JP2009029741A - Optical resolution method utilizing interlayer transfer - Google Patents

Optical resolution method utilizing interlayer transfer Download PDF

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JP2009029741A
JP2009029741A JP2007194592A JP2007194592A JP2009029741A JP 2009029741 A JP2009029741 A JP 2009029741A JP 2007194592 A JP2007194592 A JP 2007194592A JP 2007194592 A JP2007194592 A JP 2007194592A JP 2009029741 A JP2009029741 A JP 2009029741A
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Toshiyuki Inazu
敏行 稲津
Takayuki Suzuki
貴之 鈴木
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Tokai University
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of optical resolution which is simpler than a conventional method, without relying on crystallization, by utilizing the difference in properties of a diastereomer between solvents forming mutually immiscible two layers. <P>SOLUTION: The method of the optical resolution comprises dissolving a reagent for the optical resolution in one of two liquids forming two layers, and extracting one of a pair of the optical isomers dissolved in the other liquid, through the interface of the two layers to the other layer side. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

本発明は、光学分割方法に関し、さらに詳しくは、特定の光学分割剤を使用することによって、効率的に片方の光学異性体を二層間抽出する光学分割方法に関する。   The present invention relates to an optical resolution method, and more particularly, to an optical resolution method in which one optical isomer is efficiently extracted between two layers by using a specific optical resolution agent.

サリドマイド禍を引例するまでもなく、近年、光学活性体が医薬、農薬、有機材料など幅広い分野でその重要性が高まり、様々な形で利用されるようになってきている。その光学活性体を製造する不斉合成法の発達があると同時に、古くから知られている、光学活性体の分離方法である光学分割法が重要な技術として利用されている。光学分割には、光学活性な担体を用いる特許文献１に記載のクロマトグラフィー法とともに、光学分割剤を用いる方法が多用されている。その方法の多くは、ラセミ混合物をジアステレオマーに誘導して分割するもので、特許文献２に記載のいわゆる優先晶出させる方法が一般的である。すなわち、目的とする化合物のエナンチオマー混合物と、光学活性な分割剤を反応させて得られるジアステレオマーの結晶性の違いを利用している。この方法では、結晶化するかどうかが、最大の問題点であり、結晶性に優れた多くの光学分割剤が開発されてきている。しかし、目的のジアステレオマーが結晶化するかどうかは、トライアンドエラー型の予備試験や、経験に基づく方法でのみ決定される。
特開２００２−１０５０５２号公報 特開２００２−３００３２号公報 In recent years, optically active substances have become increasingly important in a wide range of fields such as pharmaceuticals, agricultural chemicals, and organic materials, and have come to be used in various forms. As well as the development of an asymmetric synthesis method for producing the optically active substance, the optical resolution method, which has been known for a long time, is used as an important technique. For optical resolution, a method using an optical resolution agent is frequently used in addition to the chromatography method described in Patent Document 1 using an optically active carrier. Many of the methods are those in which a racemic mixture is induced to be diastereomer and separated, and the so-called preferential crystallization method described in Patent Document 2 is common. That is, it utilizes the difference in crystallinity between diastereomers obtained by reacting an enantiomer mixture of a target compound with an optically active resolving agent. In this method, whether or not to crystallize is the biggest problem, and many optical resolution agents excellent in crystallinity have been developed. However, whether or not the target diastereomer is crystallized is determined only by trial and error type preliminary tests and experience-based methods.
JP 2002-105052 A JP 2002-30032 A

本発明は、互いに混じらない二層を形成する溶媒間におけるジアステレオマーの物理的および化学的性質の違いを利用することによって、結晶化に頼ることなく、従来法より簡便な光学分割する方法を提供することを課題とする。   The present invention uses a difference in the physical and chemical properties of diastereomers between solvents that form two layers that do not mix with each other, thereby enabling a simpler optical resolution method than conventional methods without resorting to crystallization. The issue is to provide.

本発明者らは、互いに混じらない二層、とりわけフルオラス溶媒／有機溶媒からなる二層に着目し、結晶化に頼らない光学分割について鋭意検討した結果、特定の光学分割剤、好ましくは高度にフッ素化された置換基を有する光学分割剤を用いることによって達成できることを見出し、本発明を完成するに至った。   The inventors of the present invention focused on bilayers that are not mixed with each other, in particular, a bilayer composed of a fluorous solvent / an organic solvent, and as a result of intensive studies on optical resolution that does not rely on crystallization, a specific optical resolution agent, preferably highly fluorine It has been found that this can be achieved by using an optical resolution agent having a substituted substituent, and the present invention has been completed.

すなわち、本発明は以下に記載した事項により特定される。
本発明は、二層を形成する２つの液体の一方に光学分割剤を溶解させ、他方の液体に溶解している一対の光学異性体の片方を、該二層の界面を経由して他層側に抽出する光学分割方法であることを特徴とする。 That is, this invention is specified by the matter described below.
In the present invention, an optical resolution agent is dissolved in one of two liquids forming two layers, and one of a pair of optical isomers dissolved in the other liquid is transferred to the other layer via the interface between the two layers. It is an optical division method for extracting to the side.

上記二層を形成する２つの液体のうち、上記光学分割剤を溶解させる液体が、フルオラス溶媒であってもよく、また、上記光学異性体は、アミンであってもよい。
また、上記光学分割剤は、好ましくは高度にフッ素化された置換基を有する誘導体であって、さらに好ましくはアミノ基を高度にフッ素化された置換基で置換されたアミノ酸である。 Of the two liquids forming the two layers, the liquid that dissolves the optical resolution agent may be a fluorous solvent, and the optical isomer may be an amine.
The optical resolution agent is preferably a derivative having a highly fluorinated substituent, and more preferably an amino acid having an amino group substituted with a highly fluorinated substituent.

なお、上記高度にフッ素化された置換基は、下記式（１）で表されるアシル基であってもよい。   The highly fluorinated substituent may be an acyl group represented by the following formula (1).

Figure 2009029741
Figure 2009029741

本発明は、フルオラス溶媒および高度にフッ素化された置換基を有する光学分割剤を好適に使用することによって、片方の光学異性体を二層間抽出する光学分割方法を提供することができる。さらに、本発明は、従来の方法のように結晶化するか否かを全く問わない点において、工業的価値やその波及効果は極めて大である。   The present invention can provide an optical resolution method in which one optical isomer is extracted between two layers by suitably using a fluorous solvent and an optical resolution agent having a highly fluorinated substituent. Furthermore, the present invention has a great industrial value and its ripple effect in that it does not matter whether or not it is crystallized as in the conventional method.

次に本発明について具体的に説明する。なお、本明細書において、「光学異性体」という用語は、「エナンチオマー」という用語と同義として使用する。
本発明において使用される二層を形成する２つの液体は、互いに混じり合わない液体同士であれば何でもよく、特に制限されない。具体的には、水／有機溶媒、水／フルオラス溶媒、有機溶媒／有機溶媒、有機溶媒／フルオラス溶媒等が挙げられる。中でも、有機溶媒／フルオラス溶媒が好ましい。それぞれの溶媒を混合した溶媒によって二層を形成してもよい。 Next, the present invention will be specifically described. In the present specification, the term “optical isomer” is used synonymously with the term “enantiomer”.
The two liquids forming the two layers used in the present invention are not particularly limited as long as they are liquids that do not mix with each other. Specific examples include water / organic solvents, water / fluorus solvents, organic solvents / organic solvents, organic solvents / fluorus solvents, and the like. Among these, an organic solvent / fluorous solvent is preferable. You may form a bilayer with the solvent which mixed each solvent.

上記「フルオラス溶媒」という用語は、「親フルオロカーボン性の溶媒」という意味の造語である。水素原子を、フッ素原子によって多数置換されたフルオラス溶媒は、他の一般的な有機溶媒や水などには難溶であるが、高度にフッ素化されたことにより親フルオロカーボン性を付与させたフルオラス化合物を良く溶解できる。本発明において使用される光学分割剤は、該フルオラス化合物である。   The term “fluorous solvent” is a coined word meaning “parent fluorocarbon solvent”. Fluorous solvents in which a large number of hydrogen atoms are substituted with fluorine atoms are poorly soluble in other common organic solvents and water, but are highly fluorinated to provide a fluorocarbon property. Can be dissolved well. The optical resolution agent used in the present invention is the fluorous compound.

二層を形成する２つの液体の一方をフルオラス溶媒とすることが好ましく、特に有機溶媒／フルオラス溶媒のような非水系二層は、光学分割の対象となるラセミ体の有機溶媒への溶解性が高い点、およびラセミ体と光学分割剤との反応に対する制限が少なくなる点において有用である。   Preferably, one of the two liquids forming the two layers is a fluorous solvent. In particular, a non-aqueous bilayer such as an organic solvent / fluorous solvent has a solubility in the organic solvent of the racemate to be optically resolved. It is useful in that it is high and there are less restrictions on the reaction between the racemate and the optical resolution agent.

上記有機溶媒としては、周知の溶媒を用いることができる。具体的には、ヘキサン、ペンタン等のアルカン類；ジエチルエーテル、テトラヒドロフラン等のエーテル類；酢酸エチルや酢酸イソアミル等のエステル類；トルエン、キシレン等の芳香族類；アセトン、メチルエチルケトン等のケトン類；メタノール、エタノール、１−ブタノール等のアルコール類；アセトニトリル等のニトリル類；Ｎ，Ｎ−ジメチルホルムアミド等の非プロトン性極性溶媒などが挙げられる。中でも、アルカン類、芳香族類、ニトリル類、アルコール類が好ましく、特にトルエン、アセトニトリル、メタノールが好ましい。上記溶媒は単独で使用してもよく、また２種以上の混合物として使用してもよい。   A known solvent can be used as the organic solvent. Specifically, alkanes such as hexane and pentane; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate and isoamyl acetate; aromatics such as toluene and xylene; ketones such as acetone and methyl ethyl ketone; Alcohols such as ethanol and 1-butanol; nitriles such as acetonitrile; and aprotic polar solvents such as N, N-dimethylformamide. Of these, alkanes, aromatics, nitriles, and alcohols are preferable, and toluene, acetonitrile, and methanol are particularly preferable. The said solvent may be used independently and may be used as a 2 or more types of mixture.

上記フルオラス溶媒としては、周知の高度にフッ素化された溶媒を用いることができる。具体的には、パーフルオロヘキサン、パーフルオロヘプタン、パーフルオロオクタンなどのパーフルオロアルカン類；パーフルオロメチルシクロヘキサン、パーフルオロ−１，２−ジメチルシクロヘキサン、パーフルオロデカリンなどのパーフルオロシクロアルカン類；パーフルオロ−２−ブチルテトラヒドロフランや高分子量のポリエーテル類をパーフルオロ化した誘導体などのパーフルオロエーテル類；パーフルオロトリブチルアミン、パーフルオロトリペンチルアミンなどのパーフルオロアミン類など、完全に水素をフッ素化した誘導体を挙げることができる。中でも、パーフルオロヘキサンが好ましい。また、パーフルオロブチルメチルエーテル等のように部分的に高度にフッ素化されたフルオラス溶媒、一部の水素を残した高度にフッ素化された誘導体等も挙げることができる。上記溶媒は単独で使用してもよく、また２種以上の混合物として使用してもよい。   As the fluorous solvent, a well-known highly fluorinated solvent can be used. Specifically, perfluoroalkanes such as perfluorohexane, perfluoroheptane, and perfluorooctane; perfluorocycloalkanes such as perfluoromethylcyclohexane, perfluoro-1,2-dimethylcyclohexane, and perfluorodecalin; Perfluoroethers such as fluoro-2-butyltetrahydrofuran and perfluorinated derivatives of high molecular weight polyethers; perfluorinated amines such as perfluorotributylamine and perfluorotripentylamine; And derivatives thereof. Of these, perfluorohexane is preferred. In addition, a partially highly fluorinated fluorous solvent such as perfluorobutyl methyl ether, a highly fluorinated derivative leaving some hydrogen, and the like can also be mentioned. The said solvent may be used independently and may be used as a 2 or more types of mixture.

さらに、パーフルオロブチルメチルエーテル等の溶媒のように、周知の有機溶媒と混和できる溶媒を用いて、様々な混合溶媒を形成できる。該混合溶媒は、二層を形成できれば、本発明に使用してもよい。   Furthermore, various mixed solvents can be formed using a solvent miscible with a known organic solvent such as a solvent such as perfluorobutyl methyl ether. The mixed solvent may be used in the present invention as long as it can form two layers.

本発明の光学分割する方法の作用原理は、以下のとおりである。
上記二層の界面において、基質である一対の光学異性体（ラセミ体）に、化学量論量より少ない光学分割剤を反応させ、共有結合あるいは適当な分子間力によって、対応するジアステレオマーが誘導される。その際、ジアステレオマー間の生成過程における速度論的な差、あるいは生成したジアステレオマー間の熱力学的な差が生じれば、その片方のジアステレオマーだけが一方の溶媒に分配され、または二層の界面を経由して層間移動する。他方、光学分割剤と反応しない、または反応したが不安定なため分解した、もう片方のエナンチオマーは元の溶媒中に残る。 The principle of operation of the method for optical division according to the present invention is as follows.
At the interface between the two layers, a pair of optical isomers (racemate) as a substrate is reacted with an optical resolving agent less than the stoichiometric amount, and the corresponding diastereomers are formed by covalent bonds or appropriate intermolecular forces. Be guided. At that time, if a kinetic difference in the formation process between diastereomers or a thermodynamic difference between the generated diastereomers occurs, only one of the diastereomers is distributed to one solvent, Or it moves between layers via the interface of two layers. On the other hand, the other enantiomer that does not react with the optical resolving agent or that has reacted but is unstable due to instability remains in the original solvent.

光学分割する上記の反応として、具体的には、酸−塩基による塩の生成反応、アルコールとカルボニル基とによるアセタール形成反応、加水分解反応、エステル化反応等が挙げられ、光学分割に利用されている周知の反応を利用できる。中でも、酸−塩基による塩の生成反応が好ましい。   Specific examples of the above-mentioned reaction for optical resolution include a salt formation reaction with an acid-base, an acetal formation reaction with an alcohol and a carbonyl group, a hydrolysis reaction, an esterification reaction, and the like. Well known reactions are available. Of these, acid-base salt formation is preferred.

本発明において使用される光学分割剤は、あるラセミ体化合物のそれぞれのエナンチオマーと共有結合、あるいは適当な分子間力によって、対応するジアステレオマーに誘導する。   The optical resolving agent used in the present invention is derivatized to the corresponding diastereomer by covalent bond or appropriate intermolecular force with each enantiomer of a racemic compound.

上記光学分割剤は、目的に応じ適宜誘導化され、上記二層を形成する液体の一方に充分溶解されることが必要である。よって、光学分割剤を充分に溶解させるためには、脂溶性、フルオラス性、水溶性など溶解を有利にする性質を付与させることが重要である。   The optical resolving agent is appropriately derivatized depending on the purpose, and needs to be sufficiently dissolved in one of the liquids forming the two layers. Therefore, in order to sufficiently dissolve the optical resolution agent, it is important to impart properties that favor dissolution, such as fat solubility, fluorous property, and water solubility.

光学分割剤の使用量は、基質のラセミ体の量に依存する。たとえば、基質全量がラセミ体（光学純度が０）の場合もあれば、既に光学純度が上がり、１／２量がラセミ体（光学純度５０％）の場合もある。いずれの場合も、対象となるラセミ体の量に対し、光学分割剤のモル比を０．０１〜０．７５、好ましくは０．３〜０．６、さらに好ましくは０．４〜０．５５で使用する。   The amount of the optical resolving agent used depends on the amount of racemic substrate. For example, the total amount of the substrate may be a racemate (optical purity is 0), or the optical purity is already increased, and a half amount may be a racemate (optical purity 50%). In any case, the molar ratio of the optical resolving agent is 0.01 to 0.75, preferably 0.3 to 0.6, more preferably 0.4 to 0.55 with respect to the amount of the racemate to be processed. Used in.

本発明において使用される光学分割の対象となるラセミ体は、何ら制限はない。アミンであってもよく、アミンとしては、具体的に、１−フェニルエチルアミン、３−（２−アミノプロピル）−７−ベンジルオキシインドール、２−アミノシクロヘキサノール、３−フェニル−２−メチルブチルアミン等が挙げられる。中でも、１−フェニルエチルアミンが好ましい。   The racemate to be optically resolved used in the present invention is not limited in any way. An amine may be used. Specific examples of the amine include 1-phenylethylamine, 3- (2-aminopropyl) -7-benzyloxyindole, 2-aminocyclohexanol, 3-phenyl-2-methylbutylamine, and the like. Is mentioned. Of these, 1-phenylethylamine is preferable.

例えば、基質としてアミンを光学分割する場合、従来方法として、光学分割剤として光学活性なカルボン酸を反応させ、互いにジアステレオマーの関係にある塩に誘導する方法がある。多くの場合には、これら２つのジアステレオマー間の結晶性や優先晶出の性質の違いを利用して光学分割されている。   For example, when an amine is optically resolved as a substrate, as a conventional method, there is a method in which an optically active carboxylic acid is reacted as an optical resolving agent to derive salts having a diastereomeric relationship with each other. In many cases, optical resolution is performed by utilizing the difference in crystallinity and preferential crystallization properties between these two diastereomers.

これに対して、本発明の光学分割する方法では、二層を形成した一方の溶媒中に対応するアミンを溶解させ、他方の溶媒に光学分割剤を溶解させることにより、塩を形成したジアステレオマーを、光学分割剤が溶解している溶媒に分配することができる。   In contrast, in the method for optical resolution of the present invention, the corresponding amine is dissolved in one solvent in which two layers are formed, and the optical resolution is dissolved in the other solvent, thereby forming a diastereomer in which a salt is formed. The mer can be distributed in a solvent in which the optical resolution agent is dissolved.

このようにして得られたジアステレオマーは周知の方法によって、元の遊離のアミンに誘導できる。他方のエナンチオマーである遊離のアミンは、アミンが溶解していた溶媒中に残る。   The diastereomers obtained in this way can be derived into the original free amine by known methods. The other enantiomer, the free amine, remains in the solvent in which the amine was dissolved.

本発明によると、アミンを光学分割する方法として、具体的には、フルオラス溶媒／有機溶媒二層系において、０．４〜０．５５当量のフルオラスカルボン酸を光学分割剤とし、一方のエナンチオマーに対応する塩であるジアステレオマーを形成させると、得られたアミン−カルボン酸塩は、フルオラス層に分配され、また、他方のエナンチオマーであるアミンは有機溶媒に残る。この場合、光学分割剤として、アミノ基を高度にフッ素化された置換基で置換されたアミノ酸を用いることが好ましい。特に、下記式（１）で表されたアシル基によって置換された誘導体が好ましい。   According to the present invention, as a method for optical resolution of an amine, specifically, in a fluorous solvent / organic solvent bilayer system, 0.4 to 0.55 equivalents of a fluorocarboxylic acid is used as an optical resolution agent, and one enantiomer is converted into one enantiomer. Upon formation of the corresponding salt diastereomer, the resulting amine-carboxylate is partitioned into the fluorous layer and the other enantiomer amine remains in the organic solvent. In this case, it is preferable to use an amino acid in which the amino group is substituted with a highly fluorinated substituent as the optical resolution agent. In particular, a derivative substituted with an acyl group represented by the following formula (1) is preferable.

また、上記アミノ酸としては、具体的に、Ｌ−チロシン、Ｌ−トリプトファン、Ｌ−フェニルアラニンなどが挙げられる。中でも、Ｌ−チロシン、Ｌ−トリプトファンが好ましい。   Specific examples of the amino acid include L-tyrosine, L-tryptophan, and L-phenylalanine. Of these, L-tyrosine and L-tryptophan are preferable.

Figure 2009029741
Figure 2009029741

次に、本発明について実施例を示してさらに詳細に説明するが、本発明はこれらによって限定されるものではない。
〔実施例１〕
上記式（１）で示したアシル基でアミノ基を保護したＬ−チロシン３３ｍｇ（２０μｍｏｌ）をＦｌｕｏｒｉｎｅｒｔ ＦＣ−７２(パーフルオロヘキサンを主成分とする市販
のフルオラス溶媒)［３Ｍ社製］１２ｍLに溶解した。これに、１−フェニルエチルアミン５μL（３９μｍｏｌ）をトルエン６ｍＬに溶解した溶液を積層し、３０分間攪拌し、そ
の後静置した。トルエン層におけるアミンの光学純度の経時変化を、光学純度検定用ＨＰＬＣカラム(ダイセルＣＲＯＷＮＰＡＫ ＣＲ（＋）)を用い測定したところ、
（ｉ） ０時間 （Ｒ）／（Ｓ）＝５０：５０、
（ｉｉ）２４時間後 （Ｒ）／（Ｓ）＝６５：３５、
（ｉｉｉ）１４日後 （Ｒ）／（Ｓ）＝６６：３４、となった。 Next, although an Example is shown and this invention is demonstrated further in detail, this invention is not limited by these.
[Example 1]
33 mg (20 μmol) of L-tyrosine in which the amino group is protected with the acyl group represented by the above formula (1) was dissolved in 12 mL of Fluorinert FC-72 (commercially available fluorous solvent based on perfluorohexane) [manufactured by 3M] did. A solution in which 5 μL (39 μmol) of 1-phenylethylamine was dissolved in 6 mL of toluene was layered thereon, stirred for 30 minutes, and then allowed to stand. When the time-dependent change of the optical purity of the amine in the toluene layer was measured using an optical purity test HPLC column (Daicel CROWNPAK CR (+)),
(I) 0 hour (R) / (S) = 50: 50,
(Ii) 24 hours later (R) / (S) = 65: 35,
(Iii) 14 days later (R) / (S) = 66: 34.

フルオラス層から得られた塩を常法にしたがい、遊離のアミンとした後、同様に測定したところ、（Ｒ）／（Ｓ）＝１０：９０であった。
〔実施例２〕
Ｌ−チロシンの代わりに、Ｌ−トリプトファンを光学分割剤として使用した以外は実施例１と同様に実験をした。その結果、
（ｉ） ０時間 （Ｒ）／（Ｓ）＝５０：５０、
（ｉｉ）２４時間後 （Ｒ）／（Ｓ）＝５４：４６、
（ｉｉｉ）１４日後 （Ｒ）／（Ｓ）＝７２：２８、となった。 According to a conventional method, the salt obtained from the fluorous layer was converted to a free amine and then measured in the same manner to find (R) / (S) = 10: 90.
[Example 2]
An experiment was performed in the same manner as in Example 1 except that L-tryptophan was used as an optical resolution agent instead of L-tyrosine. as a result,
(I) 0 hour (R) / (S) = 50: 50,
(Ii) 24 hours later (R) / (S) = 54: 46,
(Iii) 14 days later (R) / (S) = 72: 28.

本発明の光学分割方法は、トライアンドエラー型の予備試験や、経験に基づく方法に頼っていた従来法と比較し、互いに混じらない二層を形成する溶媒間におけるジアステレオマーの物理的および化学的性質の違いを利用することによって、結晶化する必要のない光学分割方法を提供することができる。これによって、医薬品、食品添加物、化粧品、液晶、電子材料、高分子モノマー機能性材料、および医療材料等のファインケミカルズの製造を容易にすることが可能となり、工業的価値やその波及効果は極めて大きい。   The optical resolution method of the present invention is based on the physical and chemical properties of diastereomers between solvents that form two layers that do not mix with each other, compared to conventional methods that have relied on trial and error-type preliminary tests and methods based on experience By utilizing the difference in physical properties, an optical resolution method that does not require crystallization can be provided. This makes it easy to manufacture fine chemicals such as pharmaceuticals, food additives, cosmetics, liquid crystals, electronic materials, polymer monomer functional materials, and medical materials, and the industrial value and its ripple effects are extremely large. .

Claims (6)

二層を形成する２つの液体の一方に光学分割剤を溶解させ、他方の液体に溶解している一対の光学異性体の片方を、該二層の界面を経由して他層側に抽出することを特徴とする光学分割方法。   The optical resolution agent is dissolved in one of the two liquids forming the two layers, and one of the pair of optical isomers dissolved in the other liquid is extracted to the other layer side via the interface between the two layers. An optical resolution method characterized by the above. 前記二層を形成する２つの液体のうち、前記光学分割剤を溶解させる液体が、フルオラス溶媒である、請求項1に記載の光学分割方法。   2. The optical resolution method according to claim 1, wherein, of the two liquids forming the two layers, the liquid that dissolves the optical resolution agent is a fluorous solvent. 前記光学分割剤が、高度にフッ素化された置換基を有する誘導体である、請求項1に記
載の光学分割方法。 2. The optical resolution method according to claim 1, wherein the optical resolution agent is a derivative having a highly fluorinated substituent. 前記光学異性体が、アミンである、請求項1に記載の光学分割方法。   2. The optical resolution method according to claim 1, wherein the optical isomer is an amine. 前記光学分割剤が、アミノ基を高度にフッ素化された置換基で置換されたアミノ酸である、請求項１または３に記載の光学分割方法。   The optical resolution method according to claim 1 or 3, wherein the optical resolution agent is an amino acid in which an amino group is substituted with a highly fluorinated substituent. 前記の高度にフッ素化された置換基が、下記式（１）で表されるアシル基である、請求項３または５に記載の光学分割方法。
Figure 2009029741
 The optical resolution method according to claim 3 or 5, wherein the highly fluorinated substituent is an acyl group represented by the following formula (1).
Figure 2009029741
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