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A kind of preparation method of irinotecan hydrochloride

A technology of irinotecan hydrochloride and irinotecan, which is applied in the direction of organic chemistry, can solve the problem of increasing reaction steps, achieve the effect of simplifying the reaction process, shortening the production cycle, and obvious advantages in industrial production

Active Publication Date: 2022-05-03
CISEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method does not use phosgene substances to activate 4-piperidinylpiperidine, but the chloroformate used in this method is still highly toxic, so the increase in reaction steps seems meaningless

Method used

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  • A kind of preparation method of irinotecan hydrochloride
  • A kind of preparation method of irinotecan hydrochloride
  • A kind of preparation method of irinotecan hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] a) 500ml three-mouth reaction bottle containing 10.0g of cotton resin complex and 0.02% water of N, N-dimethylformamide (DMF) 300mL, stirred to add 7-ethyl-10-hydroxycamptothecin (78.5g, 0.2mol), N, N,N'-carbonyldiimidazole (48.6g, 0.3mmol), room temperature continued to stir for 30min and then added 4-piperidinyl piperidine (33.7g, 0.2mol), after addition, Control the reaction liquid temperature 35 °C ~ 50 °C stirring for 4h. After the reaction is completed, transfer to 2000ml of separating funnel, add 300ml of purified water 300ml of dichloromethane, extract the dispense, the aqueous phase is extracted once with 300ml of dichloromethane, combined with the organic phase, and concentrated under reduced pressure to dry irinotecan monomer crude 107.81g, without purification.

[0020] b) 3000ml three-mouth reaction bottle added irinotecan monomer crude, add purified water 400ml, control system temperature 15 °C ~ 20 °C, stir under the drops of concentrated hydrochloric acid (36...

Embodiment 2

[0022] a) 500ml three-mouth reaction bottle was added with 10.0g of hemp cotton resin complex and 0.02% water of acetonitrile 400mL, stirred under the addition of 7-ethyl-10-hydroxycamptothecin (78.5g, 0.2mol), N,N'-carbonyldimidazole (48.6g, 0.3mmol), room temperature continued to stir for 30min and then added 4-piperidinyl piperidine (33.7g, 0.2mol), after addition, the reaction liquid temperature was controlled 45 °C ~ 50 °C stirred for 4h. After the reaction is completed, transfer to 2000ml of separating funnel, add 300ml of purified water 300ml of dichloromethane, extract the dispense, the aqueous phase is extracted once with 300ml of dichloromethane, combined with the organic phase, and concentrated under reduced pressure to dry irinotecan monomer crude, without purification.

[0023] b) 3000ml three-mouth reaction bottle added irinotecan monomer crude, add purified water 400ml, control system temperature 15 °C ~ 20 °C, stir under the drops of concentrated hydrochloric acid ...

Embodiment 3

[0025]a) 500ml three-mouth reaction bottle was added 300mL of dichloromethane containing 10.0g of hemp cotton resin complex and 0.02% water, 7-ethyl-10-hydroxycamptothecin (78.5g, 0.2mol), N,N'-carbonyldiimidazole (48.6g, 0.3mmol) was added at room temperature for 30min, and then added 4-piperidylpiperidine (33.7g, 0.2mol), after addition, the temperature of the control reaction liquid was stirred at 35 °C ~ 40 °C for 6h. After the reaction is completed, transfer to the separating funnel, add 200ml of purified water, dispense, the aqueous phase is extracted once with 300ml of dichloromethane, combined with the organic phase, and concentrated under reduced pressure to dry irinotecan monomer crude product, without purification.

[0026] b) 3000ml three-mouth reaction bottle added irinotecan monomer crude, add purified water 400ml, control system temperature 15 °C ~ 20 °C, stir under the drops of concentrated hydrochloric acid (36%) to adjust pH = 2 ~ 3, system clarification, drops ...

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Abstract

The invention relates to a preparation method of irinotecan hydrochloride. It includes the following steps: a) 4-piperidinylpiperidine and N,N'-carbonyldiimidazole react with 7-ethyl-10-hydroxycamptothecin in an aprotic solvent containing hemp cotton resin complex to generate Irinotecan monomer; b) add hydrochloric acid solution to adjust pH to 2~3 after adding water to dissolve irinotecan monomer, add the acetone of 3-5 times of water volume, crystallize, filter, reconstitute with the mixed solvent of acetone and water The finished product of irinotecan hydrochloride was obtained after the crystallization was vacuum-dried. Compared with the prior art, the present invention does not use highly toxic and dangerous reagents when preparing irinotecan hydrochloride, but uses commercially available and relatively stable N,N'-carbonyldiimidazole to introduce carbonyl groups, one-step The irinotecan monomer is obtained by the reaction, and the harsh condition that N,N'-carbonyldiimidazole needs to be anhydrous is avoided by coordinating the hemp cotton resin complex, which greatly simplifies the reaction process and shortens the production cycle. Advantages of industrial production.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical preparation technology, specifically relates to a method of preparation of irinotecan hydrochloride. Background [0002] Irinotecan Hydrochloride is a water-soluble camptothecin derivative jointly developed by Daiichi Seiyaku and Yakult Honsha in Japan. Clinically used is irinotecan hydrochloride trihydrate, chemical name: (+)-(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinylpiperidine)carbonyl]-1H-pyrano[3,4:6,7]indole[1,2b]quinoline-3,14-(4H,12H)-diketone hydrochloride, structured as follows: [0003] [0004] Chinese patent CN101314587 reports a preparation method of irinotecan, the route is 4-piperidinyl piperidine reacts with triphosgene to form 4-piperidine piperidinecarbonyl chloride, and then reacts with 7-ethyl-10-hydroxycamptothecin to give irinotecan under the action of pyridine. Pyridine has a foul odor, the test operator has dizziness and other discomfort; pyridine is easy to oxidize a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22
CPCC07D491/22
Inventor 党祥玉沈广宾
Owner CISEN PHARMA