WO2012050124A1 - クロマトグラフィー用分離剤 - Google Patents
クロマトグラフィー用分離剤 Download PDFInfo
- Publication number
- WO2012050124A1 WO2012050124A1 PCT/JP2011/073415 JP2011073415W WO2012050124A1 WO 2012050124 A1 WO2012050124 A1 WO 2012050124A1 JP 2011073415 W JP2011073415 W JP 2011073415W WO 2012050124 A1 WO2012050124 A1 WO 2012050124A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- binaphthyl
- group
- carrier
- derivative
- separation agent
- Prior art date
Links
- 238000004587 chromatography analysis Methods 0.000 title claims abstract description 7
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims abstract description 89
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 58
- 238000000926 separation method Methods 0.000 claims abstract description 21
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 20
- 125000005647 linker group Chemical group 0.000 claims abstract description 20
- 125000001424 substituent group Chemical group 0.000 claims abstract description 13
- -1 binaphthyl compound Chemical group 0.000 claims description 34
- 238000013375 chromatographic separation Methods 0.000 claims description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- DFTUKDIMHCCQIT-UHFFFAOYSA-N 3-bromo-1-(3-bromo-2-methoxynaphthalen-1-yl)-2-methoxynaphthalene Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC(Br)=C3OC)=C(OC)C(Br)=CC2=C1 DFTUKDIMHCCQIT-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 238000004381 surface treatment Methods 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 150000002334 glycols Chemical class 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 3
- 125000006353 oxyethylene group Chemical group 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 238000001459 lithography Methods 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 21
- 150000001413 amino acids Chemical class 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 230000005526 G1 to G0 transition Effects 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 150000003983 crown ethers Chemical class 0.000 description 11
- 239000000203 mixture Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007821 HATU Substances 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000013065 commercial product Substances 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 125000001165 hydrophobic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- 239000011148 porous material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000012756 surface treatment agent Substances 0.000 description 3
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000006087 Silane Coupling Agent Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- OCKPCBLVNKHBMX-UHFFFAOYSA-N butylbenzene Chemical group CCCCC1=CC=CC=C1 OCKPCBLVNKHBMX-UHFFFAOYSA-N 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- BUHGDYPBQWWWQS-UHFFFAOYSA-N 2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCOCCOCCOCCOCCOS(=O)(=O)C1=CC=C(C)C=C1 BUHGDYPBQWWWQS-UHFFFAOYSA-N 0.000 description 1
- BJAADAKPADTRCH-UHFFFAOYSA-N 2-methoxy-1-(2-methoxynaphthalen-1-yl)naphthalene Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3OC)=C(OC)C=CC2=C1 BJAADAKPADTRCH-UHFFFAOYSA-N 0.000 description 1
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- UFWVIHZFNZXHEA-UHFFFAOYSA-N COC(CCCCC(c(ccc1c2-c(c(cccc3)c3cc3-c4ccccc4)c3O)cc1cc(-c1ccccc1)c2O)=O)=O Chemical compound COC(CCCCC(c(ccc1c2-c(c(cccc3)c3cc3-c4ccccc4)c3O)cc1cc(-c1ccccc1)c2O)=O)=O UFWVIHZFNZXHEA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
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- 235000004279 alanine Nutrition 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
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- HDLGIEZOMYJKAK-UHFFFAOYSA-N methyl 6-chloro-6-oxohexanoate Chemical compound COC(=O)CCCCC(Cl)=O HDLGIEZOMYJKAK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 238000002360 preparation method Methods 0.000 description 1
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- FZMJEGJVKFTGMU-UHFFFAOYSA-N triethoxy(octadecyl)silane Chemical compound CCCCCCCCCCCCCCCCCC[Si](OCC)(OCC)OCC FZMJEGJVKFTGMU-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- 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
- B01J20/289—Phases chemically bonded to a substrate, e.g. to silica or to polymers bonded via a spacer
-
- 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
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- 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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- C07D—HETEROCYCLIC COMPOUNDS
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
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- C07F7/1804—Compounds having Si-O-C linkages
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- G—PHYSICS
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- 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
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Definitions
- the present invention relates to a chromatographic separating agent, and relates to a chromatographic separating agent containing a crown ether-like cyclic structure and an optically active binaphthyl.
- chromatographic separation agents having various specific structures are known as chromatographic separation agents depending on the compound to be separated.
- specific structure for example, a crown ether-like cyclic structure, a binaphthyl structure, a phenyl ester structure, and a phenyl carbamate structure are known.
- chromatographic separation agents containing a crown ether-like cyclic structure and a binaphthyl structure include optical isomers obtained by adsorbing a binaphthyl derivative in which a crown ether-like cyclic structure is bridged on each naphthyl ring of binaphthyl on a carrier. Separating agents are known (for example, see Patent Document 1). This optical isomer separating agent is suitable for optical resolution of a compound having an amino group such as an amino acid.
- Examples of the chromatographic separation agent in which the binaphthyl derivative is supported on the support by chemical bonding include, for example, a binaphthyl structure or a crown ether-like cyclic structure of the binaphthyl derivative of the following formula (i) or (ii) and the surface of the support.
- Chromatographic separation agents formed by chemical bonding are known (for example, see Non-Patent Documents 1 and 2 and Patent Document 2).
- the chromatographic separating agent containing the binaphthyl derivative of the formula (i) is known to have an optical resolution of amino acids, but the chromatographic separating agent containing the binaphthyl derivative of the formula (ii) It is known that it has no optical resolution ability of amino acids.
- a technique for protecting a silanol group remaining on a silica gel as a carrier by treatment with n-octyltriethoxysilane is also known (for example, Non-Patent Document 2), it is known that this treatment improves the optical resolution of ⁇ -amino acids, amines, and amino alcohols.
- the binaphthyl derivative of the formula (i) is expected as a separating agent useful for optical resolution of amino acids and can be synthesized using a commercial product as a raw material.
- the synthesis route is long, and there is still room for study from the viewpoint of productivity. Has been.
- the present invention provides a chromatographic separation agent useful for the separation of specific compounds such as optical resolution of amino acids, which contains a crown ether-like cyclic structure and optically active binaphthyl, and has higher productivity.
- the present inventors introduced a crown ether-like cyclic structure into the binaphthyl derivative after introducing a carrier linking group bound to the carrier, and chemically bonded the resulting binaphthyl derivative to the carrier to thereby obtain a crown ether-like derivative.
- the present inventors have found that a chromatographic separation agent containing a cyclic structure and optically active binaphthyl can be obtained more easily, and completed the present invention.
- the present invention relates to a chromatographic separation agent comprising a carrier and an optically active binaphthyl compound bonded to the surface of the carrier by a chemical bond, wherein the binaphthyl compound is represented by the following formula (I):
- a chromatographic separation agent is provided.
- each of R 1 and R 2 is hydrogen, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, or an arbitrary substituent. It represents a non-contiguous alkyl methylene groups to 1 carbon atoms which may be oxygen 8, or a trialkylsilyl group having a carbon number of 1 or 2 alkyl groups each, a 1 and a 2 each, binaphthyl ring Represents a group bonded to the surface of the support, which is replaced by hydrogen, l represents an integer of 4 to 6, and m and n each represents an integer of 0 to 5. However, m + n is 1 to 10.
- the present invention also provides the chromatographic separation agent, wherein l is 4, the chromatographic separation agent, wherein R 1 and R 2 are phenyl groups, and A 1 and A 2 are each a binaphthyl of the formula (I)
- the chromatographic separation agent comprising a structure represented by the following formula (II) replaced by hydrogen, the chromatographic separation agent wherein one of m and n is 1 and the other is 0, and a carrier
- the chromatographic separation agent described above has a hydrophobic surface.
- o represents an integer of 1 to 30.
- the present invention also includes a B step for obtaining a binaphthyl derivative B by introducing a carrier linking group into the binaphthyl ring of the binaphthyl derivative A represented by the following formula (III), and a methoxy group at the 2,2 ′ position of the binaphthyl derivative B.
- R 1 and R 2 are the same as R 1 and R 2 in each formula (I).
- the present invention further includes the A step of obtaining a binaphthyl derivative A by replacing the bromo group of 3,3′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl with R 1 and R 2 respectively.
- a manufacturing method is provided.
- the present invention also provides the above production method wherein the binaphthyl derivative B is obtained by reacting the binaphthyl derivative A with an aliphatic dicarboxylic acid monomethyl ester monochloride having 4 to 33 carbon atoms in the presence of iron chloride in the step B. .
- the present invention also provides a binaphthyl derivative D by reacting polyoxyethylene glycol ditosylate having 5 to 7 repeating oxyethylene groups under alkaline conditions to crosslink between the hydroxyl groups of the binaphthyl derivative C in step D.
- the manufacturing method is provided.
- the present invention provides the above production method in which, in the step E, surface-treated silica gel is used as a carrier, and the carrier linking group of the binaphthyl derivative D and the functional group by the surface treatment of silica gel are chemically bonded.
- the present invention also provides the production method described above, further comprising an F step of hydrophobizing the hydrophilic group on the surface of the carrier.
- the binaphthyl derivative in the chromatographic separation agent of the present invention can introduce a carrier linking group first into a binaphthyl derivative having a methoxy group at the 2,2 ′ position of the binaphthyl ring, and then a crown ether-like cyclic structure in this order. Therefore, it is possible to provide a chromatographic separation agent containing a crown ether-like cyclic structure and optically active binaphthyl, which is useful for optical resolution of amino acids and has higher productivity, for example.
- the chromatographic separation agent of the present invention has a carrier and an optically active binaphthyl compound bonded to the surface of the carrier by a chemical bond.
- the binaphthyl compound is represented by the following formula (I).
- the binaphthyl compound is S-form or R-form, but may be a mixture of S-form and R-form within the range showing optical resolution.
- the binaphthyl compound is usually one kind, but may contain two or more kinds having different m and n.
- each of R 1 and R 2 is hydrogen, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, or an arbitrary substituent.
- the discontinuous methylene group represents an alkyl group having 1 to 8 carbon atoms, which may be oxygen, or a trialkylsilyl group having 1 or 2 carbon atoms in each alkyl group.
- the substituent that the phenyl group or the like in R 1 and R 2 may have is a group that does not interact with an oxygen atom of a crown ether-like cyclic structure. Examples of such a substituent include a methyl group And a chloro group.
- R 1 and R 2 are preferably a phenyl group from the viewpoint of improving separation performance.
- a 1 and A 2 each represent a group bonded to the surface of the carrier, which is replaced with hydrogen of the binaphthyl ring.
- the size of A 1 and A 2 is not particularly limited, but each molecular weight is preferably 100 to 600 from the viewpoint of easy synthesis and improved separation performance.
- a 1 and A 2 can be composed of various groups such as an alkylene group having 1 to 30 carbon atoms, an arylene group having 6 to 30 carbon atoms, an ether group, a carbonyl group, an imino group, and an amide group.
- a 1 and A 2 each include a structure represented by the following formula (II) replaced with hydrogen of the binaphthyl of formula (I).
- o represents an integer of 1 to 30. o is preferably 4 to 10 from the viewpoint of easy synthesis and improved separation performance.
- l represents an integer of 4-6. Such l is preferable from the viewpoint of inclusion of ammonium ions, and more preferably 4.
- m and n each represents an integer of 0 to 5.
- m + n is 1 to 10.
- Both m and n are each preferably 1 or more from the viewpoint of ease of synthesis of the binaphthyl compound, and it is more preferable that one of m and n is 1 and the other is 0.
- m or n it means that there is no coupling
- a carrier capable of fixing the binaphthyl compound by a chemical bond can be used.
- a carrier may be an inorganic carrier or an organic carrier.
- the inorganic carrier include silica, alumina, magnesia, glass, kaolin, titanium oxide, silicate, and hydroxyapatite.
- the organic carrier include polystyrene, polyacrylamide, and polyacrylate.
- the carrier can be used in a form adapted to various types of chromatography.
- Examples of the form of such a carrier include particles and a porous cylindrical body that is liquid-tightly accommodated in a column tube.
- the carrier is preferably a porous body from the viewpoint of improving separation performance, and more preferably has a BET specific surface area of 100 to 600 m 2 / g.
- the pore diameter of the porous carrier is preferably 60 to 300 mm as measured by the mercury intrusion method from the viewpoint of improving separation performance.
- An example of a particularly preferred carrier from the viewpoint of the above-described characteristics is silica gel.
- the carrier is surface-treated with a surface treatment agent in order to form a functional group constituting a part of A 1 or A 2 of formula (I) on the surface of the carrier.
- a surface treatment agent can be appropriately determined according to the type of the carrier.
- silane coupling agent when the carrier is silica gel, a silane coupling agent can be used as the surface treatment agent.
- silane coupling agents include 3-aminopropyltriethoxysilane and 3- (2-aminoethylaminopropyl) trimethoxysilane.
- the surface of the carrier is preferably hydrophobic from the viewpoint of improving separation performance.
- examples of such a carrier include a carrier whose surface is treated with a hydrophobic group.
- the chromatographic separation agent of the present invention is used after being appropriately treated according to the type of chromatography.
- the chromatographic separation agent of the present invention when used for column chromatography, is packed or accommodated in a column tube.
- the chromatographic separation agent of the present invention is used by forming a thin layer on the surface of a substrate such as a glass plate or plastic plate in the case of a particulate separation agent. . These processes can be performed by a normal method.
- the chromatographic separation agent of the present invention can be used for separation of specific compounds other than optical isomers that interact with the structure of the binaphthyl compound, regardless of the optical properties of the binaphthyl compound.
- the binaphthyl compound may be mixed in an S form and an R form so as not to exhibit optical resolution (for example, a racemic form). Good.
- the chromatographic separation agent of the present invention includes a B step for obtaining a binaphthyl derivative B by introducing a carrier linking group into the binaphthyl ring of the binaphthyl derivative A represented by the following formula (III), and 2,2 ′ of the binaphthyl derivative B.
- It can be produced by a method comprising a step D for obtaining the derivative D and a step E for binding the binaphthyl derivative D to the surface of the carrier through a chemical bond via the carrier linking group of the binaphthyl derivative D.
- R 1 and R 2 are the same as R 1 and R 2 of formula (I).
- Binaphthyl derivative A can be obtained as a commercial product. Examples of such commercially available products include 2,2′-dimethoxy-1,1′-binaphthyl and 3,3′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl (both from Tokyo Chemical Industry Co., Ltd.). Product). Use of such a commercial product is preferable from the viewpoint of ease of synthesis of the binaphthyl compound.
- Binaphthyl derivative A can be obtained by synthesis.
- the binaphthyl derivative A can be obtained by synthesis from 3,3′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl.
- the method of the present invention comprises the step A of obtaining the binaphthyl derivative A by replacing the bromo group of 3,3′-dibromo-2,2′-dimethoxy-1,1′-binaphthyl with R 1 and R 2 respectively. Further inclusion is preferable from the viewpoint of obtaining diversity of R 1 and R 2 of the binaphthyl compound.
- the carrier linking group may be a group that binds to a functional group on the surface of the carrier, or a group that binds directly to the surface of the carrier.
- One type or two or more types of carrier linking groups may be used.
- the carrier linking group may be at least one, and may be two or more.
- the carrier linking group may be bonded to only one of the two naphthyl rings of binaphthyl, or may be bonded to both.
- the carrier linking group is preferably a group that binds to a functional group obtained by surface treatment of the carrier.
- a preferable B step for example, a step of obtaining a binaphthyl derivative B by reacting a binaphthyl derivative A with an aliphatic dicarboxylic acid monomethyl ester monochloride having 4 to 33 carbon atoms in the presence of iron chloride.
- the C step can be performed by a mild reaction since the 2,2 ′ position of binaphthyl is highly reactive among the binaphthyl derivative B.
- reaction conditions include dealkylation reaction with boron tribromide under ice cooling to room temperature. It is preferable to perform the C step under such conditions from the viewpoint of suppressing the influence on the other structure of the binaphthyl derivative B and obtaining the binaphthyl derivative C with higher yield.
- the step D can be carried out under conditions that allow polyoxyethylene to be crosslinked to the 2,2′-position hydroxyl group of the binaphthyl derivative C.
- Such crosslinking can be performed by utilizing hydrolysis, for example, by reacting polyoxyethylene glycol ditosylate having 5 to 7 repeating oxyethylene groups under alkaline conditions. .
- the E step can be appropriately performed within the scope of known techniques depending on the type of carrier linking group and carrier.
- the step E can be performed by chemically bonding the carrier linking group of the binaphthyl derivative D and the functional group obtained by the surface treatment of the silica gel.
- Such chemical bonds include, for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophosphate (HATU), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop) and 4- (4,6-dimethoxy-1,
- WSC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
- HATU 7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophosphate
- PyBop 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexa
- the binaphthyl derivative obtained in each step may be purified, or the product may be used as a raw material for the next step as it is.
- an F step of hydrophobizing the hydrophilic group on the surface of the carrier may be further included.
- the F step is preferably performed after the E step.
- a surface treating agent having a hydrophobic organic group or a hydrophobizing agent that reacts with a hydrophilic group on the surface of the carrier to form a hydrophobic group is allowed to act on the carrier or the product of the E step.
- the hydrophilic group on the surface of the carrier include a hydroxyl group and an amino group present on the surface of the carrier such as silica gel and the surface of the carrier after the surface treatment.
- Examples of the surface treating agent having a hydrophobic organic group include hexamethyldisilazane, n-octadecyltriethoxysilane, and n-octadecyltrimethoxysilane.
- the hydrophobizing agent can be appropriately determined according to the type of the hydrophilic group.
- Examples of the hydrophobizing agent include acetic anhydride, decanoic acid, and stearic acid for amino groups.
- the hydrophobic group formed on the surface of the carrier by the F step is preferably constituted by the same configuration on the same scale as (A 1 ) m and (A 2 ) n described above.
- the binaphthyl derivative A is synthesized by a four-step reaction when the synthesis of the binaphthyl derivative A is not included. Even when Step A is included, the chromatographic separation agent of the present invention can be obtained by a five-stage reaction.
- the retention coefficient, the separation coefficient, and the degree of separation are respectively defined as follows.
- a chromatographic separation agent having a binaphthyl derivative and a crown ether-like cyclic structure may have separation characteristics adjusted depending on factors such as the type of substituent introduced into the binaphthyl and the size of the crown ether-like cyclic structure.
- a chromatographic separation agent having a binaphthyl derivative and a crown ether-like cyclic structure can be synthesized more easily in about half the steps than in the prior art. There are great expectations for further elucidation of the separation characteristics of the agent and development of a separation agent having a new separation ability.
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Abstract
Description
さらに、式(i)のビナフチル誘導体を含むクロマトグラフィー用分離剤において、担体としてのシリカゲルに残存するシラノール基を、n-オクチルトリエトキシシランを用いた処理により保護する技術も知られており(例えば、非特許文献2)、この処理により、α―アミノ酸、アミン、アミノアルコールの光学分割能が向上することが知られている。
窒素気流下、(S)-3,3’-ジブロモ-2,2’-ジメトキシ-1,1’-ビナフチル0.946g、フェニルホウ酸0.736g、テトラキス(トリフェニルホスフィン)パラジウム(Pd(PPh3)4)24.8mgをトルエン20mLに溶解させた。これに飽和炭酸カリウム水溶液7mLを加え、100℃で4時間加熱した後、反応液を飽和食塩水で洗浄し、酢酸エチルで抽出し、得られた有機相を無水MgSO4で乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、下記構造式で表されるジメチルエーテル体(1-1)を得た。
合成されたキラルクラウンエーテル(1)508mg、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(WSC)156mg、1-ヒドロキシ-1H-ベンゾトリアゾール一水和物(HOBt)123mg、3-アミノプロピルシリカゲル(平均粒径5μm、平均孔径120Å、表面積330m2/g)3.31gをN,N’-ジメチルホルムアミド(DMF)66mLに溶解させ、室温で24時間撹拌した。次いで、濾過して得られた固体をDMF、希塩酸/メタノール溶液、メタノール各20mLで順次3回洗浄し、乾燥した。得られた固体2.00g、4-ジメチルアミノピリジン61.3mgをジクロロメタン10mLに溶解させ、そこへジクロロメタン10mLに溶解させた無水酢酸567mgを加えて、室温で5時間撹拌した。次いで、濾過して得られた固体をジクロロメタン、メタノール各20mLで順次2回洗浄し、乾燥して、本発明の固定相(1)を得た。元素分析結果より、キラルクラウンエーテル(1)が固定相1gあたり約0.083mmol結合されたものと算定された。
3-アミノプロピルシリカゲル(平均粒径5μm、平均孔径120Å、表面積330m2/g)1.29gをDMF10mLに分散させ、合成されたキラルクラウンエーテル(1)462mg、O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’,-テトラメチルウロニウムヘキサフルオロリン酸塩(HATU)342mg、N-メチルモルホリン99.5mgをDMF15mLに溶解させて加え、室温で24時間撹拌した。次いで、濾過して得られた固体をDMF、希塩酸/メタノール溶液、メタノール各25mLで順次3回洗浄し、さらにDMF25mL(70℃、1時間)で3回洗浄し、メタノール25mL(50℃、1時間)で3回洗浄し、乾燥して、固定相(2)を得た。元素分析結果より、キラルクラウンエーテル(1)が固定相1gあたり約0.30mmol結合されたものと算定された。
固定相(2)602mgを脱水トルエン24mLに分散させ、1,1,1,3,3,3-ヘキサメチルジシラザン1.0mLを加え、136℃で6時間撹拌した。次いで濾過して得られた固体をトルエン、酢酸エチル、メタノール各15mLで順次3回洗浄し、乾燥して、固定相(3)を得た。
固定相(2)593mgをDMF5mLに分散させ、酢酸55.1mg、HATU 245mg、N-メチルモルホリン68.4mgをDMF5mLに溶解させて加え、室温で24時間撹拌した。次いで、濾過して得られた固体をDMF、希塩酸/メタノール溶液、メタノール各15mLで順次3回洗浄し、さらにDMF15mL(70℃、1時間)で3回洗浄し、メタノール15mL(50℃、1時間)で3回洗浄し、乾燥して、固定相(4)を得た。
固定相(2)552mgをDMF5mLに分散させ、デカン酸69.0mg、HATU 228mg、N-メチルモルホリン62.2mgをDMF5mLに溶解させて加え、室温で24時間撹拌した。次いで、濾過して得られた固体をDMF、希塩酸/メタノール溶液、メタノール各15mLで順次3回洗浄し、乾燥して、固定相(5)を得た。
固定相(2)553mgをDMF5mLに分散させ、ステアリン酸114mg、HATU 228mg、N-メチルモルホリン69.2mgをDMF5mLに溶解させて加え、室温で24時間撹拌した。次いで、濾過して得られた固体をDMF、希塩酸/メタノール溶液、メタノール各15mLで順次3回洗浄し、乾燥して、固定相(6)を得た。
固定相(1)~(6)を内径2.1mm、長さ15cmのカラム管にスラリー充填法により充填し、カラム(1)~(6)を得た。
試料をそれぞれ測定する移動相に溶解し、試料濃度約1mg/1mL溶液として、下記条件でHPLCによって分析して、保持係数、分離係数及び分離度を求めた。結果を表1~6に示す。
(条件)
A-1:過塩素酸水溶液(pH1.5),25℃
A-2:過塩素酸水溶液(pH1.5),0℃
B-1:過塩素酸水溶液(pH1.5)/メタノール=80/20(v/v),25℃
B-2:過塩素酸水溶液(pH1.5)/メタノール=70/30(v/v),25℃
B-3:過塩素酸水溶液(pH1.5)/メタノール=60/40(v/v),25℃
B-4:過塩素酸水溶液(pH1.5)/メタノール=50/50(v/v),25℃
B-5:過塩素酸水溶液(pH1.5)/メタノール=80/20(v/v),0℃
C-1:過塩素酸水溶液(pH1.5)/アセトニトリル=95/5(v/v),25℃
C-2:過塩素酸水溶液(pH1.5)/アセトニトリル=90/10(v/v),25℃
C-3:過塩素酸水溶液(pH1.5)/アセトニトリル=80/20(v/v),25℃
C-4:過塩素酸水溶液(pH1.5)/アセトニトリル=70/30(v/v),25℃
C-5:過塩素酸水溶液(pH1.5)/アセトニトリル=90/10(v/v),0℃
C-6:過塩素酸水溶液(pH1.5)/アセトニトリル=80/20(v/v),0℃
D:ヘキサン/エタノール/トリフルオロ酢酸/水=50/50/0.5/0.5(v/v)25℃
Claims (12)
- 担体と、担体の表面に化学結合で結合している光学活性なビナフチル化合物とを有するクロマトグラフィー用分離剤において、
前記ビナフチル化合物が、下記式(I)で表されることを特徴とするクロマトグラフィー用分離剤。
(式(I)中、
R1及びR2はそれぞれ水素、置換基を有していてもよいフェニル基、置換基を有していてもよいナフチル基、置換基を有していてもよく任意の非連続のメチレン基が酸素であってもよい炭素数1~8のアルキル基、又は各アルキル基の炭素数が1又は2のトリアルキルシリル基を表し、
A1及びA2はそれぞれ、ビナフチル環の水素に置き換えられた、担体の表面に結合している基を表し、
lは4~6の整数を表し、m及びnはそれぞれ0~5の整数を表す。ただしm+nは1~10である。) - lが4であることを特徴とする請求項1に記載のクロマトグラフィー用分離剤。
- R1及びR2がフェニル基であることを特徴とする請求項1又は2に記載のクロマトグラフィー用分離剤。
- m及びnの一方が1であり、他方が0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クロマトグラフィー用分離剤。
- 前記担体の表面が疎水性を有することを特徴とする請求項1~5のいずれか一項に記載のクロマトグラフィー用分離剤。
- 下記式(III)で表されるビナフチル誘導体Aのビナフチル環に担体連結基を導入してビナフチル誘導体Bを得るB工程と、
ビナフチル誘導体Bの2,2’位のメトキシ基を加水分解して前記メトキシ基が水酸基になったビナフチル誘導体Cを得るC工程と、
ビナフチル誘導体Cの前記水酸基のそれぞれをポリエチレングリコール誘導体で架橋してクラウンエーテル様環状構造を有するビナフチル誘導体Dを得るD工程と、
ビナフチル誘導体Dの担体連結基を介してビナフチル誘導体Dを担体の表面に化学結合によって結合するE工程と、を含むクロマトグラフィー用分離剤の製造方法。
(式(III)中、R1及びR2はそれぞれ水素、置換基を有していてもよいフェニル基、置換基を有していてもよいナフチル基、置換基を有していてもよく任意の非連続のメチレン基が酸素であってもよい炭素数1~8のアルキル基、又は各アルキル基の炭素数が1又は2のトリアルキルシリル基を表す。) - 3,3’-ジブロモ-2,2’-ジメトキシ-1,1’-ビナフチルのブロモ基をそれぞれR1及びR2に置き換えてビナフチル誘導体Aを得るA工程をさらに含むことを特徴とする請求項7に記載のクロマトグラフィー用分離剤の製造方法。
- B工程において、ビナフチル誘導体Aと炭素数4~33の脂肪族ジカルボン酸モノメチルエステルモノクロライドとを塩化鉄の存在下で反応させてビナフチル誘導体Bを得ることを特徴とする請求項7又は8に記載のクロマトグラフィー用分離剤の製造方法。
- D工程において、オキシエチレン基の繰り返し数が5~7のポリオキシエチレングリコールジトシラートをアルカリ条件下で反応させてビナフチル誘導体Cの水酸基間を架橋してビナフチル誘導体Dを得ることを特徴とする請求項7~9のいずれか一項に記載のクロマトグラフィー用分離剤の製造方法。
- E工程において、担体に表面処理シリカゲルを用い、ビナフチル誘導体Dの担体連結基とシリカゲルの表面処理による官能基とを化学結合させることを特徴とする請求項7~10のいずれか一項に記載のクロマトグラフィー用分離剤の製造方法。
- 担体の表面の親水性基を疎水化するF工程をさらに含むことを特徴とする請求項7~11に記載のクロマトグラフィー用分離剤の製造方法。
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