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Chemical total synthesis method for wedelolactone

A technology for total synthesis of werethrin, which is applied in the field of medicine and chemical industry, can solve the problems of cumbersome operation process, high synthesis cost, and difficulty in obtaining, and achieves the effects of simplifying the operation process, reducing the cost, and reducing the synthesis cost.

Inactive Publication Date: 2010-11-03
SHANGHAI JIAO TONG UNIV
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Problems solved by technology

Indian scholar Pandey et al. reported a similar synthetic method in 1989. They used the phenoloxidase tyrosinase (EC1.14.18.1) extracted from mushrooms as a catalyst to produce catechol and 4,5-bis Hydroxy-7-methoxycoumarin reacts and cyclizes to obtain wedelolide. This synthesis method has a high yield, but the cost of the enzyme catalyst is high, and it is difficult to realize industrial production
[0005] After searching the literature of the prior art, it was found that the Chinese invention patent (CN1566116) used 3,4-diylbenzaldehyde and 2,4,6-trihydroxybenzaldehyde as starting materials to synthesize two key intermediates in a convergent manner Substituted phenylacetylene and iodine-substituted benzene, through Sonogashira coupling reaction, and then through reaction steps such as cyclization and deprotection to obtain wedelolide, the key intermediate substituted phenylacetylene in this synthesis method is not easy to obtain, the synthesis cost is high, and the operation process is cumbersome (both column chromatography), not suitable for industrialized production

Method used

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  • Chemical total synthesis method for wedelolactone
  • Chemical total synthesis method for wedelolactone
  • Chemical total synthesis method for wedelolactone

Examples

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Effect test

Embodiment 1

[0030] Preparation of 2-[(4-methoxy-2,6-dibenzyloxyphenyl)ethynyl]-4,5-dibenzyloxyaniline 7

[0031] Add 2-ethyne-5-methoxy-1,3-dibenzyloxybenzene 2 (7.4g, 21.45mmol), 2-bromo-4,5-dibenzyloxyaniline 6 (9.6 g, 25mmol) and acetonitrile (100ml), stirred for 1 hour under nitrogen protection, then added bistriphenylphosphine palladium dichloride (265mg, 0.38mmol), cuprous iodide (73mg, 0.38mmol) and triethyl Amine (18ml), reacted at room temperature under nitrogen protection for 18 hours, filtered, concentrated, extracted with ethyl acetate, washed the organic layer once with water and saturated brine, dried with magnesium sulfate, concentrated, and recrystallized with ethanol to obtain a solid , 2-[(4-methoxy-2,6-dibenzyloxyphenyl)ethynyl]-4,5-dibenzyloxyaniline 12.7g, yield 91.5%, palladium catalyst for recycling, melting point 191 -193°C.

Embodiment 2

[0033] Preparation of 2-[(4-methoxy-2,6-dibenzyloxyphenyl)ethynyl]-4,5-dibenzyloxyphenol 5

[0034] Add 2-[(4-methoxy-2,6-dibenzyloxyphenyl)ethynyl]-4,5-dibenzyloxyaniline (10.0g, 15.46mmol) and 20% sulfuric acid in a 250ml reaction flask (40mmol) was cooled to -5°C, and a solution of sodium nitrite (1.2g, 17.3mmol) and water (10ml) was added dropwise at -7°C to -5°C, and after 4 hours of reaction, the temperature was raised to 55°C to 60°C to react 1 hour, cooled, filtered, and recrystallized from isopropanol to give a white solid, 2-[(4-methoxy-2,6-dibenzyloxyphenyl)ethynyl]-4,5-dibenzyloxy Phenol 8.9g, yield 88.9%, melting point: 148°C-150°C.

Embodiment 3

[0036] Preparation of Methyl 2-[(4-methoxy-2,6-dibenzyloxyphenyl)-5,6-dibenzyloxy]-3-benzofurancarboxylate

[0037] Add 2-[(4-methoxy-2,6-dibenzyloxyphenyl)ethynyl]-4,5-dibenzyloxyphenol (6.5g, 10.0mmol) in a 500ml autoclave, iodine Cuprous chloride (191mg, 1.0mmol), urea (75mg, 1.0mmol), palladium dichloride (175mg, 1.0mmol), carbon tetrabromide (25g, 75.3mmol), cesium carbonate (25.5g, 75.3mmol) , methyl alcohol (160ml), tetrahydrofuran (80ml), feed into carbon monoxide for ventilation, under 5 atmospheres, react 5 hours under 80 ℃, cooling, after the gas in the still with nitrogen replacement, stop reaction with ammonium chloride aqueous solution (15ml), The catalyst was recovered, the reaction solution was extracted with ethyl acetate, the organic layer was washed once with saturated aqueous ammonium chloride and saturated brine, dried with magnesium sulfate, concentrated, and recrystallized with ethanol to obtain solid 2-[(4 -Methoxy-2,6-dibenzyloxyphenyl)-5,6-dibenzylox...

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Abstract

A chemical total synthesis method of wedelolactone belongs to the medical and chemical technical field, which uses 2-bromine-4, 5-bibenzyloxy aniline as raw material to process sonogashira coupling reaction with substitutedphenylethynyl, uses diazotization hydrolysis to obtain compound 2-[(4-methoxy-2, 6-bibenzyloxy phenyl)-4, 5-bibenzyloxy fenol, and uses cyclization and deprotection to obtain wedelolactone. The invention has the advantages of easily obtained material, simple process and low cost, thus is suitable for industrial production, thereby overcoming the defects of prior synthesis methods.

Description

technical field [0001] The invention relates to a synthesis method in the technical field of medicine and chemical engineering, in particular to a chemical total synthesis method of wedelolide. Background technique [0002] Wedelolactone (wedelolactone), chemical name: 7-methoxy-5,11,12-trihydroxybenzofuranocoumarin, chemical structural formula is as follows, first isolated from Wedelia Calendulacea plant by Govindachari et al. in 1956 It has the functions of anti-inflammation, hemostasis, treatment of pneumonia, liver cirrhosis, etc., and can also be used as an effective antidote for snake venom. Professor Yuan Junying from Harvard Medical School found that wedelolide can inhibit lipopolysaccharide from intervening in caspase-11 (Caspase-11) -11) can be used to treat septic shock, stroke and other inflammatory diseases. [0003] [0004] The chemical structure of wedelolide is a polyphenolic lactone, which is easy to decompose under alkaline conditions, so it is difficu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61P29/00A61P1/16
Inventor 徐德锋李绍顺
Owner SHANGHAI JIAO TONG UNIV
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