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

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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.

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

Example Embodiment

[0046] Example 1

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

[0048] b) In a reaction flask equipped with a stirring, thermometer, and condensing device, add 4-piperidinylpiperidine methyl carbonate (243 g, 1.00 mol) prepared in the previous step, 1000 mL of chloroform, 7-ethyl- After stirring the 10 hydroxycamptothecin (263 g, 0.67 mol) evenly, control the temperature of the reaction solution to 45℃~50℃ and stir for 6 hours. After the reaction is completed, add 500mL water, separate the chloroform layer, and extract the wat...

Example Embodiment

[0050] Example 2

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

[0052] b) Add the 4-piperidinylpiperidine methyl carbonate (240g, 1.00mol) prepared in the previous step into a reaction flask equipped with a stirring, thermometer, and condensing device, dichloromethane 800 mL, 7-ethyl After -10 hydroxycamptothecin (196 g, 0.50 mol) is uniformly stirred, the temperature of the reaction solution is controlled to 40℃~45℃ and stirred for 6 hours. After t...

Example Embodiment

[0054] Example 3

[0055] a) Add 4-piperidinylpiperidine (168g, 1.00 mol), 900 mL of hexamethylphosphoramide, and dimethyl carbonate (90g, 1.00 mol) into a reaction flask equipped with stirring, thermometer, and condenser. After that, the temperature of the reaction solution was controlled at 60°C to 65°C and stirred for 3 hours. After the completion of the reaction, it was concentrated to dryness under reduced pressure to obtain a viscous oily substance, weighed 240 g, and the yield was 100%. The intermediates of the reaction in this step do not need to be purified in full and 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 the 10 hydroxycamptothecin (263 g, 0.67 mol) evenly, control the temperature of the reaction solution at 45℃~50℃ and stir for 6 hours. After the reaction is completed...

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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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