CN103408423A - Nature active product L-cichoric acid synthesis process - Google Patents
Nature active product L-cichoric acid synthesis process Download PDFInfo
- Publication number
- CN103408423A CN103408423A CN2013102989733A CN201310298973A CN103408423A CN 103408423 A CN103408423 A CN 103408423A CN 2013102989733 A CN2013102989733 A CN 2013102989733A CN 201310298973 A CN201310298973 A CN 201310298973A CN 103408423 A CN103408423 A CN 103408423A
- Authority
- CN
- China
- Prior art keywords
- reaction
- acid
- organic phase
- described method
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a nature active product L-cichoric acid synthesis process, wherein methyl caffeate or ethyl caffeate is adopted as a starting raw material to prepare L-cichoric acid. The synthesis process comprises: in a stainless steel reaction kettle, adding reaction raw materials methyl caffeate or ethyl caffeate and L-tartaric acid, adding a solvent at a room temperature to dissolve, controlling the temperature at the room temperature, slowly adding a basic catalyst, stirring, slowly heating until carrying out a reflux reaction, cooling after completing the reaction, adopting dilute hydrochloric acid to adjust the pH value, adding water to extract twice, drying the organic phase overnight with a drying agent, carrying out pressure reduction concentration on the organic phase, carrying out crystallization with anhydrous ethanol, carrying out suction filtration, and carrying out double-cone drying to obtain the qualified product. The method has characteristics of simple process and simple operation, and is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic of a kind of active skull cap components L-chicoric acid, being specifically related to synthesis material is coffic acid, through coffic acid, becomes ester, then carry out transesterify under weak basic condition, obtains product L-chicoric acid.
Background technology
The L-chicoric acid, i.e. (2R, 3R)-(-)-chicoric acid, be a kind of coffic acid derivative, is mainly derived from natural Echinacea extract.Echinacea purpurea is a class Wild Chrysanthemum that originates in America and European genus echinacea, and extensive activity is arranged, and developed patent medicine three kinds of echinacea purpurea, narrow leaf echinacea purpurea and violet ash cone chrysanthemums are arranged.All at me, cross successful introduction at present, in Hunan, Sichuan, Guangxi big area artificial growth.Echinacea extract has antiphlogistic activity, antiviral, antimycotic, antibacterium and antitumor, insecticidal action, and immunocompetence is also fine.So Echinacea extract is one of best-selling product at present in U.S.'s protective foods plant extract additive.The activeconstituents contained in Echinacea extract mainly contains polysaccharide and glycoprotein, alkylamide compound and coffic acid derivative, wherein the L-chicoric acid is exactly active best coffic acid derivative, as the important detection composition of Echinacea extract quality control.
Chicoric acid, as the main active ingredient in echinacea purpurea, that bibliographical information also has is antiviral, anti-inflammatory, raising immunizing power, anti-oxidant and know the free radical function.So the exploitation of monomer chicoric acid is also that marketable value is arranged very much.But chicoric acid all lower than 0.1%, directly, from echinacea purpurea, extracting the high cost for preparing chicoric acid, is unfavorable for market and the application of chicoric acid at the content of three kinds of echinacea purpureas.From echinacea purpurea, extract chicoric acid, be difficult to obtain the elaboration of high purity and content.And, basically all to use macroporous resin purification, complex process, cost high (Guo Jianwei, chicoric acid and monocaffeyltartaric acid purifying process and chicoric acid property research in echinacea purpurea, Hunan Normal University, master thesis; Wu Qilin, the extraction and purification process of chicoric acid research in echinacea purpurea, Beijing University of Chemical Technology, master thesis; Zeng Dong, Chen Bo, Luo Xubiao etc. the research of Adsorption And Purification of Cichoric Acid In Extracts of Echinacea Purpurea With Macroporous Adsorption Resin, research and development of natural products, 2004,16 (2): 160-164).
So, develop a kind of efficiently, cheaply synthesis technique to prepare the L-chicoric acid be that marketable value is arranged very much.At present, L-chicoric acid synthetic only has the document that research is arranged abroad, all also do not have enterprise development to go out large production technique both at home and abroad.He Zhao and A.M.Lamidey report that take coffic acid is raw material, the synthetic intermediate phenolic hydroxyl group is with the coffic acid acyl chlorides of ethanoyl or lactonic ring protection, add again catalyst n, N-dicyclohexyl imines and DMAP react with L-TARTARIC ACID, hydrolysising protection base again, obtain L-chicoric acid (He Zhao, Terrence R.Burke Jr.Facile Syntheses of (2R, 3R)-(-)-and (2S, 3S)-(+)-Chicoric Acids.Synthetic Communications, 1998,28 (4): 737-740; Anne-Marie Lamidey, Lionel Fernon, Laurent Pouyseu, Charlotte Delattre, Stehane Quideau.A Convenient Synthesis of the Echinacea-Derived Immunostimulator and HIV-1 Integrase Inhibitor (-)-(2R, 3R)-Chicoric Acid.Helvetika Chimica Acta2002 (85): 2328-2334).This route is longer, and has used the not environmental protection of contamination reagent such as acyl chlorides, thionyl chloride, so industrial value is not high.
Above method is some shortcomings below preparation L-chicoric acid: (1) natural extract shortcoming has resource utilization low, after extracting the L-chicoric acid, affects extraction and the utilization of other activeconstituentss, causes cost too high; Simultaneously, use macroporous resin in the extraction sepn process, energy consumption is high, pollution is large, is difficult to obtain high purity and high-content L-chicoric acid.(2) take coffic acid and be as the synthetic L-chicoric acid shortcoming of starting raw material, route steps is longer, complex process, ultimate yield is lower, be cost is also higher, be unfavorable for industrialization promotion; In addition, also used the hazardous agents such as acyl chlorides and thionyl chloride, damage ratio is larger, large to the healthy harm of operator.
For solving the shortcoming of above-mentioned preparation L-chicoric acid, that operational path of the present invention adopts is shorter, the route of environmental protection more, directly take Methyl caffeoate or NSC 619661 to be raw material, obtains the L-chicoric acid through 1 step reaction.This route prepares that L-chicoric acid cost is low, technique is simple, environmental protection, productive rate are high, and extraordinary using value is arranged.
The different characteristics part of the present invention and aforesaid method is: (1) has adopted the new Methyl caffeoate of raw material in fact or NSC 619661, makes syntheti c route shorter, and yield is higher.(2) other supplementary materials are all conventional reaction reagent, gentle, safety, and contamination-free produces, and technique is environmental protection more.(3) route is shorter, and equipment is simpler, operates more succinct.The above route that is good suitability for industrialized production from economy, environment and Occupational health angle.
Summary of the invention
The key problem that the present invention need to solve is the shortcoming that overcomes existing L-chicoric acid preparation technology, sets up environmental friendliness, low cost, succinct from Methyl caffeoate or the synthetic L-chicoric acid industrialized producing technology of NSC 619661.
Purpose of the present invention is achieved through the following technical solutions, and concrete route is shown in Figure of description:
L-chicoric acid synthesis route is to take Methyl caffeoate or NSC 619661 to be raw material, carries out transesterification reaction through base catalysis and L-TARTARIC ACID, and the reaction end separates, concentrates, wash crystallization obtains high-content and highly purified product.Concrete steps are as follows:
1, in stainless steel cauldron, add reaction raw materials Methyl caffeoate or NSC 619661 and L-TARTARIC ACID, solubilizing agent dissolving again under room temperature, temperature control slowly adds basic catalyst in room temperature, stir and slowly be warming up to back flow reaction, to thin-layer chromatography monitoring raw material Methyl caffeoate or NSC 619661 complete reaction.
2, after having reacted, chuck passes into icy salt solution and is cooled to below 10 ℃, stirs, and adds the dilute hydrochloric acid adjust pH to 6-7, then adds water extraction secondary, and organic phase is spent the night with desiccant dryness.
3, organic phase is proceeded to band thickener crystallizer, be evaporated to dryly, then add the dehydrated alcohol heating for dissolving, then concentrating under reduced pressure goes out part ethanol, and stirring, decrease temperature crystalline.
4, crystallization completes, and decompression filters, and 50 ℃ of dry 3h of bipyramid, obtain qualified product.
The invention provides L-chicoric acid synthesis technique, take Methyl caffeoate or ethyl ester and be starting raw material, in stainless steel cauldron, complete transesterification reaction, then adjust pH, extracting and separating, crystallization purifying.Aspect reaction use reagent, supplementary material, all considering with environmental protection, efficiency.Present method has that atom economy type, equipment are simple, the production sequence environmental protection, and very large economic and social benefit is arranged.
The accompanying drawing explanation
L-chicoric acid synthetic route is shown in accompanying drawing.
Embodiment
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
Synthesizing of embodiment 1 L-chicoric acid
In the 300L stainless steel cauldron, add Methyl caffeoate 15.0kg and L-TARTARIC ACID 12.0kg, the 150L that adds methylene chloride again dissolves, stir, the logical cool brine temperature control of chuck, in below 10 ℃, adds sodium methylate 6.3kg, then slowly be warming up to backflow, approximately 40 ℃, continue stirring reaction 12h, to thin-layer chromatography monitoring raw material Methyl caffeoate complete reaction.Chuck passes into the cool brine cooling again, adds in dilute hydrochloric acid and pH value to 6.5.Add water again and carry out extracting twice, organic phase is collected, and adds anhydrous sodium sulfate drying to spend the night.Then organic phase is filtered and to be proceeded to the concentrated stainless steel crystallizer of 300L band through secondary filter, 40 ℃ of temperature controls are concentrated into dryly with interior, then add dehydrated alcohol 150L heating for dissolving.Then concentrating under reduced pressure steams about 100L ethanol, then is cooled to while stirring 10 ℃ of crystallizations.Crystal filters after separating out fully, and 50 ℃ of dry temperature controls of bipyramid, with inner drying 3h, obtain qualified L-chicoric acid 24.3kg, productive rate 90.0%, and high performance liquid phase detects, area normalization method purity 99.0%, external standard method content 99.5%.
Synthesizing of embodiment 2 L-chicoric acids
In the 300L stainless steel cauldron, add NSC 619661 16.5kg and L-TARTARIC ACID 12.0kg, adding tetrahydrofuran (THF) 120L dissolves again, stir, the logical cool brine temperature control of chuck, in below 10 ℃, adds sodium ethylate 7.9kg, then slowly be warming up to backflow, approximately 70 ℃, continue stirring reaction 5h, to thin-layer chromatography monitoring raw material NSC 619661 complete reaction.Chuck passes into the cool brine cooling again, adds in dilute hydrochloric acid and pH value to 6.5.Add water again and carry out extracting twice, organic phase is collected, and adds anhydrous sodium sulfate drying to spend the night.Then organic phase is filtered and to be proceeded to the concentrated stainless steel crystallizer of 300L band through secondary filter, 40 ℃ of temperature controls are concentrated into dryly with interior, then add dehydrated alcohol 150L heating for dissolving.Then concentrating under reduced pressure steams about 100L ethanol, then is cooled to while stirring 10 ℃ of crystallizations.Crystal filters after separating out fully, and 50 ℃ of dry temperature controls of bipyramid, with inner drying 3h, obtain qualified L-chicoric acid 24.5kg, productive rate 90.3%, and high performance liquid phase detects, area normalization method purity 99.1%, external standard method content 99.3%.
Synthesizing of embodiment 3 L-chicoric acids
In the 300L stainless steel cauldron, add Methyl caffeoate 15.0kg and L-TARTARIC ACID 12.0kg, adding ethylene dichloride 150L dissolves again, stir, the logical cool brine temperature control of chuck, in below 10 ℃, adds sodium ethylate 6.3kg, then slowly be warming up to backflow, approximately 80 ℃, continue stirring reaction 4h, to thin-layer chromatography monitoring raw material NSC 619661 complete reaction.Chuck passes into the cool brine cooling again, adds in dilute hydrochloric acid and pH value to 6.5.Add water again and carry out extracting twice, organic phase is collected, and adds anhydrous sodium sulfate drying to spend the night.Then organic phase is filtered and to be proceeded to the concentrated stainless steel crystallizer of 300L band through secondary filter, 50 ℃ of temperature controls are concentrated into dryly with interior, then add dehydrated alcohol 150L heating for dissolving.Then concentrating under reduced pressure steams about 100L ethanol, then is cooled to while stirring 10 ℃ of crystallizations.Crystal filters after separating out fully, and 50 ℃ of dry temperature controls of bipyramid, with inner drying 3h, obtain qualified L-chicoric acid 24.0kg, productive rate 89.1%, and high performance liquid phase detects, area normalization method purity 99.0%, external standard method content 99.1%.
Claims (8)
1. one kind is the method that starting raw material prepares the L-chicoric acid from Methyl caffeoate or NSC 619661, it is included in stainless steel cauldron, add reaction raw materials Methyl caffeoate or NSC 619661 and L-TARTARIC ACID, solubilizing agent dissolving again under room temperature, temperature control slowly adds basic catalyst in room temperature, stir and slowly be warming up to back flow reaction, to thin-layer chromatography monitoring raw material Methyl caffeoate or NSC 619661 complete reaction; After having reacted, chuck passes into the icy salt solution cooling, stirs, and adds the dilute hydrochloric acid adjust pH, then adds water extraction secondary, and organic phase is spent the night with desiccant dryness.Organic phase is proceeded to band thickener crystallizer, be evaporated to dryly, then add the dehydrated alcohol heating for dissolving, then concentrating under reduced pressure goes out part ethanol, and stirring, decrease temperature crystalline.Crystallization completes, and decompression filters, and the bipyramid drying, obtain qualified product.
2. according to right 1, require described method, it is characterized by and using methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), toluene etc. stable solvent is as reaction system in soda acid, its consumption is at 8-10 times of volume.
3. according to right 1, require described method, it is characterized in that transesterification catalyst is highly basic, comprise sodium methylate, sodium ethylate, consumption is 1.5-2.0 times of molar weight of raw material caffeic acid ester.
4. according to right 1, require described method, it is characterized in that feeding intake, the temperature of reaction and aftertreatment flow process key point controls, and controls and at room temperature drops into basic catalyst, temperature of reaction is at 40-90 ℃, and the dilute hydrochloric acid neutral temperature is below 10 ℃.
5. according to right 1, require described method, after it is characterized in that having reacted with the dilute hydrochloric acid adjust pH to 6-7, dilute hydrochloric acid concentration is 1-10%, best with 5%.
6. according to right 1, require described method, it is characterized in that neutralizing complete, add and the isopyknic water of organic phase extraction secondary, collect organic phase, with dried overnight such as anhydrous sodium sulphate, anhydrous magnesium sulfates.
7. according to right 1, require described method, it is characterized in that organic phase goes to crystallizer through filter, concentrated dry reaction solvent, add again the dehydrated alcohol thermosol, the dehydrated alcohol consumption is 10-15 times of volume, then concentrating under reduced pressure goes out the ethanol of 2/3 volume, the 10 ℃ of following stirred crystallization of lowering the temperature.
8. according to right 1, require described method, it is characterized in that crystallization completes, decompression filters, and obtains product, and 50 ℃ of bipyramids, with inner drying 3h, obtain qualified product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102989733A CN103408423A (en) | 2013-07-17 | 2013-07-17 | Nature active product L-cichoric acid synthesis process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102989733A CN103408423A (en) | 2013-07-17 | 2013-07-17 | Nature active product L-cichoric acid synthesis process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103408423A true CN103408423A (en) | 2013-11-27 |
Family
ID=49601482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013102989733A Pending CN103408423A (en) | 2013-07-17 | 2013-07-17 | Nature active product L-cichoric acid synthesis process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103408423A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397188A (en) * | 2016-09-07 | 2017-02-15 | 张家港威胜生物医药有限公司 | Preparation method of L-chicoric acid |
| CN113845422A (en) * | 2021-11-04 | 2021-12-28 | 山东中医药大学 | Process for preparing high-purity L-chicoric acid from echinacea purpurea in batches and application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020114853A1 (en) * | 2000-09-29 | 2002-08-22 | Krasutsky Pavel A. | Process for extracting compounds from plants |
| US20050049242A1 (en) * | 2000-12-21 | 2005-03-03 | W. Edward Robinson | Novel HIV integrase inhibitors and HIV therapy based on drug combinations including integrase inhibitors |
| CN102333455A (en) * | 2009-01-27 | 2012-01-25 | 雀巢产品技术援助有限公司 | Composition comprising chicoric acid and/or derivatives thereof |
| CN102887826A (en) * | 2012-10-23 | 2013-01-23 | 湖南师范大学 | Synthesis method of (-)-chicoric acid |
-
2013
- 2013-07-17 CN CN2013102989733A patent/CN103408423A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020114853A1 (en) * | 2000-09-29 | 2002-08-22 | Krasutsky Pavel A. | Process for extracting compounds from plants |
| US20050049242A1 (en) * | 2000-12-21 | 2005-03-03 | W. Edward Robinson | Novel HIV integrase inhibitors and HIV therapy based on drug combinations including integrase inhibitors |
| CN102333455A (en) * | 2009-01-27 | 2012-01-25 | 雀巢产品技术援助有限公司 | Composition comprising chicoric acid and/or derivatives thereof |
| CN102887826A (en) * | 2012-10-23 | 2013-01-23 | 湖南师范大学 | Synthesis method of (-)-chicoric acid |
Non-Patent Citations (1)
| Title |
|---|
| DONG JIN HWANG等: "Dicaffeoyl- or Digalloyl Pyrrolidine and Furan Derivatives as HIV Integrase Inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397188A (en) * | 2016-09-07 | 2017-02-15 | 张家港威胜生物医药有限公司 | Preparation method of L-chicoric acid |
| CN106397188B (en) * | 2016-09-07 | 2018-12-11 | 张家港威胜生物医药有限公司 | A kind of preparation method of L- Cichoric acid |
| CN113845422A (en) * | 2021-11-04 | 2021-12-28 | 山东中医药大学 | Process for preparing high-purity L-chicoric acid from echinacea purpurea in batches and application |
| CN113845422B (en) * | 2021-11-04 | 2024-01-30 | 山东中医药大学 | Process for preparing L-chicoric acid from Echinacea purpurea in batches and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103333942B (en) | A synthetic method for (R)-praziquantel | |
| CN111961018B (en) | Preparation method of high-purity butylphthalide | |
| CN109761867B (en) | Vitamin D production by using lanolin as raw material3Is a new method for industrialization | |
| CN102911022A (en) | Method for artificially synthesizing natural curcumin compound | |
| CN105152980A (en) | Chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid | |
| CN102702232A (en) | Method for preparation of fine cefamandole nafate | |
| CN111138443B (en) | Preparation method for total synthesis of 4' -demethylepipodophyllotoxin | |
| CN103601735B (en) | A kind of method of mosictin of purifying | |
| CN103408423A (en) | Nature active product L-cichoric acid synthesis process | |
| CN103012268B (en) | Novel preparation method for ivabradine | |
| CN104530090B (en) | A kind of preparation method of pyridine derivate | |
| CN103319356A (en) | One-step green synthesis process of antimalarial raw material benflumetol | |
| CN111349003B (en) | Preparation method of sodium valproate | |
| CN106397188B (en) | A kind of preparation method of L- Cichoric acid | |
| CN103709039B (en) | Method for synthesizing methyl (ethyl) gallate through catalysis of Cu-mordenite | |
| CN105218560B (en) | The synthesis technique of the chlorothiophene of 7 bromine 4 simultaneously [3,2 D] pyrimidine | |
| CN104356103A (en) | Synthetic method of 6, 7-dimethoxyl coumarin | |
| CN103044361B (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane | |
| CN102241658A (en) | Method for purifying gamma-mangostin by using high-speed countercurrent chromatography | |
| CN103012522B (en) | Purification process of astilbin | |
| CN102603819A (en) | Preparation method of rosavin | |
| CN103319454B (en) | Preparation method of high-purity tetraethyl ranelate and intermediate thereof | |
| CN101704724A (en) | Novel method for preparing high-proportion trans, trans-4-(4'-alkyl cyclohexyl) cyclohexyl alcohol liquid crystal intermediate compound | |
| CN105399718A (en) | Solid phase synthesis method of 2H-benzopyran compounds | |
| CN101880278B (en) | One-step method for synthesizing 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C05 | Deemed withdrawal (patent law before 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20131127 |