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Synthesis method of everolimus related substance D

A related substance, everolimus technology, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of low yield, complex post-processing, etc., achieve high purity, simplify the purification process, and simplify the operation

Pending Publication Date: 2022-01-14
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Aiming at the problems of low yield and complex post-treatment process in the current methods for obtaining related substance D of everolimus, the present invention provides a method for preparing related substance D of everolimus, which is simple to operate and has a high reaction rate. The process is safe and efficient, and the related substance D prepared by this method has a high purity, which can be directly used as a reference substance for everolimus impurity research or quality testing

Method used

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  • Synthesis method of everolimus related substance D
  • Synthesis method of everolimus related substance D
  • Synthesis method of everolimus related substance D

Examples

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Embodiment 1

[0054] The synthesis of embodiment 1 intermediate 1

[0055] Add 550ml of ethyl acetate into the round bottom flask, add 45.71g of rapamycin and 7.91g of pyridine under stirring, cool down to 0-5°C, add 15.52g of Fmoc-Cl, stir for 2 hours, raise the temperature to 25-30°C, keep warm Stir the reaction, TLC detects the reaction process until the rapamycin spots disappear, and the reaction is complete; add 150ml of purified water, stir for 20 minutes, extract and separate the liquid, extract the aqueous layer with 50ml ethyl acetate, combine the organic layers, and use 5% dilute Wash with 100ml of hydrochloric acid and 100ml of saturated brine, dry with anhydrous sodium sulfate for 4 hours, filter, and vacuum concentrate the filtrate to dryness at a temperature of 30-35°C, separate and purify on a silica gel column (respectively use petroleum ether / ethyl acetate=3 / 1 volume ratio and petroleum ether / ethyl acetate=2 / 1 volume ratio), the product eluate was concentrated in vacuo at 3...

Embodiment 2

[0056] The synthesis of embodiment 2 intermediate 1

[0057] Add 460ml of ethyl acetate to the round bottom flask, add 45.71g of rapamycin and 7.12g of pyridine under stirring, cool down to 0-5°C, add 13.58g of Fmoc-Cl, stir for 2 hours, heat up to 25-30°C, keep warm Stir the reaction, TLC detects the reaction process until the rapamycin spots disappear, and the reaction is complete; add 150ml of purified water, stir for 20 minutes, extract and separate the liquid, extract the aqueous layer with 50ml ethyl acetate, combine the organic layers, and use 5% dilute Wash with 100ml of hydrochloric acid and 100ml of saturated brine, dry with anhydrous sodium sulfate for 4 hours, filter, and vacuum concentrate the filtrate to dryness at a temperature of 30-35°C, separate and purify on a silica gel column (respectively use petroleum ether / ethyl acetate=3 / 1 volume ratio and petroleum ether / ethyl acetate=2 / 1 volume ratio), the product eluate was concentrated in vacuo at 30-35°C to drynes...

Embodiment 3

[0058] The synthesis of embodiment 3 intermediate 1

[0059] Add 640ml of ethyl acetate to the round bottom flask, add 45.71g of rapamycin and 8.70g of pyridine under stirring, cool down to 0-5°C, add 18.11g of Fmoc-Cl, stir for 2 hours, heat up to 25-30°C, keep warm Stir the reaction, TLC detects the reaction process until the rapamycin spots disappear, and the reaction is complete; add 150ml of purified water, stir for 20 minutes, extract and separate the liquid, extract the aqueous layer with 50ml ethyl acetate, combine the organic layers, and use 5% dilute Wash with 100ml of hydrochloric acid and 100ml of saturated brine, dry with anhydrous sodium sulfate for 4 hours, filter, and vacuum concentrate the filtrate to dryness at a temperature of 30-35°C, separate and purify on a silica gel column (respectively use petroleum ether / ethyl acetate=3 / 1 volume ratio and petroleum ether / ethyl acetate=2 / 1 volume ratio), the product eluate was concentrated in vacuo at 30-35°C to drynes...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a synthetic method of an everolimus related substance D. According to the method, fluorenylmethyl chloroformate is used as a protecting group to selectively protect 40-site hydroxyl of everolimus, so that an intermediate 1 with protected 40-site hydroxyl can be obtained at high yield, organic alkali is selected as a solvent and alkaline conditions for condensation reaction are provided, 28-site hydroxyl of the intermediate 1 reacts with a side chain to obtain an intermediate 2, and deprotection is conducted to obtain the everolimus related substance D. The purity of the everolimus related substance D provided by the method reaches 98% or above, and a high-purity reference substance can be provided for research of everolimus related substances.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method of everolimus-related substance D. 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 was approved in Japan in December 2011 for the prevention of renal transplant rejection. In March 2009, it ...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCC07D498/18Y02P20/55
Inventor 白文钦王申张贵民
Owner LUNAN PHARMA GROUP CORPORATION
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