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Preparation method of everolimus

A technology of everolimus and deprotection, which is applied in the field of preparation of everolimus, can solve the problems of many by-products, difficulty in separation, and many impurities, and achieve the goals of increasing yield, improving selectivity, and simplifying the process flow Effect

Inactive Publication Date: 2019-05-21
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The purpose of the present invention is to solve many problems such as low yield, many by-products, many impurities, and difficulty in separation in the preparation method of everolimus existing in the art, and then provides a preparation method of everolimus

Method used

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  • Preparation method of everolimus
  • Preparation method of everolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The reaction process of the present embodiment is as follows:

[0061]

[0062] (1), the synthesis of 28-O-TMS rapamycin (intermediate B-1)

[0063]

[0064] Dissolve rapamycin (5.00g, purity 98.4%) and imidazole (1.86g) in ethyl acetate (100mL), under cooling in an ice-water bath, add trimethylchlorosilane (2.97g) dropwise, and continue The reaction was stirred for 30 minutes under cooling in an ice-water bath, and TLC showed that the starting material disappeared completely.

[0065] Add 0.5M hydrochloric acid (8mL) under ice-water bath and continue to cool, and stir the reaction. TLC shows that the original small polar product completely disappears, and the polarity of the main product is between rapamycin and rapamycin. The reaction was stopped, the reaction liquid was separated, the organic phase was washed with saturated sodium bicarbonate and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtai...

Embodiment 2

[0073] In this embodiment, the reaction process is as follows:

[0074]

[0075] (1), the synthesis of 28-O-TES rapamycin (intermediate B-2)

[0076]

[0077] Dissolve rapamycin (5.00g, purity 98.4%), triethylamine (2.77g) and 4-dimethylaminopyridine (20mg) in dichloromethane (100mL), and add triethylamine dropwise under ice-water cooling Chlorosilane (4.12g), after the dropwise addition, reacted for 1 hour under cooling in an ice-water bath, then gradually warmed up to room temperature, and reacted overnight. TLC showed that the raw material disappeared completely. The reaction solution was filtered, and the filtrate was washed successively with 0.5M dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, and the organic phase was concentrated under reduced pressure.

[0078] The obtained residue was dissolved in acetone (100ml), and 0.25M dilute sulfuric acid (15mL) was added under cooling in an ice-water bath, and the reaction was stirre...

Embodiment 3

[0086] Preparation of Everolimus from 28-O-TES-42-O-THDMS Everolimus (Intermediate C-2)

[0087]

[0088] 28-O-TES-42-O-THDMS everolimus (intermediate C-2, 200 mg) was dissolved in 10 ml of tetrahydrofuran, 1 ml of hydrogen fluoride / pyridine (38.5 M) was added, followed by TLC until the raw material completely disappeared. Add ethyl acetate and saturated sodium bicarbonate, separate the layers, wash the organic phase with dilute hydrochloric acid, saturated sodium bicarbonate, wash with water, and concentrate under reduced pressure to obtain everolimus (142 mg) as an off-white solid. ESI-MS m / z 956(M-H) - .

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Abstract

The invention discloses a preparation method of everolimus. The preparation method comprises the following step of performing deprotection reaction on an everolimus intermediate C. The preparation method of everolimus adopts a manner of regioselective protection of rapamycin 28-hydroxyl, so that the selectivity of a 40-hydroxyl alkylation reaction is improved; side reactions are reduced; a total yield of everolimus calculated from rapamycin can reach above 70%; compared with yields reported in available literatures, the yield is greatly increased; a technical operation procedure is simplified;the product quality is ensured; and the preparation method has better industrial application and popularization prospects.

Description

technical field [0001] The invention relates to a preparation method of everolimus. Background technique [0002] Everolimus is a new generation of macrolide immunosuppressant and anti-tumor drug developed by Novartis, which is derived from 40-OH of rapamycin to 40-O-(2- Hydroxyethyl), so everolimus is also called 40-O-(2-hydroxyethyl)-rapamycin. [0003] [0004] Patent US5665772 was the first to report everolimus and its synthesis process (Route 1). The method uses rapamycin as a raw material to obtain everolimus through a two-step reaction: first, rapamycin and 2-(tert-butyldimethylsilyloxy)ethyl trifluoromethanesulfonate are dissolved in toluene and The intermediate was reacted in the presence of 2,6-lutidine, and the silyl ether bond of the intermediate was broken in 1N HCl / methanol to obtain the target product. But in this method, the first step reaction yield is low (5-15%), and most of raw material is not converted; Second step reaction very easily produces deg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18
Inventor 王峰
Owner SHANGHAI INST OF PHARMA IND CO LTD
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