CN103819442A - Synthesis technology of active natural product dihydromyricetin - Google Patents
Synthesis technology of active natural product dihydromyricetin Download PDFInfo
- Publication number
- CN103819442A CN103819442A CN201410071142.7A CN201410071142A CN103819442A CN 103819442 A CN103819442 A CN 103819442A CN 201410071142 A CN201410071142 A CN 201410071142A CN 103819442 A CN103819442 A CN 103819442A
- Authority
- CN
- China
- Prior art keywords
- reaction
- trihydroxy
- temperature
- described method
- require described
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
Abstract
The invention relates to a synthesis technology of (2R, 3R)-dihydromyricetin, comprising the following steps: taking 3,4,5-trihydroxy-phenylacryl chloride and phloroglucinol as raw materials; carrying out Friedel-Crafts acylation; peroxiding a double bond into an epoxy bond; opening a loop under an acidic condition and forming ether with a phenolic hydroxyl group; carrying out separation, purification and crystallization at the end of the reaction to obtain products with high content and high purity. Green environmental protection and efficiency are considered in the both aspects of reaction reagents and raw and auxiliary materials. The method provided by the invention has advantages of high atom economic type, simple equipments, green and environmental production procedure, and has great economic and social benefits.
Description
Technical field
The present invention relates to a kind of active skull cap components (2R; synthesizing of 3R)-dibydro myricetrin; being specifically related to synthesis material is 3; 4,5-trihydroxy--cinnamic acid acyl chlorides and Phloroglucinol, relate to reaction and comprise a pair gram acidylate; two key peroxides change into epoxy bond; acidic conditions open loop becomes ether with phenolic hydroxyl group again, and separation, purifying obtain (2R, 3R)-dibydro myricetrin.
Background technology
Dibydro myricetrin, chemistry (2R, 3R)-3 by name, 5,7-trihydroxy--2-(3,4,5-trihydroxy-phenyl) chromanone, is also dihydromyricetin, Ampelopstin, covers element, Ampeloptin, dihydromyricetin ampelopsin in vain.Dihydromyricetin have extensive biological activity, removes the multiple peculiar effects such as free radical, anti-oxidant, antithrombotic, antitumor, anti-inflammatory.In addition, dibydro myricetrin is as special a kind of flavonoid compound, except having the general characteristic of flavonoid compound, also has the effect such as sickness rate of removing alcoholism, prevention alcoholic liver, fatty liver, inhibition liver cell and worsen, reduce liver cancer.Be liver protecting, the non-defective unit of Dealcoholic sobering-up, adds in a lot of alcohol-neutralize healthy products the inside at present.
There are two approach in (2R, 3R)-dibydro myricetrin source, the one, from natural matter, extract to separate and obtain, the 2nd, take ampelopsin as raw material semi-synthetic.
The content in Vitaceae ampelopsis of dibydro myricetrin is the highest, comprises as ampelopsis cantoniensis, Ampelopsis grossedentata, leatherleaf Stem or leaf of Amur Ampelopsis, Northeastern Caulis seu folium ampelopsis brevipedunculatae, Ampelopsis, Stem or leaf of Amur Ampelopsis etc.Reach as high as 30% left and right of cured leaf weight, these plant resourceses are mainly distributed in (the Zhang Yousheng such as Guangdong, Guangxi, Yunnan, Hunan, Jiangxi, Sichuan and the Hubei of China, Yang Wei is beautiful, 3 is white flat. and RP-HPLC method is measured the content of ampelopsin in porcelain ampelopsis. herbal medicine. 2001,32 (11): what osmanthus rosy clouds of 983-985.. the assay of total flavones and dibydro myricetrin in Ampelopsis grossedentata. CHINA JOURNAL OF CHINESE MATERIA MEDICA. 2000,25 (7): 423-425.).From Stem or leaf of Amur Ampelopsis rattan, extract dibydro myricetrin, take water or ethanol as solvent, extraction yield is between 30-60%.After purifies and separates, with water, methyl alcohol or alcohol solvent crystallization, can obtain the dibydro myricetrin sterling that purity is higher.Although dibydro myricetrin content in Stem or leaf of Amur Ampelopsis rattan is higher, its resource-constrained.Meanwhile, it is not high that extraction, separation, purifying obtain final sterling yield, produces a large amount of waste water and high energy consumption, and cost is higher, so be unfavorable for further expanding the market requirement.Take ampelopsin as the semi-synthetic dibydro myricetrin of raw material, flow process is simple, but raw material ampelopsin still need to obtain from natural extract, and its cost is higher, does not have industrial applications to be worth.
Above method is some shortcomings below the method for preparation (2R, 3R)-dibydro myricetrin exists: (1) natural extract shortcoming has resource utilization low, extracts after dibydro myricetrin, affects extraction and the utilization of other activeconstituentss, causes cost too high.(2) simultaneously, use large water gaging and ethanol equal solvent in extraction sepn process, energy consumption is high, pollution is large, is difficult to obtain high purity and high-content dibydro myricetrin.(3) take ampelopsin as the semi-synthetic dibydro myricetrin of raw material, raw material ampelopsin still need to obtain from natural extract, and its cost is higher, produces by product simultaneously and is difficult to separate and process, and is unsuitable for industrialized production.
For solving above-mentioned preparation (2R; the shortcoming of 3R)-dibydro myricetrin; that operational path of the present invention adopts is shorter, the complete synthesis route of environmental protection more, innovation; directly with 3,4,5-trihydroxy--cinnamic acid acyl chlorides and Phloroglucinol for raw material; through gram acidylate of paying through an intermediary in a business deal; two key peroxides change into epoxy bond, then acidic conditions open loop becomes ether with phenolic hydroxyl group, and three-step reaction obtains dibydro myricetrin.This route prepares that dibydro myricetrin cost is low, technique is simple, environmental protection, productive rate are high, has extraordinary using value.
The different characteristics part of the present invention and aforesaid method is: (1) has adopted new starting raw material 3,4, and 5-trihydroxy--cinnamic acid acyl chlorides and Phloroglucinol, make syntheti c route shorter, and yield is higher.(2) other supplementary materials are all conventional reaction reagent, gentle, safety, and contamination-free produces, and technique is environmental protection more.(3) complete synthesis dibydro myricetrin has advantages of that impurity is few, purity is high and content is high, better than the dibydro myricetrin quality of natural extract, cost is low.(4) route is short, and equipment is simpler, operates more succinct.Be above the route of good suitability for industrialized production from economy, environment and Occupational health angle.
Summary of the invention
The key problem that the present invention need to solve is the shortcoming that overcomes existing dibydro myricetrin preparation technology, sets up environmental friendliness, low cost, succinct from 3,4,5-trihydroxy--cinnamic acid acyl chlorides and Phloroglucinol synthesizing dihydro ampelopsin industrialized producing technology.
Object of the present invention is achieved through the following technical solutions, and concrete route is shown in Figure of description.Dibydro myricetrin synthesis route is that 3,4,5-trihydroxy--cinnamic acid acyl chlorides and Phloroglucinol are raw material; through gram acidylate of paying through an intermediary in a business deal; two key peroxides change into epoxy bond, then acidic conditions open loop becomes ether with phenolic hydroxyl group, and reaction finishes to separate, purifying, crystallization obtain high-content and highly purified product.Concrete steps are as follows:
1, in enamel reaction still, add solvents tetrahydrofurane and reaction raw materials 3,4,5-trihydroxy--cinnamic acid acyl chlorides, chuck is cooled to 5 ℃ of left and right, adds aluminum trichloride (anhydrous) in batches, and controls temperature at 5-10 ℃, and stirring reaction 1-2 h forms complex compound.Continue to control temperature in 10 ℃, add stock yard benzenetriol in batches, and slowly rise to room temperature, then stirring reaction 3-5 h, thin-layer chromatography monitoring raw material 3,4,5-trihydroxy--cinnamic acid acyl chlorides complete reaction, is considered as acylation reaction and completes.Be cooled to again in 10 ℃, slowly add 5% sodium hydroxide solution to pH9 left and right, hydrolysis.Again with 5% dilute hydrochloric acid adjust pH to 6-7, the concentrated tetrahydrofuran (THF) of removing.With dichloromethane extraction twice, merge organic phase, dry, concentrating under reduced pressure, obtains 2-(3, and 4,5)-trihydroxy--cinnamic acid acyl group-phloroglucinol phenol intermediate crude product;
2,, in enamel reaction still, add 2-(3,4; 5-trihydroxy-)-cinnamic acid acyl group-phloroglucinol phenol is with etoh solvent stirring and dissolving; chuck is cooled to 5 ℃ of left and right, adds metachloroperbenzoic acid in batches, and controls temperature at 15-20 ℃; stirring reaction 3-4 h, thin-layer chromatography monitoring raw material 2-(3,4; 5-trihydroxy-)-cinnamic acid acyl group-1; this disappearance of 3,5-trihydroxybenzene phenolic group, is considered as oxidizing reaction and completes.Be cooled in 10 ℃, slowly add saturated sodium sulfite solution to remove peroxide metachloroperbenzoic acid, concentrating under reduced pressure, reclaims methyl alcohol.Add water and dichloromethane extraction twice again, merge organic phase, dry, concentrating under reduced pressure, obtains 1-(3,4,5-trihydroxy-)-phenyl, 2-(2,4,6-trihydroxy-) phenyl-oxyethane intermediate crude products, dry for standby;
3, in enamel reaction still, add the dry 1-(3 of solvents tetrahydrofurane and reaction raw materials, 4,5-trihydroxy-)-phenyl, 2-(2,4,6-trihydroxy-) phenyl-oxyethane intermediate, after stirring and dissolving, chuck is cooled to 5 ℃ of left and right, slowly add strong acid catalyst, and control temperature at 0-5 ℃, stirring reaction 5-8 h.Thin-layer chromatography monitoring raw material midbody complete reaction, is considered as into ether and has reacted., concentrate and remove tetrahydrofuran (THF) to 6-7 with saturated sodium bicarbonate solution adjust pH.With dichloromethane extraction twice, merge organic phase again, dry, concentrating under reduced pressure, dibydro myricetrin crude product.Crude product is with dehydrated alcohol heat of solution, and essence is filtered, and reconcentration, decrease temperature crystalline, obtain high purity, high-content (2R, 3R)-dibydro myricetrin fine work.
The invention provides (2R; 3R)-dibydro myricetrin synthesis technique; with 3; 4; 5-trihydroxy--cinnamic acid acyl chlorides and Phloroglucinol are raw material, and through gram acidylate of paying through an intermediary in a business deal, two key peroxides change into epoxy bond; acidic conditions open loop becomes ether with phenolic hydroxyl group again, and reaction finishes to separate, purifying, crystallization obtain high-content and highly purified product.Aspect reaction use reagent, supplementary material, all considering with environmental protection, efficiency.Present method has that atom economy type, equipment are simple, production sequence environmental protection, has very large economic and social benefit.
Accompanying drawing explanation
Accompanying drawing is (2R, 3R)-dibydro myricetrin synthetic route.
Embodiment
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
Embodiment 1 2-(3,4,5-trihydroxy-)-cinnamic acid acyl group-phloroglucinol phenol synthetic
In 500 L enamel reaction stills, add 200 L tetrahydrofuran (THF)s and reaction raw materials 3,4,5-trihydroxy--cinnamic acid acyl chlorides 40.0 kg, chuck is cooled to 5 ℃ of left and right, adds aluminum trichloride (anhydrous) 12.0 kg in batches, and controlling temperature at 5-10 ℃, stirring reaction 2 h, form complex compound.Continue to control temperature in 10 ℃, add stock yard benzenetriol 25.5 kg in batches, and slowly rise to room temperature, then stirring reaction 4 h, thin-layer chromatography monitoring raw material 3,4,5-trihydroxy--cinnamic acid acyl chlorides complete reaction, is considered as acylation reaction and completes.Be cooled in 10 ℃, slowly add 5% sodium hydroxide solution to pH9 left and right, hydrolysis 0.5 h.Again with 5% dilute hydrochloric acid adjust pH to 6-7, the concentrated tetrahydrofuran (THF) of removing.With 100 L dichloromethane extractions twice, merge organic phase again, dry, concentrating under reduced pressure, dry, obtain 2-(3,4,5-trihydroxy-)-cinnamic acid acyl group-phloroglucinol phenol intermediate crude product 53.5 kg.
Embodiment 2 1-(3,4,5-trihydroxy-)-phenyl, 2-(2,4,6-trihydroxy-) phenyl-oxyethane synthetic
In 500 L enamel reaction stills, add 2-(3,4; 5-trihydroxy-)-cinnamic acid acyl group-phloroglucinol phenol 53.0 kg are with 300 L ethanol stirring and dissolving; chuck is cooled to 5 ℃ of left and right, adds metachloroperbenzoic acid 40.0 kg in batches, and controls temperature at 15 ℃; stirring reaction 4 h, thin-layer chromatography monitoring raw material 2-(3,4; 5-trihydroxy-)-cinnamic acid acyl group-1; this disappearance of 3,5-trihydroxybenzene phenolic group, is considered as oxidizing reaction and completes.Be cooled in 10 ℃, slowly add saturated sodium sulfite solution 12.5 L to remove peroxide metachloroperbenzoic acid, concentrating under reduced pressure, reclaims methyl alcohol.Add 150 L water and 200 L dichloromethane extractions twice again, merge organic phase, dry, concentrating under reduced pressure, obtains 1-(3,4-dihydroxyl)-phenyl, 2-(2,4,6-trihydroxy-) phenyl-oxyethane intermediate crude products, dry and obtain 52.0 kg.
Synthesizing of embodiment 3 dibydro myricetrins
In 500 L enamel reaction stills, add 200 L tetrahydrofuran (THF)s and the dry 1-(3 of reaction raw materials, 4,5-trihydroxy-)-phenyl-2-(2,4,6-trihydroxy-) phenyl-oxyethane intermediate 50.0 kg, after stirring and dissolving, chuck is cooled to 5 ℃ of left and right, slowly adds strong acid catalyst trifluoroacetic acid 10.0 L, and control temperature at 0-5 ℃, stirring reaction 5 h.Thin-layer chromatography monitoring raw material midbody complete reaction, is considered as into ether and has reacted., concentrate and remove tetrahydrofuran (THF) to 6-7 with saturated sodium bicarbonate solution adjust pH.With 100 L dichloromethane extractions twice, merge organic phase again, dry, concentrating under reduced pressure, dry dibydro myricetrin crude product 45.8 kg that obtain.Crude product is with dehydrated alcohol 230 L heats of solution, and essence is filtered, and reconcentration, decrease temperature crystalline, obtain high purity, high-content (2R, 3R)-dibydro myricetrin fine work 42.5 kg.
Claims (6)
1. one kind with 3; 4; 5-trihydroxy--cinnamic acid acyl chlorides and Phloroglucinol are raw material; through gram acidylate of paying through an intermediary in a business deal; two key peroxides change into epoxy bond; acidic conditions open loop becomes ether with phenolic hydroxyl group again, and reaction finishes to separate, purifying, crystallization obtain high-content and highly purified (2R, 3R)-dibydro myricetrin product.
2. require described method according to right 1, it is characterized in that acylation reaction catalyst is aluminum trichloride (anhydrous), need to be at low temperature 5-10 ℃, with reaction raw materials 3,4,5-trihydroxy--cinnamic acid acyl chlorides forms complex compound.
3. require described method according to right 1, it is characterized in that forming complex compound reaction and acylation reaction solvent and be tetrahydrofuran (THF), temperature of reaction room temperature, reaction times 3-5 h.
4. require described method according to right 1, it is characterized in that oxidizing reaction reagent is metachloroperbenzoic acid, feed temperature is controlled at 3-7 ℃, and temperature of reaction is controlled at 15-20 ℃.
5. require described method according to right 1, it is characterized in that into ether reaction and use strong acid to comprise hydrogenchloride, tosic acid, methylsulfonic acid and trifluoroacetic acid, temperature of reaction is at 0-5 ℃, reaction solvent tetrahydrofuran (THF).
6. require described method according to right 1, it is characterized in that refining take dehydrated alcohol as solvent, crystallization mode is cooling stirred crystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410071142.7A CN103819442A (en) | 2014-03-01 | 2014-03-01 | Synthesis technology of active natural product dihydromyricetin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410071142.7A CN103819442A (en) | 2014-03-01 | 2014-03-01 | Synthesis technology of active natural product dihydromyricetin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103819442A true CN103819442A (en) | 2014-05-28 |
Family
ID=50754774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410071142.7A Pending CN103819442A (en) | 2014-03-01 | 2014-03-01 | Synthesis technology of active natural product dihydromyricetin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103819442A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294630A (en) * | 2015-11-20 | 2016-02-03 | 陕西嘉禾生物科技股份有限公司 | Preparation method of myricetin |
| CN116478032A (en) * | 2023-04-19 | 2023-07-25 | 中国科学院华南植物园 | 2',3,4',5,6 '-pentahydroxy-3' -isopentenyl chalcone analogues and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030162753A1 (en) * | 1999-01-21 | 2003-08-28 | Peerce Brian E. | Inhibition of intestinal apical membrane Na/phosphate co-transportation in humans |
| CN102070592A (en) * | 2011-01-26 | 2011-05-25 | 陕西嘉禾植物化工有限责任公司 | Synthesis method of dihydroquercetin |
-
2014
- 2014-03-01 CN CN201410071142.7A patent/CN103819442A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030162753A1 (en) * | 1999-01-21 | 2003-08-28 | Peerce Brian E. | Inhibition of intestinal apical membrane Na/phosphate co-transportation in humans |
| CN102070592A (en) * | 2011-01-26 | 2011-05-25 | 陕西嘉禾植物化工有限责任公司 | Synthesis method of dihydroquercetin |
Non-Patent Citations (3)
| Title |
|---|
| ASIF HUSAIN ET.AL: "《Synthesie and Antibacterial of Epoxides Derived from Chalcones》", 《ASIAN JOURNAL OF CHEMISTRY》, vol. 17, no. 1, 31 December 2005 (2005-12-31), pages 624 - 626 * |
| BIN WANG ET.AL: "《Non-heme manganese complexes of C1-symmetric N4 ligands: Synthesis,characterization and asymmetric epoxidations of a,b-enones》", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》, vol. 715, 15 September 2012 (2012-09-15), pages 9 - 12 * |
| JOHN P. GREALIS ET.AL: "《Synthesis of Isobavachalcone and Some Organometallic Derivatives》", 《EUR. J. ORG. CHEM.》, vol. 2013, 9 November 2012 (2012-11-09), pages 332 - 347 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294630A (en) * | 2015-11-20 | 2016-02-03 | 陕西嘉禾生物科技股份有限公司 | Preparation method of myricetin |
| CN116478032A (en) * | 2023-04-19 | 2023-07-25 | 中国科学院华南植物园 | 2',3,4',5,6 '-pentahydroxy-3' -isopentenyl chalcone analogues and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106046850B (en) | A kind of high-purity natural curcumin product preparation method | |
| CN102701914A (en) | Method for extracting hydroxytyrosol from olive leaves | |
| CN102942550A (en) | Method for extracting cyanidin from black bean peel | |
| CN105294632A (en) | Industrial method for preparing lonicera caerulea fruit anthocyanidin from lonicera caerulea fruits | |
| CN102964408A (en) | Method for extracting naringin from red tangerine peel | |
| CN102020544B (en) | Process for extracting chalcone type ingredients from ashitaba | |
| CN103819442A (en) | Synthesis technology of active natural product dihydromyricetin | |
| CN105131071A (en) | Synthesis method of 25-hydroxycholesteryl acetate-7-p-toluenesulfonylhydrazone | |
| CN103012518B (en) | Production process for simultaneously extracting asperuloside and chlorogenic acid from folium cortex eucommiae | |
| CN103450000B (en) | Method for extracting hypericin from hyperforin perforatum | |
| CN102093374A (en) | Method for efficiently extracting camptothecin derivative | |
| CN104193711A (en) | New method for extracting apigenin from celery | |
| CN102643285A (en) | Method for preparing magnolin from magnolia flower | |
| CN102443028A (en) | Method for extracting paeoniflorin from radix paeoniae lactiflorae | |
| CN102311379A (en) | Method for preparing 1-deoxynojirimycin by membrane separation technology | |
| CN102675106B (en) | Method for preparing high-purity chlorogenic acid by aluminum salt precipitation | |
| CN103571891B (en) | Method for extracting resveratrol from polygonum cuspidatum | |
| CN103864743B (en) | A kind of synthesis technique of natural active product dihydroquercetin | |
| CN102285976A (en) | Method for extracting isoorientin from bamboo leaf flavones | |
| CN102241658A (en) | Method for purifying gamma-mangostin by using high-speed countercurrent chromatography | |
| CN105153180A (en) | Method for extracting cinnamomum longepaniculatum essential oil and simultaneously preparing ellagic acid through hydrolyzing tannin | |
| CN102134247A (en) | Xanthotoxol derivative and new composite method thereof | |
| CN102295670A (en) | Method for extracting buddlenoid A from buddleia | |
| CN103044410A (en) | Production process for extracting isoorientin from bamboo product waste | |
| CN102659901A (en) | Method for purifying lysimachia capillipes hemsl saponin B |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140528 |