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Method of preparing (Z)-3'-hydroxyl-3,4,4',5-tetramethoxy toluylene

A technology of tetramethoxystilbene and trimethoxybenzene, which is applied in the field of medicine and chemical industry, can solve the problems of great harm to operators and the environment, low total yield, high price, etc., and achieve good sustainable development capabilities, Improvement of cis-selectivity and reduction of synthesis cost

Inactive Publication Date: 2009-04-08
GUANGZHOU INST OF GEOCHEMISTRY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there are mainly three kinds of methods for preparing (Z)-3'-hydroxyl-3,4,4',5-tetramethoxystilbene reported in the literature: (1) Wittig reaction method (J.Med.Chem, 1995, 38: 1666), this method uses the highly toxic and expensive triphenylphosphine, the free hydroxyl group of the raw material isovanillin needs to be protected, and the Wittig reaction needs to be carried out under harsh conditions such as a low temperature of -78°C and absolute anhydrous, The operation route is relatively long and the total yield is low
(2) Suzuki reaction method and its improved method, the synthesis process of the intermediate (Z)-5-(2′-bromoethylene)-2-methoxyphenol involved in the Suzuki reaction method is cumbersome, raw materials 3, 4, The price of 5-trimethoxyphenylboronic acid is expensive; Suzuki's improved method adopts reagents such as triphenylphosphine, organic palladium reagent (Ph 3 P) 4 Pd, etc. are relatively expensive, and the preparation of intermediates 1,1-dibromo-3',4',5'-trimethoxystyrene and 5-iodo-2-methoxyphenol is also difficult
(3) Perkin reaction method (Liebigs.Ann.Chem, 1996, 2107; Synthesis, 1999, 9: 1656; J.Org. Chem, 2001, 66: 8135), the petrochemical raw materials used in this reaction 3, 4, 5 - Trimethoxyphenylacetic acid is expensive and has no industrial source, and highly toxic substances such as sodium cyanide are needed in the preparation process, which causes serious environmental pollution and is very harmful to operators and the environment

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  • Method of preparing (Z)-3'-hydroxyl-3,4,4',5-tetramethoxy toluylene

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Effect test

Embodiment 1

[0038] Add 3.92g (0.02mol) of 3,4,5-trimethoxybenzaldehyde, 0.5g of tetrabutylammonium bromide (TBAB) and 25ml of chloroform in a 100ml three-necked flask equipped with a thermometer, a reflux condenser, and a dropping funnel , be warming up to 60 ℃ after stirring and dissolving, begin to drip 5ml concentration slowly and be the sodium hydroxide aqueous solution of 50%, stop reaction after reacting for 6 hours, naturally cool to room temperature, suction filter and wash with ethanol, obtain white powdery solid ( sodium chloride and 3,4,5-trimethoxysodium mandelate), recrystallized with water to obtain white crystals which were 3.18 g of 3,4,5-trimethoxysodium mandelate, and the yield was 60.2%.

Embodiment 2

[0040] Add 3,4,5-trimethoxybenzaldehyde 3.92g (0.02mol), tetraethylammonium bromide (TEAB) 0.5g and 25ml chloroform in a 100ml three-necked flask equipped with a thermometer, a reflux condenser, and a dropping funnel , be warming up to 30 ℃ after stirring and dissolving, begin to slowly add 2ml concentration and be the sodium hydroxide aqueous solution of 20%, stop reaction after reacting for 12 hours, naturally cool to room temperature, suction filter and wash with ethanol, obtain white powdery solid ( sodium chloride and 3,4,5-trimethoxysodium mandelate), recrystallized with water-ethanol to obtain white crystals which were 2.98 g of 3,4,5-trimethoxysodium mandelate, and the yield was 56.4%.

Embodiment 3

[0042] Add 3,4,5-trimethoxybenzaldehyde 3.92g (0.02mol), cetyltriethylammonium bromide (CTMAB) 0.5 g and 25ml of chloroform, stirring and dissolving, then warming up to 80°C, slowly adding 8ml of 50% sodium hydroxide aqueous solution dropwise, stopping the reaction after 2 hours of reaction, naturally cooling to room temperature, suction filtration and washing with ethanol to obtain white Powdery solid (sodium chloride and 3,4,5-trimethoxysodium mandelate), add 1:1 hydrochloric acid to acidify to PH=2~3, extract with ethyl acetate, dry over anhydrous magnesium sulfate, concentrate, and Ethyl acetate-petroleum ether was recrystallized to obtain 2.91 g of 3,4,5-trimethoxymandelic acid as a slightly yellow solid, with a yield of 60.1%.

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Abstract

The invention discloses a method for preparing (Z)-3'-hydroxy radical -3,4,4',5-tetra- methoxyl diphenyl ethylene by the material of renewable natural plant resource. Naturally sourced 3,4,5-tri-methoxybenzaldehyde (a derivative extracted from Chinese gall) is taken as the raw material; and 3,4,5-tri-methoyl mandelic acid is obtained through a dichlorocarbene insertion reaction and is reduced to obtain 3,4,5-tri-methoyl phenylacetic acid. The compound can have a Perkin reaction with naturally sourced isovanillin to construct a cis-form diphenyl ethylene backbone, and the (Z)-3'-hydroxy radical -3,4,4',5-tetra- methoxyl diphenyl ethylene is obtained after a decarboxylic reaction. The method adopts the renewable resource-isovanillin and the 3,4,5-tri-methoxybenzaldehyde rich in China to replace increasingly exhausted petrochemical materials, thereby having a good sustainable development capability and remarkable economic, environmental and ecological benefits.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a method for preparing (Z)-3'-hydroxyl-3,4,4',5-tetramethoxystilbene by using renewable natural plant resources as raw materials. Background technique [0002] (Z)-3'-Hydroxy-3,4,4',5-tetramethoxystilbene (Combretastatin A-4, referred to as CA4, see formula 1 for structure) is a natural polyhydroxy stilbene product. Studies have confirmed that the compound can selectively inhibit tubulin polymerization and anti-mitosis, has strong anti-vascular and anti-tumor activities, and can be used as a lead compound for the treatment of tumors and related diseases caused by abnormal proliferation of blood vessels. The water-soluble phosphorylated prodrug CA4P of CA4 has entered phase III clinical research in the United States and Europe, and has huge market potential. [0003] [0004] Formula 1 [0005] Combretastatin A-4 is extremely rare in nature, and is currently onl...

Claims

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Application Information

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IPC IPC(8): C07C43/23C07C41/18A61P35/00
Inventor 邹永都建立魏文陈爱民
Owner GUANGZHOU INST OF GEOCHEMISTRY - CHINESE ACAD OF SCI
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