CN109053837A - A kind of preparation method of 7-O- glycosylation myricetin - Google Patents
A kind of preparation method of 7-O- glycosylation myricetin Download PDFInfo
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- CN109053837A CN109053837A CN201810938625.0A CN201810938625A CN109053837A CN 109053837 A CN109053837 A CN 109053837A CN 201810938625 A CN201810938625 A CN 201810938625A CN 109053837 A CN109053837 A CN 109053837A
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of preparation method of 7-O- glycosylation myricetin.The preparation method step of 7-O- of the present invention glycosylation myricetin are as follows: one, myricetin obtain compound shown in 3-6 with acetic anhydride generation acetylization reaction under the alkaline condition that sodium acetate provides；Two, compound shown in 3-6 carries out glycosylation reaction with bromo sugar again and obtains compound shown in 3-16；Three, compound shown in 3-16 further passes through acid and alkali hydrolysis and reacts to obtain compound shown in 3-15, i.e. 7-O- glycosylates myricetin.Synthetic route of the present invention is short, and product yield high, agents useful for same is safety low-poison, and production cost is low, is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of preparation side of 7-O- glycosylation myricetin
Method.
Background technique
Myricetin is widely present in a variety of natural plants, is distributed mainly on Vitaceae, Myruca ceas, rosaceae, cactus
Section, Euphorbiaceae and Anacardiaceae etc. have the multiple efficacies such as anti-oxidant, anti-inflammatory, analgesia, antitumor, hypoglycemic and liver protection, especially exist
Effect is significant in terms of prevention and cure of cardiovascular disease.The effects of in view of its anti-oxidation function and reducing cholesterol, Europe is more especially
Mediterranean country lists myricetin as health food, but does not have related marketing drugs also, has very big exploitation and answers
With value.
The glycosylation of flavone compound is the hot spot of Recent study, and glycosylated flavanoid can pass through
SGLT1 active transport is hydrolyzed or can be hydrolyzed in cell surface in cytoplasm, then by diffusing into cell.Two kinds are not
Presence with the flavonoids of chemical species can produce and be conducive to the increased gradient constant of intracellular concentration.The result shows that glycosylation
Part may be by promoting flavonoids internalization to enter the pharmacological activity of cell enhancing myricetin.It is Kunming that 7-O-, which glycosylates myricetin,
One drug candidate of Long John medicine company researches and develops project, as far as we know, the preparation process of existing 7-O- glycosylation myricetin, from
Myricetin starts, and needs the reaction of 9 steps to synthesize, and total recovery is far from satisfying the demand entirely researched and developed and declares new less than 1%
The requirement of medicine.Synthetic reaction is as follows:
Therefore, to meet drug research and development and market potential demand, it is shorter to develop a kind of route, the higher synthesis of yield
Method is very important.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic routes, and short, product yield high 7-O- glycosylates the preparation of myricetin
Method.
A kind of preparation method of 7-O- glycosylation myricetin of the present invention, step are as follows:
One, myricetin obtains change shown in 3-6 with acetic anhydride generation acetylization reaction under the alkaline condition that sodium acetate provides
Close object；
Two, compound shown in 3-6 carries out glycosylation reaction with bromo sugar again and obtains compound shown in 3-16；
Three, compound shown in 3-16 further passes through acid and alkali hydrolysis and reacts to obtain compound shown in 3-15, i.e. 7-O- sugar
Base myricetin.
Chemical equation are as follows:
Acetylization reaction described in step 1 is that myricetin shown in 3-1 is dissolved in acetic anhydride, sodium acetate effect under in
Water is added into system after stopping reaction by 60~85 DEG C of 4~8h of reaction, ultrasound, filters, and filter cake is recrystallized with organic solvent, obtained
To compound shown in white solid 3-6.
The dosage of the acetic anhydride is that the molar ratio of compound myricetin shown in 3-1 and acetic anhydride is 1:20~1:25.
The dosage of the water is that the volume ratio of acetic anhydride and water is 1:3~1:5.
The dosage of the sodium acetate is 7~9 equivalents.
Glycosylation reaction described in step 2 is that compound shown in 3-6 and bromo sugar are dissolved in organic solvent, is being catalyzed
It is stirred to react 10~15h at 25~40 DEG C under agent effect, stops reaction, organic solvent extraction takes organic phase, is spin-dried for organic phase
Crude product is obtained, organic solvent recrystallization obtains compound shown in white solid 3-16.
The catalyst is one in mercuric bromide, mercury oxide, silver trifluoromethanesulfonate, silver oxide or tetrabutylammonium bromide
Kind.
The dosage of the catalyst is that the molar ratio of compound and catalyst shown in 3-6 is 1:0.5~1:1.5.
The organic solvent is the organic compound that can dissolve substance not soluble in water comprising carbon atom, including alkane
Hydrocarbon, alkene, alcohol, aldehyde, amine, ester, ether, ketone, aromatic hydrocarbon, hydrogenate hydrocarbon, terpene hydrocarbon, halogenated hydrocarbons, heterocyclic compound, nitrogenous compound or
One or more of sulphur compound.In particular one of ethyl acetate, acetone, N,N-dimethylformamide or quinoline or several
Kind.
The reaction of acid and alkali hydrolysis described in step 3 is that 3-16 compound represented addition pH value is water-soluble for 1~2 acidity
In liquid, reaction is stirred at room temperature 1~2 hour, deacetylate, then be stirred at room temperature instead in the alkaline aqueous solution that pH value is 10~12
It answers 1~2 hour, sloughs the methyl esters on gluconic acid, be spin-dried for water phase and obtain light green solid, Methanol/hexane recrystallizes to obtain 3-15
Shown compound.
The acidic aqueous solution is inorganic acid or aqueous solutions of organic acids；The inorganic acid be hydrochloric acid, sulfuric acid, nitric acid or
One of phosphoric acid；The organic acid is one of tartaric acid, citric acid, fumaric acid, malic acid or succinic acid.
The alkaline aqueous solution is inorganic base or organic aqueous alkali；The inorganic base be potassium carbonate, saleratus,
One of sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide or sodium hydrogen；The organic base is 4- diformazan
One of aminopyridine, triethylamine, sodium alkoxide or ammonium hydroxide.
Synthetic route of the present invention is short, and product yield high, agents useful for same is safety low-poison, and production cost is low, is suitable for extensive
Industrialized production.
Detailed description of the invention
Fig. 1 is compound 3-6's1H-NMR map schematic diagram.
Fig. 2 is compound 3-6's13C-NMR map schematic diagram.
Fig. 3 is compound 3-16's1H-NMR map schematic diagram；
Fig. 4 is compound 3-16's13C-NMR map schematic diagram.
Fig. 5 is compound 3-15's1H-NMR map schematic diagram.
Fig. 6 is compound 3-15's13C-NMR map schematic diagram.
Specific embodiment
Below with reference to embodiment and attached drawing, the present invention is further illustrated, but is not subject in any way to the present invention
Limitation, based on present invention teach that it is made it is any transform or replace, all belong to the scope of protection of the present invention.
Embodiment:
The preparation of full acetylated myricetin (3-6):
Sequentially add compound 3-1 myricetin (5g, 15.7mmol) in 250mL eggplant-shape bottle, sodium acetate (10.3g,
125mmol), acetic anhydride (32g, 314mmol), 80 DEG C of back flow reaction 6h.After stopping reaction, 100mL water is added into system, surpasses
Sound, filters, and filter cake re-crystallizing in ethyl acetate obtains compound 7.65g shown in white solid 3-6, yield 85%, compound structure
Confirmation data are detailed in Fig. 1 and Fig. 2.
One of 7-O- glycosylation preparation method of full acetylated myricetin:
Sequentially add 3,5,7 in 250mL round-bottomed bottle, 3 ', 4', 5 '-six acetoxyl group chromocor compound 3-6 (4.0g,
7mmol), silver oxide (2.1g, 9.1mmol), 2- bromo sugar methyl esters (5.6g, 14mmol), quinoline 40mL.After 35 DEG C of reaction 12h,
Stop reaction, 50mL water and 100mL ethyl acetate are added into reaction solution, is transferred in separatory funnel, separates organic phase, water phase
Three times with ethyl acetate 100mL extraction, merge organic phase, evaporated under reduced pressure solvent after anhydrous sodium sulfate is dry, ethyl alcohol recrystallization obtains
Compound 3.0g shown in white solid 3-16.Yield 50%, compound structure confirmation data are detailed in Fig. 3 and Fig. 4.
The two of the 7-O- glycosylation preparation method of full acetylated myricetin:
It will be added 80mLN in 18g (130mmol) potassium carbonate, in the mixed solution of dinethylformamide and 80ml acetone,
3,5,7,3 ', 4', 5 ' 5.7g (10mmol)-six acetoxyl group chromocor compound 3-6,1.6g are sequentially added after stir about 5min
(5mmol) tetrabutylammonium bromide and 12g (30mmol) 2- bromo sugar methyl esters.25 DEG C are reacted 10 hours.It is added into reaction solution
150mL water and 150mL ethyl acetate, are transferred in separatory funnel, separate organic phase, and water phase extracts three with ethyl acetate 100mL
It is secondary, merge organic phase, evaporated under reduced pressure solvent after anhydrous sodium sulfate is dry obtains the thick production of 7-O- glycosylation of full acetylated myricetin
Object, ethyl alcohol recrystallization obtain compound 7.3g shown in white solid 3-16, yield 85%, and compound structure confirmation data are detailed in Fig. 3
And Fig. 4.
7-O- glycosylates the preparation of myricetin (3-15):
3-16 (2g, 2.4mmol) is added in 100mL two-neck bottle, adjusts pH to 1~2 with 2N dilute hydrochloric acid, is stirred to react 2h,
Then 2mol/L lithium hydroxide aqueous solution (10mL) is added into system again, adjusts pH to 10~12, after 1.5h is stirred at room temperature, shallowly
Green solid is precipitated, filtering, obtains 7-O- glycosylation myricetin crude product, and Methanol/hexane recrystallizes to obtain compound shown in 3-15, receives
Rate 90%, compound structure confirmation data are detailed in Fig. 5 and Fig. 6.
Claims (10)
1. a kind of preparation method of 7-O- glycosylation myricetin, it is characterised in that step are as follows:
One, myricetin obtains compound shown in 3-6 with acetic anhydride generation acetylization reaction under the alkaline condition that sodium acetate provides；
Two, compound shown in 3-6 carries out glycosylation reaction with bromo sugar again and obtains compound shown in 3-16；
Three, compound shown in 3-16 further passes through acid and alkali hydrolysis and reacts to obtain compound shown in 3-15, i.e. 7-O- glycosylation
Myricetin.
2. the preparation method of 7-O- glycosylation myricetin as described in claim 1, it is characterised in that acetyl described in step 1
Changing reaction is that myricetin shown in 3-1 is dissolved in acetic anhydride, in 60~85 DEG C of 4~8h of reaction under sodium acetate effect, is stopped anti-
Water is added into system by Ying Hou, and ultrasound filters, and filter cake is recrystallized with organic solvent, obtains compound shown in white solid 3-6.
3. the preparation method of 7-O- glycosylation myricetin as claimed in claim 2, it is characterised in that the use of the acetic anhydride
It is 1:20~1:25 that amount, which is the molar ratio of compound myricetin and acetic anhydride shown in 3-1,.
4. the preparation method of 7-O- glycosylation myricetin as claimed in claim 2, it is characterised in that the use of the sodium acetate
Amount is 7~9 equivalents.
5. the preparation method of 7-O- glycosylation myricetin as described in claim 1, it is characterised in that glucosides described in step 2
Changing reaction is that compound shown in 3-6 and bromo sugar are dissolved in organic solvent, is stirred at 25~40 DEG C under the action of catalyst
10~15h is reacted, reaction is stopped, organic solvent extraction takes organic phase, is spin-dried for organic phase and obtains crude product, organic solvent recrystallization obtains
Compound shown in white solid 3-16.
6. the preparation method of 7-O- glycosylation myricetin as claimed in claim 5, it is characterised in that the catalyst is bromine
Change one of mercury, mercury oxide, silver trifluoromethanesulfonate, silver oxide or tetrabutylammonium bromide.
7. the preparation method of 7-O- as claimed in claim 5 glycosylation myricetin, it is characterised in that the organic solvent is
The organic compound that can dissolve substance not soluble in water comprising carbon atom, including alkane, alkene, alcohol, aldehyde, amine, ester, ether,
One or more of ketone, aromatic hydrocarbon, hydrogenate hydrocarbon, terpene hydrocarbon, halogenated hydrocarbons, heterocyclic compound, nitrogenous compound or sulphur compound.
8. the preparation method of 7-O- glycosylation myricetin as described in claim 1, it is characterised in that soda acid described in step 3
Hydrolysis is 3-16 compound represented to be added in the acidic aqueous solution that pH value is 1~2, and it is small that reaction 1~2 is stirred at room temperature
When, deacetylate, then reaction is stirred at room temperature 1~2 hour in the alkaline aqueous solution that pH value is 10~12, slough gluconic acid
On methyl esters, be spin-dried for water phase and obtain light green solid, Methanol/hexane recrystallizes to obtain compound shown in 3-15.
9. the preparation method of 7-O- glycosylation myricetin as claimed in claim 8, it is characterised in that the acidic aqueous solution
For inorganic acid or aqueous solutions of organic acids；The inorganic acid is one of hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid；Described is organic
Acid is one of tartaric acid, citric acid, fumaric acid, malic acid or succinic acid.
10. the preparation method of 7-O- glycosylation myricetin as claimed in claim 8, it is characterised in that the alkaline aqueous solution
For inorganic base or organic aqueous alkali；The inorganic base is potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, hydroxide
One of potassium, sodium hydroxide, lithium hydroxide or sodium hydrogen；The organic base be 4-dimethylaminopyridine, triethylamine, sodium alkoxide or
One of ammonium hydroxide.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101941999A (en) * | 2009-07-07 | 2011-01-12 | 昆明制药集团股份有限公司 | Method for preparing scutellarin |
| CN102702285A (en) * | 2009-02-24 | 2012-10-03 | 上海医药工业研究院 | Intermediates for flavonoid compounds and preparation method thereof |
| CN102875620A (en) * | 2012-10-16 | 2013-01-16 | 昆明龙津药业股份有限公司 | New derivatives of myricetin and application of derivatives to medicine preparation |
| CN103374050A (en) * | 2012-04-18 | 2013-10-30 | 昆明制药集团股份有限公司 | Method for preparing 5,6,4'-trihydroxy flavone-7-0-D-glucuronic acid |
| CN104761599A (en) * | 2014-01-08 | 2015-07-08 | 昆明制药集团股份有限公司 | Preparation method of 5,4'-dihydroxy flavone-7-O-D-glucuronic acid |
| CN105218606A (en) * | 2015-10-19 | 2016-01-06 | 昆明理工大学 | A kind of method preparing scutellarin |
-
2018
- 2018-08-17 CN CN201810938625.0A patent/CN109053837A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702285A (en) * | 2009-02-24 | 2012-10-03 | 上海医药工业研究院 | Intermediates for flavonoid compounds and preparation method thereof |
| CN101941999A (en) * | 2009-07-07 | 2011-01-12 | 昆明制药集团股份有限公司 | Method for preparing scutellarin |
| CN103374050A (en) * | 2012-04-18 | 2013-10-30 | 昆明制药集团股份有限公司 | Method for preparing 5,6,4'-trihydroxy flavone-7-0-D-glucuronic acid |
| CN102875620A (en) * | 2012-10-16 | 2013-01-16 | 昆明龙津药业股份有限公司 | New derivatives of myricetin and application of derivatives to medicine preparation |
| CN104761599A (en) * | 2014-01-08 | 2015-07-08 | 昆明制药集团股份有限公司 | Preparation method of 5,4'-dihydroxy flavone-7-O-D-glucuronic acid |
| CN105218606A (en) * | 2015-10-19 | 2016-01-06 | 昆明理工大学 | A kind of method preparing scutellarin |
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Application publication date: 20181221 |