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Preparation method of high-purity delafloxacin meglumine salt

A delafloxacin, high-purity technology, applied in the field of medicinal chemistry, can solve the problems of solvent residue, low yield, unsuitable for industrial production, etc., and achieve the effect of simple operation, high yield and remarkable refining effect

Active Publication Date: 2016-12-28
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solvent introduced by this method, such as N-N dimethylacetamide, has a high boiling point and is not easy to remove. There is a risk of solvent residue. At the same time, the temperature is high, the energy consumption is large, and the yield is not high.
[0015] Although the above-mentioned 3 kinds of methods obtain the delafloxacin meglumine salt of pharmaceutical grade by refining delafloxacin, there are still the defects of low yield, residual solvent, large energy consumption and unsuitability for industrialized production. , it is necessary to find a more optimized method to obtain pharmaceutical grade delafloxacin meglumine salt

Method used

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  • Preparation method of high-purity delafloxacin meglumine salt
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  • Preparation method of high-purity delafloxacin meglumine salt

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Experimental program
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Effect test

Embodiment 1

[0043] Embodiment 1 The preparation of the compound of formula 1, wherein, R1 is ethyl, R2 is isobutyryl, and the reaction formula is as follows:

[0044]

[0045]In a 100L reactor, add 5.0Kg (9.9mol) of the compound of formula 4, 25Kg ethyl acetate and 500g sulfuric acid in sequence, stir at room temperature, and slowly add dropwise a solution of 1.7Kg NCS (12.8mol) dissolved in 25Kg methyl acetate. After the dropwise addition, the mixture was stirred at room temperature for 5 hours, washed with sodium bicarbonate solution, sodium sulfite solution and saturated brine, and the organic phase was concentrated to dryness to obtain 5.0 Kg of the crude compound of formula 1 with a purity of 97%.

Embodiment 2

[0046] Embodiment 2 The purification of the compound of formula 1

[0047] Put 1Kg of the crude compound of formula 1 prepared in Example 1 into a 20L reaction flask, add 2L methanol, 3L water, heat to 50°C, turn off the heating after stirring for 1 hour, slowly cool down to room temperature, crystallize in an ice-water bath for 5h, pump After filtering, the filter cake was washed with a small amount of cold methanol, sucked dry, and the filter cake was dried under reduced pressure to constant weight to obtain 930 g of a light yellow powder with a yield of 93% and an HPLC purity of 99.1%.

Embodiment 3

[0048] Embodiment 3 The refining of formula 1 compound

[0049] Put 1Kg of the crude compound of formula 1 prepared in Example 1 into a 20L reaction flask, add 6L ethanol and 2L water, heat to 60°C and stir for 1 hour, then turn off the heating, slowly cool down to room temperature, crystallize in an ice-water bath for 7h, and filter with suction. The filter cake was washed with a small amount of cold ethanol, sucked dry, and the filter cake was dried under reduced pressure to constant weight to obtain 900 g of a light yellow powder with a yield of 90% and an HPLC purity of 99.3%.

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Abstract

The invention relates to a method for refining a delafloxacin intermediate compound shown in a formula I. The method comprises the following steps: dissolving the compound in the formula I in a good solvent, mixing the compound with a poor solvent, heating a mixture and stirring the mixture, cooling the mixture for devitrification, and separating the mixture for crystallization. The refined compound in the formula I is hydrolyzed to obtain the high-purity delafloxacin, the high-purity delafloxacin and meglumine are subjected to a reaction to generate the delafloxacin meglumine salt, and the purity of the delafloxacin meglumine salt is greater than 99.5%. The method can effectively remove the impurity, an introduced solvent and an introduced reagent are little, yield is high, the process operation is simple, and the preparation cost is effectively reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for refining delafloxacin intermediates and a preparation method for delafloxacin meglumine salt. Background technique [0002] Delafloxacin (Delafloxacin), chemical name: 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine Alkyl-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, the structural formula is shown in 2, and its corresponding meglumine salt structure is shown in formula 3: [0003] . [0004] Delafloxacin is a fluoroquinolone compound developed by Wakunaga Pharmaceutical Co., Ltd. of Japan. It is currently being developed by Melinta Therapeutics, which has obtained the QIDP qualification from the US FDA and is in phase III clinical research. Its mechanism of action is the same as that of other fluoroquinolones. It acts on bacterial DNA gyrase and topoisomerase IV. Its outstanding enzyme inhibitory activity can redu...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 潘元左小勇张上华张小成付廷印李卉时俊鹏
Owner CHONGQING PHARMA RES INST
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