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Preparation method of irinotecan hydrochloride

A technology of irinotecan hydrochloride and irinotecan, applied in the direction of organic chemistry, etc., can solve the problems of inconvenient industrial production, insoluble, poor solubility, etc., and achieve the effects of less pollution, lower production costs, and huge economic benefits

Inactive Publication Date: 2019-05-24
CISEN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the chemical properties of camptothecin are unstable and will decompose when exposed to light or heating.
Moreover, its solubility is poor, and it is insoluble in various organic solvents, which brings great difficulties to chemical synthesis.
[0008] In the process research, almost every step of the previously reported process requires column chromatography separation and purification, which increases the cost and brings inconvenience to industrial production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add FeSO to a 500mL three-necked flask 4 ·7H 2 O 4.2g (15.1mmol), propionaldehyde 2.18mL (30.2mmol), water 120mL, glacial acetic acid 105mL, camptothecin 2.1g (6mmol), stir, cool to 5°C and add concentrated sulfuric acid 30mL to obtain a yellow transparent solution. Add 30% H dropwise 2 o 2 1.86mL (17.6mmol), react at 5-8°C for 15min. Pour into 500mL of ice water, adjust the pH to 8, and a large amount of yellow solid precipitates. After filtering, the filter cake was washed with a small amount of water to obtain 1.36 g of 7-ethylcamptothecin, yield: 61%.

[0029] Add 350 mL of glacial acetic acid, 30% H 2 o 2 30mL (283.9mmol), heat to 80°C, add 1.36g (3.635mmol) of 7-ethylcamptothecin after 5h, react for 3h, concentrate to about 20mL, add 500mL of ice water, let stand for 1h, suction filter, dry 1.06 g of 7-ethyl-N-oxycamptothecin product was obtained. Yield: 69.3%.

[0030] 1.06g (2.52mmol) of 7-ethyl-N-oxycamptothecin was dissolved in dioxane-acetonitrile-...

Embodiment 2

[0035] Add FeSO to a 500mL three-necked flask 4 ·7H 2 O 4.2g (15.1mmol), propionaldehyde 2.18mL (30.2mmol), water 120mL, glacial acetic acid 105mL, camptothecin 1.75g ​​(5mmol), stir, cool to 5°C and add concentrated sulfuric acid 30mL to obtain a yellow transparent solution. Add 30% H dropwise 2 o 2 1.86mL (17.6mmol), react at 5-8°C for 15min. Pour into 500mL of ice water, adjust the pH to 8, and a large amount of yellow solid precipitates. After filtering, the filter cake was washed with a small amount of water to obtain 1.22 g of 7-ethylcamptothecin, yield: 62%.

[0036] Add 350 mL of glacial acetic acid, 30% H 2 o 2 30mL (283.9mmol), heat to 80°C, add 1.22g (3.1mmol) of 7-ethylcamptothecin after 5h, react for 3h, concentrate to about 20mL, add 500mL of ice water, let stand for 1h, suction filter, and dry 0.89 g of the product was obtained. Yield: 72%.

[0037] 0.89g (2.23mmol) of 7-ethyl-N-oxycamptothecin was dissolved in dioxane-acetonitrile-water (V:V:V=250:50...

Embodiment 3

[0042] Add FeSO to a 500mL three-necked flask 4 ·7H 2 O 4.2g (15.1mmol), propionaldehyde 2.18mL (30.2mmol), water 120mL, glacial acetic acid 105mL, camptothecin 2.45g (7mmol), stir, cool to 5°C and add concentrated sulfuric acid 30mL to obtain a yellow transparent solution. Add 30% H dropwise 2 o 2 1.86mL (17.6mmol), react at 5-8°C for 15min. Pour into 500mL of ice water, adjust the pH to 8, and a large amount of yellow solid precipitates. Filter and wash the filter cake with a small amount of water to obtain 1.66 g of 7-ethylcamptothecin, yield: 60%.

[0043] Add 350 mL of glacial acetic acid, 30% H 2 o 2 30mL (283.9mmol), heated to 80°C, 1.66g (4.27mmol) of 7-ethylcamptothecin was added after 5h, reacted for 4h, concentrated to about 20mL, added 500mL of ice water, stood for 1h, suction filtered, dried 1.07 g of product was obtained. Yield: 62%.

[0044] 1.07g (2.67mmol) of 7-ethyl-N-oxycamptothecin was dissolved in dioxane-acetonitrile-water (V:V:V=250:500:80), a...

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Abstract

The invention relates to a preparation method of irinotecan hydrochloride. The method comprises the steps that a mother ring reacts with propionaldehyde by taking camptothecin as a raw material to generate 7-ethylcamptothecin, and then hydrogen peroxide is used for oxidization to generate N-oxide-7-ethylcamptothecin; illumination rearrangement is carried out to generate 7-ethyl-10-hydroxycamptothecine; 4-piperidinopiperidine reacts with dimethyl carbonate to generate 4-piperidinopiperidine methyl carbonate; 7-ethyl-10-hydroxycamptothecine reacts with 4-piperidinopiperidine methyl carbonate togenerate irinotecan monomer; the irinotecan monomer and hydrochloric acid are salified to obtain an irinotecan hydrochloride finished product. Compared with the prior art, in the reaction process, phosgene, chloroform and other toxic substances are prevented from being used, and the irinotecan hydrochloride has the advantages of being safe, convenient to use, little in pollution and the like during production. Besides, the synthesis method avoids the defect that a chromatographic column is needed for separation and purification in the prior art, the production cost of irinotecan is reduced, and huge economic benefits are achieved.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of irinotecan hydrochloride. Background technique [0002] Irinotecan Hydrochloride is a water-soluble camptothecin derivative jointly developed by Japan's Daiichi Seiyaku Company and Yakult Honsha Company. Clinically used is the trihydrate of irinotecan hydrochloride, chemical name: (+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinylpiperidine)carbonyl ]-1H-pyrano[3,4:6,7]indolazin[1,2b]quinoline-3,14-(4H,12H)-dione hydrochloride, the structural formula is as follows: [0003] [0004] Irinotecan Hydrochloride Formula I [0005] Chinese patent CN101314587 has reported a kind of preparation method of irinotecan, and this route is that 4-piperidyl piperidine reacts with triphosgene to generate 4-piperidyl piperidine carboxylic acid chloride, and then reacts with 7-ethyl-10-hydroxyl pyridine Irinotecan is obtained by reacting tree b...

Claims

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Application Information

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IPC IPC(8): C07D491/02
Inventor 李续张萌魏衍纲
Owner CISEN PHARMA
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