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Preparation method of everolimus

A technology for preparing everolimus and liquid phase, which is applied in the field of preparation of everolimus, and can solve the problems of high synthesis cost of synthetic everolimus and high price of sirolimus

Inactive Publication Date: 2016-05-11
HARBIN PHARMA GROUP TECH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of resynthesis, due to the high price of the starting material sirolimus, the synthesis cost of everolimus is too high
At present, the purification method of everolimus is mainly obtained by preparative liquid phase purification, but in the patent literature reported this year, the purification of crude everolimus is gradually considered to be purified by column chromatography. We have tried to use column chromatography to purify Product purification, but it can only be well controlled for related substances. If you want to control the content of isomers at the level of the original drug, it is impossible to achieve only through column chromatography purification

Method used

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  • Preparation method of everolimus
  • Preparation method of everolimus

Examples

Experimental program
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Effect test

Embodiment 1

[0075] 1) Preparation of tert-butyldimethylhydroxyethoxysilane

[0076] Under nitrogen protection, triethylamine (5640 g), ethylene glycol (3450 g), and n-hexane (9.1 L) were successively added into a 50 L reaction flask. The system was stirred rapidly and cooled to -5±5°C. Dissolve tert-butyldimethylsilyl chloride (1400g) in n-hexane (4.9L), divide the prepared n-hexane solution into five times on average, control the temperature at -5°C, drop to the above reaction within 0.5-1h After the dropwise addition, the reaction solution was reacted at 0±5°C for 1 hour, and then raised to 20°C for 16 hours.

[0077] Cool the reaction solution to -5±5°C, add purified water (10 L), stir for 5-10 minutes, let stand for 5-10 minutes, and separate the liquids. Cool the organic phase to 0±5°C, add 10% acetic acid aqueous solution (10 L), stir for 5-10 min, let stand for 5-10 min, separate the liquid, and repeat the above operation twice for the organic phase. Cool the organic phase to 0±...

Embodiment 2

[0091] 1) Preparation of tert-butyldimethylhydroxyethoxysilane

[0092] Under the protection of nitrogen, triethylamine (5640 g), ethylene glycol (3450 g), and n-heptane (9.1 L) were successively added into the 50 L reaction flask. The system was stirred rapidly and cooled to -5±5°C. Dissolve TBSCl (1400g) in n-heptane (4.9L), divide the prepared n-heptane solution into five times on average, control the temperature at 0°C, drop it into the above reaction solution within 0.5-1h; dropwise addition is complete , the reaction solution was reacted at 0±5°C for 1h, then raised to 25°C, and reacted for 16h.

[0093] Cool the reaction solution to -5±5°C, add purified water (10 L), stir for 5-10 minutes, let stand for 5-10 minutes, and separate the liquids. Cool the organic phase to 0±5°C, add 10% acetic acid aqueous solution (10 L), stir for 5-10 min, let stand for 5-10 min, separate the liquid, and repeat the above operation twice for the organic phase. Cool the organic phase to ...

Embodiment 3

[0109] 1) Preparation of tert-butyldimethylhydroxyethoxysilane

[0110] Under the protection of nitrogen, triethylamine (5640 g), ethylene glycol (3450 g), and petroleum ether (9.1 L) were successively added into the 50 L reaction flask. The system was stirred rapidly and cooled to -5°C. Dissolve tert-butyldimethylsilyl chloride (1400g) in petroleum ether (4.9L), divide the prepared petroleum ether solution into five times on average, control the temperature at -10°C, drop it to the above reaction within 0.5~1h After the dropwise addition, the reaction solution was reacted at 0±5°C for 1 hour, and then raised to 15°C for 16 hours.

[0111] Cool the reaction solution to -5±5°C, add purified water (10 L), stir for 5-10 minutes, let stand for 5-10 minutes, and separate the liquids. Cool the organic phase to 0±5°C, add 10% acetic acid aqueous solution (10 L), stir for 5-10 min, let stand for 5-10 min, separate the liquid, and repeat the above operation twice for the organic phas...

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Abstract

The invention relates to a preparation method of everolimus, and belongs to the technical field of medicines. The method comprises five steps: synthesis of side chains, displacement reaction and hydrolysis reaction between side chains and primary raw material (sirolimus), and twice positive phase preparation liquid phase purification. The preparation method has the advantages of low cost, high yield, and simple and convenient operation, and can be applied to industrialization.

Description

technical field [0001] The invention relates to a preparation method of everolimus, which belongs to the technical field of medicine. Background technique [0002] The chemical name of everolimus is: [0003] (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24, 25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethyl Oxy)-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy -3H-Pyrido[2,1-c][1,4]oxazatriciocyclene-1,5,11,28,29(4H,6H,31H)-pentanone [0004] structural formula [0005] [0006] Molecular formula: C 53 h 83 NO 14 [0007] Molecular weight: 958.22 [0008] Everolimus is an inhibitor of mTOR, a multifunctional intracellular kinase on the PI3K / AKt signaling channel. The PI3K / AKt signaling channel has many functions in the human body, including regulating protein synthesis, cell metabolism, growth, proliferation and the formation of new blood vessels...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCC07D498/18
Inventor 袁淑杰杨新春于海涛齐岩孙磊刘铁城户巧芬曹翊杰
Owner HARBIN PHARMA GROUP TECH CENT
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