WO2006028068A1 - Methods of purifying l-carnitine - Google Patents

Methods of purifying 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
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Prior art keywords
lower alkyl
alkyl alcohol
water
carnitine
carcin
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PCT/JP2005/016293
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French (fr)
Japanese (ja)
Inventor
Takuhiro Kimura
Shinichi Ohsugi
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Wako Pure Chemical Industries, Ltd.
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Priority to JP2006535752A priority Critical patent/JP4967659B2/en
Publication of WO2006028068A1 publication Critical patent/WO2006028068A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38Separation; Purification; Stabilisation; Use of additives
    • C07C227/40Separation; Purification
    • C07C227/42Crystallisation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02Compounds 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
    • C07C229/04Compounds 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
    • C07C229/22Compounds 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

Abstract

Methods which yield L-carnitine having a large particle diameter and hence having reduced hygroscopicity and by which L-carnitine can be purified to a high purity. One of the methods for purifying L-carnitine is characterized by dissolving crude L-carnitine crystals in a mixed solvent comprising a lower alkyl alcohol and water and then recrystallizing the L-carnitine. The other comprises dissolving crude L-carnitine crystals in a mixed solvent comprising a lower alkyl alcohol and water and then adding an organic solvent other than the lower alkyl alcohol to recrystallize the L-carnitine.

Description

L—カルニチンの精製方法  Purification method of L-carnitine
技術分野  Technical field
[0001] 本発明は、 L-カルニチンの精製方法に関するものである。  [0001] The present invention relates to a method for purifying L-carnitine.
背景技術  Background art
[0002] L-カルニチンは脂肪燃焼に必須の生体常在成分の一つであり、脂肪代謝促進食 品を中心に現在様々な食品に添加されている。その L-カル-チンの製造方法及び 精製方法としては、例えば特開平 5-23190号公報ゃ特開平 5-117170号公報等に記 載されて!ヽるように様々な方法が試みられて!/ヽる。  [0002] 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. As 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.
[0003] しかしながら、これらの方法により得られた L-カル-チンは、粒径が小さいため(1〜 100 m)、吸湿性が高く小分けや製剤化する時の取り扱いが容易でない等の問題 点を有していた。そのため、取り扱いが容易な粒径の大きい L-カル-チンの簡易な 製造方法又は精製方法の開発が望まれて ヽた。  [0003] However, since 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.
[0004] 特許文献 1:平成 5年公開特許公報 23190号  [0004] Patent Document 1: Patent Publication No. 23190 published in 1993
特許文献 2:平成 5年公開特許公報 117170号  Patent Document 2: Patent Publication No. 117170 published in 1993
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0005] 本発明は上記状況に鑑み、 L-カル-チンの吸湿性を下げるために、粒径の大きい L-カル-チンが得られ、且つ L-カル-チンを高純度に精製し得る L-カル-チンの精 製方法の提供を課題とする。 [0005] In view of the above situation, 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.
課題を解決するための手段  Means for solving the problem
[0006] 本発明者等は、上記課題を解決するために鋭意研究を重ねた結果、粗結晶 L-力 ル-チンをアルキルアルコールに溶解させ、それを再結晶させることにより L-カル- チンを精製する方法にぉ 、て、低級アルキルアルコールと水との混合溶媒に粗結晶 L-カル-チンを溶解させた後に再結晶させることにより、精製された L-カル-チンの 粒径が大きくなること、並びに低級アルキルアルコールと混合する水の量によりその 粒径を制御できることを見出した。更に、検討を行った結果、粗結晶 L-カル-チンを 低級アルキルアルコールと水との混合溶媒に溶解させた後に低級アルキルアルコー ル以外の有機溶媒を添加して再結晶させることにより高い収率で粒径の大きな L-力 ルニチンが得られることを見出し、本発明を完成するに至った。 [0006] As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention dissolved L-force routine in alkyl alcohol and recrystallized it to dissolve L-carcin. In the method of purifying the product, 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. Furthermore, as a result of investigation, it was confirmed that crude crystalline L-carcin After dissolving in a mixed solvent of lower alkyl alcohol and water and then adding an organic solvent other than lower alkyl alcohol and recrystallizing it, it was found that L-force lunaritin with a large particle size can be obtained in high yield. The present invention has been completed.
[0007] 即ち、本発明は、「粗結晶 L-カル-チンを、低級アルキルアルコールと水との混合 溶媒に溶解させた後、再結晶させることを特徴とする L-カル-チンの精製方法」及び 「粗結晶 L-カル-チンを、低級アルキルアルコールと水との混合溶媒に溶解させた 後、更に当該低級アルキルアルコール以外の有機溶媒を添加して再結晶させる L- カル-チンの精製方法」に関する。 [0007] That is, 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".
発明の効果  The invention's effect
[0008] 本発明の精製方法によれば、精製時に用いる水の量 (L-カル-チンを溶解させた 低級アルキルアルコールと水との混合溶媒中の水分含量)を調節することで L-カル 二チンの粒径を制御できるので、純度が高く且つ粒径の大きい L-カル-チン、即ち、 吸湿性が低く取り扱いが容易な L-カル-チンを容易に得ることができる。更に、粗結 晶 L-カルニチンを低級アルキルアルコールと水との混合溶媒に溶解させた後に低級 アルキルアルコール以外の有機溶媒を添加して再結晶させることにより高い収率で 粒径の大きな L-カル-チンを得ることができる。  [0008] According to the purification method of the present invention, 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.
図面の簡単な説明  Brief Description of Drawings
[0009] 図 1は、実施例 3及び比較例 1で得られた L-カル-チンの結晶を用いた時のそれぞ れの吸湿率の変化を表したグラフである。  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.
符号の説明  Explanation of symbols
[0010] —♦—は、比較例 1で得られた L-カル-チンの吸湿性を、—國—は、実施例 3で得 られた L-カルニチンの吸湿性を表す。  [0010] — ♦ — represents the hygroscopicity of L-carnitine obtained in Comparative Example 1, and —country— represents the hygroscopicity of L-carnitine obtained in Example 3.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0011] 本発明の粗結晶 L-カル-チンとは、自体公知の方法、例えばファインケミカル 200 4年 4月号, Vol33, No.4, 5-18、し Tenud et al. EP 157.315 (1984)、 M. Kitamura et a 1. Tetrahedron Lett., 1988, 29, 1555— 1556.、 B. E. Rossiter et al. J. Org. Chem. 198 4, 3707、 K. Bock et al. Acta Chem. Scand. 1983, B37, 341.等に記載の方法により 製造された L-カル-チン等が挙げられる。 [0011] 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). M. Kitamura et a 1. Tetrahedron Lett., 1988, 29, 1555— 1556., BE Rossiter et al. J. Org. Chem. 198 4, 3707, K. Bock et al. Acta Chem. Scand. 1983, By the method described in B37, 341, etc. Examples include L-carcin produced.
[0012] 本発明に係る低級アルキルアルコールとしては、水と相溶し得るものであり、且つ L -カル-チンを容易に溶解し得るもの、好ましくは L-カル-チンを 100g/L以上溶解し 得るものであればよぐ通常炭素数が 1 6の置換基を有してもよいアルキルアルコ ール、好ましくは炭素数 1 3の置換基を有してもよいアルキルアルコール、より好ま しくは炭素数 2 3の置換基を有してもょ 、アルキルアルコール等が挙げられる。具 体的にはメタノール、エタノール、イソプロピルアルコール、 n—プロピルアルコール、 n—ブタノール、 n プタノール、 n キサノール等が挙げられ、中でも L-カル- チンを溶解し且つその溶解度が高すぎない、エタノール、イソプロピルアルコール等 が好ましぐエタノールが特に好ましい。  [0012] 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. As long as it can be used, 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. Among them, ethanol, which dissolves L-carcin and its solubility is not too high, Ethanol is particularly preferred, with isopropyl alcohol being preferred.
[0013] 本発明に係る低級アルキルアルコールと水との混合溶媒は、粗結晶 L-カル-チン を溶解させるために用いられるものである。また、ここでいう水とは通常この分野での 実験で用いられるものであれば特に限定されないが、例えば精製水、蒸留水、蒸留 精製水等を表す。  [0013] The mixed solvent of lower alkyl alcohol and water according to the present invention is used for dissolving crude crystalline L-carcin. In addition, 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.
[0014] 本発明に係る低級アルキルアルコール以外の有機溶媒 (以下、本発明に係る有機 溶媒と略記する場合がある)は、本発明に係る低級アルキルアルコール以外のもの であって上記低級アルキルアルコールと相溶し、且つ L-カル-チンを溶解しな 、又 は溶解しにく ヽものである。このような本発明に係る有機溶媒の L-カル-チンの溶解 度としては、通常 0. lgZml以下、好ましくは 0. 05gZml以下、より好ましくは 0. Olg Zml以下である。上記した性質を有する有機溶媒の中でも、 L-カル-チンが食品添 加物としてよく用いられることを考慮すると、毒性が低 、若しくは毒性を有さな!/、もの が好ましい。具体的には、例えばメチルェチルケトン、アセトン等のケトン、ジェチル エーテル、ジイソプロピルエーテル、テトラヒドロフラン、 1, 4 ジォキサン等のエーテ ル、ァセトニトリル、プロピオ-トリル等の-トリル、酢酸ブチル、酢酸ェチル等のエス テル、ジクロロ工タン、クロ口ホルム、ジクロロメタン等のハロゲン化炭化水素等が挙げ られ、中でも酢酸ェチルやアセトン等が好ましいものとして挙げられ、粒径の大きさを 制御しやす 、ものとして、酢酸ェチルが特に好まし 、。  [0014] 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. Among 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. Specifically, for example, 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. Among them, ethyl acetate and acetone are preferred, and the particle size can be easily controlled. Yetil is especially preferred.
[0015] 本発明の精製法は、粗結晶 L-カル-チンを低級アルキルアルコールと水との混合 溶媒に溶解させた後に、減圧濃縮等の方法により再結晶させることによりなされ、そ れにより、純度が高く且つ粒径の大きな精製 L-カル-チンを得ることができる。更に、 L-カルニチンを上記混合溶媒に溶解させた後、本発明に係る有機溶媒を添加して 再結晶させることにより、高い収率で上記のような純度が高く且つ粒径の大きい精製 L-カル-チンを得ることができる。尚、上記の粗結晶 L-カル-チンを低級アルキルァ ルコールと水との混合溶媒に溶解する方法としては、通常粗結晶 L-カル-チンを、 予め混合された低級アルキルアルコールと水との混合溶媒に溶解することにより行わ れる力 粗結晶 L-カル-チンを溶解した低級アルキルアルコール溶媒に水を添加混 合させることにより行ってもよい。本発明の精製法は、具体的には以下のようにしてな される。 [0015] 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. In addition, as a method for dissolving the above-mentioned crude crystalline L-cartine in a mixed solvent of lower alkyl alcohol and water, it is usual to mix crude crystalline L-cartine with a premixed lower alkyl alcohol and water. Force performed by dissolving in solvent It may be performed by adding and mixing water to a lower alkyl alcohol solvent in which crude crystalline L-carcin is dissolved. The purification method of the present invention is specifically performed as follows.
[0016] 即ち、先ず、粗結晶 L-カル-チンを低級アルキルアルコールと水との混合溶媒に、 必要であれば加熱して溶解する。尚、この際の水の量は、 L-カルニチンを溶解させ た低級アルキルアルコールと水との混合溶媒中の水の量 (水分含量) 1S 通常 0.5〜 10%、好ましくは 0.5〜6%、より好ましくは 0. 5〜4%、更に好ましくは 0. 5〜3%と なるようにすればよい。  [0016] That is, first, 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%.
[0017] その後、自体公知の再結晶方法により L-カル-チンを得ればよぐ具体的には、例 えば該溶解液を通常— 10〜30°Cで、要すれば減圧濃縮して結晶を析出させること により精製 L-カルニチンを得ることができる。  [0017] After that, it is sufficient to obtain 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.
[0018] 本発明に係る有機溶媒を添加する場合には、上記のように L-カル-チンを混合溶 媒に溶解した後、先ず、必要であれば減圧濃縮する。該濃縮により L-カル-チンの 飽和溶液とすることが好ましいが、通常全溶液量が 1Z3〜: LZ2倍量になるまで、好 ましくは 1Z3倍になるまで濃縮する。また、濃縮の際に L-カル-チンの結晶が析出 しても構わない。この濃縮後の溶液中の水分含量は、本発明に係る低級アルキルァ ルコールが蒸発するため、溶解時の値よりも多少上昇する力 通常 0. 5〜10%、好 ましくは 0.5〜6%、より好ましくは 0. 5〜4%、更に好ましくは 0. 5〜3%であれば問 題なく本発明の精製方法を行うことが出来る。また、 L-カルニチンが析出するまで濃 縮した場合、水が L-カル-チン結晶内に移行する可能性があるが、結晶が析出する 前の水分含量が上記範囲内であれば問題はない。その後、本発明に係る有機溶媒 を、濃縮後の全容液量の通常、 0. 5〜2. 0倍、好ましくは 1. 0〜1. 5倍の範囲で添 加し、通常 0〜10°C、好ましくは 0〜5°Cで 1〜2時間攪拌して結晶化することにより、 目的の精製 L-カル-チンを得ることができる。 [0018] 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%. In addition, when concentrated until L-carnitine precipitates, 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. . Then, 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.
[0019] より具体的には、例えば低級アルキルアルコールとしてエタノールを用い、上記本 発明に係る有機溶媒 (ここでは酢酸ェチル)を加える場合を例にとって、以下に説明 する。即ち、例えば粗結晶 L-カルニチンを、上記の如き水分含量となるように、ェタノ ールと水との混合溶媒に通常 40〜70°C、好ましくは 50〜60°Cで加熱して溶解し、 その後、該溶液を、通常 40〜70。C、好ましくは 50〜60。C、通常 80〜: LOOmmHG、 好ましくは 60〜70mmHGの圧力で減圧濃縮して L-カル-チンを飽和量まで溶解さ せたエタノール一水混合溶液とする。尚、この際、飽和溶液を更に濃縮しても構わな いが、その場合は、通常全溶液量が、最初にカ卩えた L-カル-チンとエタノール一水 混合溶液の総容量の 1Z3倍程度になるまで濃縮するのが好ましい。次いで、酢酸ェ チルを添加し、 0〜5°Cで 1〜2時間攪拌して結晶化する。この際に添加する酢酸ェ チルの量は、濃縮倍率により変動し、濃縮後の全容液量に対して通常 0. 5〜2. 0倍 、好ましくは 1. 0〜1. 5倍の範囲で適宜設定されればよい。その後、得られた結晶を 濾取し、例えば通常 70〜80°C、好ましくは 45〜55°C、通常 40〜60mmHG、好まし くは 10〜30mmHGで乾燥することによって目的の精製 L-カル-チンが得られる。  More specifically, for example, the case where ethanol is used as the lower alkyl alcohol and the organic solvent according to the present invention (here, ethyl acetate) is added will be described below as an example. That is, for example, 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. Then, 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. In this case, 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.
[0020] 本発明の精製方法に於いて用いられる低級アルキルアルコールの量は、用いられ る低級アルキルアルコールの種類によって多少異なる力 その下限は、少なくとも粗 結晶 L-カル-チンが溶解し得る量、即ち、粗結晶 L-カル-チン lgに対して通常 3ml 以上、好ましくは 3.5ml以上、より好ましくは 3.6mlである。また、多すぎても L-カル- チンを結晶化した際の収量が低下するので、その上限は粗結晶 L-カル-チン に 対して通常 10ml以下、好ましくは 8ml以下、より好ましくは 5ml以下である。尚、低級 アルキルアルコールとしてエタノールを用いる場合には、粗結晶 L-カル-チン lgに 対して、通常 3ml以上 10ml以下、好ましくは 3.6ml以上 5ml以下である。  [0020] 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.
[0021] 本発明の精製方法に於いて用いられる本発明に係る水の量は、 L-カルニチン溶液 の量に応じて前記水分含量となるように添加すればよい。尚、本発明の方法によれ ば、該水分含量を調節することにより得られる L-カル-チンの結晶の平均粒径を調 節することができ、例えば、低級アルキルアルコールとしてエタノールを用い、 L-カル 二チンを混合溶媒に溶解した後に減圧濃縮して飽和溶液とした場合に於!ヽて、 L-力 ル-チン溶解時の水分含量を 0. 1〜1%とすると平均粒径が150〜400 111、 1〜2 %とすると平均粒径が 300〜800 μ m、 2%以上とすると平均粒径が 150〜400 μ m の L-カル-チンを得ることが出来る。即ち、水分含量を調節することにより粒径の範 囲を特定して精製 L-カルニチンを得ることが可能となる。 [0021] 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. In addition, according to the method of the present invention, 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 μm, 2% when 1-2%. With the above, L-carcin having an average particle size of 150 to 400 μm can be obtained. That is, it is possible to obtain purified L-carnitine by specifying the particle size range by adjusting the water content.
[0022] 本発明の精製法に於ける本発明に係る有機溶媒の使用量は、 L-カル-チンを混 合溶媒に溶解した後に濃縮をしない場合には、最初に L-カル-チンを溶解するため に添加される低級アルキルアルコールの量に対して通常 0. 5〜2. 0倍量、好ましく は 1. 0〜1. 5倍量であればよい。また、濃縮する場合には、上記本発明の精製方法 の項で説明しているように、濃縮後の全容液量に対して通常 0. 5〜2. 0倍、好ましく は 1. 0〜1. 5倍の範囲で適宜設定されればよい。尚、本発明の精製法に於いては、 減圧濃縮する方が有機溶媒の使用量を抑えることができ、また、精製 L-カル-チン の収率を上げることができるので、より好まし 、方法である。  [0022] 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. In the case of 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. In the purification method of the present invention, 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.
[0023] 本発明の方法により得られる精製 L-カル-チンの平均粒径は、低級アルキルアル コールの種類や混合溶媒中の水分含量により異なる力 通常150〜1500 !^好ま し<【ま200〜1000 111、ょり好まし<【ま250〜800 111、更【こ好まし <ίま 300〜800 μ mである。粒径が 300 μ m以上となると、取り扱いが容易となるので特に好ましい。 尚、該平均粒径は上記のように混合溶媒中の水分含量を変化させることにより調節 することが出来る。  [0023] 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 μm. A particle size of 300 μm 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.
[0024] 本発明の方法によれば、粒径の大きな精製 L-カル-チンを、光学純度が 99%以上 [0024] According to the method of the present invention, purified L-cartine having a large particle size has an optical purity of 99% or more.
、好ましくは 100%で得ることが出来る。 Preferably, it can be obtained at 100%.
[0025] 以下に、比較例及び実施例を挙げて本発明を更に詳細に説明するが、本発明はこ れらにより何等限定されるものではない。 [0025] Hereinafter, the present invention will be described in more detail with reference to Comparative Examples and Examples, but the present invention is not limited to these in any way.
比較例 1  Comparative Example 1
[0026] L-カル-チン (光学純度 99%)30kgを無水エタノール 120Lに 50°Cで溶解させた後、 全容量が 95Lになるまで 50〜60°C、 62〜65mmHGで減圧濃縮した。次いで、酢酸ェ チル 60Lを添カ卩して 0〜5°Cで 1時間攪拌した後、生成物を濾取し、 70°C、 lOmmHGで 減圧乾燥して、 L-カル-チン 28.5kg (収率 95.0%)を得た。 [0026] 30 kg of L-cartine (optical purity 99%) was dissolved in 120 L of absolute ethanol at 50 ° C, and then concentrated under reduced pressure at 50 to 60 ° C and 62 to 65 mmHG until the total volume reached 95 L. Next, after adding 60 L of ethyl acetate and stirring at 0 to 5 ° C for 1 hour, the product was collected by filtration and filtered at 70 ° C and lOmmHG. After drying under reduced pressure, 28.5 kg (yield 95.0%) of L-carcin was obtained.
得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であり、極め て高純度であった。また、その平均粒子径をレーザー分光粒子径測定器 (MASTERS IZER2000, MALVERN社製)を用いて測定した結果、 74 μ mであった。  As a result of measuring the obtained L-carcin by HPLC, the optical purity was 100% ee, which was extremely high purity. In addition, 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 μm.
実施例 1  Example 1
[0027] L-カル-チン (光学純度 99%)10gを 95v/v%エタノール 20mLに 80°Cで溶解させ (溶液 中の水分含量: 5.2 w/w%)、更に 25°Cで 1時間攪拌した後、生成物を濾取し、 70°C、 10 mmHGで減圧乾燥して L-カル-チン 4.5g (収率 45.0%)を得た。  [0027] 10 g of L-carcin (optical purity 99%) was dissolved in 20 mL of 95v / v% ethanol at 80 ° C (water content in the solution: 5.2 w / w%), and further at 25 ° C for 1 hour After stirring, the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 4.5 g of L-cartine (yield 45.0%).
得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であり、極め て高純度であった。また、その平均粒子径をレーザー分光粒子径測定器 (MASTERS IZER2000, MALVERN社製)を用いて測定した結果、 335 μ mであった。  As a result of measuring the obtained L-carcin by HPLC, 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 μm.
実施例 2  Example 2
[0028] L-カル-チン (光学純度 99%)30gを、無水エタノール 108mL及び水 l.Ogに 50°Cで溶 解させた後 (溶液中の水分含量: 0.8 w/w%)、全容量が 54mLになるまで 50〜60°C、 62 〜65mmHGで減圧濃縮した。次いで、酢酸ェチル 60mLを添カ卩して 0〜5°Cで 1時間攪 拌した後、生成物を濾取し、 70°C、 lOmmHGで減圧乾燥して L-カル-チン 28.5g (収 率 95.0%)を得た。  [0028] 30 g of L-carcin (optical purity 99%) was dissolved in 108 mL of absolute ethanol and l.Og of water at 50 ° C (water content in the solution: 0.8 w / w%). The solution was concentrated under reduced pressure at 62 to 65 mmHG at 50 to 60 ° C until the volume reached 54 mL. Next, after adding 60 mL of ethyl acetate and stirring at 0-5 ° C for 1 hour, the product was collected by filtration, dried under reduced pressure at 70 ° C, lOmmHG, and 28.5 g of L-cartine (concentration). Rate 95.0%).
得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であり、極 めて高純度であった。また、その平均粒子径をレーザー分光粒子径測定器 (MASTE RSIZER2000, MALVERN社製)を用いて測定した結果、 200 μ mであった。  As a result of measuring the obtained L-cartine by HPLC, the optical purity was 100% ee, which was extremely high purity. Further, 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 μm.
実施例 3  Example 3
[0029] L-カル-チン (光学純度 99%)30kgを、無水エタノール 120L及び水 1.7kgに 50°Cで 溶解させた後 (溶液中の水分含量: 1.3 w/w%)、 50〜60°C、 62〜65mmHgで減圧濃縮 すると、エタノール力 ¾8L留去された時点で結晶が析出しはじめた (この時点での水分 含量: 1.3%)。更に、エタノールを留去し、残り全容量 54L (合計 96Lの留去)となるま で減圧濃縮した (この時点での水分含量: 1.4%、 L-カル-チン結晶析出量: 47.8%)。 次いで、酢酸ェチル 60Lを添加して 0〜5°Cで 1時間攪拌した後に生成物を濾取し、 70 °C、 1 OmmHGで減圧乾燥して L-カル-チン 28.7kg (収率 95.7 %)を得た。 得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であり、極 めて高純度であった。また、その平均粒子径をレーザー分光粒子径測定器 (MASTE RSIZER2000, MALVERN社製)を用いて測定した結果、 643 μ mであった。 [0029] After 30 kg of L-carcin (optical purity 99%) was dissolved in 120 L of absolute ethanol and 1.7 kg of water at 50 ° C (water content in the solution: 1.3 w / w%), 50-60 When the solution was concentrated under reduced pressure at ° C and 62-65 mmHg, crystals began to precipitate when 8 L of ethanol was distilled off (water content at this point: 1.3%). Further, ethanol was distilled off, and the residue was concentrated under reduced pressure until the remaining volume reached 54 L (96 L in total) (water content at this time: 1.4%, L-carcin crystal precipitation amount: 47.8%). Next, after adding 60 L of ethyl acetate and stirring at 0-5 ° C for 1 hour, 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. As a result, 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 μm.
実施例 4  Example 4
[0030] L-カル-チン (光学純度 99%)30gを、無水エタノール 108mL及び水 3.0gに 50°Cで溶 解させた後 (溶液中の水分含量: 2.3 w/w%)、全容量が 54mLになるまで 50〜60°C、 62 〜65mmHgで減圧濃縮した。次いで、酢酸ェチル 60mLを添カ卩して 0〜5°Cで 1時間攪 拌した後に生成物を濾取し、 70°C、 lOmmHGで減圧乾燥して L-カル-チン 27.9g (収 率 93.0%)を得た。  [0030] After 30 g of L-carcin (optical purity 99%) was dissolved in 108 mL of absolute ethanol and 3.0 g of water at 50 ° C (water content in the solution: 2.3 w / w%), the total volume The solution was concentrated under reduced pressure at 50 to 60 ° C. and 62 to 65 mmHg until the solution became 54 mL. Next, after adding 60 mL of ethyl acetate and stirring at 0-5 ° C for 1 hour, the product was collected by filtration, dried under reduced pressure at 70 ° C, lOmmHG, and 27.9 g (yield). 93.0%).
得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であり、極 めて高純度であった。また、その平均粒子径をレーザー分光粒子径測定器 (MASTE RSIZER2000, MALVERN社製)を用いて測定した結果、 360 μ mであった。  As a result of measuring the obtained L-cartine by HPLC, 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 μm.
実施例 5  Example 5
[0031] L-カル-チン (光学純度 99%)30gを、無水エタノール 108mL及び水 4.6gに 50°Cで溶 解させた後 (溶液中の水分含量: 3.8 w/w%)、全容量が 54mLになるまで 50〜60°C、 62 〜65mmHgで減圧濃縮した。次いで、酢酸ェチル 60mLを添カ卩して 0〜5°Cで 1時間攪 拌した後に生成物を濾取し、 70°C、 lOmmHGで減圧乾燥して L-カル-チン 25.7g (収 率 85.8%)を得た。  [0031] 30 g of L-carcin (optical purity 99%) was dissolved in 108 mL of absolute ethanol and 4.6 g of water at 50 ° C (water content in the solution: 3.8 w / w%), then the total volume The solution was concentrated under reduced pressure at 50 to 60 ° C. and 62 to 65 mmHg until the solution became 54 mL. Next, 60 mL of ethyl acetate was added, and the mixture was stirred at 0-5 ° C for 1 hour, and the product was collected by filtration, dried under reduced pressure at 70 ° C, lOmmHG, and 25.7 g (yield). 85.8%).
得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であり、極 めて高純度であった。また、その平均粒子径をレーザー分光粒子径測定器 (MASTE RSIZER2000、 MALVERN社製)を用いて測定した結果、 320 μ mであった。  As a result of measuring the obtained L-cartine by HPLC, the optical purity was 100% ee, which was extremely high purity. The average particle size was 320 μm as a result of measurement using a laser spectroscopic particle size measuring device (MASTE RSIZER2000, manufactured by MALVERN).
実施例 6  Example 6
[0032] L-カル-チン (光学純度 99%)30gを、無水エタノール 108mL及び水 6.45gに 40°Cで 溶解させた後 (溶液中の水分含量: 5.3 w/w%)、全容量が 54mLになるまで 50〜60°C、 62〜65mmHgで減圧濃縮した。次いで、酢酸ェチル 60mLを添加して 0〜5°Cで 1時間 攪拌した後に生成物を濾取し、 70°C、 lOmmHGで減圧乾燥して L-カル-チン 21.9g( 収率 73.2%)を得た。  [0032] 30 g of L-carcin (optical purity 99%) was dissolved in 108 mL of absolute ethanol and 6.45 g of water at 40 ° C (water content in the solution: 5.3 w / w%). The mixture was concentrated under reduced pressure at 50 to 60 ° C. and 62 to 65 mmHg until it reached 54 mL. Next, after adding 60 mL of ethyl acetate and stirring at 0-5 ° C for 1 hour, the product was collected by filtration, dried under reduced pressure at 70 ° C, lOmmHG, and 21.9 g of L-cartine (yield 73.2%) Got.
得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であり、極 めて高純度であった。また、その平均粒子径をレーザー分光粒子径測定器 (MASTE RSIZER2000, MALVERN社製)を用いて測定した結果、 314 μ mであった。 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 μm as a result of measurement using a laser spectral particle size measuring device (MASTE RSIZER2000, manufactured by MALVERN).
実施例 7  Example 7
[0033] L-カル-チン (光学純度 99%)30gを、無水イソプロパノール 120mL及び水 1.7gに 70 °Cで溶解させた後 (溶液中の水分含量: 1.3 w/w%)、全容量が 54mLになるまで 50〜60 。C、 62〜65mmHgで減圧濃縮した。次いで、酢酸ェチル 60mLを添加して 0〜5°Cで 1 時間攪拌した後に生成物を濾取し、 70°C、 lOmmHGで減圧乾燥して L-カル-チン 28 .2g (収率 94.0%)を得た。  [0033] After 30 g of L-carcin (optical purity 99%) was dissolved in 120 mL of anhydrous isopropanol and 1.7 g of water at 70 ° C (water content in the solution: 1.3 w / w%), the total volume was 50-60 until 54 mL. C, concentrated under reduced pressure at 62-65 mmHg. Next, after adding 60 mL of ethyl acetate and stirring at 0-5 ° C for 1 hour, the product was collected by filtration, dried under reduced pressure at 70 ° C, lOmmHG, and 28.2 g of L-cartine (yield 94.0% )
得られた L-カル-チンを HPLCで測定した結果、光学純度は 100%e.e.であった。 また、その平均粒子径をレーザー分光粒子径測定器(MASTERSIZER2000、 MALVE RN社製)を用いて測定した結果、 300 μ mであった。  As a result of measuring the obtained L-carcin by HPLC, the optical purity was 100% e.e. Further, 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 μm.
[0034] [表 1]  [0034] [Table 1]
実施例 8  Example 8
[0035] 実施例 3及び比較例 1で得られた L-カル-チンの結晶約 3gを電子天秤 (METTLER  [0035] About 3 g of the L-carcin crystals obtained in Example 3 and Comparative Example 1 were measured with an electronic balance (METTLER).
AE240)で精秤した後、該結晶を直径 8.5cm,高さ 2cmのシャーレ全体に広げ、温度: 2 0±2で,湿度:30±5%の条件で放置し、それぞれの吸湿率の変化を測定した。その結 果を図 1に示す。尚、吸湿率は以下の式より算出した。  AE240), and the crystal was spread over the whole petri dish with a diameter of 8.5 cm and a height of 2 cm, left at a temperature of 20 ± 2 and a humidity of 30 ± 5%, and each moisture absorption rate changed. Was measured. The results are shown in Fig. 1. The moisture absorption rate was calculated from the following equation.
吸湿率(%) = (増加重量 Zスタート重量) X 100  Moisture absorption (%) = (Increased weight Z Start weight) X 100
[0036] 上記結果から、明らかなように本発明に係る低級アルキルアルコールに水を少量添 加することにより、水を添加しない場合と比較して、得られる L-カル-チン結晶の平 均粒径が大きくなることが分力つた。また、無水イソプロパノールを用いた場合も水を 添加すると、 300 μ mという平均粒径の大きな L-カルニチンが得られることが分かった 。更に、吸湿性を比較した結果、平均粒径の大きい L-カル-チンの結晶は、その吸 湿性が低いことも分力つた。 [0036] From the above results, it is clear that by adding a small amount of water to the lower alkyl alcohol according to the present invention, the average grain size of the L-carcin crystals obtained compared to the case where water is not added. The increase in diameter contributed. In addition, water is also used when anhydrous isopropanol is used. When added, L-carnitine with a large average particle diameter of 300 μm was found to be obtained. Furthermore, as a result of comparing the hygroscopicity, it was found that L-carcin crystals having a large average particle size had a low hygroscopic property.

Claims

請求の範囲 The scope of the claims
[1] 粗結晶 L-カル-チンを、低級アルキルアルコールと水との混合溶媒に溶解させた後 [1] After dissolving crude crystalline L-carcin in a mixed solvent of lower alkyl alcohol and water
、再結晶させることを特徴とする L-カル-チンの精製方法。 A method for purifying L-cartine, which comprises recrystallization.
[2] 粗結晶 L-カルニチンを低級アルキルアルコールと水との混合溶媒に溶解させた後、 更に当該低級アルキルアルコール以外の有機溶媒を添加して再結晶させる、請求 項 1に記載の精製方法。 [2] The purification method according to claim 1, wherein the crude crystal L-carnitine is dissolved in a mixed solvent of a lower alkyl alcohol and water and then recrystallized by adding an organic solvent other than the lower alkyl alcohol.
[3] L-カルニチンを溶解させた低級アルキルアルコールと水との混合溶媒中の水分含量 力 .5〜10%である、請求項 1に記載の精製方法。 [3] The purification method according to claim 1, wherein the water content in the mixed solvent of lower alkyl alcohol and water in which L-carnitine is dissolved is 0.5 to 10%.
[4] 低級アルキルアルコールがエタノールである請求項 3に記載の精製方法。 4. The purification method according to claim 3, wherein the lower alkyl alcohol is ethanol.
[5] 有機溶媒が、 L-カル-チンを溶解しにくいものであって、且つ低級アルキルアルコー ルと相溶し得るものである請求項 2に記載の精製方法。 [5] The purification method according to claim 2, wherein the organic solvent is hardly soluble in L-cartine and is compatible with lower alkyl alcohol.
[6] 有機溶媒が酢酸ェチル又はアセトンである請求項 5記載の精製方法。 6. The purification method according to claim 5, wherein the organic solvent is ethyl acetate or acetone.
[7] 再結晶した L-カル-チンの平均粒径力 150〜1500 μ mである、請求項 2に記載の精 製方法。 [7] The refining method according to claim 2, wherein the recrystallized L-cartine has an average particle size of 150 to 1500 μm.
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JP2009102258A (en) * 2007-10-23 2009-05-14 Mitsubishi Rayon Co Ltd Method for purifying l-carnitine
JP2009102263A (en) * 2007-10-24 2009-05-14 Mitsubishi Rayon Co Ltd Method for isolating and purifying l-carnitine
JP2010059060A (en) * 2008-09-01 2010-03-18 Fancl Corp Carnitine-containing preparation
US20110118503A1 (en) * 2009-11-18 2011-05-19 Buechner Thomas Methods for the production of l-carnitine
CN102442918A (en) * 2011-11-03 2012-05-09 天津市汉康医药生物技术有限公司 Stable levocarnitine compound
JP2012092036A (en) * 2010-10-26 2012-05-17 Mitsubishi Rayon Co Ltd Method for producing salt of carnitine
EP2501673A1 (en) * 2009-11-18 2012-09-26 Lonza Ltd. Methods for the production of l-carnitine
KR20140019769A (en) * 2010-09-06 2014-02-17 론자 아게 (론자 엘티디.) Process for the production of l-carnitine tartrate
JP2015221807A (en) * 2009-11-18 2015-12-10 ロンザ リミテッドLonza Limited Method for producing l-carnitine

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JP2008231046A (en) * 2007-03-22 2008-10-02 Mitsubishi Rayon Co Ltd Method of purifying optically active carnitinamide halide
JP2009102258A (en) * 2007-10-23 2009-05-14 Mitsubishi Rayon Co Ltd Method for purifying l-carnitine
JP2009102263A (en) * 2007-10-24 2009-05-14 Mitsubishi Rayon Co Ltd Method for isolating and purifying l-carnitine
JP2010059060A (en) * 2008-09-01 2010-03-18 Fancl Corp Carnitine-containing preparation
US8604237B2 (en) * 2009-11-18 2013-12-10 Lonza Ltd Methods for the production of L-carnitine
EP2501673A1 (en) * 2009-11-18 2012-09-26 Lonza Ltd. Methods for the production of l-carnitine
JP2013511478A (en) * 2009-11-18 2013-04-04 ロンザ リミテッド Method for producing L-carnitine
US20110118503A1 (en) * 2009-11-18 2011-05-19 Buechner Thomas Methods for the production of l-carnitine
JP2015221807A (en) * 2009-11-18 2015-12-10 ロンザ リミテッドLonza Limited Method for producing l-carnitine
KR101823971B1 (en) * 2009-11-18 2018-01-31 론차리미티드 Methods for the production of L-carnitine
EP2501673B1 (en) * 2009-11-18 2018-02-14 Lonza Ltd. Methods for the production of L-carnitine
KR20140019769A (en) * 2010-09-06 2014-02-17 론자 아게 (론자 엘티디.) Process for the production of l-carnitine tartrate
KR101899015B1 (en) * 2010-09-06 2018-09-14 론자 리미티드 Process for the production of l-carnitine tartrate
JP2012092036A (en) * 2010-10-26 2012-05-17 Mitsubishi Rayon Co Ltd Method for producing salt of carnitine
CN102442918A (en) * 2011-11-03 2012-05-09 天津市汉康医药生物技术有限公司 Stable levocarnitine compound

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