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Preparation method of irinotecan hydrochloride

A technology for irinotecan hydrochloride and salt formation, which is applied in the field of preparation of irinotecan hydrochloride, can solve the problems of complicated reaction operation and difficult purification of crude products, and achieves low isomer content and good splitting effect. , mild reaction effect

Active Publication Date: 2017-05-10
SHANGHAI JINHE BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Even so, there are still many problems in the industrial synthesis of camptothecin so far, such as complex reaction operations, the use of many sensitive reagents, and the difficulty in purification of crude products. Therefore, it is of great significance to develop a simple and efficient synthetic route

Method used

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  • Preparation method of irinotecan hydrochloride
  • Preparation method of irinotecan hydrochloride
  • Preparation method of irinotecan hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0052] A preparation method of irinotecan hydrochloride. figure 1 It is the chemical reaction synthesis route diagram of the present invention, as figure 1 shown, including the following steps:

[0053] Add 4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-F]indolizine-3,6,10(4H)-trione (26.3g ), toluene (260ml), stirred and dissolved. Weigh 1-(2-amino-5-hydroxyphenyl)-1-propanone (18.1 g) and p-toluenesulfonic acid (12.2 g) into the solution, and replace with nitrogen. The reaction solution was heated to slight reflux, and the reaction was maintained for 4 hours. TLC detected that the raw material was completely consumed, and the reaction solution was cooled to room temperature, washed with saturated brine (3×100ml) to pH=6-8. The organic phase was taken, dried with anhydrous sodium sulfate (20 g), concentrated under reduced pressure until no liquid dripped out. The solid compound A was obtained, weighing: 42.3 g.

[0054]The solid compound A (42.3 g) obtained in the previous...

Embodiment 2

[0058] Add 4-ethyl-7,8-dihydro-4-hydroxyl-1H-pyrano[3,4-F]indolizine-3,6,10(4H)-trione (131.5g ), toluene (1.3L), stirred to dissolve. Weigh 1-(2-amino-5-hydroxyphenyl)-1-propanone (92.1 g) and p-toluenesulfonic acid (60 g) into the solution, and replace with nitrogen. The reaction solution was heated to slight reflux, and the reaction was maintained for 4 hours. TLC detected that the raw materials were completely consumed, and the reaction solution was cooled to room temperature, washed with saturated brine (3×500ml) to pH=6-8. The organic phase was taken, dried with anhydrous sodium sulfate (100 g), and concentrated under reduced pressure until no liquid dripped out. The solid compound A was obtained, dried under vacuum at 25°C for 4 hours and weighed: 206.4g.

[0059] The solid compound A (206.4 g) obtained in the previous step was dissolved in 1.0 L of methanol, and added to a 5 L reaction flask. Weigh lithium hydroxide (13g), dissolve it in 1.0L pure water, add lithiu...

Embodiment 3

[0063] Add 4-ethyl-7,8-dihydro-4-hydroxyl-1H-pyrano[3,4-F]indolizine-3,6,10(4H)-trione (263g) into the reaction flask , toluene (2.6L), stirred to dissolve. Weigh 1-(2-amino-5-hydroxyphenyl)-1-propanone (190 g) and p-toluenesulfonic acid (122 g) into the solution, and replace with nitrogen. The reaction solution was heated to slight reflux, and the reaction was maintained for 5 hours. TLC detected that the starting material was completely consumed, and the reaction solution was cooled to room temperature, washed with saturated brine (3×1.0 L) to pH=6-8. The organic phase was taken, dried with anhydrous sodium sulfate (200 g), and concentrated under reduced pressure until no liquid dripped out. Vacuum drying at 30°C for 5 hours yielded Compound A as a solid, weighing 422 g.

[0064] The solid compound A (422 g) obtained in the previous step was dissolved in 2.0 L of methanol and added to a 10 L reaction flask. Weigh lithium hydroxide (26g), dissolve it in 2.0L pure water, a...

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Abstract

The invention discloses a preparation method of irinotecan hydrochloride. The preparation method comprises following steps: 1, chemical raw materials of racemic indolizine derivatives are taken as initial raw materials, ring closing reaction and alkali ring-opening reaction are carried out so as to obtain an organic acid intermediate; 2, a chiral amine and the organic acid intermediate are subjected to salt forming resolution so as to obtain a chiral intermediate; 3, the chiral intermediate is subjected to acid ring-opening reaction so as to remove the chiral amine; 4, esterification with a piperidine derivative, and salt forming are carried out so as to obtain the target product irinotecan hydrochloride. The preparation method is used for total synthesis of irinotecan hydrochloride, large scale production is realized, reaction conditions are mild, the preparation method is easy to control, product purity is 98% or higher, and the largest individual impurity content is lower than 0.1%.

Description

technical field [0001] The invention relates to a process method of antitumor drugs, in particular to a preparation method of irinotecan hydrochloride. Background technique [0002] Irinotecan hydrochloride trihydrate is a chemical drug with the molecular formula C 33 h 39 ClN 4 o 6 , CAS No. 136572-09-3 is mainly used for the treatment of digestive system tumors such as gastric cancer, colon cancer, rectal cancer, lung cancer, etc. [0003] Irinotecan hydrochloride is an alkaloid with camptothecin as its parent ring. At present, its main source is the bark, root, fruit, and leaves of camptothecin as raw materials. [0004] Camptothecin (Camptothecin) is an alkaloid extracted from the Chinese Davidiaceae plant Camptotheca acuminata by American chemist Wall et al. Dendine is a five-ring rigid structure composed of indolizine[1,2-b]quinoline fragments fused with six-membered-hydroxylactone. The 20th carbon with the -hydroxyl is asymmetrical, which endows the molecule with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22C07B57/00
CPCC07B57/00C07B2200/07C07D491/22
Inventor 张伟中王权勇蔡志霞谢斌冯蕾宇吴玉娟仝泽彬
Owner SHANGHAI JINHE BIO TECH
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