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Preparing methods and uses of S-(-)-nadifloxacin and water soluble salt thereof

A technology of nafloxacin and water-soluble salt, which is applied in the field of preparation of S--nafloxacin water-soluble salt, can solve the problem of poor effect of racemate nafloxacin, and achieve low gastrointestinal side effects , stable yield, and reduced toxic and side effects

Inactive Publication Date: 2008-11-05
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is in order to solve the problem that the effect of racemate nafloxacin is not good, provide a kind of S-(-)-nafloxacin with wider antibacterial spectrum, better bioavailability, stronger antibacterial activity Preparation

Method used

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  • Preparing methods and uses of S-(-)-nadifloxacin and water soluble salt thereof
  • Preparing methods and uses of S-(-)-nadifloxacin and water soluble salt thereof
  • Preparing methods and uses of S-(-)-nadifloxacin and water soluble salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of (±)-5,6-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline

[0034] Step 1: Preparation of 8-bromo-5,6-difluoro-2-methylquinoline

[0035]

[0036] Add 3,4-difluoro-6-bromophenylacetamide (160g, 0.64mol), sodium m-nitrobenzenesulfonate (144g, 0.64mol) into a three-necked flask equipped with stirring, condenser and dropping funnel , ferric sulfate heptahydrate (18g, 0.03mol), boric acid (174g, 2.81mol), water (560ml) and concentrated hydrochloric acid (560ml), heated to reflux under stirring conditions for 0.5 hour, slowly added dropwise crotonaldehyde at the same temperature (79ml, 0.97mol), the dropwise addition was completed in about 1 hour, and then refluxed for 1 hour, suction filtered while it was hot, the filtrate was cooled to room temperature, methanol (2300ml) was added, and then 25% sodium hydroxide solution was used to Adjust the pH value to about 10 to completely precipitate crystals, filter with suction, and wash twice with 5...

Embodiment 2

[0040] Example 2: Preparation of S-(-)-5,6-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (Method 1)

[0041]

[0042] Add 98 g (0.27 mol) of L-2,3-dibenzoyl tartaric acid to 200 mL of ethyl acetate and stir at room temperature to dissolve, then add (±)-5,6-difluoro-2-methyl-1,2 dropwise while stirring, 100 g (0.55 mol) of 3,4-tetrahydroquinoline, after dropping, stir at room temperature for 1 hr, collect the precipitated solid by filtration, wash with ethyl acetate, recrystallize with 70% ethanol, add 500 mL of water and 500 mL of ethyl acetate to the obtained solid and mix In the solution, adjust the pH to 9-10 with 20% NaOH solution under stirring, separate the organic layer, wash with saturated NaCl solution, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 38 g of light yellow oil. Yield: 38%, m.p.: 29-30°C, [a] D 20 =-36.4 (C=0.5, methanol), M+1: 184.09. Elemental analysis, calculated...

Embodiment 3

[0043] Example 3: Preparation of S-(-)-5,6-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (method 2)

[0044] Add 98 g (0.27 mol) of L-2,3-dibenzoyl tartaric acid to 200 mL of acetone and stir at room temperature to dissolve, then add (±)-5,6-difluoro-2-methyl-1,2,3 dropwise under stirring, 100 g (0.55 mol) of 4-tetrahydroquinoline, after dropping, stir at room temperature for 1 hr, collect the precipitated solid by filtration, wash with ethyl acetate, recrystallize with 70% ethanol, add the obtained solid to a mixed solution of 500 mL of water and 500 mL of ethyl acetate , adjust pH=9-10 with 20% NaOH solution under stirring, separate the organic layer, wash with saturated NaCl solution, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 37.5 g of light yellow oil. Yield: 37.5%, m.p.: 29-30°C, [a] D 20 =-36.6 (C=0.5, methanol), M+1: 184.09. Elemental analysis, calculated value (%): C, 65.56; H,...

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Abstract

The invention discloses a preparation method of an S-(-)-Nadifloxacin. 3, 4-difluoro-acetbromanilide is taken as initial material to be synthesized by quinoline, and hydrogenated to directly split out an optical active midbody, then is formed into a ring by oxymethylene, protected by carboxyl, condensed by 4-hydroxy piperidine and finally deprotected and hydrolyzed; the S-(-)-Nadifloxacin is used for reacting with the alkali allowed in medicine to prepare S-(-)-Nadifloxacin water-soluble salt; compared with the prior arts of synthesizing and splitting the Nadifloxacin, the materials of the invention are cheap and easily obtained; the reaction is mild; the yield of the splitting technique is stable; the optical purity is high; a splitting agent can be circularly used; the preparation method of the invention is suitable for industrialization production; the S-(-)-Nadifloxacin water-soluble salt is used in clinic; the antibiotic activity is greatly improved; the toxic and side effects are reduced; and simultaneously the increasing of the water-solubility even enlarges the application of the medicament forms.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method for synthesizing S-(-)-nafloxacin by splitting key intermediates and a preparation method for S-(-)-nafloxacin water-soluble salt. Background technique [0002] Quinolones are a class of fully synthetic antibacterial drugs. Since the discovery of the first quinolone antibacterial drug nalidixic acid in the United States in the 1960s, quinolones have been widely used in clinical practice. Quinolones antibacterial drugs have the advantages of broad antibacterial spectrum, strong antibacterial activity, convenient administration, no cross-resistance with commonly used antibacterial drugs, and lower price than antibiotics with comparable efficacy. [0003] According to Andriole, quinolones are divided into 4 generations according to the Andriole-Schellhore classification organized by Schellhore: [0004] The first generation: Nalidxic acid, Cinoxac...

Claims

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Application Information

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IPC IPC(8): C07D471/06A61K31/4745A61P31/00
Inventor 张孝清朱宏彬肖涛
Owner NANJING HUAWE MEDICINE TECH DEV
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