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Combretastatin compound preparation method

A technology of disodium salt and phosphate ester, which is applied in the field of medicine, can solve problems such as harsh conditions, difficulty in industrialized large-scale production, expensive raw materials, etc., and achieve the effect of simple operation method, easy preparation, and low price

Active Publication Date: 2007-06-06
PKU HEALTHCARE CORP LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The first method of preparing CA4P has more expensive raw materials, harsh conditions, and is not easy for large-scale industrial production; the second method is a "one-pot method", although simple, but because CA4P is very soluble in water, it is difficult Separation, resulting in difficulties in product quality control

Method used

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  • Combretastatin compound preparation method
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  • Combretastatin compound preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Preparation of tert-butoxyphosphoryl dichloride

[0033] Add 30.7g (0.2mol) of phosphorus oxychloride and 20ml of dichloromethane into a 100ml reaction flask, cool to below 0°C, add 14.8g (0.2mol) of tert-butanol dropwise, then naturally warm up to room temperature and react for 3 hours. The solvent was first evaporated under reduced pressure, and then 32.3 g of the product was evaporated under reduced pressure with an oil pump, with a yield of 84.5%.

Embodiment 2

[0035] Preparation of 2-chloroethoxyphosphoryl dichloride

[0036] Add 30.7g (0.2mol) of phosphorus oxychloride and 20ml of dichloromethane into a 100ml reaction flask, cool to below 0°C, add 16.1g (0.2mol) of 2-chloroethanol dropwise, then naturally warm up to room temperature and react for 3.5 hours , first evaporate the solvent under reduced pressure, and then use an oil pump to evaporate 29.8 grams of product under reduced pressure, with a yield of 75.5%.

Embodiment 3

[0038] Synthesis of p-nitrophenoxyphosphoryl dichloride

[0039] Add 30.7g (0.2mol) of phosphorus oxychloride and 20ml of dichloromethane into a 100ml reaction flask, cool to below 0°C, add dropwise a solution of 27.8g (0.2mol) of p-nitrophenol in dichloromethane, and then raise the temperature naturally After reacting at room temperature for 3 hours, the solvent was first evaporated under reduced pressure, and recrystallized from petroleum ether to obtain 36.6 g of the product, with a yield of 71.5%.

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Abstract

The invention provides a process for preparing combretastatin-A4 disodium phosphate, which comprises using Combretastatin A-4 as raw material, first preparing phoramidic dihalides (II), then reacting Combretastatin A-4 with phoramidic dihalides (II) to obtain phosphodiester (III), finally carrying out hydrolysis and salt-forming to obtain CA4P(I).

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a new preparation method of organophosphate prodrugs. Background technique [0002] In 1971, Folkman first proposed that tumor growth is vascular-dependent. The proliferation rate of tumor vascular endothelial cells is about 50 times higher than that of endothelial cells in normal tissues. Therefore, the use of vascular inhibitors has a relatively specific effect on tumor blood vessels, but will not cause significant effects on blood vessels in normal tissues (may interfere with neovascularization of pregnancy and menstruation). With the discovery of the first angiogenesis inhibitor in 1982 and the completion of a series of work such as the purification of the first angiogenesis active protein in 1984, the above views are supported by more and more evidence, making this field a Hotspots in cancer research and new strategies for cancer treatment. [0003] Combretastatin A-4 (C...

Claims

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Application Information

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IPC IPC(8): C07F9/09
Inventor 马世宁贺清凯蔡中文左小勇
Owner PKU HEALTHCARE CORP LTD