CN105418700B - Preparation method based on the sugar compounds of anti-tumor vaccine GM3 key intermediates two - Google Patents
Preparation method based on the sugar compounds of anti-tumor vaccine GM3 key intermediates two Download PDFInfo
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- CN105418700B CN105418700B CN201510821929.5A CN201510821929A CN105418700B CN 105418700 B CN105418700 B CN 105418700B CN 201510821929 A CN201510821929 A CN 201510821929A CN 105418700 B CN105418700 B CN 105418700B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000000543 intermediate Substances 0.000 title abstract description 14
- 229960005486 vaccine Drugs 0.000 title abstract description 14
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 13
- -1 oligosaccharide compounds Chemical class 0.000 claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract description 12
- 238000006206 glycosylation reaction Methods 0.000 claims abstract description 7
- 230000013595 glycosylation Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 52
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 claims description 12
- 230000000977 initiatory effect Effects 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- 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 6
- 239000008103 glucose Substances 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 229920001542 oligosaccharide Polymers 0.000 abstract description 3
- 150000002482 oligosaccharides Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Substances [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000010438 heat treatment Methods 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 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 229940125797 compound 12 Drugs 0.000 description 5
- 150000002016 disaccharides Chemical class 0.000 description 5
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 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 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 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 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- 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 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 2
- 229940012189 methyl orange Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SQVRNKJHWKZAKO-LUWBGTNYSA-N N-acetylneuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-LUWBGTNYSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 230000008520 organization Effects 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 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
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to based on the sugar compounds of anti-tumor vaccine GM3 key intermediates two, belong to oligosaccharides synthesis technical field, its structural formula is：
Description
Technical field
The present invention relates to pharmaceutical technology field, is to be based on anti-tumor vaccine GM3 key intermediate disaccharides chemical combination specifically
The preparation method of thing.
Background technology
Malignant tumour serious threat human health, and the international cancer research institution of World Health Organization subordinate is positioned at method
The general headquarters in state Lyons deliver《World's cancer report in 2014》.This report shows that global cancer burden is with surprising speed
Degree constantly aggravates, and just has 1 people to die from cancer in average every 8 deaths.It is expected that reach annual 22000000 within 20 years in future
Level, same period number of cancer deaths will also soar to 13,000,000.Either developed country or developing country, cancer is all
One of primary killers as human death.At present, there is toxicity is big and late result is poor etc. in clinical conventional antineoplastic
Deficiency.Therefore, new construction types of anti-tumor compound is researched and developed, its synthesis condition is probed into, there is important theory significance.
Tumour antigen vaccine has become the focus of current tumor therapeutics, and prospect is considerable in terms of new drug development.Cell
Surface sugar antigens provide new direction for new antitumoral vaccine development.GM3 is the sugar antigens of important sialic acid three of cell surface,
With various biological function.GM3 can induce the differentiation of lipid cancer cell；Promote the activity of vascular endothelial cell protein kinase A,
Suppress the activity of protein kinase C, adjust blood-brain barrier；GM3 can also adjust the transmission of calcium ion between cross-film, in cell growth, divide
Played a significant role during change, important adjustment effect has been metabolized to cell some；The specific bond of acceptor and enzyme is adjusted,
Suppress immune response and knurl crosslinking；In addition, GM3 can also directly promote the regeneration of nerve fiber.GM3 has table in kinds of tumor cells
Reach, be a very important target for designing treating cancer vaccine.As what tumor therapeutics was studied deepens continuously, GM3's
Synthesis and pharmacological research are increasingly becoming focus of concern.
Synthesis for GM3, traditional method is that sialic acid carries out glycosylation reaction with the lactose protected, and is protected
Lactose conventional synthesis process be 3,4 hydroxyls are obtained by series reaction exposed, the other positions using lactose as initiation material
The lactose that hydroxyl is protected with acetyl group, the reaction efficiency of such method synthesis is relatively low, and during reaction raw materials and product
Separation has extreme difficulties.It is contemplated that synthesize the lactose protected with a kind of more easy method, be with glucose and
Galactolipin is initiation material, and its synthetic route is not reported so far.
The content of the invention
The purpose of the present invention is to be directed to deficiency of the prior art, there is provided one kind is crucial middle based on anti-tumor vaccine GM3
The sugar compounds of body two.
Another purpose of the present invention is to provide a kind of based on the sugar compounds of anti-tumor vaccine GM3 key intermediates two
Preparation method.
Another purpose of the present invention is to provide a kind of based on the sugar compounds of anti-tumor vaccine GM3 key intermediates two
Using.
To achieve the above object, the present invention adopts the technical scheme that：A kind of key intermediate disaccharides for being used to synthesize GM3
Compound, the structural formula of the described sugar compounds of key intermediate two are：
To realize above-mentioned second purpose, the present invention adopts the technical scheme that：Described preparation method using glucose as
Initiation material obtains monose acceptor compound 9 by series reaction；Obtained using galactolipin as initiation material by series reaction
To monose compound donator 15；Then monose acceptor compound 9 and monose compound donator 15 are obtained by glycosylation deprotection
Target compound；Wherein, the structural formula of monose acceptor compound 9 is：
The structural formula of monose compound donator 15 is：
The synthetic route of described preparation method is：
To realize above-mentioned 3rd purpose, the present invention adopts the technical scheme that：Described key intermediate disaccharides chemical combination
Application of the thing in anti-tumor vaccine is prepared.
Application of the described sugar compounds of key intermediate two in GM3 is prepared.
The invention has the advantages that：
1st, the invention provides one kind to be based on the sugar compounds of anti-tumor vaccine GM3 key intermediates two, the protection group of lactose
Group's benzyl incorporated above brings convenience for monitoring below, and the end position of the middle glucose of two sugar compounds introduces nitrine ethanol more
Easily.Anti-tumor vaccine GM3 can be efficiently synthesized by the sugar compounds of key intermediate two.
2nd, key intermediate disaccharides compound synthesis route of the invention is succinct, and simple to operate, cost of material is low, versatility
By force, glycosylation stereoselectivity is good, suitable for the synthesis of all kinds of oligosaccharide compounds.
Embodiment
Embodiment provided by the invention is elaborated with reference to embodiment.
The invention provides as follows based on the sugar compounds 1 of anti-tumor vaccine GM3 key intermediates two, its structure：
The structure of the target compound 1 of formula 1
The preparation method of above-claimed cpd：It is that initiation material is obtained by series reactions such as protection deprotections using glucose
Monose acceptor compound 9；It is that initiation material obtains monose donor chemical combination by series reactions such as protection deprotections using galactolipin
Thing 15；Then monose acceptor compound and monose compound donator obtain target compound 1 by glycosylation deprotection.
The synthesis of monose acceptor compound 9
It is initiation material with glucose 2, hydroxyl is protected through acetylation thereon, obtains compound 3, compound 3 is in trifluoro
Under the catalysis for changing borate ether, generation compound 4 is reacted with ethylene chlorhydrin, compound 4 obtains compound 5 with reaction of sodium azide again,
Compound 5 sloughs protection group generation compound 6, in reagent PhCH (OCH in the presence of methanolic sodium methoxide3)2Under effect, chemical combination
Hydroxyl on the selective protection C4 positions of thing 7, C6 positions, then exposed hydroxyl in compound 7 is carried out to protect to obtain compound 8,
THF.HCl and NaCNBH3In the presence of, the selective opening of compound 8, obtain disaccharides acceptor compound 9.Synthetic route is as follows：
The synthetic route of the monose acceptor compound 9 of formula 2
Reaction condition:(a)Ac2O/NaOAc,reflux,2h；(b)HOCH2CH2Cl,BF3·Et2O,M.S.,DCM,
rt,10h；(c)NaN3,DMF,18-crown-6,85℃,5h；(d)NaOCH3(cat.),MeOH,rt,2h；(e)PhCH
(OCH3)2,Camphorsulfonic acid,DMF,rt,5h；(f)Ac2O,pyridine,rt,overnight；(g)
NaCNBH3,Methyl Orange,M.S.,THF,THF.HCl,0℃,2h.
The synthesis of monose compound donator 15
It is initiation material with galactolipin 10, by acetylization reaction, its hydroxyl is protected, obtain compound 11, changes
Compound 11 reacts generation compound 12 under BFEE catalysis, with ethyl mercaptan, and compound 12 is in methanol and sodium methoxide
The lower generation compound 13 of effect, under the effect of reagent acetone fork, the selective protection C3 positions of compound 13 and C4 positions hydroxyl, Ran Houhua
Compound 14 generates compound 15 in pyridine with acetic acid anhydride reactant.Synthetic route is as follows：
The synthetic route of the compound donator 15 of formula 3
Reaction condition:(a)Ac2O/NaOAc,reflux,3h；(b)EtSH,BF3·Et2O,M.S.,DCM,rt,
10h；(c)NaOCH3(cat.),MeOH,rt,2h；(d)Me2C(OCH3)2,(1S)-(+)-10-Camphorsulfonic
acid,DMF,rt,3h；(e)Ac2O,pyridine,rt,overnight.
The synthesis of target compound 1
Monose compound donator 15 and monose acceptor compound 9, glycosylation reaction generates two sugar compounds 16, in 65% vinegar
In the presence of acid, compound 16 takes off protection group acetonylidene, obtains disaccharides acceptor compound 1.Synthetic route is as follows：
The synthetic route of the target compound 1 of formula 4
Reaction condition:(a)NIS,M.S.,AgOTf,DCM,0℃,2h；(b) 65%acetic acid in H2O,
65℃,3h
Preparing for the particular compound being related in above-mentioned preparation method is as follows：
The preparation of the compound 3 of embodiment 1
1000ml three-necked bottles, add NaOAc (16.0g, 0.20mol), 200ml Ac2O is dissolved, heating stirring, when
When temperature rises to 100 DEG C, compound 2 (53.0g, 0.32mol), and 76ml Ac are slowly added into reaction bulb2O, continue to add
Thermal response 3h.TLC(PE:EA=1:1,Rf=0.5) detect, after reaction completely, stop heating, and rapidly shift reaction system
Methanol 250ml is added dropwise dropwise thereto into ice-water bath, and with constant temperature and pressure dropping funel, removes unnecessary acetic anhydride.Reaction
Liquid is extracted with ethyl acetate, and organic phase is washed twice with water, then is distinguished with saturated sodium bicarbonate solution and saturated nacl aqueous solution
Wash twice, anhydrous sodium sulfate drying.Filtering, is concentrated under reduced pressure, solvent evaporated, solid recrystallizing methanol.Obtain white foam
Solid 3 (80.0g, 52.3%).1H NMR(300MHz,CDCl3)δ:5.72 (d, J=8.2Hz, 1H), 5.30-5.21 (t, J=
9.0Hz, 1H), 5.19-5.10 (m, 2H), 4.30 (dd, J=12.5,4.5Hz, 1H), 4.11 (dd, J=12.5,2.1Hz,
1H),3.84(m,1H),2.12,2.09,2.04,2.04,2.02(5s,5×3H,-OAc).
The preparation of the compound 4 of embodiment 2
100ml eggplant-shape bottles, 17 (5.0g, 11.98mmol) are added, add 15ml dichloromethane and dissolved, added
HOCH2CH2Cl (1.6ml, 23.96mmol), and powdered molecular sieve 2.5g, 1h is stirred at room temperature under nitrogen protection.TLC(PE:
EA=1:1,Rf=0.7) detect, reaction is complete.Reaction system is transferred to ice-water bath, is being slowly added to BF thereto3 .Et2O
(6.0ml, 47.92mmol), continue to react 9h.The pH of reaction solution is adjusted to 7~8 with triethylamine, and is extracted with ethyl acetate, is had
Machine is mutually washed twice with water, then is washed twice respectively with saturated nacl aqueous solution with saturated sodium bicarbonate solution, anhydrous sodium sulfate
Dry.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:EA=1.5:1).Obtain white foam solid 4 (3.2g, 60.0%).
The preparation of the compound 5 of embodiment 3
100ml eggplant-shape bottles, compound 4 (2.6g, 6.33mmol) is added, 15ml DMF are dissolved, and add Azide
Sodium (2.1g, 31.62mmol), 18-O-6 (167mg, 0.63mmol), 85 DEG C of heating response 5h.TLC(PE:EA=1:1,Rf=
0.6) detect, reaction is complete.The pH of reaction solution is adjusted to 7~8 with triethylamine, and is extracted with ethyl acetate, organic phase is washed with water
Wash twice, then washed twice respectively with saturated nacl aqueous solution with saturated sodium bicarbonate solution, anhydrous sodium sulfate drying.Filtering,
It is concentrated under reduced pressure, silica gel column chromatography (PE:EA=1.5:1).Obtain white foam solid 5 (2.05g, 99.0%).1H NMR
(300MHz,CDCl3)δ:5.22 (t, J=9.4Hz, 1H), 5.15-4.97 (m, 2H), 4.61 (t, J=8.4Hz, 1H), 4.31-
4.11(m,2H),4.04(m,1H),3.78-3.62(m,2H),3.50(m,1H),3.37-3.23(m,1H),2.09(s,3H,-
OAc),2.06(s,3H,-OAc),2.03(s,3H,-OAc),2.01(s,3H,-OAc).
The preparation of the compound 6 of embodiment 4
50ml eggplant-shape bottles, compound 5 (500mg, 1.20mmol) is added, add 10ml methanol and dissolved, added
NaOCH3(12.9mg, 0.24mmol), the lower room temperature reaction 2h of nitrogen protection.TLC(PE:EA=1:1,Rf=0.05) detect, reaction
Completely.The pH of reaction solution is adjusted to 4~5 with acid-exchange resin, filtering, is concentrated under reduced pressure, centrifugal drying.Brown is obtained to consolidate
Body 6 (280mg, 93.3%), continue to react in next step.
The preparation of the compound 7 of embodiment 5
50ml eggplant-shape bottles, 6 (280mg, 1.12mmol) are added, add 10ml DMF and dissolved, add phCH
(OMe)2(0.25ml, 1.69mmol), D- camphor -10- sulfonic acid (26mg, 0.11mmol), the lower room temperature reaction 5h of argon gas protection.
TLC(EA:MeOH=8:1,Rf=0.8) detect, reaction is complete.The pH of reaction solution is adjusted to 7~8 with triethylamine, is concentrated under reduced pressure,
Obtain off-white powder 7 (2.0g, 55.6%).1H NMR(300MHz,CDCl3)δ:7.58-7.44(m,2H,aromatic H),
7.44-7.33(m,3H,aromatic H),5.56(s,1H,phCH(O)2-), 4.47 (d, J=7.7Hz, 1H, H-1), 4.36
(dd, J=10.5,4.9Hz, 1H), 4.15-4.03 (m, 1H), 3.92-3.72 (m, 3H), 3.65-3.46 (m, 4H), 3.41 (m,
1H).
The preparation of the compound 8 of embodiment 6
Compound 7, DMAP (6mg, 0.05mmol) and Ac are added in 50ml eggplant-shape bottles2O 4ml, pyridine 8ml is added, mixed
Even, argon gas protection is lower to be reacted at room temperature.TLC(PE:EA=1:1,Rf=0.8) detect, reaction is complete.Removed with methanol in reaction solution
Unnecessary acetic anhydride, reaction solution are extracted with ethyl acetate, and organic phase is washed twice with water, then with saturated sodium bicarbonate solution with satisfying
Washed twice respectively with sodium chloride solution, anhydrous sodium sulfate drying.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:EA=2.5:
1).Obtain off-white powder 8 (290mg, 90.8%).1H NMR(300MHz,CDCl3)δ:7.70-7.32(m,5H,aromatic
H),5.52(s,1H,phCH(O)2-), 5.34 (t, J=9.4Hz, 1H), 5.11-4.98 (m, 1H), 4.68 (d, J=7.8Hz,
1H, H-1), 4.38 (dd, J=10.5,4.8Hz, 1H), 4.10-3.99 (m, 1H), 3.88-3.66 (m, 3H), 3.62-3.41
(m,2H),3.32(m,1H),2.08(s,3H,-OAc),2.06(s,3H,-OAc).
The preparation of the compound 9 of embodiment 7
100ml eggplant-shape bottles, compound 8 (1.43g, 3.41mmol) is added, add 20ml tetrahydrofurans (steaming again) its is molten
Solution, adds NaCHBH3(2.2g, 34.1mmol), appropriate methyl orange, and powdered molecular sieve 2.0g, mix, argon gas is protected
The lower room temperature reaction 2h of shield.TLC(PE:EA=2:1,Rf=0.3) detect, reaction is complete.During with triethylamine, reaction solution pH is adjusted to
Property, and be extracted with ethyl acetate, organic phase is washed twice with water, then is divided with saturated sodium bicarbonate solution and saturated nacl aqueous solution
Do not wash twice, anhydrous sodium sulfate drying.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:EA=2:1).Viscous brown shape is obtained to consolidate
Body 9 (1.2g, 90.3%).1H NMR(300MHz,CDCl3)δ:7.42-7.29 (m, 5H, aromatic H), 5.05 (t, J=
9.3Hz,1H),4.99-4.91(m,1H),4.74-4.48(m,3H),4.08-3.94(m,1H),3.84-3.61(m,4H),
3.60-3.39(m,2H),3.34-3.19(m,1H),3.06(s,1H),2.08(s,3H,-OAc),2.05(s,3H,-OAc).
The preparation of the compound 11 of embodiment 8
500ml single port bottles, 10 (53.0g, 0.32mol), acetic anhydride 370ml and sodium acetate (16.0g, 0.20mol) are added,
Heating response under the conditions of 140 DEG C.TLC(PE:EA=1:1,Rf=0.5) detect, after reaction completely, reaction system is transferred to ice
In water-bath, and 350ml methanol is slowly added to thereto, react 2h.Reaction solution is extracted with ethyl acetate, and organic phase is washed with water two
It is secondary, then washed twice respectively with saturated nacl aqueous solution with saturated sodium bicarbonate solution, anhydrous sodium sulfate drying.Filtering, decompression
Concentration, silica gel column chromatography (PE:EA=1:1).Obtain white foam solid 11 (80.0g, 52.3%).1H NMR(300MHz,
CDCl3)δ:5.70 (d, J=8.3Hz, 1H), 5.43 (d, J=3.2Hz, 1H), 5.34 (m, 1H), 5.08 (dd, J=10.4,
3.4Hz, 1H), 4.14 (m, 2H), 4.06 (dd, J=12.2,5.5Hz, 1H), 2.17,2.13,2.05,2.05,2.00 (5s, 5
×3H,-OAc).
The preparation of the compound 12 of embodiment 9
The synthetic route of the compound 12 of formula 5
250ml eggplant-shape bottles, compound 11 (10.0g, 0.0256mol) is added, add 25ml dichloromethane and dissolved, then
Add ethyl mercaptan 3.84ml and powdered molecular sieve 5.0g, the lower room temperature reaction 1h of nitrogen protection.Reaction system is transferred to frozen water
In bath, and BFEE 12.8ml is slowly added dropwise thereto, continues reaction overnight.TLC(PE:EA=1:1,Rf=0.55)
Detection, reaction are complete.Filtering, collect filtrate, organic phase is washed twice with water, then with saturated sodium bicarbonate solution and saturation chlorination
Sodium solution washes twice respectively, anhydrous sodium sulfate drying.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:EA=1:1).Obtain yellowish
Color solid 12.1H NMR(300MHz,CDCl3)δ:5.44 (d, J=2.6Hz, 1H, H-1), 5.26 (m, 1H), 5.05 (dd, J=
10.0,3.4Hz, 1H), 4.50 (d, J=9.9Hz, 1H), 4.14 (m, 2H), 3.94 (t, J=6.6Hz, 1H), 2.85-2.60
(m,2H,-SCH2 CH3),2.16(s,3H,-Ac),2.07(s,3H,-Ac),2.05(s,3H,-Ac),1.99(s,3H,-Ac),
1.29 (t, J=7.4Hz, 3H ,-SCH2 CH3 ).
The preparation of the compound 13 of embodiment 10
100ml eggplant-shape bottles, compound 12 (2.0g, 5.10mmol) is added, add 20ml methanol and dissolved, add first
Sodium alkoxide (55mg, 1.02mmol), the lower room temperature reaction 2h of nitrogen protection.TLC(EA:MeOH=8:1,Rf=0.8) detect, reacted
Entirely.The pH of reaction solution is adjusted to 4~5 with acid-exchange resin, filtering, is concentrated under reduced pressure, centrifugal drying.Obtain brown solid 13
(1161mg, 93.3%), continue to react in next step.
The preparation of the compound 14 of embodiment 11
100ml eggplant-shape bottles, compound 13 (1150mg, 5.10mmol) is added, add 20ml DMF and dissolved, added
Me2C(OMe)2(0.95ml, 7.70mmol), p-methyl benzenesulfonic acid (98mg, 0.51mmol), nitrogen protection is lower to be reacted at room temperature.TLC
(PE:EA=1:1,Rf=0.2) detect, reaction is complete.The pH of reaction solution is adjusted to 7~8 with triethylamine, and extracted with ethyl acetate
Taking, organic phase is washed twice with water, then washs organic phase respectively twice with saturated sodium bicarbonate solution and saturated nacl aqueous solution,
Anhydrous sodium sulfate drying.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:EA=1:1).Brown solid 14 (1.1g,
86.1%).1H NMR(300MHz,CDCl3)δ:4.27 (d, J=10.2Hz, 1H, H-1), 4.22 (m, 1H), 4.14-4.07 (m,
1H), 3.99 (m, 1H), 3.93-3.86 (m, 1H), 3.81 (dd, J=11.2,3.8Hz, 1H), 3.57 (dd, J=10.2,
7.1Hz,1H),2.81-2.72(m,2H,-SCH2 CH3),1.53(s,3H,-CH3),1.37(s,3H,-CH3),1.35-1.27
(m,3H,-SCH2 CH3 ).
The preparation of the compound 15 of embodiment 12
100ml eggplant-shape bottles, compound 14 (1.0g, 3.78mmol) is added, add 10ml pyridines and dissolved, added
DMAP (46mg, 0.38mmol), Ac2O (5.3ml, 56.75mmol), mix, argon gas protection is lower to be reacted at room temperature.TLC(PE:EA=
1:1,Rf=0.8) detect, reaction is complete.Acetic anhydride unnecessary in reaction solution is removed with methanol, and is extracted with ethyl acetate, is had
Machine is mutually washed twice with water, then is washed twice respectively with saturated nacl aqueous solution with saturated sodium bicarbonate solution, anhydrous sodium sulfate
Dry.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:EA=1:1).Obtain viscous brown shape solid 15 (624mg, 65.0%).1H
NMR(300MHz,CDCl3)δ:5.01(m,1H),4.42-4.29(m,3H),4.23-4.14(m,2H),4.04-3.94(m,
1H),2.77-2.61(m,2H,-SCH2 CH3),2.11(s,3H,-OAc),2.09(s,3H,-OAc),1.55(s,3H,-CH3),
1.34(s,3H,-CH3), 1.27 (t, J=7.4Hz, 3H ,-SCH2 CH3 ).
The preparation of the compound 16 of embodiment 13
100ml eggplant-shape bottles, compound 9 (1.23g, 3.54mmol) and 15 (1.0g, 2.36mmol) are added, add 15ml bis-
Chloromethanes is dissolved, and adds powdered molecular sieve 1.0g, is mixed, and is stirred overnight at room temperature under argon gas protection.Again to reactant
NIS (1.60g, 7.09mmol) is added in system, continues to stir 1h；Reaction system is transferred in ice-water bath, and added thereto
AgOTf (61mg, 0.21mmol), react 1h.TLC(PE:EA=2:1,Rf=0.4) detect, reaction is complete.Filter (diatomite
Drainage), filter cake is washed with dichloromethane, collects filtrate, organic phase is washed twice with 15% sodium thiosulfate, saturated sodium bicarbonate
Solution washes twice respectively with saturated nacl aqueous solution, anhydrous sodium sulfate drying.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:
EA=4:1~PE:EA=3:1).Obtain light tan solid 16 (1.0g, 59.8%).HR-MS Calcd for C32H43N3O15[M+
Na]+:732.2592；found:732.2587.
The preparation of the target compound 1 of embodiment 14
100ml eggplant-shape bottles, 16 (820mg, 1.16mmol) are added, 15ml 65% acetic acid is dissolved, under the conditions of 75 DEG C
Heating response 1.5h.TLC(EA,Rf=0.3) detect, reaction is complete.Stop heating, be cooled to room temperature.Reaction solution acetic acid second
Ester extracts, and organic phase is washed twice with water, then is washed twice respectively with saturated nacl aqueous solution with saturated sodium bicarbonate solution, nothing
Aqueous sodium persulfate is dried.Filtering, is concentrated under reduced pressure, silica gel column chromatography (PE:EA=3:1~PE:EA=2:1).Obtain brown solid 1
(360mg, 46.5%).
Embodiment 15GM3 preparation
Target compound 1 and N-acetyl-neuraminate, the ceramide (Cer) etc. of lipophilic are synthesized by series reaction
GM3.Through1H NMR analyses are GM3, and yield is high.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (2)
1. a kind of preparation method for being used to synthesize the GM3 sugar compounds of key intermediate two, described key intermediate two are saccharified
The structural formula of compound is：
Characterized in that, described preparation method obtains monose acceptor chemical combination using glucose as initiation material by series reaction
Thing 9；Monose compound donator 15 is obtained by series reaction using galactolipin as initiation material；Then monose acceptor compound 9
Target compound is obtained by glycosylation deprotection with monose compound donator 15；Wherein, the structural formula of monose acceptor compound 9
For：
The structural formula of monose compound donator 15 is：
2. the preparation method of the sugar compounds of key intermediate two as claimed in claim 1, it is characterised in that described preparation side
The synthetic route of method is：
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Citations (2)
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|---|---|---|---|---|
| CN1135756A (en) * | 1994-08-16 | 1996-11-13 | 大金工业株式会社 | Ganglioside GM3 analog Having sialic acid residue fluorinated at the 9-position and intermediate thereof |
| CN103157112A (en) * | 2011-12-19 | 2013-06-19 | 沈阳药科大学 | Application of sialic acid derivatives in preparation of polyethylene glycol (PEG) lipid derivative modifying agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1135756A (en) * | 1994-08-16 | 1996-11-13 | 大金工业株式会社 | Ganglioside GM3 analog Having sialic acid residue fluorinated at the 9-position and intermediate thereof |
| CN103157112A (en) * | 2011-12-19 | 2013-06-19 | 沈阳药科大学 | Application of sialic acid derivatives in preparation of polyethylene glycol (PEG) lipid derivative modifying agent |
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| Title |
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| 《Neoglycoprotein cancer vaccines: synthesis of an azido derivative of GM3 and its efficient coupling to proteins through a new linker》;Jie Xue, Yanbin Pan and Zhongwu Guo;《Tetrahedron Letters》;20021231;第43卷;1600页scheme2 * |
| 神经节苷脂GM3的有效合成;朱振元;《化学学报》;20071231;第65卷(第24期);全文 * |
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