easy to cause conjunctivitis. For some strains resistant to quinolones, Also has antibacterial effect. Besifloxacin hydrochloride was developed by Bausch & Lomb Inc. of the United States and was approved for marketing by the Food and Drug Administration of the United States on May 28, 2009. The trade name of the drug is Besi-vance, which is 0.6% besifloxacin hydroch...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 燕立波王丽南秋利程思
Owner FARMASINO PHARMA ANHUI
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