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Derivative compound of ethylene glycol

A compound and ethylene glycol technology, applied in the application field of the preparation of everolimus, can solve the problems of low yield of the target product, many by-products, poor stability, etc., achieve a reliable process route, less impurities, reduce degradation and The effect of impurity generation

Pending Publication Date: 2022-03-01
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the hydroxyethylation reaction of macrocyclic compounds disclosed in the prior art, especially the hydroxyl group in rapamycin derivatives, the yield of the target product is low due to the poor stability of the existing ethylene glycol derivatives, and there are many by-products and more difficult to remove

Method used

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  • Derivative compound of ethylene glycol
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  • Derivative compound of ethylene glycol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]Add 62.1g of ethylene glycol and 370ml of tetrahydrofuran into the round-bottomed flask, stir and cool down to -5~5°C, add 40g of sodium hydride in batches, after the addition is complete, slowly rise to room temperature, and continue the reaction until the reaction is complete (monitored by TLC) , cooled to 5 ~ 10 ° C, under stirring, dropwise added 850ml of Fmoc-Cl (284.57g) tetrahydrofuran solution, after the dropwise addition was completed, it was raised to room temperature, and the reaction was continued until the reaction was complete (monitored by TLC); filtered, the filtrate was collected, evaporated under reduced pressure Remove the solvent, add 900ml ethyl acetate and 500ml purified water to the residue, extract and separate the liquid, wash with 300ml saturated brine, add an appropriate amount of anhydrous sodium sulfate to dry, evaporate the solvent under reduced pressure, rectify under reduced pressure, and collect the vacuum The fraction not lower than -0.09...

Embodiment 2

[0044] In the round bottom flask, add 62.1g of ethylene glycol and 310ml of tetrahydrofuran, stir to cool down to -5~5°C, add 36g of sodium hydride in batches, after the addition is completed, slowly rise to room temperature, and continue the reaction. After the reaction is complete (monitored by TLC ), cooled to 5-10°C, under stirring, added dropwise 850ml of Fmoc-Cl (271.6g) tetrahydrofuran solution, after the dropwise addition was completed, it was raised to room temperature, and the reaction was continued until the reaction was complete (monitored by TLC); filtered, and the filtrate was collected under reduced pressure Evaporate the solvent, add 900ml ethyl acetate and 500ml purified water to the residue, extract and separate the liquid, wash with 300ml saturated brine, add an appropriate amount of anhydrous sodium sulfate to dry, evaporate the solvent under reduced pressure, rectify under reduced pressure, collect the vacuum The fraction 191.8g with a temperature not lower...

Embodiment 3

[0047] In the round bottom flask, add 62.1g ethylene glycol and 420ml tetrahydrofuran, stir and cool down to -5~5°C, add 43.8g sodium hydride in batches, after the addition is completed, slowly rise to room temperature, and continue the reaction. After the reaction is complete (TLC monitoring), cooled to 5-10°C, and under stirring, added dropwise 900ml of Fmoc-Cl (310.4g) tetrahydrofuran solution, after the dropwise addition, rose to room temperature and continued to react until the reaction was complete (monitored by TLC); filtered, collected the filtrate, and reduced Remove the solvent by pressure evaporation, add 900ml ethyl acetate and 500ml purified water to the residue, extract and separate the liquid, wash with 300ml saturated brine, add an appropriate amount of anhydrous sodium sulfate to dry, evaporate the solvent under reduced pressure, rectify under reduced pressure, and collect The fraction 188.1g with a vacuum degree not lower than -0.095MPa and a fraction temperat...

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Abstract

The invention provides an ethylene glycol derivative compound II which has better stability and can be used for hydroxyethylation reaction, the compound II has higher stability and reaction activity, can effectively reduce the degradation of reactants and the generation of impurities in the reaction, and is efficient in reaction, few in impurities and convenient to purify especially in the application of everolimus preparation. The invention provides a method for preparing the compound II, which comprises the following steps: by taking ethylene glycol as a starting material, reacting ethylene glycol with fluorenylmethoxycarbonyl chloride and trifluoromethanesulfonic anhydride in sequence to obtain the compound II; the method is simple and efficient, raw materials are easy to obtain, post-treatment is simple, product purity is high, and a reliable process route is provided for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a derivative compound of ethylene glycol, a preparation method thereof and its application in hydroxyethylation reaction, especially the preparation of everolimus. Background technique [0002] Everolimus (Everolimus, structure as follows), which is derived from 40-OH of rapamycin to 40-O-(2-hydroxyethyl), so Everolimus is also called 40-O-(2 -hydroxyethyl)-rapamycin. It is a new generation of mammalian target of rapamycin (mTOR) inhibitor. Everolimus was developed by Novartis in Switzerland, and it was launched in Germany in April 2004 for the prevention of heart and kidney transplant rejection, and it was launched in other European countries in 2005; everolimus was approved and launched in the United States in April 2010 It is used to prevent renal transplant rejection in adults; it was launched in Japan in March 2007 for heart transplant rejection, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C309/65C07C303/28C07D498/18
CPCC07C309/65C07C303/28C07C68/02C07D498/18C07C2603/18C07C69/96Y02P20/55
Inventor 白文钦张永波
Owner LUNAN PHARMA GROUP CORPORATION
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