WO2006028068A1 - Procedes de purification de la l-carnitine - Google Patents

Procedes de purification de la l-carnitine Download PDF

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Publication number
WO2006028068A1
WO2006028068A1 PCT/JP2005/016293 JP2005016293W WO2006028068A1 WO 2006028068 A1 WO2006028068 A1 WO 2006028068A1 JP 2005016293 W JP2005016293 W JP 2005016293W WO 2006028068 A1 WO2006028068 A1 WO 2006028068A1
Authority
WO
WIPO (PCT)
Prior art keywords
lower alkyl
alkyl alcohol
water
carnitine
carcin
Prior art date
Application number
PCT/JP2005/016293
Other languages
English (en)
Japanese (ja)
Inventor
Takuhiro Kimura
Shinichi Ohsugi
Original Assignee
Wako Pure Chemical Industries, 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 Wako Pure Chemical Industries, Ltd. filed Critical Wako Pure Chemical Industries, Ltd.
Priority to JP2006535752A priority Critical patent/JP4967659B2/ja
Publication of WO2006028068A1 publication Critical patent/WO2006028068A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms

Definitions

  • the present invention relates to a method for purifying L-carnitine.
  • L-carnitine is one of the living body indispensable components for fat burning, and is currently added to various foods, mainly fat metabolism promoting foods.
  • various methods for producing and purifying the L-carcin various methods have been tried as described in, for example, JP-A-5-23190 and JP-A-5-117170! / Speak.
  • L-carcin obtained by these methods has a small particle size (1 to 100 m), it has high hygroscopicity and is not easy to handle when subdivided or formulated. Had. Therefore, it has been desired to develop a simple production method or purification method for L-cartine having a large particle size that can be easily handled.
  • Patent Document 1 Patent Publication No. 23190 published in 1993
  • Patent Document 2 Patent Publication No. 117170 published in 1993
  • the present invention can obtain L-cartine having a large particle size and reduce L-cartine with high purity in order to reduce the hygroscopicity of L-cartine.
  • the objective is to provide a method for refining L-carcin.
  • the inventors of the present invention dissolved L-force routine in alkyl alcohol and recrystallized it to dissolve L-carcin.
  • the particle size of the purified L-cartine is increased by dissolving the crude crystal L-cartine in a mixed solvent of lower alkyl alcohol and water and then recrystallizing it. And the particle size can be controlled by the amount of water mixed with the lower alkyl alcohol.
  • the present invention relates to "a method for purifying L-cartine, characterized in that crude crystal L-cartine is dissolved in a mixed solvent of a lower alkyl alcohol and water and then recrystallized. ”And“ Purification of L-carcin, in which crude crystalline L-cartine is dissolved in a mixed solvent of lower alkyl alcohol and water, and then an organic solvent other than the lower alkyl alcohol is added and recrystallized. On “Method”.
  • the amount of water used during purification (the water content in a mixed solvent of a lower alkyl alcohol and water in which L-cartine is dissolved) is adjusted to adjust the amount of L-calcium. Since the particle size of nitine can be controlled, L-cartine having a high purity and a large particle size, that is, L-cartine having a low hygroscopic property and easy to handle can be easily obtained. Further, by dissolving crude crystalline L-carnitine in a mixed solvent of lower alkyl alcohol and water and then adding an organic solvent other than lower alkyl alcohol and recrystallizing, L-carnitine having a large particle size with high yield is obtained. -You can get chin.
  • FIG. 1 is a graph showing the change in moisture absorption when L-carcin crystals obtained in Example 3 and Comparative Example 1 were used.
  • ⁇ represents the hygroscopicity of L-carnitine obtained in Comparative Example 1
  • —country— represents the hygroscopicity of L-carnitine obtained in Example 3.
  • the crude crystalline L-cartine of the present invention is a method known per se, such as Fine Chemical, April 2004, Vol 33, No. 4, 5-18, and Tenud et al. EP 157.315 (1984).
  • Examples include L-carcin produced.
  • the lower alkyl alcohol according to the present invention is one that is compatible with water and that can easily dissolve L-cartine, preferably 100 g / L or more of L-carcin.
  • L-cartine preferably 100 g / L or more of L-carcin.
  • it is usually an alkyl alcohol which may have a substituent having 16 carbon atoms, preferably an alkyl alcohol which may have a substituent having 13 carbon atoms, more preferably An alkyl alcohol or the like may be used even if it has a C 23 substituent.
  • Specific examples include methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, n-butanol, n-xanol, etc.
  • ethanol which dissolves L-carcin and its solubility is not too high, Ethanol is particularly preferred, with isopropyl alcohol being preferred.
  • the mixed solvent of lower alkyl alcohol and water according to the present invention is used for dissolving crude crystalline L-carcin.
  • the water here is not particularly limited as long as it is usually used in experiments in this field. For example, it represents purified water, distilled water, distilled purified water, and the like.
  • the organic solvent other than the lower alkyl alcohol according to the present invention (hereinafter sometimes abbreviated as the organic solvent according to the present invention) is other than the lower alkyl alcohol according to the present invention, It is compatible and does not dissolve L-cartine or is difficult to dissolve.
  • the solubility of L-cartine in the organic solvent according to the present invention is usually at most 0.1 lgZml, preferably at most 0.05 gZml, more preferably at most 0. Olg Zml.
  • the organic solvents having the above-mentioned properties considering that L-cartine is often used as a food additive, those having low toxicity or non-toxicity are preferable.
  • ketones such as methyl ethyl ketone and acetone
  • ethers such as jetyl ether, diisopropyl ether, tetrahydrofuran and 1,4 dioxane
  • -tolyl such as acetonitrile, propio-tolyl
  • butyl acetate, ethyl acetate and the like examples include halogenated hydrocarbons such as ester, dichlorotechtane, black-form, and dichloromethane.
  • ethyl acetate and acetone are preferred, and the particle size can be easily controlled. Yetil is especially preferred.
  • the purification method of the present invention comprises mixing crude crystalline L-cartine with a lower alkyl alcohol and water. After dissolving in a solvent, recrystallization is performed by a method such as concentration under reduced pressure, whereby purified L-carcin having a high purity and a large particle size can be obtained. Further, after dissolving L-carnitine in the above mixed solvent, the organic solvent according to the present invention is added and recrystallized to obtain purified L- Carcin can be obtained.
  • crude crystalline L-cartine is dissolved in a mixed solvent of lower alkyl alcohol and water, if necessary, by heating.
  • the amount of water at this time is the amount of water in the mixed solvent of lower alkyl alcohol and water in which L-carnitine is dissolved (water content) 1S usually 0.5 to 10%, preferably 0.5 to 6%.
  • the content is preferably 0.5 to 4%, more preferably 0.5 to 3%.
  • L-carcin by a recrystallization method known per se. Specifically, for example, the solution is usually -10 to 30 ° C, and if necessary, concentrated under reduced pressure. Purified L-carnitine can be obtained by precipitating crystals.
  • the organic solvent according to the present invention When the organic solvent according to the present invention is added, after L-carcin is dissolved in the mixed solvent as described above, first, if necessary, it is concentrated under reduced pressure. It is preferable to obtain a saturated solution of L-carcin by the concentration, but usually the total solution is concentrated to 1Z3 to: LZ2 times, preferably 1Z3 times. In addition, L-carcin crystals may be precipitated during concentration.
  • the water content in the concentrated solution is a force that is slightly higher than the value at the time of dissolution because the lower alkyl alcohol according to the present invention evaporates, usually 0.5 to 10%, preferably 0.5 to 6%,
  • the purification method of the present invention can be carried out without any problem as long as it is more preferably 0.5 to 4%, and still more preferably 0.5 to 3%.
  • water may migrate into the L-carnitine crystals, but there is no problem if the water content before the crystals are precipitated is within the above range. .
  • the organic solvent according to the present invention Is usually added in the range of 0.5 to 2.0 times, preferably 1.0 to 1.5 times the total liquid volume after concentration, and usually 0 to 10 ° C, preferably 0 to 5 °.
  • the target purified L-carcin can be obtained by crystallization by stirring for 1-2 hours at C.
  • ethanol used as the lower alkyl alcohol and the organic solvent according to the present invention (here, ethyl acetate) is added
  • the organic solvent according to the present invention here, ethyl acetate
  • crude crystalline L-carnitine is dissolved in a mixed solvent of ethanol and water so that the water content is as described above, usually by heating at 40 to 70 ° C, preferably 50 to 60 ° C.
  • the solution is usually 40-70. C, preferably 50-60. C, usually 80 to: LOOmmHG, preferably 60 to 70 mmHG, and concentrated under reduced pressure to obtain a mixed ethanol / water solution in which L-carcin is dissolved to a saturated amount.
  • the saturated solution may be further concentrated, but in that case, the total amount of the solution is usually 1Z3 times the total volume of the L-carrot and ethanol monohydrate mixture initially prepared. It is preferred to concentrate to a degree. Then, ethyl acetate is added and the mixture is stirred at 0-5 ° C for 1-2 hours for crystallization. The amount of ethyl acetate added at this time varies depending on the concentration ratio, and is usually 0.5 to 2.0 times, preferably 1.0 to 1.5 times the total volume after concentration. What is necessary is just to set suitably. Thereafter, the obtained crystals are collected by filtration and dried at, for example, 70 to 80 ° C, preferably 45 to 55 ° C, usually 40 to 60 mmHG, preferably 10 to 30 mmHG. -Chin is obtained.
  • the amount of the lower alkyl alcohol used in the purification method of the present invention is somewhat different depending on the type of the lower alkyl alcohol used.
  • the lower limit is an amount at which at least crude L-carcin can be dissolved, That is, the amount is usually 3 ml or more, preferably 3.5 ml or more, more preferably 3.6 ml with respect to crude crystalline L-carcin lg. If the amount is too large, the yield when L-carcin is crystallized decreases, so the upper limit is usually 10 ml or less, preferably 8 ml or less, more preferably 5 ml or less for crude crystalline L-carcin. It is. When ethanol is used as the lower alkyl alcohol, the amount is usually 3 ml or more and 10 ml or less, preferably 3.6 ml or more and 5 ml or less with respect to the crude crystalline L-carcin lg.
  • the amount of water according to the present invention used in the purification method of the present invention may be added so as to have the water content according to the amount of the L-carnitine solution.
  • the average particle size of L-carcin crystals obtained by adjusting the water content is adjusted. For example, when ethanol is used as the lower alkyl alcohol and L-carnitine is dissolved in a mixed solvent and then concentrated under reduced pressure to obtain a saturated solution!
  • the average particle size is 150-400 111 when the water content at dissolution of L-force routine is 0.1-1%, and the average particle size is 300-800 ⁇ m, 2% when 1-2%.
  • L-carcin having an average particle size of 150 to 400 ⁇ m can be obtained. That is, it is possible to obtain purified L-carnitine by specifying the particle size range by adjusting the water content.
  • the amount of the organic solvent according to the present invention used in the purification method of the present invention is such that when L-cartine is dissolved in a mixed solvent and is not concentrated, L-cartine is first added.
  • the amount of the lower alkyl alcohol added for dissolution is usually 0.5 to 2.0 times, preferably 1.0 to 1.5 times the amount.
  • concentration as explained in the above section of the purification method of the present invention, it is usually 0.5 to 2.0 times the total volume after concentration, preferably 1.0 to 1. It may be set appropriately within the range of 5 times.
  • it is more preferable to concentrate under reduced pressure because the amount of organic solvent used can be reduced and the yield of purified L-carcin can be increased. Is the method.
  • the average particle size of the purified L-cartine obtained by the method of the present invention varies depending on the type of lower alkyl alcohol and the water content in the mixed solvent, usually 150 to 1500! ⁇ Preferable ⁇ 200-1000 111, Prefer ⁇ 250-800 111, Prefer ⁇ 300-300 ⁇ m. A particle size of 300 ⁇ m or more is particularly preferred because it is easy to handle. The average particle size can be adjusted by changing the water content in the mixed solvent as described above.
  • purified L-cartine having a large particle size has an optical purity of 99% or more.
  • the optical purity was 100% ee, which was extremely high purity.
  • the average particle size was measured using a laser spectral particle size measuring device (MASTERS IZER2000, manufactured by MALVERN), and as a result, it was 74 ⁇ m.
  • the optical purity was 100% ee, which was extremely high purity.
  • the average particle size was measured using a laser spectral particle size measuring device (MASTERS IZER2000, manufactured by MALVERN), and as a result, it was 335 ⁇ m.
  • the optical purity was 100% ee, which was extremely high purity.
  • the average particle size was measured using a laser spectral particle size measuring device (MASTE RSIZER2000, manufactured by MALVERN), and as a result, it was 200 ⁇ m.
  • the product was collected by filtration, dried under reduced pressure at 70 ° C and 1 OmmHG, and 28.7 kg of L-cartine (yield 95.7% )
  • the obtained L-carcin was measured by HPLC.
  • the optical purity was 100% ee, which was extremely high.
  • the average particle size was measured using a laser spectroscopic particle size measuring device (MASTE RSIZER2000, manufactured by MALVERN). As a result, it was 643 ⁇ m.
  • the optical purity was 100% ee, which was extremely high purity.
  • the average particle size was measured using a laser spectroscopic particle size measuring device (MASTE RSIZER2000, manufactured by MALVERN). As a result, it was 360 ⁇ m.
  • the optical purity was 100% ee, which was extremely high purity.
  • the average particle size was 320 ⁇ m as a result of measurement using a laser spectroscopic particle size measuring device (MASTE RSIZER2000, manufactured by MALVERN).
  • the obtained L-carcin was measured by HPLC. As a result, the optical purity was 100% ee. High purity.
  • the average particle size was 314 ⁇ m as a result of measurement using a laser spectral particle size measuring device (MASTE RSIZER2000, manufactured by MALVERN).
  • the optical purity was 100% e.e.
  • the average particle size was measured using a laser spectral particle size measuring device (MASTERSIZER2000, manufactured by MALVE RN), and as a result, it was 300 ⁇ m.
  • Moisture absorption (%) (Increased weight Z Start weight) X 100

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des procédés de production de L-carnitine ayant un diamètre de particule élevé et ayant ainsi une hygroscopie réduite et par lesquels la L-carnitine peut être purifiée à une haute pureté. Un des procédés de purification de la L-carnitine est caractérisé par la dissolution de cristaux de L-carnitine brute dans un solvant mixte comprenant un alcool alkylique inférieur et de l'eau puis par la recristallisation de la L-carnitine. Les autres procédés comprennent la dissolution de cristaux de L-carnitine brute dans un solvant mixte comprenant un alcool alkylique inférieur et de l'eau puis l'adjonction d'un solvant organique autre que l'alcool alkylique inférieur pour recristalliser la L-carnitine.
PCT/JP2005/016293 2004-09-08 2005-09-06 Procedes de purification de la l-carnitine WO2006028068A1 (fr)

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Application Number Priority Date Filing Date Title
JP2006535752A JP4967659B2 (ja) 2004-09-08 2005-09-06 Ｌ−カルニチンの精製方法

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JP2004-260613 2004-09-08

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008231046A (ja) * 2007-03-22 2008-10-02 Mitsubishi Rayon Co Ltd 光学活性カルニチンアミドハロゲン化物の精製方法
JP2009102258A (ja) * 2007-10-23 2009-05-14 Mitsubishi Rayon Co Ltd Ｌ−カルニチンの精製方法
JP2009102263A (ja) * 2007-10-24 2009-05-14 Mitsubishi Rayon Co Ltd Ｌ−カルニチンの単離精製方法
JP2010059060A (ja) * 2008-09-01 2010-03-18 Fancl Corp カルニチン含有製剤
US20110118503A1 (en) * 2009-11-18 2011-05-19 Buechner Thomas Methods for the production of l-carnitine
CN102442918A (zh) * 2011-11-03 2012-05-09 天津市汉康医药生物技术有限公司 稳定的左卡尼汀化合物
JP2012092036A (ja) * 2010-10-26 2012-05-17 Mitsubishi Rayon Co Ltd カルニチンの塩の製造方法
EP2501673A1 (fr) * 2009-11-18 2012-09-26 Lonza Ltd. Procédés de production de l-carnitine
KR20140019769A (ko) * 2010-09-06 2014-02-17 론자 아게 (론자 엘티디.) L-카르니틴 타르트레이트의 제조방법
JP2015221807A (ja) * 2009-11-18 2015-12-10 ロンザ リミテッドＬｏｎｚａ Ｌｉｍｉｔｅｄ Ｌ−カルニチンの製造方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59183694A (ja) * 1983-04-05 1984-10-18 Hamari Yakuhin Kogyo Kk 光学活性なカルニチンの生化学的製造法
JPS63185947A (ja) * 1987-01-26 1988-08-01 Kanegafuchi Chem Ind Co Ltd カルニチンの精製法
JP2000516967A (ja) * 1997-07-28 2000-12-19 サムソン ファイン ケミカルズ カンパニ リミテッド Ｌ−カルニチンの製造方法

Family Cites Families (1)

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JPS6191160A (ja) * 1984-10-09 1986-05-09 Nisshin Flour Milling Co Ltd Ｌ−カルニチンの製造法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59183694A (ja) * 1983-04-05 1984-10-18 Hamari Yakuhin Kogyo Kk 光学活性なカルニチンの生化学的製造法
JPS63185947A (ja) * 1987-01-26 1988-08-01 Kanegafuchi Chem Ind Co Ltd カルニチンの精製法
JP2000516967A (ja) * 1997-07-28 2000-12-19 サムソン ファイン ケミカルズ カンパニ リミテッド Ｌ−カルニチンの製造方法

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008231046A (ja) * 2007-03-22 2008-10-02 Mitsubishi Rayon Co Ltd 光学活性カルニチンアミドハロゲン化物の精製方法
JP2009102258A (ja) * 2007-10-23 2009-05-14 Mitsubishi Rayon Co Ltd Ｌ−カルニチンの精製方法
JP2009102263A (ja) * 2007-10-24 2009-05-14 Mitsubishi Rayon Co Ltd Ｌ−カルニチンの単離精製方法
JP2010059060A (ja) * 2008-09-01 2010-03-18 Fancl Corp カルニチン含有製剤
US8604237B2 (en) * 2009-11-18 2013-12-10 Lonza Ltd Methods for the production of L-carnitine
EP2501673A1 (fr) * 2009-11-18 2012-09-26 Lonza Ltd. Procédés de production de l-carnitine
JP2013511478A (ja) * 2009-11-18 2013-04-04 ロンザ リミテッド Ｌ−カルニチンの製造方法
US20110118503A1 (en) * 2009-11-18 2011-05-19 Buechner Thomas Methods for the production of l-carnitine
JP2015221807A (ja) * 2009-11-18 2015-12-10 ロンザ リミテッドＬｏｎｚａ Ｌｉｍｉｔｅｄ Ｌ−カルニチンの製造方法
KR101823971B1 (ko) * 2009-11-18 2018-01-31 론차리미티드 Ｌ-카르니틴의 제조 방법
EP2501673B1 (fr) * 2009-11-18 2018-02-14 Lonza Ltd. Procédés pour la production de L-carnitine
KR20140019769A (ko) * 2010-09-06 2014-02-17 론자 아게 (론자 엘티디.) L-카르니틴 타르트레이트의 제조방법
KR101899015B1 (ko) * 2010-09-06 2018-09-14 론자 리미티드 L-카르니틴 타르트레이트의 제조방법
JP2012092036A (ja) * 2010-10-26 2012-05-17 Mitsubishi Rayon Co Ltd カルニチンの塩の製造方法
CN102442918A (zh) * 2011-11-03 2012-05-09 天津市汉康医药生物技术有限公司 稳定的左卡尼汀化合物

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