JP5212973B2 - Glycolipid derivative synthesis intermediate and production method thereof, and glycolipid derivative and production method thereof - Google Patents
Glycolipid derivative synthesis intermediate and production method thereof, and glycolipid derivative and production method thereof Download PDFInfo
- Publication number
- JP5212973B2 JP5212973B2 JP2007532018A JP2007532018A JP5212973B2 JP 5212973 B2 JP5212973 B2 JP 5212973B2 JP 2007532018 A JP2007532018 A JP 2007532018A JP 2007532018 A JP2007532018 A JP 2007532018A JP 5212973 B2 JP5212973 B2 JP 5212973B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- protecting group
- general formula
- glycolipid derivative
- 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.)
- Active
Links
- 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 class 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 74
- 230000015572 biosynthetic process Effects 0.000 title claims description 60
- 238000003786 synthesis reaction Methods 0.000 title claims description 60
- 238000004519 manufacturing process Methods 0.000 title claims description 27
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 170
- 150000001875 compounds Chemical class 0.000 claims description 86
- 125000006239 protecting group Chemical group 0.000 claims description 64
- 238000006243 chemical reaction Methods 0.000 claims description 58
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 39
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 235000000346 sugar Nutrition 0.000 claims description 22
- -1 phosphonium halogen compound Chemical class 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 13
- 125000001033 ether group Chemical group 0.000 claims description 12
- 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 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 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 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- 150000008300 phosphoramidites Chemical class 0.000 claims description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 150000001720 carbohydrates Chemical group 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 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 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 3
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 9
- 150000002431 hydrogen Chemical class 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 2
- 150000002771 monosaccharide derivatives Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 44
- 125000004432 carbon atom Chemical group C* 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 24
- 238000001308 synthesis method Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 125000000217 alkyl group Chemical group 0.000 description 22
- 150000002430 hydrocarbons Chemical group 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 230000002194 synthesizing effect Effects 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 12
- 230000002378 acidificating effect Effects 0.000 description 10
- 150000004665 fatty acids Chemical class 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 10
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 10
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 9
- 101100268446 Pseudomonas putida (strain ATCC 47054 / DSM 6125 / CFBP 8728 / NCIMB 11950 / KT2440) proR gene Proteins 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical compound OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 description 8
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 229940126214 compound 3 Drugs 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 6
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229940125797 compound 12 Drugs 0.000 description 6
- 229940125758 compound 15 Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- 229940126657 Compound 17 Drugs 0.000 description 5
- 229930186217 Glycolipid Natural products 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 229940125773 compound 10 Drugs 0.000 description 5
- 229940125810 compound 20 Drugs 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 5
- 150000002772 monosaccharides Chemical group 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical group OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 229940126086 compound 21 Drugs 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 230000001766 physiological effect Effects 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-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
- 0 C*CC1***C1 Chemical compound C*CC1***C1 0.000 description 3
- 241000202952 Mycoplasma fermentans Species 0.000 description 3
- 229910004161 SiNa Inorganic materials 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 150000001728 carbonyl compounds Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 3
- 229930182830 galactose Natural products 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 3
- 125000000962 organic group Chemical group 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- HOVAGTYPODGVJG-UVSYOFPXSA-N (3s,5r)-2-(hydroxymethyl)-6-methoxyoxane-3,4,5-triol Chemical compound COC1OC(CO)[C@@H](O)C(O)[C@H]1O HOVAGTYPODGVJG-UVSYOFPXSA-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
- PYTMBSDYMPHFOQ-UHFFFAOYSA-N 2,2,2-trichloro-n-[4-(trifluoromethyl)phenyl]acetamide Chemical compound FC(F)(F)C1=CC=C(NC(=O)C(Cl)(Cl)Cl)C=C1 PYTMBSDYMPHFOQ-UHFFFAOYSA-N 0.000 description 2
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 2
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 229940039227 diagnostic agent Drugs 0.000 description 2
- 239000000032 diagnostic agent Substances 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- HOVAGTYPODGVJG-VOQCIKJUSA-N methyl beta-D-galactoside Chemical compound CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O HOVAGTYPODGVJG-VOQCIKJUSA-N 0.000 description 2
- HOVAGTYPODGVJG-UHFFFAOYSA-N methyl beta-galactoside Natural products COC1OC(CO)C(O)C(O)C1O HOVAGTYPODGVJG-UHFFFAOYSA-N 0.000 description 2
- ZQRBSCXRHDJZBS-UHFFFAOYSA-N n,n-dibutylbutan-1-amine;hydrofluoride Chemical compound F.CCCCN(CCCC)CCCC ZQRBSCXRHDJZBS-UHFFFAOYSA-N 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- AFINAILKDBCXMX-PBHICJAKSA-N (2s,3r)-2-amino-3-hydroxy-n-(4-octylphenyl)butanamide Chemical compound CCCCCCCCC1=CC=C(NC(=O)[C@@H](N)[C@@H](C)O)C=C1 AFINAILKDBCXMX-PBHICJAKSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- GOEGBJDTWXTPHP-UHFFFAOYSA-N 4-diphenylphosphanyl-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 GOEGBJDTWXTPHP-UHFFFAOYSA-N 0.000 description 1
- SAVQKMWTUAWFSN-UHFFFAOYSA-N 4-methoxyphenol;sodium Chemical compound [Na].COC1=CC=C(O)C=C1 SAVQKMWTUAWFSN-UHFFFAOYSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 206010061619 Deformity Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 239000004146 Propane-1,2-diol Substances 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- WWTBYVQANMUFPG-UHFFFAOYSA-L [Ag+2].[O-]C(=O)C1=CC=CC=N1.[O-]C(=O)C1=CC=CC=N1 Chemical compound [Ag+2].[O-]C(=O)C1=CC=CC=N1.[O-]C(=O)C1=CC=CC=N1 WWTBYVQANMUFPG-UHFFFAOYSA-L 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- SVABQOITNJTVNJ-UHFFFAOYSA-N diphenyl-2-pyridylphosphine Chemical compound C1=CC=CC=C1P(C=1N=CC=CC=1)C1=CC=CC=C1 SVABQOITNJTVNJ-UHFFFAOYSA-N 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UHNSRFWQBVXBSK-UHFFFAOYSA-N methanol;2,2,2-trifluoroacetic acid Chemical compound OC.OC(=O)C(F)(F)F UHNSRFWQBVXBSK-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000002525 phosphocholine group Chemical group OP(=O)(OCC[N+](C)(C)C)O* 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000307 polymer substrate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 description 1
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
- C07H15/06—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical being a hydroxyalkyl group esterified by a fatty acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、新規な糖脂質誘導体及びその製造方法、並びにそれら糖脂質誘導体の合成過程において有益な糖脂質誘導体合成中間体及びその製造方法に関する。 The present invention relates to a novel glycolipid derivative and a production method thereof, a glycolipid derivative synthesis intermediate useful in the synthesis process of the glycolipid derivative, and a production method thereof.
慢性関節リウマチは、関節の痛み、腫れ、変形を伴う慢性の自己免疫疾患であり、人口の１％に及ぶ患者がいるとされている。しかし、原因は不明なため、病気の診断法や根本的な治療法はまだない。
近年、マイコプラズマファーメンタンスと慢性関節リウマチとの関連が報告されている。マイコプラズマファーメンタンスの膜脂質成分である下記化合物（以下、「GGPL-III」と称する）が重要な生理活性を担うものとして注目されている(特開平７−２７８１７４号公報、特開平７−２７８１７５号公報及び特開平８−４８６９３号公報)。
GGPL-IIIの合成方法は本願発明者の一人である西田らが他に先駆けて報告している（特開平７−３０４７８９号公報、Y.Nishida et al,Tetrahedron Letters 40, 1999,2371-2374）。
Rheumatoid arthritis is a chronic autoimmune disease with joint pain, swelling, and deformity, and is reported to have as many as 1% of the population. However, since the cause is unknown, there is still no diagnosis or fundamental cure for the disease.
In recent years, an association between mycoplasma fermentans and rheumatoid arthritis has been reported. The following compound (hereinafter referred to as “GGPL-III”), which is a membrane lipid component of Mycoplasma fermentans, has attracted attention as one that bears an important physiological activity (JP-A-7-278174, JP-A-7-278175). And JP-A-8-48693).
A method for synthesizing GGPL-III has been previously reported by Nishida et al., One of the inventors of the present application (JP-A-7-304789, Y. Nishida et al, Tetrahedron Letters 40, 1999, 2371-2374). .
ところで、ＧＧＰＬ−ＩＩＩを診断薬に利用する場合、従来の合成法では収率が低く、十分な量を供給することが困難であり、収率の高い合成法が望まれている。また、ＧＧＰＬ−ＩＩＩはいわゆる糖脂質の一種であり、糖や脂質の誘導体は生理活性を有するものが多いので、ＧＧＰＬ−ＩＩＩに対して、エステル結合しているカルボン酸の炭素数が異なる化合物、糖部分の立体構造がグルコース以外の糖に由来する化合物、その他の立体異性体についても、有用な生理活性を有する化合物が存在することが期待される。従って、ＧＧＰＬ−ＩＩＩなどと関連する糖脂質誘導体の生理活性を利用・研究するための一助としての多面的な合成法の確立が望まれている。
本発明は上記実情に鑑み完成されたものであり、ＧＧＰＬ−ＩＩＩに代表される糖脂質誘導体を効率よく合成できる製造方法を提供することを解決すべき課題とする。
更に、上記ＧＧＰＬ−ＩＩＩの合成方法の研究において発見した有用な合成中間体及びその製造方法についても提供することを解決すべき課題とする。By the way, when GGPL-III is used as a diagnostic agent, the conventional synthesis method has a low yield, it is difficult to supply a sufficient amount, and a synthesis method with a high yield is desired. Further, GGPL-III is a kind of so-called glycolipid, and many sugars and lipid derivatives have physiological activity. It is expected that compounds having useful physiological activity also exist for compounds in which the steric structure of the sugar moiety is derived from sugars other than glucose and other stereoisomers. Therefore, establishment of a multifaceted synthesis method is desired as an aid for utilizing and researching the physiological activity of glycolipid derivatives related to GGPL-III and the like.
The present invention has been completed in view of the above circumstances, and an object to be solved is to provide a production method capable of efficiently synthesizing a glycolipid derivative typified by GGPL-III.
Furthermore, it is an object to be solved to provide useful synthetic intermediates discovered in the above research on the synthesis method of GGPL-III and a production method thereof.
上記課題を解決する目的で本発明者らはGGPL-IIIの合成方法について鋭意検討を行った結果、従来とは異なる特徴を持つ方法を見いだし、その方法を完成させる過程において有用な新規糖脂質誘導体及びその新規合成方法を完成させた。
特許文献４に示す製造方法は、出発原料として脂肪酸を持つ糖脂質を用いていないので、脂肪酸を導入するための煩雑な操作と反応を最終段階で行うため効率的ではなかった。また、従来方法では、ホスホコリン基を導入する反応においてコリントシレートを用いていたが、コリントシレートは吸湿性であり、また反応溶媒に溶けにくいなどの理由から著しい収率の低下がみられた。本発明方法では新たな反応経路をもつ反応を見いだし、大幅な収率の改善を行った。そして、従来方法では、ホスホリルセリノール基の前駆体としてｐ−メトキシフェニル基を保護基として持つ化合物を用いていたが、ｐ−メトキシフェニル基をはずす反応は高価で有毒な銀塩を必要とすること、また、精製操作が煩雑になるなどの難点であったが、本発明方法では上記の問題点を解決した。以下、GGPL-IIIを合成する反応、並びにその反応過程において発見された有益な反応を挙げて説明する。
（１）本発明の化合物の説明のために参考となる合成法１：一般式(VIII)などのグリセロ型の糖脂質は、植物や微生物に多く見出される糖脂質であり、それらの細胞膜成分である。近年の研究において、グリセロ糖脂質に抗炎症作用や抗癌作用が見られることなどが報告されており、その生理機能が注目されている。同時に、安全性が高い界面活性化合物であり、化粧品や医薬品としての応用も期待される。
本発明において、特にα型の糖鎖結合を持つグリセロ糖脂質は、慢性関節炎リウマチの原因菌として疑われているマイコプラズマファーメンタンスが細胞膜に高濃度で有する糖リン脂質の鍵構造である。この糖リン脂質は、本菌の病原性の本体の一つであることから、関節炎リウマチをはじめとする自己免疫疾患の診断法、さらには治療法の開発において、重要な鍵化合物である。そのため、一般式(VIII)の効率的な合成が鍵となる。しかしながら、一般式(VIII)の立体選択的な合成手法は、α型のグリコシド結合の構築とグリセロール部分の立体の両方を制御するという、技術的に困難な２点のため、報告例はほとんどない。一般式(VIII)の化合物を得るために、α型のグリコシド結合の構築とグリセロール部分の立体の両方を制御する手法について、鋭意検討を行った。
すなわち、本発明者らが検討した糖脂質誘導体の合成方法は、１位以外のＯＨ基について保護基を導入した糖類であるドナー化合物に対して、ホスホニウムハロゲン化合物及び塩基性溶媒の存在下、光学活性なグリシドール又はグリシドールから誘導される光学活性なグリセロール骨格をもつ誘導体をアクセプター化合物として反応させ、α−グリコシル結合およびグリセロール部分の立体構造制御を同時に構築する工程を有することを特徴とする。
ここで、ドナー化合物としての糖類においては、１位のＯＨ基とそれ以外のＯＨ基とは反応性がわずかに異なるので、他のＯＨ基と異なった官能基を１位のＯＨ基に導入したり、官能基を導入しなかったりすることが比較的容易にできる。例えば、前記ドナー化合物は、Ｄ−グルコース又はＤ−ガラクトースの２〜４位のＯＨ基にエーテル系の保護基を導入し、６位のＯＨ基にエステル系の保護基を導入した糖誘導体であることが望ましい。
ホスホニウムハロゲン化合物は特に限定しないが、Ｇ３Ｐ（Ｇは芳香族基、アルキル、アルケン類を含む炭化水素基やヘテロ原子を含む−ＯＧ’及び−ＮＧ’２から独立して選択可能である。Ｇ’は炭化水素基、又は、Ｇと同様の基準で選択できる。）とＣＨｍＸ４−ｍ（式中、Ｘはハロゲン、好ましくはＢｒ又はＩ、更に好ましくはＢｒ；０≦ｍ≦２）とを反応させた化合物が例示できる。
Ｇ３ＰにおけるＧとしては芳香族性基や炭化水素性基のほか、ヘテロ原子を含む官能基を採用することもできる。Ｇはすべて異なるものを採用しても良いし、同じものを採用しても良い。そして、それぞれのＧとして採用できる炭化水素基は炭素数１〜１０、特に好ましくは炭素数２〜８の炭化水素基（例えばアルキル基）を採用することができる。例えば、Ｇとしてはフェニル基、シクロヘキシル基、ブチル基、ヘキシル基、オクチル基などが採用できる。
更に、Ｇとしては、前述したアルキル基や基などの炭化水素基のほか、炭素原子や水素原子の幾つかをハロゲン、酸素、窒素、イオウ原子により置換した基も採用できる。また、ピリジンなどのような複素環式芳香族化合物や多重環式化合物を採用することもできる。例えば、ジフェニル(２-ピリジル)ホスフィン（Ｒ＝フェニル基、２−ピリジル基）や(４-ジメチルアミノフェニル)ジフェニルホスフィン（Ｒ＝フェニル基、４−ジメチルアミノフェニル基）などが例示できる。これらの化合物は酸性水溶液で洗浄することで有機層から容易に取り除くことができる。更に、１以上のＲを介してポリマーなどからなる基材に結合させることで、後処理における除去が容易になる。例えば、Ｇとしてスチリル基などのビニル基を有する基を導入し、そのビニル基によりポリマー基材状にグラフト化するなどの手法が挙げられる。
これらの混合物を塩基性溶媒の存在下、反応させることで目的とする化合物が得られる。塩基性溶媒としては以下の溶媒や以下の溶媒を主要成分として含有するものが例示できる。すなわち、（ａ）ジメチルホルムアミド、ジエチルホルムアミドなどのホルムアミド系溶媒、（ｂ）ホルムアミド系溶媒と有機溶媒とを混合させた溶媒（有機溶媒としてはトルエンなどの非プロトン性溶媒やジクロロメタンなどの含ハロゲン溶媒）、（ｃ）テトラメチル尿素と有機溶媒とを混合させた溶媒（有機溶媒としてはトルエンなどの非プロトン性溶媒やジクロロメタンなどの含ハロゲン溶媒）である。
アクセプター化合物（光学活性なグリシドール又はグリシドールから誘導される光学活性なグリセロール骨格をもつ誘導体）としては下式に示すようなグリシドール及びグリシドール誘導体が挙げられる。２位の不斉炭素における立体構造が制御されており、その立体構造が最終生成物の立体構造を決定する。これら誘導体は目的の立体構造をもつグリシドールにハロゲンイオン（臭素やヨウ素イオンなど）を反応させることで得ることができる。
（２）新規化合物：ここで、（１）の本発明の化合物の説明のために参考となる合成法１の合成方法に関連して中間体として現れる糖脂質誘導体合成中間体のうち、以下の一般式（Ｉ）及び（II）で表される糖脂質誘導体合成中間体は新規化合物であり、本反応過程において非常に重要且つ有用な鍵となる化合物である。
Ｙとしての保護基は特に限定しないが、例えば、ベンジル基などのエーテル系保護基、アセチル基などのエステル系保護基、tert−ブチル−ジメチルシリル基（ＴＢＤＭＳ基）などのシリルエーテル系保護基が挙げられる。Ｙはすべて異なるものでもよく、同一のものでも良い。その後の反応における脱離などの必要性に応じて適宜選択できる。本発明では糖類由来の糖骨格における６位のＯＨ基を保護する保護基（Ｙ）が糖骨格における他のＯＨ基（２〜４位）を保護する保護基（Ｙ）と異なるものを選択することが望ましい。
式(I)、(II)の化合物を得る方法としては（１）の本発明の化合物の説明のために参考となる合成法１にて説明した合成方法にて、対応する立体構造をもつ糖類及びグリシドール（誘導体）を反応させた後、得られた化合物にグリシドール由来部分のＯＨ基に、対応するＲをもつカルボン酸をエステル化することで得ることができる。エステル化の方法としては通常のエステル化法のほか、対応するカルボン酸の酸クロライドなどを反応させることで容易に行うことができる。
（３）参考となる化合物：更に、GGPL-IIIの合成中間体として用いられる下式（III）又は(IV)に記載の糖脂質誘導体合成中間体が有用な化合物として挙げられる。
（４）本発明の化合物の説明のために参考となる合成法２：これらの一般式（III）及び(IV)で表される化合物は以下の方法で合成できる。すなわち、下式(V)に記載の化合物に対して、開環しながらＵで表されるエーテル置換基を導入して、対応する立体構造をもつ下記（VI）に記載の化合物とする工程と、
前記式（VI）中のＯＨ基をアジド化する工程と、
前記Ｕで示されるエーテル置換基及び前記Ｔで示されるエーテル系保護基のうち、該Ｕで示されるエーテル置換基を酸化反応で選択的に脱離し、対応する立体構造をもつ式（III）又は（IV）に記載のセリノール誘導体を得る工程と、
（５）新規化合物：下記一般式（VII）に記載の糖脂質誘導体合成中間体。
一般式（VII)の化合物は後述する（６）の新規合成法３の方法で合成可能である。ここで、一般式（VII）の（Ａ）で示される糖骨格の立体構造がＤ−グルコースと同じであるものが例示される。また、アジド基が結合する炭素は不斉炭素であり、後述する（６）の新規合成法１の反応で式(III)及び(IV)のいずれを採用するかで、その立体構造を制御できる。
Ｙとしては特に限定しないが、例えば、ベンジル基などのエーテル系保護基、ＴＢＤＭＳ基などのシリルエーテル系保護基が挙げられる。Ｙはすべて異なるものでもよく、同一のものでも良い。その後の反応における脱離などの必要性に応じて適宜選択できる。
Ｑとしての保護基は特に限定されず、一般的なリンの保護基が採用できる。例えば、２−シアノエチル基、アリル基、ベンジル基、ｔ−ブチル基が挙げられる。
（６）新規合成法１：立体構造が制御された下記一般式（VIII）で表される糖脂質誘導体合成中間体に対して、ホスホロアミダイト誘導体と下記一般式（III）又は（IV）で表される化合物とを活性化剤の存在下、反応させるアミダイト法により、下記一般式（IX）で表される糖脂質誘導体合成中間体を得る工程を有することを特徴とする糖脂質誘導体合成中間体の製造方法。
Ｙとしては特に限定しないが、例えば、ベンジル基などのエーテル系保護基、ＴＢＤＭＳ基などのシリルエーテル系保護基が挙げられる。Ｙはすべて異なるものでもよく、同一のものでも良い。その後の反応における脱離などの必要性に応じて適宜選択できる。
Ｑは特に限定されず、一般的なリンの保護基が採用できる。例えば、２−シアノエチル基、アリル基、ベンジル基、ｔ−ブチル基が挙げられる。
（７−１）新規合成法２：GGPL-IIIを合成する製造方法として、Ｄ−グルコース又はＤ−ガラクトースの２〜４位のＯＨ基にエーテル系の保護基を導入し、６位のＯＨ基にエステル系の保護基を導入した糖誘導体をドナー化合物とし、前述の（１）の本発明の化合物の説明のために参考となる合成法１に記した糖脂質誘導体合成中間体の製造方法により下記一般式（Ｘ）で表される糖脂質誘導体合成中間体を合成する工程と、
Ｙとしては特に限定しないが、例えば、ベンジル基などのエステル系保護基、アセチル基などのアシル系保護基、ＴＢＤＭＳ基などのシリルエーテル系保護基が挙げられる。Ｙはすべて異なるものでもよく、同一のものでも良い。その後の反応における脱離などの必要性に応じて適宜選択できる。本発明では糖類由来の糖骨格における６位のＯＨ基を保護する保護基（Ｙ）が糖骨格における他のＯＨ基（２〜４位）を保護する保護基（Ｙ）と異なるものを選択することが望ましい。
該一般式（Ｘ）に示された糖脂質誘導体合成中間体における、グリシドールに由来するエポキシ構造又は３−ハロゲン化−プロパン−１，２−ジオール由来の部分構造がもつハロゲン基又はＯＨ基に対して、炭素数２〜３１（好ましくは炭素数７〜２７）の脂肪酸（つまり、Ｒとしては炭素数１〜３０（好ましくは炭素数６〜２６、更に好ましくは炭素数１２〜２０））によりエステル化して下記一般式（XI）で表される糖脂質誘導体合成中間体を得る工程と、
該一般式（XI）で表される糖脂質誘導体合成中間体の糖由来の部分構造がもつ６位のＯＨ基に対して、リン酸ジエステル化試薬を用いたアミダイト法にて前述の（４）の本発明の化合物の説明のために参考となる合成法２に記載の製造方法により合成された一般式（III）又は（IV）の化合物をリン酸エステル結合で導入し、（III）又は（IV）由来の部分構造がもつＴで示されるエーテル系保護基を脱離してＯＨ基とし、下記一般式（XII）で表される糖脂質誘導体合成中間体を得る工程と、
Ｑは特に限定されず、一般的なリンの保護基が採用できる。例えば、２−シアノエチル基、アリル基、ベンジル基、ｔ−ブチル基が挙げられる。
該一般式（XII）で表される糖脂質誘導体合成中間体に対して、リン酸ジエステル化試薬を用いたアミダイト法にて２−ハロゲン化エタノール（例えば２−ブロモ−エタノール又は２−ヨード−エタノール）をリン酸エステル結合で導入して下記一般式（XIII）で表される糖脂質誘導体合成中間体を得る工程と、
該一般式（XIII）で表される糖脂質誘導体合成中間体にアミン化合物(１級、２級及び３級アミンから選択させる。例えばトリメチルアミン、トリエチルアミン、トリアルキルアミン、トリフェニルアミンなど）を反応させた後、前記一般式（III）又は（IV）由来の部分構造がもつアジド基を還元し、Yで示される糖部分の水酸基の保護基を脱保護して立体構造が制御された下記一般式（XIV）で表される糖脂質誘導体を得る工程と、
を有することを特徴とする糖脂質誘導体の製造方法である。
(７−２)上記合成法は以下の２つの方法の組み合わせでも表記できる。
すなわち、（ａ）一般式（XII）で表される糖脂質誘導体合成中間体に対して、ホスホロアミダイト誘導体と２−ハロゲン化エタノールとを活性化剤の存在下、反応させるアミダイト法により、下記一般式（XIII）で表される糖脂質誘導体合成中間体を得る工程を有することを特徴とする糖脂質誘導体合成中間体の製造法と、（ｂ）一般式（XIII）で表される糖脂質誘導体合成中間体に対して、1級、2級および3級アミンから選択させるアミン化合物を反応させることにより、下記一般式（XV）で表させる糖脂質誘導体を得る工程を有することを特徴とする糖脂質誘導体合成中間体の製造法である。
ここで、前記一般式（Ｘ）中で表される糖脂質誘導体合成中間体、並びに、得られる前記一般式（XIV）及び（ＸＶ）で表される糖脂質誘導体中の（Ｂ）で表される糖由来の部分構造は、Ｄ−グルコース又はＤ−ガラクトースと同一の立体構造をもつものが好ましいものとして挙げられる。
一般式（XII）で表される糖脂質誘導体合成中間体に対して、リン酸ジエステル化試薬を用いたアミダイト法にて２−ブロモ−エタノール、２−ヨード−エタノールなどの２−ハロゲン化エタノールをリン酸エステル結合で導入して下記一般式（XIII）で表される糖脂質誘導体合成中間体を得る工程において、リン酸ジエステル化試薬とは特に限定しないが、ホスホアミダイト誘導体が好ましい。またリン酸エステルとして導入する試薬としては、塩素などのハロゲンや窒素などのヘテロ原子により活性化されたリン酸誘導体を選択することができる。
（８）ここで、前記糖脂質誘導体及び糖脂質誘導体合成中間体並びにその合成方法において、用いられているＱで表されたリンの保護基は２−シアノエチル基、アリル基、ベンジル基及びｔ−ブチル基からそれぞれ独立して選択することができる。
（９）なお、前述した一般式における保護基（Ｙ、Ｑ及びＴ）については特に記載がない場合でも独立して水素に置換した化合物を採用することができる。また、反応及び／又は使用の都合上、含有するＯＨ基について、反応性などを調節する目的で任意の保護基を置換・導入することができる。
（１０）上述の各一般式にて表した化合物におけるＲとして鎖式又は脂環式の炭化水素基が採用されてあり、且つ、それら化合物を本発明の製造方法にて製造する場合に、具現化する製造条件によっては、それら化合物中のＲで表される炭化水素基としては多重結合を有しないことが好ましい場合も想定できる。その場合に好適なＲとしては鎖式又は脂環式のアルキル基が挙げられる。
例えば、Ｒとしてエチレン性の二重結合を有する場合に、強い還元条件を採用すると、二重結合の部分から開裂などしてＲ部分が変化することが考えられる。Ｒ部分が変化した後の化合物が望む化合物でなければ、二重結合を含まないＲを採用するか、後に変化したＲ部分を望む置換基に変換乃至置換することが望まれる。
（１１）糖脂質誘導体合成中間体を合成する方法としては上述したような方法のほか、以下に示すような方法も採用できる。この方法は上述の方法よりもステップ数は多いものの、副反応が進行し難く合成操作が簡便になるという利点がある。具体的には上述した一般式（Ｘ）から一般式（XI）に至る合成経路を置き換えるものである。
すなわち、下記一般式（Ｘ）で表される糖脂質誘導体合成中間体に対して、酸性条件にて一般式（１）：Ｒ１ＣＯＲ２（Ｒ１及びＲ２はそれぞれ独立してアルキル基から選択される。Ｒ１及びＲ２にて環を形成することもできる。）で表されるカルボニル化合物を反応させ、下記一般式（２）で表される糖脂質誘導体合成中間体を得る工程と、
前記一般式（２）で表される糖脂質誘導体合成中間体をプロトン酸で処理し、下記一般式（３）で表される糖脂質誘導体合成中間体を得る工程と、
前記一般式（３）で表される糖脂質誘導体合成中間体に対して、脂肪酸をエステル化して下記一般式（４）で表される糖脂質誘導体合成中間体を得る工程と、
前記一般式（４）で表される糖脂質誘導体合成中間体に対してフッ化物イオンを反応させることで該一般式（４）で表される糖脂質誘導体合成中間体から置換基Ｙ１を脱保護し下記一般式（５）とする工程と、
を有することを特徴とする糖脂質誘導体合成中間体の製造方法である。
一般式（Ｘ）で表される糖脂質誘導体合成中間体におけるグリセロール由来のＯＨ基をカルボニル化合物により保護すると共に、糖の６位由来のＯＨ基を置換基Ｙ１にて保護するものである。ここで、保護基として導入した２つの保護基の間で導入条件及び脱離条件が相違するものを選択することで、それぞれのＯＨ基に目的の基を導入することができる。
具体的に望ましいものとしては以下の通りである。前記一般式（２）の糖脂質誘導体合成中間体を得る工程は、前記一般式（Ｘ）における糖由来の骨格の６位に結合した−ＯＹの保護基Ｙを脱保護する工程と、前記ケトン化合物を反応させる工程と、前記糖由来の骨格の６位に結合した−ＯＨ基に保護基Ｙ１を導入する工程とをもつことが望ましい。
前記一般式（２）〜（４）における置換基Ｙ１はtert−ブチル−ジフェニルシリル基であることが望ましい。その場合に、前記フッ化物イオンはトリブチルアミンハイドロフッ化物又はテトラブチルアンモニウムフッ化物由来であることが望ましい。
そして、前記カルボニル化合物はアセトンおよびその誘導体であることが望ましい。
また、前記一般式（３）で表される糖脂質誘導体合成中間体を得る工程において用いる前記プロトン酸は、官能基としてスルホ基をもつ陽イオン交換樹脂に由来することが望ましい。陽イオン交換樹脂としては、一般的なスチレン−ジビニルベンゼン共重合体にスルホ基を導入した樹脂（例えば、Amberlyst15；オルガノ株式会社製）が例示できる。
そして、前記一般式（４）で表される糖脂質誘導体合成中間体を得る工程は前記一般式（３）で表される糖脂質誘導体合成中間体にエステル化する前記脂肪酸に対応する脂肪酸クロライドを反応させる工程を採用することで簡単に導入することができる。
In order to solve the above-mentioned problems, the present inventors have intensively studied a method for synthesizing GGPL-III. As a result, they have found a method having characteristics different from the conventional ones, and are useful in the process of completing the method. And a novel synthesis method thereof.
Since the production method shown in Patent Document 4 does not use glycolipids having fatty acids as starting materials, it is not efficient because complicated operations and reactions for introducing fatty acids are performed at the final stage. In addition, in the conventional method, choline tosylate was used in the reaction for introducing a phosphocholine group, but choline tosylate is hygroscopic and has a remarkable decrease in yield because it is difficult to dissolve in the reaction solvent. . In the method of the present invention, a reaction having a new reaction route was found, and the yield was greatly improved. In the conventional method, a compound having a p-methoxyphenyl group as a protective group is used as a precursor of the phosphoryl serinol group. However, the reaction for removing the p-methoxyphenyl group requires an expensive and toxic silver salt. In addition, the above-described problems have been solved by the method of the present invention, although the purification operation is difficult. Hereinafter, the reaction for synthesizing GGPL-III and the beneficial reaction discovered in the reaction process will be described.
(1) Synthetic method 1 used as a reference for explaining the compounds of the present invention : Glycero-type glycolipids such as the general formula (VIII) are glycolipids frequently found in plants and microorganisms, and are cell membrane components thereof. is there. In recent studies, it has been reported that glyceroglycolipids have anti-inflammatory and anti-cancer effects, and their physiological functions are attracting attention. At the same time, it is a highly safe surface active compound and is expected to be applied as a cosmetic or pharmaceutical product.
In the present invention, glyceroglycolipid having an α-type sugar chain bond is a key structure of glycophospholipid that mycoplasma fermentans suspected as a causative agent of rheumatoid arthritis has a high concentration in the cell membrane. Since this glycophospholipid is one of the pathogenic main bodies of this bacterium, it is an important key compound in the diagnosis of autoimmune diseases such as rheumatoid arthritis and the development of therapeutic methods. Therefore, efficient synthesis of general formula (VIII) is the key. However, since the stereoselective synthesis method of the general formula (VIII) is technically difficult to control both the construction of the α-type glycoside bond and the stereo of the glycerol moiety, there are few reports. . In order to obtain the compound of the general formula (VIII), intensive studies were conducted on a method for controlling both the construction of the α-type glycosidic bond and the steric structure of the glycerol moiety .
That is , the method for synthesizing the glycolipid derivative investigated by the present inventors is based on an optical method in the presence of a phosphonium halogen compound and a basic solvent against a donor compound that is a saccharide introduced with a protecting group for the OH group other than the 1-position. It has a step of reacting an active glycidol or a derivative having an optically active glycerol skeleton derived from glycidol as an acceptor compound, and simultaneously constructing a three-dimensional structure control of an α-glycosyl bond and a glycerol moiety.
Here, in the saccharide as the donor compound, the reactivity of the OH group at the 1st position is slightly different from that of the other OH groups, so a functional group different from the other OH groups is introduced into the OH group at the 1st position. Or no functional group can be introduced relatively easily. For example, the donor compound is a sugar derivative in which an ether-based protecting group is introduced into the OH group at positions 2 to 4 of D-glucose or D-galactose, and an ester-based protecting group is introduced into the OH group at position 6. It is desirable.
The phosphonium halogen compound is not particularly limited, but can be independently selected from G3P (G is a hydrocarbon group containing an aromatic group, alkyl, alkene, or -OG 'and -NG'2 containing a hetero atom. G' Can be selected on the basis of a hydrocarbon group or the same criteria as G) and CHmX4-m (wherein X is halogen, preferably Br or I, more preferably Br; 0 ≦ m ≦ 2). The compound which can be illustrated.
As G in G3P, in addition to an aromatic group or a hydrocarbon group, a functional group containing a hetero atom can also be employed. Different G may be employed, or the same one may be employed. And the hydrocarbon group which can be employ | adopted as each G can employ | adopt a C1-C10, especially preferably C2-C8 hydrocarbon group (for example, alkyl group). For example, as G, a phenyl group, a cyclohexyl group, a butyl group, a hexyl group, an octyl group, or the like can be employed.
Further, as G, in addition to the above-described hydrocarbon groups such as alkyl groups and groups, groups in which some of carbon atoms and hydrogen atoms are substituted with halogen, oxygen, nitrogen, and sulfur atoms can be employed. Moreover, a heterocyclic aromatic compound such as pyridine or a polycyclic compound can also be employed. For example, diphenyl (2-pyridyl) phosphine (R = phenyl group, 2-pyridyl group) and (4-dimethylaminophenyl) diphenylphosphine (R = phenyl group, 4-dimethylaminophenyl group) can be exemplified. These compounds can be easily removed from the organic layer by washing with an acidic aqueous solution. Furthermore, by bonding to a base material made of a polymer or the like via one or more R, removal in post-treatment becomes easy. For example, a method in which a group having a vinyl group such as a styryl group is introduced as G and grafted onto the polymer substrate by the vinyl group can be used.
The desired compound is obtained by reacting these mixtures in the presence of a basic solvent. Examples of the basic solvent include the following solvents and those containing the following solvents as main components. That is, (a) a formamide solvent such as dimethylformamide and diethylformamide, (b) a solvent obtained by mixing a formamide solvent and an organic solvent (the organic solvent is an aprotic solvent such as toluene or a halogen-containing solvent such as dichloromethane) ), (C) A solvent in which tetramethylurea and an organic solvent are mixed (the organic solvent is an aprotic solvent such as toluene or a halogen-containing solvent such as dichloromethane).
Examples of the acceptor compound (optically active glycidol or a derivative having an optically active glycerol skeleton derived from glycidol) include glycidol and glycidol derivatives as shown in the following formula. The steric structure at the asymmetric carbon at the 2-position is controlled, and the steric structure determines the steric structure of the final product. These derivatives can be obtained by reacting glycidol having a desired steric structure with a halogen ion (such as bromine or iodine ion).
(2) Novel compound: Here, among the synthetic intermediates of glycolipid derivatives that appear as intermediates in connection with the synthesis method of synthesis method 1 which is a reference for explaining the compound of the present invention of (1), the following The intermediates for synthesizing glycolipid derivatives represented by the general formulas (I) and (II) are novel compounds and are very important and useful key compounds in this reaction process.
The protecting group as Y is not particularly limited. For example, ether protecting groups such as benzyl group, ester protecting groups such as acetyl group, and silyl ether protecting groups such as tert-butyl-dimethylsilyl group (TBDMS group) Can be mentioned. Y may be all different or the same. It can select suitably according to the necessity, such as detachment | desorption in subsequent reaction. In the present invention, a protecting group (Y) that protects the OH group at the 6-position in the sugar skeleton derived from a saccharide is selected from a protecting group (Y) that protects the other OH groups (positions 2 to 4) in the sugar skeleton. It is desirable.
As a method of obtaining the compounds of the formulas (I) and (II), a saccharide having a corresponding three-dimensional structure can be obtained by the synthesis method described in Synthesis Method 1 which serves as a reference for explaining the compound of the present invention in (1). And glycidol (derivative), the resulting compound can be obtained by esterifying a carboxylic acid having R corresponding to the OH group of the glycidol-derived moiety. As the esterification method, in addition to the usual esterification method, it can be easily carried out by reacting the corresponding acid chloride of carboxylic acid.
(3) Reference compound: Further, a glycolipid derivative synthesis intermediate described in the following formula (III) or (IV) used as a synthesis intermediate of GGPL-III is a useful compound.
(4) Synthesis method 2 which serves as a reference for explaining the compound of the present invention : These compounds represented by the general formulas (III) and (IV) can be synthesized by the following method. That is, with respect to the compound described in the following formula (V), an ether substituent represented by U is introduced while ring-opening to obtain a compound described in the following (VI) having a corresponding steric structure; ,
A step of azidating the OH group in the formula (VI);
Of the ether substituent represented by U and the ether-based protecting group represented by T, the ether substituent represented by U is selectively eliminated by an oxidation reaction, and has the corresponding steric structure (III) or Obtaining a serinol derivative according to (IV);
(5) Novel compound: a glycolipid derivative synthesis intermediate described in the following general formula (VII).
The compound of general formula (VII) is compoundable by the method of the novel synthesis method 3 of (6) mentioned later. Here, the thing whose steric structure of the sugar skeleton shown by (A) of general formula (VII) is the same as D-glucose is illustrated. The carbon to which the azide group is bonded is an asymmetric carbon, and the three-dimensional structure can be controlled by adopting any one of formulas (III) and (IV) in the reaction of the novel synthesis method 1 (6) described later. .
Although it does not specifically limit as Y, For example, silyl ether type protecting groups, such as ether type protecting groups, such as a benzyl group, and a TBDMS group, are mentioned. Y may be all different or the same. It can select suitably according to the necessity, such as elimination | elimination in subsequent reaction.
The protecting group as Q is not particularly limited, and a general phosphorus protecting group can be adopted. For example, 2-cyanoethyl group, allyl group, benzyl group, t-butyl group can be mentioned.
(6) Novel synthesis method 1: With respect to a glycolipid derivative synthesis intermediate represented by the following general formula (VIII) whose steric structure is controlled, a phosphoramidite derivative and the following general formula (III) or (IV) A glycolipid derivative synthesis intermediate characterized by having a step of obtaining a glycolipid derivative synthesis intermediate represented by the following general formula (IX) by an amidite method in which the compound represented by the present invention is reacted in the presence of an activator: Body manufacturing method.
Although it does not specifically limit as Y, For example, silyl ether type protecting groups, such as ether type protecting groups, such as a benzyl group, and a TBDMS group, are mentioned. Y may be all different or the same. It can select suitably according to the necessity, such as detachment | desorption in subsequent reaction.
Q is not particularly limited, and a general phosphorus protecting group can be employed. For example, 2-cyanoethyl group, allyl group, benzyl group, t-butyl group can be mentioned.
(7-1) Novel synthesis method 2: As a production method for synthesizing GGPL-III, an ether-based protecting group is introduced into the OH group at positions 2 to 4 of D-glucose or D-galactose, and the OH group at position 6 A sugar derivative having an ester-based protecting group introduced therein as a donor compound, and a method for producing a glycolipid derivative synthesis intermediate described in Synthesis Method 1 described above as a reference for explaining the compound of the present invention of (1) Synthesizing a glycolipid derivative synthesis intermediate represented by the following general formula (X);
Y is not particularly limited, and examples thereof include ester-based protecting groups such as benzyl group, acyl-based protecting groups such as acetyl group, and silyl ether-based protecting groups such as TBDMS group. Y may be all different or the same. It can select suitably according to the necessity, such as elimination | elimination in subsequent reaction. In the present invention, a protecting group (Y) that protects the OH group at the 6-position in the sugar skeleton derived from a saccharide is selected from a protecting group (Y) that protects the other OH groups (positions 2 to 4) in the sugar skeleton. It is desirable.
In the glycolipid derivative synthesis intermediate represented by the general formula (X), the epoxy group derived from glycidol or the halogen group or OH group of the partial structure derived from 3-halogenated-propane-1,2-diol And an ester by a fatty acid having 2 to 31 carbon atoms (preferably 7 to 27 carbon atoms) (that is, R is 1 to 30 carbon atoms (preferably 6 to 26 carbon atoms, more preferably 12 to 20 carbon atoms)). And obtaining a glycolipid derivative synthesis intermediate represented by the following general formula (XI):
With respect to the 6-position OH group of the sugar-derived partial structure of the glycolipid derivative synthesis intermediate represented by the general formula (XI), the above-mentioned (4) by the amidite method using a phosphodiesterization reagent The compound of the general formula (III) or (IV) synthesized by the production method described in Synthesis method 2 to be referred for explaining the compound of the present invention is introduced by a phosphate ester bond, and (III) or ( IV) a step of removing the ether-based protecting group represented by T in the partial structure derived from OH group to obtain a glycolipid derivative synthesis intermediate represented by the following general formula (XII);
Q is not particularly limited, and a general phosphorus protecting group can be employed. For example, 2-cyanoethyl group, allyl group, benzyl group, t-butyl group can be mentioned.
2-halogenated ethanol (for example, 2-bromo-ethanol or 2-iodo-ethanol) by the amidite method using a phosphodiesterization reagent for the glycolipid derivative synthesis intermediate represented by the general formula (XII) ) With a phosphate ester bond to obtain a glycolipid derivative synthetic intermediate represented by the following general formula (XIII):
The glycolipid derivative synthesis intermediate represented by the general formula (XIII) is reacted with an amine compound (selected from primary, secondary and tertiary amines. For example, trimethylamine, triethylamine, trialkylamine, triphenylamine, etc.). Thereafter, the azide group of the partial structure derived from the general formula (III) or (IV) is reduced, and the steric structure is controlled by deprotecting the protecting group of the hydroxyl group of the sugar moiety represented by Y. Obtaining a glycolipid derivative represented by (XIV);
It is a manufacturing method of the glycolipid derivative characterized by having.
(7-2) The above synthesis method can be expressed by a combination of the following two methods.
That is, (a) an amidite method in which a phosphoramidite derivative and 2-halogenated ethanol are reacted in the presence of an activating agent with respect to a glycolipid derivative synthetic intermediate represented by the general formula (XII), A process for producing a glycolipid derivative synthetic intermediate represented by the general formula (XIII), and (b) a glycolipid represented by the general formula (XIII). It has a step of obtaining a glycolipid derivative represented by the following general formula (XV) by reacting an amine compound selected from primary, secondary and tertiary amines with a derivative synthesis intermediate. This is a method for producing a glycolipid derivative synthetic intermediate.
Here, the glycolipid derivative synthesis intermediate represented by the general formula (X), and (B) in the obtained glycolipid derivatives represented by the general formulas (XIV) and (XV) As the partial structure derived from sugar, those having the same steric structure as D-glucose or D-galactose are preferable.
A 2-halogenated ethanol such as 2-bromo-ethanol, 2-iodo-ethanol or the like is synthesized on the glycolipid derivative synthesis intermediate represented by the general formula (XII) by an amidite method using a phosphodiesterization reagent. In the step of obtaining a glycolipid derivative synthesis intermediate represented by the following general formula (XIII) by introducing a phosphate ester bond, the phosphoric acid diesterification reagent is not particularly limited, but a phosphoramidite derivative is preferred. As a reagent to be introduced as a phosphoric acid ester, a phosphoric acid derivative activated by a halogen such as chlorine or a heteroatom such as nitrogen can be selected.
(8) Here, in the glycolipid derivative, the glycolipid derivative synthesis intermediate and the synthesis method thereof, the phosphorus protecting group represented by Q used is 2-cyanoethyl group, allyl group, benzyl group and t- Each can be independently selected from a butyl group.
(9) In addition, about the protective group (Y, Q, and T) in the general formula mentioned above, the compound substituted with hydrogen independently can be employ | adopted even if there is no description in particular. In addition, for the convenience of reaction and / or use, any protecting group can be substituted / introduced for the purpose of adjusting the reactivity of the contained OH group.
(10) When a chain or alicyclic hydrocarbon group is employed as R in the compounds represented by the above general formulas, and these compounds are produced by the production method of the present invention, the present invention is realized. Depending on the production conditions to be converted, it may be assumed that the hydrocarbon group represented by R in these compounds preferably does not have multiple bonds. Suitable R in that case includes a chain or alicyclic alkyl group.
For example, when R has an ethylenic double bond and a strong reduction condition is adopted, it is conceivable that the R portion changes due to cleavage from the double bond portion. If the compound after the change of the R moiety is not the desired compound, it is desirable to adopt R that does not contain a double bond, or to convert or substitute the R moiety that has been changed to a desired substituent.
(11) As a method for synthesizing a glycolipid derivative synthesis intermediate, the following method can be employed in addition to the method described above. Although this method has a larger number of steps than the above-mentioned method, there is an advantage that the side reaction is difficult to proceed and the synthesis operation is simple. Specifically, the synthesis route from the general formula (X) to the general formula (XI) is replaced.
That is, for the glycolipid derivative synthesis intermediate represented by the following general formula (X), the general formula (1): R1COR2 (R1 and R2 are each independently selected from alkyl groups under acidic conditions. And R2 can also form a ring.) By reacting with a carbonyl compound represented by the following general formula (2):
Treating the glycolipid derivative synthesis intermediate represented by the general formula (2) with a protonic acid to obtain a glycolipid derivative synthesis intermediate represented by the following general formula (3);
A step of esterifying a fatty acid with respect to the glycolipid derivative synthetic intermediate represented by the general formula (3) to obtain a glycolipid derivative synthetic intermediate represented by the following general formula (4);
The substituent Y1 is deprotected from the glycolipid derivative synthetic intermediate represented by the general formula (4) by reacting the glycolipid derivative synthetic intermediate represented by the general formula (4) with a fluoride ion. And the following general formula (5):
It is a manufacturing method of the glycolipid derivative synthetic intermediate characterized by having.
The glycerol-derived OH group in the glycolipid derivative synthesis intermediate represented by the general formula (X) is protected with a carbonyl compound, and the OH group derived from the 6-position of the sugar is protected with a substituent Y1. Here, the target group can be introduced into each OH group by selecting those having different introduction conditions and elimination conditions between the two protective groups introduced as protective groups.
Specifically desirable are as follows. The step of obtaining the intermediate for synthesizing the glycolipid derivative of the general formula (2) includes the step of deprotecting the protecting group Y of -OY bonded to the 6-position of the skeleton derived from the sugar in the general formula (X), and the ketone It is desirable to have a step of reacting a compound and a step of introducing a protecting group Y1 to the —OH group bonded to the 6-position of the sugar-derived skeleton.
The substituent Y1 in the general formulas (2) to (4) is preferably a tert-butyl-diphenylsilyl group. In that case, the fluoride ion is desirably derived from tributylamine hydrofluoride or tetrabutylammonium fluoride.
The carbonyl compound is preferably acetone or a derivative thereof.
Moreover, it is desirable that the protonic acid used in the step of obtaining the glycolipid derivative synthetic intermediate represented by the general formula (3) is derived from a cation exchange resin having a sulfo group as a functional group. Examples of the cation exchange resin include a resin in which a sulfo group is introduced into a general styrene-divinylbenzene copolymer (for example, Amberlyst 15; manufactured by Organo Corporation).
The step of obtaining the glycolipid derivative synthetic intermediate represented by the general formula (4) comprises the step of obtaining a fatty acid chloride corresponding to the fatty acid to be esterified into the glycolipid derivative synthetic intermediate represented by the general formula (3). It can be easily introduced by adopting a reaction step.
本発明の糖脂質誘導体の製造方法は脂質誘導体を効率的に製造することができる。本発明の脂質誘導体合成中間体はその製造方法における鍵となる化合物である。 The method for producing a glycolipid derivative of the present invention can efficiently produce a lipid derivative. The lipid derivative synthesis intermediate of the present invention is a key compound in its production method.
（合成例１）
下記反応式に示す方法でＤ−グルコース（１位のＯＨ基がメチル化されている）から化合物７ａ（一般式（ＶＩＩＩ）の化合物に相当：単糖部分はグルコース由来、グリシドール由来の部分は（Ｓ）−グリシドール由来、Ｙはベンジル基、Ｒは炭素数１５のアルキル基）を合成した。以下に反応の概略を説明する。
また、下記各段階の一部において、用いる化合物を変更することで、化合物７ｂ、７ｃ、７ｄについても合成できる。
・第１段階
メチルグルコシドを出発原料とし、２，３，４，６位をエーテル系の保護基で保護する。この化合物を無水酢酸に溶かし、そこに酸触媒を加えることによって、１位と６位の水酸基がアセチル化される。さらに１位のアセチル基のみを脱保護することによって化合物３（前述の（１）の新規合成法１におけるドナー化合物に相当）を得る。ここで、ドナー化合物としてガラクトースを採用すると、対応する立体構造をもつ最終生成物が得られる（下記反応式参照）。
・第２段階
化合物３をドナー化合物とし、光学活性（Ｓ）−グリシドールをアクセプター化合物とする新規合成法１を行い、鍵となる立体骨格をもつ化合物４を合成する。ここで、アクセプター化合物として（Ｒ）−グリシドールを採用すると、対応する立体構造をもつ最終生成物が得られる（下記反応式参照）。
・第３段階
化合物４（化合物４−ａ及び化合物４−ｂの混合物；一般式（Ｘ）の化合物に相当：６位のＯＨ基はアセチル基、２〜４位のＯＨ基はベンジル基、ＸはＢｒ）の糖の６位水酸基の保護基を脱保護した後、グリセロールのｓｎ−１位に脂肪酸を導入する。
・第４段階
化合物５の糖の６位水酸基（一級）をＴＢＤＭＳ基で保護し、グリセロールのｓｎ−２位の水酸基（２級）に脂肪酸を導入した後、ＴＢＤＭＳ基を脱保護することにより、化合物７ａを合成する。
（合成）
化合物３の合成：メチルグルコシド（１０ｇ）をＤＭＦ３００ｍＬに溶解し、ＮａＨ（１２．４ｇ）を０℃で加えて０℃で３０分攪拌した。その後、ＢｎＢｒ（５３．９ｍＬ）を０℃で加えて、室温で５時間攪拌した。反応終了後、メタノールを加えて試薬を分解したのち、目的物を有機層に抽出して、洗浄、乾燥、濃縮し、残渣をシリカゲルカラムを用いたクロマトグラフィーで精製し、化合物１を得た。
化合物１を無水酢酸（１４０ｍＬ）に溶解し、硫酸（１２０μＬ）を０℃で加えて室温で約３時間攪拌した。反応後、溶液を中和したのち、目的物を有機層に抽出して、洗浄、乾燥、濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２を得た。
化合物２をＴＨＦ（１００ｍＬ）に溶解し、ベンジルアミン（８．９ｇ）を加えて室温で約２日間攪拌した。溶液を洗浄、乾燥、濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物３を得た。収量１６．１ｇ（α：β＝２：１）、シロップ状、収率５９％（３ステップ）。
１Ｈ−ＮＭＲ（５００ＭＨｚ，ｒｔ，ＣＤＣｌ３）：ａ−ａｎｏｍｅｒ，ｄＨ７．２５〜７．３５（ｍ，５Ｈｘ３，−Ｂｎ），５．２０（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．５５〜５．００（ｄ，２Ｈｘ３，−ＣＨ２Ｐｈ），４．２７（ｍ，２Ｈ，Ｈ−６），４．１０（ｍ，１Ｈ，Ｈ−５），４．００（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．５６（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），３．５０（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ １０．０Ｈｚ，Ｈ−４），２．０３（ｓ，３Ｈ，−ＯＡｃ）；ｂ−ａｎｏｍｅｒ，ｄＨ７．２５〜７．３５（ｍ，５Ｈｘ３，−Ｂｎ），４．７４（ｄ，１Ｈ，Ｊ＝８．０Ｈｚ，Ｈ−１），４．５５〜５．００（ｄ，２Ｈｘ３，−ＣＨ２Ｐｈ），４．３４ ａｎｄ ４．１９（ｄｄ，２Ｈ，Ｈ−６），３．９６（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．５５（ｄｄ，１Ｈ，Ｊ＝８．０ ａｎｄ ９．５Ｈｚ，Ｈ−２），３．４１（ｄｄ，１Ｈ，Ｊ＝７．５ ａｎｄ ９．０Ｈｚ，Ｈ−４），２．０５（ｓ，３Ｈ，−ＯＡｃ）．
化合物４の合成：化合物３（５．０ｇ）をＤＭＦに溶解し、Ｐｈ３Ｐ（７．９ｇ）とＣＢｒ４（１０ｇ）を０℃で加え、室温で１４時間攪拌した。反応終了後、目的物を酢酸エチルで抽出し、この溶液を洗浄し、乾燥、濃縮した。
残渣に含まれるＰｈ３Ｐ＝０をジエチルエーテル−ヘキサンで結晶化させて濾過により取り除き、ろ液を濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーによって精製した。時間や条件によって、化合物４−ａのエポキシの一部がブロモアニオンで開環された化合物４−ｂが生成するが、これは混合物のまま次の反応に用いた。
化合物５の合成：得られた残渣をメタノール（２００ｍＬ）に溶解し、Ｋ２ＣＯ３（１．５ｇ）を加えて約３時間攪拌した。反応終了後、溶液を洗浄し、乾燥、濃縮させ、得られた残渣を真空雰囲気下で乾燥させた。次にこの残渣を２ｍＬのＤＭＦに溶解した溶液を、パルミチン酸Ｃｓ（３６ｇ）をＤＭＦ（２００ｍＬ）に加え１００℃〜１１０℃に加熱した反応液中に滴下し、そのまま１００℃〜１１０℃で約１時間攪拌した。
反応終了後、溶液を冷却し、酢酸エチルを加えて未反応のパルミチン酸Ｃｓを析出させ、ろ過により取り除いた。得られたろ液を洗浄、乾燥、濃縮し、得られた残渣をシリカゲルカラムにより精製した。収量３．８７ｇ、収率５０％（化合物３から３ステップ）。
１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）；ｄＨ７．４０〜７．２３（ｍ，５Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），４．９６〜４．６４（ｄ，２Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），４．７３（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．１８（ｄｄ，１Ｈ，Ｊ＝４．５ ａｎｄ １２Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＳ），４．１３（ｄｄ，１Ｈ，Ｊ＝５．５ ａｎｄ １１．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ），４．０５（ｂ，１Ｈ，ｇｌｙｃｅｒｏｌ Ｈ−２），３．９８（ｄｄ，１Ｈ，Ｊ＝９．５ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．７６（ｄｄ，１Ｈ，Ｊ＝４．０ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＲ），３．６５〜３．８０（ｂ，２Ｈ，Ｈ−６ＰｒｏＲ ａｎｄ Ｈ−６ｐｒｏＳ），３．６８（ｍ，１Ｈ，Ｈ−５），３．５２（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−４），３．５１（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），３．４０（ｄｄ，１Ｈ，Ｊ＝７．５ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ），２．３４（ｔ，２Ｈ，Ｊ＝７．５Ｈｚ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．６２（ｂ，２Ｈ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｂ，２４Ｈ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）．
化合物７ａの合成：化合物５（２．３ｇ）をピリジン１４０ｍＬに溶解し、Ｎ，Ｎ−ジメチルアミノピリジン（ＤＭＡＰ：触媒量）を加え、さらにＴＢＤＭＳＣｌ（６７６ｍｇ）を加えて約１２時間室温で攪拌した。反応終了後、溶液にメタノールを加えて１２時間攪拌し試薬を分解させた後、濃縮し、残渣をシリカゲルカラムクロマトグラフィーで粗精製した。得られたシロップをピリジン（４０ｍＬ）に溶解し、ＤＭＡＰ（触媒量）を加え、パルミチン酸Ｃｌ（１．３５ｍＬ）を滴下して約３時間室温で攪拌した。
反応終了後、溶液にメタノールを加えて１２時間攪拌し試薬を分解させた後、濃縮した。この残渣に３０％トリフルオロ酢酸−メタノール：クロロホルム＝２：１溶液（３０ｍＬ）を加えて３０分室温で攪拌した。反応終了後、溶液を濃縮し、残渣をシリカゲルカラムを用いたクロマトグラフィーで精製した。収量１．９６ｇ、収率６５％。
［α］Ｄ ２２＝＋２３．０（ｃ ０．２７，ＣＨＣｌ３）．１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）；ｄＨ７．４０〜７．２３（ｍ，５Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），５．２３（ｂ，１Ｈ，ｇｌｙｃｅｒｏｌ Ｈ−２），４．９６〜４．６４（ｄ，２Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），４．７０（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．４０（ｄｄ，１Ｈ，Ｊ＝４．０ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＳ），４．１９（ｄｄ，１Ｈ，Ｊ＝６．０ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ），３．９６（ｄｄ，１Ｈ，Ｊ＝９．５ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．７２（ｄｄ，１Ｈ，Ｊ＝５．５ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＲ），３．７２ ａｎｄ ３．６６（ｂ，２Ｈ，Ｈ−６ＰｒｏＲ ａｎｄ Ｈ−６ｐｒｏＳ），３．６５（ｍ，１Ｈ，Ｈ−５），３．５４（ｄｄ，１Ｈ，Ｊ＝５．５ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ），３．５０（ｄｄ，１Ｈ，Ｊ＝９．５ ａｎｄ １０．０Ｈｚ，Ｈ−４），３．４９（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），２．２９（ｍ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５８（ｂ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｂ，２４Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，３Ｈｘ２，Ｊ＝７．０Ｈｚ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）．ＭＳ（ＦＡＢ）；１０２４［Ｍ＋Ｎａ］＋．
化合物７ｂの合成：化合物７ｂ（一般式（ＶＩＩ）において、単糖部分はグルコース由来、グリシドール由来の部分は（Ｒ）−グリシドール由来、Ｙはベンジル基、Ｒは炭素数１５のアルキル基である化合物）の合成は、化合物３から４を合成する反応において（Ｒ）−グリシドールを用いて合成した。他の反応は化合物７ａと同様の反応にて行った。最終的な収率も同程度であった。
７ｂ：［α］Ｄ３２＝＋１８．５（ｃ １．０，ＣＨＣｌ３）；ＩＲ（ＫＢｒ ｆｉｌｍ）：３４５２，２９２４，２８５４，１７３９，１５８６，１４５５，１２９６，１１５９，１０９５，７１０ｃｍ￣１；１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）：δＨ７．４０〜７．２３（ｍ，５Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），５．２３（ｂ，１Ｈ，ｇｌｙｃｅｒｏｌ Ｈ−２），４．９６〜４．６３（ｄ，２Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），４．７５（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．３８（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＲ），４．２１（ｄｄ，１Ｈ，Ｊ＝６．５ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ），３．９６（ｄｄ，１Ｈ，Ｊ＝９．５ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．７３（ｄｄ，１Ｈ，Ｊ＝６．０ ａｎｄ １１．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＳ），３．７６ ａｂｄ ３．６６（ｂ，２Ｈ，Ｈ−６ＰｒｏＲ ａｎｄ Ｈ−６ｐｒｏＳ），３．６５（ｍ，１Ｈ，Ｈ−５），３．５７（ｄｄ，１Ｈ，Ｊ＝５．５ ａｎｄ １１．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ），３．５１（ｄｄ，１Ｈ，Ｊ＝９．５ ａｎｄ １０．０Ｈｚ，Ｈ−４），３．５０（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ， Ｈ−２），２．２９（ｂ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５９（ｂ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｂ，２４Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，３Ｈｘ２，Ｊ＝７．０Ｈｚ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＭＳ（ＦＡＢ）：ｍ／ｚ ｃａｌｃｄ ｆｏｒ Ｃ６２Ｈ９６Ｏ１０Ｎａ［Ｍ＋Ｎａ］＋１０２３．７．
化合物７ｃの合成：化合物７ｃ（一般式（ＶＩＩ）において、単糖部分はガラクトース由来、グリシドール由来の部分は（Ｓ）−グリシドール由来、Ｙはベンジル基、は炭素数１５のアルキル基である化合物）の合成は、出発原料としてメチルガラクトシドを用いて合成した。他の反応は化合物７ａと同様の反応にて行った。最終的な収率も同程度であった。
７ｃ：［α］Ｄ３３＝＋１８．８（ｃ ０．９，ＣＨＣｌ３）；ＩＲ（ＫＢｒ ｆｉｌｍ）：３４３２，２９２３，２８５３，１７４０，１５８６，１４６０，１３５０，１１５３，１０５４，６９７ｃｍ−１；１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）：δＨ７．４０〜７．２３（ｍ，５Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），５．２５（ｂ，１Ｈ，ｇｌｙｃｅｒｏｌ Ｈ−２），４．９６〜４．６３（ｄ，２Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），４．８３（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．３４（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＳ），４．１８（ｄｄ，１Ｈ，Ｊ＝６．０ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ），４．０５（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），３．９０（ｄｄ，１Ｈ，Ｈ−３），３．８９ ａｎｄ ３．６８（ｂ，２Ｈ，Ｈ−６ｐｒｏＲ ａｎｄ Ｈ−６ｐｒｏＳ），３．７３（ｂｔ，１Ｈ，Ｊ＝５．５ ａｎｄ ６．０Ｈｚ，Ｈ−４），３．７１（ｄｄ，１Ｈ，Ｊ＝５．５ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＲ），３．５８（ｄｄ，１Ｈ，Ｊ＝６．０ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ），３．４７（ｍ，１Ｈ，Ｈ−５），２．２８（ｍ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５６（ｂ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｂ，２４Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，３Ｈｘ２，Ｊ＝７．０Ｈｚ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＭＳ（ＦＡＢ）：ｍ／ｚ ｃａｌｃｄ ｆｏｒ Ｃ６２Ｈ９６Ｏ１０Ｎａ［Ｍ＋Ｎａ］＋１０２３．７．
化合物７ｄの合成：化合物７ｄ（一般式（ＶＩＩ）において、単糖部分はガラクトース由来、グリシドール由来の部分は（Ｒ）−グリシドール由来、Ｙはベンジル基、Ｒは炭素数１５のアルキル基である化合物）の合成は、出発物質としてメチルガラクトシド、化合物３から４を合成する反応において（Ｒ）−グリシドールを用いて合成した。他の反応は化合物７ａと同様の反応にて行った。最終的な収率も同程度であった。
７ｄ：［α］Ｄ３３＋８．４２（ｃ １．０，ＣＨＣｌ３）；ＩＲ（ＫＢｒ ｆｉｌｍ）：３４１１，２９２４，２８５３，１７４１，１５８７，１４６０，１３５０，１１５０，１０５４，６９７ｃｍ−１；１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）：δＨ７．４０〜７．２３（ｍ，５Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），５．２３（ｍ，１Ｈ，ｇｌｙｃｅｒｏｌ Ｈ−２），４．９６〜４．６３（ｄ，２Ｈｘ３，−ＣＨ２Ｃ６Ｈ５），４．８７（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．４１（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＲ），４．１４（ｄｄ，１Ｈ，Ｊ＝６．５ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ），４．０５（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ １０．０Ｈｚ，Ｈ−２），３．９０（ｄｄ，１Ｈ，Ｈ−３），３．９０ ａｂｄ ３．６９（ｂ，２Ｈ，Ｈ−６ｐｒｏＲ ａｎｄ Ｈ−６ｐｒｏＳ），３．７６（ｂｔ，１Ｈ，Ｊ＝５．５ ａｎｄ ６．０Ｈｚ，Ｈ−４），３．７２（ｄｄ，１Ｈ，Ｊ＝５．０ ａｎｄ １１．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＳ），３．６２（ｄｄ，１Ｈ，Ｊ＝６．０ ａｎｄ １１．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ），３．４７（ｍ，１Ｈ，Ｈ−５），２．２８（ｂ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５７（ｂ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｂ，２４Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，３Ｈｘ２，Ｊ＝７．０Ｈｚ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＭＳ（ＦＡＢ）；ｍ／ｚ ｃａｌｃｄ ｆｏｒ Ｃ６２Ｈ９６Ｏ１０Ｎａ［Ｍ＋Ｎａ］＋１０２３．７．
・第１段階
化合物７ａ（合成例１の最終生成物。化合物７ｂ、７ｃ、７ｄについても同様に以下の反応に供することができ、その場合に、単糖由来部分やグリシドール由来の部分の構造が化合物７ｂ、７ｃ、７ｄ由来の構造をもつ化合物が合成される。）を出発原料とし、ホスホロアミダイト法を用いて、セリノール部分となる化合物８（合成例３にて合成法を後述する）をリン酸トリエステルを介して導入する反応を行い、化合物９を合成する。続いて、化合物９のセリノール基の保護を酸により脱保護して、化合物１０（一般式（ＸＩＩ）に相当：Ｙはベンジル基、Ｒは炭素数１５のアルキル基、Ｑは２−シアノエチル基、立体構造は図示の通り）を合成する。
・第２段階
化合物１０に対して、ホスホロアミダイト法を用いて、２−ブロモエタノールをリン酸トリエステルを介して導入する反応を行い、化合物１１（一般式（ＸＩＩＩ）に相当：Ｙはベンジル基、Ｒは炭素数１５のアルキル基、Ｑは２−シアノエチル基、ＸはＢｒ、立体構造は図示の通り）を合成する。
・第３段階
化合物１１に対して、トリメチルアミン水溶液を有機溶媒中で反応させることにより、化合物１２を合成する。
・第４段階
最後に、糖の水酸基の脱保護とアジドの還元を行うことにより、化合物１３（一般式（ＸＩＶ）に相当：Ｒは炭素数１５のアルキル基）を合成する。
化合物１０の合成：脱水処理した２口ナスフラスコに化合物７ａ（２００ｍｇ，０．２０ｍｍｏｌ）と２−シアノエチル−Ｎ，Ｎ，Ｎ’，Ｎ’−テトライソプロピルホスホロジアミジド（７２．３ｍｇ，０．２４ｍｍｏｌ，１．２ｅｑｕｉｖ）をジクロロメタン１０ｍＬに溶解させてシリンジで注入し、１Ｈ−テトラゾール（２８．０ｍｇ，０．４０ｍｍｏｌ，２．０ｅｑｕｉｖ）を加えて、室温で１．５時間攪拌させた。反応中、モレキュラーシーブ（ＭＳ３Ａ）などを加えることもできる。
次に１Ｈ−テトラゾール（９．１ｍｇ，０．１３ｍｍｏｌ，０．６５ｅｑｕｉｖ）と化合物８（２１５．７ｍｇ，０．６ｍｍｏｌ，３．０ｅｑｕｉｖ）を加え、室温で１．５時間攪拌した。続いて水（約１ｍＬ）を加えた後、ｍ−クロロ過安息香酸（リンの酸化剤として添加している。ｍＣＰＢＡ（５１．５ｍｇ，０．３０ｍｍｏｌ，１．５ｅｑｕｉｖ）を０℃で加え、室温で１０分攪拌した。反応終了後、反応溶液を１０％亜硫酸ナトリウム水溶液、重曹水、水、食塩水で洗浄し、乾燥、濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィーによって精製し、シロップ状の化合物９を得た。
この化合物９をジクロロメタン１０ｍＬに溶解し、ジクロロ酢酸（トリフルオロ酢酸でも可）を最終的に４ｍＬ加えて室温で磁気撹拌した。反応の進行状況はＴＬＣによって追跡した。反応終了後、溶液を重曹水および食塩水で洗浄し、乾燥、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、シロップ状の化合物１０を得た。収量１４１ｍｇ、収率５７％。構造の確認はＩＲ，１Ｈ−ＮＭＲ，ＦＡＢ−ＭＳで行った。
化合物１０：ＩＲ（ＫＢｒ）：２９２５，２８５６，２１１９，１７３９，１４５７，１２５３，１１５７，１０２５，７４８，７０１ｃｍ−１；１Ｈ−ＮＭＲ（５００ＭＨｚ，ｒｔ，ＣＤＣｌ３）：ｄＨ７．２５〜７．３５（ｍ，５Ｈｘ３，−Ｂｎ），５．２３（ｍ，１Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−２），４．９７，４．９１，４．８０，４，７４，４．６３，ａｎｄ ４．６１（ｄｘ６，２Ｈｘ３，−Ｂｎ），４．７５（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．３８ ａｎｄ ４．２２（ｄｄ，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−３），４．２８ ａｎｄ ４．２３（ｍｘ２，２Ｈ，Ｈ−６），４．２５（ｍ，２Ｈ，ＰＯＣＨ２ＣＨＮ３ＣＨ２ＯＨ），４．１８（ｍ，２Ｈ，ＰＯＣＨ２ＣＨ２ＣＮ），３．９６（ｔ，Ｊ＝９．０，９．０Ｈｚ，１Ｈ，Ｈ−３），３．７８（ｍ，１Ｈ，Ｈ−５），３．７３ ａｎｄ ３．５２（ｄｄｘ２，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−１），３．６９（ｍ，２Ｈ，ＰＯＣＨ２ＣＨＮ３ＣＨ２ＯＨ），３．６５（ｍ，１Ｈ，ＰＯＣＨ２ＣＨＮ３ＣＨ２ＯＨ），３．５１（ｄｄ，Ｊ＝３．５ ａｎｄ １０Ｈｚ，Ｈ１，Ｈ−２），３．４９（ｄｄ，Ｊ＝９．５ ａｎｄ ９．５Ｈｚ，１Ｈ，Ｈ−４），２．７０（ｔ，２Ｈ，ＰＯＣＨ２ＣＨ２ＣＮ），２．２９（ｍ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５９（ｂ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｓ，４８Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，６Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＭＳ（ＦＡＢ）；１２５６［Ｍ＋１］＋．
化合物１１の合成：脱水処理した２口ナスフラスコに、化合物１０（３００ｍｇ，０．２５ｍｍｏｌ）と２−シアノエチル−Ｎ，Ｎ，Ｎ’，Ｎ’−テトライソプロピルホスホロジアミジド（１１９ｍｇ，０．３８ｍｍｏｌ，１．５ｅｑｕｉｖ）をジクロロメタン１０ｍＬに溶解させてシリンジで注入し、１Ｈ−テトラゾール（３５ｍｇ，０．５０ｍｍｏｌ，２．０ｅｑｕｉｖ）を加えて、室温で１．５時間攪拌させた。次に１Ｈ−テトラゾール（１１ｍｇ，０．１６ｍｍｏｌ，０．６５ｅｑｕｉｖ）と２−ブロモエタノール（６２ｍｇ，０．５０ｍｍｏｌ，２．０ｅｑｕｉｖ）とを加え、室温で１．５時間攪拌した。
続いて水（約１ｍＬ）を加えた後、ｍ−クロロ過安息香酸（６５ｍｇ，０．３８ｍｍｏｌ，１．５ｅｑｕｉｖ）を０℃で加え、室温で１０分攪拌した。反応終了後、反応溶液を１０％亜硫酸ナトリウム水溶液、重曹水、水、食塩水で洗浄し、乾燥、濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィーによって精製し、シロップ状の化合物１１を得た。
収量２４０ｍｇ、収率７１％。構造の確認はＩＲ，１Ｈ−ＮＭＲ，ＦＡＢ−ＭＳで行った。
化合物１１：ＩＲ（ＫＢｒ）：２９２３，２８５３，２１２１，１７３８，１４９７，１４５５，１４１６，１３５９，１３３９，１２７６，１１５７，１０７２，１００９，８８９，７３７ｃｍ−１；１Ｈ−ＮＭＲ（５００ＭＨｚ，ｒｔ，ＣＤＣｌ３）：ｄＨ７．２５〜７．３５（ｍ，５Ｈｘ３，−Ｂｎ），５．２３（ｍ，１Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−２），４．９３，４．８３，４．７９，４，７４，４．７２，ａｎｄ ４．６２（ｄｘ６，２Ｈｘ３，−Ｂｎ），４．７５（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．３７ ａｎｄ〜４．２（ｄｄ，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−３），〜４．３（ｍ，２Ｈｘ２，ＰＯＣＨ２ＣＨＮ３ＣＨ２ＯＰ），〜４．２（ｍｘ２，２Ｈ，Ｈ−６），〜４．２（ｍ，２Ｈｘ２，ＰＯＣＨ２ＣＨ２ＣＮ），３．９４（ｄｄ，Ｊ＝９．０，９．５Ｈｚ，１Ｈ，Ｈ−３），３．９２（ｍ，１Ｈ，ＰＯＣＨ２ＣＨＮ３ＣＨ２ＯＰ），３．７５（ｍ，１Ｈ，Ｈ−５），３．７５ ａｎｄ ３．５２（ｄｄｘ２，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−１），３．５６（ｍ，２Ｈ，ＰＯＣＨ２ＣＨ２Ｂｒ），３．５１（ｄｄ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ１，Ｈ−２），〜３．５１（ｄｄ，１Ｈ，Ｈ−４），２．７〜２．８（ｔ，２Ｈｘ２，−ＰＯＣＨ２ＣＨ２ＣＮ），２．２９（ｍ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５９（ｂ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｓ，４８Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，６Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＦＡＢ−ＭＳ：１４７４［Ｍ＋Ｎａ］＋，１４７６［Ｍ＋２＋Ｎａ］＋．
化合物１２の合成：化合物１２（２４０ｍｇ）を１０ｍＬのアセトニトリル：イソプロパノール：クロロホルム＝１．５：１．５：０．９溶液に溶解し、３０％トリメチルアミン（目的物に対応する構造をもつアミン。最終生成物の構造に応じて選択する）水溶液を４ｍＬ加えて室温で３０時間時期攪拌した。なお、ここで、用いた溶媒の混合比は、化合物１１を溶解させ、またトリメチルアミン水溶液も溶解させるための混合比である。ＤＭＦを使用することもできる。ＤＭＦを使うと、トリメチルアミンの溶解性が上がり望ましい。
反応溶液を濃縮し、残渣をカラムクロマトグラフィーにより精製し、化合物１２を得た。収量１５７ｍｇ、収率７１％。構造の確認はＩＲ，１Ｈ−ＮＭＲ，ＦＡＢ−ＭＳで行った。
化合物１２：ＩＲ（ＫＢｒ）：３４０４，２９２３，２８５３，２１１０，１７３９，１４９６，１４５４，１３６０，１２４４，１１５８，１０８７，１０７０，１０２８，９６９，８７４，８２４，７４０ｃｍ−１；１Ｈ−ＮＭＲ（５００ＭＨｚ，ｒｔ，ＣＤＣｌ３）：ｄＨ７．２５〜７．３５（ｍ，１５Ｈ，−Ｂｎ），５．２４（ｍ，１Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−２），４．９３，４．８４，４．７９，４，７７，４．７２，ａｎｄ ４．６５（ｄｘ６，６Ｈ，−Ｂｎ），４．７８（ｄ，Ｊ＝３．５Ｈｚ，１Ｈ，Ｈ−１），４．４０ ａｎｄ ４．１８（ｄｄ，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−３），４．２８（ｍ，２Ｈ，ＰＯＣＨ２ＣＨ２Ｎ＋（ＣＨ３）３），４．２８（ｍ，４Ｈ，ＰＯＣＨ２ＣＨ（Ｎ３）ＣＨ２ＯＰ），４．１５ ａｎｄ ４．０９（ｍ ２，２Ｈ，Ｈ−６），３．９６（ｂ，１Ｈ，Ｈ−３），３．７８（ｍ，１Ｈ，Ｈ−５），３．７９ ａｎｄ ３．５５（ｄｄｘ２，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−１），３．６６（ｍ，１Ｈ，ＰＯＣＨ２ＣＨ（Ｎ３）ＣＨ２ＯＰ），３．６３（ｍ，２Ｈ，ＰＯＣＨ２ＣＨ２Ｎ＋（ＣＨ３）３），３．６２（ｂ，１Ｈ，Ｈ−４），３．５０（ｄｄ，Ｊ＝３．５ ａｎｄ １０Ｈｚ，Ｈ１，Ｈ−２），３．２１（ｓ，９Ｈ，ＰＯＣＨ２ＣＨ２Ｎ＋（ＣＨ３）３），２．２８（ｍ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５９（ｂ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｓ，４８Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，６Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＦＡＢ−ＭＳ：１０４６［Ｍ＋１］＋．
化合物１３の合成：化合物１２（１５７ｍｇ）を３０ｍＬのメタノールに溶解して酢酸２０μＬを加えた。水酸化パラジウムカーボン（１００ｍｇ）を加えて水素雰囲気下で約８時間室温で磁気撹拌した。反応後、パラジウムを濾過によりのぞき、濃縮した残渣をイアトロビーズカラムクロマトグラフィーによって精製し、化合物１３を得た。収量７７ｍｇ、収率６４％。構造の確認はＩＲ，１Ｈ−ＮＭＲ，ＦＡＢ−ＭＳで行った。
化合物１３：ＩＲ（ＫＢｒ）：３２６９，２９１８，２８５１，１７３６，１６４１，１５４９，１４６７，１４１５，１３７８，１３４３，１２２３，１１５４，１０５３，１０２２，９６８，８７１，８２５，７６５，７１９ｃｍ−１；１Ｈ−ＮＭＲ（５００ＭＨｚ，ｒｔ，ＣＤＣｌ３）：δＨ５．２４（ｍ，１Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−２），４．８１（ｄ，Ｊ＝３．５Ｈｚ，１Ｈ，Ｈ−１），４．４１ ａｎｄ ４．１６（ｄｄ，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−３），４．３１（ｍ，２Ｈ，ＰＯＣＨ２ＣＨ２Ｎ＋（ＣＨ３）３），４．２０〜４．２７（ｂ，４Ｈ，ＰＯＣＨ２ＣＨ（ＮＨ３）ＣＨ２ＯＰ），４．１５〜４．０９（ｍ ２，２Ｈ，Ｈ−６），３．９５（ｔ，１Ｈ，Ｈ−３），３．７７ ａｎｄ ３．６１（ｄｄｘ２，２Ｈ，Ｇｌｙｃｅｒｏｌ Ｈ−１），３．５７（ｍ，１Ｈ，ＰＯＣＨ２ＣＨ（ＮＨ３）ＣＨ２ＯＰ），３．６８（ｍ，２Ｈ，ＰＯＣＨ２ＣＨ２Ｎ＋（ＣＨ３）３），３．４１〜３．４８（ｂ，１Ｈ，Ｈ−４），３．４１〜３．４８（ｄｄ，Ｊ＝３．５ ａｎｄ １０Ｈｚ，Ｈ１，Ｈ−２），３．２１（ｓ，９Ｈ，ＰＯＣＨ２ＣＨ２Ｎ＋（ＣＨ３）３），２．３０（ｍ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５９（ｂ，４Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２６（ｓ，４８Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），０．８８（ｔ，６Ｈ，ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＦＡＢ−ＭＳ：１０４９［Ｍ＋１］＋．
（合成例３）
・第一段階
（Ｒ）−グリシドールの水酸基をトリチル基（トリフェニルメチル基：Ｔｒ−）で保護し（化合物１４）、ｐ−メトキシフェノールのナトリウム塩でエポキシを開環して化合物１５（一般式（ＩＩＩ）に相当）を合成する。反対の立体構造の化合物（一般式（ＩＶ）に相当）を得る場合には（Ｒ）−グリシドールに代えて、（Ｓ）−グリシドールを使用する。
・第２段階
化合物１５の２位の水酸基をメシル化、アジド化し、化合物１７を合成する。
・第３段階
化合物１７におけるｐ−メトキシフェニル基のみを弱い酸性条件化で脱保護することにより化合物８を合成する。
化合物１５の合成：脱水処理した反応系において（Ｒ）−グリシドール（５ｇ）をジクロロメタン２００ｍＬに溶解させ、トリエチルアミン４７ｍＬを加えた。トリチルクロライドを０℃で加えて約１２時間０℃で攪拌した。
反応溶液を洗浄、乾燥、濃縮し、残渣をシリカゲルカラムクロマトグラフィーで粗精製し、化合物１４とトリチルアルコールの混合物を得た。この混合化合物をＤＭＦ５００ｍＬに溶解し、ｐ−メトキシフェノールナトリウム塩５４ｇを加えて１００℃約７時間攪拌した。目的物を有機層に抽出し、洗浄、乾燥、濃縮し、得られた残査をシリカゲルカラムクロマトグラフィーで精製し、化合物１５を得た。収量２３．８ｇ、収率８０％。
化合物１５：［α］Ｄ２５−３．０（ｃ ０．１１，ＣＨＣｌ３）．ＩＲ（ＫＢｒ）１５０４，１４４８，１２２６，１０３３，８０４，７０３，６３０，５０５ｃｍ−１．１Ｈ−ＮＭＲ（２００ＭＨｚ，ｒｔ，ＣＤＣｌ３）ｄＨ７．３ ａｎｄ ７．４５（ｍｘ２，１５Ｈ，−Ｔｒ），６．８５（ｓ，４Ｈ，ｐＭＰ），４．１５（ｍ，１Ｈ，Ｈ２），４．００ ａｎｄ ４．０５（ｄｄｘ２，２Ｈ，Ｈ１），３．８（ｓ，３Ｈ，ｐＭＰ），３．３５（ｄｄ，２Ｈ，Ｈ３）．ＥＩ−ＭＳ ４４０［Ｍ＋］．
化合物１６の合成：化合物１５（２３．８ｇ）をジクロロメタン４００ｍＬに溶解し、トリエチルアミン３７．７ｍＬを加えた。この溶液を０℃に冷却しメタンスルホニルクロリド（６．２７ｍＬ）を滴下し、室温で約５時間攪拌した。溶液を洗浄、乾燥、濃縮し、残査をシリカゲルカラムクロマトグラフィーで精製し、化合物１６を得た。収量２７．４ｇ、収率９８％。
化合物１６：［ａ］Ｄ２６−６．２（ｃ ０．４６，ＣＨＣｌ３）．ＩＲ（ＫＢｒ）３０５６，２９４０，２８３２，１５０４，１３５５，１２３０，１１７４，１０９５，１０３７，９７０，９２９，８２１，７６３，７０５，６３４，５２８ｃｍ−１．１Ｈ−ＮＭＲ（２００ＭＨｚ，ｒｔ，ＣＤＣｌ３）ｄＨ７．３ ａｎｄ ７．４５（ｍｘ２，１５Ｈ，−Ｔｒ），６．８５（ｓ，４Ｈ，ｐＭＰ），５．０（ｍ，１Ｈ，Ｈ２），４．１（ｄｄｘ２，２Ｈ，Ｈ１），３．７５（ｓ，３Ｈ，ｐＭＰ），３．５（ｍ，２Ｈ，Ｈ３），３．１（ｓ，３Ｈ，−Ｍｓ）．ＥＩ−ＭＳ：５１８［Ｍ＋］．
化合物１７の合成：化合物１６（２７．４ｇ）をＤＭＦ４００ｍＬに溶解し、アジ化ナトリウム（１７．２ｇ）を加えて１００℃で約時間攪拌した。目的物を有機層に抽出し、洗浄、乾燥、濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィーによって精製した。収量２３．３ｇ、収率９２％。
化合物１７：ＩＲ（ＫＢｒ）２９４０，２０９８，１５９０，１５０２，１２２６，１０７４，１０３３，８２７，７５０，７０１，６３０，５１１ｃｍ−１．１Ｈ−ＮＭＲ（５００ＭＨｚ，ｒｔ，ＣＤＣｌ３）ｄＨ７．３ ａｎｄ ７．４５（ｍｘ２，１５Ｈ，−Ｔｒ），６．８５（ｓ，４Ｈ，ｐＭＰ），４．０５（ｄｄｘ２，２Ｈ，Ｈ１），３．８０（ｍ，１Ｈ，Ｈ２），３．７５（ｓ，３Ｈ，ｐＭＰ），３．３５（ｓ，２Ｈ，Ｈ３）．ＥＩ−ＭＳ ４６５［Ｍ＋］．
化合物８の合成：化合物１７（２３．３ｇ）をＣＨ２ＣＮ：ＣＨ３ＯＨ：Ｈ２Ｏ＝４：１：１の溶液７５０ｍＬに溶解し、ｓｉｌｖｅｒ（ＩＩ）ｄｉｐｉｃｏｌｉｎａｔｅ（１１０．６ｇ）を加えて約３時間室温で攪拌した。反応終了後、セライト濾過によりピコリン酸を除去し、目的物を有機層に抽出し、洗浄、乾燥、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにより精製した。収量９．０ｇ、収率５０％。
化合物８：［ａ］Ｄ２６＋６．３５（ｃ １．０，ＣＨＣｌ３）．ＩＲ（ＫＢｒ）３４２４，３０６０，２９３１，２８７７，２１００，１４８８，１３２８，１２７０，１２２０，１０８１，１０３１，７５９，７０１，６３４ｃｍ−１．１Ｈ−ＮＭＲ（５００ＭＨｚ，ｒｔ，ＣＤＣｌ３）ｄ７．３ ａｎｄ ７．４５（ｍｘ２，１５Ｈ，−Ｔｒ），３．６０（ｍ，１Ｈ，Ｈ２），３．５（ｍ，２Ｈ，Ｈ１），３．２５（ｄｄ，２Ｈ，Ｈ３）．なお、光学純度については、不斉誘導体化試薬ＴＢＭＢカルボン酸を用いて不斉誘導体化し、その１Ｈ−ＮＭＲのスペクトルから＞９９％ｅｅであることを確認した。
（合成例４）
上述した合成方法のほか以下の方法によっても目的の糖脂質誘導体を製造することができる。具体的には化合物４ａ及び４ｂから化合物７に至る合成経路を以下の方法に置き換えるものである。
化合物１９から化合物２０：イソプロピリデン基を酸性条件で選択的に脱保護する反応である。糖の６位のシリル基も酸性条件によって脱離するため、シリル基の中ではもっとも酸性条件に強いものの一つであるＴＢＤＰＳ基（ｔｅｒｔ−ｂｕｔｙｌｄｉｐｈｅｎｙｌｓｉｌｙｌ基）を用いることによりグリセロール部分に保護基として導入したイソプロピリデン基との差異を発現させた。
また、適当な酸性条件を実現する試薬を検討したところオルガノ株式会社製のＡｍｂｅｒｌｙｓｔ１５が有効であり、これを用いることによってイソプロピリデン基のみを選択的に脱保護することができた。
化合物２１から化合物７：ＴＢＤＰＳ基をフッ化物イオンにより脱保護する反応である。上記のようにＴＢＤＰＳ基は酸性条件による加水分解でも脱保護が可能である。しかし、ＴＢＤＰＳ基の脱保護にはかなり強い酸性条件が要求される。化合物２１には不安定な脂肪酸部分のアシル基があり、ＴＢＤＰＳ基を脱保護するような強い酸性条件ではこのアシル基部分が耐えられない可能性があった。よって、フッ化物イオンによる脱保護を検討した。
シリル系保護基の脱保護にもっともよく利用されるのはＴＢＡＦ（ｔｅｔｒａｂｕｔｙｌａｍｍｏｎｉｕｍ ｆｌｕｏｒｉｄｅ）である。ＴＢＡＦ意外にも、よりマイルドな試薬としてＴＢＡＨＦ（Ｔｒｉｂｕｔｙｌａｍｉｎｅ Ｈｙｄｒｏｆｌｕｏｒｉｄｅ，Ｒｅｆ．Ｆｕｒｕｓａｗａ，Ｋ．Ｔｈｅ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ ｏｆ Ｊａｐａｎ，１９８９，５０９．）が開発されており、ＴＢＡＨＦを化合物２１に対して適用・検討したところ、ＴＢＡＦを用いた場合よりも副生成物が生じることなく反応はほぼ完全に進行し、化合物７を得ることができた。
化合物１８の合成：
化合物３（２．０ｇ）から合成例１に記述の方法により合成した粗精製物４−ａ＋４−ｂをＤＭＦ（５０ｍＬ）に溶解し、１００℃付近まで加熱した。ＣｓＯＡｃ（３．９０ｇ）を加え、１００℃で約３時間攪拌した。目的物を酢酸エチル層に抽出し、食塩水で洗浄、乾燥、濃縮した。次に得られた残査をメタノール（１００ｍＬ）に溶解し、Ｋ２ＣＯ３（６１７ｍｇ）を加えて約１時間時期攪拌した。反応終了後、溶液をアンバーリストにより中和した後、アンバーリストを濾過により取り除いてろ液を濃縮した。次に得られた残査をアセトン（３００ｍＬ）に溶解し、Ｐ−トルエンスルホン酸（ｐ−ＴｓＯＨ；１．０ｇ）を加えて室温で約３０分磁気攪拌した。溶液にトリエチルアミンを加えて反応を停止した後、３分の１程度濃縮して、残りの溶液を分液洗浄、乾燥、濃縮し、残査をシリカゲルカラムクロマトグラフィーで精製した。収量１．４０ｇ、収率６１％（化合物３から４ステップ）。白色ワックス状。
［α］Ｄ ２８＝＋３０．３（ｃ １．０，ＣＨＣｌ３）；ＩＲ（ＫＢｒ ｆｉｌｍ）ν／ｃｍ−１：３４８２，３３１４，３０３０，２９８５，２９２０，２８５３，１６４２，１４５５，１３７０，１２１２，１１５６，１０７０，１０２８，９１２，８３９，７３８，６９８，６１４，５１６，５４７，４１７；１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）δＨ７．４０〜７．２５（ｍ，５Ｈｘ３，−ＣＨ２Ｃ６ Ｈ ５ ），４．９８〜４．６３（ｄ，２Ｈｘ３，−ＣＨ ２ Ｃ６Ｈ５），４．８２（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．３６（ｔ，１Ｈ，Ｊ＝６．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−２），４．０７ ａｎｄ ３．７３（ｄｄ，１Ｈｘ２，Ｊ＝６．５ ａｎｄ ７．５，Ｊ＝６．０ ａｎｄ ７．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ ｏｒ Ｈ−１ｐｒｏＳ），３．９８（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．７６ ａｎｄ ３．６９（ｍ，２Ｈ，Ｈ−６ｐｒｏＲ ａｎｄ ｐｒｏＳ），〜３．７０（ｍ，１Ｈ，Ｈ−５），３．６０ ａｎｄ ３．５５（ｄｄ，１Ｈｘ２，Ｊ＝５．５ ａｎｄ １０．５，Ｊ＝６．０ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ ｏｒ Ｈ−３ｐｒｏＲ），３．５２（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−４），３．５１（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），１．４３ ａｎｄ １．３７（ｓ，３Ｈｘ２，ｉｓｏｐｒｏｐｙｌ）；ＨＲＭＳ（ＦＡＢ）：ｍ／ｚ ｃａｌｃｄ．ｆｏｒ Ｃ３３Ｈ４０Ｏ８Ｎａ［Ｍ＋Ｎａ＋］５８７．２６２１；ｆｏｕｎｄ ５８７．２６３９．
化合物７の合成
化合物１８（１．４０ｇ）をピリジン（２０ｍＬ）に溶解しジメチルアミノピリジン（ＤＭＡＰ）を触媒量加えた溶液に、氷浴中でＴＢＤＰＳＣｌ（１．０８ｍＬ）を滴下して加え、室温で約１７時間時期攪拌した。メタノールを加えて試薬を分解した後、トルエンとの共沸操作によりピリジンを除去した残査を１Ｎ ＨＣｌ ａｑ．ＮａＨＣＯ３ａｑ．ＮａＣｌａｑ．で順次洗浄し、乾燥、濃縮し、シロップ状の化合物１９を得た。
次にこの化合物１９をクロロホルム（２５ｍＬ）−メタノール（１２ｍＬ）混合溶媒に溶解し、アンバーリスト（Ａｍｂｅｒｌｙｓｔ１５，オルガノ株式会社製）（７００ｍｇ）を加えて室温で磁気攪拌した。濾過によりＡｍｂｅｒｌｙｓｔを取り除き、ろ液をトリエチルアミンで中和後、濃縮して、シロップ状の化合物２０を得た。次に化合物２０をピリジン（２０ｍＬ）に溶解し、触媒量のＤＭＡＰを加え、氷浴中にてパルミチン酸Ｃｌ（２．０２ｍＬ）を加え、室温で約５時間磁気攪拌した。メタノールを加えることにより試薬を分解した後、共沸操作によりピリジンを除去した残査を１Ｎ ＨＣｌ ａｑ． ＮａＨＣＯ３ａｑ．ＮａＣｌ ａｑ．で洗浄、乾燥、濃縮し、シロップ状の化合物２１を得た。次に化合物２０をＴＨＦ（２００ｍＬ）に溶解し、調整した２Ｍ ＴＢＡＨＦ／ＴＨＦ ｓｏｌｕｔｉｏｎ（全量２００ｍＬ）を加え、室温で時期攪拌した。反応の進行状況を確認しながら適宜ＴＢＡＨＦ溶液を追加した。反応は２４時間で終了し、目的物を酢酸エチル層に抽出してＮａＨＣＯ３ａｑ．ＮａＣｌ ａｑ．で洗浄、乾燥、濃縮し、残査をシリカゲルカラムクロマトグラフィーで精製して白色ろう状の化合物７を得た。収量１．７０ｇ（α体のみの分取量）、収率６８％（化合物１８より４ステップ）。
化合物１９（無色シロップ状）：［α］Ｄ ３１＝＋１９．１（ｃ １．０，ＣＨＣｌ３）；ＩＲ（ＫＢｒ ｆｉｌｍ）ν／ｃｍ−１：３０３１，２９８６，２９２９，２８５８，１７３３，１４５５，１４２７，１３６５，１２５６，１２１２，１１５５，１１０７，８２５，７３６，７０１，６１３，５０５；１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）δＨ７．６５〜７．７，７．２４〜７．４３，７．２５（ｍ，５Ｈｘ５，−ＣＨ２Ｃ６ Ｈ ５ ａｎｄ ｄｉｐｈｅｎｙｌ ｇｒｏｕｐ ｏｆ ＴＢＤＦＰＳ），４．９８〜４．５９（ｄ，２Ｈｘ３，−ＣＨ ２ Ｃ６Ｈ５），４．９０（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．３４（ｔ，１Ｈ，Ｊ＝６．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−２），３．９８（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．８６（ｄ，１Ｈｘ２，Ｈ−６ ｐｒｏＲ ａｎｄ ｐｒｏｓ），〜３．７０（ｍ，１Ｈ，Ｈ−５），４．０４ ａｎｄ ３．６８（ｄｄ，１Ｈｘ２，Ｊ＝６．０ ａｎｄ ８．０，Ｊ＝２．５ ａｎｄ ８．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ ｏｒ Ｈ−１ｐｒｏＳ），３．６２（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ １０．０Ｈｚ，Ｈ−４），３．５７ ａｎｄ ３．５６（ｄｄ，１Ｈｘ２，Ｊ＝６．０ ａｎｄ １１．０，Ｊ＝５．０ ａｎｄ １１．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ ｏｒ Ｈ−３ｐｒｏＲ），３．５６（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），１．４０ ａｎｄ １．３４（ｓ，３Ｈｘ２，ｉｓｏｐｒｏｐｙｌ），１．０４（ｓ，９Ｈ，ｔ−ｂｕｔｙｌ ｇｒｏｕｐ ｏｆ ＴＢＤＰＳ）；ＨＲＭＳ（ＦＡＢ）：ｍ／ｚ ｃａｌｃｄ．ｆｏｒ Ｃ４９Ｈ５８Ｏ８ＳｉＮａ［Ｍ＋Ｎａ＋］８２５．３７９９；ｆｏｕｎｄ ８２５．３７９８．
化合物２０（無色シロップ状）：［α］Ｄ ３１＝＋１５．３（ｃ １．０，ＣＨＣｌ３）；ＩＲ（ＫＢｒ ｆｉｌｍ）ν／ｃｍ−１：３４３２，３３０１，３０３２，２９２８，２８５８，１７３３，１４５４，１４２６，１３５９，１２１０，１１５６，１０６９，８２３，７３６，７００，６１５，５０４，４１９；１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）δＨ７．６５〜７．７，７．２４〜７．４３，７．２５（ｍ，５Ｈｘ５，−ＣＨ２Ｃ６ Ｈ ５ ａｎｄ ｄｉｐｈｅｎｙｌ ｇｒｏｕｐ ｏｆ ＴＢＤＦＰＳ），４．９３〜４．５９（ｄ，２Ｈｘ３，−ＣＨ ２ Ｃ６Ｈ５），４．７６（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），３．９８（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−３），３．８５（ｍ，１Ｈｘ２，Ｈ−６ ｐｒｏＲ ａｎｄ ｐｒｏｓ），〜３．７５（ｍ，１Ｈ，Ｈ−５），３．７９ ａｎｄ ３．４３（ｄｄｘ２，１Ｈｘ２，Ｊ＝３．５ ａｎｄ １０．５，Ｊ＝７．０ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＲ ｏｒ Ｈ−３ｐｒｏＳ），３．６３（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５０Ｈｚ，Ｈ−４），〜３．７０ ａｎｄ〜３．５８（ｍｘ２，１Ｈｘ２，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＳ ｏｒ Ｈ−１ｐｒｏＲ），３．５６（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），２．２７（ｄｄ，１Ｈ，Ｊ＝５．５ ａｎｄ ７．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−２），１．０４（ｓ，９Ｈ，ｔ−ｂｕｔｙｌ ｇｒｏｕｐ ｏｆ ＴＢＤＰＳ）；ＨＲＭＳ（ＦＡＢ）：ｍ／ｚ ｃａｌｃｄ．ｆｏｒ Ｃ４６Ｈ５４Ｏ８ＳｉＮａ［Ｍ＋Ｎａ＋］７８５．３４８６；ｆｏｕｎｄ ７８５．３４８３．
化合物２１（無色シロップ状）：［α］Ｄ ２７＝＋１４．６（ｃ １．０，ＣＨＣｌ３）；ＩＲ（ＫＢｒ ｆｉｌｍ）ν／ｃｍ−１：３０３１，２９２５，２８５４，１７４３，１４５９，１４２７，１３６１，１１５７，１１０８，８２３，７３６，７０１，６１１，５０４；１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）δＨ７．６５〜７．７，７．２４〜７．４３，７．２５（ｍ，５Ｈｘ５，−ＣＨ２Ｃ６ Ｈ ５ ａｎｄ ｄｉｐｈｅｎｙｌ ｇｒｏｕｐ ｏｆ ＴＢＤＦＰＳ），５．２３（ｍ，１Ｈ，ｇｌｙｃｅｒｏｌ Ｈ２），４．９４〜４．６１（ｄ，２Ｈｘ３，−ＣＨ ２ Ｃ６Ｈ５），４．７９（ｄ，１Ｈ，Ｊ＝３．５Ｈｚ，Ｈ−１），４．３９（ｄｄ，１Ｈ，Ｊ＝４．０ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＳ），４．１５（ｄｄ，１Ｈ，Ｊ＝６．０ ａｎｄ １２．０Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−１ｐｒｏＲ），３．９７（ｄｄ，１Ｈ，Ｊ＝９．０ ａｎｄ ９．５Ｈｚ，Ｈ−３），〜３．８５（ｍ，１Ｈ，Ｈ−５），〜３．８５ ａｎｄ〜３．６７（ｍ，１Ｈｘ２，Ｈ−６ｐｒｏＲ ａｎｄ ｐｒｏＳ），３．７２（ｄｄ，１Ｈ，Ｊ＝６．０ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＲ），〜３．６７（ｍ，１Ｈ，Ｈ−４），３．５５（ｄｄ，１Ｈ，Ｊ＝３．５ ａｎｄ ９．５Ｈｚ，Ｈ−２），３．５３（ｄｄ，１Ｈ，Ｊ＝５．５ ａｎｄ １０．５Ｈｚ，ｇｌｙｃｅｒｏｌ Ｈ−３ｐｒｏＳ），２．２４（ｍ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．５４（ｂ，２Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．２５（ｂ，２４Ｈｘ２，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３），１．０４（ｓ，９Ｈ，ｔ−ｂｕｔｙｌ ｇｒｏｕｐ ｏｆ ＴＢＤＰＳ），０．８８（ｔ，３Ｈｘ２，Ｊ＝７．０Ｈｚ，−ＯＣＯＣＨ２ＣＨ２（ＣＨ２）１２ＣＨ３）；ＨＲＭＳ（ＦＡＢ）：ｍ／ｚ ｃａｌｃｄ．ｆｏｒ Ｃ７８Ｈ１１４Ｏ１０ＳｉＮａ［Ｍ＋Ｎａ＋］１２６１．８０７９；ｆｏｕｎｄ １２６１．８０８７．
(Synthesis Example 1)
D-glucose (corresponding to the compound of general formula (VIII): from D-glucose (methylated at the 1-position OH group) by the method shown in the following reaction formula: the monosaccharide part is derived from glucose, and the part derived from glycidol is ( S) -glycidol, Y is a benzyl group, and R is an alkyl group having 15 carbon atoms). The outline of the reaction is described below.
In addition, compounds 7b, 7c, and 7d can be synthesized by changing the compounds used in some of the following steps.
・ First stage
Methyl glucoside is used as a starting material, and the 2, 3, 4, and 6 positions are protected with an ether-based protecting group. By dissolving this compound in acetic anhydride and adding an acid catalyst thereto, the hydroxyl groups at the 1- and 6-positions are acetylated. Further, only the acetyl group at the 1-position is deprotected to obtain compound 3 (corresponding to the donor compound in novel synthesis method 1 of (1) described above). Here, when galactose is employed as a donor compound, a final product having a corresponding three-dimensional structure is obtained (see the following reaction formula).
・ Second stage
The novel synthesis method 1 using compound 3 as a donor compound and optically active (S) -glycidol as an acceptor compound is performed to synthesize compound 4 having a key steric skeleton. Here, when (R) -glycidol is adopted as an acceptor compound, a final product having a corresponding steric structure is obtained (see the following reaction formula).
・ 3rd stage
Compound 4 (mixture of compound 4-a and compound 4-b; equivalent to compound of general formula (X): OH group at 6-position is acetyl group, OH group at 2-4 position is benzyl group, X is Br) After deprotecting the protecting group at the 6-position hydroxyl group of the sugar, a fatty acid is introduced into the sn-1 position of glycerol.
・ Fourth stage
Compound 7a is synthesized by protecting the 6-position hydroxyl group (primary) of the sugar of compound 5 with a TBDMS group, introducing a fatty acid into the hydroxyl group (secondary) at the sn-2 position of glycerol, and then deprotecting the TBDMS group. To do.
(Synthesis)
Synthesis of Compound 3: Methyl glucoside (10 g) was dissolved in 300 mL of DMF, NaH (12.4 g) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. Thereafter, BnBr (53.9 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, methanol was added to decompose the reagent, the target product was extracted into the organic layer, washed, dried and concentrated, and the residue was purified by chromatography using a silica gel column to obtain Compound 1.
Compound 1 was dissolved in acetic anhydride (140 mL), sulfuric acid (120 μL) was added at 0 ° C., and the mixture was stirred at room temperature for about 3 hours. After the reaction, the solution was neutralized, the target product was extracted into an organic layer, washed, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 2.
Compound 2 was dissolved in THF (100 mL), benzylamine (8.9 g) was added, and the mixture was stirred at room temperature for about 2 days. The solution was washed, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 3. Yield 16.1 g (α: β = 2: 1), syrupy, 59% yield (3 steps).
1H-NMR (500 MHz, rt, CDCl3): A-anomer, dH7.25~7.35 (m, 5Hx3, -Bn), 5.20 (d, 1H, J = 3.5 Hz, H-1), 4.55~5.00 (d, 2Hx3, -CH2Ph), 4.27 (m, 2H, H-6), 4.10 (m, 1H, H-5), 4.00 (dd, 1H, J = 9.0 and 9.5 Hz, H-3) ), 3.56 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 3.50 (dd, 1H, J = 9.0 and 10.0 Hz, H-4), 2. 03 (s, 3H, -OAc); b-anomer, dH7.25~7.35 (m, 5Hx3, -Bn), 4.74 (d, 1H, J = 8.0 Hz, H-1), 4.55~5.00 (d, 2Hx3, -CH2Ph), 4.34 and 4.19 (dd, 2H, H-6), 3.96 (dd, 1H, J = 9.0 and 9.5 Hz, H-3), 3.55 (dd, 1H) , J = 8.0 and 9.5 Hz, H-2), 3.41 (dd, 1H, J = 7.5 and 9.0 Hz, H-4), 2.05 (s, 3H, -OAc) .
Synthesis of Compound 4: Compound 3 (5.0 g) was dissolved in DMF and Ph3P (7.9 g) and CBr4(10 g) was added at 0 ° C., and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the target product was extracted with ethyl acetate, and this solution was washed, dried and concentrated.
Ph contained in residue3P = 0 was crystallized from diethyl ether-hexane and removed by filtration. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography. Depending on the time and conditions, compound 4-b in which a part of the epoxy of compound 4-a was ring-opened with a bromoanion was produced. This was used in the next reaction as a mixture.
Synthesis of Compound 5: The obtained residue was dissolved in methanol (200 mL), and K2CO3(1.5 g) was added and stirred for about 3 hours. After completion of the reaction, the solution was washed, dried and concentrated, and the resulting residue was dried in a vacuum atmosphere. Next, a solution obtained by dissolving the residue in 2 mL of DMF was added dropwise to a reaction solution in which palmitic acid Cs (36 g) was added to DMF (200 mL) and heated to 100 ° C. to 110 ° C. Stir for 1 hour.
After completion of the reaction, the solution was cooled and ethyl acetate was added to precipitate unreacted palmitic acid Cs, which was removed by filtration. The obtained filtrate was washed, dried and concentrated, and the obtained residue was purified by a silica gel column. Yield 3.87 g, yield 50% (3 steps from compound 3).
1H-NMR (500 MHz, CDCl3; DH7.40~7.23 (m, 5Hx3, -CH2C6H5), 4.96~4.64 (d, 2Hx3, -CH2C6H5), 4.73 (d, 1H, J = 3.5 Hz, H-1), 4.18 (dd, 1H, J = 4.5 and 12 Hz, glycerol H-1)proS), 4.13 (dd, 1H, J = 5.5 and 11.5 Hz, glycerol H-1proR), 4.05 (b, 1H, glycerol H-2), 3.98 (dd, 1H, J = 9.5 and 9.5 Hz, H-3), 3.76 (dd, 1H, J = 4) 0.0 and 10.5 Hz, glycerol H-3proR), 3.65~3.80 (b, 2H, H-6ProR and H-6proS), 3.68 (m, 1H, H-5), 3.52 (dd, 1H, J = 9.0 and 9.5 Hz, H-4), 3.51 (dd, 1H, J = 3. 5 and 9.5 Hz, H-2), 3.40 (dd, 1H, J = 7.5 and 10.5 Hz, glycerol H-3proS), 2.34 (t, 2H, J = 7.5 Hz, -OCOCH2CH2(CH2)12CH3), 1.62 (b, 2H, -OCOCH2CH2(CH2)12CH3), 1.25 (b, 24H, -OCOCH2CH2(CH2)12CH3), 0.88 (t, 3H, J = 7.0 Hz, -OCOCH2CH2(CH2)12CH3).
Synthesis of Compound 7a: Compound 5 (2.3 g) was dissolved in 140 mL of pyridine, N, N-dimethylaminopyridine (DMAP: catalytic amount) was added, TBDMSCl (676 mg) was further added, and the mixture was stirred at room temperature for about 12 hours. . After completion of the reaction, methanol was added to the solution and stirred for 12 hours to decompose the reagent, followed by concentration, and the residue was roughly purified by silica gel column chromatography. The obtained syrup was dissolved in pyridine (40 mL), DMAP (catalytic amount) was added, Cl palmitate (1.35 mL) was added dropwise, and the mixture was stirred at room temperature for about 3 hours.
After completion of the reaction, methanol was added to the solution and stirred for 12 hours to decompose the reagent and then concentrated. A 30% trifluoroacetic acid-methanol: chloroform = 2: 1 solution (30 mL) was added to the residue, and the mixture was stirred for 30 minutes at room temperature. After completion of the reaction, the solution was concentrated, and the residue was purified by chromatography using a silica gel column. Yield 1.96 g, 65% yield.
[Α]D 22= +23.0 (c 0.27, CHCl3).1H-NMR (500 MHz, CDCl3; DH7.40~7.23 (m, 5Hx3, -CH2C6H5), 5.23 (b, 1H, glycerol H-2), 4.96.~4.64 (d, 2Hx3, -CH2C6H5), 4.70 (d, 1H, J = 3.5 Hz, H-1), 4.40 (dd, 1H, J = 4.0 and 12.0 Hz, glycerol H-1proS), 4.19 (dd, 1H, J = 6.0 and 12.0 Hz, glycerol H-1).proR), 3.96 (dd, 1H, J = 9.5 and 9.5 Hz, H-3), 3.72 (dd, 1H, J = 5.5 and 10.5 Hz, glycerol H-3)proR), 3.72 and 3.66 (b, 2H, H-6)ProR and H-6proS), 3.65 (m, 1H, H-5), 3.54 (dd, 1H, J = 5.5 and 10.5 Hz, glycerol H-3)proS), 3.50 (dd, 1H, J = 9.5 and 10.0 Hz, H-4), 3.49 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 2. 29 (m, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.58 (b, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.25 (b, 24Hx2, -OCOCH2CH2(CH2)12CH3), 0.88 (t, 3Hx2, J = 7.0 Hz, -OCOCH2CH2(CH2)12CH3). MS (FAB); 1024 [M + Na]+.
Synthesis of Compound 7b: Compound 7b (in the general formula (VII), the monosaccharide moiety is derived from glucose, the glycidol-derived moiety is derived from (R) -glycidol, Y is a benzyl group, and R is an alkyl group having 15 carbon atoms) ) Was synthesized using (R) -glycidol in the reaction of synthesizing compounds 3 to 4. Other reactions were carried out in the same manner as for compound 7a. The final yield was similar.
7b: [α]D32= + 18.5 (c 1.0, CHCl3); IR (KBr film): 3452, 2924, 2854, 1739, 1586, 1455, 1296, 1159, 1095, 710 cm￣1;1H-NMR (500 MHz, CDCl3): ΔH7.40 to 7.23 (m, 5Hx3, -CH2C6H5), 5.23 (b, 1H, glycerol H-2), 4.96 to 4.63 (d, 2Hx3, -CH2C6H5), 4.75 (d, 1H, J = 3.5 Hz, H-1), 4.38 (dd, 1H, J = 3.5 and 12.0 Hz, glycerol H-3)proR), 4.21 (dd, 1H, J = 6.5 and 12.0 Hz, glycerol H-3)proS), 3.96 (dd, 1H, J = 9.5 and 9.5 Hz, H-3), 3.73 (dd, 1H, J = 6.0 and 11.0 Hz, glycerol H-1)proS), 3.76 abd 3.66 (b, 2H, H-6)ProR and H-6proS), 3.65 (m, 1H, H-5), 3.57 (dd, 1H, J = 5.5 and 11.0 Hz, glycerol H-1proR), 3.51 (dd, 1H, J = 9.5 and 10.0 Hz, H-4), 3.50 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 2. 29 (b, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.59 (b, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.25 (b, 24Hx2, -OCOCH2CH2(CH2)12CH3), 0.88 (t, 3Hx2, J = 7.0 Hz, -OCOCH2CH2(CH2)12CH3); MS (FAB): m / z calcd for C62H96O10Na [M + Na]+1023.7.
Synthesis of Compound 7c: Compound 7c (In General Formula (VII), the monosaccharide moiety is derived from galactose, the glycidol-derived moiety is derived from (S) -glycidol, Y is a benzyl group, and is a C15 alkyl group) Was synthesized using methyl galactoside as a starting material. Other reactions were carried out in the same manner as for compound 7a. The final yield was similar.
7c: [α]D33= + 18.8 (c 0.9, CHCl3); IR (KBr film): 3432, 2923, 2853, 1740, 1586, 1460, 1350, 1153, 1054, 697 cm-1;1H-NMR (500 MHz, CDCl3): ΔH7.40 to 7.23 (m, 5Hx3, -CH2C6H5), 5.25 (b, 1H, glycerol H-2), 4.96 to 4.63 (d, 2Hx3, -CH2C6H5), 4.83 (d, 1H, J = 3.5 Hz, H-1), 4.34 (dd, 1H, J = 3.5 and 12.0 Hz, glycerol H-1proS), 4.18 (dd, 1H, J = 6.0 and 12.0 Hz, glycerol H-1).proR), 4.05 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 3.90 (dd, 1H, H-3), 3.89 and 3.68 (b, 2H, H-6proR and H-6proS), 3.73 (bt, 1H, J = 5.5 and 6.0 Hz, H-4), 3.71 (dd, 1H, J = 5.5 and 10.5 Hz, glycerol H-3)proR), 3.58 (dd, 1H, J = 6.0 and 10.5 Hz, glycerol H-3)proS), 3.47 (m, 1H, H-5), 2.28 (m, 2Hx2, -OCOCH)2CH2(CH2)12CH3), 1.56 (b, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.25 (b, 24Hx2, -OCOCH2CH2(CH2)12CH3), 0.88 (t, 3Hx2, J = 7.0 Hz, -OCOCH2CH2(CH2)12CH3); MS (FAB): m / z calcd for C62H96O10Na [M + Na]+1023.7.
Synthesis of Compound 7d: Compound 7d (in the general formula (VII), the monosaccharide moiety is derived from galactose, the glycidol-derived moiety is derived from (R) -glycidol, Y is a benzyl group, and R is an alkyl group having 15 carbon atoms) ) Was synthesized using (R) -glycidol in a reaction of synthesizing methyl galactoside and compounds 3 to 4 as starting materials. Other reactions were carried out in the same manner as for compound 7a. The final yield was similar.
7d: [α]D33+8.42 (c 1.0, CHCl3); IR (KBr film): 3411, 2924, 2853, 1741, 1587, 1460, 1350, 1150, 1054, 697 cm-1;1H-NMR (500 MHz, CDCl3): ΔH7.40 to 7.23 (m, 5Hx3, -CH2C6H5), 5.23 (m, 1H, glycerol H-2), 4.96 to 4.63 (d, 2Hx3, -CH2C6H5), 4.87 (d, 1H, J = 3.5 Hz, H-1), 4.41 (dd, 1H, J = 3.5 and 12.0 Hz, glycerol H-3)proR), 4.14 (dd, 1H, J = 6.5 and 12.0 Hz, glycerol H-3proS), 4.05 (dd, 1H, J = 3.5 and 10.0 Hz, H-2), 3.90 (dd, 1H, H-3), 3.90 abd 3.69 (b, 2H, H-6proR and H-6proS), 3.76 (bt, 1H, J = 5.5 and 6.0 Hz, H-4), 3.72 (dd, 1H, J = 5.0 and 11.0 Hz, glycerol H-1proS), 3.62 (dd, 1H, J = 6.0 and 11.0 Hz, glycerol H-1proR), 3.47 (m, 1H, H-5), 2.28 (b, 2Hx2, -OCOCH)2CH2(CH2)12CH3), 1.57 (b, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.25 (b, 24Hx2, -OCOCH2CH2(CH2)12CH3), 0.88 (t, 3Hx2, J = 7.0 Hz, -OCOCH2CH2(CH2)12CH3MS (FAB); m / z calcd for C62H96O10Na [M + Na]+1023.7.
・ First stage
Compound 7a (final product of Synthesis Example 1. Compounds 7b, 7c, and 7d can be similarly subjected to the following reaction. In this case, the structure of the monosaccharide-derived moiety or the glycidol-derived moiety is the compound 7b, 7c. And a compound having a structure derived from 7d is synthesized as a starting material, and phosphoryl ester of compound 8 (the synthesis method will be described later in Synthesis Example 3), which becomes a serinol moiety, using the phosphoramidite method. The compound 9 is synthesized by carrying out the reaction introduced via Subsequently, the protection of the serinol group of compound 9 was deprotected with an acid to give compound 10 (corresponding to general formula (XII): Y is a benzyl group, R is an alkyl group having 15 carbon atoms, Q is a 2-cyanoethyl group, The three-dimensional structure is synthesized as shown).
・ Second stage
The compound 10 is subjected to a reaction by introducing 2-bromoethanol via a phosphoric acid triester using a phosphoramidite method, and the compound 11 (corresponding to the general formula (XIII): Y is a benzyl group, R is A C15 alkyl group, Q is a 2-cyanoethyl group, X is Br, and the three-dimensional structure is as shown).
・ 3rd stage
Compound 12 is synthesized by reacting compound 11 with an aqueous trimethylamine solution in an organic solvent.
・ Fourth stage
Finally, compound 13 (corresponding to general formula (XIV): R is an alkyl group having 15 carbon atoms) is synthesized by deprotecting the hydroxyl group of the sugar and reducing the azide.
Synthesis of Compound 10: Compound 7a (200 mg, 0.20 mmol) and 2-cyanoethyl-N, N, N ′, N′-tetraisopropylphosphorodiamidide (72.3 mg, 0.20 mmol) were added to a dehydrated two-necked eggplant flask. 24 mmol, 1.2 equiv) was dissolved in 10 mL of dichloromethane and injected with a syringe, 1H-tetrazole (28.0 mg, 0.40 mmol, 2.0 equiv) was added, and the mixture was stirred at room temperature for 1.5 hours. During the reaction, molecular sieve (MS3A) or the like can be added.
Next, 1H-tetrazole (9.1 mg, 0.13 mmol, 0.65 equiv) and compound 8 (215.7 mg, 0.6 mmol, 3.0 equiv) were added, and the mixture was stirred at room temperature for 1.5 hours. Subsequently, water (about 1 mL) was added, and then m-chloroperbenzoic acid (added as an oxidizing agent for phosphorus. MCPBA (51.5 mg, 0.30 mmol, 1.5 equiv) was added at 0 ° C. After completion of the reaction, the reaction solution was washed with 10% aqueous sodium sulfite solution, aqueous sodium bicarbonate, water and brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain a syrup. A compound 9 was obtained.
This compound 9 was dissolved in 10 mL of dichloromethane, and finally 4 mL of dichloroacetic acid (or trifluoroacetic acid was acceptable) was added and magnetically stirred at room temperature. The progress of the reaction was followed by TLC. After completion of the reaction, the solution was washed with aqueous sodium hydrogen carbonate and brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain syrupy compound 10. Yield 141 mg, 57% yield. Confirmation of the structure is IR,1H-NMR and FAB-MS were used.
Compound 10: IR (KBr): 2925, 2856, 2119, 1739, 1457, 1253, 1157, 1025, 748, 701 cm-1;1H-NMR (500 MHz, rt, CDCl3): DH7.25~7.35 (m, 5Hx3, -Bn), 5.23 (m, 1H, Glycerol H-2), 4.97, 4.91, 4.80, 4, 74, 4.63, and 4.61 (Dx6, 2Hx3, -Bn), 4.75 (d, 1H, J = 3.5 Hz, H-1), 4.38 and 4.22 (dd, 2H, Glycerol H-3), 4.28 and 4.23 (mx2, 2H, H-6), 4.25 (m, 2H, POCH2CHN3CH2OH), 4.18 (m, 2H, POCH2CH2CN), 3.96 (t, J = 9.0, 9.0 Hz, 1H, H-3), 3.78 (m, 1H, H-5), 3.73 and 3.52 (ddx2, 2H) , Glycerol H-1), 3.69 (m, 2H, POCH2CHN3CH2OH), 3.65 (m, 1H, POCH2CHN3CH2OH), 3.51 (dd, J = 3.5 and 10 Hz, H1, H-2), 3.49 (dd, J = 9.5 and 9.5 Hz, 1H, H-4), 2.70. (T, 2H, POCH2CH2CN), 2.29 (m, 4H, OCOCH2CH2(CH2)12CH3), 1.59 (b, 4H, OCOCH2CH2(CH2)12CH3), 1.25 (s, 48H, OCOCH2CH2(CH2)12CH3), 0.88 (t, 6H, OCOCH2CH2(CH2)12CH3); MS (FAB); 1256 [M + 1]+.
Synthesis of Compound 11: Compound 10 (300 mg, 0.25 mmol) and 2-cyanoethyl-N, N, N ′, N′-tetraisopropylphosphorodiamidide (119 mg, 0.38 mmol) were added to a dehydrated two-necked eggplant flask. , 1.5equiv) was dissolved in 10 mL of dichloromethane and injected with a syringe, 1H-tetrazole (35 mg, 0.50 mmol, 2.0equiv) was added, and the mixture was stirred at room temperature for 1.5 hours. Next, 1H-tetrazole (11 mg, 0.16 mmol, 0.65 equiv) and 2-bromoethanol (62 mg, 0.50 mmol, 2.0 equiv) were added, and the mixture was stirred at room temperature for 1.5 hours.
Subsequently, water (about 1 mL) was added, m-chloroperbenzoic acid (65 mg, 0.38 mmol, 1.5 equiv) was added at 0 ° C., and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solution was washed with 10% aqueous sodium sulfite solution, sodium bicarbonate water, water and brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain syrup-like compound 11 It was.
Yield 240 mg, 71% yield. The structure was confirmed by IR, 1H-NMR, and FAB-MS.
Compound 11: IR (KBr): 2923, 2853, 2121, 1738, 1497, 1455, 1416, 1359, 1339, 1276, 1157, 1072, 1009, 889, 737 cm-1;1H-NMR (500 MHz, rt, CDCl3): DH7.25~7.35 (m, 5Hx3, -Bn), 5.23 (m, 1H, Glycerol H-2), 4.93, 4.83, 4.79, 4, 74, 4.72, and 4.62. (Dx6, 2Hx3, -Bn), 4.75 (d, 1H, J = 3.5 Hz, H-1), 4.37 and~4.2 (dd, 2H, Glycerol H-3),~4.3 (m, 2Hx2, POCH2CHN3CH2OP),~4.2 (mx2, 2H, H-6),~4.2 (m, 2Hx2, POCH2CH2CN), 3.94 (dd, J = 9.0, 9.5 Hz, 1H, H-3), 3.92 (m, 1H, POCH2CHN3CH2OP), 3.75 (m, 1H, H-5), 3.75 and 3.52 (ddx2, 2H, Glycerol H-1), 3.56 (m, 2H, POCH2CH2Br), 3.51 (dd, J = 3.5 and 9.5 Hz, H1, H-2),~3.51 (dd, 1H, H-4), 2.7~2.8 (t, 2Hx2, -POCH2CH2CN), 2.29 (m, 4H, OCOCH2CH2(CH2)12CH3), 1.59 (b, 4H, OCOCH2CH2(CH2)12CH3), 1.25 (s, 48H, OCOCH2CH2(CH2)12CH3), 0.88 (t, 6H, OCOCH2CH2(CH2)12CH3FAB-MS: 1474 [M + Na]+, 1476 [M + 2 + Na]+.
Synthesis of Compound 12: Compound 12 (240 mg) was dissolved in 10 mL of acetonitrile: isopropanol: chloroform = 1.5: 1.5: 0.9 solution, and 30% trimethylamine (an amine having a structure corresponding to the target product. Final. 4 mL of an aqueous solution was added and stirred at room temperature for 30 hours. In addition, the mixing ratio of the solvent used here is a mixing ratio for dissolving the compound 11 and also dissolving the trimethylamine aqueous solution. DMF can also be used. When DMF is used, the solubility of trimethylamine increases, which is desirable.
The reaction solution was concentrated, and the residue was purified by column chromatography to give compound 12. Yield 157 mg, 71% yield. Confirmation of the structure is IR,1H-NMR and FAB-MS were used.
Compound 12: IR (KBr): 3404, 2923, 2853, 2110, 1739, 1496, 1454, 1360, 1244, 1158, 1087, 1070, 1028, 969, 874, 824, 740 cm-1;1H-NMR (500 MHz, rt, CDCl3): DH7.25~7.35 (m, 15H, -Bn), 5.24 (m, 1H, Glycerol H-2), 4.93, 4.84, 4.79, 4, 77, 4.72, and 4.65. (Dx6, 6H, -Bn), 4.78 (d, J = 3.5 Hz, 1H, H-1), 4.40 and 4.18 (dd, 2H, Glycerol H-3), 4.28 ( m, 2H, POCH2CH2N+(CH3)3), 4.28 (m, 4H, POCH2CH (N3) CH2OP), 4.15 and 4.09 (m 2, 2H, H-6), 3.96 (b, 1H, H-3), 3.78 (m, 1H, H-5), 3.79. and 3.55 (ddx2, 2H, Glycerol H-1), 3.66 (m, 1H, POCH2CH (N3) CH2OP), 3.63 (m, 2H, POCH2CH2N+(CH3)3), 3.62 (b, 1H, H-4), 3.50 (dd, J = 3.5 and 10 Hz, H1, H-2), 3.21 (s, 9H, POCH2CH2N+(CH3)3), 2.28 (m, 4H, OCOCH2CH2(CH2)12CH3), 1.59 (b, 4H, OCOCH2CH2(CH2)12CH3), 1.25 (s, 48H, OCOCH2CH2(CH2)12CH3), 0.88 (t, 6H, OCOCH2CH2(CH2)12CH3FAB-MS: 1046 [M + 1]+.
Synthesis of Compound 13: Compound 12 (157 mg) was dissolved in 30 mL of methanol and 20 μL of acetic acid was added. Palladium hydroxide carbon (100 mg) was added and magnetically stirred at room temperature for about 8 hours under hydrogen atmosphere. After the reaction, palladium was removed by filtration, and the concentrated residue was purified by iatrobead column chromatography to obtain Compound 13. Yield 77 mg, 64% yield. The structure was confirmed by IR, 1H-NMR, and FAB-MS.
Compound 13: IR (KBr): 3269, 2918, 2851, 1736, 1641, 1549, 1467, 1415, 1378, 1343, 1223, 1154, 1053, 1022, 968, 871, 825, 765, 719 cm-1;1H-NMR (500 MHz, rt, CDCl3): ΔH5.24 (m, 1H, Glycerol H-2), 4.81 (d, J = 3.5 Hz, 1H, H-1), 4.41 and 4.16 (dd, 2H, Glycerol H-3) 4.31 (m, 2H, POCH2CH2N+(CH3)3), 4.20~4.27 (b, 4H, POCH2CH (NH3) CH2OP), 4.15~4.09 (m 2, 2H, H-6), 3.95 (t, 1H, H-3), 3.77 and 3.61 (ddx2, 2H, Glycerol H-1), 3.57 (m , 1H, POCH2CH (NH3) CH2OP), 3.68 (m, 2H, POCH2CH2N+(CH3)3), 3.41~3.48 (b, 1H, H-4), 3.41~3.48 (dd, J = 3.5 and 10 Hz, H1, H-2), 3.21 (s, 9H, POCH2CH2N+(CH3)3), 2.30 (m, 4H, OCOCH2CH2(CH2)12CH3), 1.59 (b, 4H, OCOCH2CH2(CH2)12CH3), 1.26 (s, 48H, OCOCH2CH2(CH2)12CH3), 0.88 (t, 6H, OCOCH2CH2(CH2)12CH3FAB-MS: 1049 [M + 1]+.
(Synthesis Example 3)
·the first stage
The hydroxyl group of (R) -glycidol is protected with a trityl group (triphenylmethyl group: Tr-) (compound 14), and the epoxy is opened with sodium salt of p-methoxyphenol to give compound 15 (general formula (III)). Equivalent). (S) -glycidol is used instead of (R) -glycidol when a compound having the opposite stereo structure (corresponding to the general formula (IV)) is obtained.
・ Second stage
Compound 17 is synthesized by mesylating and azidating the hydroxyl group at the 2-position of compound 15.
・ 3rd stage
Compound 8 is synthesized by deprotecting only the p-methoxyphenyl group in Compound 17 under weak acidic conditions.
Synthesis of Compound 15: In the dehydrated reaction system, (R) -glycidol (5 g) was dissolved in 200 mL of dichloromethane, and 47 mL of triethylamine was added. Trityl chloride was added at 0 ° C., and the mixture was stirred at 0 ° C. for about 12 hours.
The reaction solution was washed, dried and concentrated, and the residue was roughly purified by silica gel column chromatography to obtain a mixture of compound 14 and trityl alcohol. This mixed compound was dissolved in 500 mL of DMF, 54 g of p-methoxyphenol sodium salt was added, and the mixture was stirred at 100 ° C. for about 7 hours. The target product was extracted into an organic layer, washed, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 15. Yield 23.8 g, yield 80%.
Compound 15: [α]D25-3.0 (c 0.11, CHCl3). IR (KBr) 1504, 1448, 1226, 1033, 804, 703, 630, 505cm-1.1H-NMR (200 MHz, rt, CDCl3) DH7.3 and 7.45 (mx2, 15H, -Tr), 6.85 (s, 4H, pMP), 4.15 (m, 1H, H2), 4.00 and 4.05 (ddx2, 2H, H1), 3.8 (s, 3H, pMP), 3.35 (dd, 2H, H3). EI-MS 440 [M+].
Synthesis of Compound 16: Compound 15 (23.8 g) was dissolved in 400 mL of dichloromethane, and 37.7 mL of triethylamine was added. The solution was cooled to 0 ° C., methanesulfonyl chloride (6.27 mL) was added dropwise, and the mixture was stirred at room temperature for about 5 hours. The solution was washed, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 16. Yield 27.4 g, yield 98%.
Compound 16: [a]D26-6.2 (c 0.46, CHCl3). IR (KBr) 3056, 2940, 2832, 1504, 1355, 1230, 1174, 1095, 1037, 970, 929, 821, 763, 705, 634, 528 cm-1.1H-NMR (200 MHz, rt, CDCl3) DH7.3 and 7.45 (mx2, 15H, -Tr), 6.85 (s, 4H, pMP), 5.0 (m, 1H, H2), 4.1 (ddx2, 2H, H1), 3 .75 (s, 3H, pMP), 3.5 (m, 2H, H3), 3.1 (s, 3H, -Ms). EI-MS: 518 [M+].
Synthesis of Compound 17: Compound 16 (27.4 g) was dissolved in 400 mL of DMF, sodium azide (17.2 g) was added, and the mixture was stirred at 100 ° C. for about an hour. The target product was extracted into an organic layer, washed, dried and concentrated, and the resulting residue was purified by silica gel column chromatography. Yield 23.3 g, 92% yield.
Compound 17: IR (KBr) 2940, 2098, 1590, 1502, 1226, 1074, 1033, 827, 750, 701, 630, 511 cm-1.1H-NMR (500 MHz, rt, CDCl3) DH7.3 and 7.45 (mx2, 15H, -Tr), 6.85 (s, 4H, pMP), 4.05 (ddx2, 2H, H1), 3.80 (m, 1H, H2), 3 .75 (s, 3H, pMP), 3.35 (s, 2H, H3). EI-MS 465 [M+].
Synthesis of Compound 8: Compound 17 (23.3 g) was dissolved in 750 mL of a CH2CN: CH3OH: H2O = 4: 1: 1 solution, and silver (II) dipicolinate (110.6 g) was added and stirred at room temperature for about 3 hours. did. After completion of the reaction, picolinic acid was removed by Celite filtration, the target product was extracted into an organic layer, washed, dried and concentrated, and the resulting residue was purified by silica gel column chromatography. Yield 9.0 g, yield 50%.
Compound 8: [a]D26+6.35 (c 1.0, CHCl3). IR (KBr) 3424, 3060, 2931, 2877, 2100, 1488, 1328, 1270, 1220, 1081, 1031, 759, 701, 634 cm-1.1H-NMR (500 MHz, rt, CDCl3) D7.3 and 7.45 (mx2, 15H, -Tr), 3.60 (m, 1H, H2), 3.5 (m, 2H, H1), 3.25 (dd, 2H, H3). The optical purity was confirmed to be> 99% ee from the spectrum of 1H-NMR by asymmetric derivatization using an asymmetric derivatization reagent TBMB carboxylic acid.
(Synthesis Example 4)
In addition to the synthesis method described above, the target glycolipid derivative can also be produced by the following method. Specifically, the synthetic route from compounds 4a and 4b to compound 7 is replaced with the following method.
Compound 19 to Compound 20: Reaction in which the isopropylidene group is selectively deprotected under acidic conditions. Since the silyl group at the 6-position of the sugar is also eliminated under acidic conditions, it is introduced as a protective group into the glycerol moiety by using the TBDPS group (tert-butyldiphenylsilyl group), which is one of the most resistant to acidic conditions among the silyl groups. The difference with the isopropylidene group was expressed.
Further, when a reagent that realizes an appropriate acidic condition was examined, Amberlyst 15 manufactured by Organo Corporation was effective, and by using this, only the isopropylidene group could be selectively deprotected.
Compound 21 to Compound 7: Reaction in which the TBDPS group is deprotected with fluoride ions. As described above, the TBDPS group can be deprotected even by hydrolysis under acidic conditions. However, fairly strong acidic conditions are required for deprotection of the TBDPS group. Compound 21 has an acyl group of an unstable fatty acid moiety, and this acyl group moiety may not be able to withstand strong acidic conditions that deprotect the TBDPS group. Therefore, deprotection with fluoride ions was studied.
TBAF (tetrabutylammonium fluoride) is most often used for the deprotection of silyl protecting groups. In addition to TBAF, TBAHF (Tributylamine Hydrofluoride, Ref. Furusawawa, K. The Chemical Society of Japan, 1989, 509.) has been developed as a milder reagent. As a result, the reaction proceeded almost completely with no by-product as compared with the case of using TBAF, and Compound 7 was obtained.
Synthesis of compound 18:
Crude product 4-a + 4-b synthesized from compound 3 (2.0 g) by the method described in Synthesis Example 1 was dissolved in DMF (50 mL) and heated to around 100 ° C. CsOAc (3.90 g) was added, and the mixture was stirred at 100 ° C. for about 3 hours. The desired product was extracted into an ethyl acetate layer, washed with brine, dried and concentrated. Next, the obtained residue was dissolved in methanol (100 mL).2CO3(617 mg) was added and stirred for about 1 hour. After completion of the reaction, the solution was neutralized with amberlist, the amberlist was removed by filtration, and the filtrate was concentrated. Next, the obtained residue was dissolved in acetone (300 mL), P-toluenesulfonic acid (p-TsOH; 1.0 g) was added, and magnetically stirred at room temperature for about 30 minutes. The reaction was stopped by adding triethylamine to the solution, and the solution was concentrated by about one third. The remaining solution was separated, washed and concentrated, and the residue was purified by silica gel column chromatography. Yield 1.40 g, 61% yield (4 steps from compound 3). White waxy.
[Α]D 28= +30.3 (c 1.0, CHCl3); IR (KBr film) ν / cm-1: 3482, 3314, 3030, 2985, 2920, 2853, 1642, 1455, 1370, 1212, 1156, 1070, 1028, 912, 839, 738, 698, 614, 516, 547, 417;1H-NMR (500 MHz, CDCl3) ΔH7.40~7.25 (m, 5Hx3, -CH2C6 H 5 ), 4.98~4.63 (d, 2Hx3, -CH 2 C6H5), 4.82 (d, 1H, J = 3.5 Hz, H-1), 4.36 (t, 1H, J = 6.0 Hz, glycerol H-2), 4.07 and 3.73 (dd , 1Hx2, J = 6.5 and 7.5, J = 6.0 and 7.5 Hz, glycerol H-1proR or H-1proS), 3.98 (dd, 1H, J = 9.0 and 9.5 Hz, H-3), 3.76 and 3.69 (m, 2H, H-6proR and proS),~3.70 (m, 1H, H-5), 3.60 and 3.55 (dd, 1Hx2, J = 5.5 and 10.5, J = 6.0 and 10.5 Hz, glycerol H-3proS or H-3proR), 3.52 (dd, 1H, J = 9.0 and 9.5 Hz, H-4), 3.51 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 1. 43 and 1.37 (s, 3Hx2, isopropyl); HRMS (FAB): m / z calcd. for C33H40O8Na [M + Na+] 587.2621; found 58.72639.
Synthesis of compound 7
To a solution obtained by dissolving compound 18 (1.40 g) in pyridine (20 mL) and adding a catalytic amount of dimethylaminopyridine (DMAP), TBDPSCl (1.08 mL) was added dropwise in an ice bath, and the mixture was stirred at room temperature for about 17 hours. Stir for a period. After decomposing the reagent by adding methanol, the residue from which pyridine was removed by azeotropic operation with toluene was added to 1N HCl aq. NaHCO3aq. NaClaq. The solution was sequentially washed with, dried and concentrated to obtain a syrup-like compound 19.
Next, this compound 19 was dissolved in a mixed solvent of chloroform (25 mL) -methanol (12 mL), Amberlyst (Amberlyst 15, manufactured by Organo Corporation) (700 mg) was added, and magnetically stirred at room temperature. Amberlyst was removed by filtration, and the filtrate was neutralized with triethylamine and then concentrated to obtain syrup-like compound 20. Next, compound 20 was dissolved in pyridine (20 mL), a catalytic amount of DMAP was added, and Cl palmitate (2.02 mL) was added in an ice bath, and magnetically stirred at room temperature for about 5 hours. After decomposing the reagent by adding methanol, the residue from which pyridine was removed by azeotropic operation was treated with 1N HCl aq. NaHCO3aq. NaCl aq. Wash, dry, and concentrate to obtain a syrupy compound 21. Next, compound 20 was dissolved in THF (200 mL), adjusted 2M TBAHF / THF solution (total amount 200 mL) was added, and the mixture was stirred at room temperature for a while. While confirming the progress of the reaction, a TBAHF solution was appropriately added. The reaction was completed in 24 hours, and the target product was extracted into an ethyl acetate layer and extracted with NaHCO 3.3aq. NaCl aq. The residue was purified by silica gel column chromatography to obtain a white waxy compound 7. Yield 1.70 g (amount of α form alone), yield 68% (4 steps from compound 18).
Compound 19 (colorless syrup): [α]D 31= + 19.1 (c 1.0, CHCl3); IR (KBr film) ν / cm-1: 3031, 2986, 2929, 2858, 1733, 1455, 1427, 1365, 1256, 1212, 1155, 1107, 825, 736, 701, 613, 505;1H-NMR (500 MHz, CDCl3) ΔH7.65~7.7, 7.24~7.43, 7.25 (m, 5Hx5, -CH2C6 H 5 and diphenyl group of TBDFPS), 4.98.~4.59 (d, 2Hx3, -CH 2 C6H5), 4.90 (d, 1H, J = 3.5 Hz, H-1), 4.34 (t, 1H, J = 6.0 Hz, glycerol H-2), 3.98 (dd, 1H, J = 9.0 and 9.5 Hz, H-3), 3.86 (d, 1Hx2, H-6 proR and pros),~3.70 (m, 1H, H-5), 4.04 and 3.68 (dd, 1Hx2, J = 6.0 and 8.0, J = 2.5 and 8.0 Hz, glycerol H-1proR or H-1proS), 3.62 (dd, 1H, J = 9.0 and 10.0 Hz, H-4), 3.57 and 3.56 (dd, 1Hx2, J = 6.0 and 11.0, J = 5) 0.0 and 11.0 Hz, glycerol H-3proS or H-3proR), 3.56 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 1.40 and 1.34 (s, 3Hx2, isopropyl), 1.04 (s, 9H, t− butyl group of TBDPS); HRMS (FAB): m / z calcd. for C49H58O8SiNa [M + Na+] 825.3799; found 825.3798.
Compound 20 (colorless syrup): [α]D 31= + 15.3 (c 1.0, CHCl3); IR (KBr film) ν / cm-1: 3432, 3301, 3032, 2928, 2858, 1733, 1454, 1426, 1359, 1210, 1156, 1069, 823, 736, 700, 615, 504, 419;1H-NMR (500 MHz, CDCl3) ΔH7.65~7.7, 7.24~7.43, 7.25 (m, 5Hx5, -CH2C6 H 5 and diphenyl group of TBDFPS), 4.93.~4.59 (d, 2Hx3, -CH 2 C6H5), 4.76 (d, 1H, J = 3.5 Hz, H-1), 3.98 (dd, 1H, J = 9.0 and 9.5 Hz, H-3), 3.85 (m, 1Hx2, H-6 proR and pros),~3.75 (m, 1H, H-5), 3.79 and 3.43 (ddx2, 1Hx2, J = 3.5 and 10.5, J = 7.0 and 10.5 Hz, glycerol H-3proR or H-3proS), 3.63 (dd, 1H, J = 9.0 and 9.50 Hz, H-4),~3.70 and~3.58 (mx2,1Hx2, glycerol H-1proS or H-1proR), 3.56 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 2.27 (dd, 1H, J = 5.5 and 7.5 Hz, glycerol H-2), 1 .04 (s, 9H, t-butyl group of TBDPS); HRMS (FAB): m / z calcd. for C46H54O8SiNa [M + Na+] 785.3486; found 785.3483.
Compound 21 (colorless syrup): [α]D 27= + 14.6 (c 1.0, CHCl3); IR (KBr film) ν / cm-1: 3031,925,2854,1743,1459,1427,1361,1157,1108,823,736,701,611,504;1H-NMR (500 MHz, CDCl3) ΔH7.65~7.7, 7.24~7.43, 7.25 (m, 5Hx5, -CH2C6 H 5 and diphenyl group of TBDFPS), 5.23 (m, 1H, glycerol H2), 4.94.~4.61 (d, 2Hx3, -CH 2 C6H5), 4.79 (d, 1H, J = 3.5 Hz, H-1), 4.39 (dd, 1H, J = 4.0 and 12.0 Hz, glycerol H-1proS), 4.15 (dd, 1H, J = 6.0 and 12.0 Hz, glycerol H-1).proR), 3.97 (dd, 1H, J = 9.0 and 9.5 Hz, H-3),~3.85 (m, 1H, H-5),~3.85 and~3.67 (m, 1Hx2, H-6proR and proS), 3.72 (dd, 1H, J = 6.0 and 10.5 Hz, glycerol H-3proR),~3.67 (m, 1H, H-4), 3.55 (dd, 1H, J = 3.5 and 9.5 Hz, H-2), 3.53 (dd, 1H, J = 5.5 and 10.5Hz, glycerol H-3proS), 2.24 (m, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.54 (b, 2Hx2, -OCOCH2CH2(CH2)12CH3), 1.25 (b, 24Hx2, -OCOCH2CH2(CH2)12CH3), 1.04 (s, 9H, t-butyl group of TBDPS), 0.88 (t, 3Hx2, J = 7.0 Hz, -OCOCH2CH2(CH2)12CH3); HRMS (FAB): m / z calcd. for C78H114O10SiNa [M + Na+] 1261.8079; found 1261.8887.
本発明の糖脂質誘導体の製造方法が製造対象とする脂質誘導体はリウマチなどの診断薬などへの応用が期待でき、本発明の脂質誘導体の製造ではその脂質誘導体を効率的に製造することができる。 The lipid derivative to be produced by the method for producing a glycolipid derivative of the present invention can be expected to be applied to diagnostic agents such as rheumatism, and the lipid derivative of the present invention can be efficiently produced. .
Claims (14)
（式（VII）中、Ｘはハロゲン；Ｒは炭化水素基から独立して選択可能であり；Ｑは独立して選択できるリン酸の保護基又は水素であり、該リン酸の保護基が２−シアノエチル基、アリル基、ベンジル基若しくはｔ−ブチル基であり；Ｙはそれぞれ独立して選択できるＯＨ基の保護基又は水素であり、該ＯＨ基の保護基がベンジル基若しくはＴＢＤＭＳ基である） A glycolipid derivative synthetic intermediate described in the following general formula (VII).
(In the formula (VII), X is a halogen; R is independently selectable from a hydrocarbon group; Q is an independently selectable phosphoric acid protecting group or hydrogen, and the phosphoric acid protecting group is 2 - cyanoethyl group, allyl group, a benzyl group or a t- butyl group; Y is Ri protecting group or hydrogen der OH groups which can be selected independently, the OH group protecting group is benzyl or TBDMS Motodea of )
前記ドナー化合物は、Ｄ−グルコース又はＤ−ガラクトースの２〜４位のＯＨ基にエーテル系の保護基を導入し、６位のＯＨ基にエステル系の保護基を導入した単糖誘導体である、
請求項１〜３のうちの何れか１項に記載の糖脂質誘導体合成中間体を製造することを特徴とする糖脂質誘導体合成中間体の製造方法。 An optically active glycidol or a derivative having an optically active glycerol skeleton derived from glycidol in the presence of a phosphonium halogen compound and a basic solvent for a donor compound that is a saccharide introduced with a protecting group for an OH group other than the 1-position Reacting as an acceptor compound and simultaneously constructing the α-glycosyl bond and the three-dimensional structure of the glycerol moiety,
The donor compound is a monosaccharide derivative in which an ether-based protecting group is introduced into the OH group at positions 2 to 4 of D-glucose or D-galactose, and an ester-based protecting group is introduced into the OH group at position 6.
A method for producing a glycolipid derivative synthetic intermediate according to any one of claims 1 to 3, wherein the glycolipid derivative synthetic intermediate according to any one of claims 1 to 3 is produced.
（式（VIII）中、Ｒは炭化水素基から独立して選択可能であり；Ｙはそれぞれ独立して選択できるＯＨ基の保護基である）
（式（III）及び（IV）中、Ｔはエーテル系保護基を表す。）
（式（IX）中、Ｒは炭化水素基から独立して選択可能であり；Ｑは前記ホスホロアミダイト由来のリン酸の保護基であり；Ｙはそれぞれ独立して選択できるＯＨ基の保護基又は水素であり；Ｔはエーテル系保護基を表す。） Activates a phosphoramidite derivative and a compound represented by the following general formula (III) or (IV) for a glycolipid derivative synthetic intermediate represented by the following general formula (VIII) whose steric structure is controlled. A method for producing a glycolipid derivative synthetic intermediate comprising a step of obtaining a glycolipid derivative synthetic intermediate represented by the following general formula (IX) by an amidite method in which reaction is performed in the presence of an agent.
(In formula (VIII), R can be independently selected from a hydrocarbon group; Y is a protecting group for an OH group that can be independently selected)
(In the formulas (III) and (IV), T represents an ether protecting group.)
(In the formula (IX), R can be independently selected from a hydrocarbon group; Q is a protecting group for phosphoric acid derived from the phosphoramidite; Y is a protecting group for an OH group that can be independently selected; Or hydrogen; T represents an ether-based protecting group.)
（式（XII）中、Ｙはそれぞれ独立して選択できるＯＨ基の保護基であり；Ｑは独立して選択できるリン酸の保護基であり、前記リン酸エステル化剤由来である；Ｒは炭化水素基から独立して選択される。）
（式（XIII）中、Ｘはハロゲンであり；Ｙはそれぞれ独立して選択できるＯＨ基の保護基であり；Ｑは独立して選択可能なリン酸の保護基であり、前記リン酸エステル化剤に由来する；Ｒは炭化水素基から独立して選択される。） A glycolipid derivative synthesis intermediate represented by the following general formula (XII) is reacted with a phosphoramidite derivative and 2-halogenated ethanol in the presence of an activator by the amidite method, and the following general formula (XIII A process for obtaining a glycolipid derivative synthetic intermediate represented by the formula:
(In the formula (XII), Y is a protecting group for an OH group which can be independently selected; Q is a protecting group for a phosphoric acid which can be independently selected, and is derived from the phosphate esterifying agent; Independently selected from hydrocarbon groups.)
(In the formula (XIII), X is halogen; Y is a protecting group for the OH group which can be selected independently; Q is a protecting group of selectable independently phosphate, the phosphoric acid ester of Derived from the agent; R is independently selected from a hydrocarbon group.)
（式（IX）中、Ｒは炭化水素基から独立して選択可能であり；Ｑは前記ホスホロアミダイト由来のリン酸の保護基であり、該リン酸の保護基が２−シアノエチル基、アリル基、ベンジル基若しくはｔ−ブチル基であり；Ｙはそれぞれ独立して選択できるＯＨ基の保護基又は水素であり、該ＯＨ基の保護基がベンジル基若しくはＴＢＤＭＳ基であり、；Ｔはエーテル系保護基であり、トリチル基若しくはメトキシトリチル基を表す。） A glycolipid derivative synthetic intermediate represented by the following general formula (IX):
(In the formula (IX), R can be independently selected from a hydrocarbon group; Q is a phosphoric acid protecting group derived from the phosphoramidite, and the phosphoric acid protecting group is a 2-cyanoethyl group, allyl group, a benzyl group or a t- butyl group; Y is a protecting group or hydrogen of the OH groups which can be selected independently, protecting group of the OH group is benzyl group or TBDMS group,; T of the ether (Protecting group , which represents a trityl group or a methoxytrityl group .)
（式（IX）中、Ｒは炭化水素基から独立して選択可能であり；Ｙはそれぞれ独立して選択できるＯＨ基の保護基又は水素であり、該ＯＨ基の保護基がベンジル基若しくはＴＢＤＭＳ基であり、；
Ｑ及びＴは、Ｑ及びＴが水素であるか、Ｑが水素でありＴがトリチル基若しくはメトキシトリチル基であるか、又は、Ｑが２−シアノエチル基、アリル基、ベンジル基若しくはｔ−ブチル基でありＴが水素を表す。） Glycolipid derivatives synthetic intermediate which is characterized by being represented by the following general formula (IX).
(In the formula (IX), R can be independently selected from a hydrocarbon group; Y is a protecting group for an OH group or hydrogen which can be independently selected, and the protecting group for the OH group is a benzyl group or a TBDMS; A group;
Q and T are Q and T are hydrogen, Q is hydrogen and T is a trityl group or a methoxytrityl group, or Q is a 2-cyanoethyl group, an allyl group, a benzyl group or a t-butyl group And T represents hydrogen. )
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007532018A JP5212973B2 (en) | 2005-08-22 | 2006-02-21 | Glycolipid derivative synthesis intermediate and production method thereof, and glycolipid derivative and production method thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005240468 | 2005-08-22 | ||
| JP2005240468 | 2005-08-22 | ||
| PCT/JP2006/303538 WO2007023583A1 (en) | 2005-08-22 | 2006-02-21 | Intermediate in synthesizing glycolipid derivative and method of producing the same, and glycolipid derivative and method of producing the same |
| JP2007532018A JP5212973B2 (en) | 2005-08-22 | 2006-02-21 | Glycolipid derivative synthesis intermediate and production method thereof, and glycolipid derivative and production method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2007023583A1 JPWO2007023583A1 (en) | 2009-02-26 |
| JP5212973B2 true JP5212973B2 (en) | 2013-06-19 |
Family
ID=37771338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007532018A Active JP5212973B2 (en) | 2005-08-22 | 2006-02-21 | Glycolipid derivative synthesis intermediate and production method thereof, and glycolipid derivative and production method thereof |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP5212973B2 (en) |
| WO (1) | WO2007023583A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5252468B2 (en) * | 2007-06-27 | 2013-07-31 | エム バイオ テック株式会社 | Method for synthesizing mycoplasma pneumoniae specific antigen glycolipid |
| CN102448488B (en) | 2009-06-04 | 2014-10-15 | 独立行政法人产业技术综合研究所 | Vaccine for mycoplasma infection |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05124921A (en) * | 1991-11-07 | 1993-05-21 | Kao Corp | Cosmetic |
| JPH0648916A (en) * | 1992-07-30 | 1994-02-22 | Kao Corp | Cosmetic |
| JPH07149786A (en) * | 1993-11-26 | 1995-06-13 | Sagami Chem Res Center | Glyceroglycolipid and carcinogenic promoter inhibitor |
| JPH07252494A (en) * | 1991-12-31 | 1995-10-03 | Unilever Nv | Glycolipid surfactant and composition containing the surfactant |
| JPH07278174A (en) * | 1994-02-18 | 1995-10-24 | Ube Ind Ltd | Glyceroglycolipid compound containing phosphorylcholine |
| JPH07278175A (en) * | 1994-02-18 | 1995-10-24 | Ube Ind Ltd | Glyceroglycolipid compound containing phosphorylcholine |
| JPH07304789A (en) * | 1994-03-18 | 1995-11-21 | Ube Ind Ltd | Method for producing glycero glucolipid compound |
| JPH0848693A (en) * | 1994-06-03 | 1996-02-20 | Seikagaku Kogyo Co Ltd | New glyceroglycophospholipid, its antibody and method for detecting mycoplasma |
| WO2005049631A1 (en) * | 2003-11-18 | 2005-06-02 | The Malaghan Institute Of Medical Research | Synthetic molecules having immune activity |
-
2006
- 2006-02-21 WO PCT/JP2006/303538 patent/WO2007023583A1/en active Application Filing
- 2006-02-21 JP JP2007532018A patent/JP5212973B2/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05124921A (en) * | 1991-11-07 | 1993-05-21 | Kao Corp | Cosmetic |
| JPH07252494A (en) * | 1991-12-31 | 1995-10-03 | Unilever Nv | Glycolipid surfactant and composition containing the surfactant |
| JPH0648916A (en) * | 1992-07-30 | 1994-02-22 | Kao Corp | Cosmetic |
| JPH07149786A (en) * | 1993-11-26 | 1995-06-13 | Sagami Chem Res Center | Glyceroglycolipid and carcinogenic promoter inhibitor |
| JPH07278174A (en) * | 1994-02-18 | 1995-10-24 | Ube Ind Ltd | Glyceroglycolipid compound containing phosphorylcholine |
| JPH07278175A (en) * | 1994-02-18 | 1995-10-24 | Ube Ind Ltd | Glyceroglycolipid compound containing phosphorylcholine |
| JPH07304789A (en) * | 1994-03-18 | 1995-11-21 | Ube Ind Ltd | Method for producing glycero glucolipid compound |
| JPH0848693A (en) * | 1994-06-03 | 1996-02-20 | Seikagaku Kogyo Co Ltd | New glyceroglycophospholipid, its antibody and method for detecting mycoplasma |
| WO2005049631A1 (en) * | 2003-11-18 | 2005-06-02 | The Malaghan Institute Of Medical Research | Synthetic molecules having immune activity |
Non-Patent Citations (22)
| Title |
|---|
| JPN6012015445; Ｏｒｇ． Ｂｉｏｍｏｌ． Ｃｈｅｍ． １, 2003, ２５１８-２５２１ * |
| JPN6012015446; Ｃａｒｂｏｈｙｄｒ． Ｒｅｓ． １０８, 1982, Ｃ５-Ｃ９ * |
| JPN6012015447; Ａｇｒｉｃ． Ｂｉｏｌ． Ｃｈｅｍ． ５０, 1986, ２２５１-２２５９ * |
| JPN6012015448; Ｔｅｔｒａｈｅｄｒｏｎ ４４, 1988, ２９５７-２９６２ * |
| JPN6012015449; Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ． ３５, 1994, ５４６５-５４６８ * |
| JPN6012015450; Ｔｅｔｒａｈｅｄｒｏｎ ５８, 2002, ５１０９-５１１７ * |
| JPN6012015451; Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ． ４０, 1999, ２３７１-２３７４ * |
| JPN6012015452; Ａｕｓｔ． Ｊ． Ｃｈｅｍ． ４０, 1987, １９０１-１９０８ * |
| JPN6012015453; Ａｕｓｔ． Ｊ． Ｃｈｅｍ． ４３, 1990, １３９１-１４０５ * |
| JPN6012015454; Ａｕｓｔ． Ｊ． Ｃｈｅｍ． ５０, 1997, １１０５-１１０７ * |
| JPN6012015455; Ａｕｓｔ． Ｊ． Ｃｈｅｍ． ５１, 1998, ４７１-４８２ * |
| JPN6012015456; Ｃａｒｂｏｈｙｄｒ． Ｒｅｓ． ９３, 1981, １４１-１４３ * |
| JPN6012015457; Ｔｅｔｒａｈｅｄｒｏｎ： Ａｓｙｍｍｅｔｒｙ ８, 1997, ７６５-７７３ * |
| JPN6012015458; Ｊ． Ｃａｒｂｏｈｙｄｒ． Ｃｈｅｍ． １７, 1998, ９３７-９６８ * |
| JPN6012031689; Ｃｈｅｍｉｓｔｒｙ ＆ Ｂｉｏｌｏｇｙ ９, 2002, ７１３-７２０ * |
| JPN6012031691; Ｂｉｏｏｒｇ． Ｍｅｄ． Ｃｈｅｍ． Ｌｅｔｔ． ５, 1995, ２３２１-２３２４ * |
| JPN6012031692; Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ． ３６, 1995, ４８６５-４８６８ * |
| JPN6012031695; Ｂｉｏｏｒｇ． Ｍｅｄ． Ｃｈｅｍ． Ｌｅｔｔ． ４, 1994, １６１９-１６２２ * |
| JPN6012031696; Ｃｈｅｍｉｓｔｒｙ ａｎｄ Ｐｈｙｓｉｃｓ ｏｆ Ｌｉｐｉｄｓ １０, 1973, ２６７-２８５ * |
| JPN6012031697; Ｂｉｏｃｈｉｍｉｃａ ｅｔ Ｂｉｏｐｈｙｓｉｃａ Ａｃｔａ， Ｌｉｐｉｄｓ ａｎｄ Ｌｉｐｉｄ Ｍｅｔａｂｏｌｉｓｍ ２３１, 1971, ５３７-５４４ * |
| JPN6012031699; Ｊ． Ｏｒｇ． Ｃｈｅｍ． ３３, 1968, ３１３９-３１４４ * |
| JPN6012031701; Ｐｈｙｔｏｃｈｅｍｉｓｔｒｙ ２２, 1983, １７４１-１７４４ * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2007023583A1 (en) | 2009-02-26 |
| WO2007023583A1 (en) | 2007-03-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2518739B2 (en) | Tumor suppressive saccharide conjugate | |
| JP7208995B2 (en) | Method for preparing the outer core octacarbon sugar of Helicobacter pylorilipopolysaccharide | |
| JP5212973B2 (en) | Glycolipid derivative synthesis intermediate and production method thereof, and glycolipid derivative and production method thereof | |
| US4973674A (en) | Chiral synthesis of anthracyclines from substituted anthraquinones | |
| JP4691101B2 (en) | 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative and method for producing the same | |
| US5220003A (en) | Process for the synthesis of 2',3'-dideoxynucleosides | |
| HU198505B (en) | Process for producing antitumour anthracycline glycosides | |
| KR20080079833A (en) | Methods for the stereoselective preparation and separation of tri-o-acetyl-5-deoxy-beta;-d-ribofuranose | |
| JP5252468B2 (en) | Method for synthesizing mycoplasma pneumoniae specific antigen glycolipid | |
| CA2574954C (en) | 1-.alpha.-halo-2,2-difluoro-2-deoxy-d-ribofuranose derivatives and process for the preparation thereof | |
| CA1320720C (en) | Sialosyl glyceride and process for producing the same | |
| Ross et al. | Parasite glycoconjugates. Part 16: Synthesis of a disaccharide and phosphorylated di-and tri-saccharides from Leishmania lipophosphoglycan | |
| Zamyatina et al. | The synthesis of 1-O-(2-N-stearoyl-D-erythro-sphinganinel-phosphoryl)-2-O-(α-D-mannopyranosyl-D-myo-inositol: a fragment of the naturally occurring inositol-containing glycophosphosphingolipids | |
| JP2696524B2 (en) | New synthesis method of ganglioside GM (3) | |
| JP3163359B2 (en) | Sulfated oligosaccharide compounds | |
| JP2625620B2 (en) | Fucosyl-glucosamine derivatives | |
| Ivanova et al. | Parasite glycoconjugates. Part 9. 1 Synthesis of dec-9-enyl β-D-galactopyranosyl-(1→ 4)-α-D-mannopyranosyl phosphate and its epimers at the D-galactose moiety, substrate analogues for the elongating α-D-mannopyranosylphosphate transferase in the Leishmania | |
| EP0901498B1 (en) | Method for synthesizing c-glycosides of ulosonic acids | |
| JPH10310596A (en) | Digalactosylceramide derivative and its production | |
| JP2006083091A (en) | Method for producing trehalose type disaccharide and its derivative and new trehalose type disaccharide derivative | |
| IE910491A1 (en) | Method for the preparation of polyphosphorylated derivatives¹of galactopyranosides with a potential insulin-like activity | |
| Soli | Recent advancements in the preparation of carbon-and nitrogen-linked glycoconjugates | |
| JP4212087B2 (en) | C, C-glycopyranosyl compound and process for producing the same | |
| Nakamura et al. | Synthesis of ceramidated GLA-60 derivatives | |
| JPH09241288A (en) | Stereoselective production of glycosyl compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090216 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120327 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120528 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120529 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20120619 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120918 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120919 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20121024 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20121122 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121130 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130122 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130219 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5212973 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20160308 Year of fee payment: 3 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |