A kind of method for preparing irinotecan hydrochloride

A technology of irinotecan hydrochloride and irinotecan, which is applied in the direction of organic chemistry, can solve the problems affecting the purity and color of the final product, the easy oxidation and discoloration of pyridine, and the easy deterioration of irinotecan, so as to reduce the treatment cost and shorten the reaction time , the effect of not easy to separate

Active Publication Date: 2011-11-30
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pyridine has a foul smell, and the test operator feels dizzy and other discomforts; pyridine is easy to oxidize and change color, which affects the purity and color of the final product; Pressure distillation makes irinotecan easy to deteriorate

Method used

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  • A kind of method for preparing irinotecan hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1) Preparation of irinotecan

[0047] Add 7-ethyl-10-hydroxycamptothecin (10.0g) into dichloromethane (250mL) and stir, add triethylamine (3mL), 4-dimethylaminopyridine (0.5g), 4-piperidine hydrochloride Piperidinecarbonyl chloride (7.0 g), stirred at room temperature overnight (20° C.), and filtered to remove insoluble matter. Wash twice with 10% sodium bicarbonate solution (100 mL), wash twice with saturated sodium chloride solution (100 mL), separate the organic layer, add anhydrous magnesium sulfate (5 g) and dry for 0.5 hour, remove magnesium sulfate by filtration, Chloromethane (50 mL) was used to rinse the filter cake twice, and the organic layers were combined. The solvent was distilled off under reduced pressure at 30°C to obtain solid crude irinotecan (14 g).

[0048] 2) preparation of irinotecan hydrochloride

[0049] Add the irinotecan crude product obtained in step 1) to methanol (100 mL), add a methanol solution of hydrogen chloride (20%) until the pH v...

Embodiment 2

[0053] Add 7-ethyl-10-hydroxycamptothecin (10g) into dichloromethane (250mL) and stir, add triethylamine (25mL) and 4-dimethylaminopyridine (1g), heat to reflux, within 1 hour 4-Piperidinylpiperidinecarbonyl chloride hydrochloride (7 g) was added in portions, and reflux was continued for 60 minutes. Cool and filter to remove insoluble matter. Slowly added to a rapidly stirred petroleum ether solution (2500 mL), a large amount of solid was precipitated, filtered, and dried under reduced pressure to obtain solid irinotecan crude product. The preparation and purification methods of irinotecan hydrochloride were the same as in Example 1, and 13.5 g of refined product was obtained, with a purity of 99.9%, and a simple and complex <0.05% (area normalization method).

Embodiment 3

[0055] 1) Preparation of irinotecan

[0056] Add 7-ethyl-10-hydroxycamptothecin (10g) into dichloromethane (250mL) and stir, add triethylamine (25mL), 4-dimethylaminopyridine (0.5g), 4-piperidinyl hydrochloride Piperidinecarbonyl chloride (10 g), stirred overnight, and after the reaction was complete, insoluble matter was removed by filtration. Wash twice with water (100mL), wash twice with saturated sodium chloride solution (100mL), separate the organic layer, add anhydrous sodium sulfate (5g) to dry for 2 hours, filter to remove magnesium sulfate, dichloromethane (50mL) to rinse and filter Cake twice and combine the organic layers. The solvent was distilled off under reduced pressure at 30°C to obtain 13.2 g of solid irinotecan crude product.

[0057] 2) preparation of irinotecan hydrochloride

[0058] The crude irinotecan hydrochloride obtained in step 1) was added with 12 mol / L hydrochloric acid solution until the pH was 1-2 to obtain about 14.7 g of crude irinotecan hy...

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Abstract

The invention provides a method for preparing irinotecan hydrochloride. The method reacts the intermediate 7-ethyl-10-hydroxycamptothecin with 4-piperidinylpiperidine carboxylic acid chloride or its salt in the presence of 4-dimethylaminopyridine or its salt, or its analogue, The final product is obtained through steps such as concentration, washing, and salt formation. The method of the invention avoids the use of malodorous and easily discolored pyridine to participate in the reaction, reduces side reactions, improves the purity and yield of the product, improves the color of the product at the same time, and is easy for large-scale production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically, to a method for preparing irinotecan hydrochloride. Background technique [0002] Irinotecan hydrochloride is a drug of choice for the treatment of colorectal cancer, and it is still effective for fluorouracil-resistant cases. Listed in more than 100 countries around the world. Clinically used is the trihydrate of irinotecan hydrochloride, the molecular formula is C 33 h 38 N 4 o 6 ·3H 2 O HCl, the structural formula is as follows: [0003] [0004] At present, the main synthetic route of irinotecan is that 4-piperidino piperidine (4-piperidino piperidine) reacts with triphosgene to generate 4-piperidinyl piperidine carboxylic acid chloride, and then reacts with 7-ethyl-10-hydroxy camptotree The base (7-Ethyl-10-Hydroxy-Campothecin, SN-38) reacts under the action of pyridine to obtain Irinotecan. Pyridine has a foul smell, and the test operator feels dizzy and othe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22
Inventor 陈言德肖灿储结根韩立王延松王文娣尹必喜
Owner YANGTZE RIVER PHARM GRP CO LTD
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