CN103570508B - Total synthesis method of trans-resveratrol - Google Patents
Total synthesis method of trans-resveratrol Download PDFInfo
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- CN103570508B CN103570508B CN201310531378.XA CN201310531378A CN103570508B CN 103570508 B CN103570508 B CN 103570508B CN 201310531378 A CN201310531378 A CN 201310531378A CN 103570508 B CN103570508 B CN 103570508B
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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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- C07C41/00—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
- C07C41/26—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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- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
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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 be present in plant, mainly through removing or suppressing free radical to generate, anti-lipid peroxidation, regulated the mechanisms play 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, be thus 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.But obtaining the traditional method of trans-resveratrol is Extraction and separation from natural phant, due to the excessive collection of natural pharmaceutical resources in recent years, natural resources is deficient, obtains by plant extraction process the demand that trans-resveratrol can not meet market.Therefore, obtain by organic synthesis mode the important channel that trans-resveratrol become current.
At present, the method for synthesizing resveratrol mainly contains three kinds: witting reaction, heck reaction and perkin reaction.But all there is limitation and defect in above method: although witting reacts mild condition, product yield is low; Heck reaction scheme is short, but severe reaction conditions, and raw material sources are limited; Be easy to get although perkin reacts raw material, reaction scheme is long, easily produces isomer in reaction.
Summary of the invention
Technical problem to be solved by this invention is, provide a kind of raw material sources extensive, reaction conditions is gentle, 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 and methyl-sulfate react, and generate 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;
The mass ratio of described 3,5-resorcylic acids and anhydrous propanone is 1:4 ~ 5, and the mass ratio of described 3,5-resorcylic acids and Anhydrous potassium carbonate is 1:3 ~ 6, and the mass ratio of described 3,5-resorcylic acids and methyl-sulfate is 1:1 ~ 3;
(2) 3,5-dimethoxy p-methyls and reductive agent react, preparation 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 proportions 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, the mass ratio of described 3,5-dimethoxy p-methyls 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:
Be dissolved in methylene dichloride by 3,5-3,5-dimethoxybenzoic alcohol, be cooled to less than 6 DEG C, add phosphorus tribromide at this temperature, after insulation reaction is complete, be washed to neutrality, concentrated crystallization, filters, dry, obtains 3,5-dimethoxy benzene benzyl bromine;
The mass ratio of described 3,5-3,5-dimethoxybenzoic alcohols and methylene dichloride is 1:6 ~ 8; The mass ratio of described 3,5-3,5-dimethoxybenzoic alcohols and phosphorus tribromide is 1:1 ~ 2;
(4) 3,5-dimethoxy benzene benzyl bromines are reacted by witting-horner, preparation 3,5,4
,-trimethoxy toluylene:
By 3,5-dimethoxy benzene benzyl bromine and triethyl-phosphite mixing, be warming up to 140 DEG C ~ 160 DEG C, react and obtain intermediate A after 6 ~ 8 hours, intermediate A is dissolved in 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 water crystallization, 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, and the mass ratio of described 3,5-dimethoxy benzene benzyl bromines and sodium hydride is 1.0:0.1 ~ 0.3, the mass ratio of described 3,5-dimethoxy benzene benzyl bromines and aubepine is 1.0:0.5 ~ 0.8;
(5) by 3,5,4
,-trimethoxy toluylene prepares trans-resveratrol:
Aluminum trichloride (anhydrous) is dropped in triethylamine, and by 3,5,4
,-trimethoxy toluylene is dissolved in toluene, is added drop-wise to by toluene solution in triethylamine, is warming up to 80 DEG C ~ 100 DEG C, and insulation reaction is after 6 ~ 8 hours, and divide and remove toluene layer, 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 organic solvent is toluene, ethyl acetate, trichloromethane or methylene dichloride etc.
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, and environmental friendliness, 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 and methyl-sulfate react, and generate 3,5-dimethoxy p-methyl:
In the 50L reactor of drying, 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 and reductive agent react, preparation 3,5-3,5-dimethoxybenzoic alcohol:
In the 50L reactor of drying, drop into 15kg tetrahydrofuran (THF), and add Lithium chloride (anhydrous) 2kg, sodium borohydride 2.2kg, stir 2 hours, then the tetrahydrofuran solution dripping 3,5-dimethoxy p-methyl is (containing 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 extraction into ethyl acetate, 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 the 50L reactor of drying, first drop into 15kg methylene dichloride, then drop into 3,5-3,5-dimethoxybenzoic alcohol 2.2kg, be stirred to entirely molten, cooling down to 5 DEG C, add 4kg phosphorus tribromide at this temperature, insulation reaction is after 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 are reacted by witting-horner, preparation 3,5,4
,-trimethoxy toluylene:
In the 20L reactor of drying, drop into triethyl-phosphite 1.95kg and 3,5-dimethoxy benzene benzyl bromine 1kg, be warming up to 140 DEG C, react 6 hours (collecting by product monobromethane), underpressure distillation, to solid substance, cools, in reactor, add tetrahydrofuran (THF) 2.6kg, after dissolving, add sodium hydride 0.2kg, stirring reaction 3 hours under room temperature condition, then drip 0.6kg aubepine, stirring reaction 3 hours under room temperature condition, then add 10kg distilled water crystallization, filtration drying, obtains 3,5,4
,-trimethoxy toluylene 1.07kg;
(5) by 3,5,4
,-trimethoxy toluylene prepares trans-resveratrol:
In the 20L reactor of drying, drop into triethylamine 3kg, under stirring, add aluminum trichloride (anhydrous) 3.5kg, drip 3,5,4
,the toluene solution of-trimethoxy toluylene (containing 3,5,4
,-trimethoxy toluylene 1kg and toluene 5kg), be warming up to 90 DEG C, insulation reaction is after 8 hours, and divide and remove toluene layer, 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 and methyl-sulfate react, and generate 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;
The mass ratio of described 3,5-resorcylic acids and anhydrous propanone is 1:4 ~ 5, and the mass ratio of described 3,5-resorcylic acids and Anhydrous potassium carbonate is 1:3 ~ 6, and the mass ratio of described 3,5-resorcylic acids and methyl-sulfate is 1:1 ~ 3;
(2) 3,5-dimethoxy p-methyls and reductive agent react, preparation 3,5-3,5-dimethoxybenzoic alcohol:
Be first tetrahydrofuran (THF) or the DMF solution of proportions 3, the 5-dimethoxy p-methyl of 1:2 ~ 3 in mass ratio by step (1) gained 3,5-dimethoxy p-methyl and tetrahydrofuran (THF) or DMF;
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, the mass ratio of described 3,5-dimethoxy p-methyls 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:
Be dissolved in methylene dichloride by 3,5-3,5-dimethoxybenzoic alcohol, be cooled to less than 6 DEG C, add phosphorus tribromide at this temperature, after insulation reaction is complete, be washed to neutrality, concentrated crystallization, filters, dry, obtains 3,5-dimethoxy benzene benzyl bromine;
The mass ratio of described 3,5-3,5-dimethoxybenzoic alcohols and methylene dichloride is 1:6 ~ 8, and the mass ratio of described 3,5-3,5-dimethoxybenzoic alcohols and phosphorus tribromide is 1:1 ~ 2;
(4) 3,5-dimethoxy benzene benzyl bromines are reacted by witting-horner, preparation 3,5,4
,-trimethoxy toluylene:
By 3,5-dimethoxy benzene benzyl bromine and triethyl-phosphite mixing, be warming up to 140 DEG C ~ 160 DEG C, react and obtain intermediate A after 6 ~ 8 hours, intermediate A is dissolved in 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 water crystallization, 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, and the mass ratio of described 3,5-dimethoxy benzene benzyl bromines and sodium hydride is 1.0:0.1 ~ 0.3, the mass ratio of described 3,5-dimethoxy benzene benzyl bromines and aubepine is 1.0:0.5 ~ 0.8;
(5) by 3,5,4
,-trimethoxy toluylene prepares trans-resveratrol:
Aluminum trichloride (anhydrous) is dropped in triethylamine, and by 3,5,4
,-trimethoxy toluylene is dissolved in toluene, is added drop-wise to by toluene solution in triethylamine, is warming up to 80 DEG C ~ 100 DEG C, and insulation reaction is after 6 ~ 8 hours, and divide and remove toluene layer, 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 organic solvent is toluene, ethyl acetate, trichloromethane or methylene dichloride.
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| 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 |
| 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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| CN101868438A (en) * | 2007-10-03 | 2010-10-20 | 科莱恩特种精细化学品法国公司 | The method of synthesis of polyhydroxystilbene compounds |
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| CN101868438A (en) * | 2007-10-03 | 2010-10-20 | 科莱恩特种精细化学品法国公司 | The method of synthesis of polyhydroxystilbene compounds |
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| 刘鹏.白藜芦醇的合成工艺改进.《中国药物化学杂志》.2008,第18卷(第6期), * |
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