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Everolimus intermediate, and preparation method and application thereof

A technology for everolimus and intermediates, applied in the field of everolimus intermediates, can solve problems such as difficult separation, many by-products, and many impurities, and achieve the effects of reducing side reactions, simple preparation methods, and high yields

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 provide a kind of everolimus intermediate, its preparation method and its application

Method used

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  • Everolimus intermediate, and preparation method and application thereof
  • Everolimus intermediate, and preparation method and application thereof
  • Everolimus intermediate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] (1), the synthesis of 28-O-TMS rapamycin (intermediate B-1)

[0064]

[0065] Dissolve rapamycin (5.00g) and imidazole (1.86g) in ethyl acetate (100mL), under cooling in an ice-water bath, add trimethylchlorosilane (2.97g) dropwise, and continue cooling in an ice-water bath after the addition is complete The reaction was stirred for 30 minutes, and TLC showed that the starting material disappeared completely.

[0066] 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 obtain 28-O-TMS rapamycin (intermediate B-1, 5.89 g), as a white solid. ESI-...

Embodiment 2

[0074] In this embodiment, the reaction process is as follows:

[0075]

[0076] (1), the synthesis of 28-O-TES rapamycin (intermediate B-2)

[0077]

[0078] Dissolve rapamycin (5.00g), triethylamine (2.77g) and 4-dimethylaminopyridine (20mg) in dichloromethane (100mL), and add triethylchlorosilane (4.12 g), after the dropwise addition was completed, 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 materials disappeared completely. The reaction solution was filtered, and the filtrate was washed successively with 0.5M dilute hydrochloric acid, saturated sodium carbonate and saturated sodium chloride, and the organic phase was concentrated under reduced pressure.

[0079] 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 stirred overnight at 0-10°C. TLC showed that ...

Embodiment 3

[0087] Synthesis of 28-O-TMS-42-O-TBS Everolimus (Intermediate C-1)

[0088]

[0089]Dissolve 28-O-TMS rapamycin (3.04g), N,N-diisopropylethylamine (3.00g) in toluene (20ml) and ethylene glycol dimethyl ether (4ml), add trifluoro 2-(tert-butyldimethylsilyloxy)ethyl methanesulfonate (4.45g) was heated at 60°C for 4 hours. The reaction solution was cooled and concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain 28-O-TMS-42-O-TBS everolimus (compound 1, 2.42 g, yield 72.7%) as a white solid. 1H NMR (400MHz, CDCl 3 )δ: 0.00(m,15H),0.65-0.98(m,15H),1.05(m,9H),1.13-2.08(m,28H),2.2.-2.40(m,2H),2.75-2.90(m ,2H),3.01(1H),3.13(m,3H),3.25(m,3H),3.26-3.43(m,4H),3.50-3.89(m,8H),4.05-4.44(m,1H), 5.00-5.66 (m, 4H), 5.85-6.45 (m, 4H).

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Abstract

The invention discloses an everolimus intermediate, and a preparation method and an application of the everolimus intermediate. A structure of the everolimus intermediate C is shown as formula (1) asshown in the specification. The preparation method comprises the following step: allowing 28-monosilicon protected rapamycin (an everolimus intermediate B) to react with trifluoromethanesulfonic acidsingle-protection glycol ester in the presence of organic base. The invention further discloses the application of the everolimus intermediate C. The preparation method of the everolimus intermediateis simple and high in yield; everolimus prepared from the intermediate can reduce side reactions; a technical operation procedure is simplified; the total yield is increased; the product quality is ensured; and therefore, the preparation method has better industrial application and popularization prospects.

Description

technical field [0001] The present invention relates to an everolimus intermediate, its preparation method and application. 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; Secon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18C07F7/18G01N30/02G01N30/06
Inventor 王峰
Owner SHANGHAI INST OF PHARMA IND CO LTD
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