CN109535118A - A kind of synthetic method of fisetin - Google Patents
A kind of synthetic method of fisetin Download PDFInfo
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- CN109535118A CN109535118A CN201811592833.6A CN201811592833A CN109535118A CN 109535118 A CN109535118 A CN 109535118A CN 201811592833 A CN201811592833 A CN 201811592833A CN 109535118 A CN109535118 A CN 109535118A
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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 problem of the present invention provides a kind of synthetic methods of fisetin, solve existing fisetin synthetic method and are only applicable to laboratory, and product yield and content cannot get both.1) synthetic method is the following steps are included: use 2- butanone, benzyl chloride, 2,4-resacetophenones and anhydrous K2CO3There is the intermediate product of protecting group in generation；2) under nitrogen protection, in alkaline environment, make intermediate product and protocatechualdehyde that condensation reaction occur, generate 3 ', 4 '-dihydroxy -7- benzyl chalcones；3) 3 ', 4 '-dihydroxy -7- benzyl chalcones are restored and generates 3 ', 4 ', 7- trihydroxy chalcone；4) 3 ', 4 ', 7- trihydroxy chalcone is placed in alkaline environment upper hydroxyl, cyclization reaction is then carried out under the catalysis of p-methyl benzenesulfonic acid, generate fisetin.The synthetic method can be used for industrialized production；The synthetic method is easy to operate, raw material is easy to get, the lower production costs and yield of gained intermediate product and finished product, purity are higher, has preferable development prospect.
Description
Technical field
The invention belongs to material medicine synthetic technologys, and in particular to a kind of synthetic method of fisetin.
Background technique
Fisetin is Flavonoid substances, and No. CAS is 528-48-3, molecular formula C15H10O6, molecular weight 286.23, molecular structure
Formula:
Fisetin (Fisetin, FIS), alias fisetin, butin, fisetin, 3,3', 4', 7- kaempferol, paint
Yellow acid.Sterling is yellow needles, 330 DEG C of fusing point (decomposition), is dissolved in ethyl alcohol, acetone and acetic acid, is practically insoluble in water, second
Ether, benzene, chloroform and petroleum ether.
Fisetin is a kind of natural flavone alcohol compound extracted from the plants such as Anacardiaceae plant haze tallow tree, in Chinese littleleaf box
Content in wood is 0.8-2%；Be also present in vegetables and fruit, as apple, persimmon, grape, Kiwi berry, strawberry, onion and
Cucumber etc..
Fisetin has the pharmacological characteristics such as anti-oxidant, anti-inflammatory and neuroprotection, can pass through inducing apoptosis of tumour cell, shadow
The signal transduction pathway for ringing tumour cell, the proliferation for inhibiting tumour cell, the migration for inhibiting tumour cell and invasion etc. hair
Wave antitumor action；Studies have shown that fisetin can also be by inhibiting the monoamine of serotonin and norepinephrine system to aoxidize
Enzyme and play antidepressant effect；The hepatic injury caused by hepatitis has obvious protection and repair；It is remarkably improved immunocyte
Activity.
American Academy of Sciences report, fisetin can stimulus signal access, improve long term memory；There are also inhibit yellow bent
The effect of mycin cytotoxicity.Fisetin product in the market is more, and the paint as Doctor ' the s Best company in the U.S. produces is yellow
Cellulose capsule (30mg), product fisetin capsule (100mg) of Swanson Ultra etc. are all sales volumes preferably containing fisetin
Health product.
By literature search, from smoke tree, (Anacardiaceae smoke tree belongs to be planted the Li Jianhua of People's Armed Police Henan army unit hospital pharmacy et al.
Object) in extract fisetin (" People's Armed Police's medicine ", 03 phase in 1997).The reported extraction of document and isolation technics are appropriate only for reality mostly
Room is tested, the yield and content of product generally can not get both, it is impossible to be used in instruct industrial production.It is related that there is presently no document reports
In the synthesis route of fisetin.
Summary of the invention
It is an object of the invention to solve prior art synthesis fisetin to be only applicable to laboratory, and product yield and content
The shortcoming that cannot be got both provides one kind and is suitble to industrialized fisetin synthetic method, to ensure product yield and content
Guaranteed.
Present invention design is:
1) 2- butanone, benzyl chloride, 2,4-resacetophenones and anhydrous K are used2CO3There is protecting group (i.e. benzyl) in generation
Intermediate product；
2) under nitrogen protection, in alkaline environment, make the intermediate product of step 1) and protocatechualdehyde that condensation reaction occur, it is raw
At 3 ', 4 '-dihydroxy -7- benzyl chalcones；
3) protecting group is taken off into the reduction of 3 ', 4 '-dihydroxy -7- benzyl chalcones, generates 3 ', 4 ', 7- trihydroxy chalcone；
4) 3 ', 4 ', 7- trihydroxy chalcone is placed in alkaline environment upper hydroxyl, then under the catalysis of p-methyl benzenesulfonic acid
Cyclization reaction is carried out, target product fisetin is generated.
Specific synthetic route is as follows:
To achieve the above object, specific technical solution provided by the invention is as follows:
A kind of synthetic method of fisetin, is characterized in that, comprising the following steps:
Step 1) generates white mixture
2- butanone is uniformly mixed with benzyl chloride, adds 2,4-resacetophenones and anhydrous K2CO3, stir, heat up back
Stream is reacted, to which after reaction, processing obtains white mixture, and (white mixture is the intermediate production after upper protecting group
Object)；
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
Protocatechualdehyde and the resulting white mixture of step 1) are dissolved in dehydrated alcohol, and it is molten that potassium hydroxide is added
Liquid, under nitrogen protection, stirring, temperature rising reflux are reacted, and cooling (temperature is after of continuing rising while preventing temperature rising reflux from reacting
It is high) and pour into quenching reaction in ice water；PH to 3~5 is made using hydrochloric acid acidification, crocus solid is precipitated, processing obtains 3 ', 4 '-
Dihydroxy -7- benzyl chalcone；
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
Resulting 3 ', the 4 '-dihydroxy -7- benzyl chalcone of step 2) is dissolved in ethyl acetate, and is catalyzed in palladium carbon
Under, hydrogenation reduction obtains 3 ', 4 ', 7- trihydroxy chalcone；
Step 4) generates fisetin
4.1) by step 3) resulting 3 ', 4 ', the mixed solvent to methylene chloride and acetone is added in 7- trihydroxy chalcone
In, and buffer solution stirring is added；
4.2) aqueous solution that potassium acid sulfate complex salt is added into step 4.1) acquired solution adjusts pH value of solution to 9~9.5,
And reacted (reaction is in order to hydroxyl on 3 ', 4 ', 7- trihydroxy chalcone)；
4.3) it to after reaction, stand, extract and collect organic phase, washed, dried, filtered to organic phase, receives
Collect filtrate and the p-methyl benzenesulfonic acid that catalytic amount is added into filtrate carries out cyclization reaction, to after reaction, be recrystallized to give paint
Flavine.
Further, the step 1) comprises the concrete steps that:
1.1) 2- butanone and benzyl chloride are stirred evenly, adds 2,4-resacetophenones and anhydrous K2CO3, stir, rise
It after warm back flow reaction 12h, adds water and stirs, to promote extent of reaction；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with methanol pair
The residue is recrystallized, and white mixture is obtained.
Further, in order to react each substance adequately, the 2- butanone, benzyl chloride, 2,4- dihydroxy benzenes second
Ketone, anhydrous K2CO3Mass ratio with water is 10~11: 3: 1: 2.5~3.5: 12~13.
Further, the step 2) comprises the concrete steps that:
2.1) white mixture obtained by protocatechualdehyde and step 1) is dissolved in dehydrated alcohol, and mass concentration is added and is
30% potassium hydroxide solution, under nitrogen protection, stirring after temperature rising reflux reacts 20h, is cooled and poured into ice water and is quenched instead
It answers；
2.2) using mass concentration that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid is 3, and crocus is precipitated
Solid, filtering；
2.3) step 2.2) is filtered resulting crocus solid to wash, and is recrystallized using methanol, obtained
Crocus acicular crystal 3 ', 4 '-dihydroxy -7- benzyl chalcone.
Further, in step 2), the white mixture, protocatechualdehyde, dehydrated alcohol and mass concentration are 30%
Potassium hydroxide solution mass ratio is 0.95~1.2: 1: 5.5~6.5: 8~10.
Further, the step 3) comprises the concrete steps that: by resulting 3 ', the 4 '-dihydroxy -7- benzyl chalcone of step 2)
It is dissolved in ethyl acetate, and under palladium carbon catalysis, hydrogenation reduction, until not reabsorbing hydrogen, (i.e. the pressure of reaction kettle is no longer
Decline), it filters, steam solvent, obtain 3 ', 4 ', 7- trihydroxy chalcone.
Further, in step 3), the mass ratio of 3 ', the 4 '-dihydroxy -7- benzyl chalcone and ethyl acetate is 1:
3.5~4.5.
Further, the step 4) comprises the concrete steps that:
4.1) by step 3) resulting 3 ', 4 ', the methylene chloride and third to volume ratio for 4:3 is added in 7- trihydroxy chalcone
The in the mixed solvent of ketone, and sodium carbonate/bicarbonate buffer solution is added and is quickly vigorously stirred；
4.2) aqueous solution that potassium acid sulfate complex salt is slowly added dropwise for the first time into step 4.1) acquired solution adjusts solution
PH to 9 is reacted, and the aqueous solution to which potassium acid sulfate complex salt after reaction, is slowly added dropwise for the second time adjusts pH value of solution to 9
It is reacted；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
It is multiple that salt water washs organic phase respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and catalytic amount is added into filtrate
P-methyl benzenesulfonic acid, stirring carries out cyclization reaction at room temperature, to which after reaction, recycling design uses anhydrous methanol or dichloromethane
Alkane is recrystallized, and yellow solid fisetin is obtained.
Further, in step 4), 3 ', 4 ', the 7- trihydroxy chalcone, buffer solution, the sulfuric acid being added for the first time
The aqueous solution of hydrogen potassium complex salt, the aqueous solution of potassium acid sulfate complex salt of second of addition and the mass ratio of p-methyl benzenesulfonic acid are 1:
10~11:7~11:7~11: 0.2~0.4.
Further, in step 4.2), two secondary responses are all made of thin-layer chromatography detection and are disappeared with raw material spot for terminal.
The invention has the advantages that
The present invention synthesizes fisetin using four step rule, can be used for industrialized production；The synthetic method is easy to operate, raw material is easy
, the lower production costs and yield of gained intermediate product and finished product, purity are higher, fisetin yield is up to 95%
More than, (liquid phase) purity has preferable development prospect, while obtaining fisetin by the synthetic method, can subtract up to 98%
Few the phenomenon that causing a large amount of boxwoods to be cut down because extracting fisetin.
Detailed description of the invention
Fig. 1 is the liquid chromatogram using fisetin made from synthetic method of the present invention.
Specific embodiment
The contents of the present invention are described in further detail below in conjunction with Fig. 1 and specific embodiment:
Embodiment 1
A kind of synthetic method of fisetin, comprising the following steps:
Step 1) generates white mixture
1.1) benzyl chloride of the 2- butanone of 100ml and 24g is stirred evenly, adds the 2 of 8g, 4-resacetophenones and
The anhydrous K of 25g2CO3, stirring, after temperature rising reflux reacts 12h, the water that 100ml is added is stirred；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with 20ml first
Alcohol recrystallizes residue, obtains the white mixture powder of 13.6g, yield 75.1%.
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
2.1) protocatechualdehyde of the white mixture powder of 13.6g and 13.5g is dissolved in the dehydrated alcohol of 100ml,
The potassium hydroxide solution that 120g mass concentration is 30% is added, under nitrogen protection, stirring, temperature rising reflux 20h or so, cooling is simultaneously
Pour into quenching reaction in the ice water of 150g；
2.2) it uses the mass concentration of 1: 1 (volume ratio) that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid to be
3, crocus solid, filtering is precipitated；
2.3) step 2.2) is filtered resulting crocus solid to wash, obtains 3 ', 4 '-dihydroxy -7- benzyls and looks into
That ketone crude product, and recrystallized using the methanol of 500ml, obtain 3 ', 4 '-dihydroxy of crocus acicular crystal-of 22.95g
7- benzyl chalcone, yield 85.1%.
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
The 3 ' of 22.95g, 4 '-dihydroxy -7- benzyl chalcones are dissolved in the ethyl acetate of 100ml, and are urged in palladium carbon
Under change, hydrogenation reduction until not reabsorbing hydrogen (i.e. the pressure of reaction kettle no longer declines), filters, steams solvent, obtain
The 3 ' of 21.573g, 4 ', 7- trihydroxy chalcone, yield 94%, purity 95%.
Step 4) generates fisetin
4.1) by the 3 ' of 21.573g, 4 ', 7- trihydroxy chalcone be added to the dichloromethane-acetone of 140ml (V: V=4:
3) in the mixed solvent, be added 200ml sodium carbonate/bicarbonate buffer solution (by 8g sodium carbonate, 8g sodium bicarbonate and
The water of 200ml configures), and be vigorously mixed at room temperature for；
4.2) be slowly added dropwise for the first time into step 4.1) acquired solution 140ml potassium acid sulfate complex salt aqueous solution (by
The water of 12g potassium acid sulfate complex salt and 140ml configure), 5h is added dropwise, and reacts 16h at room temperature, and then second
The aqueous solution (being configured by the water of 12g potassium acid sulfate complex salt and 140ml) of 140ml potassium acid sulfate complex salt is slowly added dropwise,
5h is added dropwise, and 16h is reacted in continuation at room temperature, and keeping the pH of reaction system is 9, and two secondary responses are all made of thin-layer chromatography inspection
It surveys and is disappeared with raw material spot for terminal；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
Salt water washs organic phase 3 times respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and pair of 50mg is added into filtrate
Toluenesulfonic acid is stirred to react 1h at room temperature, to which after reaction, recycling design carries out weight using anhydrous methanol or methylene chloride
Crystallization, obtains the yellow solid fisetin of 20.86g, yield 96.7%, purity 98% (liquid phase).
Embodiment 2
A kind of synthetic method of fisetin, comprising the following steps:
Step 1) generates white mixture
1.1) benzyl chloride of the 2- butanone of 120ml and 29g is stirred evenly, adds the 2 of 9.6g, 4-resacetophenones
With the anhydrous K of 30g2CO3, after temperature rising reflux reacts 12h, the water stirring of 121ml is added；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with 20ml first
Alcohol recrystallizes the residue, obtains the white mixture powder of 15.6g, yield 75.1%.
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
2.1) protocatechualdehyde of the white mixture powder of 15.6g and 15.5g is dissolved in the dehydrated alcohol of 120ml,
The potassium hydroxide solution that 150g mass concentration is 30% is added, under nitrogen protection, stirring temperature rising reflux 20h or so, cooling is simultaneously
Pour into quenching reaction in the ice water of 180g；
2.2) it uses the mass concentration of 1: 1 (volume ratio) that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid to be
3, crocus solid, filtering is precipitated；
2.3) step 2.2) is filtered resulting crocus solid to wash, obtains 3 ', 4 '-dihydroxy -7- benzyls and looks into
That ketone crude product, and recrystallized using the methanol of 500ml, obtain 3 ', 4 '-dihydroxy of crocus acicular crystal-of 26.35g
7- benzyl chalcone, yield 85%.
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
The 3 ' of 26.35g, 4 '-dihydroxy -7- benzyl chalcones are dissolved in the ethyl acetate of 120ml, and are urged in palladium carbon
Under change, hydrogenation reduction until not reabsorbing hydrogen (i.e. the pressure of reaction kettle no longer declines), filters, steams solvent, obtain
The 3 ' of 24.5g, 4 ', 7- trihydroxy chalcone, yield 93%.
Step 4) generates fisetin
4.1) the 3 ' of 24.5g, 4 ', 7- trihydroxy chalcone is added to the dichloromethane-acetone of 160ml (V: V=4: 3)
In the mixed solvent, be added 240ml sodium carbonate/bicarbonate buffer solution (by 9.6g sodium carbonate, 9.6g sodium bicarbonate and
The water of 240ml configures), and be vigorously mixed at room temperature for；
4.2) be slowly added dropwise for the first time into step 4.1) acquired solution 160ml potassium acid sulfate complex salt aqueous solution (by
The water of 14g potassium acid sulfate complex salt and 160ml configure), 5h is added dropwise, and reacts 16h at room temperature, and then second
The aqueous solution (being configured by the water of 14g potassium acid sulfate complex salt and 160ml) of 160ml potassium acid sulfate complex salt is slowly added dropwise,
5h is added dropwise, and 16h is reacted in continuation at room temperature, and keeping the pH of reaction system is 9, and two secondary responses are all made of thin-layer chromatography inspection
It surveys and is disappeared with raw material spot for terminal；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
Salt water washs organic phase 3 times respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and pair of 50mg is added into filtrate
Toluenesulfonic acid is stirred to react 1h at room temperature, to which after reaction, recycling design carries out weight using anhydrous methanol or methylene chloride
Crystallization, obtains the yellow solid fisetin of 23.28g, yield 95%, purity 98% (liquid phase).
Embodiment 3
A kind of synthetic method of fisetin, comprising the following steps:
Step 1) generates white mixture
1.1) benzyl chloride of the 2- butanone of 50ml and 12g is stirred evenly, adds the 2 of 4g, 4-resacetophenones and
The anhydrous K of 13g2CO3, after temperature rising reflux reacts 12h, the water stirring of 50ml is added；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with 20ml first
Alcohol recrystallizes the residue, obtains the white mixture powder of 6.5g, yield 74.5%.
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
2.1) protocatechualdehyde of the white mixture powder of 6.5g and 6.5g is dissolved in the dehydrated alcohol of 50ml, is added
The potassium hydroxide solution that 60g mass concentration is 30%, under nitrogen protection, stirring temperature rising reflux 20h or so is cooled and poured into
Quenching reaction in the ice water of 80g；
2.2) it uses the mass concentration of 1: 1 (volume ratio) that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid to be
3, crocus solid, filtering is precipitated；
2.3) step 2.2) is filtered resulting crocus solid to wash, obtains 3 ', 4 '-dihydroxy -7- benzyls and looks into
That ketone crude product, and recrystallized using the methanol of 500ml, obtain crocus acicular crystal 3 ', 4 '-dihydroxy -7- benzyl of 11g
Base chalcone, yield 85%.
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
The 3 ' of 11g, 4 '-dihydroxy -7- benzyl chalcones are dissolved in the ethyl acetate of 50ml, and are catalyzed in palladium carbon
Under, hydrogenation reduction until not reabsorbing hydrogen (i.e. the pressure of reaction kettle no longer declines), filters, steams solvent, obtain 10g's
3 ', 4 ', 7- trihydroxy chalcone, yield 91.9%.
Step 4) generates fisetin
4.1) the 3 ' of 10g, 4 ', 7- trihydroxy chalcone is added to the dichloromethane-acetone of 70ml (V: V=4: 3)
In mixed solvent, the sodium carbonate/bicarbonate buffer solution of 100ml is added (by 4g sodium carbonate, 4g sodium bicarbonate and 100ml
Water configure), and be vigorously mixed at room temperature for；
4.2) aqueous solution of 70ml potassium acid sulfate complex salt is slowly added dropwise for the first time into step 4.1) acquired solution (by 6g
The water of potassium acid sulfate complex salt and 70ml configure), 5h is added dropwise, and reacts 16h at room temperature, then for the second time slowly
The aqueous solution (being configured by the water of 6g potassium acid sulfate complex salt and 70ml) of 70ml potassium acid sulfate complex salt is added dropwise, 5h is dripped
Finish, 16h is reacted in continuation at room temperature, and keeping the pH of reaction system is 9, and two secondary responses are all made of thin-layer chromatography detection with raw material
It is terminal that spot, which disappears,；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
Salt water washs organic phase 3 times respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and pair of 30mg is added into filtrate
Toluenesulfonic acid is stirred to react 1h at room temperature, to which after reaction, recycling design carries out weight using anhydrous methanol or methylene chloride
Crystallization, obtains the yellow solid fisetin of 9.5g, yield 95%, purity 98% (liquid phase).
Embodiment 4
A kind of synthetic method of fisetin, comprising the following steps:
Step 1) generates white mixture
1.1) benzyl chloride of the 2- butanone of 140ml and 33.6g is stirred evenly, adds the 2 of 11.2g, 4-dihydroxy benzenes
The anhydrous K of ethyl ketone and 35g2CO3, after temperature rising reflux reacts 12h, the water stirring of 140ml is added；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with 20ml first
Alcohol recrystallizes the residue, obtains the white mixture powder of 19g, yield 75%.
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
2.1) protocatechualdehyde of the white mixture powder of 19g and 19g is dissolved in the dehydrated alcohol of 140ml, is added
The potassium hydroxide solution that 168g mass concentration is 30%, under nitrogen protection, stirring temperature rising reflux 20h or so is cooled and poured into
Quenching reaction in the ice water of 210g；
2.2) it uses the mass concentration of 1: 1 (volume ratio) that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid to be
3, crocus solid, filtering is precipitated；
2.3) step 2.2) is filtered resulting crocus solid to wash, obtains 3 ', 4 '-dihydroxy -7- benzyls and looks into
That ketone crude product, and recrystallized using the methanol of 500ml, obtain crocus acicular crystal 3 ', 4 '-dihydroxy -7- benzyl of 32g
Base chalcone, yield 84%.
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
The 3 ' of 32g, 4 '-dihydroxy -7- benzyl chalcones are dissolved in the ethyl acetate of 140ml, and are catalyzed in palladium carbon
Under, hydrogenation reduction until not reabsorbing hydrogen (i.e. the pressure of reaction kettle no longer declines), filters, steams solvent, obtain 29.88g
3 ', 4 ', 7- trihydroxy chalcone, yield 93%.
Step 4) generates fisetin
4.1) by the 3 ' of 29.88g, 4 ', 7- trihydroxy chalcone be added to the dichloromethane-acetone of 200ml (V: V=4:
3) in mixed solvent, the sodium carbonate/bicarbonate buffer solution of 280ml is added (by 11.2g sodium carbonate, 11.2g bicarbonate
The water of sodium and 280ml configure), and be vigorously mixed at room temperature for；
4.2) be slowly added dropwise for the first time into step 4.1) acquired solution 200ml potassium acid sulfate complex salt aqueous solution (by
The water of 17g potassium acid sulfate complex salt and 200ml configure), 5h is added dropwise, and reacts 16h at room temperature, and then second
The aqueous solution (being configured by the water of 17g potassium acid sulfate complex salt and 200ml) of 200ml potassium acid sulfate complex salt is slowly added dropwise,
5h is added dropwise, and 16h is reacted in continuation at room temperature, and keeping the pH of reaction system is 9, and two secondary responses are all made of thin-layer chromatography inspection
It surveys and is disappeared with raw material spot for terminal；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
Salt water washs organic phase 3 times respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and pair of 70mg is added into filtrate
Toluenesulfonic acid is stirred to react 1h at room temperature, to which after reaction, recycling design carries out weight using anhydrous methanol or methylene chloride
Crystallization, obtains the yellow solid fisetin of 28.4g, yield 95%, purity 98% (liquid phase).
Embodiment 5
A kind of synthetic method of fisetin, comprising the following steps:
Step 1) generates white mixture
1.1) benzyl chloride of the 2- butanone of 150ml and 36g is stirred evenly, adds the 2 of 12g, 4-resacetophenones
With the anhydrous K of 33g2CO3, after temperature rising reflux reacts 12h, the water stirring of 150ml is added；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with 20ml first
Alcohol recrystallizes the residue, obtains the white mixture powder of 19.6g, yield 75%.
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
2.1) protocatechualdehyde of the white mixture powder of 19.6g and 20g is dissolved in the dehydrated alcohol of 150ml, is added
Enter the potassium hydroxide solution that 180g mass concentration is 30%, under nitrogen protection, stirring temperature rising reflux 20h or so, cooling is simultaneously fallen
Enter quenching reaction in the ice water of 150g；
2.2) it uses the mass concentration of 1: 1 (volume ratio) that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid to be
3, crocus solid, filtering is precipitated；
2.3) step 2.2) is filtered resulting crocus solid to wash, obtains 3 ', 4 '-dihydroxy -7- benzyls and looks into
That ketone crude product, and recrystallized using the methanol of 750ml, obtain 3 ', 4 '-dihydroxy of crocus acicular crystal-of 33.66g
7- benzyl chalcone, yield 85%.
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
The 3 ' of 33.66g, 4 '-dihydroxy -7- benzyl chalcones are dissolved in the ethyl acetate of 150ml, and are urged in palladium carbon
Under change, hydrogenation reduction until not reabsorbing hydrogen (i.e. the pressure of reaction kettle no longer declines), filters, steams solvent, obtain
The 3 ' of 31.4g, 4 ', 7- trihydroxy chalcone, yield 93.5%.
Step 4) generates fisetin
4.1) the 3 ' of 31.4g, 4 ', 7- trihydroxy chalcone is added to the dichloromethane-acetone of 210ml (V: V=4: 3)
Mixed solvent in, be added 300ml sodium carbonate/bicarbonate buffer solution (by 12g sodium carbonate, 12g sodium bicarbonate and
The water of 300ml configures), and be vigorously mixed at room temperature for；
4.2) aqueous solution of the potassium acid sulfate complex salt of 18g is slowly added dropwise for the first time into step 4.1) acquired solution
300ml, 5h are added dropwise, and react 16h at room temperature, and the water of the potassium acid sulfate complex salt of 18g is then slowly added dropwise for the second time
Solution 300ml, 5h are added dropwise, and 16h is reacted in continuation at room temperature, and keeping the pH of reaction system is 9, and two secondary responses are all made of
Thin-layer chromatography detection is disappeared with raw material spot for terminal；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
Salt water washs organic phase 3 times respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and pair of 75mg is added into filtrate
Toluenesulfonic acid is stirred to react 1h at room temperature, to which after reaction, recycling design carries out weight using anhydrous methanol or methylene chloride
Crystallization, obtains the yellow solid fisetin of 30.21g, yield 96%, purity 98% (liquid phase).
Embodiment 6
A kind of synthetic method of fisetin, comprising the following steps:
Step 1) generates white mixture
1.1) benzyl chloride of the 2- butanone of 109ml and 24g is stirred evenly, adds the 2 of 8g, 4-resacetophenones and
The anhydrous K of 20g2CO3, after temperature rising reflux reacts 12h, the water stirring of 96ml is added；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with 20ml first
Alcohol recrystallizes the residue, obtains the white mixture powder of 13.2g, yield 75%.
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
2.1) protocatechualdehyde of the white mixture powder of 13.2g and 13.8g is dissolved in the dehydrated alcohol of 96ml, is added
Enter the potassium hydroxide solution that 110.4g mass concentration is 30%, under nitrogen protection, stirring temperature rising reflux 20h or so, cooling is simultaneously
Pour into quenching reaction in the ice water of 150g；
2.2) it uses the mass concentration of 1: 1 (volume ratio) that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid to be
3, crocus solid, filtering is precipitated；
2.3) step 2.2) is filtered resulting crocus solid to wash, obtains 3 ', 4 '-dihydroxy -7- benzyls and looks into
That ketone crude product, and recrystallized using the methanol of 500ml, obtain crocus 3 ', 4 '-dihydroxy of acicular crystal -7- of 22.8g
Benzyl chalcone, yield 84.6%.
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
The 3 ' of 22.8g, 4 '-dihydroxy -7- benzyl chalcones are dissolved in the ethyl acetate of 113ml, and are urged in palladium carbon
Under change, hydrogenation reduction until not reabsorbing hydrogen (i.e. the pressure of reaction kettle no longer declines), filters, steams solvent, obtain
The 3 ' of 21.36g, 4 ', 7- trihydroxy chalcone, yield 93.1%.
Step 4) generates fisetin
4.1) by the 3 ' of 21.36g, 4 ', 7- trihydroxy chalcone be added to the dichloromethane-acetone of 140ml (V: V=4:
3) in mixed solvent, the sodium carbonate/bicarbonate buffer solution of 200ml is added (by 6.8g sodium carbonate, 6.8g sodium bicarbonate
Configured with the water of 200ml), and be vigorously mixed at room temperature for；
4.2) be slowly added dropwise for the first time into step 4.1) acquired solution 220ml potassium acid sulfate complex salt aqueous solution (by
The water of 14g potassium acid sulfate complex salt and 220ml configure), 5h is added dropwise, and reacts 16h at room temperature, and then second
The aqueous solution (being configured by the water of 14g potassium acid sulfate complex salt and 220ml) of 220ml potassium acid sulfate complex salt is slowly added dropwise,
5h is added dropwise, and 16h is reacted in continuation at room temperature, and keeping the pH of reaction system is 9, and two secondary responses are all made of thin-layer chromatography inspection
It surveys and is disappeared with raw material spot for terminal；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
Salt water washs organic phase 3 times respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and pair of 85mg is added into filtrate
Toluenesulfonic acid is stirred to react 1h at room temperature, to which after reaction, recycling design carries out weight using anhydrous methanol or methylene chloride
Crystallization, obtains the yellow solid fisetin of 20.5g, yield 95%, purity 98% (liquid phase).
Embodiment 7
A kind of synthetic method of fisetin, comprising the following steps:
Step 1) generates white mixture
1.1) benzyl chloride of the 2- butanone of 160ml and 36g is stirred evenly, adds the 2 of 12g, 4-resacetophenones
With the anhydrous K of 42g2CO3, after temperature rising reflux reacts 12h, the water stirring of 156ml is added；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with 20ml first
Alcohol recrystallizes the residue, obtains the white mixture powder of 19.2g, yield 73.6%.
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
2.1) protocatechualdehyde of the white mixture powder of 19.2g and 16g is dissolved in the dehydrated alcohol of 131ml, is added
Enter the potassium hydroxide solution that 160g mass concentration is 30%, under nitrogen protection, stirring temperature rising reflux 20h or so, cooling is simultaneously fallen
Enter quenching reaction in the ice water of 150g；
2.2) it uses the mass concentration of 1: 1 (volume ratio) that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid to be
3, crocus solid, filtering is precipitated；
2.3) step 2.2) is filtered resulting crocus solid to wash, obtains 3 ', 4 '-dihydroxy -7- benzyls and looks into
That ketone crude product, and recrystallized using the methanol of 750ml, obtain crocus 3 ', 4 '-dihydroxy of acicular crystal -7- of 33.4g
Benzyl chalcone, yield 84.3%.
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
The 3 ' of 33.4g, 4 '-dihydroxy -7- benzyl chalcones are dissolved in the ethyl acetate of 112ml, and are urged in palladium carbon
Under change, hydrogenation reduction until not reabsorbing hydrogen (i.e. the pressure of reaction kettle no longer declines), filters, steams solvent, obtain
The 3 ' of 31.2g, 4 ', 7- trihydroxy chalcone, yield 92.9%.
Step 4) generates fisetin
4.1) the 3 ' of 31.2g, 4 ', 7- trihydroxy chalcone is added to the dichloromethane-acetone of 210ml (V: V=4: 3)
Mixed solvent in, the sodium carbonate/bicarbonate buffer solution of 200ml is added (by 21.5g sodium carbonate, 21.5g sodium bicarbonate
Configured with the water of 300ml), and be vigorously mixed at room temperature for；
4.2) be slowly added dropwise for the first time into step 4.1) acquired solution 265ml potassium acid sulfate complex salt aqueous solution (by
The water of 15g potassium acid sulfate complex salt and 265ml configure), 5h is added dropwise, and reacts 16h at room temperature, and then second
The aqueous solution (being configured by the water of 15g potassium acid sulfate complex salt and 265ml) of 265ml potassium acid sulfate complex salt is slowly added dropwise,
5h is added dropwise, and 16h is reacted in continuation at room temperature, and keeping the pH of reaction system is 9, and two secondary responses are all made of thin-layer chromatography inspection
It surveys and is disappeared with raw material spot for terminal；
4.3) it to after reaction, stand, adopt and organic phase is extracted with dichloromethane, is eaten with saturated sodium thiosulfate and saturation
Salt water washs organic phase 3 times respectively, is dried, filtered using anhydrous magnesium sulfate and collects filtrate, and pair of 75mg is added into filtrate
Toluenesulfonic acid is stirred to react 1h at room temperature, to which after reaction, recycling design carries out weight using anhydrous methanol or methylene chloride
Crystallization, obtains the yellow solid fisetin of 30g, yield 95.3%, purity 98% (liquid phase).
As shown in Figure 1, to fisetin (Fisetin) obtained in above-described embodiment, liquid chromatographic detection, purity are carried out
It can reach 98%.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
Those familiar with the art can readily occur in various equivalent modifications or replace in technical scope disclosed by the invention
It changes, these modifications or substitutions should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of fisetin, which comprises the following steps:
Step 1) generates white mixture
2- butanone is uniformly mixed with benzyl chloride, adds 2,4-resacetophenones and anhydrous K2CO3, stirring, temperature rising reflux into
Row reaction, to which after reaction, processing obtains white mixture；
Step 2) generates 3 ', 4 '-dihydroxy -7- benzyl chalcones
Protocatechualdehyde and the resulting white mixture of step 1) are dissolved in dehydrated alcohol, and potassium hydroxide solution is added,
Under nitrogen protection, stirring, temperature rising reflux is reacted, and is cooled and poured into quenching reaction in ice water；Make pH to 3 using hydrochloric acid acidification
~5, crocus solid is precipitated, processing obtains 3 ', 4 '-dihydroxy -7- benzyl chalcones；
Step 3) generates 3 ', 4 ', 7- trihydroxy chalcone
Resulting 3 ', the 4 '-dihydroxy -7- benzyl chalcone of step 2) is dissolved in ethyl acetate, and under palladium carbon catalysis, is added
Hydrogen reducing obtains 3 ', 4 ', 7- trihydroxy chalcone；
Step 4) generates fisetin
4.1) by step 3) resulting 3 ', 4 ', the in the mixed solvent to methylene chloride and acetone is added in 7- trihydroxy chalcone, and
Buffer solution stirring is added；
4.2) aqueous solution that potassium acid sulfate complex salt is added into step 4.1) acquired solution adjusts pH value of solution to 9~9.5, goes forward side by side
Row reaction；
4.3) to after reaction, stand, extract and collect organic phase, washed, dried, filtered to organic phase, filter is collected
Liquid and the p-methyl benzenesulfonic acid progress cyclization reaction that catalytic amount is added into filtrate, to after reaction, be recrystallized to give fisetin.
2. the synthetic method of fisetin according to claim 1, which is characterized in that the step 1) comprises the concrete steps that:
1.1) 2- butanone and benzyl chloride are stirred evenly, adds 2,4-resacetophenones and anhydrous K2CO3, stir, heat up back
After stream reaction 12h, water is added to continue to stir；
1.2) to after reaction, be extracted with dichloromethane, rotary evaporation steams solvent, collects residue；And with methanol to described
Residue is recrystallized, and white mixture is obtained.
3. the synthetic method of fisetin according to claim 2, it is characterised in that: in step 1), the 2- butanone, benzyl
Chlorine, 2,4-dihydroxyacetophenone, anhydrous K2CO3Mass ratio with water is 10~11: 3: 1: 2.5~3.5: 12~13.
4. the synthetic method of fisetin according to claim 1 to 3, which is characterized in that the step 2) specific steps
It is:
2.1) white mixture obtained by protocatechualdehyde and step 1) is dissolved in dehydrated alcohol, and it is 30% that mass concentration, which is added,
Potassium hydroxide solution, under nitrogen protection, stirring, temperature rising reflux react 20h after, be cooled and poured into quenching reaction in ice water；
2.2) using mass concentration that step 2.1) acquired solution is acidified to pH for 18% hydrochloric acid is 3, and crocus solid is precipitated,
Filtering；
2.3) step 2.2) is filtered resulting crocus solid to wash, and is recrystallized using methanol, obtained orange
Color acicular crystal 3 ', 4 '-dihydroxy -7- benzyl chalcone.
5. the synthetic method of fisetin according to claim 4, it is characterised in that: in step 2), the white mixture,
The potassium hydroxide solution mass ratio that protocatechualdehyde, dehydrated alcohol and mass concentration are 30% is 0.95~1.2: 1: 5.5~6.5: 8
~10.
6. the synthetic method of fisetin according to claim 5, which is characterized in that the step 3) comprises the concrete steps that:
Resulting 3 ', the 4 '-dihydroxy -7- benzyl chalcone of step 2) is dissolved in ethyl acetate, and under palladium carbon catalysis, is added
Hydrogen reducing filters until not reabsorbing hydrogen, steams solvent, obtains 3 ', 4 ', 7- trihydroxy chalcone.
7. the synthetic method of fisetin according to claim 6, it is characterised in that: in step 3), 3 ', the 4 '-dihydroxy
The mass ratio of base -7- benzyl chalcone and ethyl acetate is 1: 3.5~4.5.
8. the synthetic method of fisetin according to claim 7, which is characterized in that the step 4) comprises the concrete steps that:
4.1) by step 3) resulting 3 ', 4 ', 7- trihydroxy chalcone is added to the methylene chloride and acetone that volume ratio is 4:3
In the mixed solvent, and sodium carbonate/bicarbonate buffer solution is added and quickly stirs；
4.2) aqueous solution that potassium acid sulfate complex salt is slowly added dropwise for the first time into step 4.1) acquired solution adjusts pH value of solution to 9
It is reacted, it is anti-to 9 progress that the aqueous solution to which potassium acid sulfate complex salt after reaction, is slowly added dropwise for the second time adjusts pH value of solution
It answers；
4.3) to after reaction, stand, adopt and organic phase is extracted with dichloromethane, with saturated sodium thiosulfate and saturated salt solution
Respectively washing organic phase it is multiple, using anhydrous magnesium sulfate dry, filter collect filtrate, and into filtrate be added catalytic amount to first
Benzene sulfonic acid, stirring carries out cyclization reaction at room temperature, to after reaction, recycling design, using anhydrous methanol or methylene chloride into
Row recrystallization, obtains yellow solid fisetin.
9. the synthetic method of fisetin according to claim 8, it is characterised in that: in step 4), 3 ', 4 ', the 7- tri-
Hydroxylated chalcone, buffer solution, the aqueous solution for the potassium acid sulfate complex salt being added for the first time, second of potassium acid sulfate being added are multiple
The mass ratio of the aqueous solution and p-methyl benzenesulfonic acid that close salt is 1: 10~11:7~11:7~11: 0.2~0.4.
10. the synthetic method of fisetin according to claim 9, it is characterised in that: in step 4.2), two secondary responses are adopted
It is detected with thin-layer chromatography and is disappeared with raw material spot for terminal.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217690A (en) * | 2020-01-20 | 2020-06-02 | 临沂大学 | Preparation method of propafenone hydrochloride and intermediate 2' -hydroxy dihydrochalcone thereof |
| CN114149399A (en) * | 2021-12-02 | 2022-03-08 | 陕西理工大学 | Method for synthesizing fisetin |
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2018
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217690A (en) * | 2020-01-20 | 2020-06-02 | 临沂大学 | Preparation method of propafenone hydrochloride and intermediate 2' -hydroxy dihydrochalcone thereof |
| CN111217690B (en) * | 2020-01-20 | 2023-01-13 | 临沂大学 | Preparation method of propafenone hydrochloride and intermediate 2' -hydroxy dihydrochalcone thereof |
| CN114149399A (en) * | 2021-12-02 | 2022-03-08 | 陕西理工大学 | Method for synthesizing fisetin |
| CN114149399B (en) * | 2021-12-02 | 2024-04-19 | 陕西理工大学 | Method for synthesizing fisetin |
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