Preparation method for etoposide intermediate

A technology for etoposide and intermediates, which is applied in the field of preparation of etoposide intermediates, can solve the problems of complex product post-processing, high fire protection requirements, and high impurity content, and achieve reduced post-reaction processing, high safety, and environmental friendliness Effect

Inactive Publication Date: 2012-07-25
SHANGHAI JINHE BIO TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] There are many side reactions, high impurity content, complex product post-treatment, low yield, and highly corrosive liquid bromine and flammable red phosphorus are used. During the production process, environmental protection facilities, occupational health protection measures and Higher requirements for fire protection

Method used

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  • Preparation method for etoposide intermediate
  • Preparation method for etoposide intermediate
  • Preparation method for etoposide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] (1) Preparation of compound B:

[0043] Drop into compound A (podophyllotoxin, the same below) (10kg) and dry dichloromethane (45L) respectively in the clean and dry 200L reactor, stir, then feed nitrogen into the reactor for 20 minutes to replace the Air. The temperature of the reaction solution was lowered to -10°C, and a mixed solution of iodotrimethylsilane (14Kg) and dichloromethane (15L) was added dropwise, the time was controlled at 2 hours, and the temperature of the dropping process was controlled at -10°C. After the dropwise addition, the temperature was controlled at -10°C, and the reaction was incubated for 4 hours. Thin-layer chromatography (TLC) detected that the reaction raw materials were completely consumed. Take 20L petroleum ether and add it. A large amount of powdery solids precipitated. After stirring for 20 minutes, filter to obtain the compound B (4'-desmethyl-4-iodopodophyllotoxin, the same below) crude product 10.84kg, yield: 88%, take the filt...

Embodiment 2

[0057] (1) Preparation of Compound B

[0058]Add compound A podophyllotoxin (20kg) and dry dichloromethane (90L) respectively into a clean and dry 500L reactor, stir, then feed nitrogen into the reactor for 20 minutes to replace the air in the reactor. The temperature of the reaction solution was lowered to -10°C, and a mixed solution of iodotrimethylsilane (28Kg) and dichloromethane (30L) was added dropwise, the time was controlled at 2 hours, and the temperature of the dropping process was controlled at -5°C. After the dropwise addition, the temperature was controlled at -5°C, and the reaction was kept for 4 hours. Thin-layer chromatography (TLC) detected that the reaction raw materials were completely consumed. Take 40L petroleum ether and add it. A large amount of powdery solid precipitated out. After stirring for 20 minutes, filter to obtain the compound B crude product 21.92kg, yield: 89%, take the filtrate solid and directly react in the next step.

[0059] (2) Acylati...

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Abstract

The invention discloses a preparation method for an etoposide intermediate, which comprises the following steps: (1) adding a compound A into a reaction system with dichloromethane as a solvent, then adding iodotrimethylsilane in the reaction system, cooling the reaction solution to a temperature in a range of -10 DEG C to -5 DEG C, adding n-hexane after the reaction materials are completely consumed, stirring to precipitate powdery solid, and filtering to obtain a compound B; (2) adding the compound B in dichloromethane solvent, uniformly stirring at room temperature, freezing the dissolved solution to a temperature in a range -5 DEG C to -8 DEG C, dropping pyridine, rapidly dropping dichloroacetyl chloride, and keeping stirring until the reaction is complete to obtain a compound C; (3) adding acetone, water and sodium thiosulfate into the solution obtained in the step (2), keeping stirring at 25-30 DEG C until the reaction is complete, adding water to precipitate white solid, and recrystallizing to obtain a compound D; and the specific reactive mode is as follows:. The preparation method provided by the invention is low in cost, high in efficiency, environment-friendly, moderate in reaction, high in safety and the like.

Description

technical field [0001] The invention belongs to the field of medical engineering, and specifically relates to a preparation method of an etoposide intermediate. Background technique [0002] Etoposide, also known as etoposide, is a glycoside derivative of podophyllotoxin. [0003] Etoposide has a good antitumor effect, but due to its high production cost, tumor patients are under great economic pressure. [0004] At present, there are two main processes widely used in the production of etoposide from podophyllotoxin raw materials: [0005] One is prepared by reacting podophyllotoxin with hydrobromic acid to prepare epipodophyllotoxin and then coupling with sugar. [0006] The other is obtained by converting podophyllotoxin into 4'-dichloroacetyl epipodophyllotoxin (abbreviated as acylated epipodophyllotoxin, the same below) and then coupling with sugar, wherein acylated epipodophyllotoxin is An important intermediate in the production of etoposide. [0007] The above two...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04
Inventor 张伟中王权勇张爱平尹中船黄武蔡志香仝泽彬高卅
Owner SHANGHAI JINHE BIO TECH
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