CN101735188B - Method for synthesizing brown cyanidin, hispidulin and herba lycopi flavone - Google Patents
Method for synthesizing brown cyanidin, hispidulin and herba lycopi flavone Download PDFInfo
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- CN101735188B CN101735188B CN2008102025934A CN200810202593A CN101735188B CN 101735188 B CN101735188 B CN 101735188B CN 2008102025934 A CN2008102025934 A CN 2008102025934A CN 200810202593 A CN200810202593 A CN 200810202593A CN 101735188 B CN101735188 B CN 101735188B
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Abstract
The invention discloses a method for synthesizing brown cyanidin, hispidulin and herba lycopi flavone based on 2,4,6-trihydroxyacetophenone (II). The method comprises that: the hydroxy of a compound (II) is protected by a benzyl group; the compound (II) undergoes oxidization reaction and methylation reaction; and then the compound (II) and an aryl acyl chloride compound (VI) undergo acylation reaction, ring closing reaction and protective group removing reaction to form a target compound. The reaction step in the method is a few, the reaction is performed at the lower temperature, and virulent BCl3 and strong corrosive AlCl3 are avoided in use.
Description
Technical field
The present invention relates to the artificial synthesis of activity extract palm fibre Cyanidin, dinatin and the herba lycopi flavone of Herba Saussureae Involueratae.
Background technology
The palm fibre Cyanidin, English name is Jaceosidin, chemical name is 4 ', 5,7-trihydroxy--3 ', 6-dimethoxy flavone; Dinatin, English name are Hispidulin, and chemical name is 4 ', 5,7-trihydroxy--6-methoxy flavone; Herba lycopi flavone; English name is Eupafolin, and chemical name is 3 ', 4 '; 5; 7-tetrahydroxy-6-methoxy flavone, they are three staples of flavonoid compound in Herba Saussureae Involueratae (Saussurea involucrata (Kar.et Kir.) Sch.Bip.) ethanol extraction, the existing report of wherein brown Cyanidin and dinatin possibly have a remarkable restraining effect to the DNA of ascites hepatoma cells is synthetic through dna profiling damage type mechanism.
Because the Herba Saussureae Involueratae growing environment is special, spontaneous growth is slow, artificial culture is difficult, and natural resource suffer blindly to excavate in recent years, cause present saussurea involucrata resource deficient day by day.Carry out the manual work of saussurea involucrata activeconstituents and produce, both can solve the deficient problem of natural resource, can satisfy growing clinically demand again.
In the document that can see at present, produce, mainly concentrate on the cell cultures aspect for the manual work of activeconstituents in the saussurea involucrata.But the cell cultures cost is higher; Cycle is longer; Like large scale culturing Herba Saussureae Involueratae of describing among the Chinese patent CN1337467 and the method for extracting Xinjiang Saussurea involucrate general flavone; Nearly two months of production cycle needed can obtain the total flavones crystal through the chromatographic column separation, also needed further to separate if will obtain simple compounds such as brown Cyanidin.
Aspect chemosynthesis, the method for existing two kinds of synthetic brown Cyanidin, dinatin and herba lycopi flavones.
A kind of is to be set out by 2-methoxyl group Phloroglucinol, synthetic through polystep reaction, like (Bull.Chem.Soc.Jap. such as Kenji Fukui; 43 (5), 1524 (1970)) the synthetic brown Cyanidin of five of report steps reaction, (Experientia such as K.Fukui; 25 (4); 355 (1969)) herba lycopi flavone has been synthesized in the reaction of five of report steps, and the used starting raw material 2-of these methods methoxyl group Phloroglucinol is difficult for preparation, costs an arm and a leg; Have two-step reaction to need 120-140 ℃ high reaction temperature in the route, energy consumption is high, not suitable for mass production.
Another kind is to be set out by trihydroxy-acetophenone, and is through selective protection phenolic hydroxyl groups such as methyl or sec.-propyls, synthetic through polystep reaction; But route is longer, and efficient is not high, and acidylate and acid catalysis are closed the ring two-step reaction and needed 120-140 ℃ high reaction temperature; Energy consumption is high, and often needs to use BCl
3, AlBr
3Etc. toxicity or corrosive reagents, suitable for mass production not.Synthesized dinatin like (British Journal of Pharmacology, 142,811 (2004)) such as D.Kavvadias through the reaction of nine steps, but related to repeatedly alkylation, alkylation removal, route is long, and needs to use the BCl of severe toxicity
3The AlCl very strong with corrodibility
3Deng.M.Iinuma etc. (Yakugaku Zasshi, 104 (6), 691 (1984)) have synthesized herba lycopi flavone through the method for sec.-propyl protection, but destroy the methyl ether in the product easily when removing sec.-propyl, and need to use the BCl of severe toxicity equally
3T.Horia etc. (Bull.Chem.Soc.Jap., 56 (12), 3773 (1983)) are through having synthesized dinatin and herba lycopi flavone to how methyl substituted flavones selectivity demethylation, but selectivity is wayward, and used the very strong AlBr of corrodibility
3
Summary of the invention
For solving the defective that exists in the above-mentioned prior art, the present invention aim to provide a kind of new simple to operate, reaction conditions is gentle, step is less, be fit to the method for mass preparation palm fibre Cyanidin, dinatin and herba lycopi flavone.
For this purpose, the invention provides a kind of from 2,4, the set out method of synthetic compound (I) of 6-trihydroxy-acetophenone (II),
Wherein, R is-OCH
3,-OH or H, said method comprises following process:
(1) 2; 4,6-trihydroxy-acetophenone (II) carries out the hydroxyl protection reaction with the protection base reagent of phenolic hydroxyl group, generates 2-position and the protected compound of 4-position hydroxyl (III); The basic reagent of said protection is the benzyl compounds, and P is and the corresponding benzyl class of the basic reagent of said protection phenolic hydroxyl group blocking group.
(2) compound (III) carries out oxidizing reaction with oxygenant, generates compound (IV).
(3) compound (IV) carries out methylation reaction with methylating reagent, generates compound (V).
(4) compound (V) carries out acylation reaction with aryl chloride compounds (VI), generates compound (VII), wherein, and when R is-OCH
3The time, R ' also is-OCH
3When R be-during OH, R ' is-OP "; When R was H, R ' also was H; P ' and P " respectively be benzyl class phenolic hydroxyl group blocking group; And said acylation reaction is carried out in solvent and under the condition that has alkali to exist, and temperature of reaction is 0～100 ℃.
(5) compound (VII) carries out ring closure reaction, generates compound (VIII), and wherein, said ring closure reaction carries out in solvent and under the condition that has acid to exist, and temperature of reaction is 0～80 ℃.
(6) compound (VIII) is through hydrogenation, and the whole said phenolic hydroxyl group blocking group of sloughing on it generates compound (I).
Above-mentioned each reaction is represented by the reactions formula:
In embodiments of the present invention; The basic reagent of said protection is selected from down a kind of in the material of group: the muriate of benzyl or bromide or sulphonate, to the muriate of methoxy-benzyl or bromide or sulphonate, to muriate or the bromide or the sulphonate, 2 of nitrobenzyl; The muriate of the muriate of 4-dimethoxy-benzyl or bromide or sulphonate, diphenyl-methyl or bromide or sulphonate; P is benzyl with the basic reagent of said protection accordingly then, to methoxy-benzyl, to nitrobenzyl, 2,4-dimethoxy-benzyl or diphenyl-methyl.
In embodiments of the present invention, said P ' and P " respectively be selected from down one of group: benzyl, to methoxy-benzyl, to nitrobenzyl, 2,4-dimethoxy-benzyl and diphenyl-methyl
In the present invention's one preferred implementation, the temperature of reaction of said acylation reaction is 60～90 ℃.
In the present invention's one preferred implementation, the said solvent in the said ring closure reaction is selected from: acetic acid, acetonitrile, He Shui; Said acid is selected from: sulfuric acid, hydrochloric acid and acetic acid; And temperature of reaction is 40-60 ℃.
In the present invention's one preferred implementation, said hydrogenation in solvent and have catalyzer to exist and hydrogen pressure under carry out, wherein, said catalyzer is selected from: palladium carbon, palladium lime carbonate, palladium permanent white, palladium and Palladous chloride; Said solvent is selected from: methyl alcohol, ethanol, Virahol, propyl carbinol, ETHYLE ACETATE, methyl acetate, isopropyl acetate and their mixture; Said hydrogen pressure is 1～5 normal atmosphere; Temperature of reaction is 20～50 ℃.
Compare with the brown Cyanidin of existing preparation, dinatin or herba lycopi flavone method, the invention has the advantages that: 1, the present invention has avoided the shortcoming that the production cycle is long in the cell culture method, cost is high; 2, the present invention has avoided existing with the compound method of 2-methoxyl group Phloroglucinol as starting raw material, and is raw materials used 2,4, and the 6-trihydroxy-acetophenone is with low cost, has reduced production cost; 3, the present invention through the benzyl or derivatives thereof as the phenolic hydroxyl group blocking group; Avoided changing repeatedly the method for alkyl protection base; Not only reduced reactions step, and only need carry out gentle hydrogenation, need not to use severe toxicity or corrosive BCl at the deprotection base
3Or AlCl
3Deng reagent, thereby more help mass preparation, keep the safety in production and reduce production costs; 4, the present invention's compound method high reaction temperature of 120～140 ℃ in acidylate and Guan Huan two-step reaction of having avoided bibliographical information, reaction is carried out at a lower temperature, has improved production security when cutting down the consumption of energy.In addition, the compound method of the yield of the resulting product of compound method provided by the present invention and bibliographical information is suitable.
Embodiment
Those skilled in the art elaborates in the face of the present invention down, so that can understand and embodiment of the present invention better.
The invention provides a kind of from 2,4, the set out method of synthetic compound (I) of 6-trihydroxy-acetophenone (II).
Wherein, when R be methoxyl group-OCH
3The time, target compound (I) is brown Cyanidin, promptly 4 ', 5, and 7-trihydroxy--3 ', the 6-dimethoxy flavone is designated as compound (Ia);
When R was hydroxyl-OH, then compound (I) was a herba lycopi flavone, promptly 3 ', 4 ', 5, and 7-tetrahydroxy-6-methoxy flavone is designated as compound (Ib);
When R was H, compound (I) was a dinatin, promptly 4 ', 5, and 7-trihydroxy--6-methoxy flavone is designated as compound (Ic).
Specifically describe from the process of compound (II) preparation compound (I) in the face of the present invention down.
(1) by compound (II) preparation compound (III).
Protect basic reagent to carry out the hydroxyl protection reaction compound (II) and phenolic hydroxyl group, generate 2-position and the protected compound of 4-position hydroxyl (III).
Said hydroxyl protection is reflected at and carries out under the effect of suitable alkali, and used alkali is the mineral alkali that is selected from yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, calcium hydroxide, quicklime etc.First-selected alkali is yellow soda ash, salt of wormwood, sodium hydroxide, Pottasium Hydroxide.The consumption of alkali is 0.5～5 equivalent of substrate.
Usually, said hydroxyl protection is reflected at and carries out in the organic solvent, and solvent for use is: the aromatic hydrocarbon that is selected from benzene,toluene,xylene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride; Be selected from the ether N of THF, ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dinethylformamide, DMAC N,N, HMPA; Acetone; Or acetonitrile.First-selected solvent is toluene, methylene dichloride, THF, dioxane, N, dinethylformamide, HMPA, acetone, acetonitrile.The concentration of substrate is 0.1～10 mol.
Can be used for protecting the benzyl compounds of said 2-position and 4-position hydroxyl all to can be used as hydroxyl protecting group reagent and be used for hydroxyl protection reaction of the present invention; The example of said benzyl compounds can comprise: benzyl, to methoxy-benzyl, to nitrobenzyl, 2, the muriate of 4-dimethoxy-benzyl, diphenyl-methyl or bromide or sulphonate.More specifically, the object lesson of the basic reagent of used protection comprises: cylite, Benzyl Chloride, to the nitro benzyl chloride, to the nitro bromobenzyl, to the methoxyl group benzyl chloride, to the methoxyl group bromobenzyl.P in the compound (III) then is and the corresponding benzyl class of the contained benzyl compounds of the basic reagent of used protection phenolic hydroxyl group blocking group.
Usually, said hydroxyl protection reaction can be carried out at normal temperatures, but also can under 0～100 ℃, carry out at wideer range of reaction temperature.
The present invention is roughly following from the specific operation process of compound (II) preparation compound (III):
In there-necked flask, add compound (II), protect basic reagent, alkali and solvent, stirred then 16～24 hours, filter; Gained filtrating is poured in the frozen water, acidifying, and the solid filtering of separating out is collected; Add methyl alcohol and acetone, heated and stirred dissolving, cooling; The solid filtering of separating out, the chlorine cake washs with small amount of acetone, promptly gets compound (III).
(2) by compound (III) preparation compound (IV).
Compound (III) carries out oxidizing reaction with oxygenant and generates compound (IV).
This oxidizing reaction is carried out in appropriate solvent, and solvent for use is one or more the combination in the following group: the aromatic hydrocarbon that is selected from benzene,toluene,xylene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride; Be selected from the ether of THF, ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; Acetone; Pyridine; Acetonitrile or water.First-selected solvent is toluene, methylene dichloride, chloroform, THF, acetone, pyridine, water.The concentration of reaction is 0.1～10 mol.
Said oxygenant is following a kind of: Potassium Persulphate, Sodium Persulfate, ammonium persulphate, potassium hydrogen persulfate double salt (oxone) etc.The oxygenant consumption is 0.5～10 equivalent of substrate.This oxidizing reaction temperature is 0～100 ℃.
The present invention is roughly following from the specific operation process of compound (III) preparation compound (IV):
In there-necked flask, add compound (III), oxygenant and solvent, stirring reaction 24～36 hours adds the S-WAT cancellation, adds ethyl acetate extraction, and dry concentrating the back residue and obtain compound (IV) through column chromatography for separation.
(3) by compound (IV) preparation compound (V).
Compound (IV) carries out methylation reaction with methylating reagent, generates compound (V)
Methylation reaction of the present invention carries out in appropriate solvent, and solvent for use can be: the halohydrocarbon that is selected from methylene dichloride, chloroform, ethylene dichloride; Be selected from the ether of THF, ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; Acetone; Or acetonitrile.First-selected solvent is methylene dichloride, THF, acetone or acetonitrile.The concentration of reaction is 0.1～10 mol.
Said methylation reaction is under the effect of suitable alkali, to carry out, and used alkali can be the mineral alkali that is selected from yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, calcium hydroxide, quicklime, sodium hydride etc.First-selected alkali is: salt of wormwood, sodium hydroxide, sodium hydride.The consumption of alkali is 0.5～5 equivalent of substrate.
In the said methylation reaction, used methylating reagent can be following a kind of: methyl iodide, methyl-sulfate, methylcarbonate.
The present invention is roughly following from the specific operation process of compound (IV) preparation compound (V):
In there-necked flask, add compound (IV), methylating reagent, alkali and solvent, heated and stirred 2～6 hours, cooling adds ethyl acetate extraction, and dry concentrating the back residue and obtains compound (V) through column chromatography for separation.
(4) by compound (V) preparation compound (VII).
Compound (V) carries out acylation reaction with aryl chloride compounds (VI), generates compound (VII).
Wherein, when title product of the present invention was compound (Ia), promptly R was-OCH
3The time, the R ' in this aryl chloride compounds is-OCH
3When title product of the present invention is compound (Ib), promptly R be-during OH, R ' is-OP "; When title product of the present invention is compound (Ic), when promptly R is H, R " also be H.Also have P ' and P " respectively be benzyl class phenolic hydroxyl group blocking group.
Acylation reaction of the present invention is carried out in appropriate solvent, and solvent for use can be: the aromatic hydrocarbon that is selected from benzene,toluene,xylene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride; Be selected from the ether of THF, ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; Acetone; Pyridine; Acetonitrile or water.First-selected solvent is toluene, methylene dichloride, THF, pyridine.The concentration of reaction is 0.1～10 mol.
Said acylation reaction is under the effect of suitable alkali, to carry out; Used alkali is: the mineral alkali that is selected from yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, calcium hydroxide, quicklime, sodium hydride etc.; Or be selected from triethylamine, diisopropyl ethyl amine, pyridine, 4-N, the organic bases of N-dimethyl aminopyridine.First-selected alkali is: salt of wormwood, sodium hydroxide, Pottasium Hydroxide, pyridine.The consumption of alkali is 0.5～10 equivalent of substrate.
Existing trihydroxy-acetophenone set out the preparation compound (I) acylation reaction in, temperature of reaction is 120～140 ℃.And acylation reaction according to the invention can be carried out under lower temperature, and obtain with prior art in close reaction yield.Particularly, acylation reaction of the present invention can be carried out under 0～100 ℃, and preferable temperature of reaction is 60～90 ℃, preferably 50～80 ℃.Adopt acylation reaction temperature of the present invention can reduce energy consumption of reaction, and reduce equipment requirements.
The same with aforementioned hydroxy-protective group P; P ' in the aryl chloride compounds and P " (if any) be benzyl class phenolic hydroxyl group blocking group; and concrete example is: benzyl, to methoxy-benzyl, to nitrobenzyl, 2,4-dimethoxy-benzyl, diphenyl-methyl etc.P, P ' and P " can be identical or different benzyl class group.These benzyl class groups are easy to remove in the last deprotection reaction of the inventive method.Compare with using the alkyls blocking group, use benzyl class blocking group, in subtractive process, only need gentle hydrogenation, and need not the AlCl that uses corrodibility very strong
3Or the BCl of severe toxicity
3
The present invention is roughly following from the specific operation process of compound (V) preparation compound (VII):
In there-necked flask, add compound (V), aryl acyl chlorides (VI), alkali and solvent, heated and stirred 2 hours, cooling; Add ethyl acetate extraction, dry concentrating the back residue and dissolves with appropriate solvent; Add alkali, heated and stirred 2～3 hours, cooling; Add ethyl acetate extraction, dry concentrating the back residue and obtains compound (VII) through column chromatography for separation.
(5) by compound (VII) preparation compound (VIII).
Compound (VII) carries out ring closure reaction, generates compound (VIII), and wherein, said ring closure reaction carries out in solvent and under the condition that has acid to exist.
Ring closure reaction of the present invention carries out in appropriate solvent, and solvent for use is: the aromatic hydrocarbon that is selected from benzene,toluene,xylene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride; Acetic acid; Acetonitrile or water.First-selected solvent is: acetic acid, acetonitrile, water.The concentration of reaction is 0.1～10 mol.
Said ring closure reaction is under the effect of suitable acid, to carry out, and the example of used acid has: sulfuric acid, hydrochloric acid or acetic acid.
The temperature of reaction of said ring closure reaction is 0～80 ℃, is preferably 40-60 ℃.Known ring closure reaction from trihydroxy-acetophenone preparation compound (I) carries out under 120～140 ℃ high temperature.And the used ring closure reaction temperature of the present invention is far below this temperature, and obtain with prior art in close reaction yield.Therefore, adopt ring closure reaction temperature of the present invention can reduce energy consumption of reaction, and reduce requirement equipment.
The present invention is roughly following from the specific operation process of compound (VII) preparation compound (VIII):
In there-necked flask, add compound (VII), acid and solvent, heated and stirred 2～6 hours, cooling adds ethyl acetate extraction, and dry concentrating the back residue and directly is used for next step.
(6) by compound (VIII) preparation compound (I).
Compound (VIII) is sloughed whole said phenolic hydroxyl group blocking group P, P ' and P on it through hydrogenation " (if any) generation target compound (I).
Hydrogenation of the present invention carries out in appropriate solvent, and solvent for use is alcohol or ester, particularly, can be following one or more mixture: methyl alcohol, ethanol, Virahol, propyl carbinol, ETHYLE ACETATE, methyl acetate, and isopropyl acetate.
Said hydrogenation is under suitable catalyst action, to carry out, and the example of used hydrogenation catalyst comprises: palladium carbon, palladium lime carbonate, palladium permanent white, palladium, Palladous chloride etc. are preferably palladium carbon.
The temperature of reaction of said hydrogenation is 20～50 ℃, and hydrogen pressure is 1～5 normal atmosphere.
Because hydroxy-protective group P, P ' and P that hydrogenation of the present invention need be sloughed " be the benzyl class therefore to need not the AlCl that uses corrodibility very strong
3Or the BCl of severe toxicity
3
The present invention is roughly following from the specific operation process of compound (VIII) preparation compound (I):
In there-necked flask, add compound (VIII), catalyzer and solvent, the after-filtration that finishes is reacted in hydrogenation under convenient pressure, and filtrating concentrates, and residue obtains compound (I) through column chromatography for separation.
Embodiment
Pass through embodiment further explain technical scheme of the present invention below, but protection scope of the present invention is not limited thereto.
Embodiment one
Digest compound (II), 350 milliliters of N with 33.6, dinethylformamide, 83 gram salt of wormwood add in 1000 milliliters of three mouthfuls of reaction flasks successively, are cooled to 0 ℃, drip 50 milliliters of N of 49.9 milliliters of cylites under the induction stirring; Dinethylformamide solution, 25 ℃ were stirred 16 hours down, filter; Filtrating is poured in 500 milliliters of frozen water, is acidified to pH=4 with concentrated hydrochloric acid, stirs 1 hour; Filter, filter cake gets 49.2 with methyl alcohol and acetone recrystallization and digests compound (III), yield 71%.
Digest compound (III), 10 milliliters of acetone, 10 milliliters of methylene dichloride, 20 milliliters of phosphoric acid buffers (pH=7.7) with 1.74 and add successively in 100 milliliters of three mouthfuls of reaction flasks, drip 30 ml water solution of 9.3 gram potassium hydrogen persulfate double salt (oxone) under the induction stirring, and drip 10% aqueous sodium hydroxide solution simultaneously to keep system pH=7.5～8; 25 ℃ were stirred 24 hours down, added the S-WAT cancellation, added ethyl acetate extraction; Successively with water and saturated common salt water washing; Anhydrous sodium sulfate drying filters concentrating under reduced pressure; Residue through rapid column chromatography separate 270 milligrams of compounds (IV), yield 15%.
182 milligrams of compounds (IV), 5 milliliters of acetone, 138 milligrams of salt of wormwood and 89 milligrams of methyl-sulfates are added in 10 milliliters of reaction flasks successively induction stirring refluxed reaction 2 hours, cooling; Add ethyl acetate extraction, successively with water and saturated common salt water washing, anhydrous sodium sulfate drying; Filter; Concentrating under reduced pressure, residue through rapid column chromatography separate 130 milligrams of compounds (V), yield 69%.
(be compound (VI), wherein P ' is a benzyl, and R ' is-OCH with 120 milligrams of compounds (V), 2 milliliters of pyridines and 184 milligrams of 3-methoxyl group-4-benzyloxy Benzoyl chloride 99min.s
3) add successively in 10 milliliters of reaction flasks, induction stirring was carried out acylation reaction 2 hours for following 70 ℃ ℃, and cooling adds ethyl acetate extraction; With water and saturated common salt water washing, anhydrous sodium sulfate drying filters concentrating under reduced pressure successively; In the gained residue, add 10 milliliters of pyridines and 500 milligrams of Pottasium Hydroxide, the following 70 ℃ of reactions of induction stirring 2 hours, cooling adds ethyl acetate extraction; With water and saturated common salt water washing, anhydrous sodium sulfate drying filters successively; Concentrating under reduced pressure, the gained residue through rapid column chromatography separate 148 milligrams of compounds (VII), yield 75%.
62 milligrams of compounds (VII), 5 milliliters of acetic acid and 1 vitriol oil are added in 10 milliliters of reaction flasks successively the following 80 ℃ of reactions of induction stirring 2 hours, cooling; Add ethyl acetate extraction; With water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate drying filters successively; Concentrating under reduced pressure, gained residue (VIII) directly are used for step reaction down.
To go up step reaction gained residue and be dissolved in 5 ml methanol, add 5 milligrams of palladium carbon, induction stirring; 25 ℃ were reacted 6 hours under 1 atmospheric pressure hydrogen atmospheric pressure, filtered, and filtrate decompression concentrates; Obtain compound (Ia) through column chromatography for separation, be brown Cyanidin (Jaceosidin), 18 milligrams; Yield 65%.
Embodiment two
3-in the acylation reaction of embodiment one methoxyl group-4-benzyloxy Benzoyl chloride 99min. is changed to 3, and (be compound (VI), wherein P ' is a benzyl to 4-benzyloxy Benzoyl chloride 99min.; R ' is a benzyloxy); Through similar reaction, obtain compound (Ib), i.e. herba lycopi flavone (Eupafolin).
Embodiment three
3-in the acylation reaction of embodiment one methoxyl group-4-benzyloxy Benzoyl chloride 99min. is changed to 4-benzyloxy Benzoyl chloride 99min. (be compound (VI), wherein P ' is a benzyl, and R ' is H), through similar reaction, obtains compound (Ic), i.e. dinatin (Hsipidulin).
Claims (8)
1. one kind from 2,4, the set out method of synthetic compound (I) of 6-trihydroxy-acetophenone (II),
Wherein, R is-OCH
3,-OH or H, said method comprises following process:
(1) 2,4,6-trihydroxy-acetophenone (II) carries out the hydroxyl protection reaction with the protection base reagent of phenolic hydroxyl group, generates 2-position and the protected compound of 4-position hydroxyl (III),
The basic reagent of said protection is the benzyl compounds, and P is and the corresponding benzyl class of the basic reagent of said protection phenolic hydroxyl group blocking group;
(2) compound (III) carries out oxidizing reaction with oxygenant, generates compound (IV);
Said oxygenant is selected from: Potassium Persulphate, Sodium Persulfate, ammonium persulphate, potassium hydrogen persulfate double salt;
(3) compound (IV) carries out methylation reaction with methylating reagent, generates compound (V);
(4) compound (V) carries out acylation reaction with aryl chloride compounds (VI), generates compound (VII);
Wherein, as R be-OCH
3The time, R ' also is-OCH
3When R be-during OH, R ' is-OP "; When R was H, R ' also was H; P ' and P " respectively be benzyl class phenolic hydroxyl group blocking group; And said acylation reaction is carried out in solvent and under the condition that has alkali to exist, and its temperature of reaction is 0～100 ℃;
(5) compound (VII) carries out ring closure reaction, generates compound (VIII),
Wherein, said ring closure reaction carries out in solvent and under the condition that has acid to exist, and temperature of reaction is 0～80 ℃;
(6) compound (VIII) is through hydrogenation, and the whole said phenolic hydroxyl group blocking group of sloughing on it generates compound (I).
2. the method for claim 1; Wherein, In the said process (1); The basic reagent of said protection is selected from down a kind of in the material of group: the muriate of benzyl or bromide or sulphonate, to the muriate of methoxy-benzyl or bromide or sulphonate, to muriate or the bromide or the sulphonate, 2 of nitrobenzyl; The muriate of the muriate of 4-dimethoxy-benzyl or bromide or sulphonate, diphenyl-methyl or bromide or sulphonate, P be benzyl with the basic reagent of said protection accordingly then, to methoxy-benzyl, to nitrobenzyl, 2,4-dimethoxy-benzyl or diphenyl-methyl.
3. method as claimed in claim 2, wherein, said hydroxyl protection be reflected in the organic solvent and the condition that has alkali to exist under carry out, its temperature of reaction is 0～100 ℃.
4. the oxidizing reaction in the method for claim 1, wherein said process (2) is carried out in solvent, and the consumption of said oxygenant is 0.5～10 equivalent of compound (III); Said solvent is selected from toluene, methylene dichloride, chloroform, THF, acetone, pyridine, He Shui.
5. in the method for claim 1, wherein said process (4), P ' and P " respectively be selected from down one of group: benzyl, to methoxy-benzyl, to nitrobenzyl, 2,4-dimethoxy-benzyl and diphenyl-methyl.
6. method as claimed in claim 5, the temperature of reaction of wherein said acylation reaction are 60～90 ℃.
7. the said solvent in the ring closure reaction in the method for claim 1, wherein said process (5) is selected from: acetic acid, acetonitrile, He Shui; Said acid is selected from: sulfuric acid, hydrochloric acid and acetic acid; And temperature of reaction is 40-60 ℃.
8. the hydrogenation in the method for claim 1, wherein said process (6) in solvent and have catalyzer to exist and hydrogen pressure under carry out, wherein, said catalyzer is selected from: palladium carbon, palladium lime carbonate, palladium permanent white, palladium and Palladous chloride; Said solvent is selected from: methyl alcohol, ethanol, Virahol, propyl carbinol, ETHYLE ACETATE, methyl acetate, isopropyl acetate and their mixture; Said hydrogen pressure is 1～5 normal atmosphere; Temperature of reaction is 20～50 ℃.
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