WO2007138607A1 - Méthode permettant d'obtenir de l'acide shikimique - Google Patents

Méthode permettant d'obtenir de l'acide shikimique Download PDF

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Publication number
WO2007138607A1
WO2007138607A1 PCT/IN2006/000176 IN2006000176W WO2007138607A1 WO 2007138607 A1 WO2007138607 A1 WO 2007138607A1 IN 2006000176 W IN2006000176 W IN 2006000176W WO 2007138607 A1 WO2007138607 A1 WO 2007138607A1
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Prior art keywords
shikimic acid
solution
water
aqueous
methanol
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Ceased
Application number
PCT/IN2006/000176
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English (en)
Inventor
Sankar V. Iyer
Vasudeva Pejakala
Karabasanagouda
Shivananda Wagle
Lingappa Balaya
Mahalakshmi Kanaka
Mahanthaswamy Hiremath
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/50—Use of additives, e.g. for stabilisation

Definitions

  • this invention relates to a method of extraction of shikimic acid from natural plants. More specifically but without restriction to the particular embodiment of the
  • Shikimic acid is a non-nitrogenous acid found in various plants naturally. It has two kinds of functional groups in the same molecule, three hydroxyl groups , and, carboxylic acid groups, which are optically active. They can yield various kinds of esters ,and salts.
  • Shikimic acid is a cyclitol, a polyhydroxylated cycloalkane containing at ' least three hydroxyl groups in the ring at different positions.
  • the most important feature of cyclitol is that they aic chiral isomers, key intermediates in the biosynthesis of ' aromatic compounds in living metabolism.
  • Shikimic acid is a key intermediate in the biochemical pathway from phosphoenolpyruvic acid to tyrosine.
  • Shikimic acid is a precursor to many alkaloids, aromatic amino acids and indole derivatives. Shikimic acid is widely used as a chiral building block for tlie synthesis of pharmaceuticals.
  • An example of end product is an antiviral drug jOseltamivir, a neuraminidase inhibitor used in the treatment and prophylaxis of both influenza A and influenza B.
  • jOseltamivir a neuraminidase inhibitor used in the treatment and prophylaxis of both influenza A and influenza B.
  • Recently methods have been reported for chemical synthesis of Shikimic acid but laige scale economical synthesis is still not possible. Thus star aniseeds remain the sole souicc of Shikimic acid for the industry.
  • Literature methods (Sadaka, Marian, Garcia, Antonio, Motorola, semiconductor products sector, Tempe AZ, OSA, chemical engineering communication .(1999), 173 91-102) involved tridodccylamine used as the extractant and 1-heptanol'as the diluent. Tridodccyl amine complexes with the acid resulting in an acid amine complex, which is solvatcd by alcohol diluents. Li the back extraction, Oleic acid was added to the organic r- ' phase as a displacement, oleic acid competitively displaces the carboxylic acid in the acid-amine complex. The process however, depends on back extraction and involves handling of Tridodecylamine and 1-Heptanol which is expensive.
  • Shikimic acid extraction is provided in "Isolation of Shikimic acid from star aniseeds, Journal of chemical education VoI 82 No 4 April 2005.
  • the process mentioned involves the extraction of plant material with ethanol using 24" Soxhlet extraction and subsequent purification using anion exchange and Solka-Floc.
  • the presence of the carboxylic acid functionality in the structure of Shikimic acid allows ion exchange chromatography to be utilized in the purification of Shikimic acid.
  • the main disadvantage in this method is that ethanol is relatively costly solvent, increases cost of extraction for Shikimic acid.
  • Another disadvantage of this method is that for obtaining Shikimic acid ion exchange resin is unavoidable which increases the cost and time cycle of the extraction.
  • Shikimic acid is isolated from the dried powdered seeds and carpels of the Japanese Star anise (Illicium anizatum). The process involves grounding the seeds to 30 mesh, stirring the powder for 3 hrs with 1400 cc CHCI 3 , followed by filtering the filter cake (20 Kg) and stirring it for 2 days with 2 successive 95 ltr portion of 95% ethanol. The solution is then filtered and the filtrate is concentrated to 18 ltr. This filtrate then let stand for several days deposited 600 gms crude Shikimic acid. The disadvantage of this process is the work up time and usage of huge volume of ethanol. Another disadvantage of this method is low yield.
  • JP 2000351750 to Katsuhirot discloses a method for selective isolation of shikimic acid, the method comprising efficiently and selectively isolating and purifying the subject compound in high yield by mixing a solution containing shikimic acid with ammonia or an amine, then isolating the shikimic acid as an amine salt, subsequently decomposing the amine salt and isolating the shikimic acid, wherein solution is prepared by using Escherichia coli according to fermentation.
  • a fermenting method or the like using a microorganism cam be used as the above solution containing the shikimic acid.
  • the solvent used for the solution of the shikimic acid is preferably a polar solvent
  • the amine is used in an amount of preferably 1-3 mol equivalents based on the total amount of the shikimic acid.
  • US Patent Application No. 20030138920 Al to Malmberg, Mats et al. discloses the method of isolating high purity pccas from a fermentation broth through the addition of concentrated acetic, lactic and/or propionic acid to the broth.
  • the preferred pcca is shikimic acid.
  • Said method comprising concentrating the aqueous solution of said pcca to a concentration of at least 250 grams of said pcca per liter; combiningrsaid 1 concentrated pcca with at least one acid selected from the group consisting of acetic acid, lactic acid, propionic acid and mixtures thereof to form a pcca/acid slurry; and, isolating saidicrystals from said slurry.
  • US Patent Application No. 20040009242 Al discloses a method for selectively extracting one or more non-acidic compounds from plant tissue in the presence of one or more acidic compounds.
  • the method comprising contacting a mixture of a basic component and a first solvent with the plant tissue to immobilize the acidic compound as a salt on the plant tissue; and contacting the plant tissue with a second solvent suitable to remove the one or more non-acidic compounds; thereby effectively providing a solution comprising the one or more non-acidic compounds, the said method further comprising contacting the plant tissue with an acid in a third solvent, to neutralize the salt and to remove the one or more acidic compounds from the plant tissue, wherein said acidic compounds include shikimic acid.
  • the reference discloses the use of isopropanol as a solvent in combination with acetic acid for extraction of acidic compounds.
  • the reference also discloses that water may be present during the extraction, as presence of water enhances the solubility of shikimic acid in the organic solvent.
  • the water content may be between 0 and 10%, most preferably 0 and 3%.
  • the fermentation process becomes cumbersome in practice.
  • Further object of the present invention is to provide an economical method to obtain shikimic acid in a high yield.
  • a method for extraction of shikimic acid from the natural plants wherein said plants are selected from the member of Magnolia family (Magnoliaceae), preferably star- shaped multiple fruit of a small oriental tree (Illicium verum).
  • a method for extraction of shikimic acid from star aniseeds comprising extracting shikimic acid- from dried star aniseeds using at least one aqueous polar solvent, concentrating the extract to recover the polar solvent, adding excess of water to the concentrate to prepare an aqueous solution, separating impurities from the aqueous solution by addition of at least one water immiscible polar solvent, adding at least one color absorbing substance to the solution, filtering the solution and concentrating the solution to obtain pure shikimic acid.
  • a method for extracting the shikimic acid wherein used star aniseeds of Illium verum is dried and milled and is continuously refluxed with an aqueous polar solvent, wherein the solvent in the method is recovered and reused, hence providing an economical method.
  • a method to extract shikimic acid using natural plants wherein the impurities from said aqueous solution are separated by addition of at least one water immiscible polar solvent, preferably with ethyl acetate and the remaining impurities are removed by precipitation by the addition of preferably 37% formaldehyde solution.
  • the shikimic acid extracted by the process can be used as a precursor for the synthesis of many pharmaceutical products including the antiviral drug for avian bird flue, Oseltamivir.
  • Star aniseed used in the method disclosed herein the present invention is star-shaped fruit or seed of a small oriental tree (Illicium verum).
  • the plant contains a small star- shaped fruit with eight points, and a seed is contained in each of the points.
  • Star anise can be used whole as a flavoring, its seeds can be used as a flavoring, and both are ground.
  • the fruit is antibacterial, carminative, diuretic, odontalgic, stimulant, and, stomachic. It is taken internally in 1he treatment of abdominal pain, digestive 1 disturbances and complaints such as lumbago. ,
  • the extraction according to the method disclosed herein the present invention is carried out by continuous reflux over a period of six to ten hours in presence of iso propyl alcohol.
  • Isopropyl alcohol is five to eight fold volume of the star aniseeds.
  • the ratio of water and iso propyl alcohol is in the range of 5:98 to 10:95.
  • Most preferably the aqueous solvent used is 5% aqueous isopropyl alcohol.
  • An enriched extract is obtained by using water and Isopropyl alcohol with less amount of other substances being also extracted.
  • the said extraction process may be repeated 2 to 3 times using same solvent ratios to ensure maximum extraction.
  • the concentration of the resultant extract according to the method disclosed herein could be carried out using various techniques well known in ⁇ e art.
  • the technique used for concentrating in the present invention is preferably distillation under vacuum.
  • the concentrated solution is diluted with water, wherein the amount of water used is preferably two to three times the star aniseed input.
  • the shikimic acid solution after extraction is treated with water immiscible polar solvents two to five times to separate the impurities and other fragments of extraction.
  • the water immiscible polar solvent used in the process is selected from ethyl acetate, toluene or methylisobutylketone, preferably ethyl acetate.
  • said extract is re-treated employing 37% formaldehyde solution.
  • aqueous phase is treated with 15-20% w/v of any color absorbing substance, wherein said color absorbing substance is selected from fuller's earth, clay or charcoal, preferably activated charcoal.
  • said brown liquid obtained after removal of activated charcoal by filtration is optionally subjected to complete evaporation.
  • the method disclosed herein provides concentrating the resultant extract upon purification employing about 0.5 to 1.0- fold volume of polar a solvent, wherein said polar solvent is preferably methanol, distilling the resultant mixture to remove any traces of water, refluxing the resultant with methanol for 30 minutes to two hours, preferably 45 minutes.
  • the volume of methanol used is 0.75 to 0.125 volume of the star aniseeds, preferably 0.1 volume of the star aniseeds. Cooling the resultant solution to 10 to -5 0 C, preferably 0 to -5 0 C for 2-5 hours to obtain pure Shikimic acid.
  • the residue after water distillation can directly be used for crystallization by adding 0.1 volume of methanol followed by heating and cooling the fraction.
  • the method does not require chromatography or ion exchange resin. Hence the process is simple and economical.
  • the yield of shikimic acid is 3.5 to 5.0%.
  • 5% aqueous IPA was more efficient for extracting Shikimic acid in less time period as compared to ethanol and methanol. On the basis of lower cost and rapid work up 5%- aqeous.IPA will be a suitable solvent.
  • Example-2 Dry powdered star aniseeds (50 g) were extracted by refiuxing for a period of 4 hrs with 250 ml water at 100°C temp. The extract was washed with ethyl acetate to remove impurities. The water layer is charcolized and concentrated under vacuum to obtain the residue (5 g). To the residue, methanol was added and heated and then cooled to obtain crude Shikimic acid (2 g). On purification, the pure Shikimic acid obtained was 600 mg. ExampIe-3
  • Dried powdered star aniseeds 400 g were extracted by refluxing over a period of 6 hrs with 5 fold volume (2000 ml) of 95% aqueous IPA. The extract was filtered and the residual star aniseeds were again refiuxed for 4 hrs with 95% aqueous FPA. The extracts are combined and concentrated to dryness under vacuum. The residue was dissolved in DM water (900 ml). The oily layer formed was separated. The water layer was washed with ethyl acetate 4 times (1200 ml). The water layer was treated with 37% formaldehyde solution. The precipitated impurities at 80°C were removed by filtration. The water layer was treated with color absorbing activated charcoal (60 g).
  • the present invention has the advantage that it is rapid and simple.
  • the use of isopropyl alcohol is economical as compared to ethanol described in ⁇ rior art methods. Also the solvent used, in the process can be recovered.
  • the extract obtained by using isopropyl alcohol is rich in shikimic acid and contains less of other constituents.
  • the final residue is used for crystallization of shikimic acid with methanol without column chromatography or ion exchange thus the entire process is less time consuming and economical.
  • the yield of shikimic acid obtained is also high.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une méthode simple et économique permettant d'extraire de l'acide shikimique avec un rendement élevé à partir de badianes, à l'aide d'un solvant polaire aqueux, ledit solvant polaire utilisé étant de l'isopropanol. Par ailleurs, le solvant utilisé dans cette méthode est par la suite récupéré et réutilisé.
PCT/IN2006/000176 2006-05-25 2006-05-25 Méthode permettant d'obtenir de l'acide shikimique Ceased WO2007138607A1 (fr)

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PCT/IN2006/000176 WO2007138607A1 (fr) 2006-05-25 2006-05-25 Méthode permettant d'obtenir de l'acide shikimique

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107857699A (zh) * 2017-11-10 2018-03-30 浙江工业大学上虞研究院有限公司 一种从八角中提取莽草酸的工艺
CN109369373A (zh) * 2018-12-18 2019-02-22 长江师范学院 一种从银杏叶提取物层析废液中制备莽草酸提取物的方法
CN110511135A (zh) * 2019-09-25 2019-11-29 长江师范学院 一种采用壳聚糖吸附-分离莽草酸的方法
WO2020139057A3 (fr) * 2018-12-28 2020-08-20 연세대학교 산학협력단 Composition pour prévenir et traiter une maladie musculaire ou améliorer la fonction musculaire, comprenant un extrait d'illicium verum ou de l'acide shikimique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EIJKMAN ET AL: "SUR LES PRINCIPES CONSTITUANTS DE L'ILLICIUM RELIGIOSUM (SIEB.) (SHIKIMI-NO-KI EN JAPONAIS)", 1885, RECUEIL DES TRAVAUX CHIMIQUES DES PAYS-BAS, ELSEVIER SCIENCE PUBLISHERS. AMSTERDAM, NL, PAGE(S) 32-54, ISSN: 0165-0513, XP001248814 *
PAYNE ET AL: "ISOLATION OF SHIKIMIC ACID FROM STAR ANISEED", JOURNAL OF CHEMICAL EDUCATION, AMERICAN CHEMICAL SOCIETY, US, vol. 82, no. 4, 2005, pages 599 - 600, XP009076494, ISSN: 0021-9584 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107857699A (zh) * 2017-11-10 2018-03-30 浙江工业大学上虞研究院有限公司 一种从八角中提取莽草酸的工艺
CN109369373A (zh) * 2018-12-18 2019-02-22 长江师范学院 一种从银杏叶提取物层析废液中制备莽草酸提取物的方法
CN109369373B (zh) * 2018-12-18 2021-01-08 长江师范学院 一种从银杏叶提取物层析废液中制备莽草酸提取物的方法
WO2020139057A3 (fr) * 2018-12-28 2020-08-20 연세대학교 산학협력단 Composition pour prévenir et traiter une maladie musculaire ou améliorer la fonction musculaire, comprenant un extrait d'illicium verum ou de l'acide shikimique
CN110511135A (zh) * 2019-09-25 2019-11-29 长江师范学院 一种采用壳聚糖吸附-分离莽草酸的方法
CN110511135B (zh) * 2019-09-25 2022-01-25 长江师范学院 一种采用壳聚糖吸附-分离莽草酸的方法

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