Everolimus crystallization purification method

A technology for everolimus and a purification method, which is applied in the field of everolimus crystallization and purification, can solve problems such as difficulty in purification of everolimus, and achieve the effects of good crystallization effect, removal or reduction of other impurities, and low cost.

Active Publication Date: 2013-10-23
CHENGDU YATU BIOLOGICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Obviously, unstable structures such as ethylenic bonds and ester bonds in the structure of everolimus have brought great difficulties to the purification of everolimus

Method used

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  • Everolimus crystallization purification method
  • Everolimus crystallization purification method
  • Everolimus crystallization purification method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] 20 g of the synthesized everolimus raw material was subjected to normal phase column chromatography. The normal-phase silica gel is ordinary normal-phase silica gel, the particle size is 200-300 mesh, and the dosage of silica gel is 200 g; the chromatography resolver is: ethyl acetate:petroleum ether=7:3. Collected in sections to obtain 10 g of crude everolimus (the content of everolimus is 95.51%, the content of isomers is 3.35%, and the content is determined by the area normalization method).

[0060] Take 5 g of the above-mentioned crude everolimus, dissolve the crude everolimus in 50 ml of methanol containing 5‰ V / V of water, wherein the pH value of the water is 3.0, adjust with glacial acetic acid, and stir for 2 hours at 5°C; Add 250ml of n-heptane to the above solution, continue to stir until a small amount of crystals are precipitated, then use ultrasonic crystallization until a large amount of crystals are precipitated, and filter to obtain 4.62g of everolimus ...

Embodiment 2

[0062] Take 5 g of the crude everolimus product described in Example 1, dissolve the crude product of everolimus with 50 ml of ethanol containing 6‰ V / V of water, wherein the pH value of the water is 3.0, adjust with glacial acetic acid, and stir at 7°C for 2.5 h; add 300ml of n-heptane to the above solution, continue to stir until a small amount of crystals form, then use ultrasonic crystallization until a large amount of crystals are precipitated, filter to obtain 4.65g of everolimus finished product (wherein, the content of everolimus is 98.98%, the content of isomers is 0.39%, and the individual content of other impurities is less than 0.2%, and the content is determined by the area normalization method).

Embodiment 3

[0064] 220 g of the synthesized everolimus raw material was subjected to normal phase column chromatography. The normal-phase silica gel is ordinary normal-phase silica gel, the particle size is 200-300 mesh, and the amount of silica gel is 2.2 kg; the chromatographic analytical solvent is: ethyl acetate:petroleum ether=7:3. Collected in sections to obtain 105 g of crude everolimus (wherein, the content of everolimus is 95.11%, and the content of isomers is 4.87%, and the content is determined by the area normalization method).

[0065] Take 50 g of the crude everolimus above, and dissolve the crude everolimus with 500 ml of isopropanol containing 7‰ V / V of water, wherein the pH of the water is 3.0, adjust with glacial acetic acid, and stir for 3 hours at 8°C; Then add 4000ml of n-hexane to the above solution, continue to stir until a small amount of crystals form, then use ultrasonic crystallization until a large amount of crystals are precipitated, filter to obtain 47.45g of...

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Abstract

The invention aims at overcoming everolimus crystallization difficulties caused by unstable structures such as olefinic bond and ester bond in the everolimus structure, and provides an everolimus crystallization purification method. According to the invention, a synthesized everolimus raw material is treated through normal-phase column chromatography, such that an everolimus crude product is obtained; the everolimus crude product is dissolved by using a water-containing organic solvent under low temperature, and sufficient stirring is carried out; an alkane organic is added to the everolimus solution, and stirring is continued; when a small amount of crystals appear, crystallization is changed into ultrasonic crystallization; and filtering is carried out, such that the everolimus finished product is obtained. With the method provided by the invention, everolimus crystal conversion to isomer is blocked, and the conversion from isomer to everolimus crystal is realized. Also, significant effect is provided on removing or reducing other impurities. The method also has the advantages of good crystallization effect, high yield, low cost, and low requirement on equipment.

Description

technical field [0001] The invention relates to an everolimus crystallization purification technology, in particular to an everolimus crystallization purification method. Background technique [0002] The commercial name of everolimus (everolimus) is Afinitor, and its molecular formula is C 53 h 83 NO 14 , with a relative molecular mass of 958.2, is derived from the precursor compound rapamycin (extracted from actinomycetes), therefore, everolimus is a semi-synthetic biological product. Everolimus was first developed by Novartis, Switzerland, and is mainly used to prevent rejection after kidney transplantation and heart transplantation. In addition, it can also be used for the treatment of patients with advanced kidney cancer. The mechanism of action of everolimus is to inhibit the expression of a mTOR protein kinase, thereby stopping protein synthesis and cell proliferation. Compared with traditional immunosuppressants, its oral dose and frequency of administration are ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18
Inventor 朱辉张翠英朱宇赵磊杨正强母荣光罗欢曹艳茹谢怀杰朱华勇
Owner CHENGDU YATU BIOLOGICAL TECH
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