Preparation of Everolimus

A technology of rapamycin and eluent, applied in the field of preparation of everolimus, can solve the problems of low yield, high cost, unsuitable for industrialized production and the like, and achieve the effect of reducing cost and improving utilization rate

Inactive Publication Date: 2011-07-20
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the reported preparation process of everolimus is not suitable for industrial production due to low yield...

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1. The preparation of intermediate

[0020] In a 100ml single-necked flask, add 4.61g of rapamycin and 8.64g of 2-(tert-butyldiphenylsilyl)oxyethyl trifluoromethanesulfonate respectively, then add 80ml of toluene solvent, room temperature Stirring, the solution is a milky white suspension. Then add 4.28g of diisopropylethylamine, heat up and stir, control the temperature between 50°C and 60°C, and react for 6 hours. After cooling to room temperature, the reaction solution was a light yellow clear solution. Add 100ml of ethyl acetate, wash the organic phase with 0.5M hydrochloric acid, saturated sodium bicarbonate solution and water respectively, and finally wash with saturated brine, dry with anhydrous magnesium sulfate for 6 hours, filter and concentrate under reduced pressure to obtain light yellow viscous liquid. Column chromatography, the eluent is petroleum ether and ethyl acetate (5:3), the intermediate components are separated and collected, and the...

Embodiment 2

[0022] Example 2. Preparation of Everolimus

[0023] In a 100ml single-necked flask, 1.75g ​​of the intermediate was dissolved in 60ml of tetrahydrofuran under cooling in an ice bath, and 6ml of pyridine hydrogen fluoride solution was added under stirring. The mixed solution was reacted at 0°C for half an hour, and then stirred overnight at room temperature. The reaction solution was poured into a mixed solution composed of 200ml ethyl acetate and 200ml saturated sodium bicarbonate solution, the organic phase was separated, and the aqueous phase was extracted 3 times with ethyl acetate (50ml / time). The organic phases were combined, washed with 1M hydrochloric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution respectively, dried with anhydrous magnesium sulfate for 3 hours and filtered, and the filtrate was concentrated to obtain a yellow mucus. Column chromatography separation, ethyl acetate as eluent. The solvent was removed by evapor...

Embodiment 3

[0024] Embodiment 3. The recovery of rapamycin raw material and apply mechanically to prepare intermediate

[0025] In a 50ml single-necked flask, add the 1.00g rapamycin recovered from Example 1, then add 1.89g 2-(tert-butyldiphenylsilyl)oxyethyl trifluoromethanesulfonate, 15ml toluene And 0.94g diisopropylethylamine, repeat the method described in Example 1 to carry out reaction and aftertreatment. The intermediate components were concentrated under reduced pressure to obtain 0.35 g of foamy white solid (yield: 27.0%), and the raw material components were concentrated under reduced pressure to obtain 0.15 g of white solid rapamycin (recovery rate: 15%) .

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Abstract

The invention relates to an effective preparation method of a medicine, namely, Everolimus. The preparation method comprises: reacting rapamycin, diisopropylethylamine and 2-(tert-butyldiphenylsilyl)ethoxytrifluoromethanesulfonate at 50 to 60 DEG C in toluene, and obtaining the intermediate represented by a formula (1) by separation by column chromatography; and reacting the intermediate with hydrogen fluoride-pyridine at 0 DEG C in tetrahydrofuran, reacting at room temperature and obtaining Everolimus represented by the formula (2) by separation by column chromatography. The preparation method has the advantages that: the yield is high; and the part of rapamycin serving as an initiative raw material can be recycled.

Description

technical field [0001] The invention relates to an effective preparation method of medicine everolimus. Background technique [0002] Everolimus is an orally effective analogue of rapamycin, which belongs to the new generation of macrolide immunosuppressants and antineoplastic drugs. The drug was developed by Novartis Corp. of Switzerland and first launched in Germany in March 2004. So far, it has been clinically used in dozens of countries around the world. It is mainly suitable for adults with mild to moderate immune risks in kidney, liver and Prevention of organ rejection in heart transplant recipients. So far, the patents related to the preparation of everolimus are GB92212208 (WO9409010). In addition, Hungary Tewa Pharmaceutical Co., Ltd. has applied for an invention patent in China on the crystallization and purification method of macrolide substances (including everolimus) (publication number CN1768066). In addition, there are also published papers (J.Labelled Comp...

Claims

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Application Information

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IPC IPC(8): C07D498/18
Inventor 苟少华诸海滨
Owner SOUTHEAST UNIV
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