CN110467592B - Luteolin semi-synthesis method - Google Patents
Luteolin semi-synthesis method Download PDFInfo
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- CN110467592B CN110467592B CN201910865582.2A CN201910865582A CN110467592B CN 110467592 B CN110467592 B CN 110467592B CN 201910865582 A CN201910865582 A CN 201910865582A CN 110467592 B CN110467592 B CN 110467592B
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- C07—ORGANIC CHEMISTRY
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- 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 invention belongs to the technical field of substance synthesis, and particularly relates to a luteolin semisynthesis method, which comprises the specific steps of taking rutin as a raw material and urea compounds as a reducing agent, reacting for 0.5-7h under the condition of 40 ℃ to reflux, and refining to obtain the luteolin, wherein the yield is more than 97.1%, and the purity is more than 94.22%.
Description
Technical Field
The invention belongs to the technical field of substance synthesis, and particularly relates to a semi-synthesis method of luteolin.
Background
The flavonoid compounds are widely distributed in nature, exist in a glycoside type and a free type, and arouse wide attention of scholars at home and abroad according to the diversity of biochemical and pharmacological actions, including antioxidant activity, and become hot spots of development and utilization research of natural medicaments at home and abroad. Luteolin (luteolin ) with the scientific name of 3',4',5, 7-luteolin is a very representative natural flavone, belongs to a weak acid tetrahydroxy flavonoid compound, and is widely distributed in the plant; luteolin has strong antioxidant activity; has antibacterial, antiviral, and blood lipid and cholesterol reducing effects. The luteolin has good oxidation resistance and antibacterial performance, is developed as a natural antioxidant and a preservative of food, and has wide development and application prospects.
At present, a great deal of research and investigation on luteolin extraction, semi-synthesis or synthesis at home and abroad are reported, the extraction yield of the natural product of the luteolin is low, and although the luteolin can be obtained by utilizing a synthetic approach, the yield and the safety are not ideal. The existing total synthesis method for preparing luteolin has extremely complex process and higher production cost; the semi-synthesis method also has a great room for improvement in yield, efficiency, and equipment requirements.
A process for preparing luteolin compound (Junqing, published as 10 months and 26 days in 2005) is disclosed. The method comprises the following steps: adding rutin or its derivatives into water, adding NaOH under heating and stirring until the raw materials are completely dissolved, cooling to room temperature, adjusting pH to 2-6, filtering, washing, and drying to obtain refined raw materials; adding solid alkali into water, and adding the refined product and Na2S2O4The dosage is calculated according to the molar ratio, and the raw material fine product is solid alkali Na2S2O4Wherein the water is 1:15-20:8-70:1110-3330,100-500W microwave heating reflux is carried out for 0.25-2 h, and cooling is carried outCooling to room temperature, adjusting the pH of the reaction solution to 2-7, filtering, washing and drying; and then recrystallizing by using an organic solvent. The method is an improvement of the method of the invention of H.Boolean, and the like, and mainly adopts a microwave heating reaction method; the principle is the same, namely rutin or derivatives thereof are used as raw materials for structural transformation, luteolin is semi-synthesized, the cost is low, the reaction time is short (0.25h-2h), the operation is simple and convenient, the control is easy, and the product purity and yield are high. However, the method adopts a microwave reflux heating method, and is not suitable for industrial production.
CN102002028B (published as 04/06/2011) discloses a method for synthesizing luteolin, which comprises the specific steps of adding rutin into alkaline water at room temperature of 20-30 ℃, stirring for dissolving, then adding 6.3 equivalents of reducer sodium hydrosulfite once, continuing to heat to 100 ℃, stirring for 12 hours, finishing HPLC monitoring reaction, then cooling, adding dilute hydrochloric acid or dilute sulfuric acid, adjusting pH to 3-4, standing for 24 hours, precipitating solids, filtering, washing filter cakes with water for 2 times, and removing salts contained in products. Drying to obtain crude product, and further crystallizing with ethanol to obtain pure luteolin product with purity of 95.6% and yield of 56.5%.
Therefore, the research on the preparation method of luteolin with low investment, high efficiency, high yield and environmental friendliness shows great social benefits and economic values.
The method takes the rutin as the raw material and the urea compound as the reducing agent to synthesize the luteolin under the conventional conditions, has short required reaction time and high yield, can obtain the product with the purity of 85 percent by one time, has simple equipment and operation, and is suitable for industrial production.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a luteolin semi-synthesis method, which adopts the following technical scheme:
rutin reacts under the reduction action of urea compounds to generate luteolin.
Further, the urea compound is one of thiourea, thiourea monoxide, thiourea dioxide, thiourea trioxide, 1-phenyl-2-thiourea and guanyl thiourea. Preferably, the urea compound is thiourea.
Further, rutin: water: the weight portion ratio of the urea compound is 2:200: 2.5-5. Preferably, the ratio of rutin: water: the weight ratio of the urea compound is 2:200: 5.
Further, the temperature of the reaction is from 40 ℃ to reflux temperature. Preferably, the reaction temperature is 60-80 ℃. Preferably, the reaction temperature is 80 degrees celsius.
Further, the pH of the reaction is 8 to 11. Preferably, the pH of the reaction is 8-9.
Further, the reaction time is 0.5-7 h. Preferably, the reaction time is 1-3 h. Preferably, the reaction time is 2 h.
Further, the obtained luteolin is purified using a conventional refining method.
The luteolin semi-synthesis method has the advantages of low cost, simple equipment and operation, high yield and short reaction time, and is suitable for industrial production.
Drawings
FIG. 1 shows the effect of different pH on the yield of luteolin at reflux temperature, with an average yield of 77.6% at pH8-9 and an average yield of 66.1% at pH 10-11;
FIG. 2 shows the effect of different temperatures on the yield of luteolin at pH8-9, 97.8% at 60℃, 99.0% at 80℃, and 77.6% when the temperature reaches reflux;
FIG. 3 shows the effect of different material ratios on the yield of luteolin, wherein the yield is 77.7% when the weight ratio of rutin to thiourea is 2:5 and 40.10% when the weight ratio of rutin to thiourea is 2: 2.5;
FIG. 4 is a film-unfolding test chart of the product of example 1 of the present invention, wherein band 1 is a luteolin standard, band 2 is the product of example 1, and band 3 is a quercetin standard, and it can be seen that the product of example 1 has a significant dark spot of luteolin and no other dark spots, and it can be seen that the product substantially contains only luteolin and almost no rutin as a raw material;
FIG. 5 is a HPLC assay of the product of example 1 of the invention, in methanol: 0.2% phosphoric acid-water solution 70: 30 as a mobile phase, the yield of luteolin of example 1 was measured to be 99.1%.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. Other embodiments, which can be derived by one of ordinary skill in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified; unless otherwise indicated, the examples were run according to routine experimental conditions or according to manufacturer's instructions.
Example 1
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, reacting at 60 deg.C for 2h, neutralizing pH to 2-4 with concentrated HCl, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 99.1% and purity of 95.31%, wherein the detection diagrams of thin film development method and HPLC method are respectively shown in FIG. 4 and FIG. 5.
Example 2
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, reacting at 60 deg.C for 3 hr, neutralizing pH to 2-4 with concentrated HCl, cooling, standing, crystallizing, filtering, washing with water, and drying to obtain luteolin with yield of 97.1% and purity of 95.43%.
Example 3
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, and adding NaOH to control pH to 8-9; adding thiourea, reacting at 60 deg.C for 4h, neutralizing with concentrated HCl to pH 2-4, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 97.1% and purity of 95.09%.
Example 4
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, reacting at 80 deg.C for 3 hr, neutralizing pH to 2-4 with concentrated HCl, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 99% and purity of 94.54%.
Example 5
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, reacting at 80 deg.C for 5 hr, neutralizing pH to 2-4 with concentrated HCl, cooling, standing, crystallizing, filtering, washing with water, and drying to obtain luteolin with yield of 99% and purity of 94.72%.
Example 6
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, reacting at 80 deg.C for 6 hr, neutralizing pH to 2-4 with concentrated HCl, cooling, standing, crystallizing, filtering, washing with water, and drying to obtain luteolin with yield of 99% and purity of 94.70%.
Example 7
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, reacting at 80 deg.C for 7 hr, neutralizing pH to 2-4 with concentrated HCl, cooling, standing, crystallizing, filtering, washing with water, and drying to obtain luteolin with yield of 99.1% and purity of 94.22%.
Comparative example 1
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea as reducing agent, refluxing for 2h, neutralizing pH to 2-4 with concentrated HCl, cooling, standing, crystallizing, filtering, washing with water, and drying to obtain luteolin with yield of 77.6% and purity of 94.11%.
Comparative example 2
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, refluxing for 3 hr, neutralizing with concentrated HCl to pH 2-4, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 77.6% and purity of 94.11%.
Comparative example 3
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, refluxing for 4h, neutralizing pH to 2-4 with concentrated HCl, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 77.8% and purity of 94.30%.
Comparative example 4
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, refluxing for 5 hr, neutralizing with concentrated HCl to pH 2-4, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 77.6% and purity of 93.60%.
Comparative example 5
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 10-11, adding thiourea, refluxing for 3 hr, neutralizing pH to 2-4 with concentrated HCl, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 66.1% and purity of 95.52%.
Comparative example 6
Raw materials: 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 10-11, adding thiourea, refluxing for 4h, neutralizing pH to 2-4 with concentrated HCl, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 66.1% and purity of 95.41%.
Comparative example 7
Raw materials: 800 parts of distilled water, 4 parts of rutin and 5 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, refluxing for 1h, neutralizing pH to 2-4 with concentrated HCl, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 40.0% and purity of 92.70%.
Comparative example 8
Raw materials: 800 parts of distilled water, 4 parts of rutin and 5 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, refluxing for 2 hr, neutralizing with concentrated HCl to pH 2-4, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 40.1% and purity of 90.72%.
Comparative example 9
Raw materials: 800 parts of distilled water, 4 parts of rutin and 5 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, refluxing for 3 hr, neutralizing with concentrated HCl to pH 2-4, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 40.2% and purity of 94.16%.
Comparative example 10
Raw materials: 800 parts of distilled water, 4 parts of rutin and 5 parts of thiourea.
The preparation method comprises the following steps: boiling distilled water, adding rutin, adding NaOH to control pH to 8-9, adding thiourea, refluxing for 4 hr, neutralizing with concentrated HCl to pH 2-4, cooling, standing for crystallization, filtering, washing with water, and drying to obtain luteolin with yield of 40.0% and purity of 93.70%.
Test example 1
The urea compounds are all in a medium with stronger alkalinity, and the reduction potential is higher; because the raw material rutin is easy to isomerize under the conditions of high temperature and strong alkali, the influence of different pH values on the yield is shown by taking 800 parts of distilled water, 4 parts of rutin and 10 parts of thiourea as investigation factors and taking two pH ranges of pH8-9 and pH10-11 as the following factors:
TABLE 1 investigation results of different reaction pH of thiourea semi-synthesized luteolin
As shown in Table 1 and FIG. 1, the reaction pH is preferably 8 to 9, since excessive alkali lowers the yield of luteolin.
Test example 2
The influence of the reaction time on the yield is examined by using the pH value of 8-9, the temperature of 80 ℃ respectively, the reflux, the feed amount of thiourea of 10 parts and 5 parts:
TABLE 2 investigation results of different reaction times of thiourea semi-synthesis of luteolin
As can be seen from Table 2, the reaction time has a very small influence on the yield of the synthesis reaction, the product purity and the yield. When the reaction time reaches 2 hours, the yield and purity do not increase with the increase of the reaction time, and therefore, the reaction time is suitably 1 to 3 hours.
Test example 3
The influence of temperature on the reaction is examined by taking the pH value as 8-9 and the feed amount of thiourea as 10 parts:
TABLE 3 investigation results of different reaction temperatures of thiourea semi-synthesis of luteolin
As can be seen from Table 3 and FIG. 2, the reaction yield is greatly influenced by the temperature, which is preferably not too high, particularly preferably not at reflux, and is preferably 60-80 ℃.
Test example 4
When rutin is used as a reaction raw material and thiourea is used as a reducing agent to semi-synthesize luteolin, the influence of different weight parts of reaction materials on a reaction result is as follows:
TABLE 4 investigation results of different reaction material ratios of thiourea semi-synthesized luteolin
As can be seen from table 4 and fig. 3, the material ratio has a large influence on the reaction yield and purity, and the suitable material weight ratio is rutin: water: the urea compound is 2:200: 5.
Test example 5
Selecting a thin layer developing agent, comparing 13 developing systems, as shown in Table 5, scheme 1, namely chloroform-methanol test solution (15: 5: 1), has the best separation effect on rutin and luteolin (or quercetin) and high specificity, so that the developing agent for distinguishing rutin from luteolin (or quercetin) is selected; the scheme 12, namely petroleum ether-ethyl acetate-formic acid (48:32:3), has the best separation effect on luteolin and quercetin and has high specificity, so the developing agent for distinguishing the luteolin from the quercetin is selected.
TABLE 5 selection of thin-layer developing solvent (ml)
In conclusion, the synthetic result of using urea compounds as reducing agents is more desirable than the synthetic result of using reducing sodium salts as reducing agents; the influence of various factors for preparing the luteolin by the rutin and the urea compound is as follows: the method selects the optimal reducing agent, the optimal feeding amount of the reducing agent, the optimal reaction temperature, the optimal reaction pH and the optimal reaction time.
The method takes the rutin as the raw material to synthesize the luteolin, has low cost and is environment-friendly; the invention is carried out by adopting a conventional thermal stirring device, has simple equipment and operation and is suitable for industrial production; the urea compound adopted by the invention has stable property; the luteolin synthesized by the method has high purity, high yield and short reaction time, and is suitable for industrial production.
The technical solutions of the present invention are described in more detail and detail, but the technical solutions of the present invention are not to be construed as limiting the scope of the present invention. It should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the spirit of the present invention, and these changes and modifications are within the scope of the present invention.
Claims (5)
1. A semi-synthesis method of luteolin is characterized in that rutin reacts under the reduction action of urea compounds to generate the luteolin, wherein a reducing agent used in the reduction action consists of the urea compounds; rutin: water: the weight ratio of the urea compound is 2:200: 5; the reaction temperature is 60-80 ℃; the pH value of the reaction is 8-9; the urea compound is thiourea.
2. The process of claim 1, wherein the reaction temperature is 80 ℃.
3. The process according to claim 1, wherein the reaction time is from 0.5 to 7 hours.
4. The process according to claim 3, wherein the reaction time is from 1 to 3 hours.
5. The process of claim 3, wherein the reaction time is 2 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325393A (en) * | 1998-10-30 | 2001-12-05 | 默克专利股份有限公司 | Method for producing luteolin and luteolin derivatives |
| CN110770218A (en) * | 2018-11-09 | 2020-02-07 | 邦泰生物工程(深圳)有限公司 | Method for preparing luteolin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325393A (en) * | 1998-10-30 | 2001-12-05 | 默克专利股份有限公司 | Method for producing luteolin and luteolin derivatives |
| CN110770218A (en) * | 2018-11-09 | 2020-02-07 | 邦泰生物工程(深圳)有限公司 | Method for preparing luteolin |
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