CN102060832A - Method for compounding baicalein derivative - Google Patents
Method for compounding baicalein derivative Download PDFInfo
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- CN102060832A CN102060832A CN 201010566678 CN201010566678A CN102060832A CN 102060832 A CN102060832 A CN 102060832A CN 201010566678 CN201010566678 CN 201010566678 CN 201010566678 A CN201010566678 A CN 201010566678A CN 102060832 A CN102060832 A CN 102060832A
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- LBISJWJELRIQOL-UHFFFAOYSA-N NOc(cc(c1c2ON)OC(c3ccccc3)=CC1=O)c2O Chemical compound NOc(cc(c1c2ON)OC(c3ccccc3)=CC1=O)c2O LBISJWJELRIQOL-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a method for compounding a novel baicalein derivative as shown in a formula I, wherein R can be H, hydroxyl, alkyl, alkoxy, nitro and the like. By modifying a baicalein B-ring skeleton, the baicalein derivative which has greatly-improved dissolubility and anticancer activity and the like compared with baicalein is compounded. In the method, the B-ring substituted baicalein derivative is prepared by using benzaldehyde or substituted benzaldehyde and 3,4,5-trimethoxy-phenol as basic raw materials through four steps. The method comprises the detailed steps: the benzaldehyde or the substituted benzaldehyde is subjected to a condensation reaction with anhydride under the action of a basic catalyst to obtain substituted cinnamylate; the substituted cinnamylate is subjected to a halogenating reaction under the action of a catalyst to obtain substituted cinnamoyl chloride; the substituted cinnamoyl chloride is subjected to an acylation reaction with the 3,4,5-trimethoxy-phenol under the action of a catalyst to obtain a chalcone compound; and the chalcone compound is subjected to a ring-closure reaction under the action of a catalyst to obtain the baicalein derivative. The method has the advantages of simple process, rich raw materials, high yield, good product purity and low cost, and has broad application prospect. The formula I is shown in the specification.
Description
Technical field
The present invention relates to medicine synthetic field, particularly a kind of preparation method of novel Scutellarein derivative.
Background technology
Scutellarin is the main active ingredient of baikal skullcap root; have antibiotic, antiviral, anti-inflammatory, anti-oxidant, remove oxyradical, anticancer, antitumor, anti-freezing, antithrombotic forms and multiple physiologically active and pharmacological actions such as protection liver, cardiovascular and cerebrovascular, neurone; but the scutellarin solvability is bad, has limited its application in field of medicaments.In order to improve these shortcomings and to enlarge its range of application, people transform its structure, have synthesized a series of Scutellarein derivatives, and these derivatives all have greatly improved than scutellarin at aspect such as water-soluble, fat-soluble and anticancer.
Bibliographical information (J.Med.Chem, 2004,47,5555-5566), obtained a series of Scutellarein derivatives by scutellarin A ring is carried out alkylation, strengthened it and suppressed P-glycoprotein 170 activity, the active testing result shows that these compounds have certain cytotoxicity; Other have bibliographical information (Acta Pharmaceutica Sinica, 1997,32,140-143) two benzyl oxide analog derivatives have certain HIV (human immunodeficiency virus)-resistant activity.The methylamine class Scutellarein derivative that also has patent (Chinese patent application number 02111185.5) to report that the 8-position replaces has the activity of stronger arrestin kinase c (PKC) and inhibition virus of AIDS HIV/IIIB.But relevantly modify with the bibliographical information that obtains to have stronger pharmacological action few to scutellarin B ring skeleton.The present invention has introduced the preparation method of the cyclosubstituted novel Scutellarein derivative of a class B.
Summary of the invention
The present invention mainly discloses a class abundant raw material, productive rate height, the preparation method of the Scutellarein derivative that technology is simple novel.
Organic solvent among the present invention can be selected one of toluene, ether, normal hexane, sherwood oil, tetrahydrofuran (THF), ethyl acetate and methyl-sulphoxide; The technical scheme that adopts is as follows:
(1) phenyl aldehyde of phenyl aldehyde or replacement and the diacetyl oxide 1～3h that refluxes under the basic catalyst effect after reaction finishes, extracts or carries out wet distillation, obtains a large amount of styracins or substituted cinnamic acid.
(2) styracin or the substituted cinnamic acid that obtains is dissolved in (consumption of every mol substrate, down together) in 1～3L organic solvent, under nitrogen and ice-water bath condition,, obtains the cinnamyl chloride of cinnamyl chloride or replacement behind reaction 2～4h with halogenating agent generation halogenating reaction.
(3) will go up cinnamyl chloride or the replacement cinnamyl chloride and 3 that the step obtains, 4,5-trimethoxy phenol is dissolved in 1～3L organic solvent, and reflux 0.5～2h under catalyst action is by obtaining the chalcone compounds suc as formula II after recrystallization or the silica gel chromatographic column purification.R among the formula II can be hydrogen, hydroxyl, alkyl, alkoxyl group, nitro etc.
Formula II
(4) will be dissolved in 3～5L organic solvent suc as formula the chalcone compounds shown in the II, reflux 2～5h under catalyst action, precipitation is separated out in the ice-water bath cooling, obtain suc as formula 5 shown in the I through recrystallization or silica gel chromatographic column purification, 6,7-trimethoxy Scutellarein derivative, the R among the formula I can be hydrogen, hydroxyl, alkyl, alkoxyl group, nitro etc., and wherein nitro is through SnCl
2Can obtain amino after the reduction.
Formula I
Below promptly be 5,6 of the living replacement of B environment-development disclosed in this invention, the basic process of 7-trimethoxy Scutellarein derivative.
Embodiment
Further specify flesh and blood of the present invention with example below, but they are not construed as limiting the invention.
Embodiment 1:4 '-methyl-5,6,7-trimethoxy scutellarin (formula I compound, R are 4 '-methyl)
In flask, add 17mL (150mmol) p-tolyl aldehyde, 19mL (200mmol) diacetyl oxide, 10g salt of wormwood, reflux 1.5h.(3 * 250mL) extractions, organic layer concentrate after with anhydrous sodium sulfate drying, must be to tolyl acrylic acid (20g, 82%) behind the ethyl alcohol recrystallization with ethyl acetate.
In flask, add 16.3g (100mmol) to tolyl acrylic acid, 80mL CH
2Cl
2, at N
2Protection uses the ice-water bath holding temperature at 0～5 ℃ down, splashes into 9.5mL (130mmol) SOCl
2And a spot of dry DMF, under 0～5 ℃ of condition, react 2h.Decompression steams solvent and promptly obtains methyl cinnamyl chloride (13.5g, 82%).
In flask, add 13g (80mmol) to the methyl cinnamyl chloride, 12.9g (70mmol) 3,4,5-trimethoxy phenol, 80mL BF
3-Et
2O, reflux 30min, cool to room temperature is separated out precipitation.Filter, precipitation obtains thick product with the ether washing, normal hexane and ethyl acetate (V/V=3: 1) recrystallization, obtain 6 '-hydroxy-4-methyl-2 ', 3 ', 4 '-trimethoxy cinnamophenone (18.4g, 80%).
In flask, add 16.4g (50mmol) 6 '-hydroxy-4-methyl-2 ', 3 ' 4 '-the trimethoxy cinnamophenone, 150mL DMSO, 0.75g (3mmol) I
2, reflux 2h, precipitation is separated out in the ice-water bath cooling.Filter, with the resolution of precipitate that obtains in ethyl acetate, with 10% sodium thiosulfate solution washing (3 * 250mL), ester layer anhydrous sodium sulfate drying, decompression steams solvent and obtains thick product, with ethyl alcohol recrystallization obtain yellow solid 4 '-methyl-5,6,7-trimethoxy scutellarin (14.7g, 90%).
Embodiment 2:4 ', 5,6, the preparation of 7-tetramethoxy scutellarin (formula I compound, R are 4 '-methoxyl group)
In flask, add 18.2mL (150mmol) aubepine, 19mL (200mmol) diacetyl oxide, 8g anhydrous acetic acid potassium, reflux 2h.Adding 15g yellow soda ash makes solution be slight alkalinity, carry out wet distillation till distillate does not have oil droplet, add proper amount of active carbon and boil 5～10min, suction filtration while hot, in filtrate, add the 30mL concentrated hydrochloric acid, make solution be obvious acidity, separate out a large amount of solids, suction filtration gets p-methoxycinnamic acid (23g, 85%).
In flask, add 17.8g (100mmol) p-methoxycinnamic acid, 80mL CH
2Cl
2, at N
2Protection uses the ice-water bath holding temperature at 0～5 ℃ down, splashes into 9.5mL (130mmol) SOCl
2And a spot of dry DMF, under 0～5 ℃ of condition, react 2.5h.Decompression steams solvent and promptly obtains methoxyl group cinnamyl chloride (17g, 85%).
In flask, add 16.1g (80mmol) to the methoxyl group cinnamyl chloride, 12.9g (70mmol) 3,4,5-trimethoxy phenol, 80mL BF
3-Et
2O, reflux 45min, cool to room temperature is separated out precipitation.Filter, precipitation obtains thick product with the ether washing, sherwood oil and ethyl acetate (V/V=3: 1) obtain 6 behind the recrystallization '-hydroxyl-2 ', 3 ', 4 ', 4-tetramethoxy cinnamophenone (19.6g, 85%).
In flask, add 17.2g (50mmol) 6 '-hydroxyl-2 ', 3 ', 4 ', 4-tetramethoxy cinnamophenone, 150mLDMSO, 0.75g (3mmol) I
2, reflux 2.5h, precipitation is separated out in the ice-water bath cooling.Filter, with the resolution of precipitate that obtains in ethyl acetate, with the washing of 10% sodium thiosulfate solution (3 * 250mL), ester layer anhydrous sodium sulfate drying, decompression steams solvent and obtains thick product, separate with silica gel column chromatography, normal hexane and ethyl acetate (V/V=7: be eluent 3), obtain brown solid 4 ', 5,6,7-tetramethoxy scutellarin (16g, 93%).
Embodiment 3:3 ', 5,6, the preparation of 7-tetramethoxy scutellarin (formula I compound, R are 3 '-methoxyl group)
In flask, add 18.2mL (150mmol) NSC 43794,19mL (200mmol) diacetyl oxide, 8g anhydrous acetic acid potassium, reflux 3h.With ethyl acetate (3 * 250mL) extractions, organic layer concentrate after with anhydrous sodium sulfate drying, behind the ethyl alcohol recrystallization meta-methoxy styracin (21.4g, 80%).
In flask, add 17.8g (100mmol) meta-methoxy styracin, 80mL CH
2Cl
2, at N
2Protection uses the ice-water bath holding temperature at 0～5 ℃ down, splashes into 9.5mL (130mmol) SOCl
2And a spot of dry DMF, under 0～5 ℃ of condition, react 3h.Decompression steams solvent and promptly obtains meta-methoxy cinnamyl chloride (17g, 80%).
In flask, add 16.1g (80mmol) meta-methoxy cinnamyl chloride, 12.9g (70mmol) 3,4,5-trimethoxy phenol, 80mL BF
3-Et
2O, reflux 1h, cool to room temperature is separated out precipitation.Filter, precipitation obtains thick product with the ether washing, sherwood oil and ethyl acetate (V/V=3: 1) obtain 6 behind the recrystallization '-hydroxyl-2 ', 3,3 ', 4 '-tetramethoxy cinnamophenone (21g, 80%).
In flask, add 17.2g (50mmol) 6 '-hydroxyl-2 ', 3,3 ', 4 '-the tetramethoxy cinnamophenone, 150mLDMSO, 0.75g (3mmol) I
2, reflux 3h, precipitation is separated out in the ice-water bath cooling.Filter, with the resolution of precipitate that obtains in ethyl acetate, with 10% sodium thiosulfate solution wash (3 * 250mL), ester layer anhydrous sodium sulfate drying, decompression steams solvent and obtains thick product, with ethyl alcohol recrystallization obtain brown solid 3 ', 5,6,7-tetramethoxy scutellarin (18g, 88%).
Embodiment 4:4 '-nitro-5,6, the preparation of 7-trimethoxy scutellarin (formula I compound, R are 4 '-nitro)
In flask, add 22.7g (150mmol) paranitrobenzaldehyde, 19mL (200mmol) diacetyl oxide, 10g salt of wormwood, reflux 2h.(3 * 250mL) extractions, organic layer concentrate after with anhydrous sodium sulfate drying, must be to nitrocinnamic acid (24g, 82%) behind the ethyl alcohol recrystallization with toluene.
In flask, add 15g (100mmol) to nitrocinnamic acid, 80mL CH
2Cl
2, at N
2Protection uses the ice-water bath holding temperature at 0～5 ℃ down, splashes into 9.5mL (130mmol) SOCl
2And a spot of dry DMF, under 0～5 ℃ of condition, react 3.5h.Decompression steams solvent and promptly obtains nitro cinnamyl chloride (18g, 85%).
In flask, add 16.9g (80mmol) to the nitro cinnamyl chloride, 12.9g (70mmol) 3,4,5-trimethoxy phenol, 80mL BF
3-Et
2O, reflux 1.5h, cool to room temperature is separated out precipitation.Filter, precipitation obtains thick product with the ether washing, sherwood oil and ethyl acetate (V/V=7: 3) obtain 6 behind the recrystallization '-hydroxyl-2 ', 3 ', 4 '-trimethoxy-4-nitro cinnamophenone (23g, 78%).
In flask, add 18g (50mmol) 6 '-hydroxyl-2 ', 3 ', 4 '-trimethoxy-4-nitro cinnamophenone, 150mL DMSO, 0.75g (3mmol) I
2, reflux 2h, precipitation is separated out in the ice-water bath cooling.Filter, with the resolution of precipitate that obtains in ethyl acetate, with 10% sodium thiosulfate solution washing (3 * 250mL), ester layer anhydrous sodium sulfate drying, reducing pressure steams solvent and obtains thick product, separate with silica gel column chromatography, normal hexane and ethyl acetate (V/V=3: be eluent 1), obtain orange solids 4 '-nitro-5,6,7-trimethoxy scutellarin (16g, 85%).
Embodiment 5:3 '-hydroxyl-5,6, the preparation of 7-trimethoxy scutellarin (formula I compound, R are 3 '-hydroxyl)
In flask, add 18.3g (150mmol) m-hydroxybenzaldehyde, 19mL (200mmol) diacetyl oxide, 8g anhydrous acetic acid potassium, reflux 3h.With ethyl acetate (3 * 250mL) extractions, organic layer concentrate after with anhydrous sodium sulfate drying, behind the ethyl alcohol recrystallization between hydroxycinnamic acid (21g, 85%).
In flask, add hydroxycinnamic acid between 16.4g (100mmol), 80mL CH
2Cl
2, at N
2Protection uses the ice-water bath holding temperature at 0～5 ℃ down, splashes into 9.5mL (130mmol) SOCl
2And a spot of dry DMF, under 0～5 ℃ of condition, react 4h.Decompression steams solvent and promptly obtains a hydroxyl cinnamyl chloride (15.5g, 85%).
In flask, add hydroxyl cinnamyl chloride between 14.6g (80mmol), 12.9g (70mmol) 3,4,5-trimethoxy phenol, 80mL BF
3-Et
2O, reflux 30min, cool to room temperature is separated out precipitation.Filter, precipitation obtains thick product with the ether washing, normal hexane and ethyl acetate (V/V=3: 1) obtain 3,6 behind the recrystallization '-dihydroxyl-2 ', 3 ', 4 '-trimethoxy cinnamophenone (19.7g, 85%).
In flask, add 16.5g (50mmol) 3,6 '-dihydroxyl-2 ', 3 ', 4 '-the trimethoxy cinnamophenone, 150mLDMSO, 0.75g (3mmol) I
2, reflux 5h, precipitation is separated out in the ice-water bath cooling.Filter, with the resolution of precipitate that obtains in ethyl acetate, with 10% sodium thiosulfate solution washing (3 * 250mL), ester layer anhydrous sodium sulfate drying, decompression steams solvent and obtains thick product, with ethyl alcohol recrystallization obtain yellow solid 3 '-hydroxyl-5,6,7-trimethoxy scutellarin (15.3g, 93%).
Claims (5)
1. the open cyclosubstituted Scutellarein derivative of the synthetic B of institute of the present invention is the compound that has suc as formula the I feature, and wherein R can be hydrogen, hydroxyl, alkyl, alkoxyl group, nitro etc.
Formula I
Synthetic this compounds is mainly by following 4 steps:
(1) phenyl aldehyde or substituted benzaldehyde obtain substituted cinnamic acid with diacetyl oxide generation condensation reaction earlier under the effect of basic catalyst.
(2) substituted cinnamic acid obtains replacing cinnamyl chloride with halogenating agent generation halogenating reaction under catalyst action.
(3) with 3,4,5-trimethoxy phenol generation acylation reaction obtains the chalcone compounds suc as formula II to the replacement cinnamyl chloride under catalyst action.
Formula II
(4) chalcone compounds carries out self ring-closure reaction under catalyst action, obtains suc as formula the Scutellarein derivative shown in the I.
2. the method for preparing Scutellarein derivative according to claim 1 is characterized in that: wherein the phenyl aldehyde of described phenyl aldehyde of step (1) or replacement and diacetyl oxide feed ratio are 1: 1～1: 1.5; Described alkaline catalysts can be one of anhydrous acetic acid potassium, salt of wormwood, tertiary amine; Described temperature of reaction is 140～200 ℃; The described reaction times is 1～3h.
3. the method for preparing Scutellarein derivative according to claim 1 is characterized in that: wherein the feed ratio of described substituted cinnamic acid of step (2) and halogenating agent is 1: 1～1: 3; Described halogenating agent can be one of thionyl chloride, oxalyl chloride; Described catalyzer can be N, dinethylformamide, N, one of accelerine or pyridine; Described solvent is one of methylene dichloride, chloroform; Described temperature of reaction is 0～5 ℃; The described reaction times is 2～4h.
4. the method for preparing Scutellarein derivative according to claim 1 is characterized in that: wherein step (3) is described 3,4, and 5-trimethoxy phenol is 1: 1～1: 1.5 with the feed ratio that replaces cinnamyl chloride; Described catalyzer can be one of boron trifluoride-ether, Aluminum chloride anhydrous; Used cleaning solvent can be one of ether, tetrahydrofuran (THF); Described temperature of reaction is 50～150 ℃; The described reaction times is 0.5～2h.
5. the method for preparing Scutellarein derivative according to claim 1 is characterized in that: wherein the described catalyzer of step (4) can be one of elemental iodine, Potassium Iodate; Described reaction solvent can be one of dimethyl sulfoxide (DMSO), ethyl acetate; Described temperature of reaction is 100～200 ℃; The described reaction times is 2～5h.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529973A (en) * | 2014-12-09 | 2015-04-22 | 江南大学 | Synthetic method for polysubstituted baicalein derivatives |
| CN110698649A (en) * | 2019-06-28 | 2020-01-17 | 江西瀚泰新材料科技有限公司 | Ultraviolet-resistant flame-retardant epoxy resin curing agent and preparation thereof |
| CN111349068A (en) * | 2020-03-30 | 2020-06-30 | 中国药科大学 | Organic synthesis method of scutellarein |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538298A (en) * | 2009-04-29 | 2009-09-23 | 四川抗菌素工业研究所有限公司 | A method for synthesizing 5,6,4'-trihydroxyflavone-7-0-D-glucuronic acid |
-
2010
- 2010-12-01 CN CN 201010566678 patent/CN102060832A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538298A (en) * | 2009-04-29 | 2009-09-23 | 四川抗菌素工业研究所有限公司 | A method for synthesizing 5,6,4'-trihydroxyflavone-7-0-D-glucuronic acid |
Non-Patent Citations (1)
| Title |
|---|
| 《石河子大学学报( 自然科学版)》 20080630 仲伶俐等 2-( 3-苯基-丙烯酰胺基)-乙磺酸的合成与表征 344-346，特别是345页1.2肉桂酸的合成，1.3肉硅酸酰氯的合成 1-5 第26卷, 第3期 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529973A (en) * | 2014-12-09 | 2015-04-22 | 江南大学 | Synthetic method for polysubstituted baicalein derivatives |
| CN110698649A (en) * | 2019-06-28 | 2020-01-17 | 江西瀚泰新材料科技有限公司 | Ultraviolet-resistant flame-retardant epoxy resin curing agent and preparation thereof |
| CN110698649B (en) * | 2019-06-28 | 2022-07-08 | 江西瀚泰新材料科技有限公司 | Ultraviolet-resistant flame-retardant epoxy resin curing agent and preparation thereof |
| CN111349068A (en) * | 2020-03-30 | 2020-06-30 | 中国药科大学 | Organic synthesis method of scutellarein |
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Application publication date: 20110518 |