Preparation for midbody of Irinotecan and preparation for Irinotecan

A technology for irinotecan and intermediates, which is applied in the field of synthesis of camptothecin-related compounds, can solve the problems of unfavorable high-purity target substances, long chromatography cycle, large solvent consumption, etc., and achieves reduction of treatment costs and easy recrystallization. , the effect of reducing the content of impurities

Active Publication Date: 2010-10-27
SHANGHAI JINHE BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Desiring to obtain high-purity irinotecan often requires column chromatography and multiple recrystallizations, which will undoubtedly reduce its yield
Moreover, due to the particularity of its structure, the column chromatography cycle is often longer, the workload is large, and the solvent consumption is also large.
At the same time, due to the sensitivity of irinotecan to light, long-term column chromatography and recrystallization process are unfavorable to obtain high-purity target

Method used

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  • Preparation for midbody of Irinotecan and preparation for Irinotecan
  • Preparation for midbody of Irinotecan and preparation for Irinotecan
  • Preparation for midbody of Irinotecan and preparation for Irinotecan

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Experimental program
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Effect test

Embodiment 1

[0043] Embodiment 1: the preparation method of the intermediate of irinotecan

[0044] 1. Acylation step:

[0045] 20 g (134.2 mmol) of piperidinyl piperidine was dissolved in 100 ml of dichloromethane, then 35.6 g of sodium carbonate was added, 13.9 g (147.6 mmol) of methyl chloroformate was added dropwise at room temperature, and the reaction was carried out at room temperature for 24 hours . Washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 26 g of the target product, yield: 93.6%.

[0046] 2. Hydrolysis step:

[0047]26 grams (125.6 mmol) obtained in the above steps were dissolved in 120 milliliters of methanol, then 30 milliliters of an aqueous solution of 8.5 grams of sodium hydroxide (213.5 mmol) was added, and the reaction was heated to reflux for about 5 hours. After the reaction was completed, methanol was evaporated under reduced pressure, and 50 milliliters of water, washed with 30×3 milli...

Embodiment 2

[0048] Embodiment 2: the method for preparing irinotecan using intermediate

[0049] Condensation step: 44 grams (112.3 mmol) of 7-ethyl-10-hydroxycamptothecin, 24.9 grams (118 mmol) of piperidinyl pipecolic acid were added to a 500-ml three-necked bottle, 200 milliliters of pyridine was added, dichloro 150 ml of methane, stirred and cooled to -5°C, 1 g of DMAP, 25.2 g of DCC (123.5 mmol), kept at this temperature until the end of the reaction, filtered, washed the filtrate with saturated sodium bicarbonate, washed with saturated brine, and dried over anhydrous magnesium sulfate , filtered, and concentrated to obtain 59 grams of the target product irinotecan, yield: 91%.

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Abstract

The invention provides an intermediate of Irinotecan with the advantages of simple synthetic process, mild condition and easy control and the preparation method thereof, and a method for preparing Irinotecan from the same, wherein the intermediate is 4-piperidino piperidine-1-formic acid. The preparation method of the intermediate comprises an acylation step and a hydrolysis step. Irinotecan is prepared by condensing the intermediate and 7-ethyl-10-hydroxycamptothecine. The preparation method avoids the defects of the prior art, reduces the impurity content, and shortens the production period, and can directly synthesize the target product with high purity, therefore, the preparation method is of great significance and of huge economic benefit in reducing the production cost, widening theclinical application of the Irinotecan, reducing therapeutic cost, etc.

Description

technical field [0001] The invention relates to a synthesis method of camptothecin-related compounds. In more detail, the present invention relates to the preparation method of intermediates related to the synthesis of irinotecan having antitumor activity and the use of said intermediates, and relates to the synthesis of irinotecan. Background technique [0002] Camptothecin (hereinafter referred to as CPT) isolated from the bark, root, fruit, leaf, etc. of Camptotheca acuminata native to China is a pentacyclic alkaloid known to exhibit antitumor activity by inhibiting nucleic acid synthesis active. Because camptothecin is insoluble in water, and its sodium salt is used in clinical research, it is found that its toxic and side effects are relatively large, so people have conducted extensive research on the structural modification of camptothecin, aiming at improving its solubility, reducing toxicity, and extending the lactone ring. Retention time in the body and increase p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/66C07D491/22
Inventor 张伟中蔡志香赵宏武张爱平李博仝泽彬
Owner SHANGHAI JINHE BIO TECH
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