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

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...

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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 methods to be complicated, and ion exchange resins will be used for separation and purification, which will greatly increase the cost and be more unfavorable for industrialized large-scale production

In addition to the use of (2,2,2-trichloroethyl), the above-mentioned patent application also mentioned the use of diphenyl carbon tetrabromide phosphate for the reaction. The purification method is also cumbersome and not convenient for industrialized large-scale production operations.

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