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Water-soluble 4í»-nor-epipodophyllotoxin derivant and preparation method thereof

A kind of technology of norepiopodophyllin and derivatives, which is applied in the field of derivatives of 4'-norepodophyllotoxin to achieve the effects of simplifying post-processing process, improving reaction yield and improving reaction selectivity

Inactive Publication Date: 2008-12-03
NINGBO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no scientific literature report on the modification of 4'-norpodophyllotoxin with polyethylene glycol as a modifier

Method used

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  • Water-soluble 4í»-nor-epipodophyllotoxin derivant and preparation method thereof
  • Water-soluble 4í»-nor-epipodophyllotoxin derivant and preparation method thereof
  • Water-soluble 4í»-nor-epipodophyllotoxin derivant and preparation method thereof

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preparation example Construction

[0024] The preparation route of the present invention is:

[0025] Put 4'-norepipodophyllotoxin and carboxyl monomethoxypolyethylene glycol in a reaction vessel, add dicyclohexylcarbodiimide and dimethylaminopyridine to mix the reactants evenly, and catalyze After 30 minutes of reaction, the 4'-norepipodophyllotoxin prodrug can be prepared.

Embodiment 1

[0027] In a 25ml Erlenmeyer flask, add 1.00g (0.5mmol) mPEG-COOH 2000, 0.30g (0.75mmol) 4'-norepipodophyllotoxin, 0.21g (1.0mmol) dicyclohexylcarbodiimide and 0.12 g (1.0mmol) p-N, N-dimethylaminopyridine, fully shaken to mix the reactants evenly, then placed in a Whirlpool microwave oven, and heated at a power of 510W for 30min to complete the esterification reaction until no more When the water droplets are generated. After the reacted mixture was dried and cooled in a vacuum oven, 40ml of anhydrous dichloromethane was added, shaken thoroughly, filtered, and part of the dichloromethane was evaporated from the filtrate, then 80ml of anhydrous diethyl ether was added to precipitate a white precipitate. The above sample was cooled in a refrigerator at 4-10°C, filtered with suction, and dried to obtain a white solid weighing 1.20 g.

[0028] Add 40ml of dichloromethane to the above crude product to dissolve it, then add 20ml of 10% AcOH / THF to decompose excess dicyclohexylcarbo...

Embodiment 2

[0030] In a 25ml Erlenmeyer flask, add 2.50g (0.5mmol) mPEG-COOH 5000, 0.30g (0.75mmol) 4'-norepipodophyllotoxin, 0.21g (1.0mmol) dicyclohexylcarbodiimide and 0.12 g (1.0mmol) p-N,N-dimethylaminopyridine, fully shaken to mix the reactants evenly, then placed in a Whirlpool microwave oven, and heated at a power of 510W for 30min to complete the esterification reaction until no more When the water droplets are generated. After the reacted mixture was dried and cooled in a vacuum oven, 40ml of anhydrous dichloromethane was added, shaken well, filtered, and part of the dichloromethane was evaporated from the filtrate, then 80ml of anhydrous ether was added to precipitate a white precipitate. The above sample was cooled in a refrigerator at 4-10°C, filtered with suction, and dried to obtain a white solid weighing 2.74 g.

[0031] In the above crude product, add 40ml of dichloromethane to dissolve, add 20ml of 10% AcOH / THF to decompose excess dicyclohexylcarbodiimide, wash with 20m...

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Abstract

The invention provides a derivative of a water soluble 4'-nor epipodophyllotoxin. The derivative is characterized in that the derivative is a polyethylene glycol derivative, the structure formula of which is the 4'- nor epipodophyllotoxin. The preparation method comprises the following the steps that: the 4'- nor epipodophyllotoxin, carboxyl single methoxypolyethylene glycol, dicyclohexyl imine and N dimethylaminopyridine are used as raw materials to prepare the polyethylene glycol derivative of the 4'- nor epipodophyllotoxin by the microwave catalytic action. The 4'- nor epipodophyllotoxin prodrug of the invention is good in solubility and high in stability. The preparation of the invention has the characteristics of high efficiency, rapidness, simpleness and convenience and high reaction yield.

Description

technical field [0001] The invention relates to a water-soluble derivative of 4'-norepipodophyllotoxin and a related preparation method, which is a derivative of 4'-norepipodophyllotoxin modified by polyethylene glycol. Background technique [0002] Podophyllotoxin is a natural compound with anti-tumor activity. It has strong cytotoxicity, but due to its serious toxicity, it cannot be directly used in clinical practice. It must be modified through its structure, such as: etoposide , teniposide and other podophyllotoxin derivatives have been developed into antineoplastic drugs for clinical application. The structure-activity relationship studies of podophyllotoxins show that podophyllotoxins and their analogs must meet the following conditions to maintain their anticancer activity: (1) there is a phenolic hydroxyl group at the 4'-position; (2) the C-4 substituent position is β configuration; (3) has a trans-lactone ring. Therefore, people epimerized 4'-norpodophyllotoxin on...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/365A61P35/00C07D493/04A61K47/60
Inventor 张剑锋侯琳熙
Owner NINGBO UNIV
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