CN109020938A - A kind of preparation method of myricetin - Google Patents
A kind of preparation method of myricetin Download PDFInfo
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- CN109020938A CN109020938A CN201810938621.2A CN201810938621A CN109020938A CN 109020938 A CN109020938 A CN 109020938A CN 201810938621 A CN201810938621 A CN 201810938621A CN 109020938 A CN109020938 A CN 109020938A
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- 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
- C07D311/30—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 not hydrogenated in the hetero ring, e.g. flavones
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Abstract
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of preparation method of myricetin.The preparation method step of myricetin of the present invention are as follows: one, using compound shown in 1-1 as raw material, acylation reaction occurs with methoxyacetonitrile in acid condition and obtains compound shown in 1-3；Two, again with 3,4,5- trimethoxybenzoic acid acid anhydrides occur rearrangement reaction and generate compound shown in 1-5 compound shown in 1-3；Three, demethylating reaction generation 3-1 compound represented, as myricetin occur in the dichloromethane solution of BBr3 for compound shown in 1-5.Fully synthetic route of the present invention is from phloroglucin, through three-step reaction, has successfully synthesized myricetin with 60% total recovery.Have many advantages, such as that raw material is cheap and easily-available, reaction condition is mild, synthetic route is short, product yield high, easy to operate, environmental pollution is small.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of preparation method of myricetin.
Background technique
Myricetin is also known as myricetin, myricetin.Flavone compound.3,3,4,5,5,7- hexahydroxy of chemical name is yellow
Ketone, sterling are yellow needle-like crystals.357~360 DEG C of fusing point.It is slightly soluble in boiling water, is dissolved in ethyl alcohol, is practically insoluble in chloroform and vinegar
Acid.Myricetin is widely present in the leaf, root and limb of red bayberry, has vasoconstriction, increases blood pressure, is excited heart, cholagogue, anti-inflammatory
The effects of, it is also used as treatment diabetes and cataract, by upper summary it is found that myricetin is widely present as a kind of nature
Natural products, have a series of highly important bioactivity.Myricetin, which mainly passes through, at present is extracted from plants separation and obtains
, there are serious pollutions, and the red bayberry cellulose content in natural products is very low, can not meet needs.And semisynthesis is then
To extract isolated dihydromyricetin as raw material, root problem not can solve equally.Therefore, it researches and develops a kind of efficiently fully synthetic
The method of myricetin is very necessary.
Summary of the invention
A kind of preparation method of the purpose of the present invention is to provide synthetic routes short, product yield high myricetin.
A kind of preparation method step of myricetin of the present invention are as follows:
One, using compound shown in 1-1 as raw material, acylation reaction occurs with methoxyacetonitrile in acid condition and obtains 1-
Compound shown in 3；
Two, again with 3,4,5- trimethoxybenzoic acid acid anhydrides occur rearrangement reaction and generate chemical combination shown in 1-5 compound shown in 1-3
Object；
Three, compound shown in 1-5 is in BBr3Dichloromethane solution in occur demethylating reaction generate 3-1 shown in chemical combination
Object, as myricetin.
Chemical equation of the present invention are as follows:
Acylation reaction described in step 1 be by acid ethyl acetate solution under conditions of ice-water bath is cooling to 1-1 institute
It is added dropwise in methoxyacetonitrile system shown in the phloroglucin and 1-2 shown, after being added dropwise, is warmed to room temperature 5~6h of reaction, so
Afterwards, ethyl acetate is concentrated, water is added, continues 1~2h of room temperature reaction, reaction terminates, ice-water bath 2~3h of stirring and crystallizing, filtering, very
Sky is dry, obtains compound shown in light pink solid 1-3.
The molar ratio of the phloroglucin and methoxyacetonitrile is 1:1.0~1:1.5.
The dosage that water is added are as follows: the molal volume ratio of compound and water shown in 1-1 is 0.2~0.5mol/L.
The acid ethyl acetate solution is the ethyl acetate solution of inorganic acid or organic acid；The inorganic acid is chlorine
Change one of hydrogen, sulfuric acid, nitric acid or phosphoric acid；The organic acid is tartaric acid, citric acid, fumaric acid, malic acid or fourth two
One of acid.
The molar ratio of the inorganic acid or organic acid and phloroglucin is 1:1.0~1:1.5.
Rearrangement reaction described in step 2 is that compound shown in compound shown in 1-3 and 1-4 is dissolved in triethylamine, reflux
5~6h is reacted, reaction is stopped, cooling, dilute hydrochloric acid tune pH value to 6.5~7.5, ice-water bath 2~3h of stirring and crystallizing, filtering, vacuum
It is dry, obtain compound shown in white solid 1-5.
The molar ratio of compound shown in compound shown in the 1-3 and 1-4 is 1:1.2~1:1.8.
The dosage of the triethylamine are as follows: the molal volume ratio of compound and triethylamine shown in 1-3 is 0.2~0.5mol/L.
Demethylating reaction described in step 3 is by the BBr of 1M3Dichloromethane solution be added drop-wise to compound shown in 1-5
In dichloromethane solution, 10~15 DEG C of 10~12h of reaction, ice-water bath is quenched, and dry dichloromethane is concentrated, and ethyl acetate extraction is dense
Contracting dry ethyl acetate obtains compound myricetin shown in yellow solid 3-1.
The BBr of the 1M3Dichloromethane solution be converted to BBr3Dosage be BBr3With mole of compound shown in 1-5
Than for 5:1~10:1.
Fully synthetic route of the present invention is from phloroglucin, through three-step reaction, successfully with 60% total recovery
Myricetin is synthesized.It is cheap and easily-available with raw material, reaction condition is mild, synthetic route is short, product yield high, easy to operate, ring
The advantages that border pollution is small.Agents useful for same is safety low-poison, and production cost is low, is suitable for large-scale industrial production, for a large amount of systems
It is standby to have established excellent basis.
Detailed description of the invention
Fig. 1 is compound 1-5's1H-NMR map schematic diagram.
Fig. 2 is compound 1-5's13C-NMR map schematic diagram.
Fig. 3 is compound myricetin1H-NMR map schematic diagram.
Fig. 4 is compound myricetin13C-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 intermediate 1-3:
By phloroglucin 1-1 (500mg, 4.0mmol), 100mL eggplant is added in methoxyacetonitrile 1-2 (423mg, 6.0mmol)
The Hydrochloride/ethyl acetate 2.5mL of 2N is slowly added dropwise in shape bottle, under condition of ice bath, stirs 1h, removes ice bath, be stirred at room temperature
6h.System is spin-dried for, 10mL water is added and continues to be stirred to react 1h (system becomes pale red brown by colourless), ice-water bath cooling and stirring
2h filters the solid of precipitation, and vacuum drying can obtain 785mg light pink solid 1-3, yield 99%.
1H NMR(400MHz,DMSO-d6)δ12.15(s,2H),10.40(s,1H),5.81(s,2H),4.58(s,2H),
3.34(s,3H)。
13C NMR(100MHz,DMSO-d6)δ201.7,165.4,164.5,102.9,95.0,77.5,58.9。
The synthesis of intermediate 1-5:
By 2- methoxyl group -2,4,6- trihydroxy-acetophenone 1-3 (500mg, 2.5mmol), 3,4,5- trimethoxybenzoic acids
Acid anhydride 1-4 (1.52g, 3.75mmol) is added in 100mL eggplant-shape bottle, and triethylamine 10mL, 90 DEG C of back flow reaction 6h are added, and stops adding
Heat stops reaction, cooling, and 2N dilute hydrochloric acid is added and adjusts pH to 7, and a large amount of solids are precipitated, and ice-water bath stirring and crystallizing 2h is filtered, is dry
Compound 740mg shown in dry white solid 1-5, yield 79%, compound structure confirmation data are detailed in Fig. 1 and Fig. 2.
1H NMR(400MHz,DMSO-d6)δ12.57(s,2H),7.35(s,2H),6.52(s,1H),6.23(s,1H),
3.87(s,6H),3.84(s,3H),3.77(s,3H)。
13C NMR(100MHz,DMSO-d6)δ178.5,164.8,161.7,156.9,155.4,153.2,140.4,
139.0,125.6,106.4,104.8,99.2,94.5,60.7,60.4,56.5,46.7,46.1。
The synthesis of myricetin (3-1):
Flavonols 1-5 (500mg, 1.3mmol) is placed in the eggplant-shape bottle of 100mL, is added methylene chloride (10mL), 10~15
The BBr of 1M is slowly added dropwise under the conditions of DEG C3Dichloromethane solution (10.5mL), insulation reaction 10h.Stop reaction, a large amount of ice are added
Water quenching is gone out, the methylene chloride being spin-dried in system, is extracted with ethyl acetate 3 times, and anhydrous sodium sulfate is dry, is spin-dried for obtaining yellow solid 3-
The 393.5mg of compound myricetin shown in 1, yield 95.2%.Compound structure confirmation data are detailed in Fig. 3 and Fig. 4.
1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),9.31(br,4H),7.27(s,2H),6.40(s,1H),
6.21(s,1H)。
13C NMR(100MHz,DMSO-d6)δ176.2,164.4,161.2,156.5,147.3,146.2,136.3,
121.25,107.6,103.4,98.6,93.7。
Claims (10)
1. a kind of preparation method of myricetin, it is characterised in that step are as follows:
One, using compound shown in 1-1 as raw material, acylation reaction occurs with methoxyacetonitrile in acid condition and obtains 1-3 institute
Show compound；
Two, again with 3,4,5- trimethoxybenzoic acid acid anhydrides occur rearrangement reaction and generate compound shown in 1-5 compound shown in 1-3；
Three, demethylating reaction generation 3-1 compound represented occurs in the dichloromethane solution of BBr3 for compound shown in 1-5,
As myricetin.
2. the preparation method of myricetin as described in claim 1, it is characterised in that acylation reaction described in step 1 be by
Acid ethyl acetate solution is under conditions of ice-water bath is cooling to methoxyacetonitrile shown in phloroglucin shown in 1-1 and 1-2
It is added dropwise in system, after being added dropwise, is warmed to room temperature 5~6h of reaction, then, ethyl acetate is concentrated, water is added, continues to react at room temperature
1~2h, reaction terminate, ice-water bath 2~3h of stirring and crystallizing, filter, and vacuum drying obtains compound shown in light pink solid 1-3.
3. the preparation method of myricetin as claimed in claim 2, it is characterised in that the phloroglucin and methoxyacetonitrile
Molar ratio be 1:1.0~1:1.5.
4. the preparation method of myricetin as claimed in claim 2, it is characterised in that the acid ethyl acetate solution is nothing
The ethyl acetate solution of machine acid or organic acid.
5. the preparation method of myricetin as claimed in claim 4, it is characterised in that the inorganic acid be hydrogen chloride, sulfuric acid,
One of nitric acid or phosphoric acid；The organic acid is one of tartaric acid, citric acid, fumaric acid, malic acid or succinic acid.
6. the preparation method of myricetin as described in claim 1, it is characterised in that rearrangement reaction described in step 2 is by 1-3
Compound shown in shown compound and 1-4 is dissolved in triethylamine, 5~6h of back flow reaction, stops reaction, cooling, dilute hydrochloric acid tune pH
Value filters, vacuum drying obtains compound shown in white solid 1-5 to 6.5~7.5, ice-water bath 2~3h of stirring and crystallizing.
7. the preparation method of myricetin as claimed in claim 6, it is characterised in that compound shown in the 1-3 and 1-4 institute
The molar ratio for showing compound is 1:1.2~1:1.8.
8. the preparation method of myricetin as claimed in claim 6, it is characterised in that the dosage of the triethylamine are as follows: shown in 1-3
The molal volume of compound and triethylamine ratio is 0.2~0.5mol/L.
9. the preparation method of myricetin as described in claim 1, it is characterised in that demethylating reaction described in step 3 be by
The dichloromethane solution of the BBr3 of 1M is added drop-wise in the dichloromethane solution of compound shown in 1-5, and 10~15 DEG C of reactions 10~
12h, ice-water bath are quenched, and dry dichloromethane is concentrated, and ethyl acetate extraction is concentrated dry ethyl acetate, obtains yellow solid 3-1 shownization
Close object myricetin.
10. the preparation method of myricetin as claimed in claim 9, it is characterised in that the dichloromethane solution of the BBr3 of the 1M
It is 5:1~10:1 that the dosage for being converted to BBr3, which is the molar ratio of compound shown in BBr3 and 1-5,.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054605A (en) * | 2019-05-31 | 2019-07-26 | 北京盛诺基医药科技有限公司 | A kind of preparation method of icariine intermediate |
| CN110092770A (en) * | 2019-05-31 | 2019-08-06 | 北京盛诺基医药科技有限公司 | A kind of preparation method of chromocor compound intermediate |
| CN113666899A (en) * | 2020-05-14 | 2021-11-19 | 中国人民大学 | Calcium complex of flavonoid compound and preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110054605A (en) * | 2019-05-31 | 2019-07-26 | 北京盛诺基医药科技有限公司 | A kind of preparation method of icariine intermediate |
| CN110092770A (en) * | 2019-05-31 | 2019-08-06 | 北京盛诺基医药科技有限公司 | A kind of preparation method of chromocor compound intermediate |
| CN113666899A (en) * | 2020-05-14 | 2021-11-19 | 中国人民大学 | Calcium complex of flavonoid compound and preparation method and application thereof |
| CN113666899B (en) * | 2020-05-14 | 2023-09-15 | 中国人民大学 | Calcium complex of flavonoid compound and preparation method and application thereof |
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