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Method for preparing high-purity irinotecan

A technology of purity and trihydrate, applied in the field of purification of irinotecan hydrochloride, can solve the problems of poor water solubility and ester solubility, high price, etc., and achieve the effects of less solvent consumption, good effect and short production cycle

Active Publication Date: 2011-05-18
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Registered and sold in Europe, America, Japan and many other countries, and the price is expensive
However, the water solubility and ester solubility of irinotecan hydrochloride trihydrate are relatively poor, and its synthesis needs to be further improved and improved especially in terms of purification.

Method used

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  • Method for preparing high-purity irinotecan
  • Method for preparing high-purity irinotecan
  • Method for preparing high-purity irinotecan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of 7-Ethyl-10-Hydroxycamptothecin

[0031] Dissolve 38g of 7-ethylcamptothecin in 350ml of glacial acetic acid, add 215ml of DMSO, put it in a 1L autoclave, add PtO 2 6g, reacted at 70°C, 5bar, rotating speed 800rpm, cooled to 25°C after 12 hours, exchanged hydrogen with nitrogen, filtered, washed the filter cake with 20ml of glacial acetic acid, added 110ml of water to the resulting solution, 60g of iodobenzene diacetate, in 25 Stir at ℃ for 15 minutes, concentrate, add 700ml of acetonitrile, a large amount of solid precipitates, super crushed in ultrasonic wave until uniform, filtered, and dried to obtain 31.5g of brown powder.

[0032] Dissolve the above solid in 240ml of DMF, rinse in 1200ml of ethanol, cool to room temperature, filter and wash with ethanol to obtain 25.5g of a light yellow solid, reflux the solid with 255ml of chloroform and 25.5ml of methanol for half an hour, cool to room temperature, and filter , 23.8g after drying. HP...

Embodiment 2

[0033] Example 2 Preparation of 4-piperidinylpiperidinecarbonyl chloride

[0034] Add 20.4g of triphosgene and 140ml of dichloromethane into the reaction flask, stir until dissolved, and cool to 0-5°C in an ice-salt bath. A mixture containing 11 g of 4-piperidinylpiperidine, 28 ml of triethylamine, and 140 ml of dichloromethane was added dropwise, and the drop was completed in about 1 hour. The reaction temperature was controlled below 5°C and stirred for 6 hours. When concentrated to about half the volume, filter. The filter cake was washed with a little dichloromethane, the dichloromethane layer was concentrated to a volume of about 60ml, 60ml of toluene was added, a white solid was precipitated, filtered, washed with toluene, and dried to obtain 15.7g of 4-piperidinylpiperidinecarbonyl chloride hydrochloride.

Embodiment 3

[0035] Example 3 Preparation of Crude Irinotecan

[0036] Put 15g of 7-ethyl-10-hydroxycamptothecin, 200ml of pyridine, and 100ml of dichloromethane into the reaction bottle, stir, and drop 15.7g of 4-piperidinylpiperidinecarbonyl chloride hydrochloride and di A solution of 50ml of methyl chloride was dripped for about half an hour. React at 20°C for 1 hour. Concentrate below 25°C for 10 minutes, rinse in 400ml of petroleum ether, filter, wash with petroleum ether, and dry to obtain a powdery solid.

[0037] Add 20ml of dichloromethane to dissolve the solid, adjust the pH to 1 with 4N hydrochloric acid ethanol, concentrate to dryness, add 60ml of water and 180ml of acetone, stir and crystallize overnight. The next day, 17.5 g of pale yellow crystals were obtained by filtration.

[0038] Add 90ml of methanol and 18ml of water to 17.5g of the above solid, heat and dissolve, then concentrate under reduced pressure to obtain an oily substance, add 52.5ml of water, 157.5ml of...

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Abstract

The invention provides a method for synthesizing and purifying irinotecan. The method prepares irinotecan that is an antineoplastic compound with high purity quotient through the purification of 7-ethide-10-hydroxycamptothecine that is an intermediate for synthesizing irinotecan and crystallization for impurity removal of hydrochloric piperidyl piperidine formyl chloride; secondary reaction is reduced, and the purity quotient as well as the yield of products are increased through improving the reaction condition at the same time, especially through cryoconcentration evolution; the purity quotient of the obtained products is more than 99.5 percent, and the single hetero is less than 0.1 percent. In addition, the method overcomes the disadvantages that the cycle is long, the solvent quantity is large, etc. caused by column chromatography that is used for purifying the products, and large scale production is easy to realize.

Description

technical field [0001] The invention relates to a purification method of irinotecan hydrochloride, in particular to purification of raw materials and intermediates, low-temperature treatment after reaction, purification and removal of impurities with a mixed solvent, and the like. Background technique [0002] Irinotecan is a drug of choice for the treatment of colorectal cancer. It is formed by modifying camptothecin at the 7-position and 10-position. It has stronger anti-tumor activity and less neurotoxicity than camptothecin. It is registered and sold in Europe, America, Japan and many other countries, and the price is expensive. However, the water-solubility and ester-solubility of irinotecan hydrochloride trihydrate are poor, and its synthesis, especially in terms of purification, needs to be further improved and improved. Contents of the invention [0003] In order to solve the technical problems existing in the above-mentioned prior art, the present invention proce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22
Inventor 孙飘扬王从站陈永江
Owner JIANGSU HENGRUI MEDICINE CO LTD
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