JPH0686472B2 - O-glycoside type glycolipid having serine long-chain alkyl derivative as hydrophobic part - Google Patents
O-glycoside type glycolipid having serine long-chain alkyl derivative as hydrophobic partInfo
- Publication number
- JPH0686472B2 JPH0686472B2 JP4260858A JP26085892A JPH0686472B2 JP H0686472 B2 JPH0686472 B2 JP H0686472B2 JP 4260858 A JP4260858 A JP 4260858A JP 26085892 A JP26085892 A JP 26085892A JP H0686472 B2 JPH0686472 B2 JP H0686472B2
- Authority
- JP
- Japan
- Prior art keywords
- serine
- group
- chain alkyl
- long
- chloroform
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 title claims description 18
- 125000000217 alkyl group Chemical group 0.000 title claims description 18
- 229930182473 O-glycoside Natural products 0.000 title claims description 12
- 229930186217 Glycolipid Natural products 0.000 title claims description 11
- 230000002209 hydrophobic effect Effects 0.000 title claims description 9
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 title claims description 8
- 150000008444 O-glycosides Chemical class 0.000 title claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical group OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 229960001153 serine Drugs 0.000 description 17
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- -1 bromo sugar Chemical class 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 239000010408 film Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003729 cation exchange resin Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000011968 lewis acid catalyst Substances 0.000 description 3
- 239000004973 liquid crystal related substance Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000010409 thin film Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229930182475 S-glycoside Natural products 0.000 description 2
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 2
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 2
- 150000001323 aldoses Chemical class 0.000 description 2
- 125000005233 alkylalcohol group Chemical group 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 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 2
- RBGLVWCAGPITBS-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)tin Chemical compound [Sn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F RBGLVWCAGPITBS-UHFFFAOYSA-L 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 150000004668 long chain fatty acids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 238000011403 purification operation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 150000003569 thioglycosides Chemical class 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- DMBKPDOAQVGTST-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)COCC1=CC=CC=C1 DMBKPDOAQVGTST-LBPRGKRZSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WQZGKKKJIJFFOK-WHZQZERISA-N D-aldose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-WHZQZERISA-N 0.000 description 1
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 description 1
- 239000004976 Lyotropic liquid crystal Substances 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- LPTITAGPBXDDGR-LJIZCISZSA-N [(2r,3r,4s,5r,6r)-3,4,5,6-tetraacetyloxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O LPTITAGPBXDDGR-LJIZCISZSA-N 0.000 description 1
- CYAYKKUWALRRPA-HTOAHKCRSA-N [(2r,3s,4s,5r,6r)-3,4,5-triacetyloxy-6-bromooxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O CYAYKKUWALRRPA-HTOAHKCRSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001488 beta-D-galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- 229910002056 binary alloy Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- ALECQBSCXXODGP-AWEZNQCLSA-N dodecyl (2s)-2-amino-3-hydroxypropanoate Chemical compound CCCCCCCCCCCCOC(=O)[C@@H](N)CO ALECQBSCXXODGP-AWEZNQCLSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005640 glucopyranosyl group Chemical group 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 150000002454 idoses Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biophysics (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Liquid Crystal Substances (AREA)
Description
【0001】[0001]
【産業上の利用分野】本発明は、水中に分散させること
により有機薄膜、閉鎖型の小胞体(リポソーム)、ある
いはリオトロピック液晶を形成し、また、水と油の二成
分系では乳化剤として有用なセリン長鎖アルキル誘導体
を疎水部とするO−グリコシド型糖脂質に関するもので
ある。この発明の産業上の利用分野としては、医薬・化
粧品分野などのハイテク・バイオ産業における薄膜、リ
ポソーム膜形成用材料、医薬材料として、あるいは食品
工業、農林業、繊維工業における乳化剤、安定剤、分散
剤、湿潤材として好適など、その工業的利用範囲は多岐
にわたっている。INDUSTRIAL APPLICABILITY The present invention forms an organic thin film, a closed type endoplasmic reticulum (liposome), or a lyotropic liquid crystal by dispersing in water, and is useful as an emulsifier in a binary system of water and oil. The present invention relates to an O-glycoside type glycolipid having a serine long chain alkyl derivative as a hydrophobic portion. Industrial applications of the present invention include thin film in the high-tech and bio industries such as pharmaceuticals and cosmetics, materials for forming liposome films, pharmaceutical materials, or emulsifiers, stabilizers, and dispersions in the food industry, agriculture and forestry, and the textile industry. It has a wide range of industrial uses, such as being suitable as an agent and a wetting agent.
【0002】[0002]
【従来の技術】従来の技術としては、一般式2. Description of the Related Art As a conventional technique, a general formula is used.
【化2】 (式中のS及びR、R’は前記と同じ意味をもつ)で表
わされ、高等植物の細胞膜に多く含まれる生体由来のグ
リセロ系糖脂質や、一般式[Chemical 2] (In the formula, S, R, and R ′ have the same meanings as described above), and a glyceroglycolipid derived from a living body, which is abundantly contained in the cell membranes of higher plants, and a general formula
【化3】 (式中のS及びR、R’は前記と同じ意味をもつ)で表
わされ、動物組織に多く含まれるスフィンゴ系糖脂質が
知られている(たとえば、香川靖雄著、「生体膜」、岩
波全書、37〜58頁(1978年発行))。しかし、これら生
体糖脂質の糖鎖及び疎水部骨格の構造は複雑多様であ
り、しかも、同一の糖鎖構造をもつ糖脂質でも複数の異
なる脂肪酸成分を含んでいる。そのため、生体からの分
離精製操作が複雑であったり、化学合成をする上でも熟
練した合成技術と多段階を必要とする欠点を有してい
る。したがって、界面活性剤や機能性両親媒性物質とし
ての有用性が認められているにも関わらず、高純度の単
一成分からなる糖脂質を得ることは困難であった。一
方、合成糖脂質として、グルコースを親水基とし、1,
2−O−ジアルキルグリセリドを疎水基とする、グリセ
ロ糖脂質が純物質として知られている( テトラヘドロ
ン・レターズ(Tetrahedron Letters)、第24巻、1229
頁(1983年))。しかしながら、この公知化合物は形成
される膜の固相における熱安定性が低いという欠点を有
している。[Chemical 3] (S, R, and R'in the formula have the same meanings as described above), and sphingolipid glycolipids that are abundant in animal tissues are known (for example, Yasuo Kagawa, "Biomembrane", Iwanami Zensho, pages 37-58 (issued in 1978). However, the structures of sugar chains and the hydrophobic skeleton of these biological glycolipids are complex and diverse, and even glycolipids having the same sugar chain structure contain a plurality of different fatty acid components. Therefore, it has the drawbacks that the separation and purification operation from the living body is complicated, and that a skilled synthetic technique and multiple steps are required for chemical synthesis. Therefore, it has been difficult to obtain a glycolipid consisting of a single component with high purity, although its usefulness as a surfactant or a functional amphipathic substance has been recognized. On the other hand, as a synthetic glycolipid, glucose is used as a hydrophilic group,
Glyceroglycolipids having a 2-O-dialkylglyceride as a hydrophobic group are known as pure substances (Tetrahedron Letters, Vol. 24, 1229).
Page (1983)). However, this known compound has the disadvantage that the thermal stability of the formed film in the solid phase is low.
【0003】[0003]
【発明が解決しようとする課題】本発明者は、天然物と
同等の両親媒性を有し、形成される膜の固相における熱
安定性が高く、さらにその純度が天然物に比べて飛躍的
に高く、しかも、廉価な原料から大量合成可能な新規糖
脂質を開発するため鋭意研究を重ねた結果、アミド基と
エステル基を含有する、セリン長鎖アルキル誘導体を疎
水部とするO−グリコシド型糖脂質がその目的に適合し
うることを見い出し、この知見に基づいてこの発明をな
すに至った。DISCLOSURE OF THE INVENTION The present inventors have found that they have amphipathic properties equivalent to those of natural products, have high thermal stability in the solid phase of the formed film, and have a purity higher than that of natural products. As a result of intensive research to develop a novel glycolipid that can be synthesized in large amounts from inexpensive and inexpensive raw materials, an O-glycoside having a serine long-chain alkyl derivative containing an amide group and an ester group as a hydrophobic part is obtained. It was found that the type glycolipid can be adapted to the purpose, and the present invention was completed based on this finding.
【0004】[0004]
【課題を解決するための手段】すなわち、本発明は、一
般式That is, the present invention provides a general formula
【化1】(式中のSは還元末端の炭素がO−グリコシド
結合に関与しているアルドース残基、R及びR’は炭素
数12〜18個の長鎖アルキル基である)で表わされる
セリン長鎖アルキル誘導体を疎水部とするO−グリコシ
ド型糖脂質を提供するものである。Embedded image (S in the formula is an aldose residue in which the carbon at the reducing end participates in the O-glycoside bond, and R and R ′ are long-chain alkyl groups having 12 to 18 carbon atoms). The present invention provides an O-glycoside type glycolipid having a serine long chain alkyl derivative as a hydrophobic portion.
【0005】この一般式、化1におけるSは、還元末端
の炭素がO−グリコシド結合に関与しているアルドース
であり、このようなものとしては、たとえば、グルコー
ス、ガラクトース、マンノース、アロース、アルトロー
ス、グロース、イドース、タロースなどがある。また、
R及びR’は炭素数12〜18個の長鎖アルキル基であ
り、このようなものとして、ドデシル基、テトラデシル
基、ヘキサデシル基、オクタデシル基などがある。S in the general formula (1) is an aldose in which the carbon at the reducing end participates in the O-glycoside bond. Examples of such compounds include glucose, galactose, mannose, allose and altrose. , Growth, idose, talose, etc. Also,
R and R ′ are long-chain alkyl groups having 12 to 18 carbon atoms, and examples thereof include dodecyl group, tetradecyl group, hexadecyl group, octadecyl group and the like.
【0006】この一般式、化1で表わされる化合物は、
いずれも文献未載の新規な化合物であり、たとえば、一
般式The compound represented by the general formula (1) is
Both are novel compounds that have not been published in the literature.
【化4】 (R,R’は前記と同じ意味をもつ)で表わされるセリ
ン長鎖アルキル誘導体に、一般式[Chemical 4] (R and R ′ have the same meanings as above), the serine long-chain alkyl derivative represented by the general formula
【化5】 (式中のZは還元末端以外の水酸基がすべてアセチル基
で保護されたアルドース残基、Yは還元末端におけるO
−グリコシド結合生成反応の活性基である)で表わされ
る還元末端が活性化された糖鎖成分を1〜3倍モル量反
応させてO−グリコシド結合を形成させ、そのあと、糖
鎖成分の保護基であるアセチル基を除去して製造するこ
とができる。[Chemical 5] (In the formula, Z is an aldose residue in which all hydroxyl groups other than the reducing end are protected by acetyl groups, and Y is O at the reducing end.
-A sugar chain component whose activated reducing end represented by (which is an active group for the glycoside bond formation reaction) is reacted in a molar amount of 1 to 3 times to form an O-glycoside bond, and then the sugar chain component is protected. It can be produced by removing the acetyl group as a group.
【0007】この一般式、化5におけるZ−Yは、還元
末端が活性化された糖鎖成分であり、このようなものと
しては、たとえば、トリクロロアセトイミデート(活性
基Yは、−OC(N=H)−CCl3)、ブロム糖(活
性基Yは、臭素原子)、フッ素糖(活性基Yは、フッ素
原子)、チオグリコシド(活性基Yは、チオエーテ
ル)、O−アシレート(活性基Yは、アシル基)などが
ある。Z-Y in the general formula (5) is a sugar chain component whose reducing end is activated, and examples thereof include trichloroacetimidate (active group Y is --OC ( N = H) -CCl 3), bromine sugar (active group Y is bromine atom), a fluorine sugar (active group Y is a fluorine atom), thioglycoside (active group Y is a thioether), O- acylate (active group Y is an acyl group) or the like.
【0008】原料化合物として用いられる前記一般式、
化4のセリン長鎖アルキル誘導体は、アミノ基及び水酸
基を保護したセリンを出発原料として、縮合剤の存在
下、まず長鎖アルキルアルコールと反応させる。長鎖ア
ルキルアルコールとしては、ドデシルアルコール、テト
ラデシルアルコール、ヘキサデシルアルコール、オクタ
デシルアルコールなどを用いることができる。このエス
テル結合生成反応の溶媒としては、塩化メチレン、クロ
ロホルム、ジメチルホルムアミド(DMF)、ジオキサ
ン、テトラヒドロフラン(THF)を用いることができ
る。溶解性の点から塩化メチレンが適している。縮合剤
として水溶性カルボジイミド、触媒としてジメチルアミ
ノピリジンを用いるとよい収率を与える。つぎに、セリ
ンのN端保護基を除去したのち、そこへ長鎖脂肪酸をカ
ップリングする。長鎖脂肪酸としては、ミリスチン酸、
パルミチン酸、ステアリン酸などを用いることができ
る。反応溶媒としては、クロロホルム、塩化メチレン、
DMFがよいが、反応性、溶解性の点からクロロホルム
/DMF混合溶媒系が最適である。縮合剤としては、通
常のペプチド合成において用いられている試薬、方法を
用いることができるが、収率の点から、ジエチルホスフ
ォロシアニデートが適している。一般式、化4の化合物
は、最後にセリンの水酸基の保護基を除去して得られ
る。この時の反応溶媒としては、メタノール、エタノー
ル、t−ブタノール等のアルコール系溶媒とクロロホル
ムとの混合溶媒がよい。エステル交換反応をさけるた
め、t−ブタノール/クロロホルム混合溶媒系が最適で
ある。セリンのアミノ保護基あるいは水酸基の保護基の
選択、除去は通常のペプチド合成において用いられてい
る保護基と除去法をそのまま適用することができる。製
造中間体であるペプチド誘導体はいずれも酸及びアルカ
リで洗い、再結晶、再沈澱を行うことにより、容易に単
離、精製することができる。The above general formula used as a raw material compound,
The serine long-chain alkyl derivative of Chemical formula 4 is first reacted with a long-chain alkyl alcohol in the presence of a condensing agent, starting from serine having an amino group and a hydroxyl group protected. As the long-chain alkyl alcohol, dodecyl alcohol, tetradecyl alcohol, hexadecyl alcohol, octadecyl alcohol, etc. can be used. As a solvent for this ester bond formation reaction, methylene chloride, chloroform, dimethylformamide (DMF), dioxane, or tetrahydrofuran (THF) can be used. Methylene chloride is suitable from the viewpoint of solubility. Water-soluble carbodiimide as the condensing agent and dimethylaminopyridine as the catalyst give good yields. Next, after removing the N-terminal protecting group of serine, a long chain fatty acid is coupled thereto. As long-chain fatty acids, myristic acid,
Palmitic acid, stearic acid, etc. can be used. As the reaction solvent, chloroform, methylene chloride,
DMF is preferable, but a chloroform / DMF mixed solvent system is optimal in terms of reactivity and solubility. As the condensing agent, reagents and methods used in ordinary peptide synthesis can be used, but diethylphosporocyanidate is suitable in terms of yield. The compound represented by the general formula (4) is obtained by finally removing the protective group for the hydroxyl group of serine. As the reaction solvent at this time, a mixed solvent of an alcohol solvent such as methanol, ethanol, t-butanol and the like and chloroform is preferable. The t-butanol / chloroform mixed solvent system is most suitable for avoiding the transesterification reaction. For the selection and removal of the amino-protecting group or the hydroxyl-protecting group of serine, the protecting group and the removing method used in ordinary peptide synthesis can be applied as they are. Any peptide derivative which is a production intermediate can be easily isolated and purified by washing with an acid and an alkali, recrystallization and reprecipitation.
【0009】また、もう一つの原料化合物として用いら
れる前記一般式、化5の還元末端が活性化された糖鎖成
分としてはトリクロロアセトイミデート、ブロム糖、フ
ッ素糖、チオグリコシド、O−アシレートなどを用いる
ことができる。なかでも、ブロム糖(活性基Yは、臭素
原子)やトリクロロアセトイミデート(活性基Yは、−
OC(N=H)−CCl3である)は収率よい結果を与
える。ブロム糖は、アルドースをピリジン中でアセチル
化し、そのあと、酢酸中で臭化水素の酢酸溶液を作用さ
せることにより得られる。トリクロロアセトイミデート
は、ブロム糖と同様にアルドースのアセチル化のあと、
DMF中でヒドラジン酢酸塩を作用させ還元末端のみ選
択的に脱保護された糖鎖成分を得、そのあと、塩基を触
媒としてトリクロロアセトニトリルを作用させて得られ
る。この時の反応溶媒としては、塩化メチレン、クロロ
ホルムなどのハロゲン系溶媒を用いることができる。塩
基としては水素化ナトリウム、炭酸セシウムなどが適当
である。ブロム糖を得る反応では選択的にα体が、トリ
クロロアセトイミデートを得る反応では、室温で2時間
以上反応させることで選択的にα体が得られる。一般
式、化5の化合物がα体の糖鎖成分であることは、これ
らの化合物の1H−NMRスペクトル(重クロロホルム
中、25℃)が、δ値で6.4−6.6ppmに二重線のシグナル
(スピン−スピンカップリング定数3.4-4.0Hz)を示す
ことから確認できる。Further, as the sugar chain component of the above-mentioned general formula, which is used as another starting material compound and whose reducing terminal is activated, trichloroacetimidate, bromo sugar, fluoro sugar, thioglycoside, O-acylate, etc. Can be used. Among them, bromine sugar (active group Y is a bromine atom) and trichloroacetimidate (active group Y is-
OC (N = H) -CCl is 3) gives yields good results. Brom sugar is obtained by acetylating aldose in pyridine, followed by the action of hydrogen bromide in acetic acid in acetic acid. Trichloroacetimidate, after acetylation of aldose, like bromo sugar,
It can be obtained by acting hydrazine acetate in DMF to obtain a sugar chain component in which only the reducing end is selectively deprotected, and then allowing trichloroacetonitrile to act with a base as a catalyst. As the reaction solvent at this time, a halogen-based solvent such as methylene chloride or chloroform can be used. Suitable bases are sodium hydride and cesium carbonate. The α-form is selectively obtained in the reaction for obtaining bromine sugar, and the α-form is selectively obtained by reacting at room temperature for 2 hours or more in the reaction for obtaining trichloroacetimidate. The fact that the compound of the general formula, Chemical formula 5 is the α-form sugar chain component means that the 1 H-NMR spectrum of these compounds (in deuterated chloroform at 25 ° C.) shows a doublet at δ value of 6.4 to 6.6 ppm. It can be confirmed by showing a signal (spin-spin coupling constant 3.4-4.0 Hz).
【0010】前記一般式、化4の化合物と前記一般式、
化5の化合物とのカップリング(O−グリコシド結合形
成)は、たとえば、ブロム糖化合物を糖鎖成分として用
いる場合、トリフルオロメタンスルホン酸すずを触媒と
して、塩基存在下行うことができる。反応溶媒として
は、クロロホルム、トルエンなどを用いることができる
が、溶解性の点からクロロホルム/トルエン混合溶媒系
が適している。塩基としては、2、4、6−トリメチルピリ
ジンや1、1、3、3−テトラメチル尿素が適している。反応
温度としては室温から40℃、反応時間は10〜20時間が適
当である。この時、モレキュラーシーブ4Aの共存がよ
い結果を与える。また、トリクロロアセトイミデート化
合物を糖鎖成分として用いる場合は、ルイス酸触媒共存
下で行うことができる。反応溶媒としては、クロロホル
ム、塩化メチレン、1,2−ジクロロエタンといったハロ
ゲン系溶媒、アセトニトリル、ニトロメタンを用いるこ
とができるが、塩化メチレンが適当である。この反応の
ルイス酸触媒としては、トリフルオロメタンスルホン酸
トリメチルシリル、または三フッ化ホウ素・エーテル錯
体を用いることができる。ルイス酸触媒の当量として
は、2〜3当量用いるとよい結果を与える。反応温度
は、−5〜0℃が適当である。反応時間は、2〜3時間
が適当である。モレキュラーシーブ4Aの共存のもとで
の攪拌が良い結果を与える。ブロム糖、トリクロロアセ
トイミデートいずれの場合も、β体のO−グリコシドが
選択的に得られる。このことは、これらの化合物の1H
−NMRスペクトル(重クロロホルム中、25℃)が、δ
値で4.4−4.6ppmに二重線のシグナル(スピン−スピン
カップリング定数7.8-8.0Hz)を示すことから確認でき
る。The compound of the above general formula
The coupling with the compound of Chemical formula 5 (formation of O-glycoside bond) can be carried out in the presence of a base using tin trifluoromethanesulfonate as a catalyst, when a bromine sugar compound is used as a sugar chain component. As the reaction solvent, chloroform, toluene or the like can be used, but a chloroform / toluene mixed solvent system is suitable from the viewpoint of solubility. Suitable bases are 2,4,6-trimethylpyridine and 1,1,3,3-tetramethylurea. The suitable reaction temperature is room temperature to 40 ° C., and the reaction time is 10 to 20 hours. At this time, the coexistence of the molecular sieve 4A gives good results. Moreover, when a trichloroacetimidate compound is used as a sugar chain component, it can be carried out in the presence of a Lewis acid catalyst. As the reaction solvent, halogen-based solvents such as chloroform, methylene chloride and 1,2-dichloroethane, acetonitrile and nitromethane can be used, but methylene chloride is suitable. As the Lewis acid catalyst for this reaction, trimethylsilyl trifluoromethanesulfonate or boron trifluoride / ether complex can be used. As the equivalent of the Lewis acid catalyst, a good result can be obtained by using 2 to 3 equivalents. The reaction temperature is suitably -5 to 0 ° C. A reaction time of 2 to 3 hours is suitable. Agitation under the coexistence of molecular sieve 4A gives good results. In both cases of bromine sugar and trichloroacetimidate, β-form O-glycoside can be selectively obtained. This means that the 1 H
-NMR spectrum (25 ° C in deuterated chloroform) shows δ
This can be confirmed by showing a doublet signal (spin-spin coupling constant 7.8-8.0 Hz) at a value of 4.4-4.6 ppm.
【0011】最後に、糖鎖のアセチル基の脱離反応は、
このO−グリコシドをナトリウムメトキシドまたはカリ
ウムメトキシドで処理し、強酸性カチオン交換樹脂で中
和したのち、溶媒留去によって一般式、化1で表わされ
るセリン長鎖アルキル誘導体を疎水部とする糖脂質が白
色粉末として得られる。反応温度としては室温、反応溶
媒は、メタノール、エタノールなどのアルコール系溶
媒、または、ジエチルエーテル、THF等のエーテル系
溶媒とアルコール系溶媒との混合溶媒が適当である。こ
の時、反応溶液のpHを8.0〜8.5に保持することが、エ
ステル加水分解反応などの副反応をさける点で望まし
い。このようにして得られた粗生成物はシリカゲルカラ
ムによる分離精製操作によって高純度のものとすること
ができる。Finally, the elimination reaction of the acetyl group of the sugar chain is
This O-glycoside is treated with sodium methoxide or potassium methoxide, neutralized with a strongly acidic cation exchange resin, and then the solvent is distilled off to give a sugar having a serine long-chain alkyl derivative represented by the general formula 1 as a hydrophobic moiety. The lipid is obtained as a white powder. The reaction temperature is room temperature, and the reaction solvent is preferably an alcohol solvent such as methanol or ethanol, or a mixed solvent of an ether solvent such as diethyl ether or THF and an alcohol solvent. At this time, it is desirable to keep the pH of the reaction solution at 8.0 to 8.5 in order to avoid side reactions such as ester hydrolysis reaction. The crude product thus obtained can be highly purified by a separation and purification operation using a silica gel column.
【0012】本発明の化合物は、実測の元素分析値が誤
差範囲内で計算値と一致する。さらに、赤外線吸収スペ
クトルでは、3500〜3300cm-1に水酸基に由来する特性吸
収、1730〜1750cm-1にエステルカルボニル基に由来する
特性吸収、1640〜1660cm-1にアミドカルボニル基に由来
する特性吸収を示す。1H−NMR(重クロロホルム/
重メタノール(2/1、容積比)中、25℃)において
は、δ値が0.8−0.9ppm(長鎖アルキル基のメチル基の
水素)、1.2−1.5ppm(長鎖アルキル基のメチレン基の
水素)、1.5−1.7ppm(アミド基及びエステル基に隣接
するメチレン基の隣のメチレン基の水素)、2.1−2.3pp
m(アミド基に隣接するメチレン基の水素)、3.1−4.5p
pm(セリンCβメチレン基、エステル結合に隣接するメ
チレン基、糖鎖の水素)、4.6−4.8ppm(セリンCα水
素)のシグナルが観測できる。また、13C−NMRにお
いては、δ値が14ppm、23ppm、26ppm、28ppm、30ppm、3
2ppm(これらすべて、長鎖アルキル基のメチレン及びメ
チル基の炭素)、36ppm(アミド基に隣接するメチレン
基の炭素)、50−80ppm(糖鎖の還元末端以外の炭素と
セリンCα炭素)、100−105ppm(糖鎖の還元末端炭
素)、170−172ppm(エステル基カルボニル炭素)、175
−177ppm(アミド基カルボニル炭素)のシグナルが観測
でき、以上によって生成物を同定確認することができ
る。The measured elemental analysis values of the compounds of the present invention agree with the calculated values within the error range. Furthermore, in the infrared absorption spectrum, characteristic absorption derived from a hydroxyl group in 3500~3300Cm -1, characteristic absorption derived from ester carbonyl group 1730~1750Cm -1, characteristic absorption derived from an amide carbonyl group 1640~1660Cm -1 Show. 1 H-NMR (deuterated chloroform /
In deuterated methanol (2/1, volume ratio) at 25 ° C, the δ value was 0.8-0.9ppm (hydrogen of methyl group of long-chain alkyl group), 1.2-1.5ppm (methylene group of long-chain alkyl group). Hydrogen), 1.5-1.7ppm (hydrogen of methylene group adjacent to methylene group adjacent to amide group and ester group), 2.1-2.3pp
m (hydrogen of methylene group adjacent to amide group), 3.1-4.5p
A signal of pm (serine Cβ methylene group, methylene group adjacent to ester bond, hydrogen of sugar chain) and 4.6-4.8 ppm (serine Cα hydrogen) can be observed. Further, in 13 C-NMR, the δ value is 14 ppm, 23 ppm, 26 ppm, 28 ppm, 30 ppm, 3 ppm.
2 ppm (all of these, carbon of methylene and methyl group of long chain alkyl group), 36 ppm (carbon of methylene group adjacent to amide group), 50-80 ppm (carbon other than reducing end of sugar chain and serine Cα carbon), 100 -105ppm (reducing terminal carbon of sugar chain), 170-172ppm (carbonyl carbon ester group), 175
A signal of −177 ppm (amide group carbonyl carbon) can be observed, and the product can be identified and confirmed by the above.
【0013】[0013]
【実施例】つぎに、実施例及び参考例により本発明をさ
らに詳細に説明する。EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples.
【参考例1】 N−テトラデカノイル−L−セリン−ド
デシルエステルの製造方法 t−ブチルオキシカルボニル−O−ベンジル−L−セリン
2.0g(6.8ミリモル)とドデシルアルコール1.39g(7.45ミリモ
ル)を塩化メチレン(20ml)に溶解し、触媒量のジメチ
ルアミノピリジンと水溶性カルボジイミド1.43g(7.45ミ
リモル)を加えて、0℃で3時間、つづいて室温で一昼夜
攪はんした。反応混合液を4%炭酸水素ナトリウム水溶
液、10%クエン酸水溶液、水の順で洗浄した。有機相
を分離し、無水硫酸ナトリウム上で乾燥したのち、ろ過
し、溶媒を留去した。得られた無色オイルを水中でこす
ることによって白色半固体のt−ブチルオキシカルボニ
ル−O−ベンジル−L−セリン−ドデシルエステルを得
た。これを酢酸エチル(5ml)に溶解し、4N−塩化水
素/酢酸エチル溶液(50ml)を室温で1時間作用させて
O−ベンジル−L−セリン−ドデシルエステル塩酸塩を
2.22g(5.55ミリモル)得た。これをミリスチン酸1.06g(4.
62ミリモル)とともにDMF(20ml)に溶解し、ジエチルホ
スフォロシアニデート0.95g(5.55ミリモル)とトリエチル
アミン1.42ml(10.2ミリモル)を加えた。0℃で3時間攪は
んしたのち、室温で一昼夜攪はんした。クロロホルムで
希釈し、4%炭酸水素ナトリウム水溶液、10%クエン酸
水溶液、水の順で洗浄した。有機相を分離し、無水硫酸
ナトリウム上で乾燥したのち、ろ過し、減圧下溶媒を留
去した。得られた無色のゲル状固体を水/アセトンから
結晶化させ、N−テトラデカノイル−O−ベンジル−L
−セリン−ドデシルエステル2.47g(収率93%)を得
た。O−ベンジル基の除去は、この化合物1.23g(2.14ミ
リモル)をt−ブタノール/クロロホルム(5/7、容積
比)120ml中で、5%−パラジウム炭素を触媒として接
触還元を約10時間行うことによって完了した。反応混合
液をろ過し、溶媒を留去して白色残査を得た。これを温
エタノールから再結晶し、融点73〜75℃の目的化合物82
0mg(収率79%)を白色粉末として得た。このものの13
C−NMRスペクトル(重クロロホルム中、25℃)は、
δ値で14.05ppmに長鎖アルキル基のメチル基炭素、22.6
−36.5ppmに長鎖アルキル基のメチレン基炭素、54.8ppm
にセリンCα炭素、63.8ppmにセリンCβ炭素、66.1ppm
にエステル基に連接するメチレン基の炭素、170.6ppmに
エステル基カルボニル炭素、173.8ppmにアミド基カルボ
ニル炭素にそれぞれ帰属できるシグナルを示した。 元素分析値(C29H57O4N・1/4H2Oとして) C H N 計算値(%) 71.34 11.87 2.87 実測値(%) 71.05 11.56 2.96Reference Example 1 Method for producing N-tetradecanoyl-L-serine-dodecyl ester t-butyloxycarbonyl-O-benzyl-L-serine
2.0 g (6.8 mmol) and dodecyl alcohol 1.39 g (7.45 mmol) were dissolved in methylene chloride (20 ml), catalytic amount of dimethylaminopyridine and 1.43 g (7.45 mmol) of water-soluble carbodiimide were added, and the mixture was kept at 0 ° C for 3 hours. Then, the mixture was stirred overnight at room temperature. The reaction mixture was washed with 4% aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and water in this order. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The colorless oil obtained was rubbed in water to obtain a white semi-solid t-butyloxycarbonyl-O-benzyl-L-serine-dodecyl ester. This was dissolved in ethyl acetate (5 ml) and 4N-hydrogen chloride / ethyl acetate solution (50 ml) was allowed to act at room temperature for 1 hour to give O-benzyl-L-serine-dodecyl ester hydrochloride.
2.22 g (5.55 mmol) was obtained. 1.06 g of myristic acid (4.
This was dissolved in DMF (20 ml) together with (62 mmol) and diethylphosporocyanidate (0.95 g, 5.55 mmol) and triethylamine (1.42 ml, 10.2 mmol) were added. After stirring at 0 ° C. for 3 hours, the mixture was stirred at room temperature for 24 hours. The mixture was diluted with chloroform, and washed with 4% sodium hydrogen carbonate aqueous solution, 10% citric acid aqueous solution, and water in this order. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The colorless gel-like solid obtained was crystallized from water / acetone to give N-tetradecanoyl-O-benzyl-L.
-Serine-dodecyl ester 2.47 g (yield 93%) was obtained. Removal of O-benzyl group is carried out by catalytic reduction of 1.23 g (2.14 mmol) of this compound in 120 ml of t-butanol / chloroform (5/7, volume ratio) with 5% -palladium carbon as a catalyst for about 10 hours. Completed by The reaction mixture was filtered and the solvent was distilled off to obtain a white residue. This was recrystallized from warm ethanol to give the target compound 82, mp 73-75 ° C.
0 mg (79% yield) was obtained as a white powder. 13 of this thing
The C-NMR spectrum (in deuterated chloroform, 25 ° C.) is
Methyl group carbon of long-chain alkyl group, 22.6 at 14.05ppm in δ value
Long chain alkyl group methylene group carbon at -36.5ppm, 54.8ppm
Serine Cα carbon, 63.8ppm Serine Cβ carbon, 66.1ppm
The signals that can be assigned to the carbon of the methylene group connected to the ester group, 170.6 ppm to the carbonyl carbon of the ester group, and 173.8 ppm to the carbonyl carbon of the amide group, respectively. Elemental analysis value (as C 29 H 57 O 4 N ・ 1 / 4H 2 O) C H N calculated value (%) 71.34 11.87 2.87 Measured value (%) 71.05 11.56 2.96
【0014】[0014]
【参考例2】 テトラ−O−アセチル−α−D−グルコ
ピラノシル−トリクロロアセトイミデートの製造方法 ペンタ−O−アセチル−α−D−グルコピラノ−ス15g
(38.4ミリモル)をDMF100mlに溶解し、これにヒドラジ
ン酢酸塩4.95g(53.8ミリモル)を加えたのち、50℃で2時
間加熱攪はんした。この溶液を室温まで冷却したのち、
酢酸エチル300mlで希釈し、飽和食塩水で洗浄した。有
機層を無水硫酸ナトリウム上で乾燥したのち、ろ過し、
溶媒を減圧下留去した。残査をシリカゲルカラムクロマ
トグラフィー(トルエン/アセトン=4(容積比))で
精製した。このようにして単離したテトラ−O−アセチ
ル−α−D−グルコース2.0g(5.7ミリモル)をモレキュラー
シーブ4A存在下、塩化メチレン20mlに溶解し、これに
トリクロロアセトニトリル2.3ml(23ミリモル)ついで炭酸
セシウム3.74g(11.5ミリモル)を加えた。室温で4時間攪
はんしたのち、クロロホルムで希釈し、セライト上でろ
過し、ろ液を減圧下濃縮した。残査をシリカゲルカラム
クロマトグラフィー(トルエン/アセトン=4(容積
比))で精製することにより、目的化合物1.84g(収率6
5%)を淡黄色〜無色オイルとして得た。このものの1H
−NMRスペクトル(重クロロホルム中、25℃)は、δ
値で8.69ppmにイミノNH水素に帰属できる一重線のシ
グナル、6.56ppmに還元末端炭素上の水素に帰属できる
二重線(スピン−スピンカップリング定数、3.62Hz)の
シグナルを示した。 元素分析値(C16H20O10NCl3として) C H N 計算値(%) 39.01 4.09 2.84 実測値(%) 39.08 4.17 2.81Reference Example 2 Method for producing tetra-O-acetyl-α-D-glucopyranosyl-trichloroacetimidate Penta-O-acetyl-α-D-glucopyranose 15 g
(38.4 mmol) was dissolved in 100 ml of DMF, 4.95 g (53.8 mmol) of hydrazine acetate was added thereto, and the mixture was heated with stirring at 50 ° C. for 2 hours. After cooling the solution to room temperature,
It was diluted with 300 ml of ethyl acetate and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and then filtered,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (toluene / acetone = 4 (volume ratio)). 2.0 g (5.7 mmol) of tetra-O-acetyl-α-D-glucose thus isolated was dissolved in 20 ml of methylene chloride in the presence of Molecular Sieve 4A, and 2.3 ml (23 mmol) of trichloroacetonitrile was added thereto. Cesium 3.74 g (11.5 mmol) was added. The mixture was stirred at room temperature for 4 hours, diluted with chloroform, filtered on Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / acetone = 4 (volume ratio)) to give 1.84 g of the target compound (yield 6
5%) as a pale yellow to colorless oil. 1 H of this thing
-NMR spectrum (in deuterated chloroform at 25 ° C) shows δ
As a value, a singlet signal attributable to imino NH hydrogen was shown at 8.69 ppm, and a doublet signal (spin-spin coupling constant, 3.62 Hz) attributable to hydrogen on the reducing terminal carbon was shown at 6.56 ppm. Elemental analysis value (as C 16 H 20 O 10 NCl 3 ) C H N calculated value (%) 39.01 4.09 2.84 Measured value (%) 39.08 4.17 2.81
【0015】[0015]
【実施例1】 N−テトラデカノイル−O−(β−D−
グルコピラノシル)−L−セリン−ドデシルエステルの
製造方法 モレキュラーシーブ4Aの粉末400mgを反応フラスコ
中、減圧下で加熱乾燥し、自然冷却してアルゴン雰囲気
にした。これに、N−テトラデカノイル−L−セリンド
デシルエステル(参考例1)289mg(0.59ミリモル)の塩化
メチレン溶液(5.0ml)を加えた。30分間攪はんした
のちに、テトラ−O−アセチル−α−D−グルコピラノ
シル−トリクロロアセトイミデート(参考例2)289mg
(0.59ミリモル)の塩化メチレン溶液 (2ml)を加えた。反
応フラスコを0℃に冷却しながらトリフルオロメタンス
ルホン酸トリメチルシリル260mg(1.17ミリモル)の塩化メ
チレン溶液(1.7ml)を加え、0℃で3時間攪はんし
た。0℃でこれに飽和炭酸水素ナトリウム水溶液(10m
l)を加えたのち、室温でクロロホルム50mlによりこの
溶液を希釈した。この懸濁液をセライト上でろ過し、飽
和塩化ナトリウム水溶液30mlで洗浄した。有機層を分離
し、無水硫酸ナトリウム上で乾燥、ろ過したのち、減圧
下溶媒を留去した。残査の淡黄色ゲルをシリカゲルカラ
ムクロマトグラフィー(トルエン/アセトン=15(容積
比)からトルエン/アセトン=4(容積比)までグラジ
エント溶出)で精製することにより、融点68〜69℃のN
−テトラデカノイル−O−(テトラ−O−アセチル−β
−D−グルコピラノシル)−L−セリン−ドデシルエステ
ル120mg(収率26%)を白色粉末として得た。Example 1 N-tetradecanoyl-O- (β-D-
Method for producing glucopyranosyl) -L-serine-dodecyl ester 400 mg of powder of molecular sieve 4A was dried by heating in a reaction flask under reduced pressure, and naturally cooled to an argon atmosphere. To this, a solution of N-tetradecanoyl-L-serine dodecyl ester (Reference Example 1) 289 mg (0.59 mmol) in methylene chloride (5.0 ml) was added. After stirring for 30 minutes, 289 mg of tetra-O-acetyl-α-D-glucopyranosyl-trichloroacetimidate (Reference Example 2)
A solution of (0.59 mmol) in methylene chloride (2 ml) was added. A solution of trimethylsilyl trifluoromethanesulfonate (260 mg, 1.17 mmol) in methylene chloride (1.7 ml) was added while the reaction flask was cooled to 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate solution (10 m
l) was added and the solution was diluted with 50 ml of chloroform at room temperature. The suspension was filtered over Celite and washed with 30 ml of saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The residual pale yellow gel was purified by silica gel column chromatography (gradient elution from toluene / acetone = 15 (volume ratio) to toluene / acetone = 4 (volume ratio)) to obtain N with a melting point of 68 to 69 ° C.
-Tetradecanoyl-O- (tetra-O-acetyl-β
120 mg (yield 26%) of -D-glucopyranosyl) -L-serine-dodecyl ester was obtained as a white powder.
【0016】この化合物115mg(0.141ミリモル)をメタノー
ル5.0mlに溶解したのち、1%ナトリウムメトキシドの
メタノール溶液を系のpHが約8.5になるまで(約4
滴)加えた。室温で30分間攪はんしたのち、強酸性カチ
オン交換樹脂(プロトン型)を加え、中和した。クロロ
ホルムで希釈したのち、溶媒を減圧留去し、白色固体を
得た。最後に、シリカゲルカラムクロマトグラフィー
(クロロホルム/メタノール=9(容積比))で精製す
ることにより、融点116〜117℃、比旋光度[α]D=−
9.9°(c=1.0、クロロホルム中)のN−テトラデカノ
イル−O−(β−D−グルコピラノシル)−L−セリン−
ドデシルエステル50mg(収率55%)を白色粉末として得
た。After dissolving 115 mg (0.141 mmol) of this compound in 5.0 ml of methanol, a solution of 1% sodium methoxide in methanol was added until the pH of the system reached about 8.5 (about 4
Drop) added. After stirring at room temperature for 30 minutes, a strong acid cation exchange resin (proton type) was added to neutralize. After diluting with chloroform, the solvent was distilled off under reduced pressure to obtain a white solid. Finally, the product was purified by silica gel column chromatography (chloroform / methanol = 9 (volume ratio)) to give a melting point of 116 to 117 ° C. and a specific optical rotation [α] D = −.
9.9 ° (c = 1.0 in chloroform) N-tetradecanoyl-O- (β-D-glucopyranosyl) -L-serine-
50 mg (55% yield) of dodecyl ester was obtained as a white powder.
【0017】図1に、この化合物の1H−NMRスペク
トル(重クロロホルム/重メタノール=2(容積比)
中、25℃)を示す。図2に、同じく13C−NMRスペク
トル(重クロロホルム/重メタノール=2(容積比)
中、25℃)を示す。 元素分析値(C75H67O9Nとして) C H N 計算値(%) 65.08 10.46 2.17 実測値(%) 64.82 10.55 2.29 図3に、この化合物の5重量%水溶液の示差走査熱分析
曲線を示す。水和結晶から液晶相への転移温度は72℃で
あった。FIG. 1 shows the 1 H-NMR spectrum of this compound (deuterated chloroform / deuterated methanol = 2 (volume ratio).
Medium, 25 ° C). Fig. 2 also shows the 13 C-NMR spectrum (deuterated chloroform / deuterated methanol = 2 (volume ratio).
Medium, 25 ° C). Elemental analysis value (as C 75 H 67 O 9 N) C H N calculated value (%) 65.08 10.46 2.17 Measured value (%) 64.82 10.55 2.29 Figure 3 shows the differential scanning calorimetry curve of a 5 wt% aqueous solution of this compound. Show. The transition temperature from the hydrated crystals to the liquid crystal phase was 72 ° C.
【0018】[0018]
【実施例2】 N−テトラデカノイル−O−(β−D−
ガラクトピラノシル)−L−セリン−ドデシルエステル
の製造方法 テトラ−O−アセチル−α−D−ガラクトピラノシルブ
ロミド1.28g(3.11ミリモル)、トリフルオロメタンスルホ
ン酸すず1.73g(4.14ミリモル)、及びモレキュラーシーブ
4Aの粉末1.3gを反応フラスコ中、減圧下で乾燥したの
ち、アルゴン雰囲気にした。これに、乾燥塩化メチレン
(10.0ml)を加えた。つづいて、N−テトラデカノイル
−L−セリン−ドデシルエステル500mg(1.04ミリモル)とテ
トラメチル尿素480mg(4.14ミリモル)の塩化メチレン/ト
ルエン(5/3=容積比)混合溶液(40.0ml)を滴々加
え、35℃で18時間反応させた。クロロホルムで希釈した
のち、この懸濁液をセライト上でろ過し、ろ液を飽和炭
酸水素ナトリウム水溶液20mlで洗浄した。有機層を無水
硫酸ナトリウム上で乾燥したのち、ろ過し、減圧下溶媒
を留去した。残査をシリカゲルカラムクロマトグラフィ
ー(トルエン/アセトン=15(容積比)からトルエン/
アセトン=4(容積比)までグラジエント溶出)で精製
することにより、無色シロップとしてN−テトラデカノ
イル−O−(テトラ−O−アセチル−β−D−ガラクト
ピラノシル)−L−セリン−ドデシルエステル550mg(収
率65%)を得た。Example 2 N-tetradecanoyl-O- (β-D-
Method for producing galactopyranosyl) -L-serine-dodecyl ester Tetra-O-acetyl-α-D-galactopyranosyl bromide 1.28 g (3.11 mmol), tin trifluoromethanesulfonate 1.73 g (4.14 mmol), and 1.3 g of the powder of the molecular sieve 4A was dried in a reaction flask under reduced pressure and then put in an argon atmosphere. To this was added dry methylene chloride (10.0 ml). Subsequently, a mixed solution (40.0 ml) of N-tetradecanoyl-L-serine-dodecyl ester 500 mg (1.04 mmol) and tetramethylurea 480 mg (4.14 mmol) in methylene chloride / toluene (5/3 = volume ratio) was added dropwise. And added, and reacted at 35 ° C. for 18 hours. After diluting with chloroform, the suspension was filtered over Celite, and the filtrate was washed with 20 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (toluene / acetone = 15 (volume ratio) to toluene /
N-tetradecanoyl-O- (tetra-O-acetyl-β-D-galactopyranosyl) -L-serine-dodecyl was obtained as a colorless syrup by purification with gradient elution to acetone = 4 (volume ratio). 550 mg (65% yield) of ester were obtained.
【0019】この化合物118mg(0.145ミリモル)をメタノー
ル5.0mlに溶解したのち、1%ナトリウムメトキシドの
メタノール溶液を系のpHが約8.5になるまで(約4
滴)加えた。室温で30分間攪はんしたのち、強酸性カチ
オン交換樹脂(プロトン型)を加え、中和した。クロロ
ホルムで希釈したのち、溶媒を減圧留去し、白色固体を
得た。最後に、シリカゲルカラムクロマトグラフィー
(クロロホルム/メタノール=9(容積比))で精製す
ることにより、融点129〜130℃、比旋光度[α]D=−
3.5°(c=0.5、クロロホルム中)のN−テトラデカノ
イル−O−(β−D−ガラクトピラノシル)−L−セリン
−ドデシルエステル52mg(収率56%)を白色粉末として
得た。 元素分析値(C75H67O9Nとして) C H N 計算値(%) 65.08 10.46 2.17 実測値(%) 64.90 10.42 2.34 図4に、この化合物の1H−NMRスペクトル(重クロ
ロホルム/重メタノール=2(容積比)中、25℃)を示
す。この化合物の示差走査熱分析曲線は、水和結晶から
液晶相への転移温度が102℃であることを示した。After dissolving 118 mg (0.145 mmol) of this compound in 5.0 ml of methanol, a solution of 1% sodium methoxide in methanol was added until the pH of the system reached about 8.5 (about 4).
Drop) added. After stirring at room temperature for 30 minutes, a strong acid cation exchange resin (proton type) was added to neutralize. After diluting with chloroform, the solvent was distilled off under reduced pressure to obtain a white solid. Finally, the product was purified by silica gel column chromatography (chloroform / methanol = 9 (volume ratio)) to give a melting point of 129 to 130 ° C. and a specific optical rotation [α] D = −.
52 mg (yield 56%) of N-tetradecanoyl-O- (β-D-galactopyranosyl) -L-serine-dodecyl ester at 3.5 ° (c = 0.5 in chloroform) was obtained as a white powder. Elemental analysis value (as C 75 H 67 O 9 N) C H N calculated value (%) 65.08 10.46 2.17 Measured value (%) 64.90 10.42 2.34 FIG. 4 shows the 1 H-NMR spectrum (deuterated chloroform / deuterated methanol) of this compound. = 2 (volume ratio) at 25 ° C). The differential scanning calorimetry curve of this compound showed that the transition temperature from the hydrated crystal to the liquid crystal phase was 102 ° C.
【0020】[0020]
【実施例3】実施例1におけるN−テトラデカノイル−
L−セリン−ドデシルエステルの代わりに各々アルキル
鎖長の異なるセリン長鎖アルキル誘導体を用い、同様な
操作によって、次に示す化合物を得た。 N−ヘキサデカノイル−O−(β−D−グルコピラノシ
ル)−L−セリン−テトラデシルエステル 融点 148〜150℃ N−オクタデカノイル−O−(β−D−グルコピラノシ
ル)−L−セリン−ヘキサデシルエステル 融点 152〜154℃Example 3 N-tetradecanoyl-in Example 1
By using serine long-chain alkyl derivatives each having a different alkyl chain length instead of L-serine-dodecyl ester, the following compound was obtained by the same procedure. N-hexadecanoyl-O- (β-D-glucopyranosyl) -L-serine-tetradecyl ester Melting point 148-150 ° C N-octadecanoyl-O- (β-D-glucopyranosyl) -L-serine-hexadecyl Ester melting point 152-154 ℃
【0021】[0021]
【発明の効果】本発明の化合物は、クロロホルムなどの
疎水性有機溶媒にごく微量溶解させ、気水界面上にラン
グミュアー・ブロジェット法により展開し、適当な基板
上に移しとることによって、分子オーダーの厚さを有す
る有機薄膜を得ることができる。また、これらの化合物
の濃度1重量%以下の水溶液を、手で振り混ぜるか、超
音波処理を施すことによって数十ナノメーターから数ミ
クロンの大きさを持つ小胞体を得ることができる。蒸留
水中に水溶性医薬をあらかじめ溶解させておくことによ
り、小胞体中の水溶液領域に医薬が含有した分子集合体
が、また疎水性物質と混合することにより、小胞体の境
界膜中に疎水性化合物が共存した分子集合体が得られ
る。さらに、水和結晶から液晶相への転移温度が70℃以
上であり、形成される膜の固相での熱安定性が高いこと
が確認できる。EFFECT OF THE INVENTION The compound of the present invention is dissolved in a very small amount of a hydrophobic organic solvent such as chloroform, developed on the air-water interface by the Langmuir-Blodgett method, and transferred onto an appropriate substrate to give a molecule. An organic thin film having a thickness of the order can be obtained. Further, an aqueous solution containing these compounds at a concentration of 1% by weight or less can be shaken by hand or subjected to ultrasonic treatment to obtain vesicles having a size of several tens of nanometers to several microns. By pre-dissolving a water-soluble drug in distilled water, the molecular assembly containing the drug in the aqueous solution region of the endoplasmic reticulum is mixed with a hydrophobic substance. A molecular assembly in which the compounds coexist is obtained. Further, it can be confirmed that the transition temperature from the hydrated crystal to the liquid crystal phase is 70 ° C. or higher, and the formed film has high thermal stability in the solid phase.
【0022】[0022]
【図1】実施例1の1H−NMRスペクトル(重クロロ
ホルム/重メタノール(2/1、容積比)、25℃、270M
Hz)である。FIG. 1 1 H-NMR spectrum of Example 1 (deuterated chloroform / deuterated methanol (2/1, volume ratio), 25 ° C., 270M
Hz).
【図2】実施例1の13C−NMRスペクトル(重クロロ
ホルム/重メタノール(2/1、容積比)、25℃、67.5
MHz)である。FIG. 2 13 C-NMR spectrum of Example 1 (deuterated chloroform / deuterated methanol (2/1, volume ratio), 25 ° C., 67.5)
MHz).
【図3】実施例1の示差走査熱分析曲線(5重量%水溶
液、昇温速度1.0℃/分)である。FIG. 3 is a differential scanning calorimetry curve for Example 1 (5% by weight aqueous solution, heating rate 1.0 ° C./min).
【図4】実施例2の1H−NMRスペクトル(重クロロ
ホルム/重メタノール(2/1、容積比)、25℃、270M
Hz)である。FIG. 4 1 H-NMR spectrum of Example 2 (deuterated chloroform / deuterated methanol (2/1, volume ratio), 25 ° C., 270M
Hz).
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 FI 技術表示箇所 C09K 19/06 9279−4H ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 5 Identification code Office reference number FI technical display location C09K 19/06 9279-4H
Claims (1)
与しているアルドース残基、R及びR’は炭素数12〜
18個の長鎖アルキル基である)で表わされるセリン長
鎖アルキル誘導体を疎水部とするO−グリコシド型糖脂
質。1. A general formula: (In the formula, S is an aldose residue in which the carbon at the reducing end participates in the O-glycoside bond, and R and R ′ are those having 12 to 12 carbon atoms.
An O-glycoside type glycolipid having a serine long-chain alkyl derivative represented by 18 long-chain alkyl groups) as a hydrophobic portion.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4260858A JPH0686472B2 (en) | 1992-09-03 | 1992-09-03 | O-glycoside type glycolipid having serine long-chain alkyl derivative as hydrophobic part |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4260858A JPH0686472B2 (en) | 1992-09-03 | 1992-09-03 | O-glycoside type glycolipid having serine long-chain alkyl derivative as hydrophobic part |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0680685A JPH0680685A (en) | 1994-03-22 |
JPH0686472B2 true JPH0686472B2 (en) | 1994-11-02 |
Family
ID=17353735
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP4260858A Expired - Lifetime JPH0686472B2 (en) | 1992-09-03 | 1992-09-03 | O-glycoside type glycolipid having serine long-chain alkyl derivative as hydrophobic part |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0686472B2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3598367B2 (en) * | 2000-09-07 | 2004-12-08 | 独立行政法人産業技術総合研究所 | Hollow fibrous organic nanotube and method for producing the same |
-
1992
- 1992-09-03 JP JP4260858A patent/JPH0686472B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH0680685A (en) | 1994-03-22 |
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