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

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 toobtain 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,...

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 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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