WO2010126087A1 - 光学異性体用分離剤 - Google Patents
光学異性体用分離剤 Download PDFInfo
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- WO2010126087A1 WO2010126087A1 PCT/JP2010/057581 JP2010057581W WO2010126087A1 WO 2010126087 A1 WO2010126087 A1 WO 2010126087A1 JP 2010057581 W JP2010057581 W JP 2010057581W WO 2010126087 A1 WO2010126087 A1 WO 2010126087A1
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- 0 C*(*)O[C@](C1O*)OC(CO*)[C@@](C(C)(*)*)[C@@]1(C)O* Chemical compound C*(*)O[C@](C1O*)OC(CO*)[C@@](C(C)(*)*)[C@@]1(C)O* 0.000 description 2
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
- B01J20/3206—Organic carriers, supports or substrates
- B01J20/3208—Polymeric carriers, supports or substrates
- B01J20/321—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions involving only carbon to carbon unsaturated bonds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/29—Chiral phases
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
- B01J20/3204—Inorganic carriers, supports or substrates
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
- B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
- B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3268—Macromolecular compounds
- B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
- B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3268—Macromolecular compounds
- B01J20/328—Polymers on the carrier being further modified
Definitions
- the present invention relates to a separating agent for optical isomers.
- Patent Document 1 describes a chromatographic filler in which a cellulose derivative containing an aromatic ring is supported on a carrier such as silica.
- Patent Document 2 describes a chromatographic filler in which a carbamate derivative of a polysaccharide such as amylose is supported on a carrier such as silica. Such techniques require further optical isomer resolution.
- ⁇ -conjugated polymers such as polyphenylene vinylene are known as functional substances containing various functions, and are known to be usable as conductive plastics through chemical reactions such as oxidation and reduction.
- it has been applied to optoelectronic devices such as LEDs and solar cells by taking advantage of the characteristics.
- JP 60-142930 A JP-A-60-226831
- An object of the present invention is to provide a separating agent for optical isomers excellent in optical resolution.
- the present invention has been made in view of the above circumstances, and as a result of diligent research, the present inventor carried on a carrier a clathrate complex in which a ⁇ -conjugated polymer is clathrated with a polymer compound and separated for optical isomers. As a result, it was found that this separating agent has higher optical separation ability. That is, the gist of the present invention is as follows.
- a separating agent for optical isomers in which an inclusion complex in which a ⁇ -conjugated polymer is included in a polymer compound having a hydroxyl group or an amino group is supported on a carrier.
- separating agent for optical isomers according to any one of (1) to (4), wherein the ⁇ -conjugated polymer is polyphenylene vinylene, polyphenylene ethynylene, polyphenylene, polythiophene, polypyrrole, or polyacetylene.
- optical complex according to (6), wherein the inclusion complex is obtained by polymerizing a monomer that generates a structural unit represented by the following formula (I) after polymerization in a solution in which amylose is dissolved. Separating agent for isomers.
- R ′ is an aliphatic or aromatic hydrocarbon group that may contain a hetero atom, may be unsubstituted, or may contain a hetero atom having 1 to 12 carbon atoms.
- a separating agent for optical isomers excellent in optical resolution of a specific compound for example, excellent in optical resolution of an amide compound.
- FIG. 3 is a diagram showing a 1 H NMR spectrum of an amylose-poly (phenylene vinylene) inclusion complex into which 3,5-dimethylphenylcarbamate group obtained in Example 1 was introduced at 70 ° C. and pyridine-d 5 .
- FIG. 3 is a diagram showing a 1 H NMR spectrum of an amylose-poly (phenylene vinylene) inclusion complex into which 4-chlorobenzoate group obtained in Example 2 was introduced at 70 ° C. and pyridine-d 5 .
- FIG. 3 is a diagram showing a 1 H NMR spectrum of an amylose-poly (phenylene vinylene) inclusion complex into which a 3,5-dichlorobenzoate group obtained in Example 3 was introduced at 70 ° C.
- the separating agent for optical isomers of the present invention includes an inclusion complex in which a ⁇ -conjugated polymer is included in a polymer compound having a hydroxyl group or an amino group. It is supported.
- the separating agent for optical isomers of the present invention has a carrier and an inclusion complex of a ⁇ -conjugated polymer supported on the carrier.
- the inclusion complex includes a ⁇ -conjugated polymer and a polymer compound that includes the ⁇ -conjugated polymer.
- the polymer compound may be a polymer compound having a hydroxyl group or an amino group, or a functional group in which at least a part (part or all) of the hydroxyl group or amino group of the polymer compound acts on an optical isomer. It may be a polymer compound modified with a compound having a group, or may contain both of them.
- the polymer compound used in the production of the separating agent of the present invention is preferably an optically active organic polymer compound having 20 to 40% by weight of hydroxyl group or amino group per molecule in the molecule, and is a polysaccharide. It is more preferable. Any of natural polysaccharides, synthetic polysaccharides and natural product-modified polysaccharides can be used as the polysaccharide as long as it has chirality. Among them, those having a regular bonding mode are preferable because the separation ability of optical isomers can be further enhanced.
- ⁇ -1,4-glucan cellulose
- ⁇ -1,4-glucan amylose, amylopectin
- ⁇ -1,6-glucan dextran
- ⁇ -1,6-glucan pushtulan
- ⁇ -1,3-glucan curdlan, schizophyllan
- ⁇ -1,3-glucan ⁇ -1,2-glucan (Crown Gall polysaccharide)
- ⁇ -1,4-galactan ⁇ -1,4-mannan
- ⁇ -1,6-mannan ⁇ -1,2-fructan (inulin), ⁇ -2,6-fructan (levan)
- ⁇ -1,4-xylan ⁇ -1,3-xylan
- Inulin, curdlan and the like are preferable, and cellulose and amylose are more preferable.
- the number average degree of polymerization of the polysaccharide is preferably 5 or more, more preferably 10 or more, and there is no particular upper limit, but 1,000 or less. From the viewpoint of ease of handling, it is preferably 5 to 1,000, more preferably 10 to 1,000, and particularly preferably 10 to 500.
- the inclusion complex used for manufacture of the separating agent of the present invention refers to a compound in which a ⁇ -conjugated polymer described later is incorporated (inclusion) by intermolecular force in a cavity existing in a molecule of a polymer compound. .
- the ⁇ -conjugated polymer included in the inclusion complex used for the production of the separating agent of the present invention is a polymer in which ⁇ electrons spread throughout the molecular structure.
- the ⁇ -conjugated polymer has a linear rigid polymer skeleton and a strong interaction between molecules, and is considered to affect the arrangement of the polymer compound in the inclusion complex.
- Examples of such ⁇ -conjugated polymers include polyphenylene vinylene, polyphenylene ethynylene, polyphenylene, polythiophene, polypyrrole, and polyacetylene, and polyphenylene vinylene is particularly preferable.
- the molecular weight of the ⁇ -conjugated polymer included in the inclusion complex used in the production of the separating agent of the present invention varies depending on the type and molecular weight of the high molecular compound to be included, but is preferably 1,000 or more, and several thousand. The above is particularly preferable. Although it is difficult to obtain an accurate value for this molecular weight (number average molecular weight) by analysis, it can be measured directly by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS), or the polymer In the case where it is dissolved in water, an approximate value can be measured using a gel filtration chromatography apparatus with polystyrene as the standard substance.
- MALDI-TOF MS matrix-assisted laser desorption / ionization time-of-flight mass spectrometry
- the ⁇ -conjugated polymer includes those containing a precursor portion as a constituent unit in the molecule of the ⁇ -conjugated polymer when the ⁇ -conjugated polymer is polymerized.
- the abundance ratio of the constituent unit of the precursor part is preferably 5 mol% or less with respect to the entire constituent unit of the ⁇ -conjugated polymer, and 1 mol% The following is more preferable.
- the inclusion complex can be obtained, for example, by polymerizing a monomer that forms a ⁇ -conjugated polymer in the inclusion complex in a solution in which the polymer compound is dissolved in advance.
- the solution in which the polymer compound is dissolved can be obtained by dissolving the polymer compound in DMSO (dimethyl sulfoxide), pyridine, N, N-dimethylformamide (DMF), or the like.
- Examples of the monomer include monomers that generate any one of the structural units represented by the following formulas (I) and (IV) to (VIII) after polymerization.
- Examples of the monomer that generates the structural unit described above include p-xylylene bis (tetrahydrothiophenium) dichloride that generates the structural unit of the above (I) when the ⁇ -conjugated polymer is polyphenylene vinylene.
- examples thereof include acetylene that produces the structural unit (VIII).
- the solution containing the polymer compound is made strongly basic with a basic substance such as an aqueous NaOH solution, and the monomer is polymerized under the above conditions.
- a basic substance such as an aqueous NaOH solution
- the inclusion of the ⁇ -conjugated polymer into the polymer compound is preferable because it is performed with high efficiency.
- the pH of the solution during the polymerization is preferably 7 or more, and particularly preferably 10 or more.
- the ⁇ -conjugated polymer included in the inclusion complex is polyphenylene vinylene, for example, p-xylylene-bis (tetrahydrothiophenium) dichloride is used as a monomer for forming the ⁇ -conjugated polymer, and the polymer compound An aqueous solution of this monomer is put into a solution containing, and polymerized.
- the abundance ratio of the polymer compound in the solution and the monomer that forms the ⁇ -conjugated polymer is 90:10 to 95: 5 in terms of molar ratio. From the viewpoint, 90:10 to 92: 8 is particularly preferable.
- the presence of the inclusion complex supported on the carrier of the separating agent of the present invention can be confirmed by an infrared spectrometer, a fluorescence spectrometer, solid state NMR, elemental analysis or the like.
- the functional group is a functional group that acts on the optical isomer in the sample containing the optical isomer to be separated.
- the action of the functional group on the optical isomer cannot be generally described because the type of the functional group varies depending on the type of the optical isomer to be separated, but the optical isomer is optically resolved by the polymer compound. There is no particular limitation as long as the action is sufficient.
- the functional group include a group containing an aromatic group which may have a substituent, and an aliphatic group having a cyclic structure.
- the aromatic group can also include a heterocyclic ring or a condensed ring.
- the aromatic group may be monocyclic or condensed polycyclic and is preferably monocyclic or bicyclic.
- Examples of the substituent that the aromatic group may have include an alkyl group having up to about 8 carbon atoms, a halogen, an amino group, and an alkoxyl group.
- the functional group is selected according to the type of the optical isomer to be separated.
- the compound having a functional group that acts on the optical isomer has at least a part of the hydroxyl group or amino group of the polymer compound.
- the compound having an amino group via a urethane bond, an ester bond or an ether bond In some cases, it is preferably introduced via a urea bond or an amide bond.
- the hydroxyl group is preferably introduced via a urethane bond
- the amino group is preferably introduced via a urea bond. Therefore, the compound having a functional group acting on the optical isomer is a compound having a functional group capable of reacting with the hydroxyl group or amino group of the polymer compound in addition to the functional group acting on the optical isomer.
- the compound having a functional group capable of reacting with the hydroxyl group or amino group may be any compound as long as it is an isocyanic acid derivative, carboxylic acid, acid halide, alcohol or other reactive compound.
- the introduction rate of the compound having a functional group is preferably 90 to 100%, more preferably 97 to 100%, and particularly preferably 100%.
- the introduction position of the compound having the functional group in the polymer compound is not particularly limited, and is appropriately selected according to the type of the functional group, the type of the polymer compound, and the like.
- the introduction rate (%) is defined as follows. That is, when the polymer compound has only hydroxyl groups, a value obtained by multiplying the ratio of the number of hydroxyl groups modified with the compound having a functional group acting on the optical isomer to the total number of hydroxyl groups of the polymer compound by 100. And when the polymer compound has only amino groups, the ratio of the number of amino groups modified with the compound having a functional group acting on the optical isomer to the total number of amino groups is multiplied by 100.
- the ratio of the total number of hydroxyl groups and amino groups modified with the compound having a functional group acting on the optical isomer with respect to the total number of hydroxyl groups and the total number of amino groups was multiplied by 100.
- the numerical value is the introduction rate.
- the compound having a functional group that acts on the optical isomer is preferably a compound that generates an atomic group represented by the following general formula (II) or (III). -CO-R '(II) —CO—NH—R ′ (III)
- R ′ is an aliphatic hydrocarbon group having 1 to 12 carbon atoms or a 1 to 3 ring aromatic hydrocarbon group which may contain a hetero atom, and may be unsubstituted or carbon Hydrocarbons which may contain a heteroatom having 1 to 12 carbon atoms, alkoxy, cyano, halogen, hydroxy, nitro, amino and di (alkyl having 1 to 8 carbon atoms) amino group which may contain a heteroatom having 1 to 12 carbon atoms (That is, a dialkylamino group, where the alkyl is independently a C 1-8 alkyl group) may be substituted with one or more groups selected from the group consisting of:
- Examples of the monovalent aromatic hydrocarbon group represented by R ′ include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, indanyl, furyl, thionyl, pyryl, benzofuryl, benzthionyl, indyl, pyridyl, pyrimidyl, quinolinyl and And groups such as isoquinolinyl.
- Examples of the substituent for the monovalent aromatic hydrocarbon group represented by R ′ include alkyl having 1 to 12 carbons, alkoxy having 1 to 12 carbons, alkylthio having 1 to 12 carbons, cyano, halogen, and carbon.
- the aliphatic hydrocarbon group represented by R ′ is preferably an aliphatic cyclic compound larger than a 3-membered ring, more preferably larger than a 5-membered ring, or an aliphatic cyclic compound having a bridge structure.
- a cyclohexyl group, a cyclopentyl group, a norbornyl group, a cycloadamantylpentyl group, and the like are preferable.
- Examples of the aralkyl group represented by R ′ include a 1-phenylethyl group.
- At least part of the hydroxyl group or amino group of the polymer compound is phenyl isocyanate, toluyl isocyanate, ethylphenyl isocyanate, propylphenyl isocyanate, dimethylphenyl isocyanate, chlorophenyl isocyanate, fluorophenyl isocyanate.
- a known method can be used.
- a compound having a functional group equivalent to 105 to 150 mol% of the hydroxyl group or amino group of the polymer compound is used in dimethylacetamide / lithium chloride / pyridine at 80 to 100 ° C.
- Modification of the hydroxyl group or amino group of the polymer compound in 1 to 24 hours can be mentioned.
- This operation is preferably performed on the inclusion complex obtained by inclusion of the ⁇ -conjugated polymer in the polymer compound from the viewpoint of ease of reaction, but after the operation on the polymer compound, the ⁇ A conjugated polymer may be included.
- ⁇ Carrier used for separating agent of the present invention an inclusion complex in which the ⁇ -conjugated polymer is included in the polymer compound is supported on a carrier.
- “supported” means that the inclusion complex is immobilized on the carrier by physical adsorption or by chemical bonding.
- the inclusion complex is physically adsorbed on the carrier
- a conventionally known method can be used. For example, after the solution containing the inclusion complex is applied to the carrier, the solvent of the solution is distilled off. Is done.
- the inclusion complex is chemically bonded to the carrier
- a conventionally known method can be used. For example, a bond between the carrier and the above polymer compound constituting the inclusion complex, and physical adsorption on the carrier.
- reaction with a crosslinking agent reaction with a radical generator, or light irradiation (irradiation with gamma rays, irradiation with electromagnetic waves such as microwaves)
- light irradiation irradiation with gamma rays, irradiation with electromagnetic waves such as microwaves
- the carrier and the inclusion complex are supported on the carrier in a weight ratio of 90:10 to 60:40 from the viewpoint of appropriately maintaining the optical resolution of the carrier and the inclusion complex.
- a weight ratio of 85:15 to 70:30 is more preferable.
- the abundance ratio can be adjusted by adjusting the concentration of the inclusion complex in the solution containing the inclusion complex when it is supported on the carrier.
- a known type of carrier can be used as the carrier.
- examples of such a carrier include a particulate carrier filled in a column tube and a porous monolithic (cylindrical) carrier accommodated integrally in the column tube.
- the carrier examples include a porous organic carrier and a porous inorganic carrier, and a porous inorganic carrier is preferable.
- Suitable materials for the porous organic carrier are polymeric substances composed of polystyrene, polyacrylamide, polyacrylate, etc., and suitable materials for the porous inorganic carrier are silica gel, alumina, magnesia, glass, kaolin, titanium oxide, silica. Acid salts, hydroxyapatite, zirconia and the like.
- a particularly preferable carrier is silica gel, and the particle diameter of the silica gel is 1 ⁇ m to 100 ⁇ m, preferably 3 ⁇ m to 50 ⁇ m, more preferably 3 ⁇ m to 30 ⁇ m, and the average pore diameter is 1 nm to 4000 nm, preferably 3 nm to 500 nm.
- the surface is desirably subjected to surface treatment in order to eliminate the influence of residual silanol, but may not be subjected to any surface treatment at all. Examples of the surface treatment include silane treatment with aminopropyltriethoxysilane and the like.
- the separating agent for optical isomers of the present invention is a capillary column for gas chromatography, electrophoresis, particularly capillary electrochromatography (for CEC), CZE (capillary zone electrophoresis), and MEKC (micelle electrokinetic chromatography). It can also be used as a filler.
- the present inventors have considered the following factors that cause the optical isomer separating agent of the present invention to exhibit better optical resolution compared to conventional separating agents. That is, the inventors have included a rigid ⁇ -conjugated polymer within a polymer compound such as a polysaccharide, so that the polymer compound becomes extremely rigid. As a result, the polymer compound has been flexible in the past.
- amylose used in the following examples and the like is commercially available amylose (degree of polymerization 200-300), and the silica gel is SP-1000-7-APSL (manufactured by Daiso Corporation, pore size 100 nm, particle size 7 ⁇ m).
- Example 1 (1) Synthesis of amylose-poly (phenylene vinylene) inclusion complex (APPV) 408.4 mg (2.52 mmol) of amylose was dissolved in 40 mL of dry dimethyl sulfoxide (DMSO), and 0.018 mol / L of p-xylylene-bis was dissolved. 16 mL of an aqueous solution of (tetrahydrothiophenium) dichloride (monomer 1) was added and stirred at 25 ° C. for 5 minutes. 2.8 mL of 1N NaOH aqueous solution was added there, and it stirred at 0 degreeC for 30 minutes, Then, it stirred at 20 degreeC for further 48 hours.
- DMSO dry dimethyl sulfoxide
- Peak detection and identification were performed using a UV detector (UV-970, JASCO, 254 nm) and an optical rotation detector (OR-990, JASCO).
- the theoretical plate number N was determined from the peak of benzene, and the time t 0 when the eluent passed through the column was determined from the elution time of 1,3,5-tri-tert-butylbenzene.
- the capacity ratio k1 'and the separation factor ⁇ are defined by the following equations. In the following examples and comparative examples, the capacity ratio and the separation factor were calculated using the same formula. The theoretical plate number of the column of Example 1 was 1,300.
- Example 1 A commercial column (Chiral Pak (registered trademark) AD, manufactured by Daicel Chemical Industries, 25 ⁇ , which is packed with a separating agent in which amylose tris (3,5-dimethylphenylcarbamate) is supported on silica gel, represented by the following formula: 0.46 (inner diameter) cm), the same as in Example 1, except that the inner diameter of the column is different, the racemates 1 to 10 are optically resolved according to the above condition a, and the racemates 11 to 11 are subjected to the following condition b. 33 optical resolutions were performed. The results of optical resolution of racemates 1 to 14 are shown in Table 1. The results of optical resolution of racemates 15 to 33 are shown in Table 2.
- the separating agent of Example 1 has a high resolution of amide compounds, particularly amide compounds having a three-membered ring.
- the APPV-AD column can optically resolve racemates 16, 22, and 31 as with ChiralPak AD, and the racemate 16 has a larger separation than ChiralPak AD.
- the coefficient ( ⁇ ) is shown.
- APPV-AD exhibits a stronger optical resolution for a specific compound than a separating agent carrying the same polysaccharide derivative, or a separating agent carrying the same polysaccharide derivative for a particular compound. Were confirmed to exhibit different optical separation characteristics.
- the reaction solution was added dropwise to methanol, and the methanol-insoluble part was collected by centrifugation and dried overnight using a vacuum pump to obtain 386.5 mg of the target APPV derivative (APPV-4C) represented by the following formula. It was. From 1 H-NMR measurement (AS500, manufactured by Varian) in deuterated pyridine, it was confirmed that the 4-chlorobenzoate group was introduced almost 100% with respect to the hydroxyl group of amylose. Various measurement results are shown below. Further, the 1 H NMR spectrum of APPV-4C is shown in FIG.
- a separation agent for optical isomers having APPV-4C supported on silica gel was obtained in the same manner as in Example 1 except that APPV-4C was used instead of APPV-AD.
- the separation agent was pressure packed into a stainless steel column of 25 ⁇ 0.20 (inner diameter) cm by a slurry filling method to prepare a column.
- optical resolution of 28 racemates 1 to 28 was performed according to condition a in the same manner as in Example 1.
- the results of optical resolution of racemates 1 to 28 are shown in Table 3.
- the number of theoretical plates of the column of Example 2 was 1,500.
- a separation agent for optical isomers having APPV-3,5C supported on silica gel was obtained in the same manner as in Example 1 except that APPV-3,5C was used instead of APPV-AD.
- the separation agent was pressure packed into a stainless steel column of 25 ⁇ 0.20 (inner diameter) cm by a slurry filling method to prepare a column.
- Rs in Table 3 represents the degree of separation and is obtained from the following formula.
- t 1 is the elution time of the optical isomer eluting first
- t 2 is the elution time of the optical isomer eluting later
- W 1 and W 2 are the peak widths of the respective optical isomers.
- UV spectrum of the racemic bodies 16 and 25 by the column of APPV-3, 5C separating agent and the OR spectrum of the optical rotation detector by the optical rotation detector are shown in FIGS. 4 and 5, respectively.
- APPV-4C showed the optical resolution of racemic body 16, as did amylose-4C.
- APPV-3,5C like amylose-3,5C, showed the optical resolution of racemic 25 that was not resolved by APPV-AD and Chiralpak AD in addition to the optical resolution of racemic 16.
- APPV-3,5C in which the type of polysaccharide derivative is an ester derivative and the substituent of the phenyl group is chloro, has optical separation characteristics different from APPV-AD.
- Optical resolution of optical isomers is a particularly important technique in the research and development of chiral drugs that act on living organisms.
- inclusion of a ⁇ -conjugated polymer with a polymer compound such as a polysaccharide derivative is considered to act more specifically with the optical isomer to be separated compared to optical resolution with a polymer compound.
- a separating agent having an optical resolution characteristic different from that of the compound is obtained. Therefore, the present invention is expected to greatly contribute to further development of a method for separating optical isomers and further popularization and discovery of useful optical isomers.
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Abstract
Description
-CO-R’ (II)
-CO-NH-R’ (III)
本発明の分離剤の製造に用いられる上記高分子化合物としては、分子中に水酸基又はアミノ基を1分子当たり20~40重量%有する光学活性な有機高分子化合物であることが好ましく、多糖であることがより好ましい。上記多糖としては、天然多糖類、合成多糖類及び天然物変性多糖類のいずれも問わず、キラリティーを有するものであれば好ましく用いることができる。そのなかでも結合様式が規則正しいものは、より光学異性体の分離能力を高めることが可能となり、好適である。
本発明の光学異性体用分離剤に用いられる包接錯体とは、高分子化合物の分子中に存在する空洞に後述するπ共役ポリマーが分子間力により取り込まれ(包接され)たものをいう。
上記高分子化合物は、水酸基又はアミノ基の少なくとも一部が、光学異性体に作用する官能基を有する化合物で修飾されていることが好ましい。
-CO-R’ (II)
-CO-NH-R’ (III)
本発明の光学異性体用分離剤は、上記高分子化合物に上記π共役ポリマーが包接された包接錯体が担体に担持されている。ここでいう「担持されている」とは、担体上に上記包接錯体が物理的に吸着することにより、又は化学結合により固定化されているこという。
本発明者らは、本発明の光学異性体用分離剤が従来の分離剤に比べて良好な光学分割能を奏する要因について、以下のように考察している。すなわち、本発明者らは、多糖のような高分子化合物の内部に剛直なπ共役ポリマーが包接されることで、上記高分子化合物が極めて剛直になり、結果として、従来はフレキシブルであった多糖のような高分子化合物の主鎖や側鎖の運動性が低下し、キラル分子と相互作用するであろう、例えば分離剤が有する水素結合部位の位置が厳密に固定され、鍵と鍵穴の関係のような限られた相互作用が分離剤とキラル分子との間で起こることによると考えている。
(1)アミロース-ポリ(フェニレンビニレン)包接錯体(APPV)の合成
アミロース408.4mg(2.52mmol)を乾燥ジメチルスルホキシド(DMSO)40mLに溶解させ、0.018mol/Lのp-キシリレン-ビス(テトラヒドロチオフェニウム)ジクロリド(モノマー1)水溶液を16mL加え、25℃で5分間撹拌した。そこに、1N NaOH水溶液を2.8mL加え、0℃で30分撹拌後、20℃でさらに48時間撹拌した。1N HClを2.8mL加え、反応溶液を1時間遠心分離し、上澄み液をアセトンに滴下した。生じた沈殿を遠心分離で回収し、真空ポンプを用いて一晩乾燥させ、アミロース-ポリ(フェニレンビニレン)包接錯体(APPV)254.1mg(収率58%)を得た。
APPV(199.5mg、1.15mmol)に乾燥ジメチルアセトアミド(6.4mL)、乾燥ピリジン(4.0mL)、塩化リチウム(105.6 mg, 2.5 mmol)を加え、よく撹拌した後、グルコース環ユニット中の水酸基に対して2.5倍当量の3,5-ジメチルフェニルイソシアナート(0.80mL,8.50mmol)を加え、80℃で反応させた。反応の進行はFT-IRで確認しながら行った。18時間後、FT-IR測定の結果から、反応がほぼ完全に進行しているものと判断し、加熱を停止した。反応溶液をメタノールに滴下し、メタノール不溶部を遠心分離で回収し、真空ポンプを用いて一晩乾燥させ、下記式で表される、目的とするAPPV誘導体(APPV-AD)606.8mg(収率86%)を得た。重ピリジン中の1H-NMR(AS500、バリアン社製)測定から、3,5-ジメチルフェニルカルバメート基はアミロースの水酸基に対してほぼ100%導入されていることを確認した。各種測定結果を以下に示す。また、APPV-ADの1H NMRのスペクトルを図1に示す。
Anal. Calcd for (C6H7O5)9.00(C8H6)0.99(C12H15ClS)0.01(C9H10NO)27: C, 66.18; H, 6.17; N, 6.83. Found: C, 66.27; H, 6.25; N, 7.08.
IR (KBr, cm-1) 3323 (νNH), 1720 (νC=O);
1H-NMR (500 MHz, ピリジン-d5, 70 °C) 9.71 (br, 2H, NH), 9.37 (br, 1H, NH), 7.72-6.46 (br, 9H, 芳香族), 5.88, 5.63, 5.02-4.23 (br, 7Hr,グルコース プロトン), 2.36 (s, 6H, CH3), 2.05 (s, 6H, CH3), 1.99 (s, 6H, CH3)
アミノプロピルトリエトキシシラン処理を施したシリカゲル1.2gに、ピリジンに溶解させたAPPV-AD0.3gを均一に塗布した後、溶媒を減圧留去することにより、シリカゲルにAPPV-ADが坦持された光学異性体用分離剤を得た。この分離剤を25×0.20(内径)cmのステンレス製カラムにスラリー充填法により加圧充填を行い、カラムを作製した。
上記の操作で得られたカラム(25℃)を用いて、以下に示す14種のラセミ体1~14及び15種のラセミ体16、18~22、24、25、及び27~33の光学分割を行った(PU-980、日本分光)。ラセミ体1~14の光学分割の結果を表1に示す。またラセミ体16、18~22、24、25、及び27~33の光学分割の結果を表2に示す。
(条件a)
カラム: 25×0.20cm I.D
溶離液:ヘキサン/2-プロパノール(90:10、v:v)
溶離液の流量:0.1mL/min
容量比k1’
k1’=[(対掌体の保持時間)-(t0)]/t0
[数2]
分離係数α
α=(より強く保持される対掌体の容量比)/(より弱く保持される対掌体の容量比)
下記式に表される、シリカゲルにアミロース トリス(3,5-ジメチルフェニルカルバメート)が担持された分離剤が充填された市販のカラム(Chiral Pak(登録商標)AD, ダイセル化学工業社製、25×0.46(内径)cm)を用いて、実施例1と同様に、カラムの内径が異なる以外は前記条件aに従ってラセミ体1~10の光学分割を行い、以下の条件bに従ってラセミ体11~33の光学分割を行った。ラセミ体1~14の光学分割の結果を表1に示す。ラセミ体15~33の光学分割の結果を表2に示す。比較例1のカラムの理論段数は8,000であった。
(条件b)
カラム: 25×0.46cm I.D
溶離液:ヘキサン/2-プロパノール(90:10、v:v)
溶離液の流量:0.5mL/min
4-クロロフェニルカルボニル基が導入されたAPPVの作製
APPV(170mg、0.98mmol)に乾燥ジメチルアセトアミド(5.5mL)、乾燥ピリジン(3.4mL)、塩化リチウム(93mg、2.1mmol)を加え、よく攪拌した後、グルコース環ユニット中の水酸基に対して7倍当量の4-クロロベンゾイルクロライド(1.2mL、6.8mmol)を加え、75℃で反応させた。反応の進行はFT-IRで確認しながら行った。38時間後、FT-IRの結果から、反応がほぼ完全に進行しているものと判断し、加熱を停止した。反応溶液をメタノールに滴下し、メタノール不溶部を遠心分離で回収し、真空ポンプを用いて一晩乾燥させ、下記式で表される、目的とするAPPV誘導体(APPV-4C)386.5mgを得た。重ピリジン中の1H-NMR(AS500、バリアン社製)測定から4-クロロベンゾエート基はアミロースの水酸基に対してほぼ100%導入されていることを確認した。各種測定結果を以下に示す。また、APPV-4Cの1H NMRのスペクトルを図2に示す。
Anal. Calcd for (C6H7O5)9.00(C8H6)0.99(C12H15ClS)0.01(C7H4O1Cl1)27(H2O)3: C, 56.26; H, 3.44. Found: C, 56.10; H, 3.16.
IR (KBr, cm-1): 1727 (νC=O).
1H NMR (500 MHz, ピリジン-d5, 70 °C): δ 8.28 (d, 2H, 芳香族), 7.84 (d, 2H, 芳香族), 7.66 (d, 2H, 芳香族), 7.53 (d, 2H, 芳香族), 7.28 (d, 2H, 芳香族), 7.14 (d, 2H, 芳香族), 6.46-6.30, 6.26-6.06, 5.80-5.66, 5.40-5.14, 5.10-4.90, 4.90-4.68 (br, 7H, グルコースプロトン).
3,5-ジクロロフェニルカルボニル基が導入されたAPPVの作製
APPV(170mg、0.98mmol)に乾燥ジメチルアセトアミド(5.5mL)、乾燥ピリジン(3.4mL)、塩化リチウム(93mg、2.1mmol)を加え、よく攪拌した後、グルコース環ユニット中の水酸基に対して6倍当量の3,5-ジクロロベンゾイルクロライド(1.2mL、5.7mmol)を加え、75℃で反応させた。反応の進行はFT-IRで確認しながら行った。38時間後、FT-IRの結果から、反応がほぼ完全に進行しているものと判断し、加熱を停止した。反応溶液をメタノールに滴下し、メタノール不溶部を遠心分離で回収し、真空ポンプを用いて一晩乾燥させ、下記式で表される、目的とするAPPV誘導体(APPV-3,5C)300.8mgを得た。重ピリジン中の1H-NMR(AS500、バリアン社製)測定から3,5-ジクロロベンゾエート基はアミロースの水酸基に対してほぼ100%導入されていることを確認した。各種測定結果を以下に示す。また、APPV-3,5Cの1H NMRのスペクトルを図3に示す。
Anal. Calcd for (C6H7O5)9.00(C8H6)0.99(C12H15ClS)0.01(C7H3O1Cl2)27: C, 48.37; H, 2.43. Found: C, 48.13; H, 2.42.
IR (KBr, cm-1): 1736 (νC=O).
1H NMR (500 MHz, ピリジン-d5, 70 °C): δ 8.28 (d, 2H, 芳香族), 7.80-7.46 (br, 7H, 芳香族), 6.60-6.20, 5.76-5.30, 5.20-4.80 (br, 7H, グルコースプロトン).
Rs=2(t2-t1)/(W1+W2)
APPV-ADに代えて、アミロース トリス(4-クロロベンゾエート)を用い、実施例1と同様に、アミノプロピルトリエトキシシラン処理を施したシリカゲルに均一に塗布し、次いで溶媒を減圧留去することにより、アミロース トリス(4-クロロベンゾエート)がシリカゲルに坦持された光学異性体用分離剤(アミロース-4C)を得た。この分離剤を25×0.20(内径)cmのステンレス製カラムにスラリー充填法により加圧充填を行い、カラムを作製した。
APPV-ADに代えて、アミロース トリス(3,5-ジクロロベンゾエート)を用い、実施例1と同様に、アミノプロピルトリエトキシシラン処理を施したシリカゲルに均一に塗布し、次いで溶媒を減圧留去することにより、アミロース トリス(3,5-ジクロロベンゾエート)がシリカゲルに坦持された光学異性体用分離剤(アミロース-3,5C)を得た。この分離剤を25×0.20(内径)cmのステンレス製カラムにスラリー充填法により加圧充填を行い、カラムを作製した。
Claims (12)
- 水酸基又はアミノ基を有する高分子化合物にπ共役ポリマーが包接されてなる包接錯体が、担体に担持されてなる光学異性体用分離剤。
- 前記高分子化合物が、光学活性な有機高分子化合物である、請求項1に記載の光学異性体用分離剤。
- 前記光学活性な有機高分子化合物が多糖である、請求項2に記載の光学異性体用分離剤。
- 前記多糖がアミロース又はセルロースである、請求項3に記載の光学異性体用分離剤。
- 前記π共役ポリマーがポリフェニレンビニレン、ポリフェニレンエチニレン、ポリフェニレン、ポリチオフェン、ポリピロール又はポリアセチレンである、請求項1~4のいずれか一項に記載の光学異性体用分離剤。
- 前記高分子化合物がアミロースであり、前記π共役ポリマーがポリフェニレンビニレンである、請求項5に記載の光学異性体用分離剤。
- 重合後に前記式(I)で示される単位を生じるモノマーが、p-キシリレンビス(テトラヒドロチオフェニウム)ジクロリドである、請求項7に記載の光学異性体用分離剤。
- 前記高分子化合物の水酸基又はアミノ基の少なくとも一部が、光学異性体に作用する官能基を有する化合物で修飾されてなる、請求項1~8のいずれか一項に記載の光学異性体用分離剤。
- 前記光学異性体に作用する官能基を有する化合物が、ウレタン結合、尿素結合、エステル結合又はエーテル結合を介して導入されてなる、請求項9に記載の光学異性体用分離剤。
- 前記光学異性体に作用する官能基を有する化合物が、前記高分子化合物の水酸基又はアミノ基の少なくとも一部に導入されたときに下記一般式(II)又は(III)で表された原子団を生じる化合物である、請求項10に記載の光学異性体用分離剤。
-CO-R’ (II)
-CO-NH-R’ (III)
(式(II)及び(III)中、R’はヘテロ原子を含んでもよい脂肪族又は芳香族炭化水素基であり、非置換であっても、又は炭素数1~12のヘテロ原子を含んでもよい炭化水素、炭素数1~12のヘテロ原子を含んでもよいアルコキシ、シアノ、ハロゲン、ヒドロキシ、ニトロ、アミノ及びジ(炭素数1~8のアルキル)アミノ基からなる群から選ばれた1つ以上の基によって置換されていてもよい。) - 前記光学異性体に作用する官能基を有する化合物が、3,5-ジメチルフェニルイソシアナートである、請求項11に記載の光学異性体用分離剤。
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WO2013168601A1 (ja) * | 2012-05-11 | 2013-11-14 | 国立大学法人 金沢大学 | 不斉選択性の切り替えが可能なクロマトグラフィー用充填剤 |
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CN102439438B (zh) | 2015-02-25 |
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JP5598822B2 (ja) | 2014-10-01 |
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JPWO2010126087A1 (ja) | 2012-11-01 |
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