Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt

A technology of compretin and phosphate ester, which is applied in the field of preparation of compretin A-4 phosphate disodium salt, can solve the problems of complicated purification methods, low yield, reduced yield and the like, and achieves easy industrial production. , The effect of high product yield and short reaction time

Active Publication Date: 2008-07-16
SICHUAN HENGXING BIOMEDICAL
View PDF2 Cites 11 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The purification process of this method is cumbersome
[0012] What above-mentioned patent adopts is: CA4 is the same as di-(2,2,2-trichloroethyl) chlorophosphate, its chemical property is lively, causes reaction product to be difficult for controlling, and yield is very low, and CA4P crude product is in pH value It is 12-14, the chemical properties are extremely unstable, and it will also cause a decrease in yield; at the same time, it will also cause subsequent purification met

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt
  • Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt
  • Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The investigation of embodiment 1 temperature and reaction time:

[0034] According to literature reports, the conventional CA4P synthesis reaction is carried out at low temperature, and the reaction takes a long time, which is not conducive to effective control of the reaction process. This experiment is a comprehensive verification of the reaction time and temperature, as follows:

[0035] Under nitrogen protection, 3.16g (0.01mol) of CA4, 0.06g (0.0005mol) of 4-N,N-lutidine and 1.42g (0.011mol) of diisopropylethylamine were dissolved in 20ml of dichloromethane, A solution of 2.51 g (0.011 mol) of di-(tert-butoxy)-phosphoryl chloride and 10 ml of dichloromethane was added dropwise at different temperatures. After the dropwise addition, keep the temperature and stir the reaction, monitor the reaction process with thin-layer chromatography, until the raw material point disappears, pour the reaction solution into 50ml ice water, separate the organic layer, extract the wa...

Embodiment 2

[0038]The preparation of embodiment 2 Compretastatin Combretastatin A-4 phosphate disodium salt

[0039] Under nitrogen protection, dissolve 3.16g (0.01mol) of CA4, 0.06g (0.0005mol) of 4-N,N-lutidine and 1.42g (0.011mol) of diisopropylethylamine in 20ml of dichloromethane , at 20°C, a solution of 2.51 g (0.011 mol) of di-(tert-butoxy)-phosphoryl chloride and 10 ml of dichloromethane was added dropwise. After the dropwise addition, keep the temperature and stir the reaction, monitor the reaction process with thin-layer chromatography, until the raw material point disappears, the reaction time is 0.5 hour, the reaction solution is poured into 50ml ice water, the organic layer is separated, and the water layer is refilled with 20ml diethyl alcohol. Methyl chloride was extracted once, the organic layers were combined, washed with water, dried, and evaporated to dryness to obtain a yield of 94% oil CA4-two-(tert-butoxy)-phosphate 4.77g, and put it into 50ml of pre-dried hydrogen c...

Embodiment 3

[0041] Embodiment 3 Preparation of Combretastatin Combretastatin A-4 Phosphate Disodium Salt

[0042] Under nitrogen protection, dissolve 3.16g (0.01mol) of CA4, 0.06g (0.0005mol) of 4-N,N-lutidine and 1.42g (0.011mol) of diisopropylethylamine in 20ml of dichloromethane , at 30° C., a solution of 2.45 g (0.011 mol) of bis-(2-cyanoethoxy)-phosphoryl chloride and 10 ml of dichloromethane was added dropwise. After the dropwise addition is completed, keep the temperature and stir the reaction, monitor the reaction process with thin layer chromatography, until the raw material point disappears, the reaction time is 0.8 hours, the reaction solution is poured into 50ml of ice water, the organic layer is separated, and the water layer is re-used with 20ml of two Extracted once with methyl chloride, combined the organic layers, washed with water, dried, and evaporated to dryness to obtain a yield of 93% oil CA4-two-(2-chloroethoxy)-phosphate 5.14g, which was dropped into 25ml of methan...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides a method for preparation of Combretastatin A-4 disodium phosphate. The method carries out the synthesis according to the synthesizing route shown on the right, wherein X is chlorine or bromine; are selected from tert-butyl, triphenyl methyl, 2-cynaoethyl, benzyl, phenyl, 4-nitrophenyl, 4-nitrobenzyl and 2-nitrobenzyl, R1 and R2 can be identical or different substituting groups. The method adopts bis-alkoxyl phosphoryl halide as the phosphorylation reagent, which is inexpensive and easy to acquire. Catalyst DMAP is added in the reaction to milden the reaction condition and stabilize the reaction temperature. The reaction time is short and the operation is simple. The phosphorylation intermediate needs no purification. The invention also has the advantages of high yield and quality of product and easy industrial production.

Description

technical field [0001] The invention relates to a preparation method of Combretastatin A-4 phosphate disodium salt. Background technique [0002] A major cause of death in humans as well as mammals is neoplastic disease. A distinctive feature of tumors is abnormal proliferation. Regardless of normal cells or tumor cells, the formation, differentiation and proliferation of metabolic mechanisms are inseparable from microvessels, and studies have shown that the proliferation rate of vascular endothelial cells in tumor cells is much faster than that of normal cells, so vascular inhibitors can specifically inhibit tumor blood vessels. At present, tumor blood vessel inhibitors are also a hot field in the research of antitumor drugs. [0003] Compretum A-4 (CA4) was first derived from the African willow (Combretum caffrum, Cmbretaceae) extract (Pettit, G.R., et al.; Experientia, 1989, 45, 209). The compound can significantly inhibit the polymerization of tubulin, thereby inhibit...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07F9/12
Inventor 黎鹏曾裕建邓建彬李好雨周伟陈春会
Owner SICHUAN HENGXING BIOMEDICAL
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap