CN103570508A - Total synthesis method of trans-resveratrol - Google Patents
Total synthesis method of trans-resveratrol Download PDFInfo
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- CN103570508A CN103570508A CN201310531378.XA CN201310531378A CN103570508A CN 103570508 A CN103570508 A CN 103570508A CN 201310531378 A CN201310531378 A CN 201310531378A CN 103570508 A CN103570508 A CN 103570508A
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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Abstract
The invention discloses a total synthesis method of trans-resveratrol. The total synthesis method comprises the following steps: (1) enabling 3,5-dihydroxy-benzoic acid to react with dimethyl sulfate, so as to generate 3,5-dimethoxy methyl benzoate; (2) enabling the 3,5-dimethoxy methyl benzoate to react with a reducing agent, so as to prepare 3,5-dimethoxybenzhydrol; (3) carrying out nucleophilic substitution on the 3,5-dimethoxy methyl benzoate and phosphorus tribromide, so as to generate 3,5-dimethoxy benzol benzyl bromide; (4) enabling the 3,5-dimethoxy benzol benzyl bromide to react through witting-horner, so as to prepare 3,5,4-triethoxy toluylene; and (5) preparing the trans-resveratrol from the 3,5,4-triethoxy toluylene. The total synthesis method has the advantages of being wide in material source, mild in reaction condition, friendly to environment, high in product yield, high in purity, applicable to industrialized mass production and the like.
Description
Technical field
The present invention relates to a kind of total synthesis method of trans-resveratrol.
Background technology
Trans-resveratrol, has another name called, Resveratrol, Resveratrol, resvertrol; Chemical name Resveratrolk or (E)-5-[2-(4-hydroxyphenyl)-vinyl]-Resorcinol, molecular formula: C
14h
12o
3, molecular weight: 228.24, No. CAS: 501-36-0.Trans-resveratrol was found as far back as 1940, was the natural antioxidants being present in plant, mainly by removing or suppressing free radical, generated, and suppressed lipid peroxidation, regulated the mechanism performance antioxygenations such as anti-oxidant related enzyme activity.In addition, also there is the effects such as arteriosclerosis, antithrombotic, protection cardiovascular and cerebrovascular, anti-inflammatory, antibacterial, prevention hepar damnification, anticancer anti-mutation.Because it has multiple biology and pharmacologically active, thereby be widely used in the fields such as food, medicine, healthcare products, makeup.Current most countries and regions all, at exploitation trans-resveratrol and correlated product thereof, cause market demand to increase.Yet the traditional method that obtains trans-resveratrol is to extract with separated from natural phant, due to the excessive collection of natural pharmaceutical resources in recent years, natural resources is deficient, obtains trans-resveratrol can not meet the demand in market by plant extraction process.Therefore, by organic synthesis mode, obtain trans-resveratrol and become current important channel.
At present, the method for synthesizing resveratrol mainly contains three kinds: witting reaction, heck reaction and perkin reaction.Yet all there is limitation and defect in above method: although witting reaction mild condition, product yield is low; Heck reaction scheme is short, but severe reaction conditions, and raw material sources are limited; Although perkin reaction raw material is easy to get, reaction scheme is long, easily produces isomer in reaction.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of raw material sources extensive, reaction conditions gentleness, the total synthesis method of the trans-resveratrol that product yield is high, purity is high.
The technical solution adopted for the present invention to solve the technical problems is: a kind of total synthesis method of trans-resveratrol, comprises the following steps:
(1) 3,5-resorcylic acid reacts with methyl-sulfate, generates 3,5-dimethoxy p-methyl:
In anhydrous propanone, drop into 3,5-resorcylic acid and Anhydrous potassium carbonate, after stirring, drip methyl-sulfate, after stirring reaction is complete, filter, concentrated crystallization, obtains 3,5-dimethoxy p-methyl;
Described 3, the mass ratio of 5-resorcylic acid and anhydrous propanone is 1:4～5, described 3, and the mass ratio of 5-resorcylic acid and Anhydrous potassium carbonate is 1:3～6, described 3, and the mass ratio of 5-resorcylic acid and methyl-sulfate is 1:1～3;
(2) 3,5-dimethoxy p-methyls react with reductive agent, prepare 3,5-3,5-dimethoxybenzoic alcohol:
First by step (1) gained 3,5-dimethoxy p-methyl and tetrahydrofuran (THF) or DMF(dimethyl formamide) be tetrahydrofuran (THF) or the DMF solution of ratio preparation 3, the 5-dimethoxy p-methyl of 1:2～3 in mass ratio;
Then POTASSIUM BOROHYDRIDE or sodium borohydride are dropped in tetrahydrofuran (THF) or DMF, and add Lithium chloride (anhydrous), then drip tetrahydrofuran (THF) or the DMF solution of 3,5-dimethoxy p-methyl, after back flow reaction is complete, concentrated, elutriation, organic solvent extraction, condensing crystal, filtration drying, obtains 3,5-3,5-dimethoxybenzoic alcohol;
Described 3, the mass ratio of 5-dimethoxy p-methyl and tetrahydrofuran (THF) or DMF is 1:3～6, described 3,5-dimethoxy p-methyl and POTASSIUM BOROHYDRIDE or sodium borohydride mass ratio are 1:0.5～0.8, described 3, the mass ratio of 5-dimethoxy p-methyl and Lithium chloride (anhydrous) is 1:0.5～0.8;
(3) 3,5-3,5-dimethoxybenzoic alcohols and phosphorus tribromide generation nucleophilic substitution, generate 3,5-dimethoxy benzene benzyl bromine:
3,5-3,5-dimethoxybenzoic alcohol is dissolved in methylene dichloride, is cooled to below 6 ℃, at this temperature, add phosphorus tribromide, after insulation reaction is complete, be washed to neutrality, concentrated crystallization, filters, dry, obtains 3,5-dimethoxy benzene benzyl bromine;
Described 3, the mass ratio of 5-3,5-dimethoxybenzoic alcohol and methylene dichloride is 1:6～8; Described 3, the mass ratio of 5-3,5-dimethoxybenzoic alcohol and phosphorus tribromide is 1:1～2;
(4) 3,5-dimethoxy benzene benzyl bromines react by witting-horner, prepare 3,5,4
,-trimethoxy toluylene:
3,5-dimethoxy benzene benzyl bromine and triethyl-phosphite are mixed, be warming up to 140 ℃～160 ℃, react and obtain intermediate A after 6～8 hours, intermediate A is dissolved in to tetrahydrofuran (THF) or DMF(dimethyl formamide), and add sodium hydride, under room temperature condition stirring reaction completely after, drip aubepine, under room temperature condition stirring reaction completely after, add elutriation crystalline substance, filter, dry, obtain 3,5,4
,-trimethoxy toluylene;
Described 3, the mass ratio of 5-dimethoxy benzene benzyl bromine and triethyl-phosphite is 1.0:1.5～2.0, described 3, and the mass ratio of 5-dimethoxy benzene benzyl bromine and sodium hydride is 1.0:0.1～0.3, described 3, the mass ratio of 5-dimethoxy benzene benzyl bromine and aubepine is 1.0:0.5～0.8;
(5) by 3,5,4
,-trimethoxy toluylene is prepared trans-resveratrol:
Aluminum trichloride (anhydrous) is dropped in triethylamine, and by 3,5,4
,-trimethoxy toluylene is dissolved in toluene, and toluene solution is added drop-wise in triethylamine, is warming up to 80 ℃～100 ℃, and insulation reaction, after 6～8 hours, is divided and removed toluene layer, and reactant is extracted with ethyl acetate, and concentrated, recrystallization, obtains trans-resveratrol;
Described 3,5,4
,the mass ratio of-trimethoxy toluylene and triethylamine is 1:3～6, described 3,5,4
,the mass ratio of-trimethoxy toluylene and aluminum trichloride (anhydrous) is 1:3～6, described 3,5,4
,the mass ratio of-trimethoxy toluylene and toluene is 1.0:4.5～5.5.
Further, in step (2), extraction is toluene, ethyl acetate, trichloromethane or methylene dichloride etc. with organic solvent.
Step (1), its reaction formula is:
Step (2), its reaction formula is:
Step (3), its reaction formula is:
Step (4), its reaction formula is:
Step (5), its reaction formula is:
Compared with prior art, it is extensive that the present invention has raw material sources, and reaction conditions is gentle, environmental friendliness, and product yield is high, purity is high, is suitable for the advantages such as industrialized mass production.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment
The present embodiment comprises the following steps:
(1) 3,5-resorcylic acid reacts with methyl-sulfate, generates 3,5-dimethoxy p-methyl:
In dry 50L reactor, first drop into 10kg anhydrous propanone, then drop into 3,5-resorcylic acid 2.4kg, Anhydrous potassium carbonate 10kg, after stirring, drip methyl-sulfate 5kg, stirring reaction, after 6 hours, filters, concentrated crystallization, obtains 3,5-dimethoxy p-methyl 2.8kg;
(2) 3,5-dimethoxy p-methyls react with reductive agent, prepare 3,5-3,5-dimethoxybenzoic alcohol:
In dry 50L reactor, drop into 15kg tetrahydrofuran (THF), and add Lithium chloride (anhydrous) 2kg, sodium borohydride 2.2kg, stir 2 hours, then the tetrahydrofuran solution that drips 3,5-dimethoxy p-methyl (contains 3,5-dimethoxy p-methyl 2.8kg and tetrahydrofuran (THF) 6kg), back flow reaction is after 6 hours, and being concentrated into concentrated solution is 8L, add 7kg distilled water, dispersed with stirring, then add ethyl acetate extraction, condensing crystal, filtration drying, obtains 3,5-3,5-dimethoxybenzoic alcohol 2.2kg;
(3) 3,5-3,5-dimethoxybenzoic alcohols and phosphorus tribromide generation nucleophilic substitution, generate 3,5-dimethoxy benzene benzyl bromine:
In dry 50L reactor, first drop into 15kg methylene dichloride, then drop into 3,5-3,5-dimethoxybenzoic alcohol 2.2kg, be stirred to entirely moltenly, cooling down to 5 ℃ adds 4kg phosphorus tribromide at this temperature, after insulation reaction 4 hours, in reactor, add 20kg distilled water, separate organic layer, wash with water to neutrality, concentrated crystallization, filtration drying, obtains 3,5-dimethoxy benzene benzyl bromine 2.9kg;
(4) 3,5-dimethoxy benzene benzyl bromines react by witting-horner, prepare 3,5,4
,-trimethoxy toluylene:
In dry 20L reactor, drop into triethyl-phosphite 1.95kg and 3,5-dimethoxy benzene benzyl bromine 1kg, be warming up to 140 ℃, react 6 hours (collecting by product monobromethane), underpressure distillation is to solid substance, cooling, in reactor, add tetrahydrofuran (THF) 2.6kg, after dissolving, add sodium hydride 0.2kg, under room temperature condition, stirring reaction is 3 hours, then drips 0.6kg aubepine, and under room temperature condition, stirring reaction is 3 hours, then add 10kg distilled water crystallization, filtration drying, obtains 3,5,4
,-trimethoxy toluylene 1.07kg;
(5) by 3,5,4
,-trimethoxy toluylene is prepared trans-resveratrol:
In dry 20L reactor, drop into triethylamine 3kg, under stirring, add aluminum trichloride (anhydrous) 3.5kg, drip 3,5,4
,the toluene solution of-trimethoxy toluylene (contains 3,5,4
,-trimethoxy toluylene 1kg and toluene 5kg), be warming up to 90 ℃, insulation reaction, after 8 hours, is divided and is removed toluene layer, and reactant is extracted with ethyl acetate, and concentrated, recrystallization, obtains trans-resveratrol 0.75kg.
The product yield of the present embodiment is 96.97%, and purity is 98.6%.
Claims (2)
1. a total synthesis method for trans-resveratrol, is characterized in that, comprises the following steps:
(1) 3,5-resorcylic acid reacts with methyl-sulfate, generates 3,5-dimethoxy p-methyl:
In anhydrous propanone, drop into 3,5-resorcylic acid and Anhydrous potassium carbonate, after stirring, drip methyl-sulfate, after stirring reaction is complete, filter, concentrated crystallization, obtains 3,5-dimethoxy p-methyl;
Described 3, the mass ratio of 5-resorcylic acid and anhydrous propanone is 1:4～5, described 3, and the mass ratio of 5-resorcylic acid and Anhydrous potassium carbonate is 1:3～6, described 3, and the mass ratio of 5-resorcylic acid and methyl-sulfate is 1:1～3;
(2) 3,5-dimethoxy p-methyls react with reductive agent, prepare 3,5-3,5-dimethoxybenzoic alcohol:
First, by step (1) gained 3,5-dimethoxy p-methyl and tetrahydrofuran (THF) or DMF are tetrahydrofuran (THF) or the DMF solution of ratio preparation 3, the 5-dimethoxy p-methyl of 1:2～3 in mass ratio;
Then POTASSIUM BOROHYDRIDE or sodium borohydride are dropped in tetrahydrofuran (THF) or DMF, and add Lithium chloride (anhydrous), then drip tetrahydrofuran (THF) or the DMF solution of 3,5-dimethoxy p-methyl, after back flow reaction is complete, concentrated, elutriation, organic solvent extraction, condensing crystal, filtration drying, obtains 3,5-3,5-dimethoxybenzoic alcohol;
Described 3, the mass ratio of 5-dimethoxy p-methyl and tetrahydrofuran (THF) or DMF is 1:3～6, described 3,5-dimethoxy p-methyl and POTASSIUM BOROHYDRIDE or sodium borohydride mass ratio are 1:0.5～0.8, described 3, the mass ratio of 5-dimethoxy p-methyl and Lithium chloride (anhydrous) is 1:0.5～0.8;
(3) 3,5-3,5-dimethoxybenzoic alcohols and phosphorus tribromide generation nucleophilic substitution, generate 3,5-dimethoxy benzene benzyl bromine:
3,5-3,5-dimethoxybenzoic alcohol is dissolved in methylene dichloride, is cooled to below 6 ℃, at this temperature, add phosphorus tribromide, after insulation reaction is complete, be washed to neutrality, concentrated crystallization, filters, dry, obtains 3,5-dimethoxy benzene benzyl bromine;
Described 3, the mass ratio of 5-3,5-dimethoxybenzoic alcohol and methylene dichloride is 1:6～8, described 3, and the mass ratio of 5-3,5-dimethoxybenzoic alcohol and phosphorus tribromide is 1:1～2;
(4) 3,5-dimethoxy benzene benzyl bromines react by witting-horner, prepare 3,5,4
,-trimethoxy toluylene:
3,5-dimethoxy benzene benzyl bromine and triethyl-phosphite are mixed, be warming up to 140 ℃～160 ℃, react and obtain intermediate A after 6～8 hours, intermediate A is dissolved in to tetrahydrofuran (THF) or DMF, and adds sodium hydride, under room temperature condition stirring reaction completely after, drip aubepine, under room temperature condition stirring reaction completely after, add elutriation crystalline substance, filter, dry, obtain 3,5,4
,-trimethoxy toluylene;
Described 3, the mass ratio of 5-dimethoxy benzene benzyl bromine and triethyl-phosphite is 1.0:1.5～2.0, described 3, and the mass ratio of 5-dimethoxy benzene benzyl bromine and sodium hydride is 1.0:0.1～0.3, described 3, the mass ratio of 5-dimethoxy benzene benzyl bromine and aubepine is 1.0:0.5～0.8;
(5) by 3,5,4
,-trimethoxy toluylene is prepared trans-resveratrol:
Aluminum trichloride (anhydrous) is dropped in triethylamine, and by 3,5,4
,-trimethoxy toluylene is dissolved in toluene, and toluene solution is added drop-wise in triethylamine, is warming up to 80 ℃～100 ℃, and insulation reaction, after 6～8 hours, is divided and removed toluene layer, and reactant is extracted with ethyl acetate, and concentrated, recrystallization, obtains trans-resveratrol;
Described 3,5,4
,the mass ratio of-trimethoxy toluylene and triethylamine is 1:3～6, described 3,5,4
,the mass ratio of-trimethoxy toluylene and aluminum trichloride (anhydrous) is 1:3～6, described 3,5,4
,the mass ratio of-trimethoxy toluylene and toluene is 1.0:4.5～5.5.
2. the total synthesis method of trans-resveratrol according to claim 1, is characterized in that, in step (2), extraction is toluene, ethyl acetate, trichloromethane or methylene dichloride with organic solvent.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503652A (en) * | 2015-12-30 | 2016-04-20 | 延边大学 | Cyano-containing resveratrol analogue and preparation method and purpose thereof |
| CN105523900A (en) * | 2015-12-31 | 2016-04-27 | 江西中德诚信科技有限公司 | A preparing method of resveratrol |
| CN106995364A (en) * | 2017-03-30 | 2017-08-01 | 杭州瑞树生化有限公司 | A kind of method of artificial synthesized alltrans resveratrol and its derivative |
| CN108250046A (en) * | 2018-03-16 | 2018-07-06 | 上海巧坤化工科技有限公司 | A kind of synthetic method of resveratrol |
| CN110577464A (en) * | 2018-06-09 | 2019-12-17 | 山东博奥克生物科技有限公司 | Preparation method of resveratrol |
| CN113387800A (en) * | 2021-06-09 | 2021-09-14 | 浙江理工大学 | Preparation method of 3, 5-dimethoxybenzoic acid methyl ester |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503652A (en) * | 2015-12-30 | 2016-04-20 | 延边大学 | Cyano-containing resveratrol analogue and preparation method and purpose thereof |
| CN105503652B (en) * | 2015-12-30 | 2017-12-05 | 延边大学 | Cyano-containing resveratrol analogses and its production and use |
| CN105523900A (en) * | 2015-12-31 | 2016-04-27 | 江西中德诚信科技有限公司 | A preparing method of resveratrol |
| CN106995364A (en) * | 2017-03-30 | 2017-08-01 | 杭州瑞树生化有限公司 | A kind of method of artificial synthesized alltrans resveratrol and its derivative |
| CN108250046A (en) * | 2018-03-16 | 2018-07-06 | 上海巧坤化工科技有限公司 | A kind of synthetic method of resveratrol |
| CN108250046B (en) * | 2018-03-16 | 2023-09-15 | 上海巧坤化工科技有限公司 | Synthesis method of resveratrol |
| CN110577464A (en) * | 2018-06-09 | 2019-12-17 | 山东博奥克生物科技有限公司 | Preparation method of resveratrol |
| CN113387800A (en) * | 2021-06-09 | 2021-09-14 | 浙江理工大学 | Preparation method of 3, 5-dimethoxybenzoic acid methyl ester |
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