Method for preparing (Z)-3'-hydroxy-3,4,4',5-tetramethoxy diphenyl ethylene from regenerative natural plant resource

A tetramethoxystilbene, natural plant technology, applied in the field of medicine and chemical industry, can solve the problems of great harm to operators and the environment, low total yield, long operation route, etc. The effect of improved anti-selectivity and good biocompatibility

Inactive Publication Date: 2009-01-28
GUANGZHOU INST OF GEOCHEMISTRY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

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  • Method for preparing (Z)-3'-hydroxy-3,4,4',5-tetramethoxy diphenyl ethylene from regenerative natural plant resource
  • Method for preparing (Z)-3'-hydroxy-3,4,4',5-tetramethoxy diphenyl ethylene from regenerative natural plant resource
  • Method for preparing (Z)-3'-hydroxy-3,4,4',5-tetramethoxy diphenyl ethylene from regenerative natural plant resource

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Add 14.8g (0.1mol) of anethole, 8.88g of acetic acid, and 35.52g of cyclohexane in the reaction flask, stir evenly, control the reaction temperature at 20°C, and feed 2.7L (0.12mol) of O 3 , carry out ozonation reaction, 20min oxidation ends. Add NaHSO with a concentration of 200g / L in the three-necked flask 3 Aqueous solution 57mL, then slowly add ozonide dropwise, react at 80°C for 60min, cool down to 50°C, adjust to pH ≥ 10 with sodium hydroxide solution, stand and separate layers, the upper layer is the crude product of anisaldehyde, and the lower layer is the aqueous phase with cyclohexane After extracting the alkanes, add it to the crude product of anisaldehyde. The crude product of anisaldehyde is dried with anhydrous sodium sulfate and rectified under reduced pressure. p-Methoxybenzaldehyde weighs 10.88g, and the yield is 80%.

Embodiment 2

[0051] Add 14.8g (0.1mol) of anethole, 8.88g of acetic acid, and 35.52g of cyclohexane in the reaction flask, stir evenly, control the reaction temperature at 0°C, and feed 2.24L (0.10mol) of O 3 Carry out ozonation reaction, 40min oxidation finishes. Add NaHSO with a concentration of 200g / L in the three-necked flask 3 Aqueous solution 52mL, then slowly add ozonide dropwise, react at 60°C for 90min, cool down to 50°C, adjust to pH ≥ 10 with sodium hydroxide solution, stand and separate layers, the upper layer is the crude anisaldehyde, and the lower layer is the aqueous phase with cyclohexane After extracting the alkanes, add it to the crude product of anisaldehyde. The crude product of anisaldehyde is dried with anhydrous sodium sulfate and rectified under reduced pressure. p-Methoxybenzaldehyde weighs 9.79g, and the yield is 72%.

Embodiment 3

[0053] Add 14.8g (0.1mol) of anethole and 44.4g of ethanol in the reaction flask, stir well, control the reaction temperature at 0°C, adjust the ozone flow, and then feed 4.48L (0.20mol) of O 3 Carry out ozonation reaction, 40min oxidation finishes. Add concentration of 200g / L Na in the three-necked flask 2 SO 3 Aqueous solution 57mL, then slowly add ozonide dropwise, react at 60°C for 90min, cool down to 50°C, adjust to pH ≥ 10 with sodium hydroxide solution, stand and separate layers, the upper layer is the crude product of anisaldehyde, and the lower layer is the aqueous phase with cyclohexane After extracting the alkanes, add it to the crude product of anisaldehyde. The crude product of anisaldehyde is dried with anhydrous sodium sulfate and rectified under reduced pressure. p-Methoxybenzaldehyde weighs 9.52g, and the yield is 70%.

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Abstract

The invention discloses a preparation method for (Z)-3'-hydroxyl-3,4,4',5-tetramethoxyl diphenyl ethylene. A diphenyl ethylene framework structure is built by the Perkin reaction method, and natural aniseed fat-soluble components and propenyl anisole (anethole) are taken as raw materials, and oxidized to obtain anisaldehyde; dichlorocarbene insertion reaction is carried out on the anisaldehyde to obtain p-methoxyl-mandelic acid which is reduced to obtain methoxyl-phenylacetic acid, the methoxyl-phenylacetic acid is brominized to obtain 3-bromo-4-methoxyl-phenylacetic acid. The compound and the natural 3,4,5-trimethoxybenzaldehyde (nutgall extract derivative) carry out Perkin reaction to build a cis-form diphenyl ethylene framework which is further converted and decarboxylated by functional groups to obtain the (Z)-3'-hydroxyl-3,4,4',5-tetramethoxyl diphenyl ethylene. The raw materials of the invention are reproducible natural resources-anethole which are rich in China and 3,4,5-trimethoxybenzaldehyde, and replace non-renewable petrochemical materials which are used by the prior art and become less and less so that the method has the advantages of good sustainable development capability as well as 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'-hydroxyl-3,4,4',5-tetramethoxystilbene (Combretastatin A-4, referred to as CA4, see formula (1) for structure) is a kind of polyhydroxystilbene class of natural products. 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,...

Claims

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Application Information

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IPC IPC(8): C07C43/23C07C41/18A61P35/00
Inventor 邹永都建立肖春芬林慧贞何树杰
Owner GUANGZHOU INST OF GEOCHEMISTRY - CHINESE ACAD OF SCI
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