CN1666987A - Process for synthesizing luteolin - Google Patents
Process for synthesizing luteolin Download PDFInfo
- Publication number
- CN1666987A CN1666987A CNA2004100047907A CN200410004790A CN1666987A CN 1666987 A CN1666987 A CN 1666987A CN A2004100047907 A CNA2004100047907 A CN A2004100047907A CN 200410004790 A CN200410004790 A CN 200410004790A CN 1666987 A CN1666987 A CN 1666987A
- Authority
- CN
- China
- Prior art keywords
- luteolin
- dimethoxy
- dihydroxyflavone
- reaction
- pyridine
- 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.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention relates to a new method of synthesis common mignonette element. The initial material is phloroglucin, protective group is not needed, 3',4'-dimethoxy-5,7-ferrichrysin can be got after it directly condensated and cyclizated with 3,4-dimethoxy benzoyl acetic acid ethyl ester, then common mignonette element is got after catalysis demethylate by alchlor/ pyridine, the whole yield is 34.2%.
Description
Invention field
The present invention relates to organic medicinal chemistry and functional food chemical field, particularly, the present invention relates to the new complete synthesis manufacturing process of cough-relieving, expelling phlegm drugs and functional food luteolin.
Background technology
The chemistry of luteolin is by name: 3 ', 4 ', 5, and the 7-kaempferol; English name: Luteolin.Molecular formula: C
15H
10O
6Molecular weight: 286.24; CAS:[491-70-3].
Luteolin has another name called cinaroside unit, is the common effective ingredient of separating in the Herba Ajugae of effective herbal medicine gold Herba Dracocephali Integrifolii of Xinjiang treatment trachitis and Anhui product.Its natural product have been applied to the clinical treatment cough-relieving, have eliminated the phlegm, anti-inflammatory has curative effect preferably.But because natural product extraction yield is lower, purifying is difficult, and clinical application has certain difficulty.Also many about the report of semi-synthetic luteolin both at home and abroad.Semi-synthetic major part is to be starting raw material with the hesperidine, obtain luteolin (Xing Youquan etc. through dehydrogenation, hydrolysis, demethyl three-step reaction, Chinese Journal of Pharmaceuticals, 25 (11) 484-487), or with the hesperidine is that starting raw material is through hydrolysis, demethyl and dehydrogenation, obtain product (Sun Zhizhong etc. equally, contemporary Chinese is used pharmaceutical journal, 16 (1) 30-31,1999), the technological process more complicated, cost is higher.
The report of relevant complete synthesis luteolin mainly is cinnamophenone (Chalkone) route, and report (W.A.Hutchins, J.Chem.Soc, 91-94,1939) is abroad early arranged.Domestic have a report: with the Phloroglucinol be starting raw material routinely the Hoesch rule get 2,4, the 6-trihydroxy-acetophenone, go up dihydroxyl and the synthetic corresponding cinnamophenone of isovanillin condensation, 6 days consuming time with 4,6 of methyl protections, yield is on the low side, again through the cyclization oxidation, and the hydroiodic acid HI demethylation, the luteolin total recovery is 3-5% only, and there is byproduct aurones (also claiming to do), influences quality product (Lu Yuhua etc., Acta Pharmaceutica Sinica, 15 (8), 1980); Then have report to protect the phenolic hydroxyl group elder generation synthesizing chalcone of corresponding aldehyde, ketone by chloromethyl methyl ether, and then prepare the poly-hydroxy flavones, yield is increased to 22% (Ge Xia etc., Chinese Journal of Pharmaceuticals, 34 (4) 2003).But using the carcinogenic compound chloromethyl ether is inappropriate as protective material.
In addition; complete synthesis luteolin still has 1; 3 replace method (D.Nagarathnam et al, J.Org.Chem, 56 (16) of propane diketone; 4884-4887; 1991), intermediate is wanted the protected silane hydroxyl, uses LIHMDS polyanion lithium; reaction conditions is inflated with nitrogen and-78 ℃, is difficult to realize scale production.
In the complete synthesis process of luteolin, we have studied a large amount of documents and experimentation, unit process, with reference to 3 ', 4 '-benzyloxy-5 of Robert Te Wule, the synthetic method of 7-dihydroxyflavone, (Robert Teoule, etal, Bull.Soc.Chim.France, 546,1961) invented the new complete synthesis manufacture method of luteolin, and optimized technology by pilot scale.
Goal of the invention
The purpose of this invention is to provide a kind of direct be raw material and 3 with Phloroglucinol, 4-dimethoxy benzoyl acetic acid ethyl ester, down dealcoholysis dehydration of temperature in a vacuum, cyclization after the promptly first condensation obtains 3 ', 4 '-dimethoxy-5, the 7-dihydroxyflavone; Then at catalyst A lCl
3/ pyridine exists down, and two methyl sloughing on 3 ', 4 ' promptly obtain luteolin.
Summary of the invention
One of content of the present invention has provided a kind of with intermediate 3 ', 4 '-dimethoxy-5, and the method for 7-dihydroxyflavone demethylation is made luteolin:
The present invention is with 3 ', 4 '-dimethoxy-5, and the 7-dihydroxyflavone is a raw material, with aluminum chloride/pyridine is catalyzer, is solvent with the pyridine, carries out 3-5 hour reaction in temperature under as 160 ℃ of-180 ℃ of normal pressures, be hydrolyzed, wash, remove aluminium salt mother liquor then, obtain crude product, use DMF/H
2O and 95% ethyl alcohol recrystallization.
Two of content of the present invention has provided a kind of directly with Phloroglucinol and 3, and moderate temperature (as 140 ℃-160 ℃) is carried out condensation to 4-dimethoxy malonaldehydic acid ethyl ester under vacuum, cyclization prepares intermediate 3 ', 4 '-dimethoxy-5, the 7-dihydroxyflavone:
The present invention need not to protect two hydroxyls of Phloroglucinol; directly with 3 of easy preparation; 4-dimethoxy benzoyl acetic acid ethyl ester is in the presence of high boiling solvent such as phenyl ether or oil of mirbane; moderate temperature under vacuum (as 140 ℃-160 ℃) dealcoholysis dehydration down; obtained intermediate 3 ' in coreaction 6-7 hour; 4 '-dimethoxy-5,7-dihydroxyflavone, wherein vacuum tightness 1330Pa-6600Pa preferably.
3,4-dimethoxy benzoyl acetic acid ethyl ester is by (Wu Anxin etc., " chemical reagent ", 1998,20 (6), 376-377) preparation.
Advantage of the present invention is: technological process is brief, reaction conditions is gentle, and is easy to operate, makes suitability for industrialized production feasible, do not have the aurones by product substantially, and product quality is guaranteed, luteolin total recovery 34.2%, and the yield height is better than the method for other operational paths.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment
The preparation of embodiment one, luteolin
With 30Kg 3 ', 4 '-dimethoxy-5, the pure anhydrous pyridine of 7-dihydroxyflavone and 120Kg adds in the enamel reaction still, stir, make dissolving, heating slowly is increased to temperature about 100 ℃, add aluminum chloride in batches, a large amount of heat releases, controlled temperature is no more than 180 ℃, adds aluminum chloride in about 1 hour.Adding the back and reacted 3-5 hour between 160 ℃-180 ℃, whether complete, and definite reaction times if following the tracks of demethyl by high performance liquid phase.
With 1000Kg water suction hydrolysis kettle, be cooled to 10 ℃ in advance, while hot above-mentioned reactant is put into hydrolysis kettle and stirs, get rid of gas, cooling, separate in the whizzer crude product.Use the 50Kg cold water washing, use DMF/H
2O and 95% ethanol secondary recrystallization get luteolin 22.1Kg, yield 81%, and content HPLC 〉=98.5%, product and the contrast of natural luteolin, mass spectrum, infrared spectra are all consistent.
Embodiment two, 3 ', 4 '-dimethoxy-5, the preparation of 7-dihydroxyflavone
With 20Kg Phloroglucinol and 60Kg 3,4-dimethoxy benzoyl acetic acid ethyl ester adds in the enamel reaction still, stir, dissolve, heat, be warming up to 140 ℃-160 ℃, under vacuum (1330Pa) decompression, refluxed 2 hours, cold slightly input 80Kg phenyl ether, again under vacuum (6600Pa) decompression 140 ℃-160 ℃ back flow reaction 4-5 hour, cooling, when being chilled to 30 ℃, suction filtration is used 40Kg95% alcohol immersion 30 minutes, making beating, whizzer gets rid of filter, get 3 ', 4 '-dimethoxy-5, the yellow crude product 21Kg of 7-dihydroxyflavone.The mother liquor cooling is left standstill a small amount of again crude product of after-filtration, yield 42.2%, HPLC 〉=92%.This crude product can be used for demethylating reaction, needn't be further purified.
Claims (6)
2. according to the process of claim 1 wherein that temperature of reaction is 160 ℃-180 ℃.
3. according to the method for one of claim 1-2,3 ', 4 '-dimethoxy-5 wherein, the 7-dihydroxyflavone is by Phloroglucinol and 3, and 4-dimethoxy benzoyl acetic acid ester is in the presence of high boiling solvent, and the dealcoholysis dehydration prepares under the vacuum:
4. according to the method for claim 3, wherein solvent is phenyl ether or oil of mirbane.
5. according to the method for claim 4, wherein vacuum tightness is 1330Pa-6600Pa.
6. according to the method for one of claim 4-5, wherein temperature of reaction is 140 ℃-160 ℃.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2004100047907A CN1297552C (en) | 2004-03-11 | 2004-03-11 | Process for synthesizing luteolin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2004100047907A CN1297552C (en) | 2004-03-11 | 2004-03-11 | Process for synthesizing luteolin |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1666987A true CN1666987A (en) | 2005-09-14 |
CN1297552C CN1297552C (en) | 2007-01-31 |
Family
ID=35038295
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004100047907A Expired - Fee Related CN1297552C (en) | 2004-03-11 | 2004-03-11 | Process for synthesizing luteolin |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1297552C (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102010393A (en) * | 2010-11-09 | 2011-04-13 | 杭州福斯特药业有限公司 | Method for synthesizing 5,7-dihydroxyflavone |
US7947733B2 (en) | 2007-07-31 | 2011-05-24 | Limerick Biopharma | Phosphorylated pyrone analogs and methods |
CN103833714A (en) * | 2014-02-23 | 2014-06-04 | 闻永举 | Semi-synthesis method of luteolin and galuteolin as well as luteolin rutinoside |
CN109020940A (en) * | 2018-10-24 | 2018-12-18 | 陕西嘉禾生物科技股份有限公司 | A kind of synthetic method of scutellarin |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013111148A1 (en) * | 2011-12-13 | 2013-08-01 | Laurus Labs Private Limited | Process for preparation of luteolin |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR9914814A (en) * | 1998-10-30 | 2001-07-03 | Merck Patent Gmbh | Process for the preparation of luteolin and luteolin derivatives |
-
2004
- 2004-03-11 CN CNB2004100047907A patent/CN1297552C/en not_active Expired - Fee Related
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7947733B2 (en) | 2007-07-31 | 2011-05-24 | Limerick Biopharma | Phosphorylated pyrone analogs and methods |
CN102010393A (en) * | 2010-11-09 | 2011-04-13 | 杭州福斯特药业有限公司 | Method for synthesizing 5,7-dihydroxyflavone |
CN103833714A (en) * | 2014-02-23 | 2014-06-04 | 闻永举 | Semi-synthesis method of luteolin and galuteolin as well as luteolin rutinoside |
CN103833714B (en) * | 2014-02-23 | 2016-07-13 | 闻永举 | Luteolin, luteoloside, the semisynthetic method of luteolin rutinoside |
CN109020940A (en) * | 2018-10-24 | 2018-12-18 | 陕西嘉禾生物科技股份有限公司 | A kind of synthetic method of scutellarin |
Also Published As
Publication number | Publication date |
---|---|
CN1297552C (en) | 2007-01-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106167449B (en) | A kind of synthetic method of parahydroxyacet-ophenone | |
CN102653533B (en) | Total synthesis method of mangostin | |
CN101497567B (en) | Preparation of caffeic acid 3,4-dihydroxyphenyl ethyl ester and its derivative phenyl acrylic acid phenyl alkyl ester compound | |
Lee et al. | Total synthesis of puerarin, an isoflavone C-glycoside | |
CN1297552C (en) | Process for synthesizing luteolin | |
CN109336753B (en) | Synthetic method of alpha-benzyl substituted 1, 3-diketone compound | |
CN101519393A (en) | Novel method for preparing Scopoletin | |
CN102040636A (en) | Method for synthesizing beta-arbutin by adopting alpha-D-glucose pentaacetate | |
CN101684112A (en) | Preparation method of 5,6,7,4'-tetramethoxy flavones of scutellarin and aglucone key intermediate thereof | |
CN1304360C (en) | Preparation method of N,N-dimethyl-3-hydroxy-3-aryl propyl amine | |
CN102060826A (en) | Method for synthesizing 7-methoxyl-4'-substituted flavonoids compound | |
CN102276426A (en) | Novel synthetic method of 3, 4, 5-trihydroxystilbene | |
CN110128246B (en) | Preparation method of hydroxytyrosol | |
CN112939738B (en) | Preparation method of 3, 5-dihydroxypentylbenzene | |
CN110452109A (en) | A kind of method that phenol ether goes aromatization to prepare loop coil hexadiene ketone compounds | |
CN102557902A (en) | Preparation method for 5-fluorosalicylaldehyde | |
KR100446068B1 (en) | Process for preparation of gugulsterons | |
CN101033172A (en) | Method for modifying synthetic veratric alcohol | |
CN103864747B (en) | The total synthesis method of mangostin | |
CN101792451A (en) | Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A | |
CN105622350A (en) | Synthesis method of resveratrol | |
CN102127044A (en) | Method for synthesizing 5,7-dihydroxy flavone | |
CN112047970A (en) | Method for preparing boric acid derivative | |
CN111116339A (en) | Method for artificially synthesizing curcumin and derivatives thereof | |
CN104529726A (en) | Preparation method of hydroxyacetophenone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
DD01 | Delivery of document by public notice |
Addressee: Chen Xin Document name: Notification of Termination of Patent Right |
|
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070131 Termination date: 20100311 |