JP5488967B2 - Separating agent for optical isomers having chiral porous metal-organic structure - Google Patents

Description

  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.

  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.

  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.

  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.

  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.

  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.

JP-A-57-150432 Japanese Patent Laid-Open No. 63-307829 Japanese Patent Laid-Open No. 2007-167821

Y. Okamoto, M .; Kawashima and K.K. Hatada, J. et al. Am. Chem. Soc. , 106, 5337, 1984 Yong Cui, Helen L. Ngo, Peter S .; White and Wenbin Lin, Chem. commun, 994, 2003 K. Tanaka, S .; Oda and M.M. shiro, Chem. commun, 820, 2008

  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.

  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.

  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.

  Another embodiment of the present invention is a separation column packed with the optical isomer separating agent.

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.

  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.

It is a figure which shows the peak shape which performed isolation | separation evaluation of TTB using the optically active separating agent manufactured in Example 1. FIG. It is a figure which shows the peak shape which performed isolation | separation evaluation of Binaphtol using the optically active separation agent manufactured in Example 1. FIG. It is a figure which shows the peak shape which performed the separation evaluation of MePhSO using the optically active separating agent manufactured in Example 1. It is a figure which shows the peak shape which performed isolation | separation evaluation of TTB using the optically active separating agent manufactured by the comparative example 1. It is a figure which shows the peak shape which performed isolation | separation evaluation of Binaphtol using the optically active separation agent manufactured by the comparative example 1. It is a figure which shows the peak shape which performed isolation | separation evaluation of MePhSO using the optically active separation agent manufactured by the comparative example 1. FIG. It is a figure which shows the peak shape which performed isolation | separation evaluation of TTB using the optically active separating agent manufactured in the comparative example 2. It is a figure which shows the peak shape which performed isolation | separation evaluation of Binaphtol using the optically active separating agent manufactured in the comparative example 2. FIG. It is a figure which shows the peak shape which performed the separation evaluation of MePhSO using the optically active separation agent manufactured in the comparative example 2. It is a figure explaining the numerical value of the peak symmetry which concerns on an Example.

  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.

  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.

  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.

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 .

  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 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 Non-Patent Document 2. Moreover, MOF containing the ligand shown by said Formula (3) is compoundable by the method of the nonpatent literature 3, for example. Hereinafter, the ligand used for the synthesis of MOF is also referred to as MOF ligand.

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.

  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 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.

  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.

  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.

  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.

  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.

  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.

  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.

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.

  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.

  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

  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.

  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.

  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.

<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) 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) 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) 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.).

  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).

  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).

<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 (silica gel 60, manufactured by Merck, particle size 0.063-0.200 mm) was added, and ethanol was completely distilled off using an evaporator, and (R)-(+)-2, A sample was prepared by adsorbing 2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid on silica gel. A mixture of 3.0 g of the prepared sample, 0.5 g of copper nitrate trihydrate dissolved in 1 mL of pure water, and 15 mL of dimethylformamide (DMF) was heated and stirred at 80 ° C. for 24 hours in a pressure-resistant glass container. . After cooling the solution to room temperature, the precipitated green crystals were suction filtered and washed with methanol. The obtained crystal was dried under reduced pressure at 130 ° C. for 2 hours to obtain 2.5 g of a green powder crystal product (silica gel-supported optically active MOF).
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.

<Separation evaluation 1>
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

<Separation evaluation 2>
The column used in the separation evaluation 1 was subjected to an evaluation of the asymmetry discrimination ability of the column using a sample (Binaphtol / (R)) represented by the following formula (5).
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

<Separation evaluation 3>
Using the sample (MePhSO / (R)) shown in the following formula (6) as the column used in the separation evaluation 1, the asymmetry discrimination ability of the column was evaluated.
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

<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.

<Comparative separation evaluation 1>
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 separation evaluation 1, and was 2.05.
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

<Comparative separation evaluation 2>
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

<Comparative separation evaluation 3>
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

<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.

<Comparative separation evaluation 4>
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 separation evaluation 1, and was 2.73.
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

<Comparative separation evaluation 5>
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

<Comparative separation evaluation 6>
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

  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.

  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)

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:

[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 carbon. Selected from an alkyl carboxyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, R
_{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. ] The separating agent for optical isomers according to claim 1, wherein the porous carrier is silica gel. A separation column packed with the separation agent for optical isomers according to claim 1 or 2 . A method for producing a separating agent for optical isomers carrying an optically active porous metal-organic structure on a porous carrier, comprising:
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 .

[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 carbon. containing 1-5 alkylcarboxyl group, or selected from an alkoxy group having 1 to 5 carbon atoms, one of R ₁ to R ₆ is a carboxyl group or an alkylcarboxyl group having 1 to 5 carbon atoms, R ₆ Is a group other than hydrogen. ]

Images