JPH01131143A - Optical resolution of d,l-carnitinenitrile chloride - Google Patents
Optical resolution of d,l-carnitinenitrile chlorideInfo
- Publication number
- JPH01131143A JPH01131143A JP29021687A JP29021687A JPH01131143A JP H01131143 A JPH01131143 A JP H01131143A JP 29021687 A JP29021687 A JP 29021687A JP 29021687 A JP29021687 A JP 29021687A JP H01131143 A JPH01131143 A JP H01131143A
- Authority
- JP
- Japan
- Prior art keywords
- acetyl
- carnitinenitrile
- chloride
- amount
- optical resolution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000003287 optical effect Effects 0.000 title claims abstract description 34
- ZOYKKWXSDFNANU-UHFFFAOYSA-M (3-cyano-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC#N ZOYKKWXSDFNANU-UHFFFAOYSA-M 0.000 title claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 26
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000002798 polar solvent Substances 0.000 claims abstract description 8
- RFMMMVDNIPUKGG-RXMQYKEDSA-N (2r)-2-acetamidopentanedioic acid Chemical compound CC(=O)N[C@@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-RXMQYKEDSA-N 0.000 claims abstract description 6
- 229960002989 glutamic acid Drugs 0.000 claims abstract description 4
- -1 d-carnitine nitrile Chemical class 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 27
- 229960001518 levocarnitine Drugs 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 6
- 239000004220 glutamic acid Substances 0.000 abstract description 3
- 208000019622 heart disease Diseases 0.000 abstract description 2
- VUABPTIDJBJIPI-SSDOTTSWSA-N (2R)-2-(diacetylamino)pentanedioic acid Chemical compound CC(=O)N(C(C)=O)[C@@H](C(O)=O)CCC(O)=O VUABPTIDJBJIPI-SSDOTTSWSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000013078 crystal Substances 0.000 description 25
- 229960004203 carnitine Drugs 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000002825 nitriles Chemical class 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- PHIQHXFUZVPYII-LURJTMIESA-N (S)-carnitine Chemical compound C[N+](C)(C)C[C@@H](O)CC([O-])=O PHIQHXFUZVPYII-LURJTMIESA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZOYKKWXSDFNANU-OGFXRTJISA-M [(2r)-3-cyano-2-hydroxypropyl]-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)C[C@H](O)CC#N ZOYKKWXSDFNANU-OGFXRTJISA-M 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960000678 carnitine chloride Drugs 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明はｄ，ｌ−カルニチンニトリルクロライドの光学
分割法、詳しくは極性溶媒に対して難溶性のｄ−カルニ
チンニトリル・Ｎ−アセチル−し−グルタミン酸塩又は
Ｑ−カルニチンニトリル・Ｎ−アヒチルーＤ−グルタミ
ン酸塩を晶出させてｄ，ｌ−カルニチンニトリルクロラ
イドを光学分割する方法の改良法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to an optical resolution method for d,l-carnitine nitrile chloride, specifically d-carnitine nitrile N-acetyl-glutamate, which is sparingly soluble in polar solvents. Alternatively, the present invention relates to an improved method for optically resolving d,l-carnitine nitrile chloride by crystallizing Q-carnitine nitrile/N-ahity-D-glutamate.
従来技術とその問題点
カルニチンの光学活性体であるＱ−カルニチンは、従来
より心臓疾患の治療剤としてヤ血中の脂肪を低下させる
薬剤として、殊に医薬品分野で種々利用されている。し
かしてこのＱ−力ルニチンは、化学合成法によってｄ，
ｌ−カルニチンニトリルを合成し、このラセミ体を加水
分解、光学分割する方法及び微生物や酵素を利用して生
化学的に採取する方法の２種の方法により製造されてき
ている。上記化学合成法は高濃度反応ができることや反
応時間が短くてすむこと等の工業生産上の利点及び経済
性の面から、現在も高く評価されているが、上記ラセミ
体の光学分割法の点で、尚改善されるべき問題を抱えて
いる。Prior art and its problems Q-carnitine, which is an optically active form of carnitine, has been used in various ways, particularly in the pharmaceutical field, as a therapeutic agent for heart diseases and as a drug for lowering fat in goat blood. However, this Q-lunitine can be obtained by chemical synthesis using d,
It has been produced by two methods: a method of synthesizing l-carnitine nitrile, hydrolysis and optical resolution of this racemic form, and a method of biochemical collection using microorganisms and enzymes. The above chemical synthesis method is still highly evaluated due to its advantages in industrial production such as high concentration reaction and short reaction time, as well as economic efficiency. However, there are still problems that need to be improved.
即ち、従来最も優れたものの一つとして知られている上
記ラセミ体の光学分割法は、特公昭４３−８２４８号公
報に記載されるものである。これは光学分割剤としてＮ
−アセチル−Ｄ−グルタミン酸又はＮ−アセチル−Ｌ−
グルタミン酸を用い、ｄ，ｌ−カルニチンニトリルの塩
を形成させ、得られる塩の極性溶媒に対する溶解度差を
利用するものであり，ｌ−カルニチンニトリル・Ｎ−ア
セチル−Ｄ−グルタミン酸塩及びｄ−カルニチンニトリ
ル・Ｎ−アセチル−Ｌ−グルタミン酸塩はメタノール、
エタノール等の極性溶媒に極めて難溶でおるのに対して
、之等の異性体であるｄ−カルニチンニトリル・Ｎ−ア
セチル−Ｄ−グルタミン酸塩及びＱ−カルニチンニトリ
ル・Ｎ−アセチル−１−グルタミンｒ１：を塩は上記極
性溶媒に易溶でおる性質を利用している。That is, the optical resolution method of the racemate, which is known as one of the best conventional methods, is the one described in Japanese Patent Publication No. 8248/1983. This is N as an optical resolving agent.
-acetyl-D-glutamic acid or N-acetyl-L-
This method uses glutamic acid to form a salt of d,l-carnitine nitrile, and utilizes the difference in solubility of the resulting salt in polar solvents.・N-acetyl-L-glutamate is methanol,
Although it is extremely poorly soluble in polar solvents such as ethanol, the isomers such as d-carnitine nitrile/N-acetyl-D-glutamate and Q-carnitine nitrile/N-acetyl-1-glutamine r1 : The salt utilizes the property of being easily soluble in the above polar solvent.
しかるに、上記方法においては、出発原料とするラセミ
体（ｄ，ｌ−カルニチンニトリルクロライドから誘導さ
れるｄ，ｌ−カルニチンニトリルハイドロキサイド）に
対して光学分割剤を理論反応当用以上、即ち所望の光学
活性体に対してはその２倍当量以上を必要とし、該分割
剤が比較的高価なものであることを考慮すれば経済的効
率が良くない不利がある。However, in the above method, the optical resolving agent is added to the racemate (d,l-carnitine nitrile hydroxide derived from d,l-carnitine nitrile chloride) as a starting material for more than the theoretical reaction, that is, the desired amount. For an optically active substance, more than twice the equivalent is required, and considering that the resolving agent is relatively expensive, there is a disadvantage that it is not economically efficient.
本発明者らは、上記光学分割法に見られる欠点を解消す
ることを目的として鋭意研究を重ねた結果、ｄ，ｌ−カ
ルニチンニトリルの非結晶性塩を形成可能な酸を上記光
学分割剤と併用する時には、ｄ，ｌ−カルニチンニトリ
ルの一方の光学活性体は上記光学分割剤と反応して難溶
性塩を形成するが、他方は上記酸と反応して非結晶塩を
形成し、従って光学分割剤を従来の半量に減じて、同様
の光学分割が可能となるという新しい事実を見出した。As a result of extensive research aimed at resolving the drawbacks of the above-mentioned optical resolution method, the present inventors have discovered that the above-mentioned optical resolution agent is capable of forming an amorphous salt of d,l-carnitine nitrile. When used in combination, one of the optically active forms of d,l-carnitine nitrile reacts with the optical resolving agent to form a poorly soluble salt, while the other reacts with the acid to form an amorphous salt, and therefore the optically active form We have discovered a new fact that similar optical resolution is possible by reducing the amount of resolving agent to half of the conventional amount.
本発明はかかる新知見に基づいて完成されたものである
。The present invention was completed based on this new knowledge.
同 点を解決するための ｒ
即ら、本発明は極性溶媒に対して難溶性のｄ−カルニチ
ンニトリル・Ｎ−アセチル−Ｌ−グルタミン酸塩又はＱ
−カルニチンニトリル・Ｎ−アセチル−Ｄ−グルタミン
酸塩を晶出させてｄ，ｌ−カルニチンニトリルクロライ
ドを光学分割するに当たり、光学分割剤としてのＮ−ア
セチル−Ｌ−グルタミン酸又はＮ−アセチル−Ｄ−グル
タミン酸を、ｄ，ｌ−カルニチンニトリルの非結晶性塩
を形成可能な他の酸と併用し、上記光学分割剤の使用量
を上記難溶性塩形成のための理論量の１．１〜１．３倍
当量とすることを特徴とするｄ。In order to solve the same problem, the present invention provides d-carnitine nitrile/N-acetyl-L-glutamate or Q
- N-acetyl-L-glutamic acid or N-acetyl-D-glutamic acid as an optical resolving agent when crystallizing carnitine nitrile/N-acetyl-D-glutamate and optically resolving d,l-carnitine nitrile chloride. is used in combination with another acid capable of forming an amorphous salt of d,l-carnitine nitrile, and the amount of the optical resolution agent used is 1.1 to 1.3 of the theoretical amount for forming the poorly soluble salt. d characterized in that it is double equivalent.
Ｑ−カルニチンニトリルクロライドの光学分割法に係わ
る。This invention relates to an optical resolution method for Q-carnitine nitrile chloride.
本発明方法によれば、光学分割剤の一部を安価な仙の酸
に直換えて、所望の光学分割を非常に容易且つ効率良く
行なうことができる。従って本発明方法は工業的実施に
極めて適したものであり、また経済的にも非常に優れた
効果をもたらす。According to the method of the present invention, a part of the optical resolving agent can be directly replaced with inexpensive acid, making it possible to perform desired optical resolution very easily and efficiently. Therefore, the method of the present invention is extremely suitable for industrial implementation, and also brings about excellent economical effects.
本発明方法において用いられる上記ｄ，ｌ−力ルニチン
ニトリルの非結晶性塩を形成する酸としては、之等が極
性溶媒中でカルニチンニトリルの非結晶性塩を形成でき
る限り特に限定はなく、脂肪族カルボン酸、芳香族カル
ボン酸等の各種有機酸のいずれでもよく、通常例えば酢
酸、プロピオン酸等の炭素数１〜１０の脂肪族カルボン
酸及び例えば安息香酸、メチル安息香酸等の炭素数６〜
１０の置換もしくは非置換フェニルカルボン酸を好まし
く利用できる。The acid used in the method of the present invention to form the amorphous salt of d,l-carnitine nitrile is not particularly limited as long as it can form the amorphous salt of carnitine nitrile in a polar solvent. Any of various organic acids such as aliphatic carboxylic acids and aromatic carboxylic acids may be used, usually aliphatic carboxylic acids having 1 to 10 carbon atoms such as acetic acid and propionic acid, and 6 carbon atoms such as benzoic acid and methylbenzoic acid. ~
10 substituted or unsubstituted phenylcarboxylic acids can be preferably utilized.
本発明方法は、上記酸を、光学分割剤とするＮ−アセチ
ル−Ｌ（又はＤ）−グルタミン酸と、併用することを除
き、基本的には該光学分割剤を利用する方法と同様にし
て実施することができる。The method of the present invention is basically carried out in the same manner as the method using the optical resolving agent, except that the above acid is used in combination with N-acetyl-L (or D)-glutamic acid as the optical resolving agent. can do.
その具体的−つの好ましい方法によれば、ｄ。According to one specific preferred method, d.
Ｑ−カルニチンニトリルクロライドを常法に従い処理し
て得られるｄ，ｌ−カルニチンニトリルハイドロキサイ
ドの溶液に、まず光学分割剤及び上記特定の酸を所定量
を加えて反応させて、カルニチンニトリルの一方の光学
活性体の上記光学分割剤塩（難溶性塩）及び該カルニチ
ンニトリルの他方の光学活性体の非結晶性塩をそれぞれ
生成させ、次いで反応液中より上記難溶性塩を析出させ
て、これを分離回収して一方の光学活性なカルニチンニ
トリルを収得するか、或いは上記結晶を析出分離した反
応液中に残存する上記非結晶性塩より他方の光学活性体
を単離精製させる。To a solution of d,l-carnitine nitrile hydroxide obtained by treating Q-carnitine nitrile chloride according to a conventional method, first, a predetermined amount of an optical resolution agent and the above-mentioned specific acid are added and reacted to obtain one of carnitine nitrile. The optical resolving agent salt (poorly soluble salt) of the optically active form of the carnitine nitrile and the amorphous salt of the other optically active form of the carnitine nitrile are respectively produced, and then the sparingly soluble salt is precipitated from the reaction solution. is separated and collected to obtain one optically active carnitine nitrile, or the other optically active substance is isolated and purified from the amorphous salt remaining in the reaction solution after the crystals are precipitated and separated.
上記本発明方法において、用いられる光学分割剤の使用
量は、これと反応して難溶性塩を生成する光学活性な出
発原料［ｄ （又はＱ）−力ルニチンニトリルクロライ
ド乃至はこれから誘導されるｄ（又はＱ）−カルニチン
ニトリルハイドロキサイド］と反応する理論量の約１．
１〜１．３倍当量の範囲から選択される。即ち、出発原
料としてラセミ体（ｄ：９＝１：１）混合物を用いる場
合にｔよ該ラセミ体に対して１／２倍モル量（理論量）
より若干過剰量とされる。In the above-mentioned method of the present invention, the amount of the optical resolving agent used is determined from the optically active starting material [d (or Q)-lunitine nitrile chloride or derivatives derived therefrom] which reacts with the optical resolving agent to produce a sparingly soluble salt. d(or Q)-carnitine nitrile hydroxide], the theoretical amount to react with about 1.
It is selected from the range of 1 to 1.3 times equivalent. That is, when a racemic mixture (d:9=1:1) is used as a starting material, t is 1/2 times the molar amount (theoretical amount) relative to the racemate.
It is considered to be a slightly excessive amount.
また上記他の酸は同出発原料中の他方の光学活性体と反
応する理論当量、即ち、ラセミ体に対して１／２倍モル
量又はその付近の川の使用で充分に本発明所期の効果を
奏し冑、通常出発原料ラセミ体に対して約０．５〜５倍
モル量程度範囲で用いることができる。但し上記酸は、
上記難溶性塩の溶媒としても機能するおそれがあり、従
ってこれを上記範囲を大幅に上回る量で用いる場合は、
難溶性塩が談義に溶解してしまい、その析出量が低下す
るおそれがある。In addition, the use of the above-mentioned other acid in a theoretical equivalent amount that reacts with the other optically active form in the same starting material, that is, 1/2 times the molar amount of the racemic form or around it, is sufficient to achieve the desired results of the present invention. It can be used in an amount of about 0.5 to 5 times the molar amount of the racemic starting material to achieve the desired effect. However, the above acid is
There is a risk that it may also function as a solvent for the above-mentioned poorly soluble salt, so if it is used in an amount significantly exceeding the above range,
There is a risk that the poorly soluble salt will dissolve in the solution and the amount of its precipitation will decrease.
上記範囲で光学分割剤及び他の酸を併用した本発明方法
によって、目的とする光学分割が行ない得る理由として
は、ｄ，ｌ−カルニチンニトリルの光学分割剤塩（１！
１溶性塩）と非結晶性塩とが反応液中で平衡状態にあり
、この非結晶性塩が上記難溶性塩の晶出に際して緩衝的
に作用し、従って、光学分割剤が存在する限り反応液中
の光学活性な一方のカルニチンニトリルは実質１全て選
択的に￥＃溶性塩を形成して晶出するためと考えられる
。The reason why the desired optical resolution can be achieved by the method of the present invention using an optical resolving agent and other acids in the above range is that the optical resolving agent salt of d,l-carnitine nitrile (1!
1 soluble salt) and the amorphous salt are in equilibrium in the reaction solution, and this amorphous salt acts as a buffer during the crystallization of the slightly soluble salt, and therefore, as long as the optical resolution agent is present, the reaction will not proceed. This is thought to be because substantially all of the optically active carnitine nitrile in the liquid selectively forms a ¥# soluble salt and crystallizes.
また、上記本発明方法において、出発原料としてのｄ，
ｌ−カルニチンニトリルクロライドをそのハイドロキサ
イドに変換させる手段としては、通常の各種操作、例え
ばイオン交換樹脂を用いる方法、水酸化カリウム等のア
ルカリを用いる操作等のいずれも採用でき、得られるｄ
，ｌ−カルニチンニトリルハイドロキサイドを溶解させ
るための溶媒としても、通常の極性溶媒、例えばメタノ
ール、エタノール、イソプロパツール等の低級アルコー
ル類、ジオキサン、テトラヒドロフラン、アセトニトリ
ル、アセトン等の有機溶媒、水及び之等の混合溶媒等の
各種のものを使用できる。In addition, in the method of the present invention, d as a starting material,
As a means for converting l-carnitine nitrile chloride into its hydroxide, any of various usual operations such as a method using an ion exchange resin, an operation using an alkali such as potassium hydroxide, etc. can be adopted, and the obtained d
, l-Carnitine nitrile hydroxide can be dissolved in ordinary polar solvents such as lower alcohols such as methanol, ethanol and isopropanol, organic solvents such as dioxane, tetrahydrofuran, acetonitrile and acetone, water and Various mixed solvents such as these can be used.
更に、前記方法により晶出する難溶性塩からの一方の光
学活性化合物の分離回収精製方法及び反応液中に残存す
る他方の光学活性化合物の単離′端製方法も、従来より
行なわれている各種操作に従うことができる。例えば上
記難溶性塩結晶は、これを水に溶かし、塩酸等の適当な
酸で酸性として析出する光学分割剤を濾過して除去し、
炉液を濃縮後、得られる結晶を再結晶することにより、
目的とする光学的に純粋なカルニチンニトリルクロライ
ドとすることができる。また反応液は例えばこれに塩化
水素を加えて酸性として析出する結晶を濾過後、再結晶
することにより同様に光学的に純粋なカルニチンニトリ
ルクロライドとすることができる。Furthermore, a method for separating, recovering and purifying one optically active compound from the sparingly soluble salt crystallized by the above method and a method for isolating and producing the other optically active compound remaining in the reaction solution have been conventionally carried out. Various operations can be followed. For example, the above-mentioned poorly soluble salt crystals are dissolved in water, acidified with a suitable acid such as hydrochloric acid, and the precipitated optical resolution agent is removed by filtration.
After concentrating the furnace liquid, by recrystallizing the obtained crystals,
The desired optically pure carnitine nitrile chloride can be obtained. Similarly, optically pure carnitine nitrile chloride can be obtained by acidifying the reaction solution by adding hydrogen chloride, filtering the precipitated crystals, and then recrystallizing the reaction solution.
かくして１ワられる光学的に純粋なカルニチンニトリル
クロライド、即ちＱ一体は、従来公知の各種方法、例え
ば代表的には加水分解操作等により、医薬品等として有
用なＱ−カルニチンクロライドに変換することができる
。The optically pure carnitine nitrile chloride obtained in this way, that is, Q-unit, can be converted to Q-carnitine chloride useful as a pharmaceutical product, etc. by various conventionally known methods, such as typically hydrolysis. .
発明の効果
本発明方法は、光学分割剤の使用量を減じて所望の光学
分割を非常に容易且つ効率良く行なうことができるもの
であり、工業的実施に適しており、且つ経済的にも非常
に優れたものでのる。Effects of the Invention The method of the present invention can perform desired optical resolution very easily and efficiently by reducing the amount of optical resolving agent used, and is suitable for industrial implementation and is very economical. It has excellent quality.
！−−血一一１
以下、本発明を更に詳しく説明するため実施例を挙げる
が、本発明はこれに限定されない。! -- Blood 111 Examples will be given below to explain the present invention in more detail, but the present invention is not limited thereto.
実施例１
ｄ、９−力ルニチンニトリルクロライド３．５５ｑ（２
０ｍ ｍｏｌ）を水２０ｍＧに溶かした溶液を、ＯＨ型
アンバーライトＩＲＡ−４１０樹脂（ロームアンドハー
ス社製）約４０＋１１ｆ２を充填したカラムに通した後
、これに更に上記樹脂を水洗した洗液を加えて８０ｍＱ
とする。Example 1 3.55q (2
A solution of 0mmol) dissolved in 20mG of water was passed through a column filled with OH type Amberlite IRA-410 resin (manufactured by Rohm and Haas) about 40 + 11f2, and a washing solution obtained by washing the resin with water was added thereto. 80mQ
shall be.
上記溶液にＮ−アセチル−Ｌ−グルタミン酸２．２７ｑ
（１２ｍｍｏｌ）と酢酸０．６００（１０ｍｍｏｌ）と
を加えて、かきまぜて塩を形成させた後、濃縮し、残渣
にエタノール１０ｍＱを加えて加熱溶解させ、−晩冷蔵
沖内に放置する。Add 2.27q of N-acetyl-L-glutamic acid to the above solution.
(12 mmol) and 0.600 (10 mmol) of acetic acid, stir to form a salt, concentrate, add 10 mQ of ethanol to the residue, dissolve by heating, and leave in a refrigerator overnight.
上記により析出した結晶を戸数し、エタノールで洗浄し
て、ｄ−カルニチンニトリルのＮ−アレチル−Ｌ−グル
タミン酸塩粗結晶３．４００を得る。この結晶を９５％
エタノールより再結晶して〔α） ＋１５．６°
（Ｃ＝０．２５、水）、融点：１８７〜１８８℃の結晶
２．４２ＣＩを１ｑる。The crystals precipitated as described above are collected and washed with ethanol to obtain 3.400 N-aretyl-L-glutamate crude crystals of d-carnitine nitrile. 95% of this crystal
Recrystallize from ethanol [α) +15.6°
(C=0.25, water), melting point: 187-188°C, 2.42 CI of crystals is weighed 1 q.
得られた結晶１．５０を水２戒に溶かし、濃塩酸０．４
５ｍ１２を加えることにより、Ｎ−アセチル−Ｌ−グル
タミン酸を析出させ、これを炉別後、炉液を濃縮乾固し
、残漬を熱エタノールで洗浄、乾燥して、ｄ−カルニチ
ンニトリルクロライド０．７５ＣＩを得る。Dissolve 1.50 of the obtained crystals in 2 precepts of water and add 0.4 of concentrated hydrochloric acid.
By adding 5 m12 of N-acetyl-L-glutamic acid, N-acetyl-L-glutamic acid was precipitated, which was separated in a furnace, the furnace liquid was concentrated to dryness, and the residue was washed with hot ethanol and dried to obtain 0. Obtain 75 CI.
このものは以下の性質を有する。This has the following properties.
２５＝
（α） ＋２５．６° （Ｃ＝０．２５、水）融点
：２５９〜２６１°Ｃ（分解）
一方上記粗結晶を戸数した残りの炉液に、塩化水素飽和
エタノール溶液１．１当足を加え、析出結晶を戸数し、
炉液を約４鵬に濃縮し、析出結晶を戸数し、前の結晶と
合せて，ｌ−カルニチンニトリルクロライド粗結晶１．
８３ＣＩを得る。25= (α) +25.6° (C=0.25, water) Melting point: 259-261°C (decomposition) On the other hand, add 1.1 equivalents of a hydrogen chloride saturated ethanol solution to the remaining furnace liquid from which the above crude crystals were mixed. Add the foot, count the precipitated crystals,
Concentrate the furnace liquid to about 4 liters, count the precipitated crystals, and combine them with the previous crystals to obtain l-carnitine nitrile chloride crude crystals.
Obtain 83 CI.
これをメタノールより再結晶して、精製されたＱ−カル
ニチンニトリルクロライド結晶１．０３ｑを得る。This is recrystallized from methanol to obtain 1.03q of purified Q-carnitine nitrile chloride crystals.
このものは以下の性質を有する。This has the following properties.
Ｃａ〕””＝−２５，６° （ｃ＝０．２５、水）融点
＝２５９〜２６１℃（分解）
実施例２
メタノール６鵬に水酸化カリウム１．２ｇ（２１ｍｍ０
１）を溶解ざぜ、これにｄ，ｌ−カルニチンニトリルク
ロライド３．５５ＣＩ （２０ｍ ｍｏｌ）を溶かし込
む。すぐに塩化カリウムが析出しはじめ、室温で３０分
間かきまぜた後、この析出塩を炉別し、これを冷メタノ
ールで洗浄し、上記炉液と洗浄液とを合せる。Ca]""=-25,6° (c=0.25, water) melting point=259-261°C (decomposition) Example 2 1.2 g of potassium hydroxide (21 mm
1) was dissolved, and 3.55 CI (20 mmol) of d,l-carnitine nitrile chloride was dissolved therein. Immediately, potassium chloride begins to precipitate, and after stirring at room temperature for 30 minutes, the precipitated salt is separated in the furnace, washed with cold methanol, and the above-mentioned furnace liquid and washing liquid are combined.
この液にＮ−アセチル−Ｄ−グルタミン酸２．２７０
（１２ｍｍｏｌ）と酢酸０．６０ＣＩ （１０ｍｍｏｌ
）とを加え、かきまぜて塩を形成させる。得られた塩を
含む溶液を減圧濃縮し、残渣をエタノール１０回に加熱
溶解させた後、冷蔵庫内に一晩放置する。Add 2.270 N-acetyl-D-glutamic acid to this solution.
(12 mmol) and 0.60 CI of acetic acid (10 mmol)
) and stir to form salt. The obtained salt-containing solution is concentrated under reduced pressure, and the residue is dissolved in ethanol by heating 10 times, and then left in a refrigerator overnight.
かくして析出した粗結晶を戸数して，ｌ−カルニチンニ
トリルのＮ−アセチル−Ｄ−グルタミン酸塩３．５０ｑ
を得る。この結晶を９５％エタノールより再結晶して（
α）２５＝−１５，６° （Ｃ＝０．２５、水）、融点
：１８７〜１８８℃の結晶２．４５ｇを得る。The crude crystals thus precipitated were combined to yield 3.50q of N-acetyl-D-glutamate of l-carnitine nitrile.
get. These crystals were recrystallized from 95% ethanol (
2.45 g of crystals are obtained, α) 25=-15,6° (C=0.25, water), melting point: 187-188°C.
１ｑられた結晶１．５ｑを水２ｍＱに溶かし、Ｓ塩酸０
．４５ＴＩＩＱを加えることにより、Ｎ−アセチル−Ｄ
−グルタミン酸を析出させ、これを炉別後、炉液を濃縮
乾固し、残漬を熱エタノールで洗浄、乾燥して，ｌ−カ
ルニチンニトリルクロライド０．７５０を得る。Dissolve 1.5q of the crystals obtained in 2 mQ of water, and add 0 S hydrochloric acid.
．． By adding 45TIIQ, N-acetyl-D
- Glutamic acid is precipitated, and after separation in a furnace, the furnace liquid is concentrated to dryness, and the residue is washed with hot ethanol and dried to obtain 0.750 l-carnitine nitrile chloride.
このものは以下の性質を有する。This has the following properties.
２５＝
〔α） −２５，６° （Ｃ＝０．２５、水）融点
：２５９〜２６１°Ｃ（分解）
一方上記粗結晶を戸数した残りの炉液に、塩化水素飽和
エタノール溶液１．１当量を加え、析出結晶を戸数し、
炉液を約４鵬に濃縮し、析出結晶をｔｒ取し、前の結晶
と合せて、ｄ−カルニチンニトリルクロライド粗結晶１
．７２Ｃ１を得る。25= [α) -25,6° (C=0.25, water) Melting point: 259-261°C (decomposition) On the other hand, add 1.1 liters of hydrogen chloride saturated ethanol solution to the remaining furnace liquid from which the above crude crystals were mixed. Add the equivalent amount, count the precipitated crystals,
The furnace liquid was concentrated to about 4 liters, the precipitated crystals were collected, and combined with the previous crystals, d-carnitine nitrile chloride crude crystals 1
．． Obtain 72C1.
これをメタノールより再結晶して、精製されたｄ−カル
ニチンニトリルクロライド結晶１．０３０を得る。This is recrystallized from methanol to obtain purified d-carnitine nitrile chloride crystals of 1.030.
このものは以下の性質を有する。This has the following properties.
２５＝
〔α） ＋２５．６° （Ｃ＝０．２５、水）融点
＝２５９〜２６１℃（分解〉
（以 上）25= [α) +25.6° (C=0.25, water) Melting point = 259-261°C (decomposition) (above)
Claims (1)
ル・Ｎ−アセチル−Ｌ−グルタミン酸塩又はｌ−カルニ
チンニトリル・Ｎ−アセチル−Ｄ−グルタミン酸塩を晶
出させてｄ，ｌ−カルニチンニトリルクロライドを光学
分割するに当たり、光学分割剤としてのＮ−アセチル−
Ｌ−グルタミン酸又はＮ−アセチル−Ｄ−グルタミン酸
を、ｄ，ｌ−カルニチンニトリルの非結晶性塩を形成可
能な他の酸と併用し、上記光学分割剤の使用量を上記難
溶性塩形成のための理論量の１．１〜１．３倍当量とす
ることを特徴とするｄ，ｌ−カルニチンニトリルクロラ
イドの光学分割法。(1) d,l-carnitine nitrile chloride by crystallizing d-carnitine nitrile/N-acetyl-L-glutamate or l-carnitine nitrile/N-acetyl-D-glutamate that is poorly soluble in polar solvents. N-acetyl- as an optical resolving agent in optically resolving
L-glutamic acid or N-acetyl-D-glutamic acid is used in combination with another acid capable of forming an amorphous salt of d,l-carnitine nitrile, and the amount of the optical resolution agent used is adjusted to form the poorly soluble salt. An optical resolution method for d,l-carnitine nitrile chloride, characterized in that the amount is 1.1 to 1.3 times the theoretical amount.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29021687A JPH01131143A (en) | 1987-11-16 | 1987-11-16 | Optical resolution of d,l-carnitinenitrile chloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29021687A JPH01131143A (en) | 1987-11-16 | 1987-11-16 | Optical resolution of d,l-carnitinenitrile chloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01131143A true JPH01131143A (en) | 1989-05-24 |
Family
ID=17753256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29021687A Pending JPH01131143A (en) | 1987-11-16 | 1987-11-16 | Optical resolution of d,l-carnitinenitrile chloride |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01131143A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0508133A2 (en) * | 1991-04-12 | 1992-10-14 | Degussa Ag | Method of preparation of L-Carnitine from D,L-Carnitine nitrile salts |
| EP0965591A1 (en) * | 1991-06-21 | 1999-12-22 | Boehringer Ingelheim Pharma KG | (s)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine, its salts, synthesis and use in the long term therapy of diabetes mellitus |
| US6342034B1 (en) | 1997-07-28 | 2002-01-29 | Samsung Fine Chemicals Co., Ltd. | Process for the preparation of L-carnitine |
-
1987
- 1987-11-16 JP JP29021687A patent/JPH01131143A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0508133A2 (en) * | 1991-04-12 | 1992-10-14 | Degussa Ag | Method of preparation of L-Carnitine from D,L-Carnitine nitrile salts |
| EP0965591A1 (en) * | 1991-06-21 | 1999-12-22 | Boehringer Ingelheim Pharma KG | (s)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine, its salts, synthesis and use in the long term therapy of diabetes mellitus |
| US6342034B1 (en) | 1997-07-28 | 2002-01-29 | Samsung Fine Chemicals Co., Ltd. | Process for the preparation of L-carnitine |
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