CN102060826A - Method for synthesizing 7-methoxyl-4'-substituted flavonoids compound - Google Patents
Method for synthesizing 7-methoxyl-4'-substituted flavonoids compound Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a 7-methoxyl-4'-substituted flavonoids compound represented by a formula I in the specification, wherein R is hydrogen, halogen, hydroxyl, alkyl, alkoxyl, nitryl and the like. The flavonoids compound can be used as an intermediate of anti-inflammatory and anti-cancer medicines. The method comprises the steps of: taking paeonol (2-hydroxyl-4-methoxyl acetophenone) and 4-substituted benzoyl chloride as raw materials, reacting to obtain a diaryl ester compound, then performing rearrangement to obtain a substituted 1,3-propanedione compound and then generating the 7-methoxyl-4'-substituted flavonoids compound under catalytic action of acid. According to the method disclosed by the invention, raw materials are easily obtained, of the requirements on reaction conditions and reagents are not rigorous, the steps are simple, the intermediate process is easily implemented; and the method can be used for industrial large-scale production. The formula I is shown as the specification.
Description
Technical field
The present invention relates to a kind of 7-methoxyl group-4 '-synthetic method of substituted flavonoids.
Background technology
Flavonoid compound is the natural organic-compound that a class extensively is present in occurring in nature, has found that it has multiple biological activity, as has prevented and treated diabetes and complication, and is influential to multiple biological enzyme, treatment cardiovascular disorder, anti-ageing, anticancer, anti-oxidant etc.But the natural flavone compounds is subjected to the restriction of nature content, and its separation purification also has certain degree of difficulty.Therefore, the research of flavonoid compound synthetic has important practical significance.
At present, the common methods of synthetic flavonoid compound mainly is the synthetic flavones of Baker-Venkataraman method.Other also have the Fries rearrangement method to synthesize flavones, the synthetic flavones of catalysis of iodine cyclization method, the synthetic flavones of solid supported catalyzed cyclization method, the synthetic flavones of microwave-assisted synthesis method, organic bases DBU catalyzed cyclization method etc., but these methods is that all right ripe or operational difficulty, agents useful for same is numerous and diverse, is difficult to apply to industrial production.
Summary of the invention
It is a kind of easy and simple to handle that the present invention mainly provides, the reasonably synthetic 7-methoxyl group-4 of raw material cheapness, the simple and technology of agents useful for same '-method of substituted flavonoids.
In order to reach above-mentioned requirements, the technical solution used in the present invention is as follows:
(1). Paeonol (2-hydroxyl-4-methoxyacetophenone) and 4-substituted benzoyl chloride are dissolved in 1～3L organic solvent (consumption of every mol substrate, down together), stirring reaction 3～6h at ambient temperature, after reaction finishes reaction solution poured in the hydrochloric acid ice aqueous solution that 5～10L concentration is 0.5～1mol/L and stir, separate out precipitation, filtration obtains solid, and the gained solid obtains suc as formula the diaryl ester compounds shown in the II through recrystallization or silica gel chromatographic column purification; Or use ethyl acetate extraction, and separating obtained organic layer gets decorating film through saturated common salt water washing, drying behind concentrating under reduced pressure, and purifying by recrystallization or silica gel chromatographic column obtains suc as formula the diaryl ester compounds shown in the II again.
Formula II
R among the formula II can be hydrogen, halogen, hydroxyl, alkyl, alkoxyl group, nitro etc.
(2). will be dissolved in 1～5L organic solvent suc as formula the diaryl ester compounds shown in the II, under potassium hydroxide or sodium hydroxide alkalescence condition in 50～80 ℃ of stirring reaction 1.5～4h, adding 1～4L mass concentration was 5%～10% acid solution neutralization after reaction finished, filtration obtains solid, after purifying, silica gel chromatographic column obtains the replacement 1 shown in formula III, 3-propanedione compounds.
Formula III
(3). the replacement 1 shown in formula III, 3-propanedione compounds mixes with the vitriol oil and acetic acid, at 60～100 ℃ of stirring reaction 2～6h, after reaction finishes reaction solution poured in the frozen water solution and stir, filtration obtains solid, silica gel chromatographic column purify obtain suc as formula the 7-methoxyl group-4 shown in the I '-substituted flavonoids.
Formula I
Organic solvent among the present invention can be selected one of pyridine, tetrahydrofuran (THF) and methyl-sulphoxide.
Inventing described synthetic method recommends to carry out according to following steps: add the 1mol Paeonol in reaction vessel, organic solvent and 4 '-substituted benzoyl chloride, Paeonol and 4 '-the substituted benzoyl chloride molar ratio is 1: 1～1: 1.5, consumption of organic solvent is 1～3L, stirring reaction 3～6h under the room temperature, pouring reaction solution into concentration after the end is 1mol/L, consumption is in 5～10L hydrochloric acid ice aqueous solution, filter or extract and wait until that recrystallization or silica gel column chromatography get pure product suc as formula the diaryl ester compounds crude product shown in the II; In reaction vessel, add suc as formula the 1mol diaryl ester compounds shown in the II, 1～5L organic solvent, be heated to 50～80 ℃, add alkali, stirring reaction 1.5～4h is after reaction finishes, adding mass concentration is that 5%～10% consumption is the acetum neutralization of 1～4L, filtration obtain shown in III 1,3-propanedione compounds crude product, recrystallization or silica gel column chromatography get pure product; At 1 mole 1 that adds in the reaction vessel shown in III, 3-propanedione compounds, adding consumption is the vitriol oil and the 1～5L acetic acid of 0.1～0.25L, mixture is at 10～100 ℃ of stirring reaction 2～6h, be cooled to room temperature, reaction solution is poured in the frozen water, filter suc as formula the 7-methoxyl group-4 shown in the I '-the substituted flavonoids crude product, the pure product of recrystallization or silica gel column chromatography.
Advantage of the present invention is embodied in:
(1) the used raw material Paeonol of invention is easy to get.
(2) the used solvent of invention is the common solvent in laboratory or enterprise, and toxicity is less; Used soda acid also is a soda acid common on the market.
(3) reactions steps is simple, the device simple that needs, and easy handling, the separation and purification difficulty is little, reduces cost.
(4) technology is reasonable, the reaction conditions gentleness.
Embodiment
Following case study on implementation can make those skilled in the art comprehensively understand the present invention, but does not limit the present invention in any way.
The preparation of embodiment 1:7-methoxy flavone (formula I compound, R are hydrogen)
In flask, add 16.6g (100mmol) Paeonol, the 100mL pyridine, and add 13.8mL (120mmol) Benzoyl chloride, stirring reaction 4h under the mixture room temperature.After reaction was finished, adding 1L concentration in mixed solution was the hydrochloric acid ice aqueous solution of 0.5mol/L, with ethyl acetate (250mL * 3) extraction, organic layer concentrate after with anhydrous sodium sulfate drying phenylformic acid (2-ethanoyl-5-methoxyl group) phenyl ester (26g, 83%).
In flask, add 13.5g (50mmol) phenylformic acid (2-ethanoyl-5-methoxyl group) phenyl ester; 8.4g (15mmol) potassium hydroxide; and adding 100mL pyridine; at 30 ℃ of stirring reaction 6h; in reaction system, add 500mL water then; and with the neutralization of 0.5% acetum; mixture extracts with ethyl acetate (200mL * 4); and, use anhydrous sodium sulfate drying with the sodium bicarbonate washing, underpressure distillation obtains crude product; separate with silica gel column chromatography; hexane and ethyl acetate (V/V=4: be eluent 1), obtain 1-phenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-propanedione (12.2g, 90%).
In flask, add 12.2g (40mmol) 1-phenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-propanedione, add the 100mL acetic acid and the 5mL vitriol oil, 100 ℃ of stirring reaction 5h are cooled to room temperature, and reaction solution is poured in the frozen water, and use ethyl acetate extraction, after concentrating, organic layer gets crude product, again through silica gel column chromatography, and hexane and ethyl acetate (V/V=3: 1) be eluent, obtain the pure product of 7-methoxy flavone (8.9g, 88.3%).
Embodiment 2:7-methoxyl group-4 '-preparation (formula I compound, R are nitro) of nitro flavones
In flask, add the 100mmol Paeonol, the 200mL methyl-sulphoxide, and add 24.1g (130mol) paranitrobenzoyl chloride, mixture at room temperature stirs 3h.After reaction was finished, adding 1L concentration in mixed solution was the hydrochloric acid ice aqueous solution of 0.5mol/L, and filtration and washing obtain crude product, get p-nitrobenzoic acid (2-ethanoyl-5-methoxyl group) the pure product of phenyl ester (29g, 90.1%) through chloroform and normal hexane silica gel column chromatography.
In flask, add 29g (90mmol) p-nitrobenzoic acid (2-ethanoyl-5-methoxyl group) phenyl ester; add the 200mL methyl-sulphoxide; be heated to 50 ℃, add 12.5g (22.5mmol) potassium hydroxide, stirring reaction 2h; in reaction system, add 250mL concentration then and be 10% acetic acid; obtain crude product after the filtration, silica gel column chromatography, chloroform are eluent; get 1-p-nitrophenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-pure product of propanedione (25g, 88.1%).
In flask, add 25g (80mmol) 1-p-nitrophenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-propanedione, add acetic acid 400mL and vitriol oil 20mL, 100 ℃ of stirring reaction 2h, be cooled to room temperature, reaction solution poured in the frozen water, filter crude product, silica gel column chromatography, chloroform is an eluent, 7-methoxyl group-4 '-the pure product of nitro flavones (18g, 80.1%).
Embodiment 3:7-methoxyl group-4 '-preparation (formula I compound, R are chlorine) of chlorine flavones
In flask, add 16.6g (100mmol) Paeonol, the 300mL tetrahydrofuran (THF), and add 17.5g (100mmol) parachlorobenzoyl chloride, stir 3h under the mixture room temperature.After reaction was finished, adding 500mL concentration in mixed solution was the hydrochloric acid ice aqueous solution of 1mol/L, and filtration and washing obtain crude product, get Chlorodracylic acid (2-ethanoyl-5-methoxyl group) the pure product of phenyl ester (27.3g, 89.8%) through ethyl alcohol recrystallization.
In flask, add 24.5g (80mmol) Chlorodracylic acid (2-ethanoyl-5-methoxyl group) phenyl ester; add the 200mL tetrahydrofuran (THF); be heated to 40 ℃; add 11.2g (200mmol) potassium hydroxide; stirring reaction 2h adds 500mL concentration and is 10% acetic acid then in reaction system, obtain crude product after the filtration; behind ethyl alcohol recrystallization, get 1-rubigan-3-(2-hydroxyl-4-p-methoxy-phenyl)-pure product of propanedione (22.0g, 89.8%).
In flask, add 18.8g (60mmol) 1-rubigan-3-(2-hydroxyl-4-p-methoxy-phenyl)-propanedione, add acetic acid 400mL and vitriol oil 20mL, 80 ℃ of stirring reaction 2h, be cooled to room temperature, reaction solution is poured in the frozen water, filter crude product, behind ethyl alcohol recrystallization 7-methoxyl group-4 '-the pure product of chlorine flavones (13.8g, 85.0%).
Embodiment 4:7-methoxyl group-4 '-preparation (formula I compound, R are methoxyl group) of methoxy flavone
In flask, add 16.6g (100mmol) Paeonol, the 200mL pyridine, and add 20.5g (120mmol) anisoyl chloride, stir 5h under the mixture room temperature.After reaction is finished; adding 600mL concentration in mixed solution is the hydrochloric acid ice aqueous solution of 1mol/L; filtration and washing obtain crude product, get anisic acid (2-ethanoyl-5-methoxyl group) the pure product of phenyl ester (27.6g, 92.0%) through silica gel column chromatography (hexane and ethyl acetate are eluent).
In flask, add 24.0g (80mmol) anisic acid (2-ethanoyl-5-methoxyl group) phenyl ester; add in the 250mL pyridine; be heated to 60 ℃; add 11.2g (200mmol) potassium hydroxide; stirring reaction 4h adds 500mL concentration and is 10% acetic acid then in reaction system, obtain crude product after the filtration; behind silica gel column chromatography (chloroform is an eluent), get 1-p-methoxyphenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-pure product of propanedione (21.2g, 88.3%).
In flask, add 18.0g 1-p-methoxyphenyl-3-(2-hydroxyl-4-p-methoxy-phenyl)-propanedione, add acetic acid 400mL and vitriol oil 20mL, 80 ℃ of stirring reaction 4h, be cooled to room temperature, reaction solution is poured in the frozen water, filter crude product, behind silica gel column chromatography (chloroform is an eluent) 7-methoxyl group-4 '-methoxy flavone (13.9g, 87.1%).
Claims (5)
- The open institute of the present invention synthetic suc as formula the 7-methoxyl group-4 shown in the I '-substituted flavonoids is that the compound with following feature: R can be hydrogen, halogen, hydroxyl, alkyl, alkoxyl group, nitro etc.
Formula I - Suc as formula the 7-methoxyl group-4 shown in the I '-synthetic method of substituted flavonoids, it is characterized in that described synthetic method can be divided into three steps, the middle generation respectively suc as formula the replacement 1 shown in diaryl ester compound shown in the II and the formula III, this two compounds of 3-propanedione compound, wherein R can be hydrogen, halogen, hydroxyl, alkyl, alkoxyl group, nitro etc.Formula II formula IIIStep 1: with 4-substituted benzoyl chloride compound dissolution in organic solvent, add Paeonol (2-hydroxyl-4-methoxyacetophenone), stirring reaction certain hour at room temperature, reaction is poured reaction solution in the hydrochloric acid ice aqueous solution into after finishing, filtering-depositing or use ethyl acetate extraction, separating purifies obtains suc as formula the diaryl ester compounds shown in the II.Step 2: will arrive certain temperature suc as formula diaryl ester compounds shown in the II and organic solvent Hybrid Heating, add a certain amount of alkali then, stirring reaction for some time, after the cooling, add the acid solution neutralization, filtering-depositing or use ethyl acetate extraction, replacement 1 that must be shown in formula III after the purification, 3-propanedione compounds.Step 3: replacement 1 that will be shown in formula III, 3-propanedione compounds mixes with acid, and mixture heating up to certain temperature, is reacted for some time, cool to room temperature.Mixed solution is poured in the frozen water, filtering-depositing or use ethyl acetate extraction, purify suc as formula the 7-methoxyl group-4 shown in the I '-substituted flavonoids.
- 3. step 1 as claimed in claim 2 is characterized in that described organic solvent is one of pyridine, tetrahydrofuran (THF) or methyl-sulphoxide; Solvent load is 1～3L/mol (consumption that refers to every mol substrate, down together); Described temperature is a room temperature, and the described reaction times is 3～6h, and described Paeonol and 4-substituted benzoyl chloride molar ratio are 1: 1～1: 1.5; The concentration of the described hydrochloric acid ice aqueous solution is 0.5～1mol/L, and consumption is 5～10L; Described separation method is for filtering or extraction, and method of purification is recrystallization or column chromatography.
- 4. step 2 as claimed in claim 2 is characterized in that described solvent is one of pyridine, tetrahydrofuran (THF) or methyl-sulphoxide, and described solvent load is 1～5L/mol; Described alkali is potassium hydroxide or sodium hydroxide, and consumption is 1～5mol/mol; Described temperature of reaction is 50～80 ℃; The described reaction times is 1～4h; Described acid solution is an acetic acid, and mass concentration is 5%～10%, and consumption is 1～4L/mol; Described separation method is for filtering or extraction, and method of purification is recrystallization or column chromatography.
- 5. step 3 as claimed in claim 2 is characterized in that used acid is the vitriol oil and acetic acid, and the consumption of described acid is respectively 0.1～0.25 flat L/mol and 1～5L/mol; Described temperature of reaction is 10～100 ℃; The described reaction times is 2～6h; Described separating and purifying method is recrystallization or column chromatography.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993149A (en) * | 2012-12-17 | 2013-03-27 | 江南大学 | Method for microwave-assisted synthesis of B-ring substituted flavone compound |
| CN104447661A (en) * | 2014-12-09 | 2015-03-25 | 江南大学 | Synthetic method of multi-substituted flavonoid compounds |
| CN106083793B (en) * | 2016-06-08 | 2018-04-10 | 嘉兴学院 | A kind of preparation method of 7 methoxy flavone |
| CN108947953A (en) * | 2018-05-16 | 2018-12-07 | 江西科技师范大学 | A kind of synthetic method of flavone derivative |
-
2010
- 2010-12-01 CN CN 201010566692 patent/CN102060826A/en active Pending
Non-Patent Citations (3)
| Title |
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| 《Anti-Cancer Drug Design》 19921231 Bernadette D.M.Cunningham et al. Synthesis and biological evaluation of a series of flavones designed as inhibitors of protein tyrosine kinases 第7卷, 2 * |
| 《Chem.Med.Chem.》 20091231 Stefano Rizzo et al. Structure-Activity Relationships and Binding Mode in the Human Acetylcholinesterase Active Site of Pseudo-Irreversible Inhibitors Related to Xanthostigmine 第4卷, 2 * |
| 《SYNTHESIS》 19920930 Akira Nishinaga et al. A New Metal Comples Promoted System for Highly Selective Synthesis of 4H-Chromen-4-ones(Chromones) , 2 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993149A (en) * | 2012-12-17 | 2013-03-27 | 江南大学 | Method for microwave-assisted synthesis of B-ring substituted flavone compound |
| CN104447661A (en) * | 2014-12-09 | 2015-03-25 | 江南大学 | Synthetic method of multi-substituted flavonoid compounds |
| CN106083793B (en) * | 2016-06-08 | 2018-04-10 | 嘉兴学院 | A kind of preparation method of 7 methoxy flavone |
| CN108947953A (en) * | 2018-05-16 | 2018-12-07 | 江西科技师范大学 | A kind of synthetic method of flavone derivative |
| CN108947953B (en) * | 2018-05-16 | 2022-03-01 | 江西科技师范大学 | Synthetic method of flavonoid derivative |
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Application publication date: 20110518 |