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Purification salt conversion method of micafungin

A micafungin and salt conversion technology, which is applied in the field of medicinal chemistry, can solve the problems of easy hydrolysis, unfavorable product quality control, and unfavorable industrial scale-up production, etc., and achieve the effect of ensuring product quality

Active Publication Date: 2016-01-20
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, micafungin is prone to hydrolysis in the preparation environment to generate impurity compounds III and IV (its structure is shown below), which is not conducive to product quality control
And use a large amount of sodium chloride, which is very corrosive to the preparation of the liquid phase system, which is not conducive to industrial scale-up production

Method used

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  • Purification salt conversion method of micafungin
  • Purification salt conversion method of micafungin
  • Purification salt conversion method of micafungin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Preparation of 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzoic acid-1-benzotriazole ester

[0058]

[0059] Add 4-(5-(4-(pentyloxy)phenyl) isoxazol-3-yl) benzoic acid-1-benzoic acid 0.61kg, DMF5L, THF5L, HOBt0.35kg and EDC.HCl0.61kg, react at room temperature for 3-3.5 hours. After the reaction, 20 L of ethyl acetate and 5 L of purified water were added, filtered and dried to obtain 680 g of the white target product.

Embodiment 2

[0060] Embodiment 2: the preparation of compound II

[0061]

[0062] Add FR1796421.00kg (calculated as anhydrous matter) and DMF10L into a 30L glass reactor, stir and dissolve, and then add DIPEA (N,N-diisopropylethylamine) 0.21kg. Cool the reaction solution to 0-20°C, add the intermediate ① obtained in the previous step, and control the reaction temperature to 0-20°C.

[0063] After the reaction was completed, the reaction solution was poured into 100L of ethyl acetate, and a white solid was precipitated. The white solid was obtained by filtration and dried in vacuo to obtain 1500 g of Compound II.

Embodiment 3

[0064] Embodiment 3: conversion salt purification

[0065]

[0066] Dissolve 500g of compound II in purified water, apply the sample, and elute under the chromatographic conditions in the table below to collect the target components.

[0067]

[0068]

[0069] The prepared solution was collected and concentrated to dryness under reduced pressure to obtain the white product micafungin sodium, which was dried to obtain 235 g.

[0070] Gained sample carries out RP-HPLC detection, and purity: 99.1%, and its pattern is as follows image 3 shown.

[0071] Residue on ignition of the sample obtained: 5.5%.

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Abstract

The present invention relates to a purification salt conversion method of micafungin. According to the present invention, the method is mainly characterized in that a buffer solution of a corresponding salt and a micafungin N, N-diisopropylethylamine salt are subjected to ion exchange on a reverse phase preparative chromatographic column so as to complete salt conversion, remove the related impurities, and achieve the purification effect; and the process has characteristics of stable and controllable process, easy and convenient operation, easy industrial production achieving, and easy product quality control.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for purifying and converting micafungin salt. Background of the invention [0002] Micafungin sodium is an echinocandin antibacterial drug that inhibits the growth of pathogenic fungi by inhibiting the synthesis of fungal cell walls. Clinically used to treat the following infections caused by Aspergillus and Candida: fungemia, respiratory mycosis, gastrointestinal mycosis. With its strong anti-fungal infection and drug safety, the drug has become the drug of choice for the treatment of invasive fungal infections in ICU, and has broad market prospects. [0003] Micafungin Sodium was developed by Astellas, Japan, and has been marketed in many places. Its structural formula is shown in compound I: [0004] [0005] Various methods for the preparation and purification of micafungin sodium have been reported and disclosed, such as patents WO9611210, WO2004014879 and p...

Claims

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Application Information

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IPC IPC(8): C07K7/56C07K1/20
Inventor 周明孙长安王瑞军朱后田
Owner JIANGSU HANSOH PHARMA CO LTD
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