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Process for preparing hemihydrate of levofloxacin

A technology for preparing levofloxacin and its preparation technology, which is applied in the field of preparation technology of levofloxacin hemihydrate, which can solve the problems of unfavorable quality and yield of levofloxacin hemihydrate finished product, complicated operation procedures, difficult microbial degradation, etc., and achieve mild polarity, color and luster Good, good solubility effect

Inactive Publication Date: 2008-11-19
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Through the analysis of the above patent documents, it is concluded that there are mainly the following defects: first, the operating procedures in the industrial production process are relatively complicated, and the production cycle is relatively long; , and it is difficult to recycle; thirdly, using halogenated hydrocarbons, DMSO and DMA as organic solvents, it is not only difficult for microorganisms to degrade when discharged into wastewater, but also inhibits or even poisons the growth of microorganisms; fourthly, using polar solvents that are too strong The crude product of levofloxacin synthesized by crystallization and purification with an organic solvent with too weak polarity is not conducive to the improvement of the quality and yield of the finished product of levofloxacin hemihydrate

Method used

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  • Process for preparing hemihydrate of levofloxacin

Examples

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Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 n-Butanol: Water (90:10, w / w)

[0022] 50 grams of levofloxacin (0.1778 moles), 36 grams of N-methylpiperazine (0.3594 moles) were dropped into 1000 milliliters of reaction flasks equipped with a reflux device, then 500 g of DMF was added, stirred, heated and heated at 90 ~95°C heat preservation reaction for 6 hours. After the reaction is complete, recover the solvent under reduced pressure to dryness, add 400 ml of water to the residue in the bottle, stir at 60-65°C until the system is basically clear, add 1 g of activated carbon, keep warm for 0.5 hours to decolorize, filter, and add 500 ml of water to the filtrate Chloroform, stirred and extracted for 1 hour, the water layer was adjusted to pH 7.0-8.0 with liquid caustic soda, the extracted oil layer was stirred and washed with 300 ml of water for 15 minutes, left to stand for 1 hour, the organic layer of chloroform was separated, and heated and recovered to dryness to obtain Crude levofloxacin. Add 450 g...

Embodiment 2

[0023] Example 2 Isobutanol: water (90:10, w / w)

[0024] 50 grams of levofloxacin (0.1778 moles), 45 grams of N-methylpiperazine (0.4493 moles) were dropped into 1000 milliliters of reaction flasks equipped with a reflux device, then 450 g of DMSO was added, stirred, heated and heated at 100 ~105°C heat preservation reaction for 4 hours. After the reaction is complete, recover the solvent under reduced pressure to dryness, add 320 ml of water to the residue in the bottle, stir at 70-75°C until the system is basically clear, add 1.5 g of activated carbon, keep warm for 0.5 hours to decolorize, filter, and add 500 ml of water to the filtrate Dichloromethane, stirred and extracted for 1 hour, the water layer was adjusted to pH 7.0-8.0 with liquid alkali, the extracted oil layer was stirred and washed with 350 ml of water for 15 minutes, left to stand for 1 hour, the organic layer of dichloromethane was separated, and heated and recovered to dryness to obtain Crude levofloxacin. ...

Embodiment 3

[0025] Example 3 tert-butanol: water (90:10, w / w)

[0026]50 grams of levofloxacin (0.1778 moles) and 60 grams of N-methylpiperazine (0.5990 moles) were dropped into 1000 milliliters of reaction flasks equipped with a reflux device, then 550 g of DMSO was added, stirred, heated and heated at 100 ~105°C heat preservation reaction for 3.5 hours. After the reaction is complete, recover the solvent under reduced pressure to dryness, add 320 ml of water to the residue in the bottle, stir at 70-75°C until the system is basically clear, add 1.5 g of activated carbon, keep warm for 0.5 hours to decolorize, filter, and add 600 ml of water to the filtrate Toluene, stirred and extracted for 1 hour, the water layer was adjusted to pH 7.0-8.0 with liquid alkali, the extracted oil layer was stirred and washed with 400 ml of water for 15 minutes, left to stand for 1 hour, the toluene organic layer was separated, heated and recovered to dryness, and the crude product of levofloxacin was obtai...

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Abstract

The invention discloses a process for preparing a levofloxacin hemihydrate. The prior method which uses an organic solvent with stronger polarity or weaker polarity to purify a levofloxacin crude product is disadvantageous to the quality and the yield of a levofloxacin hemihydrate finished product; the organic solvent with a higher boiling point not only consumes large energy, but also is difficult to reclaim, when the organic solvent is reclaimed. The method comprises the following steps of: dissolving the levofloxacin crude product into a dissolvent system consisting of water and an organic solvent, wherein the organic solvent selects any composition or multiple compositions of normal butanol, isobutyl alcohol, 2-butanol and tertiary butanol; and discoloring, filtering, crystallizing, crystal-growing, pumping filtering, rinsing and drying the mixed solution to produce an acicular levofloxacin hemihydrate crystal. The hydrous composite solvent adopted by the method has the advantages of suitable polarity, low boiling point, easy reclaiming and small energy consumption; and the product has high purity, and high bioavailability after a preparation which is prepared by the product is taken by a human body.

Description

technical field [0001] The invention discloses a preparation process in the preparation process of levofloxacin hemihydrate. Background technique [0002] Levofloxacin (Levofloxacin) is a high-efficiency, broad-spectrum, low-toxic antibacterial fluoroquinolone drug developed by Japan's Daiichi Pharmaceutical Company. Its chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3 -Methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3,-de]-[1,4]benzoxazine-6- Carboxylic acid (CAS Registry No. 100986-85-4). Levofloxacin includes anhydrous levofloxacin and levofloxacin hydrate, anhydrous levofloxacin has polymorphism, and its crystal forms include α-type, β(b) and γ(g)-type, and levofloxacin hydrate includes levofloxacin hemihydrate and levofloxacin Monohydrate, its crystal form is a pseudopolymorph. The crystal forms of levofloxacin are not fixed, and they can be transformed into each other under certain conditions. In the case of continuous heating, the pseudopolymorph levofloxaci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/06A61P31/04
Inventor 张永塘刘杰吴源王小祥施燕忠丁伟东
Owner ZHEJIANG JINGXIN PHARMA
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