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WO2007010838A1 - Procédé servant à produire un sel de métal alcalinoterreux de l'acide (-)-hydroxycitrique - Google Patents

Procédé servant à produire un sel de métal alcalinoterreux de l'acide (-)-hydroxycitrique Download PDF

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Publication number
WO2007010838A1
WO2007010838A1 PCT/JP2006/314024 JP2006314024W WO2007010838A1 WO 2007010838 A1 WO2007010838 A1 WO 2007010838A1 JP 2006314024 W JP2006314024 W JP 2006314024W WO 2007010838 A1 WO2007010838 A1 WO 2007010838A1
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WIPO (PCT)
Prior art keywords
earth metal
alkaline earth
hydrate
metal salt
acid
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.)
Ceased
Application number
PCT/JP2006/314024
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English (en)
Japanese (ja)
Inventor
Shinji Yoshikawa
Shoichi Komai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Shinyaku Co Ltd
Original Assignee
Nippon Shinyaku Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nippon Shinyaku Co Ltd filed Critical Nippon Shinyaku Co Ltd
Priority to JP2007525985A priority Critical patent/JP4998264B2/ja
Publication of WO2007010838A1 publication Critical patent/WO2007010838A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

  • the present invention relates to an alkaline earth metal salt (hereinafter referred to as "compound (1)”) represented by the following general structural formula (1): (1) -hydroxyquenic acid (hereinafter referred to as "HCA”) Or a new method for producing the hydrate.
  • compound (1) alkaline earth metal salt represented by the following general structural formula (1): (1) -hydroxyquenic acid (hereinafter referred to as "HCA”) Or a new method for producing the hydrate.
  • HCA is known as a substance abundant in the skin of Garcinia, and inhibits ATP citrate lyase, one of the enzymes on the pathway to synthesize citrate fat. It is known to be useful in the treatment of obesity because it suppresses the increase in fat mass (see, for example, Patent Document 1).
  • HCA can be obtained by extraction from the skin of Garcinia by the method of Lewis, YS, and the like, and its salt can be obtained from HCA by a conventional method (for example, , Non-Patent Document 1, Non-Patent Document 2, and Patent Document 2;).
  • HCA and its salts can be produced according to the method described in Patent Documents 3, 4, 5, 6, 7 in addition to the method of Lewis, Y. S. et al.
  • these methods cannot remove all impurities such as bectin and organic acids such as citrate, malic acid and tartaric acid, and it is difficult to produce high-purity HCA and the like.
  • the calcium salt of HCA can be produced by reacting an excess amount of calcium hydroxide with garcinia extract.
  • pectin contained in the extract forms a hard gel with calcium hydroxide. It is also known to obtain a high-purity substance because citrate and maleic acid form calcium salts that are sparingly soluble in water. It is difficult with the manufacturing method.
  • Patent Document 1 US Patent No. 3764692
  • Patent Document 2 Indian Patent No. 160753
  • Patent Document 3 Pamphlet of International Publication No. 99Z03464
  • Patent Document 4 US Patent No. 6875891
  • Patent Document 5 International Publication No. 2004Z100682 Pamphlet
  • Patent Document 6 US Pat. No. 6,160,172
  • Patent Document 7 European Patent No.866866
  • Non-patent literature l "Phytochemistry, 1965, 4 ⁇ , p. 619—625
  • Non-Patent Document 2 Lewis, Y. S. et al., “Methods In Enzymology”, 1969, 13 ⁇ , p. 613-617
  • An object of the present invention is mainly to provide a novel production method for obtaining a highly pure compound (1).
  • high purity means 96% or more, preferably 98% or more, and more preferably 99% or more.
  • compound (2) an alkaline earth metal salt of a rataton HCA represented by the following general structural formula (2), which is an intermediate of compound (1). Or a production method for easily obtaining the hydrate thereof with high purity.
  • Examples of the present invention include a method for producing compound (1) or a hydrate thereof having at least the following steps a to e.
  • Step b A step of depositing a product by leaving or cooling the reaction solution of Step a
  • Step c A step of obtaining the precipitate
  • Step d a step of reacting the obtained precipitate with an alkaline earth metal salt or hydrate thereof and a base
  • Step e A step of obtaining an alkaline earth metal salt of HCA or a hydrate thereof from the reaction solution in step d.
  • the present invention can include a method for producing compound (2) or a hydrate thereof having at least the following steps a 'to c'.
  • Step a Alkaline earth metal oxide or alkaline earth metal hydroxide in a range of 0.5 times or more and less than 0.9 times in molar ratio to Garcinia extract and HCA contained in Garcinia Reacting the product or its hydrate,
  • Step b ′ a step of depositing a product by leaving or cooling the reaction liquid in step a ′
  • step c ′ a step of acquiring the precipitate and recrystallizing the acquired precipitate.
  • Fig. 1 shows a chromatogram obtained by HPLC analysis.
  • the vertical axis represents time (minutes) and the horizontal axis represents absorption intensity.
  • FIG. 2 Shows the chromatogram obtained by HPLC analysis.
  • the vertical axis represents time (minutes) and the horizontal axis represents absorption intensity.
  • FIG. 3 Shows a chromatogram obtained by HPLC analysis.
  • the vertical axis represents time (minutes) and the horizontal axis represents absorption intensity.
  • FIG. 4 A chromatogram obtained by HPLC analysis is shown.
  • the vertical axis represents time (minutes) and the horizontal axis represents absorption intensity.
  • FIG. 5 A chromatogram obtained by HPLC analysis is shown. In the figure, the vertical axis represents time (minutes) and horizontal The axis indicates the absorption intensity.
  • FIG. 6 A chromatogram obtained by HPLC analysis is shown.
  • the vertical axis represents time (minutes) and the horizontal axis represents absorption intensity.
  • FIG. 7 shows a chromatogram obtained by HPLC analysis.
  • the vertical axis represents time (minutes) and the horizontal axis represents absorption intensity.
  • FIG. 8 shows a chromatogram obtained by HPLC analysis.
  • the vertical axis represents time (minutes) and the horizontal axis represents absorption intensity.
  • Ganorescinia extract is an extract that contains a large amount of HCA. It can be obtained by performing an extraction operation.
  • Garcinia extract contains a small amount of strength, for example, polysaccharides such as pectin, and organic acids such as citrate, lingoic acid and tartaric acid. Even a garshi layer containing such impurities can be used in the present invention.
  • Garcinia extract is marketed as an aqueous solution containing HCA in the range of 10% to 70% by weight.
  • examples of such commercial products include Garcinia Extract S (manufactured by Nippon Shinyaku Co., Ltd.), Garcitric Gold (registered trademark) (manufactured by Renaissance Herb (USA), Citrin (registered trademark) (manufactured by Sabinsa (USA)). Citrimax (registered trademark) (manufactured by Interhealth (USA)).
  • the concentration of HCA contained in the garcinia extract is suitably within the range of 5% to 90% by weight, preferably within the range of 7% to 80% by weight, more preferably 10% to 70% by weight. Is within the range. If necessary, water may be added to adjust the concentration of HCA contained in the Garcinia extract.
  • Garcinia extract and alkaline earth metal hydroxide or alkaline earth metal hydroxide The reaction with the hydrate is carried out by, for example, stirring the garcinia extract and the alkaline earth metal oxide or alkaline earth metal hydroxide or hydrate in an aqueous solution while heating and stirring. Can be performed. At that time, if necessary, an appropriate amount of activated carbon may be added.
  • the “alkaline earth metal oxides” include acid calcium.
  • Examples of the “alkaline earth metal hydroxide or hydrate thereof” include calcium hydroxide or a hydrate thereof. Among these, calcium hydroxide dihydrate is particularly preferable.
  • the amount of the alkaline earth metal oxide or alkaline earth metal hydroxide or hydrate thereof is not particularly limited as long as the reaction solution does not show basicity.
  • the molar ratio with respect to HCA contained in the Garcinia extract is suitably in the range of 0.5 times or more and less than 0.9 times, preferably in the range of 0.7 times or more and less than 0.9 times, more preferably 0.
  • the amount of activated carbon used varies depending on the garcinia extract used, but is suitably in the range of 1 to 10% by weight with respect to the HCA contained in the garcinia extract, preferably 2 It is in the range of 7% by weight to 7% by weight, more preferably in the range of 3% to 4% by weight.
  • the reaction temperature varies depending on the concentration of HCA contained in the Garcinia extract and the amount of alkaline earth metal oxide or alkaline earth metal hydroxide used. Usually 20 ° C to 10 ° C
  • the range of 0 ° C is suitable, preferably within the range of 40 ° C to 95 ° C, more preferably 60 ° C.
  • reaction time varies depending on the reaction temperature, etc., it is suitable within the range of 1 minute to 24 hours.
  • This step can be performed, for example, by leaving the reaction solution of step a as it is at room temperature after completion of the reaction of step a. It can also be carried out by cooling the reaction solution in step a, and it is preferable to cool it rather than leaving it at room temperature.
  • the effective cooling temperature is usually in the range of 10 ° C to 30 ° C, preferably in the range of 5 ° C to 25 ° C. Within the range, more preferably within the range of 0 ° C to 20 ° C.
  • the cooling time is suitably in the range of 1 minute to 48 hours, preferably in the range of 10 minutes to 36 hours, and more preferably in the range of 20 minutes to 24 hours.
  • This step can be performed by performing a filtration operation by a conventional method.
  • the precipitates that can be produced in this step c are substantially free of impurities such as bectin, which is a polysaccharide, citrate, malic acid, tartaric acid, which are organic acids, which have been difficult to remove completely until now. Contained in a way.
  • This step can be carried out, for example, by dissolving the precipitate obtained in step c with heating in water, adding an alkaline earth metal salt or hydrate thereof and a base, and stirring with heating. If necessary, a filtering operation can be performed after adding the alkaline earth metal salt.
  • the amount of water used is, for example, suitably in the range of 5 to 100 times by weight with respect to the precipitate, preferably in the range of 10 to 70 times, more preferably 20 to 40 times. Within double range.
  • alkaline earth metal salts include calcium salts.
  • examples of the “calcium salt” include calcium chloride, calcium sulfate, calcium carbonate, and calcium bromide. Of these, calcium chloride dihydrate is particularly preferred.
  • the amount of the alkaline earth metal salt or hydrate thereof used is, for example, suitably in the range of 0.40 times to 0.70 times, preferably 0.45 times the molar ratio to the precipitate. Within the range of ⁇ 0.65 times, more preferably within the range of 0.50 times to 0.660 times.
  • base examples include amines such as aqueous ammonia, pyridine, and trimethylamine.
  • the amount of base used is, for example, suitably in the range of 0.5 to 2.0 times in molar ratio to the precipitate, preferably in the range of 0.9 to 1.5 times, More preferably, it is in the range of 1.0 times to 1.2 times.
  • the reaction temperature is usually within the range of 20 ° C to 100 ° C, preferably 30 ° C to 9 ° C. It is within the range of 5 ° C, more preferably within the range of 40 ° C to 90 ° C.
  • the reaction time varies depending on the reaction temperature and the like, but is suitably in the range of 1 minute to 12 hours, preferably in the range of 5 minutes to 7 hours, and more preferably in the range of 10 minutes to 2 hours.
  • the compound (1) in the reaction liquid in the step d can be obtained by performing a known solid-liquid separation operation.
  • the compound (1) can be washed with water.
  • the solid-liquid separation operation include a filtration operation, a dehydration operation using a centrifuge, or a juicer.
  • the compound (1) can be further purified. Specifically, the purity can be further increased by, for example, stirring the water of 10 to 20 times by weight with respect to the obtained compound (1) and performing the above solid-liquid separation operation. it can. If necessary, the mixture may be heated and stirred within a range of 40 ° C to 60 ° C.
  • the compound (1) obtained by performing the solid-liquid separation operation contains a large amount of water, it is preferable to perform a drying operation.
  • drying operation examples include drying under reduced pressure.
  • the vacuum force for example, 1. 0xl0 _13 Pa ⁇ l. 0xl0 5 Pa and is suitably within the range of, the good Mashiku 1. 0xl0 _9 Pa ⁇ l. 0xl0 4 within the Pa, more preferably 1. 0xl0 " 5 Pa ⁇ l. Within the range of 0xl0 3 Pa.
  • the drying temperature is, for example, suitably in the range of 50 ° C to 140 ° C, preferably in the range of 60 ° C to 130 ° C, more preferably in the range of 70 ° C to 120 ° C. .
  • the drying time is suitably in the range of 1 hour to 96 hours, preferably in the range of 12 hours to 72 hours, more preferably in the range of 24 hours to 48 hours.
  • step c the precipitate produced in step c from which impurities such as bectin, a polysaccharide, and organic acids such as citrate, malic acid, and tartaric acid are removed is used. Therefore, the highly pure compound (1) can be easily obtained.
  • the compound (1) produced in the present invention uses only water as a reaction solvent and a washing solvent used in the production process, methanol, ethanol, butanol, chloroform, methylene chloride, acetonitrile, Dimethylformamide, acetone, dimethyl Since organic solvents such as til sulfoxide are not used, there is no concern about residual solvents that are harmful to humans and animals.
  • This step is the same as step a in I above.
  • This process is the same as the process b in I above.
  • This step can be carried out by recrystallizing the precipitate after performing a filtration operation by a conventional method to obtain the precipitate.
  • the compound (2) can be produced by cooling and recrystallization.
  • the effective cooling temperature is usually in the range of 10 ° C to 30 ° C, preferably in the range of 5 ° C to 25 ° C, more preferably in the range of 0 ° C to 20 ° C.
  • the cooling time is suitably in the range of 1 minute to 48 hours, preferably in the range of 10 minutes to 36 hours, and more preferably in the range of 20 minutes to 24 hours.
  • the compound (2) that can be produced in this step has been difficult to completely remove until now, such as polysaccharides bectin, organic acids such as citrate, malic acid, tartaric acid, etc. Contain substantially no impurities.
  • the compound (2) produced in the present invention uses only water as the reaction solvent and washing solvent used in the production process, methanol, ethanol, butanol, chloroform, methylene chloride, acetonitrile, Since organic solvents such as dimethylformamide, acetone, and dimethyl sulfoxide are not used, there is no concern about residual solvents that are harmful to humans and animals.
  • Example 1 While stirring 30 mL of water in 20 g of Garcinia Extract (Garcitric Gold (registered trademark) Liquid; made in Renaissance Herbnet (USA); containing 60.75 wt% as HCA), 3.03 g, 3.46 g, 3. Add 89g, 4.33g or 4.76g of calcium hydroxide and 85. Each reaction solution stirred for 30 minutes at C was allowed to stand at 5 ° C for 2 days, and the resulting precipitate was collected by filtration. The results are shown in Table 1.
  • H PLCJ high performance liquid chromatography
  • HPLC system Liquid feed: LC-7A (manufactured by Shimadzu Corporation)
  • SPD 10AV (manufactured by Shimadzu Corporation)
  • UV-visible spectrometer detection wavelength 210nm
  • peak 1 represents impurities contained in the mobile phase
  • peak 2 represents HCA ratatones
  • peak 3 represents HCA
  • peak 4 represents the organic acid citrate.
  • Example 1 only the mobile phase used was analyzed by HPLC. Mouth matogram was obtained.
  • Example 2 As a result of HPLC analysis of the garcinia extract used in Example 1, a chromatogram as shown in FIG. 2 was obtained. It was confirmed that the garcinia extract contained at least citrate (a substance having a retention time of about 8 minutes) as an impurity.
  • Example 1 the results of using 0.9% molar ratio of calcium hydroxide to HCA contained in the Garcinia extract used in Fig. 5 are used in Example 1.
  • Fig. 6 shows the results when calcium hydroxide is used at a molar ratio of HCA contained in Garcinia extract.
  • Example 1,! / The precipitate obtained when using 0.9 times the molar ratio of calcium hydroxide and calcium hydroxide with respect to the HCA contained in the Garcinia extract used, It was confirmed that the impurity citrate (peak 4 in Figs. 5 and 6) was included.
  • Example 1 the result of using 0.7% molar ratio of calcium hydroxide with respect to HCA contained in the Garcinia extract used in FIG. 3 is used in Example 1.
  • Figure 4 shows the results of using 0.8 times the molar ratio of calcium hydroxide relative to the HCA contained in Garcinia extract.
  • Example 1! Precipitates obtained when calcium hydroxide with a molar ratio of 0.8 times or less with respect to HCA contained in the used Garcinia extract has been difficult to remove completely until now.
  • impurities such as polysaccharides such as bectine, organic acids such as citrate, malic acid and tartaric acid were not included.
  • Example 1 each precipitate obtained when 0.7 times and 0.8 times the molar ratio of calcium hydroxide was used with respect to the HCA contained in the Garcinia extract used in Example 1. 10 mL of water was added, dissolved by heating at 90 ° C, and then the precipitate obtained by standing was subjected to HPLC measurement and measurement of the amount of calcium contained in the precipitate. The amount of calcium contained in the precipitate was measured according to a known method using 0.05M ethylenediamine tetraacetic acid aqueous solution. It was confirmed that the recrystallized precipitates were only HCA rataton calcium salts (peak 2 in Figs. 7 and 8) (see Figs. 7 and 8).
  • the filtrate was allowed to stand overnight at 5 ° C, and 1.5 kg of the deposited precipitate (HCA rataton calcium salt) was collected by filtration.
  • the amount of calcium contained in the precipitate was measured according to a known method using 0.05 M ethylenediamine tetraacetic acid aqueous solution.
  • the obtained crude calcium salt of HCA was charged with 8.25 L of water, heated to 50 ° C. and stirred for 5 minutes, and then subjected to solid-liquid separation with a centrifuge for 10 minutes. The obtained solid was collected and the same purification operation was performed again. The obtained solid was dried at 100 ° C for 1 hour, and then the solid was pulverized, and then dried at 80 ° C for 41 hours and 115 ° C for 7 hours to obtain 0.62 kg of the target compound (yield: 53% ).
  • compound (1) Since no organic solvent is used in the production process of compound (1), compound (1) can be produced safely and at low cost, and there is no concern about residual organic solvent. In addition, since a precipitate from which impurities such as citrate, malic acid, tartaric acid, etc., which are organic acids, such as bectin, which is a polysaccharide contained in Garcinia extract, is removed, a high-purity compound ( 1) can be manufactured.

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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

Nouveau procédé servant à produire des sels de métaux alcalinoterreux de l'acide (-)-hydroxycitrique (ci-après appelés 'composés (1)') représentés par la formule de structure générale : (1) où M est un métal alcalinoterreux. L'invention concerne un procédé servant à produire des composés (1), comprenant les étapes consistant à faire réagir un extrait de Garcinia cambogia avec un oxyde de métal alcalinoterreux ou un hydroxyde de métal alcalinoterreux ou un hydroxyde de ceux-ci en proportion molaire de 0,5 à 0,9 fois la quantité d'acide (-)-hydroxycitrique contenue dans Garcinia cambogia, de préférence refroidir après cela, et recueillir le dépôt résultant ; et à faire réagir le dépôt recueilli avec un sel de métal alcalinoterreux et une base et séparer les composés (1).
PCT/JP2006/314024 2005-07-15 2006-07-14 Procédé servant à produire un sel de métal alcalinoterreux de l'acide (-)-hydroxycitrique Ceased WO2007010838A1 (fr)

Priority Applications (1)

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JP2007525985A JP4998264B2 (ja) 2005-07-15 2006-07-14 （−）−ヒドロキシクエン酸のアルカリ土類金属塩の製造法

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JP2005-207259 2005-07-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099413A3 (fr) * 2007-02-16 2009-04-16 Vittal Mallya Scient Res Found Dérivés de sel de métal de l'acide (-) hydroxycitrique de grande pureté et leur procédé de préparation
EP3762357A4 (fr) * 2018-03-07 2021-12-08 Glykon Technologies Group, LLC Composés hétérocycliques métalliques d'acide hydroxycitrique présentant des caractéristiques covalentes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015051A1 (fr) * 1998-09-14 2000-03-23 Interhealth Nutraceuticals, Inc. Compositions d'acide hydroxycitrique
US20040229953A1 (en) * 2003-05-12 2004-11-18 Gokaraju Ganga Raju Process for preparing highly water soluble double salts of hydroxycitric acid particularly alkali and alkaline earth metal double salts
WO2004100682A1 (fr) * 2003-05-19 2004-11-25 Indfrag Limited Nouvelle composition de sel de metal complexe d'acide garcinique, methode de preparation et d'utilisation de la composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015051A1 (fr) * 1998-09-14 2000-03-23 Interhealth Nutraceuticals, Inc. Compositions d'acide hydroxycitrique
US20040229953A1 (en) * 2003-05-12 2004-11-18 Gokaraju Ganga Raju Process for preparing highly water soluble double salts of hydroxycitric acid particularly alkali and alkaline earth metal double salts
WO2004100682A1 (fr) * 2003-05-19 2004-11-25 Indfrag Limited Nouvelle composition de sel de metal complexe d'acide garcinique, methode de preparation et d'utilisation de la composition

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099413A3 (fr) * 2007-02-16 2009-04-16 Vittal Mallya Scient Res Found Dérivés de sel de métal de l'acide (-) hydroxycitrique de grande pureté et leur procédé de préparation
EP2125691A4 (fr) * 2007-02-16 2012-02-01 Vittal Mallya Scient Res Foundation Dérivés de sel de métal de l'acide (-) hydroxycitrique de grande pureté et leur procédé de préparation
EP3762357A4 (fr) * 2018-03-07 2021-12-08 Glykon Technologies Group, LLC Composés hétérocycliques métalliques d'acide hydroxycitrique présentant des caractéristiques covalentes
US11292759B2 (en) 2018-03-07 2022-04-05 Nutrition Research Group, Limited Hydroxycitric acid metal heterocyclic compounds with covalent characteristics
US11795187B2 (en) 2018-03-07 2023-10-24 Glykon Technologies Group, Llc Hydroxycitric acid metal heterocyclic compounds with covalent characteristics

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JP4998264B2 (ja) 2012-08-15

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