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Preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene

A technology of dihydroxystilbene and tetramethoxy, which is applied in ether preparation, organic chemistry, etc., can solve the problems of difficult preparation of intermediates, expensive raw materials and palladium catalysts, and difficulty in obtaining industrial applications, and achieves cis The effect of high selectivity, low cost and easy operation

Inactive Publication Date: 2014-08-20
GUANGZHOU CHEM CO LTD CHINESE ACADEMY OF SCI
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

Bui and Odlo used Suzuki and Sonogashira reactions to synthesize CA1 respectively, and the cis-selectivity was greatly improved compared with the Wittig reaction (Document: Tetrahedron Letters, 2002, 43:2839-2841; Tetrahedron Letters, 2006, 47: 1101-1103.) , but the intermediates involved, such as aryl borate and aryl halide, are not easy to prepare, and the raw materials and palladium catalysts are relatively expensive, and low temperature reaction conditions of -78°C are required
The above synthesis method is difficult to obtain industrial application

Method used

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  • Preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene
  • Preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] (1) Add 82.38g (216mmol) of borax and 500ml of purified water into a 1000ml three-neck flask, add 16.70g (108mmol) of 2,3,4-trihydroxybenzaldehyde while vigorously stirring, stir at 20°C for 30min, and add dropwise Dimethyl sulfate 21ml (216mmol) and NaOH solution (8.86g NaOH+90mlH 2 O), continue to stir for 15 hours, then add concentrated hydrochloric acid (37% by mass) to adjust to pH = 2, extract 3 times with chloroform, take the chloroform extraction layer, wash with saturated brine and wash with anhydrous Na 2 SO 4 After drying, a light yellow solid was obtained, which was recrystallized from chloroform / petroleum ether to obtain 11.79 g of 2,3-dihydroxy-4-methoxybenzaldehyde as a bright yellow needle-like solid, with a yield of 65.0%;

[0076] The characterization parameters of 2,3-dihydroxy-4-methoxybenzaldehyde are as follows:

[0077] EI-Ms m / z:168(M + ),150(M + -H 2 O);

[0078] 1 HNMR (400Hz, CDCl 3 ): δ11.08(s,1H,CHO),9.71(s,1H,2-OH,D 2 Oexchangeable...

Embodiment 2

[0100] (1) Add 80.09g (210mmol) of borax and 500ml of purified water into a 1000ml three-necked flask, and add 15.46g (100mmol) of 2,3,4-trihydroxybenzaldehyde while vigorously stirring, stir at 30°C for 30min, and add dropwise Dimethyl sulfate 20.4ml (216mmol) and NaOH solution (8.90g NaOH+90mlH 2 O), continue to stir for 16 hours, then add concentrated hydrochloric acid with a mass percentage of 37% to pH = 3, extract 3 times with chloroform, take the chloroform layer, wash it with saturated saline and wash it with anhydrous Na 2 SO 4 After drying, a light yellow solid was obtained, which was recrystallized from chloroform / petroleum ether to obtain 11.85 g of bright yellow needle-like solid 2,3-dihydroxy-4-methoxybenzaldehyde, with a yield of 65.3%;

[0101] (2) Add 6.72g (40mmol) of 2,3-dihydroxy-4-methoxybenzaldehyde, 70ml of DMF, anhydrous K 2 CO 3 11.04g (80mmol), heat to 60°C, add 7.5ml (80mmol) of bromoisopropane dropwise, keep the temperature in the reaction bottle...

Embodiment 3

[0106] (1) Add 82.38g (216mmol) of borax and 500ml of purified water into a 1000ml three-neck flask, add 16.70g (108mmol) of 2,3,4-trihydroxybenzaldehyde while vigorously stirring, stir at 20°C for 30min, and add dropwise Dimethyl sulfate 26ml (270mmol) and NaOH solution (8.86g NaOH+90mlH 2 O), continue to stir for 17 hours, then add concentrated hydrochloric acid with a mass percentage of 37% to pH = 3, extract 3 times with chloroform, take the chloroform layer, wash it with saturated saline and wash it with anhydrous Na 2 SO 4 After drying, a light yellow solid was obtained, which was recrystallized from chloroform / petroleum ether to obtain 11.91 g of 2,3-dihydroxy-4-methoxybenzaldehyde as a bright yellow needle-like solid, with a yield of 65.6%;

[0107] (2) Add 6.72g (40mmol) of 2,3-dihydroxy-4-methoxybenzaldehyde, 70ml of DMF, anhydrous K 2 CO 3 13.80g (100mmol), heat to 60°C, add 11.2ml (120mmol) of bromoisopropane dropwise, keep the temperature in the reaction bottle...

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Abstract

The invention discloses a preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene. The preparation method comprises the following steps of: taking 2,3,4-trihydroxy phenylfluorone as a raw material; carrying out single methylation on the 2,3,4-trihydroxy phenylfluorone; carrying out substitution reaction on the methylated 2,3,4-trihydroxy phenylfluorone with bromopropane so as to obtain 2,3-diisopropoxy-4-methoxybenzaldehyde; carrying out Perkin reaction on 2,3-diisopropoxy-4-methoxybenzaldehyde with 3,4,5-trimethoxyphenylacetic acid so as to obtain E-2-(3,4,5-trimethoxyphenyl)-3-(2',3'-diisopropoxy-4'-methoxyphenyl)acrylic acid; carrying out decarboxylation to obtain Z-3,4,4',5-tetramethoxy-2',3'-diisopropoxy diphenylethylene; and finally obtaining Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene after carrying out deprotection. The synthetic route provided by the invention is simple and direct, cis-selectivity is higher, and the yield of the Perkin reaction as well as the total yield of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene are both higher. The preparation method disclosed by the invention has the characteristics of simpleness and feasibility for operation, low price and easy obtainment of used raw materials and reagents, small pollution on environment, good atom economy, low cost and capability of being applied to industrialized production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxystilbene. Background technique [0002] Studies have confirmed that Z-3,4,4′,5-tetramethoxy-2′,3′-dihydroxystilbene (CombretastatinA-1, referred to as CA1) and its derivatives are a class of tubulin inhibitory The compounds with vascular blocking and anti-tumor activities can be applied to the treatment of diseases caused by abnormal proliferation of tumors and blood vessels. The structural formula of CA1 is shown in Formula 1: [0003] [0004] CA1 is a polysubstituted cis-stilbene compound isolated from the bark of the African shrub Combretum Caffrum. Combretastatin A-1Prodrug (CA1P), the phosphorylated precursor compound of CA1, has strong anti-vascular and anti-tumor effects, and its in vivo activity is 8-10 times stronger than that of the first-generation angioblocker CA4P. It is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C43/253C07C41/01
Inventor 邹永吕泽良肖春芬刘现可吴伟
Owner GUANGZHOU CHEM CO LTD CHINESE ACADEMY OF SCI
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