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Preparation method of etoposide

A technology of etoposide and structural formula, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of increasing difficulty in purification of etoposide, increasing production costs, and many impurities, and achieving less The difficulty of purification, the effect of improving yield and high yield

Inactive Publication Date: 2011-09-14
SHANGHAI HENGHE MEDICAL TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0008] Two kinds of catalysts are generally used in the above-mentioned hydrogenation deprotection process: one is to use palladium black, the catalytic effect is very good, but the cost is too high; the other is to use palladium carbon, but it is easy to produce a large amount of isomers with structural formula IV Body α-glucoside, can produce a large amount of etoposide isomers of structural formula V in the synthesis of the etoposide of structural formula VI owing to can not obtain the β-glucoside of higher purity structural formula V, use BF simultaneously 3 More impurities are produced by Lewis acid catalysis, which makes the purification of etoposide more difficult and the yield is lower, which greatly increases the production cost

Method used

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  • Preparation method of etoposide

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Experimental program
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Effect test

Embodiment 1

[0029] 1. Structural formula is the preparation of β-glucoside of (2):

[0030] Take the compound (250g, 545mmol) of structural formula (1) and add it to a 5L four-necked reaction flask, then add 3.0L ethyl acetate and Pd / C (30g), install a hydrogen balloon, replace the hydrogen gas 3 times, and cool the reaction solution When the temperature is lower than -10°C, TLC detects that the reaction raw materials are completely consumed, filter off Pd / C, concentrate ethyl acetate under reduced pressure to about 500mL, take 2.0L of petroleum ether and add it to a 5L beaker, stir vigorously, and pour the concentrate into In petroleum ether, a large amount of white powdery solids were precipitated, filtered after stirring for 20 minutes, and dried at 45° C. to obtain 168 g (518 mmol) of β-glucoside with structural formula (2), with a yield of 95.1%. The purity of β-glucoside detected by HPLC was 95%. %, α-glucoside is 0.8%.

[0031] 2. Coupling reaction

[0032] Take 1,2-dichloroethan...

Embodiment 2

[0036] 1. Structural formula is the preparation of β-glucoside of (2):

[0037] Take the compound (500g, 1.09mol) with structural formula (1) and add it to a 10L four-necked reaction flask, then add 6.0L ethyl acetate and Pd / C (60g), install a hydrogen balloon, and replace the reaction solution with hydrogen for 3 times. Cool to below -10°C, TLC detects that the reaction raw materials are completely consumed, filter off Pd / C, concentrate ethyl acetate under reduced pressure to about 1L, take 4.0L of petroleum ether and add it to a 10L beaker, stir vigorously, pour the concentrate Put into petroleum ether, a large amount of white powdery solids precipitated, stirred for 20 minutes, filtered, and dried at 45°C to obtain 331g (1.02mol) of β-glucoside with structural formula (2), the yield was 93.8%, and the purity of β-glucoside was detected by HPLC 94.5% and 0.7% for α-glucoside.

[0038] 2. Coupling reaction

[0039] Take 1,2-dichloroethane (6.0L) and pour it into a 10L four-...

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Abstract

The invention discloses a preparation method of etoposide, which includes the following steps: preparation of beta-glucoside, coupling reaction and preparation of etoposide. In the step of the preparation of the beta-glucoside, methoxybenzylidene is protected to increase the content of the beta-glucoside; in the step of the coupling reaction, TiCl4 is used as a Lewis acid catalyst to enable the reaction to have better selectivity, so as to improve the conversion rate of a target product, reduce the generation of impurities accordingly, reduce the difficulty of purification for the etoposide, improve the yield and reduce the cost; and in the step of the preparation of the etoposide, diluted hydrochloric acid is used for being stirred at room temperature to obtain a target compound with higher purity, and the purity of obtained etoposide coarse product can reach about 90%, so as to avoid column purification, and also reduce the number of times of recrystallization. The preparation method is simple in operation, also very easy in post-treatment, and high in yield.

Description

technical field [0001] The invention relates to a preparation method of etoposide. 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] Currently, the widely used process for the production of etoposide uses epipodophyllotoxin derivatives and β-glucosides as raw materials. 3 Under the catalysis of a series of Lewis acids, the C-9 position of the podophyllotoxin derivatives forms a carbocation. Affected by steric factors, the β-glucoside attacks from the side with less steric hindrance to generate the 9β-condensate of the structural formula I, namely It is the precursor of etoposide. [0005] [0006] In the production of β-glucosides, dichloroacetyl groups are generally used to protect the hydroxyl groups at the 2 and 3 positions to obtain compounds of the following str...

Claims

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Application Information

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IPC IPC(8): C07H17/04C07H1/00
Inventor 张伟中王权勇张爱平仝泽彬黄武尹中船蔡志香高卅
Owner SHANGHAI HENGHE MEDICAL TECH
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