WO2011024718A1 - 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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- WO2011024718A1 WO2011024718A1 PCT/JP2010/064074 JP2010064074W WO2011024718A1 WO 2011024718 A1 WO2011024718 A1 WO 2011024718A1 JP 2010064074 W JP2010064074 W JP 2010064074W WO 2011024718 A1 WO2011024718 A1 WO 2011024718A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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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
- B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
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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
- B01J20/3231—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
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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
- B01J20/3276—Copolymers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G61/02—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes
- C08G61/04—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/30—Monomer units or repeat units incorporating structural elements in the main chain
- C08G2261/33—Monomer units or repeat units incorporating structural elements in the main chain incorporating non-aromatic structural elements in the main chain
- C08G2261/332—Monomer units or repeat units incorporating structural elements in the main chain incorporating non-aromatic structural elements in the main chain containing only carbon atoms
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8877—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample optical isomers
Definitions
- the present invention relates to a separating agent for optical isomers, and relates to a separating agent for optical isomers having a polymer having a helical structure.
- Optical isomers are used as medicines and their raw materials. In such an application to act on a living body, only one optical isomer is usually used as the optical isomer, and a very high optical purity is required.
- a column containing a separation agent for optical isomers having optical resolution is used, such as liquid chromatography, simulated moving bed chromatography, supercritical fluid chromatography, etc.
- a method for separating one optical isomer from a mixture of optical isomers such as a racemate is known (see, for example, Patent Document 1).
- separating agent for optical isomers a polymer having an optically active site can be used.
- a separating agent for optical isomers is usually composed of a carrier such as silica gel and the polymer supported on the surface thereof, accommodated in a column tube and used for optical resolution.
- various polymers are known as polymers having optically active sites.
- a polymer for example, a right-handed or left-handed made of the same monomer obtained by living polymerizing an aromatic isonitrile having an amide group in which an optically active amino acid or derivative thereof is amino-bonded to an aromatic ring.
- a polyaromatic isocyanide derivative having a main chain structure composed of a helical structure is known (see, for example, Patent Document 2 and Non-Patent Document 1).
- a separating agent for optical isomers comprising this polyaromatic isocyanide derivative is not known.
- the present invention provides a novel separating agent for optical isomers using a polymer having an optically active site.
- separating agent for optical isomers various separating agents for optical isomers using polymers having optically active sites are known. Such a separation agent for optical isomers may show excellent properties in solvent resistance and optical resolution depending on the physical properties of the polymer in optical resolution. Depending on factors such as the shape and the positional relationship of effective functional groups, the expected optical resolution may not be obtained, or an optical resolution higher than expected may be obtained.
- the present inventors have found that the polyaromatic isocyanide derivative is supported on a carrier by chemical bonding, and that the obtained support exhibits optical resolution for various optical isomers.
- the present invention has been completed.
- Ar independently represents an aromatic group or a heteroaromatic group
- R 1 independently has 1 carbon atom which may have a hetero atom and may contain an aromatic ring.
- R 2 independently represents a hydrocarbon group having 1 to 20 carbon atoms
- n represents an integer of 5 or more.
- B independently represents a group bonded to the surface of the support, x represents an integer of 1 or more, Ar, R 1 , R 2 , and n are the same as in the formula (1). is there.
- the separating agent for optical isomers of the present invention is obtained by supporting a helical polymer having a structure represented by the formula (1) on a carrier. Therefore, according to the present invention, a novel separating agent for optical isomers using a polymer having an optically active site is provided.
- the separating agent for optical isomers of the present invention comprises a helical polymer having a structure represented by the following formula (1) and a carrier supporting the helical polymer, and the end of the helical polymer and the carrier A helical polymer is supported on a carrier by chemical bonding with the surface.
- Ar independently represents an aromatic group or a heteroaromatic group
- R 1 independently has 1 carbon atom which may have a hetero atom and may contain an aromatic ring.
- R 2 independently represents a hydrocarbon group having 1 to 20 carbon atoms
- n represents an integer of 5 or more.
- the spiral polymer may be either left-handed or right-handed. Since the optical resolution by the separating agent for optical isomers of the present invention is due to the interaction between the helical polymer and the target of optical resolution, the optical resolution of the separating agent for optical isomers of the present invention depends on the target. Different. It is expected that the optical resolution for a specific target will be expressed or improved by making the helical polymer a helical polymer in one of the left-handed and right-handed winding directions.
- Ar represents an aromatic group or a heteroaromatic group.
- the aromatic group may contain a hetero atom such as oxygen, nitrogen, and sulfur or a halogen atom.
- the heteroaromatic group refers to an aromatic group obtained by replacing a part of carbon atoms constituting the aromatic ring with a heteroatom among the aromatic groups.
- the aromatic group may include a plurality of types or a single type.
- the aromatic group preferably has 5 to 14 carbon atoms, and more preferably 6 to 10 carbon atoms, from the viewpoint of easy handling when producing the helical polymer.
- Examples of such an aromatic group include a divalent aromatic group having another bonding site at an arbitrary position of the monovalent group shown below, including a phenylene group. It is preferable that the aromatic group is single from the viewpoint of the ease of handling described above and the expectation of the expression and improvement of the optical resolution for a specific object.
- Specific examples of such Ar include a phenylene group.
- R 1 may be a monovalent organic group having an asymmetric carbon as the carbon atom between the amide group and the carbonyl group in the amino acid residue in formula (1). May be included. R 1 is preferably single from the viewpoint of expecting the expression and improvement of the optical resolution for a specific object. Examples of R 1 include a side chain group of a natural amino acid excluding glycine.
- R 2 is a hydrocarbon group having 1 to 20 carbon atoms, which may be single or plural.
- the structure of the hydrocarbon group is not particularly limited, and may be a linear or branched chain, or a cyclic ring such as an aliphatic ring or an aromatic ring, and includes both of these. May be.
- R 2 may contain a hetero atom such as oxygen, nitrogen, and sulfur, or a halogen atom.
- the R 2 is preferably single from the viewpoint of ease of handling when the helical polymer is produced and from the viewpoint of expecting the expression and improvement of the optical resolution for a specific object.
- a linear alkyl group having a number of 1 to 20 is preferable.
- a specific example of such R 2 is an n-decyl group.
- n may be 5 or more, and is preferably large from the viewpoint of expression of optical resolution or improvement thereof, and ease of handling in the production of the helical polymer and the separation agent for optical isomers. From the viewpoint, it is preferable to have a certain upper limit value. From these viewpoints, n is preferably 10 to 300, and more preferably 50 to 200.
- the number average molecular weight (Mn) and the weight average molecular weight (Mw) of the helical polymer are preferably large from the viewpoint of expression of optical resolution or improvement thereof, and from the viewpoint of solubility of the helical polymer in a solvent. It is preferable to have a certain upper limit. From these viewpoints, it is preferably 20,000 to 1,000,000.
- the molecular weight dispersion (Mw / Mn) of the helical polymer is not particularly limited as long as the winding direction of the helical polymer is the same.
- the Mn, Mw, and Mw / Mn of the helical polymer can be determined by size exclusion chromatography (SEC).
- SEC size exclusion chromatography
- the n can be determined by specifying the structural unit of the helical polymer by ordinary structural analysis means such as NMR or IR.
- the Mn and Mw of the helical polymer can be adjusted by the molar ratio of a complex (initiator) used as a catalyst in the living polymerization described later and a monomer.
- the Mw / Mn of the helical polymer can be reduced by using the initiator as compared with the case where the helical polymer is produced by a method other than living polymerization.
- the helical polymer includes an optically active amino acid residue including R 1 .
- This amino acid residue may be an optically active amino acid residue.
- the amino acid residue may include residues of both L-type amino acids and D-type amino acids, or may be only residues of L-type amino acids, or residues of D-type amino acids. It may be only.
- the amino acid residue may include a plurality of optically active amino acid residues, or may be a single optically active amino acid residue. By making the amino acid residue a residue of an optically active single amino acid, it is expected that the optical resolution for a specific target will be expressed or improved.
- the optical resolution of a specific target substance is expressed or further improved by using a helical polymer in a specific winding direction having the amino acid residue having a specific optical activity. Furthermore, it is expected that the optical resolution of a specific target will be exhibited or further improved by using a spiral polymer having a specific winding direction and having a single amino acid residue having a specific optical activity. Is done.
- Examples of such a helical polymer expected to exhibit and improve optical resolution are, for example, Ar is a phenylene group, R 1 is an amino acid residue in the formula (1), and an L-alanine residue. And a left-handed helical polymer, and R 2 is an n-decyl group.
- the helical polymer can be obtained by living polymerization of an aromatic isonitrile composed of predetermined Ar, R 1 and R 2 .
- a binuclear platinum-palladium- ⁇ -ethynediyl complex cross-linked with acetylene represented by the following formula (3) is used as a catalyst having living polymerization characteristics of aromatic isonitrile in the presence of a polymerization solvent. It can be suitably performed.
- the winding direction of the helical polymer can be controlled by the polarity of the polymerization solvent in the living polymerization, and the left-handed helical polymer and the right-handed helical polymer in the product utilize the difference in solubility in organic solvents. Can be separated.
- the winding direction of the helical polymer can be determined from the sign of the CD spectrum. That is, if the peak appearing in the CD spectrum around 300 to 400 nm, which is the main chain absorption band of the helical polymer, is positive, the helical polymer is a right-handed helical polymer, and the CD spectrum around 300 to 400 nm. If the peak appearing at is negative, it can be seen that the helical polymer is a left-handed helical polymer.
- the helical polymer is supported on a carrier.
- a carrier housed in a column tube and having chemical and physical durability in optical resolution can be used.
- a known carrier can be used as a carrier for a separation agent for optical isomers.
- inorganic materials such as silica, alumina, magnesia, glass, kaolin, titanium oxide, silicate, and hydroxyapatite.
- the carrier include organic carriers such as polystyrene, polyacrylamide, and polyacrylate.
- the carrier is preferably porous from the viewpoint of increasing the optical resolution for the target.
- the carrier may be in the form of particles or may be an integral carrier that is integrally accommodated in the column tube, but from the viewpoint of the production of the separating agent for optical isomers and the ease of handling at that time, It is preferably in the form of particles.
- a specific example of such a carrier is silica gel.
- the end portion of the helical polymer is supported (fixed) on the carrier by chemical bonding to the surface of the carrier.
- a chemical bond is formed by further forming a bond portion that binds to the surface of the carrier at the end of the helical polymer, and treating the surface of the carrier so that an appropriate bonding group is formed on the surface of the carrier.
- the surface treatment carrier can be used.
- the surface treatment of the carrier can be appropriately performed by a known technique depending on the type of the carrier.
- the surface treatment agent include organosilicon compounds having an amino group or a glycidyl group.
- Examples of the bonding part in the helical polymer include a functional group that binds to a bonding group on the surface of the surface treatment carrier by a reaction such as dehydration condensation or a structural unit having the functional group.
- a binding part is obtained by using R 2 in the formula (1) at the end of the helical polymer as a binding part, or introducing a structural unit that becomes a binding part at the end of the helical polymer. Can be introduced into the end of the helical polymer.
- Examples of the helical polymer bonded to the carrier by the bonding portion include a helical polymer represented by the following formula (2).
- B independently represents a group bonded to the surface of the carrier, and x represents an integer of 1 or more.
- Ar, R 1 , R 2 , and n are the same as those in the formula (1).
- the B may be a group bonded to the bonding group in the carrier, and may include a plurality of types of groups or a single group.
- B is preferably a single group from the viewpoint of easy control of chemical bonding with the carrier.
- Examples of B include an oxy group that is a residue of a hydroxyl group and an imino group that is a residue of an amino group.
- the x may be at least 1 or more, but is preferably large from the viewpoint of increasing the strength of bonding with the surface of a single substance, and has a certain upper limit according to the viewpoint of increasing the amount of the helical polymer supported. It is preferable. From such a viewpoint, x is preferably 1 to 10, and more preferably 1 to 5.
- the monomer (aromatic isonitrile) serving as the structural unit is subsequently subjected to living polymerization after living polymerization of the aromatic isonitrile serving as the structural unit represented by the formula (1).
- the precursor of B may be protected with a protecting group, if necessary.
- the helical polymer and the carrier can be chemically bonded by reacting the precursor of B with the linking group after deprotecting if necessary.
- Ar in the formula (2) may be the same as or different from Ar represented by the formula (1), but from the viewpoint of ease of living polymerization, Ar represented by the formula (1) Preferably they are the same.
- the helical polymer has a side chain represented by the formula (1), and can be suitably used for separation of optical isomers having a specific structure.
- Ar is phenylene
- the amino acid residue containing R 1 is a residue of L-alanine
- R 2 is an n-decyl group.
- An optical isomer having a carbonyl group or an amide group, an optical isomer having a single ring structure without a condensed ring, and an optical isomer having both characteristics are advantageous for optical resolution.
- the optical isomer having a carbonyl group or an amide group preferably has two or more carbonyl groups or amide groups.
- the carbon adjacent to the carbonyl group or amide group is preferably an asymmetric carbon.
- the ring structure of the optical isomer having a single ring structure may be a monocyclic aromatic ring such as phenyl or a single aliphatic ring.
- the number of single ring structures is one or more, and the number of carbon atoms in the aliphatic ring is preferably 3 or more, and more preferably 4-6.
- the separation agent for optical isomers of the present invention is used as a filler in various chromatographies such as HPLC, simulated moving bed chromatography, supercritical fluid chromatography, etc., so that optical resolution and production of optical isomers thereby are achieved.
- chromatographies such as HPLC, simulated moving bed chromatography, supercritical fluid chromatography, etc.
- optical resolution liquids such as various organic solvents, mixed solvents thereof, mixed solvents of organic solvents and water can be used for the mobile phase, and in particular, solvents having high solubility such as THF are used. It can be used as a mobile phase, and depending on the type and composition of the mobile phase, it is expected to exhibit optical resolution for optical isomers of various structures.
- NMR spectra were measured using a Varian VXR-500S spectrometer (manufactured by Varian) at 500 MHz and using tetramethylsilane (TMS) as an internal standard substance.
- the IR spectrum was measured using a JASCO FT / IR-680 spectrophotometer (manufactured by JASCO Corporation).
- the absorption spectrum and the circular dichroism (CD) spectrum were measured using a JASCO V570 spectrophotometer and a JASCO J820 spectroscopic dichroism meter using a quartz cell with an optical path length of 1.0 mm at 25 ° C., respectively.
- the concentration of the polymer was calculated based on the monomer unit and was 0.2 mg / mL.
- the optical rotation was measured with a JASCO P-1030 polarimeter using a quartz cell with an optical path length of 2.0 cm.
- the number average molecular weight (Mn) and weight average molecular weight (Mw) of the polymer were determined from size exclusion chromatography (SEC). SEC was performed using a JASCO PU-2080 liquid chromatograph equipped with an ultraviolet / visible detector (JASCO UV-2070) and a CD detector (JASCO CD-2095). Two Tosoh TSKgel Multipore H XL -M SEC columns (30 cm, manufactured by Tosoh Corporation) were used as the column, and the eluent contained 0.1 wt% tetra-n-butylammonium bromide (TBAB). Tetrahydrofuran (THF) was used and the flow rate was 1.0 mL / min. The molecular weight calibration curve was obtained using a polystyrene standard (manufactured by Tosoh Corporation).
- Scattered light intensity was measured with 18 light scattering detectors at different angles.
- the intrinsic refractive index increment dn / dc of the polymer for the mobile phase at 25 ° C. was also measured with an Optical rEX interference refractometer (manufactured by Wyatt Technology).
- Thermogravimetric analysis was performed with an EXSTAR6000 TG / DTA6200 manufactured by Seiko Instruments Inc. at a heating rate of 10 ° C./min and a nitrogen flow rate of 200 mL / min.
- Measured values of mass spectrometry are values measured at the analysis center of the Nagoya University Faculty of Agriculture.
- L-1 is amidated by reacting nitrobenzoic acid and L-alanine decyl ester, as described in paragraphs 0043 and 0044 of Patent Document 2, and the nitro group of the obtained amide is converted according to a conventional method.
- the product was reduced to an amino group, further reacted with formic acid to form N-formyl, and further reacted in the presence of triphosgene, which was used.
- the platinum-palladium- ⁇ -ethynediyl complex is prepared by the method of Onizuka et al. (K. Onitsuka, K. Yanai, F. Takei, T. Joh, S. Takahashi) as described in paragraph 0066 of Patent Document 2. , Organometallics 1994, 13, 3862-3867. K. Onitsuka, T. Joh, S. Takahashi, Bull. Chem. Soc. Jpn. 1992, 65, 1179-1181.) And used.
- the physical properties of the obtained comonomer 2 are shown below.
- L-1 (2.00 g, 5.60 mmol) was put in a polymerization tube, and nitrogen substitution was performed three times.
- L-1 was dissolved in 22.5 mL of distilled tetrahydrofuran (THF), and 0.010 mol / L platinum-palladium- ⁇ -ethynediyl complex in THF (5.5 mL, 0.056 mmol) was added to the resulting solution. added.
- the temperature of the obtained solution was raised from room temperature to 55 ° C. and stirred for 20 hours. After returning to room temperature and distilling off the solvent under reduced pressure to about half, it was added dropwise to a large amount of methanol.
- the resulting precipitate was collected by centrifugation and dried overnight with a vacuum pump to obtain a living polymer poly-L-1 (1.86 g, yield: 93.0%).
- the poly-L-1 obtained by the following operation was converted to a polymer having a right-handed helical structure (P-poly-L-1 (+)) by utilizing the difference in solubility of the polymer in acetone.
- the polymer was fractionated into a left-handed helical polymer (M-poly-L-1 ( ⁇ )).
- poly-L-1 (1.72 g, 4.80 mmol) was suspended in 500 mL of acetone, stirred at room temperature for 2 hours, and separated into a soluble part and an insoluble part by centrifugation. In the soluble part, the solvent was distilled off under reduced pressure and dried overnight with a vacuum pump, and the polyphenylisocyanide derivative P-poly-L-1 (+) having a right-handed helical structure (226 mg, yield: 13%) Got.
- P-poly-L-1 (+) and M-poly-L-1 (-) were determined by size exclusion chromatography (TSKgel Multipore HXL) using a light scattering detector (DAWN HELEOS, manufactured by Wyatt Technology). -M, manufactured by Tosoh Corporation).
- TSKgel Multipore HXL size exclusion chromatography
- DAWN HELEOS light scattering detector
- -M manufactured by Tosoh Corporation
- M-poly-L-1 ( ⁇ ) (299 mg, 0.83 mmol) and comonomer 2 (22 mg, 0.083 mmol) were placed in a polymerization tube, and nitrogen substitution was performed three times. These compounds were dissolved in 8.4 mL of distilled tetrahydrofuran (THF), and the temperature of the resulting solution was raised from room temperature to 55 ° C. and stirred for 20 hours. After returning to room temperature and distilling off the solvent under reduced pressure to about half, it was added dropwise to a large amount of methanol.
- THF distilled tetrahydrofuran
- P-poly-L-1 (+) 150 mg, 0.42 mmol
- comonomer 2 11 mg, 0.042 mmol
- THF distilled tetrahydrofuran
- M-poly-L-1 ( ⁇ )-b-2 (251.7 mg, 0.72 mmol) was dissolved in dry THF (25 mL), and tetrabutylammonium fluoride (TBAF, 1 mol / LTHF solution) was added to this solution. (410 ⁇ L, 0.41 mmol) was added and stirred at room temperature. After 3 hours, the reaction solution was added dropwise to an excessive methanol / 1N HCl (5/1, v / v) mixed solution. The resulting precipitate was collected by centrifugation, dried using a vacuum pump, and M-poly-L in which the tert-butyldimethylsilyl group of M-poly-L-1 ( ⁇ )-b-2 was replaced with hydrogen. -1 ( ⁇ )-b-3 (216.0 mg, yield: 88%) was obtained.
- TBAF tetrabutylammonium fluoride
- silica gel treated with aminopropyltriethoxysilane SP-1000-7-APSL, manufactured by Daiso Corp., particle size 7 ⁇ m, average pore size 100 nm
- 4.5 mL of dry pyridine and 57.6 mg of the condensing agent DMT-MM were added, and the mixture was stirred at room temperature for 7 hours to immobilize the polyphenyl isocyanide derivative on silica gel.
- the resulting filler is recovered with a membrane filter, washed sequentially with pyridine, THF, and methanol, then vacuum-dried and dispersed in a diazomethane / diethyl ether solution for 1 hour to methylate the unreacted carboxylic acid moiety. went.
- the resulting filler is then dispersed in chloroform, filtered through a membrane filter, washed sequentially with chloroform, THF, and methanol, and then vacuum dried to fix the polyphenylisocyanide derivative having a left-handed helical structure to silica gel.
- the obtained filler Iso-L ( ⁇ ) (927.2 mg) was obtained.
- the polyphenylisocyanide derivative binding rate of the obtained filler was 9.9% by weight as calculated from thermogravimetric analysis of the filler.
- silica gel treated with aminopropyltriethoxysilane (SP-1000-7-APSL, manufactured by Daiso Corporation, particle size 7 ⁇ m, average pore size 100 nm) was added to P-poly-L-1 (+)-b- 3 (80.7 mg), dry pyridine 4.5 mL, and condensing agent DMT-MM 37.3 mg were added, and the mixture was stirred at room temperature for 7 hours to immobilize the polyphenyl isocyanide derivative on silica gel.
- SP-1000-7-APSL aminopropyltriethoxysilane
- the resulting filler is recovered with a membrane filter, washed sequentially with pyridine, THF, and methanol, then vacuum-dried and dispersed in a diazomethane / diethyl ether solution for 1 hour to methylate the unreacted carboxylic acid moiety. went. Then, the obtained filler is dispersed in chloroform, filtered through a membrane filter, washed successively with chloroform, THF, and methanol, and then vacuum-dried. The polyphenylisocyanide derivative having a right-handed helical structure is converted into silica gel. Immobilized filler Iso-L (+) (460.6 mg) was obtained. The polyphenylisocyanide derivative binding rate of the obtained filler was 4.7% by weight as calculated from the thermogravimetric analysis of the filler.
- liquid chromatography was performed using the mixed solvents shown in Tables 1 to 3 as the mobile phase in the optical resolutions shown in Tables 1 to 3, using a flow rate of 0.1 mL / min, a detection wavelength of 254 nm, The temperature was 25 ° C.
- the number of theoretical plates of the column was determined using benzene, it was about 2,600 for column L ( ⁇ ) and about 2,000 for column L (+).
- the retention time was evaluated using the elution time (t 0 ) of 1,3,5-tri-tert-butylbenzene.
- the detected optical isomer was identified using a UV / Vis multi-wavelength detector (MD-2010 Plus, JASCO, 254 nm) and an optical rotation detector (OR-2090 Plus, JASCO).
- a circular dichroism detector CD-2095, JASCO, 254 nm
- the retention coefficient k 1 ′ was obtained by the following equation (1).
- the separation factor ⁇ is the ratio of k 2 'to k 1 '.
- the degree of separation Rs was obtained from the following formula (2).
- Retention coefficient (k n ′) (t n ⁇ t 0 ) / t 0 (1)
- t n represents the retention time of the n-th optical isomer detected.
- Degree of separation (Rs) 2 ⁇ L / W (2)
- L represents the distance between the peaks of both optical isomers
- W represents the sum of the bandwidths of both peaks.
- Iso-L (-) and Iso-L (+) have the same side chain chirality and differ in the winding direction of the helix of the polymer main chain.
- the winding direction of the helical polymer affects the optical resolution.
- the expression of the optical resolution of the helical polymer is also affected by the eluent.
- the optical isomer separating agent of the present invention is excellent in solvent resistance. Therefore, a highly polar solvent such as THF can be used for the mobile phase in the optical resolution.
- a highly polar solvent such as THF
- THF a highly polar solvent
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Polyoxymethylene Polymers And Polymers With Carbon-To-Carbon Bonds (AREA)
Abstract
Description
なお、以下の実施例において、NMRスペクトルは、Varian VXR-500S分光計(Varian社製)を用いて、500MHzで操作し、内部標準物質としてテトラメチルシラン(TMS)を用いて測定した。
MP:101.8~102.2℃;
IR:(KBr、cm-1):2122(νC=N)、1693(νC=O);
1H NMR(CDCl3、rt、500MHz):δ0.38(s,CH3,6H)、δ1.02(s,CH3,9H)、δ7.44(d,J=8.5Hz,aromatic,2H)、δ8.06(d,J=8.5Hz,aromatic,2H);
元素分析
理論値(C14H19NO2Si):C 64.33;H 7.33;N 5.36;
実測値:C 64.45;H 7.38;N 5.29;
IR(film、cm-1):3279(νN-H)、1748(νC=O ester)、1634(amide I)、1537(amide II);
1H NMR(THF-d8、55℃、500MHz):δ0.20-0.80(broad,CH3,0.6H)、δ0.89(broad,CH3,3.9H)、δ1.29(broad,CH2,14H)、δ1.55(broad,CH3 and CH2,5H)、δ4.09(broad,CH2,2H)、δ4.30-4.80(broad,CH,1H)、δ4.8-7.8(broad,aromatic,4.4H)、δ8.0-9.0(broad,NH,1H);
元素分析
理論値(C21H30N2O3)10(C14H19NO2Si)1・(H2O)1.4:C 69.49;H 8.38;N 7.60;
実測値:C 69.51;H 8.28;N 7.60;
IR (film2、cm-1):3262(νN-H)、1749(νC=O ester)、1634(amide I)、1537(amide II);
1H NMR(CDCl3、55℃、500MHz):δ0.20-0.80(broad,CH3,0.6H)、δ0.91(broad,CH3,3.9H)、δ1.31(broad,CH2,14H)、δ1.62(broad,CH3 and CH2,5H)、δ4.11(broad,CH2,2H)、δ4.52(broad,CH,1H)、δ4.8-7.8(broad,aromatic,4.4H)、δ8.3-9.2(broad,NH,1H);
元素分析
理論値(C21H30N2O3)10(C14H19NO2Si)1(H2O)3.8:C 68.73;H 8.41;N 7.51;
実測値:C 68.25;H 7.97;N 7.44;
充填剤Iso-L(-)を25cm×0.20cm(i.d.)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し、カラムL(-)を作製した。同様に、充填剤Iso-L(+)を25cm×0.20cm(i.d.)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し、カラムL(+)を作製した。
これらのカラムを用い、液体クロマトグラフィー法により、以下に示す化合物の不斉識別能(保持係数k1’、分離係数α、分離度Rs)の評価を行った。カラムL(-)を用いたHPLCによるラセミ化合物1~18の光学分割の結果を表1及び2に、カラムL(+)を用いたHPLCによるラセミ化合物1~18の光学分割の結果を表3に、カラムL(-)及びカラムL(+)を用いたHPLCによるラセミ化合物10~14の光学分割の結果を表4にそれぞれ示す。
保持係数(kn’)=(tn-t0)/t0 (1)
(式中、tnはn番目に検出される光学異性体の保持時間を示す。)
分離度(Rs)=2×L/W (2)
(式中、Lは両光学異性体のピーク間の距離を示し、Wは両ピークのバンド幅の合計を示す。)
Claims (11)
- 前記らせん高分子が左巻きであることを特徴とする請求項1に記載の光学異性体用分離剤。
- 式(1)中のアミノ酸残基が、一方の光学活性のアミノ酸の残基であることを特徴とする請求項1又は2に記載の光学異性体用分離剤。
- 式(1)中のアミノ酸残基が、L型のアミノ酸の残基であることを特徴とする請求項3に記載の光学異性体用分離剤。
- 式(1)中のアミノ酸残基が、単一のアミノ酸の残基であることを特徴とする請求項1~4のいずれか一項に記載の光学異性体用分離剤。
- 式(1)中のアミノ酸残基が、L-アラニンの残基であることを特徴とする請求項5に記載の光学異性体用分離剤。
- Arがフェニレン基であることを特徴とする請求項1~6のいずれか一項に記載の光学異性体用分離剤。
- R2が炭素数1~20の直鎖のアルキル基であることを特徴とする請求項1~7のいずれか一項に記載の光学異性体用分離剤。
- R2がn-デシル基であることを特徴とする請求項8に記載の光学異性体用分離剤。
- 前記担体がシリカゲルであることを特徴とする請求項1~9のいずれか一項に記載の光学異性体用分離剤。
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JP2011528763A JP5741858B2 (ja) | 2009-08-26 | 2010-08-20 | 光学異性体用分離剤 |
US13/391,768 US20120149851A1 (en) | 2009-08-26 | 2010-08-20 | Separating agent for optical isomers |
CN201080046937.2A CN102667466B (zh) | 2009-08-26 | 2010-08-20 | 光学异构体用分离剂 |
EP10811768.0A EP2472255B1 (en) | 2009-08-26 | 2010-08-20 | Separating agent for optical isomer |
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WO2013168783A1 (ja) | 2012-05-10 | 2013-11-14 | 国立大学法人名古屋大学 | 光学異性体用分離剤 |
JP7337535B2 (ja) | 2019-04-25 | 2023-09-04 | キヤノン株式会社 | アミド結合を有し、かつアルコキシシリル基を有する化合物の製造方法 |
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CN112062901B (zh) * | 2020-08-14 | 2023-03-21 | 合肥工业大学 | 一种螺旋荧光异腈共聚物及其制备方法 |
CN113150192B (zh) * | 2021-04-30 | 2022-04-12 | 华中科技大学 | 一种负载手性螺旋的芳香酰胺型树脂及其制备方法和应用 |
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WO2002030853A1 (fr) | 2000-10-13 | 2002-04-18 | Daicel Chemical Industries, Ltd. | Matiere de remplissage pour separation d'isomeres optiques et procede permettant la separation d'isomeres optiques au moyen de cette matiere de remplissage |
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CN100391593C (zh) * | 2003-04-24 | 2008-06-04 | 大赛璐化学工业株式会社 | 光学异构体用分离剂 |
US20070163961A1 (en) * | 2004-03-04 | 2007-07-19 | Yasuhiro Kagamihara | Separating agent for enantiomeric isomer |
JP2008291207A (ja) * | 2007-04-27 | 2008-12-04 | Kyowa Hakko Kirin Co Ltd | 塩基性アミノ酸を有するらせん状ポリマー |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013168783A1 (ja) | 2012-05-10 | 2013-11-14 | 国立大学法人名古屋大学 | 光学異性体用分離剤 |
CN104428667A (zh) * | 2012-05-10 | 2015-03-18 | 国立大学法人名古屋大学 | 光学异构体用分离剂 |
US20150141241A1 (en) * | 2012-05-10 | 2015-05-21 | National University Corporation Nagoya University a corporation | Separating agent for optical isomer |
EP2848932A4 (en) * | 2012-05-10 | 2015-11-18 | Univ Nagoya Nat Univ Corp | RELEASE FOR AN OPTICAL ISOMER |
JPWO2013168783A1 (ja) * | 2012-05-10 | 2016-01-07 | 国立大学法人名古屋大学 | 光学異性体用分離剤 |
CN104428667B (zh) * | 2012-05-10 | 2017-06-09 | 国立大学法人名古屋大学 | 光学异构体用分离剂 |
JP7337535B2 (ja) | 2019-04-25 | 2023-09-04 | キヤノン株式会社 | アミド結合を有し、かつアルコキシシリル基を有する化合物の製造方法 |
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EP2472255A1 (en) | 2012-07-04 |
EP2472255B1 (en) | 2016-05-25 |
CN102667466A (zh) | 2012-09-12 |
US20120149851A1 (en) | 2012-06-14 |
EP2472255A4 (en) | 2013-11-27 |
JPWO2011024718A1 (ja) | 2013-01-31 |
CN102667466B (zh) | 2014-09-10 |
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