JP5738272B2 - 6’−シアリルラクトース塩並びに6’−シアリルラクトース塩及び他のa−シアリルオリゴ糖の合成方法 - Google Patents
6’−シアリルラクトース塩並びに6’−シアリルラクトース塩及び他のa−シアリルオリゴ糖の合成方法 Download PDFInfo
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- JP5738272B2 JP5738272B2 JP2012502871A JP2012502871A JP5738272B2 JP 5738272 B2 JP5738272 B2 JP 5738272B2 JP 2012502871 A JP2012502871 A JP 2012502871A JP 2012502871 A JP2012502871 A JP 2012502871A JP 5738272 B2 JP5738272 B2 JP 5738272B2
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- formula
- compound
- lactose
- sialyl
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- 238000000034 method Methods 0.000 title claims description 32
- 229920001542 oligosaccharide Polymers 0.000 title claims description 20
- TYALNJQZQRNQNQ-JLYOMPFMSA-N alpha-Neup5Ac-(2->6)-beta-D-Galp-(1->4)-beta-D-Glcp Chemical class O1[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](O)C[C@@]1(C(O)=O)OC[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)O[C@@H]2CO)O)O1 TYALNJQZQRNQNQ-JLYOMPFMSA-N 0.000 title claims description 11
- 230000002194 synthesizing effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 19
- 239000008101 lactose Substances 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 claims description 15
- 150000002482 oligosaccharides Chemical class 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 229910052698 phosphorus Inorganic materials 0.000 claims description 14
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 150000002772 monosaccharides Chemical class 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000002016 disaccharides Chemical class 0.000 claims description 8
- TYALNJQZQRNQNQ-UHFFFAOYSA-N #alpha;2,6-sialyllactose Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OCC1C(O)C(O)C(O)C(OC2C(C(O)C(O)OC2CO)O)O1 TYALNJQZQRNQNQ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 239000000543 intermediate Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 238000006945 Knorr synthesis reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 235000013350 formula milk Nutrition 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- 229960001375 lactose Drugs 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 15
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- -1 6'-N-acetylneuraminyl-lactose sodium salt Chemical class 0.000 description 10
- 239000011575 calcium Substances 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 239000011777 magnesium Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 8
- JWXINSMWFMIRCL-RWNQQKCBSA-N [(2R,3R,4S,5R,6S)-4,5,6-triacetyloxy-3-[(2S,3R,4S,5S,6R)-3,4-diacetyloxy-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methyl acetate Chemical compound C(C)(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](O)[C@H](O2)CO)[C@H](O1)COC(C)=O JWXINSMWFMIRCL-RWNQQKCBSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
- 235000020357 syrup Nutrition 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 239000000370 acceptor Substances 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 239000000538 analytical sample Substances 0.000 description 5
- 159000000007 calcium salts Chemical class 0.000 description 5
- 238000006206 glycosylation reaction Methods 0.000 description 5
- 235000020256 human milk Nutrition 0.000 description 5
- 210000004251 human milk Anatomy 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 229930182830 galactose Natural products 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 3
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 3
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 3
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960002442 glucosamine Drugs 0.000 description 3
- 239000008103 glucose Chemical group 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- KFEUJDWYNGMDBV-UHFFFAOYSA-N (N-Acetyl)-glucosamin-4-beta-galaktosid Natural products OC1C(NC(=O)C)C(O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 KFEUJDWYNGMDBV-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- CILYIEBUXJIHCO-UHFFFAOYSA-N 102778-91-6 Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OC1C(O)C(OC2C(C(O)C(O)OC2CO)O)OC(CO)C1O CILYIEBUXJIHCO-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical group N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- DVGKRPYUFRZAQW-UHFFFAOYSA-N 3 prime Natural products CC(=O)NC1OC(CC(O)C1C(O)C(O)CO)(OC2C(O)C(CO)OC(OC3C(O)C(O)C(O)OC3CO)C2O)C(=O)O DVGKRPYUFRZAQW-UHFFFAOYSA-N 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 208000007976 Ketosis Diseases 0.000 description 2
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 2
- PNIWLNAGKUGXDO-UHFFFAOYSA-N Lactosamine Chemical group OC1C(N)C(O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 PNIWLNAGKUGXDO-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CILYIEBUXJIHCO-UITFWXMXSA-N N-acetyl-alpha-neuraminyl-(2->3)-beta-D-galactosyl-(1->4)-beta-D-glucose Chemical compound O1[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](O)C[C@@]1(C(O)=O)O[C@@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)O[C@@H]2CO)O)O[C@H](CO)[C@@H]1O CILYIEBUXJIHCO-UITFWXMXSA-N 0.000 description 2
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 2
- KFEUJDWYNGMDBV-LODBTCKLSA-N N-acetyllactosamine Chemical compound O[C@@H]1[C@@H](NC(=O)C)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KFEUJDWYNGMDBV-LODBTCKLSA-N 0.000 description 2
- HESSGHHCXGBPAJ-UHFFFAOYSA-N N-acetyllactosamine Natural products CC(=O)NC(C=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O HESSGHHCXGBPAJ-UHFFFAOYSA-N 0.000 description 2
- OIZGSVFYNBZVIK-UHFFFAOYSA-N N-acetylneuraminosyl-D-lactose Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1O OIZGSVFYNBZVIK-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 102000003838 Sialyltransferases Human genes 0.000 description 2
- 108090000141 Sialyltransferases Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical group OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001804 chlorine Chemical class 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960003082 galactose Drugs 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 150000002584 ketoses Chemical class 0.000 description 2
- DOVBXGDYENZJBJ-ONMPCKGSSA-N lactosamine Chemical group O=C[C@H](N)[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O DOVBXGDYENZJBJ-ONMPCKGSSA-N 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 229950006780 n-acetylglucosamine Drugs 0.000 description 2
- 229940060155 neuac Drugs 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 125000005630 sialyl group Chemical group 0.000 description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
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- A—HUMAN NECESSITIES
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Description
[式中、Rは遊離の水酸基を有する単糖、二糖、又はオリゴ糖の残基である]で示されるα−シアリルオリゴ糖は、哺乳動物や鳥類の組織にリポオリゴ糖、リポ多糖、又は糖タンパク質の糖鎖の主要な形態で存在する。α−シアリルオリゴ糖は種々のグリコシド結合、より典型的には、α(2−3)ガラクトース、α(2−6)ガラクトース又はα(2−3)ラクトース、α(2−6)ラクトースに存在する。これらのシアロシドの機能は、オリゴ糖部分の構造不均一性により動物に依って大きく異なる。シアロシドは多くの病原体の生理と成長に特に重要な役割を果たす細胞間及び細胞内イベントのメディエイターである(DK Ress他、Current Organic Synthesis,2004,1,31〜46)。
1)酵素の入手可能性が限られていること
2)活性化基質CMP−NeuAc又はPNP−NeuAcの供与体の合成が必要であること
3)天然シアロシド合成のための使用での柔軟性を低下させるシアリルトランスフェラーゼの厳密な特異性(Ichigawa Y.他、Analytical Biochem 1992,202,215〜238,S.Sabesan他、J.Am.Chem.Soc.,1986,108,2068〜2080,O.Hindsgaul他、J.Biol.Chem.,1991,266,17858〜17862,H.J.Gross他、Eur.J.Biochem.1988,177,583〜589)。
[式中、Pは適切な保護基であり、R1はアルキル基であり、Xは塩素である](R.Kuhn他、Chem.Ber.,1966,99,611、A.Marra他、Carb.Res.,1989,190,317〜322、及びNF Byramova他、Carb.Res,1992,237,161〜175で報告される方法により得られる)。この理由は、単純なシアリル誘導体は、非常に毒性の強い反応物質を使用することなく簡単に工業的規模に合成することができ、グリコシル化反応中にα結合の特異的な形成を誘導するからである。しかし、シアル酸供与体は最初に使用された後、その使用は著しく減少し、現在の技術は、より一段と複雑な供与体を目指して取り組んでいる。
[式中、Mn+は、K+、Ca2+、Mg2+、Sr2+、Fe2+及びAl3+からなる群より選択される]により解決する。更に本発明の主題は、式(I)のα−シアリルオリゴ糖の化合物
[式中、Rは、遊離水酸基を有する単糖、二糖、又はオリゴ糖の残基である]の合成方法である。前記方法は、以下の少なくとも1つのステップ
a)式(II)のシアル酸供与体
[式中、Pは適切な保護基であり、R1はアルキル基であり、Xはハロゲンである]の、式R’OHの受容体[式中、R’は保護基P’により適切に保護された単糖、二糖、又はオリゴ糖の残基であり、0個、1個又は複数の遊離の水酸基を含み、これらの保護基P’は同一でも互いに異なっていても、前記供与体中に存在する保護基と異なってもよい]とのケーニッヒ・クノール反応によるカップリングによって、式(III)の中間体
[式中、P、R1及びR’は、上記で定義された通りである]
を得るステップであって、
このケーニッヒ・クノール反応は、Ag(I)系の金属プロモーターを受容体のモル数に対して0.5〜2.0当量のモル量で使用すること特徴とするステップを含む。
[式中、Mn+は、K+、Ca2+、Mg2+、Sr2+、Fe2+、Al3+からなる群より選択され、Mの酸化状態に対応して、n=1、2、3である]の化合物である。好ましくは、Mn+は、Ca2+、Mg2+、又はK+である。
カルシウム塩は、骨の成長を促進するのに潜在的に有用である。
カリウム塩及びマグネシウム塩は、生体膜を通る適切な輸送及び生理学的な膜内外の電位差を維持、促進及び回復するのに潜在的に有用である。
鉄塩は、Feの集成が必要な全ての病的状態に潜在的に有用である。
[式中、Rは、遊離の水酸基を有する単糖、二糖、又はオリゴ糖の残基であり、好ましくは、Rは、ガラクトース、グルコース、グルコサミン、ラクトース、ラクトサミン、フコシルラクトースの中から選択され、より好ましくは、Rは6’−ガラクトース、3’−グルコース、3’−グルコサミン、6’−ラクトース、3’−ラクトース、6’−ラクトサミン、3’−ラクトサミン、3’−3−フコシルラクトースの中から選択される]の合成方法に関する。
前記方法は、以下の少なくとも1つのステップ:
a)式(II)のシアル酸供与体
[式中、
Pは適切な保護基であり、
R1はアルキル基、好ましくはMe、Et、又はPrであり、
Xはハロゲン、好ましくは塩素である]の
式R’OHの適切に保護された受容体[式中、R’は保護基P’により適切に保護された単糖、二糖、又はオリゴ糖の残基であり、0個、1個又は複数の遊離の水酸基を含み、これらの保護基P’は同一でも互いに異なっていても、前記供与体中に存在する保護基と異なっていてもよい]とのケーニッヒ・クノール反応によるカップリングによって、式(III)の中間体
[式中、P、R1及びR’は上記に定義された通りである]を得るステップであって、
このケーニッヒ・クノール反応は、Ag(I)系の金属プロモーターを受容体のモル数に対して0.5〜2.0当量のモル量で使用すること特徴とするステップを含む。
b)保護基P、P’及びR1を除去して、上記の式(I)の化合物を得るステップ
を含む。
[式中、P’は適切な保護基であり、好ましくはP’はアシルであり、より好ましくはアセチルである]である。
の化合物であるこのカップリング反応は、式(IIIa)
の化合物を提供する。式(IIIa)の化合物は、粗製混合物から得られるので、驚くべきことに、シアル酸のアノマー炭素及び式(Ia)の化合物6’SLの生成に対する水酸基及びカルボキシル官能基の連続的脱保護の後続反応に使用できる。好適には、最初にアセチル基の除去を始め、次にメチルエステルの加水分解を進めるべきである。
4’,6’−ジ−O−ベンジリデンラクトースの調製
1H NMR(DMSOd6,300MHz):δ ppm 7.51〜7.34(5H,m,Ph);6.36(d,JOH−1=4.8Hz,1H,C1−OH);5.58(s,1H,PhCH);5.28(d,J=4.2Hz,1H,OH);5.01(d,J=5.7Hz,OH);4.92(擬似t,J1−OH=J1〜2=4.0Hz,1H,H−1);4.68(d,J=6.9Hz,1H,OH);4.45(m,2H,2×OH);4.37(d,J1’−2’=7.5Hz,1H,H−1’);4.16〜3.95(m,3H);3.84〜3.11(m,9H)(H−2,H−3,H−4,H−5,CH2−6,H−2’,H−3’,H−4’,H−5’,CH2−6’)。
13C NMR(DMSOd6,75MHz):δ ppm 138.5、128.6、127.9、126.2(Ph);103.1(C−1’);99.8(PhCH);92.1(C−1);79.6、75.8、72.2、71.6、71.3、69.9、69.8、68.5(C2,C2’,C3,C3’,C4,C4’,C5,C5’);66.2(C6’);60.3(C6)。
Rf(薬局方、可視紫外分光法及びナフトレゾルシン)=0.7
4’,6’−O−p−メトキシベンジリデンラクトースの調製
1H NMR(DMSOd6,300MHz):δ ppm 7.38(d,J=8.7Hz,2H)、6.93(d,J=8.7Hz,2H)(Ph);6.70(d,JOH−1=6.6Hz,1H,C1−OH β);6.36(d,JOH−1=4.1Hz,1H,C1−OH α);5.52(s,1H,PhCH α+β);5.27(m,1H,OHα+β);5.04〜4.95(m,1H,OHα+β);4.92(擬似t,J=4.1Hz,H−1 α);4.72〜4.60(m,1H,OHα+β);4.56〜4.28(m,H−1’ α+β+H−1 β+2×OHα+β);4.12〜3.92(m,3H);3.76(s,3H,OMe);3.80〜3.11(m,9H);2.98(m,1H β)。
13C NMR(DMSOd6,75MHz):δ ppm 159.4、130.9、127.6、113.2(Ph);103.0(C−1’ α+β);99.7(PhCHα+β);96.7(C−1β);92.1(C−1α);79.6、79.2、75.7、74.9、74.8、74.6、72.2、71.6、71.3、69.9、69.8、68.4(C2,C2’,C3,C3’,C4,C4’,C5,C5’ α+β);66.2(C6’ α+β);60.4,60.3(C6α+β);55.1(OMeα+β)。
Rf(薬局方、可視紫外分光法及びナフトレゾルシン)=0.8
1,2,3,6,2’,3’−ヘキサ−O−アセチル−4’,6’−O−ベンジリデン−β−D−ラクトースの調製
1H NMR(CDCl3,300MHz):δ ppm 7.54〜7.34(m,5H,Ph);5.68(d,J1〜2=8.4Hz,1H,H−1)、5.47(擬似s,1H,CHPh);5.32〜5.21(m,2H,H−3+H−2’)、5.07(dd,J2〜3=9.6Hz e J2〜1=8.4Hz,1H,H−2)、4.87(dd,J3’−2’=10.4Hz e J3’−4’=3.8Hz,1H,H−3’)、4.54〜4.43(m,2H,H−1’+H−6a)、4.38〜4.25(m,2H,H−4’+H−6’a)、4.14(dd,J6b−6a=12.2 e J6b−5=4.6Hz,1H,H−6b)、4.04(d,J6’b−6’a=12.3Hz,1H,H−6’b)、3.90〜3.70(m,2H,H4+H5);3.46(擬似s,1H,H−5’)、2.14〜2.00(6×COCH3)。
13C NMR(CDCl3,75MHz):δ ppm 170.8、170.4、170.1、169.7、169.0、168.9(6×COCH3);137.5、129.3、128.3、126.6(Ph);101.4(CHPh);101.1(C−1’);91.8(C−1);75.5、73.8、73.2、72.4、72.2、70.5、69.0、68.5(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’);66.6(C−6’);61.8(C−6)、20.9〜20.7(6×COCH3)。
Rf(AcOEt:ヘキサン=1:1、可視紫外分光法及びH2SO4/MeOH)=0.3
1,2,3,6,2’,3’−ヘキサ−O−アセチル−4’,6’−O−p−メトキシベンジリデン−β−D−ラクトースの調製
1H NMR(CDCl3,300MHz):δ ppm 7.36(d,J=8.7Hz,2H)、6.88(d,J=8.7Hz,2H)(Ph);5.66(d,J1〜2=8.4Hz,1H,H−1);5.40(擬似s,1H,CHPh);5.24(擬似t,J3〜2=J3〜4=9.6Hz,1H,H−3);5.23(dd,J2’−3’=10.2Hz e J2’−1’=7.8Hz,1H,H−2’);5.04(dd,J2〜3=9.6Hz e J2〜1=8.4Hz,1H,H−2);4.84(dd,J3’−2’=10.2Hz e J3’−4’=3.6Hz,1H,H−3’)、4.46(dd,J6a−6b=12.0Hz e J6a−5=1.5Hz,1H,H−6a);4.44(d,J1’−2’=7.8Hz,1H,H−1’);4.28(d,J4’−3’=3.6Hz,1H,H−4’);4.25(d,J6’a−6’b=12.6Hz,1H,H−6’a);4.12(dd,J6b−6a=12.0 e J6b−5=4.5Hz,1H,H−6b)、4.00(dd,J6’b−6’a=12.6Hz e J6’b−5’=1.5Hz,1H,H−6’b);3.87〜3.69(m,2H,H4+H5);3.79(s,3H,OMe);3.42(擬似s,1H,H−5’);2.09、2.07、2.03、2.02、2.00(6×COCH3)。
13C NMR(CDCl3,75MHz):δ ppm 170.8、170.4,170.1、169.6、168.93、168.89(6×COCH3);160.3、130.1、127.9、113.7(Ph);101.3(CHPh);101.1(C−1’);91.8(C−1);75.5、73.8、73.2、72.4、72.1、70.5、69.0、68.4(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’);66.5(C−6’);61.8(C−6)、55.4(OMe);20.9〜20.6(6×COCH3)。
Rf(AcOEt:ヘキサン=1:1、可視紫外分光法及びH2SO4/MeOH)=0.2
1,2,3,6,2’,3’−ヘキサ−O−アセチル−β−D−ラクトースの調製
融点 188〜190℃
1H NMR(CDCl3,300MHz):δ ppm 5.68(d,J1〜2=8.1Hz,1H,H−1)、5.24(擬似t,J3〜2=J3〜4=9.3Hz,1H,H−3)、5.19(dd,J2’−3’=10.2Hz e J2’−1’=7.8Hz,1H,H−2’)、5.05(dd,J2〜3=9.3Hz e J2〜1=8.1Hz,1H,H−2)、4.88(dd,J3’−2’=10.2Hz e J3’−4’=3.3Hz,1H,H−3’)、4.49(d,J1’−2’=7.8Hz,1H,H−1’)、4.49(dd,J6a−6b=11.1Hz e J6a−5=1.8Hz,1H,H−6a)、4.15〜4.05(m,2H,H−4’+H−6b)、4.00〜3.70(m,4H,H−4+H−5+H−6’a+H−6’b)、3.56(擬似t,J=5.4Hz,1H,H−5’)、2.96(d,JOH−4’=4.2Hz,C4’−OH)、2.59(dd,JOH−6’=7.5 e 4.8Hz,C6’−OH)、2.11、2.09、2.08、2.07 2.04、2.03(6×COCH3)。
13C NMR(CDCl3,75MHz):δ ppm 170.6、170.4、170.3、169.7、169.6、169.0(6×COCH3);101.2(C−1’)、91.7(C−1)、75.9(C−4)、74.6(C−5’)、73.7(C−3’)、73.6(C−5)、73.1(C−3)、70.7(C−2)、69.7(C−2’)、67.8(C−4’)、62.1、62.0(C−6,C−6’)、20.9、20.8、20.7(6×COCH3)。
Rf(AcOEt、可視紫外分光法及びH2SO4/MeOH)=0.4
ジ1,2,3,6,2’,3’−ヘキサ−O−アセチル−β−D−ラクトースの調製
(メチル5−アセトアミド−4,7,8,9−テトラ−O−アセチル−3,5−ジデオキシ−D−グリセロ−α−D−ガラクト−ノノ−2−ウロピラノシルオナート)−(2→6)−2,3−ジ−O−アセチル−β−D−ガラクトピラノシル−(1→4)−1,2,3,6−テトラ−O−アセチル−β−D−グルコピラノースの調製
1H NMR(CDCl3,300MHz):δ ppm 5.66(d,J1〜2=8.4Hz,1H,H−1);5.42〜5.10(m,5H,H−3+H−2’+H−7”+H−8”+NH);5.01(擬似t,J2〜1=8.4Hz,1H,H−2);4.94〜4.78(m,2H,H−3’+H−4”);4.53〜4.27(m,3H,H−1’+H−6a+H−9”);4.24〜3.92(m,5H,H−6b+H−4’+H−5”+H−6”+H−9”b);3.92〜3.50(m,5H,H−4+H−5+H−5’+H−6’a+H−6’b);3.80(s,3H,COOCH3)、2.93(広幅なs,1H,OH);2.55(dd,J3”eq−3”ax=12.6 e J3”eq−4”=4.5Hz,1H,H−3”eq);2.17〜1.97(31H,10×CH3CO e H−3”ax)、1.86(s,3H,NHCOCH3)。
13C NMR(CDCl3,75MHz):δ ppm 171.05、170.98、170.5、170.4、170.29、170.28、170.24、170.0、169.6、169.4、169.0、168.0(OAc,NHAc,COOMe);100.8(C−1’);99.1(C−2”);91.7(C−1);75.7、73.7、73.6、72.94、72.90、72.4、70.7、69.7、68.95、68.87、67.4、66.3(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’,C−4”,C−6”,C−7”,C−8”);62.6、62.4、62.1(C−6,C−6’,C−9”);53.2(OCH3);49.4(C−5”);37.4(C−3”);23.2(NHCOCH3)、21.1、20.9、20.8、20.74、20.67(10×CH3CO)。
(メチル5−アセトアミド−3,5−ジデオキシ−D−グリセロ−α−Dガラクト−ノノ−2−ウロピラノシルオナート)−(2→6)−β−D−ガラクトピラノシル−(1→4)−(α/β)−D−グルコピラノースの調製
1H NMR(D2O,300MHz):δ ppm 5.21(d,J1〜2 3.6Hz,1H,H−1α)、4.66(d,J1〜2 7.8Hz,1H,H−1β)、4.42(d,J1’−2’:7.5Hz,1H,H−1’)、4.15〜3.45(m,19H)、3.89(s,3H,COOCH3)、3.29(m,1H)、2.70(dd,J3”eq−3”ax 12.9 e J3”eq−4” 4.8Hz,H−3”eq)、2.03(s,3H,NHCOCH3)、1.88(擬似t,J3”ax−3”eq=J3”ax−4” 12.9Hz,H−3”ax)。
13C NMR(D2O,75MHz):δ ppm 175.5(NHCOCH3)、170.4(COOMe)、103.9(C−1’)、99.6(C−2”)、96.3(C−1β)、92.5(C−1α)、80.5,80.4,75.2(2C)、74.4、74.0、73.5、73.0、72.2、71.7、71.3、71.2、70.5、69.0(2C)、67.9(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’,C−4”,C−6”,C−7”,C−8”)、64.0(C−6’)、63.8(C−9”)、60.8 e 60.7(C−6α+β)、54.1(COOCH3)、52.3(C−5”)、39.6(C−3”)、22.8(NHCOCH3)。
ナトリウム5−アセトアミド−3,5−ジデオキシ−D−グリセロ−α−D−ガラクト−ノノ−2−ウロピラノシルオナート)−(2→6)−β−D−ガラクトピラノシル−(1→4)−(α/β)−D−グルコピラノースの調製
当該化合物の1H NMRデータ及び13C NMRデータは、文献(L.Dorland他、Eur.J.Biochem.1978,87,323;J.P.Kamerling他、Carbohydr.Res.1982,100,331)で報告されるデータと一致した。
1H NMR(D2O,300MHz):δ ppm 5.22(d,J1〜2 3.8Hz,1H,H−1α)、4.66(d,J1〜2 7.8Hz,1H,H−1β)、4.43(d,J1’−2’:7.6Hz,1H,H−1’)、4.02〜3.48(m,19H)、3.31(m,1H)、2.71(dd,J3”eq−3”ax 12.5 e J3”eq−4” 4.7Hz,H−3”eq)、2.03(s,3H,NHCOCH3)、1.74(擬似t,J3”ax−3”eq=J3”ax−4” 12.5Hz,H−3”ax)。
13C NMR(D2O,75MHz,外部標準アセトン):δ ppm 175.6(NHCOCH3)、174.1(COO−)、103.9(C−1’)、100.9(C−2”)、96.3(C−1β)、92.5(C−1α)、80.4、80.3、75.30、75.26、74.4、74.3、73.2、73.0、72.4、72.3、71.7、71.4、70.6、69.2、69.04、69.01(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’,C−4”,C−6”,C−7”,C−8”)、64.2(C−6’)、63.3(C−9”)、60.9 e 60.8(C−6α+β)、52.4(C−5”)、40.7(C−3”)、22.7(NHCOCH3)。
[α]D 20℃:+9.3°(c:1%,H2O)
融点: 191.4−194.2°C(T 分解)
カルシウム5−アセトアミド−3,5−ジデオキシ−D−グリセロ−α−D−ガラクト−ノノ−2−ウロピラノシルオナート)−(2→6)−β−D−ガラクトピラノシル−(1→4)−(α/β)−D−グルコピラノースの調製
1H NMR(D2O,300MHz):δ ppm 5.22(d,J1〜2 3.8Hz,1H,H−1α)、4.66(d,J1〜2 7.8Hz,1H,H−1β)、4.43(d,J1’−2’:7.8Hz,1H,H−1’)、4.02〜3.48(m,19H)、3.31(m,1H)、2.71(dd,J3”eq−3”ax 12.0 e J3”eq−4” 4.5Hz,H−3”eq)、2.03(s,3H,NHCOCH3)、1.74(擬似t,J3”ax−3”eq=J3”ax−4” 12.0Hz,H−3”ax)。
13C NMR(D2O,75MHz,内部標準アセトニトリル):δ ppm 175.5(NHCOCH3)、174.1(COO−)、103.8(C−1’)、100.9(C−2”)、96.2(C−1β)、92.4(C−1α)、80.3、80.3、75.26、75.22、74.4、74.3、73.1、73.0、72.4、72.2、71.7、71.4、70.5、69.1、69.13、69.00(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’,C−4”,C−6”,C−7”,C−8”)、64.2(C−6’)、63.2(C−9”)、60.9 e 60.7(C−6α+β)、52.4(C−5”)、40.7(C−3”)、22.7(NHCOCH3)。
Ca2+の分析 98.3%
[α]D 20°C:+10°(c:1%、H2O)
融点:204,5−206,6°C(T 分解)
IRνKBr max:3400、1612、1380、1033cm−1.
カリウム5−アセトアミド−3,5−ジデオキシ−D−グリセロ−α−D−ガラクト−ノノ−2−ウロピラノシルオナート)−(2→6)−β−D−ガラクトピラノシル−(1→4)−(α/β)−D−グルコピラノースの調製
1H NMR(D2O,200MHz):δ ppm 5.22(d,J1〜2 3.8Hz,1H,H−1α)、4.66(d,J1〜2 7.8Hz,1H,H−1β)、4.43(d,J1’−2’:7.6Hz,1H,H−1’)、4.02〜3.48(m,19H)、3.31(m,1H)、2.71(dd,J3”eq−3”ax 12.0 e J3”eq−4” 4.4Hz,H−3”eq)、2.03(s,3H,NHCOCH3)、1.74(擬似t,J3”ax−3”eq=J3”ax−4” 12.0Hz,H−3”ax)。
13C NMR(D2O,75MHz,内部標準アセトン):δ ppm 175.5(NHCOCH3)、174.0(COO−)、103.8(C−1’)、100.9(C−2”)、96.2(C−1β)、92.4(C−1α)、80.3、80.2、75.22、75.19、74.4、74.3、73.1、72.9、72.4、72.2、71.7、71.4、70.5、69.1、69.04、69.01(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’,C−4”,C−6”,C−7”,C−8”)、64.1(C−6’)、63.2(C−9”)、60.8 e 60.7(C−6α+β)、52.4(C−5”)、40.7(C−3”)、22.6(NHCOCH3)。
[α]D 20℃:+9.8°(c:1%,H2O)
融点179.3−182.8°C(T 分解)
IRνKBr max:3391、1612、1379、1034cm−1
マグネシウム5−アセトアミド−3,5−ジデオキシ−D−グリセロ−α−D−ガラクト−ノノ−2−ウロピラノシルオナート)−(2→6)−β−D−ガラクトピラノシル−(1→4)−(α/β)−D−グルコピラノースの調製
1H NMR(D2O,300MHz):δ ppm 5.22(d,J1〜2 3.6Hz,1H,H−1α)、4.66(d,J1〜2 8.1Hz,1H,H−1β)、4.43(d,J1’−2’:7.5Hz,1H,H−1’)、4.02〜3.48(m,19H)、3.31(m,1H)、2.71(dd,J3”eq−3”ax 12.3 e J3”eq−4” 4.5Hz,H−3”eq)、2.03(s,3H,NHCOCH3)、1.74(擬似t,J3”ax−3”eq=J3”ax−4” 12.3Hz,H−3”ax)。
13C NMR(D2O,75MHz,内部標準アセトニトリル):δ ppm 175.5(NHCOCH3)、174.1(COO−)、103.8(C−1’)、100.9(C−2”)、96.3(C−1β)、92.4(C−1α)、80.3、80.2、75.26、75.23、74.4、74.3、73.1、73.0、72.4、72.2、71.7、71.4、70.6、69.1、69.00、68.96(C−2,C−3,C−4,C−5,C−2’,C−3’,C−4’,C−5’,C−4”,C−6”,C−7”,C−8”)、64.2(C−6’)、63.3(C−9”)、60.9 e 60.7(C−6α+β)、52.4(C−5”)、40.7(C−3”)、22.7(NHCOCH3)。
Mg2+の分析97.5%
[α]D 20°C+9.8°(c:1%、H2O)
融点183.1−185.1°C(T 分解)
IRνKBr max:3391、1634、1379、1035cm−1
Claims (9)
- Mn+が、K+、Ca2+、Mg2+からなる群の中から選択される、請求項1に記載の化合物。
- 6’−シアリルラクトース(6’SL)から始まる、請求項1又は2で定義された式(Ib)の化合物の調製方法であって、6’SL溶液にM(n+)を含む塩基を添加して8〜10のpH値を得ることを含む方法。
- 式(I)
[式中、Rは、遊離の水酸基を有する単糖、二糖、又はオリゴ糖の残基である]のα−シアリルオリゴ糖の化合物の調製方法であって、以下の少なくとも1つのステップ
a)式(II)のシアル酸供与体
[式中、Pは適切な保護基であり、R1はアルキル基であり、Xはハロゲンである]の、式R’OHの受容体[式中、R’は保護基P’により適切に保護された単糖、二糖、又はオリゴ糖の残基であり、0個、1個又は複数の遊離の水酸基を含み、前記保護基P’は同一でも互いに異なっていても、前記供与体中に存在する保護基と異なっていてもよい]とのケーニッヒ・クノール反応によるカップリングによって、式(III)の中間体
[式中、P、R1及びR’は上記で定義した通りである]を得るステップであって、
前記ケーニッヒ・クノール反応は、Ag(I)系の金属プロモーターを受容体のモル数に対して0.5〜2.0当量のモル量で使用し、この混合物を5日〜10日間、20℃〜40℃の温度で撹拌して達成することを特徴とするステップを含む方法。 - ステップ(a)の後に、以下のステップ
b)保護基P、P’及びR1を除去し、請求項4で定義した式(I)の化合物を得るステップ
を更に含む請求項4に記載の方法。 - Rが6’−ラクトースである請求項4又は5に記載の6’SLの調製方法。
- 薬剤及び食品インテグレーターとして使用するための請求項1又は2に記載の式(Ib)の化合物。
- 請求項1又は2に記載の式(Ib)の化合物と少なくとも薬剤として又は食品として許容される他の成分とを含有する医薬組成物及び食品組成物。
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NL2007931C2 (en) | 2011-12-07 | 2013-06-10 | Friesland Brands Bv | Methods for providing sialylated oligosaccharides and products obtainable thereby. |
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CN103551562B (zh) * | 2013-10-21 | 2015-07-15 | 中国科学院微生物研究所 | 唾液酸寡糖-金纳米粒子及其制备方法与应用 |
US10745432B2 (en) * | 2015-11-18 | 2020-08-18 | Kyowa Hakko Bio Co., Ltd. | Crystal of 6′-sialyllactose sodium salt, and process for producing same |
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JP6696056B1 (ja) | 2017-01-23 | 2020-05-20 | シノビゼン・カンパニー・リミテッド | シアリルラクトースまたはその塩を有効成分として含む退行性関節炎の予防用または治療用の組成物 |
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