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Method for preparing Combretastatin A-1 phosphate ester tetrasodium salt

A technology of compretidine and phosphate, which is applied in the field of synthesis and preparation of the antineoplastic drug compretidine phosphate tetrasodium salt, can solve the problems of unsuitable for large-scale industrial production, harsh reaction conditions, high process cost, etc., and achieve the reaction cost Savings, mild response requirements, simple and convenient operation

Active Publication Date: 2009-08-26
NANJING CHENGONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Using DIPEA to react with compretidine A-1, not only the reaction conditions are relatively harsh, but the reaction needs to be carried out at -20°C, which is not suitable for large-scale industrial production; this method needs to use carbon tetrachloride, which is highly toxic and harmful to the environment, as the initiator of the reaction agent, so that the production of this product is further restricted; at the same time, the method for removing benzyl groups uses more expensive TMSCl, sodium iodide, etc., resulting in higher cost of the whole process

Method used

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  • Method for preparing Combretastatin A-1 phosphate ester tetrasodium salt
  • Method for preparing Combretastatin A-1 phosphate ester tetrasodium salt
  • Method for preparing Combretastatin A-1 phosphate ester tetrasodium salt

Examples

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Embodiment 1

[0041] This example illustrates R 1 , R 2 When both are hydrogen atoms and X is a chlorine atom, that is, when dihydrocarbyloxyphosphoryl chloride / bromine is chlorophosphoric acid, the preparation method of compretidine A-1 phosphate tetrasodium salt.

[0042] Preparation of chlorophosphoric acid:

[0043] Add phosphorus oxychloride (153.3 g, 1.0 mol) to the reaction flask equipped with agitator, thermometer, dropping funnel and hydrogen chloride tail gas absorption device, and add 36 L of deoxygenated water dropwise from the dropping funnel under ice-water bath cooling, During this process, hydrogen chloride gas is generated, so sodium hydroxide solution can be used as an absorbent. After the dropwise addition, the ice-water bath was removed, and stirred at room temperature for 0.5 h, and the obtained chlorophosphoric acid was directly used in the next reaction.

[0044] 1. Preparation of phosphonate ester of compretidine A-1:

[0045]Add compretidine A-1 (166.2g, 0.5mol)...

Embodiment 2

[0047] This example illustrates R 1 , R 2 When both are tert-butyl and X is a bromine atom, that is, the preparation method of compretidine A-1 phosphate tetrasodium salt when dihydrocarbyloxyphosphoryl chloride / bromine is di-(tert-butyl)-phosphoryl bromide .

[0048] In a reaction flask equipped with a stirrer, a thermometer and a dropping funnel, add compretidine A-1 (166.2g, 0.5mol), triethylamine (101g, 1.0mol) and 1,1-dichloromethane 1660mL, Di-(tert-butyl)-phosphoryl bromide (228.7 g, 1.0 mol) was added dropwise under cooling in an ice-water bath, and the reaction temperature was controlled at 10°C. The organic layer was taken out, and the aqueous layer was extracted once with 1000mL 1,1-dichloromethane. The organic layers were combined, washed with water, dried, and evaporated to dryness to obtain Compreletin A-1 di-(tert-butyl)phosphonate (420g, 0.48mol), put it into 1500mL methanol solution, add dropwise 300mL of 8N hydrogen chloride methanol solution under ice-wat...

Embodiment 3

[0050] This example illustrates R 1 , R 2 When both are benzyl and X is a chlorine atom, that is, when dihydrocarbyloxyphosphoryl chloride / bromine is di-(benzyl)-phosphoryl chloride, the preparation method of compretidine A-1 phosphate tetrasodium salt.

[0051] In the reaction flask equipped with stirrer, thermometer and dropping funnel, add compretidine A-1 (166.2g, 0.5mol), triethylamine (101g, 1.0mol) and N,N-dimethylformamide 1660mL, add di-(benzyl)-phosphoryl chloride (296.7g, 1.0mol) dropwise under ice-water bath cooling, control the reaction temperature at 30°C, after the dropwise addition, stir at room temperature for 1.5h, pour the reaction solution into 1000mL ice water, The organic layer was separated, and the aqueous layer was extracted once with 1000mL N, N-dimethylformamide, and the organic layers were combined, washed with water, dried, and evaporated to dryness to obtain Compreletin A-1 di-(benzyl)phosphate (456g, 0.45mol), it was dropped into 1000mL N,N-dim...

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Abstract

The invention relates to a method for synthesizing and preparing antineoplastic Combretastatin A-1 phosphate ester tetrasodium salt, comprising the steps: under the anhydrous condition, Combretastatin A-1 is dissolved in aprotic polar solvent, and dialkyl oxyl phosphoryl chloride / bromine (chloride / bromine phosphoric acid when R1 and R2 are hydrogen atoms) is dipped into the solution when acid-binding agent exists for reaction, and water is added into the reaction solution for stopping the reaction when the reaction is finished; products are extracted by the aprotic polar solvent, and then is decompressed and concentrated until being dried, so that the Combretastatin A-1 phosphate ester is obtained; (2) the obtained Combretastatin A-1 phosphate ester is dissolved into polar organic solvent to remove R1 and R2 radicals, and then obtained product is salified with sodium methoxide, finally, the Combretastatin A-1 phosphate ester tetrasodium salt is obtained. The method has simple and convenient technique, high yield coefficient and utilization rate of the Combretastatin A-1, and low production cost.

Description

technical field [0001] The invention relates to the synthesis and preparation of an antitumor drug Combretastatin A-1 phosphate tetrasodium salt, belonging to the technical field of pharmaceutical engineering. Background technique [0002] Cancer has become the second killer of human after cardiovascular disease. Currently commonly used methods of anti-cancer chemotherapy and radiotherapy can cause severe side effects that are harmful to the human body. Combretastatin A-1 is a polyhydroxy stilbene natural product isolated from the bark of the African shrub Combretum Caffrum for the first time. It is a tubulin binding agent and can interfere with tumor vascular endothelial cells. It has a strong anti-vascular effect, inhibits the growth of cancer cells, inhibits tubulin aggregation and sensitizes radiotherapy and chemotherapy. The chemical structural formula of compretin A-1 is as follows: [0003] [0004] The water solubility of compretidine A-1 is extremely poor, so ...

Claims

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Application Information

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IPC IPC(8): C07F9/12
Inventor 郭昭
Owner NANJING CHENGONG PHARM CO LTD
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