JP4967659B2 - Method for purifying L-carnitine - Google Patents
Method for purifying L-carnitine Download PDFInfo
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- JP4967659B2 JP4967659B2 JP2006535752A JP2006535752A JP4967659B2 JP 4967659 B2 JP4967659 B2 JP 4967659B2 JP 2006535752 A JP2006535752 A JP 2006535752A JP 2006535752 A JP2006535752 A JP 2006535752A JP 4967659 B2 JP4967659 B2 JP 4967659B2
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims description 110
- 238000000034 method Methods 0.000 title claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 39
- 239000002245 particle Substances 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 239000012046 mixed solvent Substances 0.000 claims description 22
- 239000013078 crystal Substances 0.000 claims description 20
- 238000000746 purification Methods 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 18
- 230000003287 optical effect Effects 0.000 description 17
- 238000001914 filtration Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 230000003595 spectral effect Effects 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960004203 carnitine Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
Description
本発明は、L-カルニチンの精製方法に関するものである。 The present invention relates to a method for purifying L-carnitine.
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-カルニ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号公報や特開平5-117170号公報等に記載されているように様々な方法が試みられている。 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 a method for producing and purifying L-carnitine, various methods have been tried as described in, for example, JP-A-5-23190 and JP-A-5-117170.
しかしながら、これらの方法により得られたL-カルニチンは、粒径が小さいため（1〜100μｍ）、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-カルニチンの簡易な製造方法又は精製方法の開発が望まれていた。 However, since L-carnitine obtained by these methods has a small particle size (1 to 100 μm), it has problems such as high hygroscopicity and difficulty in handling when subdividing and formulating. Therefore, development of a simple production method or purification method of L-carnitine having a large particle size that is easy to handle has been desired.
本発明は上記状況に鑑み、L-カルニチンの吸湿性を下げるために、粒径の大きいL-カルニチンが得られ、且つL-カルニチンを高純度に精製し得るL-カルニチンの精製方法の提供を課題とする。 In view of the above situation, the present invention provides a method for purifying L-carnitine that can obtain L-carnitine having a large particle size and can purify L-carnitine with high purity in order to reduce the hygroscopicity of L-carnitine. Let it be an issue.
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-カルニ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-カルニチンを精製する方法において、低級アルキルアルコールと水との混合溶媒に粗結晶L-カルニ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-カルニ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。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained a method for purifying L-carnitine by dissolving crude crystal L-carnitine in alkyl alcohol and recrystallizing it. By dissolving the crude crystalline L-carnitine in a mixed solvent of alcohol and water and then recrystallizing it, the particle size of the purified L-carnitine is increased and the amount of water mixed with the lower alkyl alcohol is increased. It has been found that the particle size can be controlled. Furthermore, as a result of investigation, it was found that the crude crystal L-carnitine was dissolved in a mixed solvent of lower alkyl alcohol and water and then recrystallized by adding an organic solvent other than lower alkyl alcohol in a high yield. Of large L-carnitine was obtained, and the present invention was completed.
即ち、本発明は、「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、再結晶させることを特徴とするL-カルニチンの精製方法」及び「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L-カルニチンの精製方法」に関する。 That is, the present invention relates to “a method for purifying L-carnitine, wherein crude crystal L-carnitine is dissolved in a mixed solvent of a lower alkyl alcohol and water and then recrystallized” and “crude crystal L- The present invention relates to a “purification method for L-carnitine, wherein 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”.
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）を調節することでL-カルニ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-カルニチン、即ち、吸湿性が低く取り扱いが容易なL-カルニ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-カルニチンを得ることができる。 According to the purification method of the present invention, the particle size of L-carnitine is controlled by adjusting the amount of water used during purification (water content in a mixed solvent of lower alkyl alcohol and water in which L-carnitine is dissolved). Therefore, L-carnitine having a high purity and a large particle size, that is, L-carnitine having a low hygroscopic property and easy to handle can be easily obtained. Furthermore, by dissolving crude crystal 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 it, L-carnitine having a large particle size can be obtained in a high yield. Obtainable.
図１は、実施例３及び比較例１で得られたL-カルニ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 changes in moisture absorption when L-carnitine crystals obtained in Example 3 and Comparative Example 1 were used.
−◆−は、比較例１で得られたL-カルニチンの吸湿性を、−■−は、実施例３で得られたL-カルニチンの吸湿性を表す。 -♦-represents the hygroscopicity of L-carnitine obtained in Comparative Example 1, and-■-represents the hygroscopicity of L-carnitine obtained in Example 3.
本発明の粗結晶L-カルニチンとは、自体公知の方法、例えばファインケミカル 2004年４月号, Vol33, No.4, 5-18、L．Tenud et al. EP 157.315 (1984)、M. Kitamura et al. Tetrahedron Lett., 1988, 29, 1555-1556.、B. E. Rossiter et al. J. Org. Chem. 1984, 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-カルニチン等が挙げられる。 The crude crystalline L-carnitine of the present invention is a method known per se, for example, fine chemical April 2004 issue, Vol 33, No. 4, 5-18, L. Tenud et al. EP 157.315 (1984), M. Kitamura et al. Tetrahedron Lett., 1988, 29, 1555-1556., BE Rossiter et al. J. Org. Chem. 1984, 3707, K. Bock et al. L-carnitine produced by the method described in Acta Chem. Scand. 1983, B37, 341.
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-カルニチンを容易に溶解し得るもの、好ましくはL-カルニチンを 100g/L以上溶解し得るものであればよく、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よい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−ヘプタノール、ｎ−ヘキサノール等が挙げられ、中でもL-カルニ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く、エタノールが特に好ましい。 The lower alkyl alcohol according to the present invention is not particularly limited as long as it is compatible with water and can easily dissolve L-carnitine, and preferably can dissolve 100 g / L or more of L-carnitine. In general, an alkyl alcohol which may have a substituent having 1 to 6 carbon atoms, preferably an alkyl alcohol which may have a substituent having 1 to 3 carbon atoms, more preferably a substituent having 2 to 3 carbon atoms. And alkyl alcohols which may have Specific examples include methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, n-heptanol, n-hexanol, etc. Among them, ethanol, isopropyl which dissolves L-carnitine and its solubility is not too high. Alcohol and the like are preferable, and ethanol is particularly preferable.
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-カルニ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。 The mixed solvent of lower alkyl alcohol and water according to the present invention is used for dissolving crude crystalline L-carnitine. In addition, the water here is not particularly limited as long as it is usually used in experiments in this field, and for example, it represents purified water, distilled water, distilled purified water, or the like.
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-カルニチンを溶解しない又は溶解しにくいものである。このような本発明に係る有機溶媒のL-カルニチンの溶解度としては、通常０．１ｇ／ml以下、好ましくは０．０５ｇ／ml以下、より好ましくは０．０１ｇ／ml以下である。上記した性質を有する有機溶媒の中でも、L-カルニ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、毒性が低い若しくは毒性を有さないものが好ましい。具体的には、例えばメチルエチルケトン、アセトン等のケトン、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４−ジオキサン等のエーテル、アセトニトリル、プロピオニトリル等のニトリル、酢酸ブチル、酢酸エチル等のエステル、ジクロロエタン、クロロホルム、ジクロロメタン等のハロゲン化炭化水素等が挙げられ、中でも酢酸エ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いものとして、酢酸エチルが特に好ましい。 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 and is compatible with the lower alkyl alcohol. In addition, L-carnitine is not dissolved or hardly dissolved. The solubility of L-carnitine as the organic solvent according to the present invention is usually 0.1 g / ml or less, preferably 0.05 g / ml or less, more preferably 0.01 g / ml or less. Among the organic solvents having the above properties, those having low toxicity or non-toxicity are preferable in consideration that L-carnitine is often used as a food additive. Specifically, for example, ketones such as methyl ethyl ketone and acetone, diethyl ether, diisopropyl ether, tetrahydrofuran, ethers such as 1,4-dioxane, nitriles such as acetonitrile and propionitrile, esters such as butyl acetate and ethyl acetate, dichloroethane, Examples thereof include halogenated hydrocarbons such as chloroform and dichloromethane. Among them, ethyl acetate and acetone are preferable, and ethyl acetate is particularly preferable because the particle size can be easily controlled.
本発明の精製法は、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、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-カルニ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-カルニチンを得ることができる。尚、上記の粗結晶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する方法としては、通常粗結晶L-カルニチンを、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が、粗結晶L-カルニ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。 The purification method of the present invention is performed by dissolving crude crystalline L-carnitine in a mixed solvent of lower alkyl alcohol and water and then recrystallizing it by a method such as concentration under reduced pressure. Large purified L-carnitine can be obtained. Furthermore, after dissolving L-carnitine in the above mixed solvent, the organic solvent according to the present invention is added and recrystallized, so that purified L- Carnitine can be obtained. In addition, as a method of dissolving the above-mentioned crude crystalline L-carnitine in a mixed solvent of lower alkyl alcohol and water, usually crude crystalline L-carnitine is dissolved in a mixed solvent of lower alkyl alcohol and water mixed in advance. However, it may be carried out by adding water to a lower alkyl alcohol solvent in which crude crystalline L-carnitine is dissolved. The purification method of the present invention is specifically performed as follows.
即ち、先ず、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、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）が、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。 That is, first, crude crystalline L-carnitine is dissolved in a mixed solvent of lower alkyl alcohol and water, if necessary, by heating. In this case, the amount of water is usually 0.5 to 10%, preferably 0.5, in a mixed solvent of lower alkyl alcohol and water in which L-carnitine is dissolved. ˜6%, more preferably 0.5 to 4%, still more preferably 0.5 to 3%.
その後、自体公知の再結晶方法によりL-カルニチンを得ればよく、具体的には、例えば該溶解液を通常−１０〜３０℃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。 Thereafter, L-carnitine may be obtained by a recrystallization method known per se. Specifically, for example, the solution is usually purified at −10 to 30 ° C., if necessary, under reduced pressure to precipitate crystals. L-carnitine can be obtained.
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-カルニ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-カルニ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１／３〜１／２倍量になるまで、好ましくは１／３倍になるまで濃縮する。また、濃縮の際にL-カルニ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ア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が、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-カルニ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℃、好ましくは０〜５℃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-カルニチンを得ることができる。 In the case of adding the organic solvent according to the present invention, L-carnitine is dissolved in a mixed solvent as described above, and then concentrated under reduced pressure if necessary. Although it is preferable to make it a saturated solution of L-carnitine by the concentration, it is usually concentrated until the total solution amount becomes 1/3 to 1/2 times, preferably 1/3 times. Further, L-carnitine crystals may be precipitated during the concentration. The water content in the concentrated solution is slightly higher than the value at the time of dissolution because the lower alkyl alcohol according to the present invention evaporates, but is usually 0.5 to 10%, preferably 0.5 to 6%. More preferably, the purification method of the present invention can be carried out without problems if it is 0.5 to 4%, more preferably 0.5 to 3%. Further, when concentrated until L-carnitine precipitates, water may migrate into the L-carnitine crystals, but there is no problem as long as the water content before the crystals are precipitated is within the above range. Thereafter, 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. Preferably, the desired purified L-carnitine can be obtained by crystallization by stirring at 0-5 ° C. for 1-2 hours.
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（ここでは酢酸エチル）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、エタノールと水との混合溶媒に通常４０〜７０℃、好ましくは５０〜６０℃で加熱して溶解し、その後、該溶液を、通常４０〜７０℃、好ましくは５０〜６０℃、通常８０〜１００mmHG、好ましくは６０〜７０mmHGの圧力で減圧濃縮してL-カルニチンを飽和量まで溶解させたエタノール−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、最初に加えたL-カルニチンとエタノール−水混合溶液の総容量の１／３倍程度になるまで濃縮するのが好ましい。次いで、酢酸エチルを添加し、０〜５℃で１〜２時間攪拌して結晶化する。この際に添加する酢酸エチルの量は、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℃、好ましくは４５〜５５℃、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-カルニチンが得られる。 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 as to have the water content as described above, usually by heating at 40 to 70 ° C., preferably 50 to 60 ° C. The solution is usually concentrated under reduced pressure at a pressure of 40 to 70 ° C., preferably 50 to 60 ° C., usually 80 to 100 mmHG, preferably 60 to 70 mmHG, to obtain an ethanol-water mixed solution in which L-carnitine is dissolved to a saturated amount. . In this case, the saturated solution may be further concentrated. In this case, the total amount of the solution is usually about 1/3 times the total volume of the L-carnitine and ethanol-water mixed solution added first. It is preferable to concentrate until. Next, 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. It only has to be set. Thereafter, the obtained crystals are collected by filtration and dried at, for example, usually 70 to 80 ° C., preferably 45 to 55 ° C., usually 40 to 60 mmHG, preferably 10 to 30 mmHG, to obtain the desired purified L-carnitine.
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が、その下限は、少なくとも粗結晶L-カルニチンが溶解し得る量、即ち、粗結晶L-カルニチン１ｇ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-カルニ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-カルニチン１ｇ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-カルニチン１ｇ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。 The amount of the lower alkyl alcohol used in the purification method of the present invention varies somewhat depending on the type of the lower alkyl alcohol used, but the lower limit is an amount at which at least the crude crystalline L-carnitine can be dissolved, ie, the crude crystalline L -It is usually 3 ml or more, preferably 3.5 ml or more, more preferably 3.6 ml with respect to 1 g of carnitine. If the amount is too large, the yield when L-carnitine is crystallized decreases, so the upper limit is usually 10 ml or less, preferably 8 ml or less, more preferably 5 ml or less, per 1 g of crude crystalline L-carnitine. 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 1 g of crude crystalline L-carnitine.
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-カルニ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-カルニ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いて、L-カルニチン溶解時の水分含量を０．１〜１％とすると平均粒径が１５０〜４００μｍ、１〜２％とすると平均粒径が３００〜８００μｍ、２％以上とすると平均粒径が１５０〜４００μｍのL-カルニ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。 What is necessary is just to add the quantity of the water based on this invention used in the purification method of this invention so that it may become the said water content according to the quantity of L-carnitine solution. According to the method of the present invention, the average particle size of the crystals of L-carnitine obtained by adjusting the water content can be adjusted. For example, ethanol is used as the lower alkyl alcohol, and L-carnitine is In the case of dissolving in a mixed solvent and then concentrating under reduced pressure to obtain a saturated solution, assuming that the water content during dissolution of L-carnitine is 0.1 to 1%, the average particle size is 150 to 400 μm and 1 to 2%. When the average particle size is 300 to 800 μm and 2% or more, L-carnitine 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.
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-カルニ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-カルニ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-カルニチンの収率を上げることができるので、より好ましい方法である。 The amount of the organic solvent according to the present invention used in the purification method of the present invention is lower than that added to dissolve L-carnitine first when L-carnitine is dissolved in a mixed solvent and is not concentrated. The amount is usually 0.5 to 2.0 times, preferably 1.0 to 1.5 times the amount of alkyl alcohol. Moreover, when concentrating, as demonstrated in the above-mentioned section of the purification method of the present invention, the total liquid volume after concentration is usually 0.5 to 2.0 times, preferably 1.0 to 1. It may be set appropriately within a range of .5 times. In the purification method of the present invention, concentration under reduced pressure is a more preferable method because the amount of the organic solvent used can be suppressed and the yield of purified L-carnitine can be increased.
本発明の方法により得られる精製L-カルニチンの平均粒径は、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が、通常１５０〜１５００μm、好ましくは２００〜１０００μｍ、より好ましくは２５０〜８００μｍ、更に好ましくは３００〜８００μｍである。粒径が３００μｍ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。 The average particle size of purified L-carnitine 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, but is usually 150-1500 μm, preferably 200-1000 μm, more preferably 250-800 μm. More preferably, it is 300-800 micrometers. A particle size of 300 μm or more is particularly preferable because handling becomes easy. The average particle size can be adjusted by changing the water content in the mixed solvent as described above.
本発明の方法によれば、粒径の大きな精製L-カルニチンを、光学純度が99％以上、好ましくは100％で得ることが出来る。 According to the method of the present invention, purified L-carnitine having a large particle size can be obtained with an optical purity of 99% or more, preferably 100%.
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。 Hereinafter, the present invention will be described in more detail with reference to Comparative Examples and Examples, but the present invention is not limited thereto.
L-カルニチン(光学純度 99%)30kgを無水エタノール120Lに５０℃で溶解させた後、全容量が95Lになるまで50〜60℃、62〜65mmHGで減圧濃縮した。次いで、酢酸エチル60Lを添加して0〜5℃で1時間攪拌した後、生成物を濾取し、70℃、10mmHGで減圧乾燥して、L-カルニチン28.5kg(収率95.0％)を得た。
得られたL-カルニチンを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（MASTERSIZER2000、MALVERN社製）を用いて測定した結果、74μmであった。30 kg of L-carnitine (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 0-5 ° C. for 1 hour, the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 28.5 kg of L-carnitine (yield 95.0%). It was.
As a result of measuring the obtained L-carnitine by HPLC, the optical purity was 100% ee, which was extremely high purity. Further, the average particle diameter was measured using a laser spectral particle diameter measuring instrument (MASTERSIZER2000, manufactured by MALVERN), and as a result, it was 74 μm.
L-カルニチン(光学純度 99%)10gを95v/v%エタノール20mLに８０℃で溶解させ(溶液中の水分含量：5.2 w/w%)、更に25℃で1時間攪拌した後、生成物を濾取し、70℃、10mmHGで減圧乾燥してL-カルニチン4.5g(収率45.0％)を得た。
得られたL-カルニチンを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（MASTERSIZER2000、MALVERN社製）を用いて測定した結果、335μmであった。10 g of L-carnitine (99% optical purity) was dissolved in 20 mL of 95 v / v% ethanol at 80 ° C. (water content in the solution: 5.2 w / w%) and further stirred at 25 ° C. for 1 hour. It was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 4.5 g of L-carnitine (yield 45.0%).
As a result of measuring the obtained L-carnitine 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 (MASTERSIZER2000, manufactured by MALVERN), and as a result, it was 335 μm.
L-カルニチン(光学純度 99%)30gを、無水エタノール108mL及び水1.0gに５０℃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℃、62〜65mmHGで減圧濃縮した。次いで、酢酸エチル60mLを添加して0〜5℃で1時間攪拌した後、生成物を濾取し、70℃、10mmHGで減圧乾燥してL-カルニチン28.5g(収率95.0％)を得た。
得られたL-カルニチンを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（MASTERSIZER2000、MALVERN社製）を用いて測定した結果、200μmであった。30 g of L-carnitine (optical purity 99%) was dissolved in 108 mL of absolute ethanol and 1.0 g of water at 50 ° C. (moisture content in the solution: 0.8 w / w%), and then 50 to 50 mL until the total volume reached 54 mL. The solution was concentrated under reduced pressure at 60 ° C. and 62-65 mmHG. Next, 60 mL of ethyl acetate was added and stirred at 0-5 ° C. for 1 hour, and then the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 28.5 g (yield 95.0%) of L-carnitine. .
The obtained L-carnitine was measured by HPLC. As a result, the optical purity was 100% ee, which was extremely high purity. Further, the average particle diameter was measured using a laser spectral particle diameter measuring device (MASTERSIZER2000, manufactured by MALVERN), and as a result, it was 200 μm.
L-カルニチン(光学純度 99%)30kgを、無水エタノール120L及び水1.7kgに５０℃で溶解させた後(溶液中の水分含量：1.3 w/w%)、50〜60℃、62〜65mmHgで減圧濃縮すると、エタノールが38L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-カルニチン結晶析出量：47.8％)。次いで、酢酸エチル60Lを添加して0〜5℃で1時間攪拌した後に生成物を濾取し、70℃、10mmHGで減圧乾燥してL-カルニチン28.7kg(収率95.7％)を得た。
得られたL-カルニチンを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（MASTERSIZER2000、MALVERN社製）を用いて測定した結果、643μmであった。After dissolving 30 kg of L-carnitine (99% optical purity) 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 ° C., 62-65 mmHg When concentrated under reduced pressure, crystals began to precipitate when 38 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 was 54 L (total 96 L was distilled off) (water content at this time: 1.4%, L-carnitine crystal precipitation amount: 47.8%). Next, 60 L of ethyl acetate was added and the mixture was stirred at 0 to 5 ° C. for 1 hour, and then the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 28.7 kg (yield 95.7%) of L-carnitine.
The obtained L-carnitine was measured by HPLC. As a result, 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 (MASTERSIZER2000, manufactured by MALVERN), and as a result, it was 643 μm.
L-カルニチン(光学純度 99%)30gを、無水エタノール108mL及び水3.0gに５０℃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℃、62〜65mmHgで減圧濃縮した。次いで、酢酸エチル60mLを添加して0〜5℃で1時間攪拌した後に生成物を濾取し、70℃、10mmHGで減圧乾燥してL-カルニチン27.9g(収率93.0％)を得た。
得られたL-カルニチンを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（MASTERSIZER2000、MALVERN社製）を用いて測定した結果、360μmであった。30 g of L-carnitine (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%), and then 50 to 50 mL until the total volume reached 54 mL. The solution was concentrated under reduced pressure at 60 ° C. and 62 to 65 mmHg. Next, 60 mL of ethyl acetate was added and stirred for 1 hour at 0 to 5 ° C., and then the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 27.9 g of L-carnitine (yield 93.0%).
The obtained L-carnitine was measured by HPLC. As a result, 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 (MASTERSIZER2000, manufactured by MALVERN), and as a result, it was 360 μm.
L-カルニチン(光学純度 99%)30gを、無水エタノール108mL及び水4.6gに５０℃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℃、62〜65mmHgで減圧濃縮した。次いで、酢酸エチル60mLを添加して0〜5℃で1時間攪拌した後に生成物を濾取し、70℃、10mmHGで減圧乾燥してL-カルニチン25.7g(収率85.8％)を得た。
得られたL-カルニチンを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（MASTERSIZER2000、MALVERN社製）を用いて測定した結果、320μmであった。30 g of L-carnitine (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%), and then 50 to 50 mL until the total volume reached 54 mL. The solution was concentrated under reduced pressure at 60 ° C. and 62 to 65 mmHg. Next, 60 mL of ethyl acetate was added and stirred for 1 hour at 0 to 5 ° C., and then the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 25.7 g of L-carnitine (yield 85.8%).
The obtained L-carnitine was measured by HPLC. As a result, 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 spectral particle size measuring device (MASTERSIZER2000, manufactured by MALVERN).
L-カルニチン(光学純度 99%)30gを、無水エタノール108mL及び水6.45gに４０℃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℃、62〜65mmHgで減圧濃縮した。次いで、酢酸エチル60mLを添加して0〜5℃で1時間攪拌した後に生成物を濾取し、70℃、10mmHGで減圧乾燥してL-カルニチン21.9g(収率73.2％)を得た。
得られたL-カルニチンを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（MASTERSIZER2000、MALVERN社製）を用いて測定した結果、314μmであった。30 g of L-carnitine (99% optical purity) 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%), and then 50 to 50 mL until the total volume reached 54 mL. The solution was concentrated under reduced pressure at 60 ° C. and 62 to 65 mmHg. Next, 60 mL of ethyl acetate was added and stirred for 1 hour at 0 to 5 ° C., and then the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 21.9 g (yield 73.2%) of L-carnitine.
The obtained L-carnitine was measured by HPLC. As a result, the optical purity was 100% ee, which was extremely high purity. The average particle size was 314 μm as a result of measurement using a laser spectral particle size measuring device (MASTERSIZER2000, manufactured by MALVERN).
L-カルニチン(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℃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℃、62〜65mmHgで減圧濃縮した。次いで、酢酸エチル60mLを添加して0〜5℃で1時間攪拌した後に生成物を濾取し、70℃、10mmHGで減圧乾燥してL-カルニチン28.2g(収率94.0%)を得た。
得られたL-カルニチンを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、MALVERN社製）を用いて測定した結果、300μmであった。30 g of L-carnitine (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%), and then 50 to 50 mL until the total volume reached 54 mL. The solution was concentrated under reduced pressure at 60 ° C. and 62 to 65 mmHg. Next, 60 mL of ethyl acetate was added and stirred for 1 hour at 0 to 5 ° C., and then the product was collected by filtration and dried under reduced pressure at 70 ° C. and 10 mmHG to obtain 28.2 g of L-carnitine (yield 94.0%).
As a result of measuring the obtained L-carnitine by HPLC, the optical purity was 100% ee. Further, the average particle diameter was measured using a laser spectral particle diameter measuring device (MASTERSIZER2000, manufactured by MALVERN), and as a result, it was 300 μm.
実施例３及び比較例１で得られたL-カルニチンの結晶約3gを電子天秤（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:20±2℃,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。
吸湿率（％）＝（増加重量／スタート重量）×100After about 3 g of L-carnitine crystals obtained in Example 3 and Comparative Example 1 were precisely weighed with an electronic balance (METTLER AE240), the crystals were spread over a petri dish having a diameter of 8.5 cm and a height of 2 cm, and the temperature: 20 The sample was allowed to stand at ± 2 ° C and humidity: 30 ± 5%, and the change in each moisture absorption rate was measured. The result is shown in FIG. The moisture absorption rate was calculated from the following equation.
Moisture absorption rate (%) = (increase weight / start weight) x 100
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-カルニチン結晶の平均粒径が大きくなることが分かった。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、300μｍ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-カルニチンの結晶は、その吸湿性が低いことも分かった。
From the above results, it is clear that the average particle size of the obtained L-carnitine crystals is increased by adding a small amount of water to the lower alkyl alcohol according to the present invention, compared to the case where water is not added. It was. It was also found that when anhydrous isopropanol was used, L-carnitine having a large average particle diameter of 300 μm was obtained when water was added. Furthermore, as a result of comparison of hygroscopicity, it was also found that crystals of L-carnitine having a large average particle diameter have low hygroscopicity.
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