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Preparation method of irinotecan hydrochloride

A technology of irinotecan hydrochloride and irinotecan, which is applied in the direction of organic chemistry, can solve problems such as environmental pollution, hidden dangers in production safety, and increased reaction steps, and achieve the effects of easy transportation, safe use, and pollution reduction

Active Publication Date: 2012-08-08
NANJING CHENGONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the above reactions, phosgene or phosgene substitutes: liquid diphosgene or solid triphosgene will inevitably be used in the reaction process. The use of this highly toxic substance has brought safety production problems. Hidden dangers, causing pollution to the environment
Method 3 does not use phosgene to activate 4-piperidinylpiperidine, but the chloroformate used in this method is still highly toxic, so the increase in reaction steps is meaningless

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] a) Add 4-piperidinyl piperidine (168 g, 1.00 mol), N, N-dimethylformamide (DMF) 900 mL, dimethyl carbonate ( 90 g, 1.00 mol) after the addition, control the temperature of the reaction solution at 60°C to 65°C and stir for 3 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure to obtain a viscous oily substance, weighing 243g, with a yield of 100%. The intermediates in this step did not need to be purified in full to continue.

[0048] b) In a reaction flask equipped with stirring, thermometer, and condensing device, add 4-piperidinylpiperidine methyl carbonate (243 g, 1.00mol) prepared in the previous step, 1000 mL of chloroform, 7-ethyl- After the 10-hydroxycamptothecin (263 g, 0.67 mol) was stirred evenly, the temperature of the reaction solution was controlled at 45°C to 50°C and stirred for 6 hours. After the reaction was completed, 500 mL of water was added, and the chloroform layer was separated. The water layer was extra...

Embodiment 2

[0051] a) Add 4-piperidinylpiperidine (168g, 1.00 mol), acetonitrile 900mL, and dimethyl carbonate (90g, 1.00 mol) into a reaction flask equipped with stirring, thermometer, and condensing device, then control the reaction The liquid temperature was 60°C to 65°C and stirred for 3 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure to obtain a viscous oily substance, weighing 240 g, with a yield of 100%. The intermediates of this step did not need to be purified in full to continue.

[0052] b) Add 4-piperidinylpiperidine methyl carbonate (240g, 1.00mol) prepared in the previous step reaction, 800 mL of dichloromethane, 7-ethyl -10-Hydroxycamptothecin (196 g, 0.50 mol) was stirred evenly, and the temperature of the reaction solution was controlled at 40°C to 45°C and stirred for 6 hours. Methane was extracted once, the combined dichloromethane layers were concentrated to dryness under reduced pressure, then 1150 mL of absolute ethanol...

Embodiment 3

[0055] a) Add 4-piperidinylpiperidine (168g, 1.00 mol), hexamethylphosphoramide 900mL, and dimethyl carbonate (90g, 1.00 mol) into a reaction flask equipped with stirring, thermometer, and condensing device After that, control the temperature of the reaction solution at 60° C. to 65° C. and stir for 3 hours. After the reaction was completed, it was concentrated to dryness under reduced pressure to obtain a viscous oily substance, weighing 240 g, with a yield of 100%. The intermediates of this step did not need to be purified in full to continue.

[0056] b) In a reaction flask equipped with stirring, thermometer, and condensing device, add 4-piperidinylpiperidine methyl carbonate (240g, 1.00mol) prepared in the previous step, petroleum ether 1000 mL, 7-ethyl- After stirring 10-hydroxycamptothecin (263 g, 0.67 mol) evenly, control the temperature of the reaction solution at 45°C to 50°C and stir for 6 hours. After the reaction, add 500mL of water to separate the petroleum ether...

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Abstract

The invention relates to a preparation method of irinotecan hydrochloride. The preparation method comprises the following steps: 1, reacting 4-piperidylpiperidine with dimethyl carbonate in a dipolar aprotic solvent to generate 4-piperidylpiperidine dimethyl carbonate; 2, reacting 4-piperidylpiperidine dimethyl carbonate with 7-ethyl-10-hydroxycamptothecin in a nonpolar solvent to generate irinotecan monomers; and 3, adding water to dissolve the irinotecan monomers, adding a hydrochloric acid solution to adjust the pH value of the obtained solution to 3-4, adding acetone, crystallizing, filtering, and carrying out vacuum drying to obtain finished irinotecan hydrochloride. The preparation method which introduces carbonyl groups to the active substance dimethyl carbonate during preparation of irinotecan hydrochloride has the characteristics of safe use, convenience, small pollution, easy transportation and the like in production; the preparation method which allows use of phosgene substances to be completely avoided and pollution to the environment to be correspondingly migrated is green; and an acid binding agent is not needed by the method, and methanol which is the only byproduct is a volatile substance with a low boiling point, so post-processing is simple.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical engineering, and in particular relates to a preparation method of an antitumor drug irinotecan hydrochloride. Background technique [0002] Irinotecan Hydrochloride (CPT-11) is the most representative water-soluble camptothecin derivative jointly developed by Japan's Daiichi Seiyaku Company and Yakult Honsha Company. The trade name is Capto, and the specification is 2mL: 40mg and 5mL: 100mg. Since it was first launched in Japan in 1994, large-scale clinical studies have shown that irinotecan hydrochloride has obvious inhibitory effects on a variety of tumors such as colon cancer, small cell lung cancer, rectal cancer, leukemia, etc., and is still effective for fluorouracil-resistant cases . Therefore, irinotecan hydrochloride has attracted worldwide attention. [0003] CAS of irinotecan hydrochloride: 100286-90-6, chemical name: (+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinylpiperidine...

Claims

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Application Information

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IPC IPC(8): C07D491/22
Inventor 郭昭
Owner NANJING CHENGONG PHARM CO LTD
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