Docetaxel conjugate preparation method based on mesoporous material self-assembly system

A technology of docetaxel and docetaxel ester, which is applied in chemical instruments and methods, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., and can solve unfavorable industrial production, long reaction time, and multiple reactions. Steps and other issues, to achieve the effect of promoting esterification steps, simplifying the process flow, and simple operation

Inactive Publication Date: 2018-09-11
张海英
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, the docetaxel conjugate method disclosed in the prior art has obvious disadvantages in the preparation process: almost all require longer reaction time and more reaction steps, as well as necessary intermediate separation and purification steps , resulting in low yield and low purity of the product; unfavorable for industrialized production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0057] Preparation of carboxyl-modified mesoporous materials:

[0058] (1) Preparation of mesoporous silica particles:

[0059] Mix 700mmol of ethanol, 5.8g of cetyltrimethylammonium chloride (CTAC), and 150ml of deionized water, add 30ml of triethanolamine, stir and raise the temperature to 55°C, replace with nitrogen, and add 15ml of orthosilicic acid dropwise at 2mL / min Ethyl ester (TEOS), then reacted for 1 hour, cooled to room temperature, centrifuged at 9000r / min for 10min, washed the solid with water and ethanol respectively, then dispersed in 600ml ethanol and 100ml 38wt% hydrochloric acid mixed solution system, and refluxed at 55°C for 3h. After reflux, wash with water and ethanol respectively, centrifuge, and dry in vacuum to obtain mesoporous silica particles for future use.

[0060] (2) 0.5mol succinic anhydride and 0.25mol polyaminosilane coupling agent N-(β-aminoethyl)-γ-aminopropylmethyldimethoxy were stirred and reacted for 5 minutes under ice bath conditions,...

Embodiment 1b

[0063] Preparation of carboxyl-modified mesoporous materials:

[0064] (1) 0.4mol succinic anhydride and 0.2mol polyaminosilane coupling agent N-(β-aminoethyl)-γ-aminopropylmethyldimethoxy were stirred and reacted for 5min under ice-bath conditions, and placed in an ice-water bath Cool for 10 minutes, filter under reduced pressure, and dry to obtain a solid carboxysilane coupling agent;

[0065] (2) Weigh 100g of commercially available mesoporous silica particles (40-50nm particle size) and 8g of carboxysilane coupling agent solids, and disperse them in 500ml of ethanol, adjust the pH to 9, stir and react at 35°C for 5h, and the reaction ends Finally, centrifuge, wash the solid matter twice with absolute ethanol, disperse it in methanol, add 100ml of 38% concentrated hydrochloric acid solution, and reflux at 50°C for 3h; centrifuge after the end of reflux, wash with anhydrous methanol, and vacuum dry. Carboxyl-modified mesoporous silica particles were obtained.

Embodiment 2

[0067] Preparation of paclitaxel ester-mesoporous silica self-assembly:

[0068] Add 10mmol of docetaxel, 10g of the carboxy-modified silica particles prepared in Example 1a and 0.5mmol of p-toluenesulfonic acid-4-(dimethylamino)pyridinium salt into a reaction vessel with a stirring bar, and Atmosphere replacement, then add 150ml of ethylene dichloride / pyridine composite solvent with a volume ratio of 3:1, stir and react at room temperature for 3h to carry out self-assembly to obtain a paclitaxel ester-mesoporous silica self-assembly mixture, and place the resulting mixture in Concentrate in vacuo at 50°C, wash the concentrate with dilute hydrochloric acid aqueous solution, and dry the obtained organic phase with anhydrous sodium sulfate, then evaporate most of the solvent to obtain 25 ml of paclitaxel ester-mesoporous silica self-assembly concentrate.

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Abstract

The invention provides a method for preparing a docetaxel conjugate under a carboxyl-modified mesoporous silica self-assembly system. The method comprises the following steps: preparing carboxyl-modified mesoporous silica particles; preparing a docetaxel ester-mesoporous silica self-assembly body; in the presence of a catalyst PyBOP and a reaction assistant n-propyl phosphoric anhydride, adding acondensating agent, enabling the prepared docetaxel ester-mesoporous silica self-assembly body and a coupling component to perform an esterification reaction in a dimethylsulfoxide solvent, and generating the docetaxel conjugate. The method is capable of, through using the combination of the modification mesoporous material and a catalyst / promoter system, forming a reaction interface on the surface of the mesoporous material, promoting a coupled reaction to be performed, and greatly improving the reaction efficiency.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical compound, in particular to a method for synthesizing a docetaxel conjugate, and belongs to the fields of organic synthesis and pharmaceutical chemical synthesis. Background technique [0002] Taxol (Paclitaxel, trade name Taxol), is a taxane diterpenoid compound isolated from Taxus (Taxus) plants. One of the good anticancer drugs. After the United States, paclitaxel as a first-line anticancer drug has been approved for marketing in more than 40 countries. [0003] Docetaxel (Docetaxel, trade name Taxotere), chemical name 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytaxane-11-en-9-one-4,10- Diacetate-2-benzoate-13-[(2'R,3'S)-N-benzoyl-3-phenylisoserine ester is a chemically modified derivative of paclitaxel, and its mechanism of action is similar to that of Paclitaxel is similar in that it promotes tubulin polymerization, inhibits microtubule depolymerization, and inhibits cell division,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/61A61K47/54A61K47/52A61K31/337A61P35/00B01J31/02
CPCA61K31/337A61K47/52A61K47/542A61K47/61A61P35/00B01J31/0274
Inventor 张海英周兰兰
Owner 张海英
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