JP5488967B2 - Separating agent for optical isomers having chiral porous metal-organic structure - Google Patents
Separating agent for optical isomers having chiral porous metal-organic structure Download PDFInfo
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- JP5488967B2 JP5488967B2 JP2009269867A JP2009269867A JP5488967B2 JP 5488967 B2 JP5488967 B2 JP 5488967B2 JP 2009269867 A JP2009269867 A JP 2009269867A JP 2009269867 A JP2009269867 A JP 2009269867A JP 5488967 B2 JP5488967 B2 JP 5488967B2
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- optical isomers
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- 238000000926 separation method Methods 0.000 claims description 52
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000000741 silica gel Substances 0.000 claims description 12
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- 150000002736 metal compounds Chemical class 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
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- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
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- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
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- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 description 8
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- 239000013078 crystal Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- LLLSLJDCDSXRAA-UHFFFAOYSA-N 5-(6-carboxy-2-hydroxynaphthalen-1-yl)-6-hydroxynaphthalene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C2C(C=3C4=CC=C(C=C4C=CC=3O)C(=O)O)=C(O)C=CC2=C1 LLLSLJDCDSXRAA-UHFFFAOYSA-N 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
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- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 6
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 6
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- 229910052751 metal Inorganic materials 0.000 description 4
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- QBWXQZHHVDIJSF-UHFFFAOYSA-N methyl 6-hydroxynaphthalene-1-carboxylate Chemical compound OC1=CC=C2C(C(=O)OC)=CC=CC2=C1 QBWXQZHHVDIJSF-UHFFFAOYSA-N 0.000 description 4
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- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 description 3
- JCJUKCIXTRWAQY-UHFFFAOYSA-N 6-hydroxynaphthalene-1-carboxylic acid Chemical compound OC1=CC=C2C(C(=O)O)=CC=CC2=C1 JCJUKCIXTRWAQY-UHFFFAOYSA-N 0.000 description 3
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- 238000006243 chemical reaction Methods 0.000 description 3
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 3
- 239000012973 diazabicyclooctane Substances 0.000 description 3
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- ZPZDIFSPRVHGIF-UHFFFAOYSA-N 3-aminopropylsilicon Chemical compound NCCC[Si] ZPZDIFSPRVHGIF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- JPIIRRQDOZQCAC-UHFFFAOYSA-N COC(=O)C=1C=C2C=CC(=C(C2=CC1)C1=C(C=CC2=CC(=CC=C12)C(=O)O)O)O Chemical compound COC(=O)C=1C=C2C=CC(=C(C2=CC1)C1=C(C=CC2=CC(=CC=C12)C(=O)O)O)O JPIIRRQDOZQCAC-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
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- 239000010949 copper Substances 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- VMKYLARTXWTBPI-UHFFFAOYSA-N copper;dinitrate;hydrate Chemical compound O.[Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O VMKYLARTXWTBPI-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
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- 239000002638 heterogeneous catalyst Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
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- 238000002844 melting Methods 0.000 description 2
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- 238000001144 powder X-ray diffraction data Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- XAQWSUIEIBDENV-UHFFFAOYSA-N 5-(5-carboxy-2-hydroxynaphthalen-1-yl)-6-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C3=C4C=CC=C(C4=CC=C3O)C(=O)O)=C(O)C=CC2=C1C(O)=O XAQWSUIEIBDENV-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 108010064983 Ovomucin Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- FNGGVJIEWDRLFV-UHFFFAOYSA-N anthracene-1,2-dicarboxylic acid Chemical compound C1=CC=CC2=CC3=C(C(O)=O)C(C(=O)O)=CC=C3C=C21 FNGGVJIEWDRLFV-UHFFFAOYSA-N 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-N benzene-dicarboxylic acid Natural products OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
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- 229910052802 copper Inorganic materials 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- SXTLQDJHRPXDSB-UHFFFAOYSA-N copper;dinitrate;trihydrate Chemical compound O.O.O.[Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O SXTLQDJHRPXDSB-UHFFFAOYSA-N 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
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- 239000011982 enantioselective catalyst Substances 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- LEENMPKUUNPLHM-UHFFFAOYSA-N methyl 2-hydroxynaphthalene-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=C(O)C=CC2=C1 LEENMPKUUNPLHM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- KYTZHLUVELPASH-UHFFFAOYSA-N naphthalene-1,2-dicarboxylic acid Chemical compound C1=CC=CC2=C(C(O)=O)C(C(=O)O)=CC=C21 KYTZHLUVELPASH-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
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- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 150000003627 tricarboxylic acid derivatives Chemical class 0.000 description 1
- PTVDYMGQGCNETM-UHFFFAOYSA-N trityl 2-methylprop-2-enoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OC(=O)C(=C)C)C1=CC=CC=C1 PTVDYMGQGCNETM-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、キラルな多孔性金属−有機構造体を用いた光学異性体用分離剤、該分離剤を充填した分離カラム、および該分離剤の製造方法に関する。 The present invention relates to a separation agent for optical isomers using a chiral porous metal-organic structure, a separation column packed with the separation agent, and a method for producing the separation agent.
実像と鏡像の関係を有する光学異性体には、物理的、化学的性質、例えば沸点、融点、溶解度などの物性が全く同一であるが、生体に対する相互作用、例えば味、匂いなどの生理活性に差異がみられるケースが往々にしてある。特に医薬品の分野においては、光学異性体間でその薬効、毒性の点で顕著な差が見られる。このため、厚生労働省は、医薬品製造指針において「当該薬物がラセミ体である場合には、それぞれの異性体について、吸収、分布、代謝、排泄動態を検討しておくことが望ましい」と記載している。 Optical isomers that have a relationship between a real image and a mirror image have the same physical and chemical properties, such as boiling point, melting point, solubility, etc., but they interact with living organisms, for example, physiological activities such as taste and smell. There are often cases of differences. Particularly in the field of pharmaceuticals, there are significant differences between the optical isomers in terms of their efficacy and toxicity. For this reason, the Ministry of Health, Labor and Welfare stated in the pharmaceutical manufacturing guidelines that "when the drug is a racemate, it is desirable to study the absorption, distribution, metabolism, and excretion dynamics of each isomer." Yes.
先に述べたように、光学異性体の物理的、化学的性質、例えば沸点、融点、溶解度といった物性は全く同一であるために、古典的な通常の分離手段では、個々の光学異性体を分離することができず、個々の光学異性体の生体に対する相互作用を研究することができなかった。そこで、幅広い種類の光学異性体を簡便に、かつ精度良く分析するために、光学異性体を分離する技術の研究が精力的に行われてきた。 As mentioned earlier, the physical and chemical properties of optical isomers, such as their physical properties such as boiling point, melting point, and solubility, are exactly the same. It was not possible to study the interaction of individual optical isomers with living organisms. Thus, in order to analyze a wide variety of optical isomers simply and accurately, research on techniques for separating optical isomers has been vigorously conducted.
そして、これらの要求に応える分離手法として、高性能液体クロマトグラフィー（ＨＰＬＣ）による光学分割法、とくにＨＰＬＣ用の光学異性体用分離カラムによる光学分割方法が進歩してきた。ここで言う光学異性体用分離カラムでは、不斉識別剤そのもの、あるいは不斉識別剤を適当な担体上に担持させたキラル固定相が使用されている。 As a separation technique that meets these requirements, an optical resolution method using high performance liquid chromatography (HPLC), in particular, an optical resolution method using a separation column for optical isomers for HPLC has progressed. In the separation column for optical isomers referred to here, the chiral stationary phase in which the chiral discriminating agent itself or the chiral discriminating agent is supported on an appropriate carrier is used.
前記不斉識別剤としては、例えば光学活性ポリメタクリル酸トリフェニルメチル（例えば、特許文献１参照。）、セルロース、アミロース誘導体（例えば、非特許文献１参照。）、タンパク質であるオボムコイド（例えば、特許文献２参照。）等が知られている。 Examples of the asymmetric identifier include optically active poly (triphenylmethyl methacrylate) (see, for example, Patent Document 1), cellulose, amylose derivatives (see, for example, Non-Patent Document 1), and ovomucoid (for example, patents). Reference 2) is known.
一方、多孔性金属−有機構造体（以下ＭＯＦともいう。）は、金属原子または金属イオンを有機分子または有機イオンが囲繞するように配位結合した構造であり、ゲスト分子が存在しない場合であっても安定な多孔性構造を維持する。ＭＯＦは、その機能性材料としての適用可能性から、最近盛んに研究が行われている。例えば、水素ガスの吸着材への適用や（例えば、特許文献３参照。）、不均一系触媒や光学分割への適用の可能性（例えば、非特許文献２）、不均一系不斉触媒としての応用（例えば、非特許文献３）、が検討されている。 On the other hand, a porous metal-organic structure (hereinafter also referred to as MOF) is a structure in which a metal atom or metal ion is coordinated and bound so that an organic molecule or organic ion surrounds it, and there is no guest molecule. However, it maintains a stable porous structure. MOF has been actively studied recently because of its applicability as a functional material. For example, application to an adsorbent of hydrogen gas (for example, see Patent Document 3), possibility of application to a heterogeneous catalyst or optical resolution (for example, Non-Patent Document 2), as a heterogeneous asymmetric catalyst (For example, Non-Patent Document 3) are being studied.
本発明者らは、ＭＯＦを用いた光学分割への応用について研究をすすめ、その潜在的不斉識別能力を確認した。しかしながら、ＭＯＦは溶媒に全く溶解しないため、カラムに充填させようとしても、コーティングなど従来の方法により担体に担持させることができず、その光学分割性能を十分に発揮できなかった。そのため、ＭＯＦに関しては、光学分割への応用の検討はされているものの、担体へ担持させたもので、十分な光学分割性能を有するものは知られていなかった。 The present inventors investigated the application to optical resolution using MOF, and confirmed its potential asymmetric discrimination ability. However, since MOF does not dissolve in a solvent at all, even if it is intended to be packed in a column, it cannot be supported on a carrier by a conventional method such as coating, and its optical resolution performance cannot be fully exhibited. Therefore, although MOF has been studied for application to optical resolution, it has been known that it is supported on a carrier and has sufficient optical resolution performance.
本発明は、上記の課題を解決するものであり、溶媒に難溶なＭＯＦを担体に担持させることにより、優れた光学分割性能を有する光学異性体用分離剤を提供することを課題とする。 This invention solves said subject and makes it a subject to provide the separation agent for optical isomers which has the outstanding optical resolution performance by carrying | supporting MOF which is hardly soluble in a solvent on a support | carrier.
本発明者らは、ＭＯＦを担体に担持させる方法を鋭意検討した結果、多孔質担体上でＭＯＦを結晶化させることに成功し、本発明を完成させた。すなわち本発明は、多孔質担体に光学活性な多孔性金属−有機構造体（ＭＯＦ）を担持した光学異性体用分離剤である。 As a result of intensive studies on a method for supporting MOF on a carrier, the present inventors have succeeded in crystallizing MOF on a porous carrier and completed the present invention. That is, the present invention is a separating agent for optical isomers in which an optically active porous metal-organic structure (MOF) is supported on a porous carrier.
また本発明の別の形態は、上記光学異性体用分離剤を充填した分離カラムである。 Another embodiment of the present invention is a separation column packed with the optical isomer separating agent.
また本発明の別の形態は、多孔質担体に光学活性な多孔性金属−有機構造体を担持した光学異性体用分離剤を製造する方法であって、
前記光学活性な多孔性金属−有機構造体を構成する配位子を多孔質担体に吸着させ、その後金属化合物と混合することを特徴とする、光学異性体用分離剤の製造方法である。
Another embodiment of the present invention is a method for producing a separating agent for optical isomers in which an optically active porous metal-organic structure is supported on a porous carrier,
A method for producing a separating agent for optical isomers, wherein a ligand constituting the optically active porous metal-organic structure is adsorbed on a porous carrier and then mixed with a metal compound.
本発明の光学異性体用分離剤によれば、ＭＯＦの有する潜在的不斉識別能力を十分に引き出すことができる光学異性体用分離剤を提供することができる。 According to the separation agent for optical isomers of the present invention, it is possible to provide a separation agent for optical isomers that can sufficiently bring out the potential chiral discrimination ability of MOF.
本発明の光学異性体用分離剤は、多孔質担体に光学活性な多孔性金属−有機構造体（ＭＯＦ）を担持した光学異性体用分離剤である。本発明者らは、溶媒に難溶であるＭＯＦを担体に担持させることに成功し、本発明の光学異性体分離剤を製造することが可能となった。 The separating agent for optical isomers of the present invention is a separating agent for optical isomers in which an optically active porous metal-organic structure (MOF) is supported on a porous carrier. The present inventors have succeeded in supporting MOF, which is hardly soluble in a solvent, on a carrier, and can produce the optical isomer separating agent of the present invention.
ＭＯＦは、上述のとおり、金属原子または金属イオンを有機分子または有機イオンが囲繞するように配位結合した構造であり、ゲスト分子が存在しない場合であっても安定な多孔性構造を維持するため、ガス吸着材や不均一系触媒など、その適用可能性が広く検討されている。 As described above, the MOF is a structure in which a metal atom or metal ion is coordinated and bound so that the organic molecule or organic ion surrounds it, and maintains a stable porous structure even when no guest molecule is present. The applicability of gas adsorbents and heterogeneous catalysts has been widely studied.
ＭＯＦを構成する配位子としては、ジカルボン酸、トリカルボン酸、イミダゾール、ピピリジン、又はこれらの誘導体などが挙げられる。上記配位子がジカルボン酸の場合には、芳香族カルボン酸が好ましく用いられ、例えばベンゼンジカルボン酸、ナフタレンジカルボン酸、アントラセンジカルボン酸、ビベンゼンジカルボン酸、ビナフタレンジカルボン酸、又はこれらの誘導体などがあげられる。本発明において好ましく用いられるものは、下記式（１）で表されるビナフタレンジカルボン酸の誘導体であり、より具体的には、下記式（２）に示す２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸、および、下記式（３）に示す２，２'−ジヒドロキシ−１，１'−ビナフタレン−５，５'−ジカルボン酸であることが好ましい。 Examples of the ligand constituting MOF include dicarboxylic acid, tricarboxylic acid, imidazole, piperidine, and derivatives thereof. When the ligand is a dicarboxylic acid, an aromatic carboxylic acid is preferably used, such as benzene dicarboxylic acid, naphthalene dicarboxylic acid, anthracene dicarboxylic acid, bibenzene dicarboxylic acid, binaphthalenedicarboxylic acid, or derivatives thereof. can give. What is preferably used in the present invention is a derivative of binaphthalenedicarboxylic acid represented by the following formula (1), more specifically, 2,2′-dihydroxy-1,1 represented by the following formula (2). '-Binaphthalene-6,6'-dicarboxylic acid and 2,2'-dihydroxy-1,1'-binaphthalene-5,5'-dicarboxylic acid represented by the following formula (3) are preferable.
上記一般式（１）中、Ｒ1〜Ｒ6は、独立して、水素、ハロゲン、炭素数１〜５のアルキル基、ヒドロキシル基、炭素数１〜５のアルキルヒドロキシ基、カルボキシル基、炭素数１〜５のアルキルカルボキシル基、又は炭素数１〜５のアルコキシ基から選択され、Ｒ1〜Ｒ6のうちの１つはカルボキシル基又は炭素数１〜５のアルキルカルボキシル基であり、Ｒ6は水素以外の基である。上記炭素数１〜５のアルキル基としては−ＣＨ3、−Ｃ2Ｈ5、又はＣ3Ｈ7であることが好ましく、上記炭素数１〜５のアルキルヒドロキシ基としては−ＣＨ2ＯＨ、−Ｃ2Ｈ4ＯＨ、又は−Ｃ3Ｈ6ＯＨであることが好ましく、上記炭素数１〜５のアルキルカルボキシル基としては、−ＣＨ2ＣＯＯＨ、−Ｃ2Ｈ4ＣＯＯＨ、又は−Ｃ3
Ｈ6ＣＯＯＨであることが好ましく、上記炭素数１〜５のアルコキシ基としては、−ＯＣＨ3、−ＯＣ2Ｈ5、−ＯＣ3Ｈ7であることが好ましい。
In the general formula (1), R 1 to R 6 are independently hydrogen, halogen, an alkyl group having 1 to 5 carbon atoms, a hydroxyl group, an alkylhydroxy group having 1 to 5 carbon atoms, a carboxyl group, or a carbon number. Is selected from 1 to 5 alkyl carboxyl groups or C 1 to C 5 alkoxy groups, one of R 1 to R 6 is a carboxyl group or a C 1 to C 5 alkyl carboxyl group, and R 6 is A group other than hydrogen. -CH 3 Examples of the alkyl group having 1 to 5 carbon atoms, -C 2 H 5, or C 3 is preferably H is 7, the alkyl hydroxy group in the 1 to 5 carbon atoms -CH 2 OH, - C 2 H 4 OH or —C 3 H 6 OH is preferable. Examples of the alkyl carboxyl group having 1 to 5 carbon atoms include —CH 2 COOH, —C 2 H 4 COOH, and —C 3.
H 6 COOH is preferable, and the alkoxy group having 1 to 5 carbon atoms is preferably —OCH 3 , —OC 2 H 5 , —OC 3 H 7 .
ＭＯＦを構成する金属原子としては、Ｚｎ、Ｓｃ、Ｔｉ、Ｖ、Ｃｒ、Ｍｎ、Ｆｅ、Ｃｏ、Ｎｉ、Ｃｕ、Ａｌ、Ｒｕ、Ｒｈ、Ｐｄ、Ａｇ、Ｐｔが挙げられ、特にＣｕであることが好ましい。 Examples of metal atoms constituting MOF include Zn, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Al, Ru, Rh, Pd, Ag, and Pt, and particularly Cu. preferable.
ＭＯＦは、既知の方法で合成することが可能であり、上記式（２）で示される配位子を含むＭＯＦは、例えば非特許文献２に記載の方法により合成することができる。また、上記式（３）で示される配位子を含むＭＯＦは、例えば非特許文献３に記載の方法により合成することができる。以下、ＭＯＦの合成に用いる配位子をＭＯＦ配位子ともいう。
MOF can be synthesized by a known method, and MOF including a ligand represented by the above formula (2) can be synthesized by, for example, the method described in
具体的に、上記式（２）で示されるＭＯＦ配位子を含むＭＯＦの合成方法を説明する。
６−ヒドロキシナフト酸を濃硫酸の存在下、メタノール溶媒中で加熱還流を行うことで６−ヒドロキシナフト酸メチルエステルを得る。得られた６−ヒドロキシナフト酸メチルエステルを、水中において塩化第二鉄・６水和物の存在下で反応させ、反応物を加水分解
することで、ＭＯＦ配位子である、ラセミ体の２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸を得る。
Specifically, a method for synthesizing MOF including the MOF ligand represented by the above formula (2) will be described.
6-hydroxynaphthoic acid methyl ester is obtained by heating and refluxing 6-hydroxynaphthoic acid in a methanol solvent in the presence of concentrated sulfuric acid. The obtained 6-hydroxynaphthoic acid methyl ester is reacted in water in the presence of ferric chloride hexahydrate, and the reaction product is hydrolyzed, whereby the racemic 2 which is an MOF ligand is obtained. 2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid is obtained.
上記ラセミ体の２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸は、光学分割によりＲ体とＳ体に分割され、それぞれ硝酸銅水和物と反応させることで、ＭＯＦを合成することができる。上記光学分割は、ラセミ体とブルシン（２，３−ジメトキシストリキニジン−１０−オン）をメタノール中で混合することにより行うことができる。 The racemic 2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid is divided into R-form and S-form by optical resolution, and each is reacted with copper nitrate hydrate. , MOF can be synthesized. The above optical resolution can be carried out by mixing a racemate and brucine (2,3-dimethoxytriquinidin-10-one) in methanol.
ＭＯＦは、上述のとおり溶媒に全く溶解しない。そのため、担体への担持が不可能であり、カラム中に保持することが困難であるため、ＭＯＦが有する十分な分離性能を引き出すことができなかった。具体的には、後述する比較例において示すが、ｉ）乳鉢で磨り潰した後、担体と混合する方法や、ｉｉ）乳鉢で磨り潰した後、溶媒に分散させ、担体と混合する方法、などの方法により、光学異性体用分離剤を製造したが、多孔質担体に担持された光学活性分離剤とはいえず、十分な分離性能は発揮されなかった。 MOF does not dissolve in the solvent at all as described above. Therefore, it cannot be supported on a carrier and is difficult to hold in a column, so that sufficient separation performance of MOF could not be obtained. Specifically, as shown in Comparative Examples described later, i) a method of grinding with a mortar and then mixing with a carrier, ii) a method of grinding with a mortar and then dispersing in a solvent and mixing with a carrier, etc. By this method, a separation agent for optical isomers was produced, but it was not an optically active separation agent supported on a porous carrier, and sufficient separation performance was not exhibited.
本発明では、光学活性なＭＯＦ配位子と金属化合物を混合する前に、光学活性なＭＯＦ配位子を多孔質担体に吸着させ、その後金属化合物と混合することにより、多孔質担体に担持されたＭＯＦを製造することが可能となった。以下、この点について説明する。 In the present invention, before mixing the optically active MOF ligand and the metal compound, the optically active MOF ligand is adsorbed on the porous carrier, and then mixed with the metal compound to be supported on the porous carrier. MOF can be manufactured. Hereinafter, this point will be described.
本発明に用いられる多孔質担体は、特に限定されず、クロマトグラフィーで使用されることが知られている種々の多孔質担体を用いることができる。例えば多孔質有機担体や多孔質無機担体等が挙げられ、好ましくは多孔質無機担体である。前記多孔質有機担体としては、例えばポリスチレン、ポリアクリルアミド、ポリアクリレート及びこれらの誘導体等の高分子物質等が挙げられる。前記多孔質無機担体としては、例えばシリカゲル、アルミナ、マグネシア、ガラス、カオリン、酸化チタン、ケイ酸塩、ヒドロキシアパタイト、ジルコニア等が挙げられ、特にシリカゲルが好ましい。 The porous carrier used in the present invention is not particularly limited, and various porous carriers known to be used in chromatography can be used. Examples thereof include a porous organic carrier and a porous inorganic carrier, and a porous inorganic carrier is preferable. Examples of the porous organic carrier include polymer substances such as polystyrene, polyacrylamide, polyacrylate, and derivatives thereof. Examples of the porous inorganic carrier include silica gel, alumina, magnesia, glass, kaolin, titanium oxide, silicate, hydroxyapatite, zirconia, and silica gel is particularly preferable.
本発明において用いられる多孔質担体の粒径は０．１μｍ〜１０ｍｍであることが好ましく、１μｍ〜３００μｍであることがより好ましい。多孔質担体にシリカゲルを用いる場合、シリカゲルの表面は残存シラノールの影響を排除するために表面処理が施されていることが望ましいが、全く表面処理が施されていないものを使用してもよい。表面処理は公知の方法によって行うことが出来る。 The particle size of the porous carrier used in the present invention is preferably 0.1 μm to 10 mm, and more preferably 1 μm to 300 μm. When silica gel is used for the porous carrier, the surface of the silica gel is desirably surface-treated in order to eliminate the influence of residual silanol, but may be one that has not been surface-treated at all. The surface treatment can be performed by a known method.
光学活性なＭＯＦ配位子を多孔質担体に吸着させる方法は特段限定されず、例えば光学活性なＭＯＦ配位子を溶媒に溶解し、該溶液を多孔質担体と混合し、溶媒を留去する方法が例示できる。多孔質担体に吸着させるＭＯＦ配位子の量は、多孔質担体の種類にもよるが、多孔質担体１００重量部に対し、１〜８０重量部であることが好ましく、５〜４０重量部であることがより好ましい。 The method for adsorbing the optically active MOF ligand to the porous carrier is not particularly limited. For example, the optically active MOF ligand is dissolved in a solvent, the solution is mixed with the porous carrier, and the solvent is distilled off. A method can be exemplified. The amount of the MOF ligand to be adsorbed on the porous carrier is preferably 1 to 80 parts by weight, preferably 5 to 40 parts by weight with respect to 100 parts by weight of the porous carrier, although it depends on the kind of the porous carrier. More preferably.
上記光学活性なＭＯＦ配位子を溶解する溶媒は、ＭＯＦ配位子の種類により適宜選択することが可能であり、上記一般式（１）で表されるビナフタレンジカルボン酸誘導体であれば、エタノールなどのアルコール溶媒、を用いることができる。 The solvent for dissolving the optically active MOF ligand can be appropriately selected depending on the type of MOF ligand, and ethanol can be used as long as it is a binaphthalenedicarboxylic acid derivative represented by the general formula (1). Alcohol solvents such as can be used.
光学活性なＭＯＦ配位子を吸着させた多孔質担体は、金属化合物との加熱反応により多孔質担体担持ＭＯＦを得ることができる。具体的には、溶剤下でＭＯＦ配位子を吸着させた多孔質担体と金属化合物を混合し、混合溶液を加熱攪拌し、その後該混合溶液を冷却することで、多孔質担体担持ＭＯＦの結晶を析出させることができる。 A porous carrier on which an optically active MOF ligand is adsorbed can obtain a porous carrier-supported MOF by a heating reaction with a metal compound. Specifically, the porous support on which the MOF ligand is adsorbed in a solvent is mixed with the metal compound, the mixed solution is heated and stirred, and then the mixed solution is cooled, so that crystals of the porous support-carrying MOF are crystallized. Can be deposited.
上記金属化合物は、上述したＭＯＦを構成する金属原子を含み、錯体の形成に用いられ
る金属化合物を使用することができる。具体的には、硝酸銅、若しくはその水和物、硝酸亜鉛、若しくはその水和物、硫酸銅若しくはその水和物、酢酸銅若しくはその水和物、塩化銅、塩化亜鉛などが挙げられ、ＭＯＦ配位子が上記一般式（１）で表されるビナフタレンジカルボン酸誘導体であれば、硝酸銅、若しくはその水和物が好ましく用いられる。また、上記ＭＯＦ配位子を吸着させた多孔質担体と混合させる金属化合物の量は、用いるＭＯＦ配位子を吸着させた多孔質担体と金属化合物の種類によるが、多孔質担体１００重量部に対し、１〜１００重量部であることが好ましく、５〜８０重量部混合させることがより好ましい。
The metal compound includes a metal atom constituting the MOF described above, and a metal compound used for forming a complex can be used. Specific examples include copper nitrate or hydrate thereof, zinc nitrate or hydrate thereof, copper sulfate or hydrate thereof, copper acetate or hydrate thereof, copper chloride, zinc chloride, and the like. If the ligand is a binaphthalenedicarboxylic acid derivative represented by the general formula (1), copper nitrate or a hydrate thereof is preferably used. The amount of the metal compound to be mixed with the porous carrier on which the MOF ligand is adsorbed depends on the kind of the porous carrier on which the MOF ligand to be adsorbed and the metal compound is used. On the other hand, the amount is preferably 1 to 100 parts by weight, and more preferably 5 to 80 parts by weight.
上記、加熱反応に用いる溶剤は、極性溶剤が好ましく用いられ、特にジメチルホルムアルデヒドなどの非プロトン系の極性溶剤が好ましく用いられる。また、加熱反応の際の混合溶液の加熱攪拌は、１〜１００℃で１〜３００時間行うことが好ましく、１５〜４０℃で１０〜１００時間行うことが、より好ましい。加熱攪拌後の冷却は、結晶を析出させるために通常行う方法であれば良く、室温に静置することで結晶を析出させることができる。 The solvent used for the heating reaction is preferably a polar solvent, and particularly preferably an aprotic polar solvent such as dimethylformaldehyde. Moreover, it is preferable to carry out heating stirring of the mixed solution in the case of a heating reaction at 1-100 degreeC for 1 to 300 hours, and it is more preferable to carry out for 10 to 100 hours at 15-40 degreeC. Cooling after heating and stirring may be a method that is usually performed for precipitating crystals, and crystals can be precipitated by standing at room temperature.
本発明において多孔質担体へのＭＯＦの担持量は、多孔質担体やＭＯＦの種類により異なるが、多孔質担体１００重量部に対して１〜８０重量部であることが好ましく、５〜４０重量部であることがより好ましい。 In the present invention, the amount of MOF supported on the porous carrier varies depending on the kind of the porous carrier and the MOF, but is preferably 1 to 80 parts by weight, preferably 5 to 40 parts by weight with respect to 100 parts by weight of the porous carrier. It is more preferable that
なお、本発明において、多孔質担体にＭＯＦが担持されているか否かは、粉末Ｘ線回折によりパターンを確認することで判別することができる。 In the present invention, whether or not MOF is supported on the porous carrier can be determined by confirming the pattern by powder X-ray diffraction.
多孔質担持体に光学活性な多孔性金属−有機構造体（ＭＯＦ）を担持した光学異性体用分離剤は、クロマトグラフィーの固定相として用いることができ、分離カラムに充填し、ガスクロマトグラフィー、液体クロマトグラフィー、薄層クロマトグラフィー、超臨界流体クロマトグラフィー、電気泳動等に適用することができ、特に（連続式）液体クロマトグラフィー法、薄層クロマトグラフィー、電気泳動に好適である。 The optical isomer separation agent carrying an optically active porous metal-organic structure (MOF) on a porous carrier can be used as a stationary phase for chromatography, packed in a separation column, gas chromatography, It can be applied to liquid chromatography, thin layer chromatography, supercritical fluid chromatography, electrophoresis, etc., and is particularly suitable for (continuous) liquid chromatography, thin layer chromatography, and electrophoresis.
以下、実施例により本発明を詳細に説明するが、これにより本発明が実施例に限定されるものではない。なお、分析条件における溶解液又は移動相の組成は容積比である。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to an Example by this. The composition of the solution or mobile phase under the analysis conditions is a volume ratio.
＜合成例：光学活性な２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸の合成＞
ｉ）６−ヒドロキシナフト酸のメチルエステル化反応
定法に従い、６−ヒドロキシナフト酸２５ｇに対して、触媒量１０ｍＬの濃硫酸存在下、メタノール溶媒中で４時間の加熱還流を行うことで、６−ヒドロキシナフト酸メチルエステル２５ｇを得た（収率９４％）。
<Synthesis Example: Synthesis of optically active 2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid>
i) Methyl esterification reaction of 6-hydroxynaphthoic acid According to a conventional method, 6 g-hydroxynaphthoic acid is heated and refluxed in a methanol solvent for 4 hours in the presence of 10 mL of concentrated sulfuric acid with respect to 25 g of 6-hydroxynaphthoic acid. 25 g of hydroxynaphthoic acid methyl ester was obtained (yield 94%).
ｉｉ）６−ヒドロキシナフト酸メチルエステルのカップリング反応
２５０ｍＬの水中において、触媒量６７ｇの塩化第二鉄・６水和物の存在下、上記得られた６−ヒドロキシナフト酸メチルエステル２５ｇを７０℃で２０時間反応させることで、（ｒａｃ）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸メチルエステル１３ｇを得た（収率５３％）。
ii) Coupling reaction of 6-hydroxynaphthoic acid methyl ester In 250 mL of water, 25 g of the obtained 6-hydroxynaphthoic acid methyl ester was treated at 70 ° C. in the presence of a catalytic amount of 67 g of ferric chloride hexahydrate. For 20 hours to obtain 13 g of (rac) -2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid methyl ester (yield 53%).
ｉｉｉ）（ｒａｃ）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸メチルエステルの加水分解
（ｒａｃ）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸メチルエステル１２ｇ、およびＮａＯＨ１０ｇを１００ｍＬの水中に添加し、１時間の
加熱還流により、（ｒａｃ）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸１１ｇを得た（収率９８％）。
iii) Hydrolysis of (rac) -2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid methyl ester (rac) -2,2′-dihydroxy-1,1′-binaphthalene- 12 g of 6,6′-dicarboxylic acid methyl ester and 10 g of NaOH were added to 100 mL of water, and heated to reflux for 1 hour to (rac) -2,2′-dihydroxy-1,1′-binaphthalene-6,6 ′. -11 g of dicarboxylic acid was obtained (yield 98%).
ｉｖ）（ｒａｃ）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸の光学分割
（ｒａｃ）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸０．２０ｇとブルシン（２，３−ジメトキシストリキニジン−１０−オン）０．４２ｇをメタノール２４０ｍＬに溶解させ、室温で１２時間の静置後、得られた固体錯体（無色プリズム状、０．３２ｇ）を濾取することで、（Ｒ）−（＋）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸・ブルシン錯体を粗生成物として取り出した。これをメタノール２００ｍＬに溶解させ再結晶し、得られた（Ｒ）−（＋）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸・ブルシン錯体（０．２０ｇ、ｍｐ：２３３−２３５℃）に希硫酸を作用させブルシンを取り除き、酢酸エチルで抽出することにより光学活性な（Ｒ）−（＋）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸０．０５３ｇを得た（収率５３％、光学純度９９％ｅｅ、ｍｐ：３２６−３２７℃）。
iv) Optical resolution of (rac) -2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid (rac) -2,2′-dihydroxy-1,1′-binaphthalene-6 0.20 g of 6′-dicarboxylic acid and 0.42 g of brucine (2,3-dimethoxytriquinidin-10-one) were dissolved in 240 mL of methanol and allowed to stand at room temperature for 12 hours, and then the resulting solid complex (colorless prism) (R)-(+)-2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid / brucine complex as a crude product I took it out. This was dissolved in 200 mL of methanol and recrystallized, and the obtained (R)-(+)-2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid / brucine complex (0.20 g , Mp: 233-235 ° C.), by removing dilute sulfuric acid to remove brucine and extracting with ethyl acetate, optically active (R)-(+)-2,2′-dihydroxy-1,1′-binaphthalene- 0.053 g of 6,6′-dicarboxylic acid was obtained (yield 53%, optical purity 99% ee, mp: 326-327 ° C.).
一方、上記無色プリズム状の固体錯体を濾取した後の濾液に対し、希硫酸を作用させブルシンを取り除き、酢酸エチルで抽出することにより、粗生成物として、（Ｓ）−（−）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸を得た。これにメタノール中、ジアザビシクロオクタン（ＤＡＢＣＯ）を作用させ、（ｒａｃ）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸をＤＡＢＣＯの錯体として取り除くことにより、光学活性な（Ｓ）−（−）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸０．０３０ｇ（収率３０％、光学純度：９９％ｅｅ、ｍｐ：３２２−３２３℃）を得た。 On the other hand, the filtrate after the colorless prism-like solid complex is filtered off is treated with dilute sulfuric acid to remove brucine and extracted with ethyl acetate to give (S)-(-)-2 as a crude product. 2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid was obtained. This was treated with diazabicyclooctane (DABCO) in methanol, and (rac) -2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid was removed as a complex of DABCO, Optically active (S)-(−)-2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid 0.030 g (yield 30%, optical purity: 99% ee, mp: 322-323 ° C).
それぞれの光学活性体の光学純度は、ダイセル化学工業（株）社製、ＣＨＩＲＡＬＰＡＫ ＡＳ（０．４６φ×２５ｃｍ）、分析条件は、溶解液：ｎ−ヘキサン／ＥｔＯＨ／ＴＦＡ＝７５／２５／０．１、流速：１．０ｍｌ／ｍｉｎ、検出：ＵＶ２５４ｎｍにより測定した（（Ｓ）体：１４分、（Ｒ）体：１７分）。 The optical purity of each optically active substance was manufactured by Daicel Chemical Industries, Ltd., CHIRALPAK AS (0.46φ × 25 cm), and the analysis conditions were dissolved solution: n-hexane / EtOH / TFA = 75/25/0. 1. Flow rate: 1.0 ml / min, detection: measured by UV254 nm ((S) body: 14 minutes, (R) body: 17 minutes).
＜実施例：シリカゲル担持光学活性ＭＯＦの合成＞
合成例で得た（Ｒ）−（＋）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸０．５ｇをエタノール５０ｍＬに溶解して均一溶液とした。この溶液にシリカゲル（シリカゲル６０、メルク製、粒径０．０６３−０．２００ｍｍ）２．５ｇを加えて、エバポレーターを用いてエタノールを完全に留去し、（Ｒ）−（＋）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸をシリカゲルに吸着させた試料を作成した。作成した試料３．０ｇ、硝酸銅・三水和物０．５ｇを純水１ｍＬに溶解したもの、およびジメチルホルムアミド（ＤＭＦ）１５ｍＬの混合物を、耐圧ガラス容器中、８０℃で２４時間加熱攪拌した。溶液を室温まで冷却したのち、析出した緑色結晶を吸引濾過し、メタノールで洗浄した。得られた結晶を１３０℃で２時間減圧下乾燥すると、緑色粉末結晶の生成物（シリカゲル担持光学活性ＭＯＦ）が２．５ｇ得られた。
得られた緑色粉末結晶の粉末Ｘ線回折（ＰＸＲＤ）パターンを確認すると、ＭＯＦの粉末Ｘ線回折（ＰＸＲＤ）パターンに類似しており、シリカゲル担持光学活性ＭＯＦの合成されたことを確認した。
<Example: Synthesis of silica gel-supported optically active MOF>
0.5 g of (R)-(+)-2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid obtained in the synthesis example was dissolved in 50 mL of ethanol to obtain a homogeneous solution. To this solution, 2.5 g of silica gel (
When the powder X-ray diffraction (PXRD) pattern of the obtained green powder crystal was confirmed, it was similar to the powder X-ray diffraction (PXRD) pattern of MOF, and it was confirmed that silica gel-supported optically active MOF was synthesized.
＜分離評価１＞
上記シリカゲル担持光学活性ＭＯＦを、０．４６φ×５ｃｍＬステンレス製カラムに、スラリー充填法により充填し、カラムを作製した。作製したカラムに、下記式（４）に示すサンプル（ＴＴＢ）を用いて、カラムの分離性能評価を行った。
なお、カラムの分析条件を以下に示し、結果を図１−１に示す。
加えて、図１−１についてピーク対称性を下記計算式に基づき算出したところ、１．６７であった。ピーク対称性の説明を図４に示す。
ピーク対称性＝Ｗ0.05／２×ｆ
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
背圧： １．７ＭＰａ
サンプル打ち込み量： １．０ｍｇ／ｍｌ（移動相）×１０μＬ
<
The silica gel-supported optically active MOF was packed into a 0.46φ × 5 cmL stainless steel column by a slurry filling method to prepare a column. The separation performance of the column was evaluated using a sample (TTB) represented by the following formula (4) for the prepared column.
The column analysis conditions are shown below, and the results are shown in FIG. 1-1.
In addition, the peak symmetry of FIG. 1-1 was calculated based on the following calculation formula, and was 1.67. An explanation of peak symmetry is shown in FIG.
Peak symmetry = W 0.05 / 2 × f
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Back pressure: 1.7 MPa
Sample injection amount: 1.0 mg / ml (mobile phase) × 10 μL
＜分離評価２＞
分離評価１で用いたカラムに、下記式（５）に示すサンプル（Ｂｉｎａｐｈｔｏｌ／（Ｒ））を用いて、カラムの不斉識別能力評価を行った。
なお、カラムの分析条件を以下に示し、結果を図１−２に示す。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
サンプル打ち込み量： １．０ｍｇ／ｍｌ（移動相）×１５μＬ
<
The column used in the
The column analysis conditions are shown below, and the results are shown in FIG.
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Sample injection amount: 1.0 mg / ml (mobile phase) × 15 μL
＜分離評価３＞
分離評価１で用いたカラムに、下記式（６）に示すサンプル（ＭｅＰｈＳＯ／（Ｒ））を用いて、カラムの不斉識別能力評価を行った。
なお、カラムの分析条件を以下に示し、結果を図１−３に示す。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
サンプル打ち込み量： １．０ｍｇ／ｍｌ（移動相）×１５μＬ
<
Using the sample (MePhSO / (R)) shown in the following formula (6) as the column used in the
The column analysis conditions are shown below, and the results are shown in FIGS. 1-3.
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Sample injection amount: 1.0 mg / ml (mobile phase) × 15 μL
＜比較例１：シリカゲル混合光学活性ＭＯＦの合成＞
合成例で得た（Ｒ）−（＋）−２，２'−ジヒドロキシ−１，１'−ビナフタレン−６，６'−ジカルボン酸０．４ｇをメタノール６０ｍＬに溶解させ、硝酸銅１水和物０．２６ｇと混合し、デシケーター中でジメチルアニリンの蒸気と接触反応させながら室温で１日から１週間程度静置することで、緑色の針状結晶である光学活性ＭＯＦを得た（収率３７％）。
得られた光学活性ＭＯＦ１２０ｍｇをメノウ乳鉢で磨り潰し、磨り潰した光学活性ＭＯＦとクロマトグラフ用シリカゲル（ＳＰ−１２０−５−ＡＰＳ、ダイソー社製、粒径０．００５ｍｍ、アミノプロピルシラン処理）３６０ｍｇを十分に混合し、得られた粉体をそのまま０．４６φ×５ｃｍＬステンレス製カラムに、タッピング法により充填を行い、カラムを作製した。タッピング法とは、充填剤を固体のまま直接カラム管に入れ、ある密な充填がなされるまでタッピングを繰り返すことでカラム充填を行う方法である。
<Comparative Example 1: Synthesis of silica gel mixed optically active MOF>
(R)-(+)-2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid 0.4 g obtained in the synthesis example was dissolved in 60 mL of methanol, and copper nitrate monohydrate was obtained. This was mixed with 0.26 g and allowed to stand at room temperature for about 1 day to 1 week while being contacted with dimethylaniline vapor in a desiccator to obtain an optically active MOF as a green needle crystal (yield 37). %).
The obtained optically active MOF (120 mg) was ground in an agate mortar, and the ground optically active MOF and chromatographic silica gel (SP-120-5-APS, manufactured by Daiso Corporation, particle size 0.005 mm, aminopropylsilane treatment) (360 mg) The mixture was sufficiently mixed, and the obtained powder was directly packed in a 0.46φ × 5 cmL stainless steel column by a tapping method to produce a column. The tapping method is a method of filling a column by putting a packing material directly into a column tube as a solid and repeating tapping until a certain dense packing is achieved.
＜比較分離評価１＞
比較例１で作製したカラムに、上記式（４）に示すサンプル（ＴＴＢ）を用いて、カラムの分離性能評価を行った。
なお、カラムの分析条件を以下に示し、結果を図２−１に示す。
加えて、図２−１についてピーク対称性を分離評価１と同様にして算出したところ、２．０５であった。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
背圧： 〜０．２ＭＰａ
サンプル打ち込み量： １．０ｍｇ／ｍｌ（移動相）×１０μＬ
<
The separation performance of the column was evaluated using the sample (TTB) represented by the above formula (4) for the column produced in Comparative Example 1.
The column analysis conditions are shown below, and the results are shown in FIG.
In addition, the peak symmetry with respect to FIG. 2-1 was calculated in the same manner as in the
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Back pressure: ~ 0.2MPa
Sample injection amount: 1.0 mg / ml (mobile phase) × 10 μL
＜比較分離評価２＞
比較例１で作製したカラムに、上記式（５）に示すサンプル（Ｂｉｎａｐｈｔｏｌ／（
Ｒ））を用いて、カラムの分離性能評価を行った。
なお、カラムの分析条件を以下に示し、結果を図２−２に示す。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
サンプル打ち込み量： １．５ｍｇ／ｍｌ（移動相）×１０μＬ
<
In the column produced in Comparative Example 1, the sample (Binaphtol / (
R)) was used to evaluate the separation performance of the column.
The column analysis conditions are shown below, and the results are shown in FIG.
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Sample injection amount: 1.5 mg / ml (mobile phase) × 10 μL
＜比較分離評価３＞
比較例１で作製したカラムに、上記式（６）に示すサンプル（ＭｅＰｈＳＯ／（Ｒ））を用いて、カラムの分離性能評価を行った。
なお、カラムの分析条件を以下に示し、結果を図２−３に示す。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
サンプル打ち込み量： １．５ｍｇ／ｍｌ（移動相）×１０μＬ
<
The separation performance of the column was evaluated using the sample (MePhSO / (R)) shown in the above formula (6) for the column manufactured in Comparative Example 1.
The column analysis conditions are shown below, and the results are shown in FIG.
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Sample injection amount: 1.5 mg / ml (mobile phase) × 10 μL
＜比較例２：シリカゲル混合光学活性ＭＯＦの合成＞
比較例１で用いた光学活性ＭＯＦ１２０ｍｇをメノウ乳鉢で磨り潰し、磨り潰した光学活性ＭＯＦをメタノール１２ｍＬに添加し、よく分散させた。この懸濁液をクロマトグラフ用シリカゲル（ＳＰ−１２０−５−ＡＰＳ、ダイソー社製、粒径０．００５ｍｍ、アミノプロピルシラン処理）４００ｍｇに均一に振り混ぜ、ＭｅＯＨを留去させた。これを数回繰り返すことで、シリカゲルへ混合させた。得られた粉体をそのまま０．４６φ×５ｃｍＬステンレス製カラムに、タッピング法により充填を行い、カラムを作製した。
<Comparative Example 2: Synthesis of silica gel mixed optically active MOF>
120 mg of the optically active MOF used in Comparative Example 1 was ground in an agate mortar, and the ground optically active MOF was added to 12 mL of methanol and well dispersed. The suspension was uniformly shaken and mixed with 400 mg of chromatographic silica gel (SP-120-5-APS, manufactured by Daiso Corporation, particle size 0.005 mm, aminopropylsilane treatment) to distill off MeOH. By repeating this several times, the silica gel was mixed. The obtained powder was directly packed into a 0.46φ × 5 cmL stainless steel column by a tapping method to produce a column.
＜比較分離評価４＞
比較例２で作製したカラムに、上記式（４）に示すサンプル（ＴＴＢ）を用いて、カラムの分離性能評価を行った。
なお、カラムの分析条件を以下に示し、結果を図３−１に示す。
加えて、図３−１についてピーク対称性を分離評価１と同様にして算出したところ、２．７３であった。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
背圧： 〜０．２ＭＰａ
サンプル打ち込み量： １．０ｍｇ／ｍｌ（移動相）×１０μＬ
<
The separation performance of the column was evaluated using the sample (TTB) represented by the above formula (4) for the column produced in Comparative Example 2.
The column analysis conditions are shown below, and the results are shown in FIG.
In addition, the peak symmetry with respect to FIG. 3-1 was calculated in the same manner as in the
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Back pressure: ~ 0.2MPa
Sample injection amount: 1.0 mg / ml (mobile phase) × 10 μL
＜比較分離評価５＞
比較例２で作製したカラムに、上記式（５）に示すサンプル（Ｂｉｎａｐｈｔｏｌ／（Ｒ））を用いて、カラムの分離性能評価を行った。
なお、カラムの分析条件を以下に示し、結果を図３−２に示す。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
サンプル打ち込み量： １．５ｍｇ／ｍｌ（移動相）×１０μＬ
<
The separation performance of the column was evaluated using the sample (Binaphtol / (R)) shown in the above formula (5) for the column produced in Comparative Example 2.
The column analysis conditions are shown below, and the results are shown in FIG. 3-2.
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Sample injection amount: 1.5 mg / ml (mobile phase) × 10 μL
＜比較分離評価６＞
比較例２で作製したカラムに、上記式（６）に示すサンプル（ＭｅＰｈＳＯ／（Ｒ））を用いて、カラムの分離性能評価を行った。
なお、カラムの分析条件を以下に示し、結果を図３−３に示す。
移動相： ヘキサン／２−ＰｒＯＨ＝９／１
温度： ２５℃
流速： ０．２ｍＬ／ｍｉｎ
検出： ＵＶ２５４ｎｍ
サンプル打ち込み量： １．５ｍｇ／ｍｌ（移動相）×１０μＬ
<
The separation performance of the column was evaluated using the sample (MePhSO / (R)) represented by the above formula (6) for the column prepared in Comparative Example 2.
The column analysis conditions are shown below, and the results are shown in FIG.
Mobile phase: Hexane / 2-PrOH = 9/1
Temperature: 25 ° C
Flow rate: 0.2 mL / min
Detection: UV254nm
Sample injection amount: 1.5 mg / ml (mobile phase) × 10 μL
比較例１および２においては、ＴＴＢの分離についてはある程度可能であるが、Ｂｉｎａｐｈｔｏｌ／（Ｒ）、およびＭｅＰｈＳＯ／（Ｒ）などの化合物については、明確に分離することは難しい。しかしながら、本発明の光学異性体用分離剤を用いた場合には、Ｂｉｎａｐｈｔｏｌ／（Ｒ）、およびＭｅＰｈＳＯ／（Ｒ）であっても、明確に分離することができる。 In Comparative Examples 1 and 2, it is possible to separate TTB to some extent, but it is difficult to clearly separate compounds such as Binaphtol / (R) and MePhSO / (R). However, when the separating agent for optical isomers of the present invention is used, even Binaphtol / (R) and MePhSO / (R) can be clearly separated.
本発明の光学異性体用分離剤を用いることで、ラセミ体の光学分割を効率良く行うことが可能となる。その結果、医薬分野や食品分野において、光学異性他の生産性の向上に貢献することができる。 By using the separating agent for optical isomers of the present invention, it is possible to efficiently perform optical resolution of racemates. As a result, it can contribute to the improvement of productivity of optical isomerism and the like in the pharmaceutical field and food field.
Claims (4)
前記光学異性体用分離剤は、多孔質担体に光学活性な多孔性金属−有機構造体が担持されているものであり、前記光学活性な多孔性金属−有機構造体は、下記一般式（１）で示される配位子を含む、光学異性体用分離剤。
1 〜Ｒ 6 のうちの１つはカルボキシル基又は炭素数１〜５のアルキルカルボキシル基であり、Ｒ 6 は水素以外の基である。］ For optical isomers produced by a method for producing a separating agent for optical isomers comprising a step of adsorbing a ligand constituting an optically active porous metal-organic structure on a porous carrier and then mixing with a metal compound A separating agent,
The optical isomer separating agent is one in which an optically active porous metal-organic structure is supported on a porous carrier , and the optically active porous metal-organic structure is represented by the following general formula (1 A separating agent for optical isomers , comprising a ligand represented by:
One of 1 to R 6 is a carboxyl group or an alkyl carboxyl group having 1 to 5 carbon atoms, and R 6 is a group other than hydrogen. ]
前記光学活性な多孔性金属−有機構造体を構成する配位子を多孔質担体に吸着させ、その後金属化合物と混合する工程を含み、前記多孔性金属−有機構造体は、下記一般式（１）で示される配位子を含む、光学異性体用分離剤の製造方法。
A step of adsorbing a ligand constituting the optically active porous metal-organic structure onto a porous carrier and then mixing with a metal compound , wherein the porous metal-organic structure is represented by the following general formula (1) The manufacturing method of the separating agent for optical isomers containing the ligand shown by this .
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