CN111484538B - Preparation method of homoplantaginoside - Google Patents
Preparation method of homoplantaginoside Download PDFInfo
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- CN111484538B CN111484538B CN201910083892.9A CN201910083892A CN111484538B CN 111484538 B CN111484538 B CN 111484538B CN 201910083892 A CN201910083892 A CN 201910083892A CN 111484538 B CN111484538 B CN 111484538B
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- scutellarin
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- methyl ester
- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
- C07H1/08—Separation; Purification from natural products
Abstract
The invention relates to the field of chemical synthesis, and relates to a novel preparation method of homoplantaginin. The method takes scutellarin as a raw material, and can highly efficiently semi-synthesize the hispidoside from the scutellarin through three reactions of carboxyl esterification, selective methylation and ester group reduction. The method has the advantages of short reaction steps, high reaction yield, mild reaction conditions and easy operation, provides a necessary material basis for further research on the biological activity of the homoplantaginin, and has good application and development prospects.
Description
Technical Field
The invention relates to the field of chemical synthesis, relates to a novel preparation method of homoplantain, and particularly relates to a novel method for preparing and synthesizing homoplantain by using scutellarin as a raw material.
Background
The data discloses that homoplantaside, also called homoplantanin, is an effective component of flavonoid glycosides extracted from sage (Salvia plexian) of the genus Salvia of the family Labiatae. In recent years, domestic and foreign researches show that the homoeoside has biological activities of resisting oxidation (Weng x.c. et al. Food chem.2000,71, 489-493), reducing blood sugar, regulating blood fat (wufeihua et al, ZL 201110024707), relieving cough and asthma, inhibiting bacteria and eliminating phlegm (ge Ting et al, J.experimenta, 2012,18, 59-61), improving liver injury (Qu x.j.et al. Food chem.toxicol.2009,47, 1710-1715) and improving vascular endothelial insulin resistance (Wu f.h.et al.biol.pharm.Bull.2012,35, 1171-1177) caused by free fatty acid.
Based on the fact that homoplantaginin has wide biological activity, the obtaining of homoplantaginin in the prior art is limited to the extraction and separation of natural plants so far, and practice shows that the amount of target compounds obtained by extraction and separation is less due to limited plant resources required by extraction and separation, so that the requirement of research on the pharmacological activity of homoplantaginin is difficult to meet.
Based on the current situation of the prior art, the inventor of the application intends to provide a novel preparation method of homoplantaginoside
Disclosure of Invention
The invention aims to provide a synthesis method of homoplantaginoside based on the current situation of the prior art and aiming at solving the defects of the prior art. The invention semi-synthesizes and prepares the homoplantaginoside by using the scutellarin as the starting material, and the method has the advantages of short synthesis step, low cost, high yield and high product purity.
In order to achieve the purpose, the invention adopts the following technical scheme:
the preparation method adopts the following reaction formula:
the invention provides a synthesis method of hispidulin, which specifically comprises the following steps:
using scutellarin as a starting material, and carrying out methyl esterification on carboxyl under the catalysis of acid to obtain scutellarin methyl ester (compound 2);
b, carrying out nucleophilic substitution reaction on the generated scutellarin methyl ester (compound 2) and methyl iodide in the presence of an acid binding agent to generate 6-OMe scutellarin methyl ester (compound 3);
c, carrying out hydrolysis reaction on the generated compound 3 under an acidic condition to obtain a target compound 4.
In the present invention, the reaction solvent used in the step a is methanol.
In the present invention, the acidic catalyst used in the step a is one of or a mixture of thionyl chloride, perchloric acid, concentrated sulfuric acid, concentrated nitric acid, trifluoroacetic acid and concentrated hydrochloric acid, and preferably thionyl chloride or concentrated sulfuric acid.
In the present invention, the concentration of scutellarin in the methanol solution in the step a of the reaction is preferably 10-100 mg mL -1 More preferably 20 to 30mg mL -1 。
In the invention, the acid-binding agent adopted in the step b is inorganic base such as: one or a mixture of potassium carbonate, cesium carbonate, sodium hydride, potassium bicarbonate and sodium bicarbonate; organic bases such as: one or a mixture of N, N-diisopropylethylamine, triethylamine, ethylenediamine and DBU, and preferably inorganic base potassium carbonate.
In the present invention, the organic solvent used in the step b is one or a mixture of N, N-dimethylformamide, N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran, chloroform and ethyl acetate, preferably N, N-dimethylformamide or N, N-dimethylacetamide.
In the present invention, the molar ratio of scutellarin methyl ester to methyl iodide in the step b of the reaction is preferably 1.
In the present invention, the reducing agent adopted in the step c of the reaction is one of sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or a mixture thereof, preferably sodium borohydride.
In the present invention, the reaction solvent used in the reaction c step is one or a mixture of methanol, ethanol, isopropanol and acetonitrile, preferably methanol.
The invention provides a novel preparation method of hispidoside, which takes scutellarin as a raw material and can efficiently semi-synthesize the hispidoside from the scutellarin through three steps of carboxyl esterification, selective methylation and ester group reduction. The method has the advantages of short reaction steps, high reaction yield, mild reaction conditions and easy operation.
Compared with the prior art, the invention has the following advantages:
in the prior art, the acquisition of the homoplantaginoside is limited only by extraction and separation of natural plants so far, plant resources required by the extraction and separation are limited, the amount of target compounds obtained by the extraction and separation is small, and the requirement of pharmacological activity research of the homoplantaginoside is difficult to meet; the invention adopts a chemical synthesis mode to complete the mass preparation of the homoplantaginoside for the first time, and can meet the urgent need of the pharmacological activity research; the invention takes commercially available scutellarin as a starting material, and completes the preparation of the hispidoside by 3 steps of reaction; the reaction reagent is cheap and easy to obtain, and the production cost is low; the reaction condition is mild, and the preparation method can be used for large-scale preparation.
Detailed Description
The invention will be better understood from the following examples. However, one skilled in the art will readily appreciate that the specific material ratios, process conditions, and results thereof described in the examples are merely illustrative of the invention and should not, nor should they, limit the invention as described in detail in the claims.
Example 1: synthesis of scutellarin methyl ester 2
500mL circle200mL of anhydrous methanol is added into a bottom-burning bottle, and SOCl is slowly added dropwise under ice bath 2 (7.25mL, 100mmol), removing ice bath after dropwise addition, stirring at room temperature for 1h, adding scutellarin 1 (4.62g, 10mmol), stirring at room temperature for 9h, and TLC (V) Ethyl acetate :V Isopropanol (I-propanol) :V Water (W) 1) completely reacting, and directly filtering to obtain scutellarin methyl ester 2 (4.67g, 98%); 1 H-NMR(400MHz,DMSO-d 6 )δ12.85(s,1H,5-OH),10.39(s,1H,4’-OH),7.93(d,J＝9.0Hz,2H,H-2’,H-6’),7.00(s,1H,H-8),6.94(d,J＝9.0Hz,2H,H-3’,H-5’),6.81(s,1H,H-3),5.28(d,J＝7.0Hz,1H,H-1”),4.20(d,J＝6.0Hz,1H,H-2”),3.70-3.90(3H,m,other sugar protons),3.68(3H,s,-OCH3)； 13 C-NMR(125MHz,DMSO-d 6 ):δ182.8,169.7,164.5,161.6,151.3,149.4,147.3,130.8,128.9,121.7,116.4,106.3,102.9,100.2,93.9,75.7,75.4,73.1,71.8,52.4(-OCH 3 )。
example 2: synthesis of scutellarin methyl ester 2
Scutellarin 1 (4.62g, 10mmol) was suspended in 300mL of anhydrous methanol in a 500mL round-bottomed flask, and concentrated sulfuric acid (0.03 mL) was slowly added dropwise at room temperature. After the addition was complete, the mixture was refluxed for 3 hours by heating, and then TLC (V) Ethyl acetate :V Isopropanol (I-propanol) :V Water (I) 1), completely reacting, naturally cooling to room temperature, and concentrating under reduced pressure to obtain scutellarin methyl ester 2 (4.72g, 98%);
example 3: synthesis of scutellarin methyl ester 2
Scutellarin 1 (4.62g, 10mmol) was suspended in 200mL of anhydrous methanol in a 500mL round-bottomed flask, and 70% perchloric acid (0.03 mL) was slowly added dropwise at room temperature. After the addition was complete, the mixture was refluxed for 3 hours by heating, and then TLC (V) Ethyl acetate :V Isopropanol (I-propanol) :V Water (W) = 4.
Example 4: synthesis of 6-OMe scutellarin methyl ester 3
In a 250mL round-bottomed flask, compound 2 (3.81g, 8.0 mmol) was dissolved in 50mL of N, N-dimethylformamide, and anhydrous K was added thereto with stirring at room temperature 2 CO 3 (1.66g, 12.0 mmol). MeI (0.60mL and 9.6 mmol) is added dropwise under the protection of nitrogen, and after stirring overnight at 40 ℃,TLC(V methylene dichloride :V Methanol = 20) raw materials disappear, the reaction system is poured into 50mL of ice water, ethyl acetate (25 mL × 3) is extracted, the mixture is washed with saturated salt water, dried by anhydrous sodium sulfate, concentrated and subjected to dry loading column chromatography to obtain a compound 3 (1.53g, 39%); 1 H NMR(400MHz,DMSO-d 6 )δ12.98(s,1H,5-OH),10.42(s,1H,4’-OH),7.95(d,J＝7.8Hz,2H,H-2’,H-6’),7.07(s,1H,H-8),6.95(d,J＝8.1Hz,2H,H-3’,H-5’),6.86(s,1H,H-3),5.62(d,J＝3.9Hz,1H),5.52(d,J＝5.3Hz,1H,H-1”),5.36(d,J＝4.9Hz,2H),4.20(d,J＝9.1Hz,1H),3.76(s,3H,-OCH3),3.66(s,3H,-OCH3)； 13 C-NMR(125MHz,DMSO-d 6 ):δ182.33,169.22,164.38,161.38,155.94,152.68,152.13,132.53,128.59,121.11,116.02,105.92,102.77,99.39,93.91,75.67,75.30,72.81,71.34,60.33,52.03.。
example 5: synthesis of 6-OMe scutellarin methyl ester 3
In a 250mL round-bottomed flask, compound 2 (3.81g, 8.0 mmol) was dissolved in 50mL of N, N-dimethylacetamide, and anhydrous K was added thereto with stirring at room temperature 2 CO 3 (1.66g, 12.0 mmol). MeI (0.75mL, 12.0 mmol) was added dropwise under nitrogen, stirred overnight at 40 deg.C, and then TLC (V) Methylene dichloride :V Methanol = 20) raw material disappeared, the reaction system was poured into 50mL of ice water, extracted with ethyl acetate (25 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to dry column chromatography to obtain compound 3 (1.26g, 32%).
Example 6: synthesis of 6-OMe scutellarin methyl ester 3
In a 250mL round-bottomed flask, compound 2 (3.81g, 8.0 mmol) was dissolved in 50mL of N, N-dimethylformamide, and anhydrous DIPEA (1.98mL, 12.0 mmol) was added with stirring at room temperature. MeI (0.60mL, 9.6 mmol) was added dropwise under nitrogen, and after stirring overnight at 40 ℃, TLC (V) Methylene dichloride :V Methanol = 20). The reaction system was poured into 50mL of ice water, extracted with ethyl acetate (25 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to dry column chromatography to give Compound 3 (1.14g, 29%).
Example 7: synthesis of hispidoside 4
Compound 3 (1.47g, 3.0 mmol) was suspended in 60mL of methanol,sodium borohydride (1.14g, 30.0mmol) was added in small portions with vigorous stirring at room temperature. TLC (V dichloromethane: V methanol =10 = 1) detection after 1h showed the reaction was complete. Adding 30mL of 10% acetic acid solution into a reaction system, extracting with ethyl acetate (50 mL multiplied by 3), concentrating the organic phase under reduced pressure to obtain a crude product, suspending the crude product in 20mL of ethyl acetate, heating and refluxing for 30 minutes, naturally cooling, filtering, washing a filter cake with ethyl acetate, and drying in vacuum to obtain 1.09g of pale yellow solid homoplantain with the yield of 79%. 1 H-NMR(400MHz,DMSO-d 6 )δ12.96(s,1H),10.46(s,1H),7.96(d,J＝8.5Hz,2H),7.02(s,1H),6.94(d,J＝8.5Hz,2H),6.87(s,1H),5.48(s,1H),5.19(s,1H),5.15–5.08(m,2H),4.68(s,1H),3.76(s,3H),3.72(s,1H),3.33(s,2H),3.21(s,1H)； 13 C-NMR(125MHz,DMSO-d 6 ):δ182.15,164.13,161.18,156.30,152.27,151.97,132.33,128.41,120.91,115.83,105.55,102.50,100.01,94.18,77.09,76.55,73.00,69.40,60.44,60.14。
Example 8: synthesis of hispidoside 4
Compound 3 (1.47g, 3.0 mmol) was suspended in 60mL of methanol, and sodium borohydride (1.71g, 45.0 mmol) was added in small portions with vigorous stirring at room temperature. TLC (V dichloromethane: V methanol =10 = 1) detection after 1h showed the reaction was complete. Adding 30mL of 10% acetic acid solution into a reaction system, extracting with ethyl acetate (50 mL multiplied by 3), concentrating the organic phase under reduced pressure to obtain a crude product, suspending the crude product in 20mL of ethyl acetate, heating and refluxing for 30 minutes, naturally cooling, filtering, washing a filter cake with ethyl acetate, and drying in vacuum to obtain light yellow solid homoplantain 4.16g with the yield of 84%.
Claims (14)
1. A method for synthesizing homoplantaginoside, which comprises the steps of:
using scutellarin as a starting material, and carrying out methyl esterification on carboxyl under the action of an acidic catalyst to obtain scutellarin methyl ester;
b, carrying out nucleophilic substitution reaction on the generated scutellarin methyl ester and methyl iodide in the presence of an acid binding agent to generate 6-OMe scutellarin methyl ester;
c, carrying out ester group reduction reaction on the generated 6-OMe scutellarin methyl ester in the presence of a reducing agent to prepare the homoplantaginin;
wherein, the acidic catalyst in the step a is one of or a mixture of thionyl chloride, perchloric acid, concentrated sulfuric acid, concentrated nitric acid, concentrated hydrochloric acid and trifluoroacetic acid.
2. The process of claim 1, wherein the reaction solvent used in step a is methanol; the concentration of scutellarin in the methanol solution is 10-100 mg mL -1 。
3. The method of claim 2, wherein the concentration of scutellarin in the methanol solution is 20-30 mg mL -1 。
4. The method of claim 1, wherein the acidic catalyst in step a is thionyl chloride or concentrated sulfuric acid.
5. The method of claim 1, wherein in step b, the acid scavenger used is an inorganic base selected from the group consisting of: one or a mixture of potassium carbonate, cesium carbonate, sodium hydride, potassium bicarbonate and sodium bicarbonate; an organic base selected from: one or a mixture of N, N-diisopropylethylamine, triethylamine, ethylenediamine and DBU.
6. The method of claim 5, wherein in step b, the acid scavenger used is an inorganic base, potassium carbonate.
7. The method according to claim 1, wherein the organic solvent used in step b is one of N, N-dimethylformamide, N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, or a mixture thereof.
8. The method of claim 7, wherein the organic solvent used in step b is N, N-dimethylformamide or N, N-dimethylacetamide.
9. The method of claim 1, wherein in the step b, the molar ratio of the methyl scutellarin to the methyl iodide is 1.
10. The method of claim 9, wherein in step b, the molar ratio of scutellarin methyl ester to methyl iodide is 1.2.
11. The method of claim 1, wherein the reducing agent used in step c is one of sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or a mixture thereof.
12. The method of claim 11, wherein the reducing agent used in step c is sodium borohydride.
13. The method of claim 1, wherein the reaction solvent used in step c is one of methanol, ethanol, isopropanol, acetonitrile or a mixture thereof.
14. The method of claim 13, wherein the reaction solvent used in step c is methanol.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746351A (en) * | 2012-07-23 | 2012-10-24 | 上海蓝木化工有限公司 | Method for preparing scutellarin and analogues thereof |
| CN104311518A (en) * | 2014-11-18 | 2015-01-28 | 南京中医药大学 | Preparation method for 6-methoxyscutellarin |
| CN105713057A (en) * | 2014-12-03 | 2016-06-29 | 广州市恒诺康医药科技有限公司 | Scutellarin compounds and preparation method and application thereof |
| CN106883277A (en) * | 2017-03-10 | 2017-06-23 | 沈阳药科大学 | One class has furazan class NO donator type scutellarin derivatives of antitumor activity and its production and use |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746351A (en) * | 2012-07-23 | 2012-10-24 | 上海蓝木化工有限公司 | Method for preparing scutellarin and analogues thereof |
| CN104311518A (en) * | 2014-11-18 | 2015-01-28 | 南京中医药大学 | Preparation method for 6-methoxyscutellarin |
| CN105713057A (en) * | 2014-12-03 | 2016-06-29 | 广州市恒诺康医药科技有限公司 | Scutellarin compounds and preparation method and application thereof |
| CN106883277A (en) * | 2017-03-10 | 2017-06-23 | 沈阳药科大学 | One class has furazan class NO donator type scutellarin derivatives of antitumor activity and its production and use |
Non-Patent Citations (2)
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| A convenient and efficient approach to synthesize negletein from baicalin;Guihua He et al.;《Tetrahedron Letters》;20160329;第 57 卷;第2001–2005页 * |
| 荔枝草中高车前苷的提取与分析;孔庆新等;《江苏农业科学》;20141231;第42卷(第12期);第304-306页 * |
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