CN118271376A - 一种制备硫苷化合物的方法 - Google Patents
一种制备硫苷化合物的方法 Download PDFInfo
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- CN118271376A CN118271376A CN202410443231.3A CN202410443231A CN118271376A CN 118271376 A CN118271376 A CN 118271376A CN 202410443231 A CN202410443231 A CN 202410443231A CN 118271376 A CN118271376 A CN 118271376A
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- Prior art keywords
- alkyl
- substituted
- unsubstituted
- compound
- halogen
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- -1 thio-glycoside compound Chemical class 0.000 title claims abstract description 77
- 229930182475 S-glycoside Natural products 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 40
- 239000000348 glycosyl donor Substances 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000000937 glycosyl acceptor Substances 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 11
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 239000003504 photosensitizing agent Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000002994 raw material Substances 0.000 abstract description 18
- 238000002360 preparation method Methods 0.000 abstract description 11
- 229930182478 glucoside Natural products 0.000 abstract description 6
- 238000007348 radical reaction Methods 0.000 abstract description 3
- 150000003254 radicals Chemical class 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 103
- 238000005160 1H NMR spectroscopy Methods 0.000 description 64
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 238000001035 drying Methods 0.000 description 26
- 238000005406 washing Methods 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 239000004201 L-cysteine Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 238000012512 characterization method Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 229930182470 glycoside Natural products 0.000 description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 150000003568 thioethers Chemical class 0.000 description 6
- NZEDMAWEJPYWCD-UHFFFAOYSA-N 3-prop-2-enylsulfonylprop-1-ene Chemical compound C=CCS(=O)(=O)CC=C NZEDMAWEJPYWCD-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002338 glycosides Chemical class 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000003147 glycosyl group Chemical group 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229910052717 sulfur Chemical group 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- MCYHPZGUONZRGO-VKHMYHEASA-N L-cysteine methyl ester hydrochloride Natural products COC(=O)[C@@H](N)CS MCYHPZGUONZRGO-VKHMYHEASA-N 0.000 description 2
- 229910013990 M1NH2 Inorganic materials 0.000 description 2
- WHOHXJZQBJXAKL-DFWYDOINSA-N Mecysteine hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CS WHOHXJZQBJXAKL-DFWYDOINSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ZBQKPDHUDKSCRS-UHFFFAOYSA-N $l^{1}-oxidanyl acetate Chemical group CC(=O)O[O] ZBQKPDHUDKSCRS-UHFFFAOYSA-N 0.000 description 1
- OGOMAWHSXRDAKZ-RUOAZZEASA-N (2s,3r,4s,5r,6r)-3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-ol Chemical compound C([C@H]1O[C@@H]([C@@H]([C@@H](OCC=2C=CC=CC=2)[C@@H]1OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)O)OCC1=CC=CC=C1 OGOMAWHSXRDAKZ-RUOAZZEASA-N 0.000 description 1
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 description 1
- BFHKYHMIVDBCPC-UHFFFAOYSA-N 1,3,5,7-tetrahydro-[1,3]oxazolo[3,4-c][1,3]oxazol-7a-ylmethanol Chemical compound C1OCN2COCC21CO BFHKYHMIVDBCPC-UHFFFAOYSA-N 0.000 description 1
- RXYYZDMPIXKVOX-PSHIPCJZSA-N 1-hydroxy-1-[(2R,3R,4S,5S,6R)-3,4,5-triacetyl-3,4,5-trihydroxy-6-methyl-6-sulfanyloxan-2-yl]propan-2-one Chemical compound CC(=O)C([C@@H]1[C@@]([C@]([C@@]([C@@](O1)(C)S)(C(=O)C)O)(C(=O)C)O)(C(=O)C)O)O RXYYZDMPIXKVOX-PSHIPCJZSA-N 0.000 description 1
- BAVQGBXKGOEGQQ-FJVJWUHISA-N 1-hydroxy-1-[(2R,3R,4S,5S,6R)-3,4,5-triacetyl-3,4,5-trihydroxy-6-phenyl-6-sulfanyloxan-2-yl]propan-2-one Chemical compound CC(=O)C([C@@H]1[C@@]([C@]([C@@]([C@@](O1)(C2=CC=CC=C2)S)(C(=O)C)O)(C(=O)C)O)(C(=O)C)O)O BAVQGBXKGOEGQQ-FJVJWUHISA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- UFJYVTQALAAQEQ-UHFFFAOYSA-N 2-methylprop-2-ene-1-thiol Chemical compound CC(=C)CS UFJYVTQALAAQEQ-UHFFFAOYSA-N 0.000 description 1
- RMMHOFFPGKSRDI-UHFFFAOYSA-N 3-bromoprop-1-en-2-ylbenzene Chemical compound BrCC(=C)C1=CC=CC=C1 RMMHOFFPGKSRDI-UHFFFAOYSA-N 0.000 description 1
- FKUBQFNUFKOTJJ-UHFFFAOYSA-N 5-(trifluoromethyl)-2-[[5-(trifluoromethyl)pyridin-2-yl]disulfanyl]pyridine Chemical compound N1=CC(C(F)(F)F)=CC=C1SSC1=CC=C(C(F)(F)F)C=N1 FKUBQFNUFKOTJJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
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- 108010031186 Glycoside Hydrolases Proteins 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
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Abstract
本发明公开了一种制备硫苷化合物的方法,属于合成化学以及药物化学技术领域。具体提供了一种利用式I所示的糖基供体制备式III所示的硫苷类化合物的方法。本发明提供的糖基供体结构新颖,制备方法简单;本发明以上述糖基供体为原料,利用自由基反应,制备得到了硫苷类化合物,其中大部分具有特殊的α构型,该制备方法简单、反应条件温和、收率高,具有非常好的应用前景。
Description
本申请是对申请号为2020800488733,申请日为2020年7月21日,发明名称为“一种新的糖基供体及其制备方法和用途”的发明专利提出的分案申请。
技术领域
本发明涉及合成化学以及药物化学技术领域,具体涉及一种新的糖基供体及其制备方法和用途,以及一种制备硫苷化合物的方法。
背景技术
糖类物质是生物体(包括动物、植物、微生物)的重要组成部分。多糖、寡糖及其与蛋白质、酯类等结合成的糖复合物涉及到细胞,特别是多细胞生命的全部时间和空间过程,它们作为信息分子参与细胞的各种识别过程:传递生物信息、参与机体的免疫调节,并与细胞分化、受精、胚胎发育、血液***、感染、衰老等多方面功能密切相关。近年来,由于糖类化合物显著的生理活性,越来越引起化学家们广泛的研究兴趣。糖苷(Glycosides)是糖在自然界存在的重要形式,它广泛存在于生物体内,具有特殊的生物活性,担负着重要的生理功能。糖苷是糖的半缩醛羟基与配基缩合失去一分子水或其它小分子化合物而形成的一类非常重要的化合物,其中糖部分称为糖基,非糖部分称为配基。根据糖苷化合物分子结构中的配基与糖环碳原子相连的原子类型可把糖苷化合物分为氧苷化合物、氮苷化合物、硫苷化合物和碳苷化合物,它们大都表现出很好的生物学功能,如糖苷酶抑制活性抗菌、抗病毒和抗肿瘤活性等。
目前已有很多构建糖苷类化合物的方法,但是,这些方法条件不够温和、官能团兼容性差。同时,大部分现有方法很难高立体选择性地制备α构型的糖苷化合物。
因此,研究结构新颖的、制备方法简单的糖基供体,对进一步制备各种糖苷化合物(比如氧苷化合物、氮苷化合物、硫苷化合物和碳苷化合物)具有非常大的应用价值。
发明内容
为了解决上述问题,本发明提供了一种结构新颖的烯丙基砜类糖基供体,并以该烯丙基砜类糖基供体为原料制得了硫苷化合物。
本发明提供了一种糖基供体、或其盐、或其立体异构体、或其旋光异构体,所述糖基供体的结构如式I所示:
其中,A环选自R1、R2、R3、R4各自独立地选自H、C1-6烷基、芳基或者杂芳基取代的C1-12烷基、C1-6烷氧基、C2-8炔基、C2-8烯基、芳香基、杂芳基、环烷基、M1OH、M1NH2、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTMS、M1OTBS、 或者R1、R2、R3、R4中的任意2个连接成环;M1选自0-3个亚甲基;M2、M3、M4选自H、C1-6烷基、芳基或者杂芳基取代的C1-12烷基、C2-8炔基、C2-8烯基、芳香基、杂芳基,或者M3、M4连接成环;
R5选自C1-10烷基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、C1~10烷氧基、卤素、氰基、羧基、酯基;
R6、R7、R8、R9各自独立地选自H、卤素、C1-6烷基、C1-6烷氧基、M1OH、C2-8炔基、C2-8烯基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、氰基、酯基;M1选自0-3个亚甲基。
进一步地,所述糖基供体的结构如式II-1或II-2所示:
其中,R1、R2、R3、R4各自独立地选自H、C1-6烷基、C1-6烷氧基、C2-6炔基、C2-6烯基、芳香基、杂芳基、环烷基、M1OH、M1NH2、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTMS、M1OTBS、或者R1、R2、R3、R4中的任意2个连接成取代或未取代的环,该环上的取代基各自独立的选自1个或多个氢、氘、C1-8烷基、C1~8烷氧基、C2-8炔基、C2-8烯基、芳香基、杂芳基、卤素、氰基、羧基或酯基;
M1选自0-3个亚甲基;
R5选自C1-8烷基、饱和环烷基、饱和杂环基、H、芳香基、杂芳基、C1~8烷氧基、卤素、氰基、羧基、酯基;
优选地,所述R1、R2、R3、R4各自独立地选自H、C1-6烷基、C1-6烷氧基、C2-3炔基、C2-3烯基、芳香基、杂芳基、环烷基、M1OH、M1NHAc、M1OAc、M1OBz、或者R1、R2、R3、R4中的任意2个连接成环,该环上的取代基各自独立的选自1个或多个氢、氘、C1-4烷基、C1~4烷氧基、C2-3炔基、C2-3烯基、苯基、杂芳基、卤素、氰基、羧基或酯基;M1选自0-1个亚甲基;
R5选自H、苯基、C1-8烷基。
进一步地,所述糖基供体的结构选自:
进一步地,所述糖基供体的结构选自:
其中,表示或二者的任意比例混合物。
本发明还提供了一种硫苷化合物、或其盐、或其立体异构体、或其旋光异构体,所述硫苷化合物的结构如式III所示:
其中,R10选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、肽链去掉一个氢原子后剩下的基团,所述取代基选自卤素、卤代烷基;上述m表示1-5的整数;
上述Y选自无、NH或O;R1a、R2a选自各自独立地选自H、Boc、Bz、C1-6烷基、C1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、其中m1、m2各自独立地选自0-5的整数;Ra1选自取代或未取代的C1-6烷基,所述取代基选自卤素、羟基;Ra3选自取代或未取代的C1-6烷基、芳基、杂芳基,所述取代基选自卤素、羟基;
A环选自
R1、R2、R3、R4如上所述。
进一步地,所述硫苷化合物的结构如式III-1、III-2、III-3或III-4所示:
式III-1和式III-3中:当Y选自O时,R1a选自甲基,R2a选自Bz、H、当Y选自NH时,R1a选自R2a选自Boc;当Y选自无时,R1a选自甲氧基,R2a选自Bz;
式III-2和式III-4中:R10选自取代或未取代的苯环、取代或未取代的氮杂芳环、甲基、所述取代基选自卤素、卤代烷基;
式III-1、式III-2、III-3和III-4中:R1、R2、R3、R4如上所述。
进一步地,所述硫苷化合物的结构选自:
进一步地,所述硫苷化合物的结构选自:
本发明还提供了上述的糖基供体在制备硫苷化合物化合物中的用途;优选的,所述硫苷化合物如上所述。
本发明还提供了一种制备上述糖基供体的方法,所述方法包括以下步骤:
(1)原料Y1与乙酸酐反应,得到化合物Y2;
(2)化合物Y2先与硫脲反应,再加入化合物Y3,继续反应,得到化合物Y4;
(3)化合物Y4与mCPBA反应,得到糖基供体;
其中,原料Y1的结构为化合物Y2的结构为化合物Y3的结构为化合物Y4的结构为
X选自卤素,优选为溴;
R1、R2、R3、R4、R5、R6、R7、R8、R9如上所述。
进一步地,步骤(1)中,所述乙酸酐与原料Y1上羟基的摩尔比为(0.8~1.5):1;反应是在三乙胺和DMAP的作用下进行的;反应温度为室温;反应溶剂为二氯甲烷;
步骤(2)中,化合物Y2、硫脲、化合物Y3的摩尔比为1:(1.5~4.5):(1.2~2);加入化合物Y3前的反应温度为加热回流,反应时间为(2~6)小时;加入Y3前的反应是在三氟化硼***的作用下进行的;加入Y3后的反应温度为加热回流,反应时间为(4~8)小时;加入Y3后的反应是在三乙胺的作用下进行的;反应溶剂为乙腈;
步骤(3)中,化合物Y4与mCPBA的摩尔比为1:(1.5~4.5);反应时间为1~3小时;反应溶剂为二氯甲烷;
优选地,
步骤(1)中,所述乙酸酐与原料Y1上羟基的摩尔比为1.2:1;
步骤(2)中,化合物Y2、硫脲、化合物Y3的摩尔比为1:3:1.5;加入化合物Y3前的反应时间为4小时;加入Y3后的反应时间为6小时;
步骤(3)中,化合物Y4与mCPBA的摩尔比为1:2.5;反应温度为室温,反应时间为2小时。
本发明还提供了一种制备上述硫苷化合物的方法,所述方法为:将上述的糖基供体与糖基受体反应,得到硫苷化合物;
其中,所述糖基受体的结构为
R5s选自
R10如上所述。
进一步地,所述R5s选自R10如上所述;
所述糖基供体与糖基受体的摩尔比为1:(1.1~2.5),优选为1:(1.2~2);
所述反应是在氮气氛围中、蓝色LED的照射下进行的;
所述反应的温度为20~45℃,优选为室温~45℃;反应时间为1.5~5小时,优选为2~4小时;
所述反应是在光敏剂的作用下进行的,光敏剂选自
Ir[dF(CF3)(ppy)2](dtbbpy)PF6,优选为Ir[dF(CF3)(ppy)2](dtbbpy)PF6,更优选为Ir[dF(CF3)(ppy)2](dtbbpy)PF6;
所述反应的溶剂选自水或者1,2-DCE、DMSO、EtOAc、glyme、1,4-dioxane、THF、MeOH、DMF、MeCN、MeCN中的一种或多种与水在任意比例下组成的混合溶液。
糖基供体是指合成糖苷时,含有糖苷键的原料,或含有参加反应的端基异头碳的原料;而与之反应的另一种原料被称为糖基受体。
本发明的糖基供体可以采用糖基供体的合成实施例路线1~4中的任意一条制得,也可以采用其他的方法来制备。
试验证明,本发明提供的糖基供体结构新颖,具有特殊的烯丙基砜结构,并且其制备方法简单;本发明进一步以上述的糖基供体为原料,利用自由基反应,制备得到了硫苷类化合物,其中大部分具有特殊的α构型,该制备方法简单、反应条件温和、收率高,具有非常好的应用前景。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca-b烷基表示任何含“a”至“b”个碳原子的烷基。例如,C1-8烷基是指包含1-8个碳原子的直链或支链的烷基。
类似的,C1-8烷氧基是指包含1-8个碳原子的直链或支链的烷氧基。
本发明中,Ac表示乙酰基,结构为Ph表示苯基,结构为Bz表示苯甲酰基,结构为Boc表示叔丁氧羰基,结构为Me表示甲基。
本发明中,肽链是指由多个氨基酸相互连接形成的含有多个肽键的链状结构。
“mCPBA”为间氯过氧苯甲酸。
本发明中,芳基即芳香基;Ar表示芳基。芳基指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
杂芳基指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
“环烷基”指饱和或不饱和的环状烃取代基,环状烃可以是单环也可以是多环。“饱和环烷基”指饱和的环烷基。
“杂环基”指饱和或不饱和的环状烃取代基,环状烃可以是单环也可以是多环,且携带至少一个环杂原子(包括但不限于O、S或N)。“饱和杂环基”指饱和的杂环基。
“盐”是将化合物与无机和/或有机酸和/或碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。
本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
合成糖基供体:
采用以下合成路线,制备本发明的合成糖基供体:
以下为本发明烯丙基砜类糖基供体的合成实施例。
1,合成路线1
1),合成路线
2),操作步骤详述(以化合物3-1合成为例)
a),室温下全乙酰基保护的底物1-1(10mmol)溶于乙腈(40mL),加入硫脲(1.5eq)和三氟化硼***(3eq),回流4h,冷却至室温。加入3-溴-2甲基丙烯(1.5eq)和三乙胺(3eq)回流6h后却至室温。减压旋干乙腈后二氯甲烷溶解,饱和食盐水溶液洗涤,二氯甲烷萃取,无水硫酸钠干燥,抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的硫醚中间体2-1。
b),冰浴下将上步所得化合物2-1溶于二氯甲烷中,缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤,用二氯甲烷洗涤固体。将滤液用饱和Na2S2O3溶液洗涤一次,饱和Na2CO3溶液洗涤二次,二氯甲烷萃取,无水硫酸钠干燥,抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-1,纯度大于90%,总收率为75%。
其结构表征如下:1H NMR(400MHz,Chloroform-d)δ5.53(t,J=9.6Hz,1H),5.31(t,J=9.3Hz,1H),5.27(t,J=1.6Hz,1H),5.20(d,J=1.4Hz,1H),5.10(t,J=9.8Hz,1H),4.58(d,J=9.9Hz,1H),4.31-4.17(m,2H),3.98(d,J=13.6Hz,1H),3.80(ddd,J=10.1,5.1,2.7Hz,1H),3.66(d,J=13.6Hz,1H),2.09(s,3H),2.05(s,3H),2.04(s,3H),2.03(s,3H),1.98(s,3H).
其他3-2至3-11化合物的合成采取与上述3-1相同的路线合成,其结构与表征数据如下:
纯度大于90%,总收率为62%,1H NMR(400MHz,Chloroform-d)(α:β=1:6)(β-isomer)δ5.72(t,J=9.9Hz,1H),5.47(d,J=3.3Hz,1H),5.27(s,1H),5.20(s,1H),5.15(dd,J=10.1,3.3Hz,1H),4.57(d,J=9.8Hz,1H),4.19(m,J=5.4Hz,2H),4.07(t,J=6.3Hz,1H),3.99(d,J=13.6Hz,1H),3.69(d,J=13.6Hz,1H),2.19(s,3H),2.06(s,6H),2.00(s,3H),1.98(s,3H).
纯度大于90%,总收率为62%,1H NMR(400MHz,Chloroform-d)δ5.94(dd,J=3.8,2.1Hz,1H),5.59(dd,J=9.2,3.6Hz,1H),5.29(t,J=9.7Hz,1H),5.27-5.24(m,1H),5.21-5.18(m,1H),4.99(d,J=2.1Hz,1H),4.70(ddd,J=9.9,5.8,2.4Hz,1H),4.27(dd,J=12.5,5.8Hz,1H),4.17(dd,J=12.5,2.5Hz,1H),4.00(d,J=13.9Hz,1H),3.67(d,J=13.9Hz,1H),2.17(s,3H),2.11(s,3H),2.07(s,3H),2.01(s,3H),1.98(s,3H).
纯度大于90%,总收率为51%,1H NMR(400MHz,Chloroform-d)(α:β=2:1)(α-isomer)δ5.47(ddd,J=9.7,7.7,5.1Hz,1H),5.25(s,1H),5.18(s,1H),5.05-4.94(m,2H),4.68-4.58(m,1H),4.27(dd,J=12.5,5.6Hz,1H),4.15(dd,J=12.4,2.5Hz,1H),3.98(d,J=13.8Hz,1H),3.65(d,J=13.8Hz,1H),2.82(ddd,J=14.8,5.2,3.4Hz,1H),2.18-2.11(m,1H),2.10(s,3H),2.06(s,3H),2.05(s,3H),1.98(d,J=1.4Hz,3H).
纯度大于90%,总收率为35%,1H NMR(400MHz,Chloroform-d)δ5.68(t,J=9.9Hz,1H),5.31(dd,J=3.4,1.1Hz,1H),5.27(t,J=1.5Hz,1H),5.15(s,1H),5.12(dd,J=10.0,3.4Hz,1H),4.47(d,J=9.9Hz,1H),3.96-3.93(m,1H),3.92(d,J=0.9Hz,1H),3.73(d,J=13.5Hz,1H),2.20(s,3H),2.06(s,3H),2.00(s,3H),1.98(s,3H),1.28(d,J=6.4Hz,3H).
纯度大于90%,总收率为58%,1H NMR(400MHz,Chloroform-d)δ5.93(dd,J=3.7,2.0Hz,1H),5.53(dd,J=9.4,3.7Hz,1H),5.25(p,J=1.5Hz,1H),5.17(s,1H),5.10(t,J=9.5Hz,1H),4.94(d,J=2.0Hz,1H),4.55(dq,J=9.6,6.2Hz,1H),3.97(d,J=13.9Hz,1H),3.66(d,J=13.9Hz,1H),2.16(s,3H),2.06(s,3H),2.00(s,3H),1.98(s,3H),1.29(d,J=6.2Hz,3H).
纯度大于90%,总收率为63%,1H NMR(400MHz,Chloroform-d)δ5.51(t,J=9.1Hz,1H),5.30(t,J=8.9Hz,1H),5.26(t,J=1.5Hz,1H),5.13(s,1H),5.02(td,J=9.0,5.3Hz,1H),4.54(d,J=9.2Hz,1H),4.39(dd,J=11.6,5.3Hz,1H),3.91(d,J=13.4Hz,1H),3.69(d,J=13.4Hz,1H),3.47(dd,J=11.6,9.1Hz,1H),2.10-2.00(m,9H),1.97(s,3H).
纯度大于90%,总收率为56%,1H NMR(400MHz,Chloroform-d)δ5.75(dd,J=7.3,3.4Hz,1H),5.49(dd,J=5.8,3.5Hz,1H),5.26(p,J=1.5Hz,1H),5.16(s,1H),5.01(ddd,J=5.9,4.3,3.0Hz,1H),4.76(d,J=7.3Hz,1H),4.17(dd,J=12.4,4.4Hz,1H),4.01(dd,J=12.4,3.0Hz,1H),3.94(d,J=13.6Hz,1H),3.69(d,J=13.6Hz,1H),2.14(s,1H),2.12(s,3H),2.09(s,3H),1.98(s,3H).
纯度大于90%,总收率为33%,1H NMR(400MHz,Chloroform-d)δ5.73(t,J=9.4Hz,1H),5.35(tt,J=2.7,1.5Hz,1H),5.27(t,J=1.5Hz,1H),5.22-5.10(m,1H),4.47(d,J=9.3Hz,1H),4.24(dd,J=12.9,2.6Hz,1H),3.92(d,J=13.4Hz,1H),3.80(dd,J=13.0,1.5Hz,1H),3.77-3.73(d,J=13.4Hz,1H),2.18(s,3H),2.08(s,3H),2.04(s,3H),1.98(s,3H).
化合物3-10与化合物3-1合成步骤相同,只需在第一步中使用3-溴丙烯替代3-溴-2甲基丙烯即可,纯度大于90%,总收率为75%,
1H NMR(400MHz,Chloroform-d)δ5.99-5.79(m,1H),5.58-5.47(m,3H),5.31(t,J=9.3Hz,1H),5.10(t,J=9.8Hz,1H),4.56(d,J=9.9Hz,1H),4.34-4.16(m,2H),3.98(dd,J=13.9,8.4Hz,1H),3.83-3.73(m,2H),2.10(s,3H),2.05(s,3H),2.05(s,3H),2.03(s,3H).
化合物3-11与化合物3-1合成步骤相同,只需在第一步中使用3-溴-2苯基丙烯替代3-溴-2甲基丙烯即可,纯度大于90%,总收率为71%,
1H NMR(400MHz,Chloroform-d)δ7.50-7.46(m,2H),7.43-7.36(m,3H),5.77(s,1H),5.60(s,1H),5.50(t,J=9.6Hz,1H),5.16(t,J=9.3Hz,1H),5.03(t,J=9.8Hz,1H),4.51(d,J=14.2Hz,1H),4.17(d,J=9.9Hz,1H),4.10-4.03(m,3H),3.29(dt,J=10.1,3.5Hz,1H),2.10(s,3H),2.02(s,3H),2.01(s,3H),2.00(s,3H).
2,合成路线2
1),合成路线
2),操作步骤详述(以化合物3-12合成为例)
a),0℃下,全乙酰基基保护的2-氨基葡萄糖底物1-12(10mmol)溶于DCM(30mL)中,缓慢滴加33%氢溴酸乙酸溶液(30mL)并搅拌5小时。原料反应完全后,用冰水淬灭,在冰水浴下用饱和碳酸钾水溶液中和反应液,用二氯甲烷萃取,冰的饱和碳酸氢钠水溶液和冰的饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤,在空气冷凝下旋干滤液,得到粗品1-12-1。无需纯化,直接投下一步;
b),粗品1-12-1和硫脲(1.5eq)溶于丙酮(20mL)中,60℃下回流搅拌10分钟,有大量固体析出。待反应液降至室温后,抽滤得到固体即为中间体1-12-2。
c),中间体1-12-2和无水碳酸钾(2.0eq)溶于丙酮/水(2:1,20mL)中,滴加3-溴-2甲基丙烯(1.5eq)室温搅拌过夜,旋干溶剂后,经二氯甲烷萃取,水和饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤并旋干滤液,采用柱层析法纯化得到硫醚中间体2-12。
d),冰浴下将上步所得化合物2-12溶于二氯甲烷中,缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤,用二氯甲烷洗涤固体。将滤液用饱和Na2S2O3溶液洗涤一次,饱和Na2CO3溶液洗涤二次,二氯甲烷萃取,无水硫酸钠干燥,抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-12,纯度大于90%,总收率为31%。
其表征数据如下:
1H NMR(400MHz,Chloroform-d)δ6.07(d,J=7.9Hz,1H),5.72(t,J=9.7Hz,1H),5.25(s,1H),5.21-5.15(m,2H),5.05(t,J=9.2Hz,1H),4.25(dd,J=12.6,2.5Hz,1H),4.20(dd,J=12.6,5.3Hz,1H),4.10-4.03(m,1H),4.00(d,J=13.6Hz,1H),3.89(ddd,J=10.3,5.2,2.5Hz,1H),3.69(d,J=13.5Hz,1H),2.09(s,3H),2.05(d,J=1.6Hz,6H),1.96(s,3H),1.94(s,3H).
化合物3-13的合成路线与3-12相同,使用全乙酰基2-氨基半乳糖为起始原料即可获得产物3-13.纯度大于90%,其表征数据如下:
1H NMR(400MHz,Chloroform-d)δ6.28(d,J=8.0Hz,1H),5.72(dd,J=10.8,3.3Hz,1H),5.46(d,J=3.3Hz,1H),5.20(s,1H),5.17(d,J=10.2Hz,1H),4.25(m,1H),4.22-4.11(m,3H),4.02(d,J=13.5Hz,1H),3.73(d,J=13.5Hz,1H),2.18(s,3H),2.05(s,3H),2.01(s,3H),1.96(s,3H),1.94(s,3H).3,合成路线3
1),合成路线
2),操作步骤详述(以化合物3-14合成为例)
a),0℃下,化合物1-14(10mmol)溶于二氯甲烷(30mL)中,先后缓慢滴加硫代乙酸(24mmol)和三氟化硼***(30mmol),随后升至室温搅拌过夜。原料反应完全后,用冰水淬灭,二氯甲烷萃取,饱和碳酸氢钠水溶液、饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤并旋干滤液,得到中间体1-14-1。
b),中间体1-14-1和半胱酸甲酯盐酸盐(2.05g,12mmol)溶于DMF(10mL)中,加入三乙胺(1.7mL,12mmol)室温搅拌8小时。TLC监测中间体1-14-1反应完全后,经乙酸乙酯萃取,半饱和食盐水洗涤后,用无水硫酸钠干燥有机相,抽滤并旋干滤液,采用柱层析法纯化得到产物中间体1-14-2。
c),物中间体1-14-2和无水碳酸钾(2.5eq)溶于丙酮/水(2:1,20mL)中,滴加3-溴-2甲基丙烯(2.5eq)室温搅拌过夜,旋干溶剂后,经二氯甲烷萃取,水和饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤并旋干滤液,采用柱层析法纯化得到硫醚物中间体2-14。
d),冰浴下将上步所得化合物2-14溶于二氯甲烷中,缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤,用二氯甲烷洗涤固体。将滤液用饱和Na2S2O3溶液洗涤一次,饱和Na2CO3溶液洗涤二次,二氯甲烷萃取,无水硫酸钠干燥,抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-14,纯度大于90%,总收率为48%。
其表征数据如下:
1H NMR(400MHz,Chloroform-d)δ5.41(d,J=4.1Hz,1H),5.39-5.32(m,3H),5.27(t,J=1.5Hz,1H),5.21(s,1H),5.05(t,J=9.9Hz,1H),4.87(dd,J=10.6,4.0Hz,1H),4.73-4.67(m,1H),4.64(dd,J=12.4,2.6Hz,1H),4.24(ddd,J=24.7,12.4,4.6Hz,2H),4.08(dd,J=12.4,2.3Hz,1H),4.04-3.94(m,3H),3.79(ddd,J=9.7,5.1,2.5Hz,1H),3.59(d,J=13.7Hz,1H),2.14(s,3H),2.11(s,3H),2.06-2.01(m,12H),2.00(s,3H),1.97(s,3H).
化合物3-15的合成路线与3-14相同,使用全乙酰基麦芽糖为起始原料即可获得产物3-15.纯度大于90%,其表征数据如下:
1H NMR(400MHz,Chloroform-d)δ5.47(t,J=9.4Hz,1H),5.38-5.35(m,1H),5.32(d,J=9.0Hz,1H),5.27-5.23(m,1H),5.18(s,1H),5.11(dd,J=10.5,7.9Hz,1H),4.98(dd,J=10.4,3.4Hz,1H),4.65-4.57(m,2H),4.52(d,J=7.8Hz,1H),4.18-4.04(m,3H),3.97(d,J=13.7Hz,1H),3.89(t,J=6.7Hz,1H),3.82(t,J=9.4Hz,1H),3.76-3.66(m,1H),3.57(d,J=13.7Hz,1H),2.15(s,3H),2.12(s,3H),2.07(s,3H),2.06(s,3H),2.05(s,3H),2.04(s,3H),1.97(s,6H).
4,合成路线4
1),合成路线
2),操作步骤详述(以化合物3-16合成为例)
a),0℃下,化合物1-16(10mmol)溶于二氯甲烷(30mL)中,先后缓慢滴加3-巯基-2甲基丙烯(2.5eq)和三氟化硼***(30mmol),0℃搅拌8h。原料反应完全后,用冰水淬灭,二氯甲烷萃取,饱和碳酸氢钠水溶液、饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤并旋干滤液,得到硫醚中间体2-16。
b),冰浴下将上步所得化合物2-16溶于二氯甲烷中,缓慢加入m-CPBA(2.5eq)后,升至室温反应2h。抽滤,用二氯甲烷洗涤固体。将滤液用饱和Na2S2O3溶液洗涤一次,饱和Na2CO3溶液洗涤二次,二氯甲烷萃取,无水硫酸钠干燥,抽滤、浓缩后使用柱层析(300目-400目硅胶)分离得到相应的产物,即化合物3-16,纯度大于90%,总收率为48%。
其表征数据如下:
1H NMR(400MHz,Chloroform-d)δ5.95-5.85(m,1H),5.68(t,J=3.2Hz,1H),5.54(dd,J=8.2,3.2Hz,1H),5.47(t,J=6.1Hz,1H),5.30-5.21(m,2H),5.21-5.08(m,2H),5.04(d,J=2.6Hz,1H),4.74(m,2H),4.50(dd,J=12.3,3.4Hz,1H),4.45-4.37(m,1H),4.21(m,2H),3.94(m,2H),3.82(dd,J=11.2,9.0Hz,1H),3.68(d,J=13.5Hz,1H),3.60(t,J=14.7Hz,1H),2.16(s,3H),2.15(s,3H),2.11(s,6H),2.07(s,3H),2.05(s,3H),1.98(s,3H),1.97(s,3H).
利用上述路线1-4均可对底物3-1至3-16进行合成,各实施例表明了此4条合成路线的有效性。
化合物3-17至3-19的合成
具体步骤如下:
室温下,将由上述1-4路线合成的全乙酰基保护的糖基溶解在10mL甲醇中,然后将反应液降至0℃,缓慢加入氢氧化锂固体(0.5eq),加入完毕后继续保持0℃反应4h;反应结束后,直接在反应液中加入2g硅胶,减压蒸馏甲醇后过柱纯化得到目标产物。
化合物3-17至3-19均按照上述方法制得,其表征数据如下:
纯度大于90%,1H NMR(400MHz,Methanol-d4)δ5.14(m,2H),4.37(d,J=9.6Hz,1H),4.05(d,J=13.6Hz,1H),3.81(dd,J=12.5,2.1Hz,1H),3.77-3.67(m,2H),3.58(dd,J=12.5,6.2Hz,1H),3.36(t,J=8.9Hz,1H),3.34-3.28(m,1H),3.23-3.18(t J=9.4Hz,1H),1.87(s,3H).
纯度大于90%,1H NMR(400MHz,Deuterium Oxide)δ5.28-5.24(m,1H),5.13(s,1H),4.67(d,J=10.3Hz,1H),4.37(t,J=10.3Hz,1H),4.11(d,J=13.7Hz,1H),3.96(d,J=3.2Hz,1H),3.91(d,J=13.7Hz,1H),3.77(m,3H),3.74-3.67(m,1H),1.93(s,3H),1.84(s,3H).
纯度大于90%,1H NMR(400MHz,Deuterium Oxide)δ5.27(s,1H),5.14(s,1H),4.45(d,J=8.0Hz,1H),4.11(d,J=14.0Hz,1H),3.98-3.75(m,5H),3.66(m,4H),3.45-3.20(m,5H),1.86(s,3H).
化合物3-20的合成
具体步骤如下:
室温下,将化合物3-17,苯甲酰氯(6.0eq),三乙胺(6.0eq),DMAP(0.2eq)在20mL二氯甲烷中,室温搅拌12h;反应结束后,加入冰山50Ml,二氯甲烷萃取,合并有机层,饱和柠檬酸水溶液洗涤,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,柱柱纯化得到目标产物3-20,纯度大于90%。其表征数据如下:1H NMR(400MHz,Chloroform-d)δ8.04-7.99(m,1H),7.97-7.86(m,3H),7.85-7.80(m,1H),7.61-7.27(m,10H),6.07(t,J=9.5Hz,1H),5.99(t,J=9.3Hz,1H),5.69(t,J=9.6Hz,1H),5.25-5.11(m,2H),4.93(d,J=9.6Hz,1H),4.73(dd,J=12.5,2.8Hz,1H),4.53(dd,J=12.5,5.7Hz,1H),4.28(ddd,J=8.6,5.5,2.7Hz,1H),4.05(d,J=13.6Hz,1H),3.71(d,J=13.6Hz,1H),1.94(s,3H).
化合物3-21的合成
具体步骤如下:
(1)2,3,4,6-四-o-苄基-D-吡喃葡萄糖(即1-21,5.4g,10mmol)溶于50mL二氯甲烷中,0℃下,向反应液中缓慢滴加草酰氯(1.7mL,20mmol),随后升至室温搅拌18h。加入冰水淬灭草酰氯至不再有气体放出,加入二氯甲烷萃取,合并有机层,用饱和食盐水洗涤,无水硫酸钠干燥,抽滤并旋干滤液,得到中间体1-21-1,无需纯化直接投下一步。
(2)将中间体1-21-1与硫脲(1.2g,15mmol)溶于乙睛(30mL)中,回流2h,冷却至室温,依次加入三乙胺(15mmol),3-溴-2甲基丙烯(15mmol),回流4h后却至室温。减压旋干乙腈后加入二氯甲烷与水,二氯甲烷萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤、浓缩后得到相应的中间体2-21,无需纯化直接投下一步。
(3)0℃下,上步所得粗品中间体2-21溶解于二氯甲烷(10mL)中,缓慢加入间氯过氧苯甲酸(2.5eq),继续搅拌2小时。TLC监测中间体2-21反应完全后,抽滤,将滤液用饱和碳酸氢钠水溶液、饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤并旋干滤液,采用柱层析法纯化得到产物3-21(4.5g,纯度大于90%,三步总收率70%)(即化合物3-21)。
1H NMR(CDCl3,400MHz)δ:7.44-7.22(m,18H),7.16(dd,J=6.1,3.1Hz,2H),5.21(s,0.32H),5.16(d,J=1.6Hz,1H),5.09(s,0.68H),5.04(d,J=6.0Hz,0.69H),4.99(d,J=9.7Hz,0.33H),4.94(d,J=11.1Hz,0.34H),4.90-4.66(m,4.6H),4.58-4.38(m,4.0H),4.15-4.06(m,1H),4.04(d,J=13.7Hz,0.34H),3.94(d,J=13.5Hz,0.69H),3.80-3.74(m,0.35H),3.74-3.50(m,4.6H),1.96(s,1H),1.94(s,2H).
化合物3-22至3-38的合成
具体步骤如下:
a),室温下,将由上述1-4路线合成的全乙酰基保护的硫醚底物溶解在10mL甲醇中,然后将反应液降至0℃,缓慢加入氢氧化锂固体(0.5eq),加入完毕后继续保持0℃反应1h;反应结束后,旋干,粗品溶于DMF(10mL),0℃下分批缓慢加入60% NaH(-OH/1.5eq),搅拌30Min,加入苄溴(-OH/1.5eq),搅拌30Min后移至室温,继续搅拌12h,反应完全后,加入冰水,二氯甲烷萃取,合并有机层,水洗,饱和食盐水洗涤,无数硫酸钠干燥,过滤,浓缩,柱柱纯化得全苄基保护的硫醚中间体。
b),0℃下,上步所得中间体溶解于二氯甲烷(10mL)中,缓慢加入间氯过氧苯甲酸(2.5eq),继续搅拌2小时。TLC监测原料反应完全后,抽滤,将滤液用饱和碳酸氢钠水溶液、饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤并旋干滤液,采用柱层析法纯化得到产物3-22至3-38。
其表征数据如下
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.42-7.20(m,20H),5.14(d,J=1.6Hz,2H),4.96(d,J=11.5Hz,2H),4.82(d,J=9.7Hz,1H),4.74(d,J=2.6Hz,2H),4.61(d,J=11.7Hz,1H),4.48-4.38(m,4H),3.97(d,J=13.7Hz,1H),3.88(d,J=2.7Hz,1H),3.68-3.56(m,4H),3.49(dd,J=7.9,4.4Hz,1H),1.95(d,J=1.3Hz,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.43-7.24(m,15H),5.17(t,J=1.6Hz,1H),5.08(s,1H),5.01(d,J=11.7Hz,1H),4.97(d,J=9.7Hz,1H),4.83(d,J=9.7Hz,1H),4.78(d,J=11.9Hz,1H),4.74(d,J=11.8Hz,1H),4.70(d,J=11.7Hz,1H),4.49-4.38(m,2H),3.96(d,J=13.6Hz,1H),3.69-3.51(m,4H),1.96(d,J=1.1Hz,3H),1.24(d,J=6.4Hz,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.39-7.24(m,15H),5.17(t,J=1.6Hz,1H),5.11(s,1H),4.92(d,J=2.4Hz,1H),4.84(d,J=11.2Hz,1H),4.69(d,J=11.9Hz,1H),4.63(dd,J=12.2,6.0Hz,3H),4.56(d,J=11.1Hz,1H),4.44(t,J=2.9Hz,1H),4.35-4.26(m,1H),4.08(dd,J=8.4,3.4Hz,1H),3.90(d,J=13.8Hz,1H),3.60(t,J=8.8Hz,1H),3.54(d,J=13.8Hz,1H),1.92(s,3H),1.31(d,J=6.2Hz,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.40-7.24(m,15H),5.20(t,J=1.6Hz,1H),5.08(s,1H),4.94-4.90(m,1H),4.90-4.84(m,2H),4.78(d,J=9.8Hz,1H),4.69(d,J=11.7Hz,1H),4.59(d,J=11.6Hz,1H),4.46(d,J=9.2Hz,1H),4.11(dd,J=11.4,5.0Hz,1H),4.05(t,J=8.8Hz,1H),3.89(d,J=13.6Hz,1H),3.76-3.64(m,2H),3.61(d,J=13.5Hz,1H),3.30(dd,J=11.5,9.1Hz,1H),1.95(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.39-7.19(m,15H),5.17(t,J=1.7Hz,1H),5.09(s,1H),4.85(d,J=6.8Hz,1H),4.67(dd,J=11.7,3.5Hz,2H),4.58(dd,J=11.7,5.8Hz,2H),4.50(d,J=3.1Hz,2H),4.35(dd,J=6.8,3.0Hz,1H),4.02(dd,J=11.9,4.3Hz,1H),3.93-3.83(m,3H),3.67-3.63(m,1H),3.61(d,J=13.7Hz,1H),1.94(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.42-7.26(m,15H),5.18(q,J=1.6Hz,1H),5.08(s,1H),4.90(d,J=10.0Hz,1H),4.85(d,J=10.0Hz,1H),4.75(d,J=12.5Hz,1H),4.71-4.59(m,3H),4.51-4.38(m,2H),4.23(dd,J=12.4,3.0Hz,1H),3.91(d,J=13.6Hz,1H),3.76(td,J=3.0,1.4Hz,1H),3.71-3.61(m,2H),3.38(dd,J=12.5,1.5Hz,1H),1.96(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.34-7.12(m,35H),5.51(d,J=3.7Hz,1H),5.17(s,2H),4.95-4.72(m,6H),4.64-4.34(m,9H),4.16(t,J=8.8Hz,1H),4.09-3.97(m,2H),3.87(t,J=9.4Hz,2H),3.80-3.68(m,3H),3.68-3.52(m,4H),3.48(dt,J=10.5,3.1Hz,2H),1.96(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.37-7.22(m,15H),5.18(ddt,J=7.4,5.7,2.9Hz,1H),4.90(t,J=10.1Hz,1H),4.81-4.37(m,7H),4.26-4.11(m,1H),3.99(dd,J=26.0,13.7Hz,1H),3.78-3.53(m,4H),3.53-3.45(m,1H),1.94(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.37-7.26(m,13H),7.19(dd,J=7.3,2.3Hz,2H),5.77(d,J=7.0Hz,1H),5.22-5.10(m,3H),4.85(d,J=11.5Hz,1H),4.81(d,J=11.0Hz,1H),4.68(d,J=11.5Hz,1H),4.57(d,J=10.8Hz,1H),4.55-4.46(m,3H),3.97(d,J=13.6Hz,1H),3.79-3.43(m,7H),1.92(s,3H),1.85(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.44-7.26(m,13H),7.16(dd,J=7.3,2.3Hz,2H),5.26-5.20(m,1H),5.17(s,1H),4.91(d,J=1.8Hz,1H),4.81(d,J=11.1Hz,1H),4.75(s,2H),4.58(d,J=12.1Hz,1H),4.51-4.45(m,3H),4.42(ddd,J=9.8,5.1,2.3Hz,1H),4.34(dd,J=8.7,3.9Hz,1H),3.97(d,J=13.9Hz,1H),3.85(t,J=9.2Hz,1H),3.69-3.54(m,3H),1.94(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.42-7.24(m,48H),7.16(dd,J=7.0,2.5Hz,6H),5.98-5.80(m,3H),5.51-5.33(m,6H),5.00(d,J=6.3Hz,2H),4.96(d,J=6.5Hz,1H),4.92(d,J=7.9Hz,1H),4.87(d,J=4.2Hz,2H),4.83(d,J=9.0Hz,2H),4.78(d,J=8.3Hz,3H),4.76-4.73(m,2H),4.70(d,J=11.5Hz,2H),4.55(d,J=11.6Hz,3H),4.51(d,J=11.8Hz,3H),4.48(d,J=9.1Hz,2H),4.46-4.43(m,2H),4.43-4.36(m,3H),4.13-4.05(m,3H),3.98(dt,J=13.9,8.8Hz,3H),3.77(t,J=8.5Hz,1H),3.74-3.48(m,12H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.33-7.19(m,15H),5.17(s,1H),5.14(t,J=1.6Hz,1H),4.94(d,J=9.7Hz,1H),4.89(d,J=11.0Hz,1H),4.82(d,J=11.0Hz,1H),4.78(d,J=11.0Hz,1H),4.71(d,J=9.7Hz,1H),4.59(d,J=11.0Hz,1H),4.45(d,J=9.5Hz,1H),4.07-3.95(m,2H),3.83-3.66(m,3H),3.58-3.47(m,2H),3.34(ddd,J=9.7,5.1,1.8Hz,1H),1.93(d,J=1.2Hz,3H),0.84(s,9H),0.02(s,3H),0.00(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.32-7.28(m,13H),7.17(dt,J=7.2,2.4Hz,2H),5.00(d,J=9.7Hz,1H),4.97(d,J=11.1Hz,1H),4.89(d,J=10.7Hz,1H),4.85(d,J=7.8Hz,1H),4.84(s,1H),4.74(d,J=9.7Hz,1H),4.59(d,J=10.8Hz,1H),4.48(dd,J=12.1,1.7Hz,1H),4.03-3.97(m,1H),3.79(t,J=8.6Hz,1H),3.70-3.63(m,2H),3.60-3.51(m,4H),2.04(s,3H),1.98(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.58-7.27(m,15H),5.59(s,1H),5.22(s,1H),5.07(s,1H),5.02-4.75(m,4H),4.58(d,J=9.4Hz,1H),4.37(dd,J=10.5,5.0Hz,1H),4.16(t,J=8.9Hz,1H),3.96-3.81(m,3H),3.77(t,J=9.4Hz,1H),3.66(d,J=13.6Hz,1H),3.52(dt,J=9.8,4.9Hz,1H),1.97(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.47-7.41(m,2H),7.39-7.27(m,8H),5.14(p,J=1.5Hz,1H),4.99-4.90(m,2H),4.84(d,J=10.5Hz,1H),4.77(d,J=10.5Hz,1H),4.64(d,J=11.9Hz,1H),4.53-4.44(m,2H),4.38(dq,J=9.0,6.1Hz,1H),3.89(d,J=13.0Hz,1H),3.71(d,J=12.8Hz,1H),3.52(dd,J=8.9,4.3Hz,1H),1.89(t,J=1.2Hz,3H),1.32(d,J=6.1Hz,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.41-7.17(m,15H),5.23(t,J=1.6Hz,1H),5.18(s,1H),4.96(d,J=3.6Hz,1H),4.74(dd,J=4.8,3.7Hz,1H),4.70(d,J=11.7Hz,1H),4.59-4.43(m,6H),4.22(dd,J=8.5,4.8Hz,1H),3.96(d,J=13.7Hz,1H),3.75-3.62(m,2H),3.56(dd,J=11.5,4.5Hz,1H),1.99(s,3H).
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ7.39-7.24(m,15H),5.20(t,J=1.6Hz,1H),5.15(s,1H),5.02(d,J=1.5Hz,1H),4.68(d,J=11.8Hz,1H),4.61-4.42(m,6H),4.39(d,J=11.6Hz,1H),4.02(dd,J=8.2,5.2Hz,1H),3.87(d,J=13.8Hz,1H),3.69(dd,J=11.0,3.1Hz,1H),3.61(dd,J=11.0,6.5Hz,1H),3.52(d,J=13.7Hz,1H),1.94(s,3H).
3-39至3-40化合物的合成采取与上述3-1相同的路线合成,其结构与表征数据如下:
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ5.96(ddt,J=16.6,10.0,5.9Hz,1H),5.32(dd,J=17.2,1.7Hz,1H),5.24-5.18(m,2H),5.13(s,1H),4.44(d,J=7.9Hz,1H),4.37-4.22(m,4H),4.17(dd,J=12.6,4.3Hz,1H),4.11(dd,J=8.0,6.1Hz,1H),3.95(d,J=13.6Hz,1H),3.89(dd,J=12.5,4.0Hz,1H),3.67(d,J=13.6Hz,1H),1.98(d,J=1.4Hz,3H),1.54(s,3H),1.37(s,3H).
(2R,3R,4S,5R)-2-(acetoxymethyl)-6-((2-methylenedecyl)sulfonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
纯度大于90%,1H NMR(400MHz,Chloroform-d)δ5.53(t,J=9.6Hz,1H),5.31(t,J=9.4Hz,1H),5.28-5.19(m,2H),5.10(t,J=9.8Hz,1H),4.57(d,J=10.0Hz,1H),4.25(dd,J=5.4,3.8Hz,2H),3.95(d,J=13.6Hz,1H),3.80(dq,J=7.4,2.5Hz,1H),3.68(d,J=13.6Hz,1H),2.26(t,J=7.7Hz,2H),2.19-1.95(m,12H),1.46(dt,J=14.7,7.2Hz,2H),1.38-1.15(m,10H),0.88(t,J=6.6Hz,3H).13C NMR(101MHz,Chloroform-d)δ170.37,170.09,169.20,169.13,136.99,119.74,85.59,73.16,67.54,66.11,61.64,55.84,35.73,31.85,29.41,29.23,29.09,27.33,22.65,20.68,20.60,20.54,20.52,14.10.
合成硫苷化合物:
然后利用以上制得的烯丙基砜类糖基供体为原料,与糖基受体反应,合成本发明的硫苷化合物。以上述化合物3-1作为原料为例,合成路线如下所示:
路线1:在氮气氛围下,将化合物3-1(1.0equiv)、糖基受体a(1.2equiv)、光敏剂Ir[dF(CF3)(ppy)2](dtbbpy)PF6(0.01equiv)加入到催化反应瓶中,加入乙腈(使化合物3-1的浓度为0.1mol/L),在Blue LED的照射下室温搅拌4h,即得硫苷化合物S-a。
其中,Y选自NH或O,R1选自甲基、R2选自Bz、H、Boc。
路线2:在氮气氛围下,将化合物3-1(1.0equiv)、二硫化合物b(2.0equiv)、光敏剂Ir[dF(CF3)(ppy)2](dtbbpy)PF6(0.01equiv)加入到催化反应瓶中,加入乙腈(使化合物3-1的浓度为0.1mol/L),在Blue LED的照射下45℃搅拌2h,即得硫苷化合物S-b。
其中,Ar表示芳基。
路线3:在氮气氛围下,将化合物3-1(1.0equiv)、二硫化合物c(2.0equiv)、光敏剂Ir[dF(CF3)(ppy)2](dtbbpy)PF6(0.01equiv)加入到催化反应瓶中,加入乙腈(0.1mol/L),室温下Blue LED照射下反应2h,即得硫苷化合物S-c。
其中,Alkyl表示烷基。
路线4:在氮气氛围下,将化合物3-x(1.0equiv)、糖基二硫受体d(1.2equiv)、光敏剂Ir[dF(CF3)(ppy)2](dtbbpy)PF6(0.01equiv)加入到催化反应瓶中,加入乙腈(使化合物3-1的浓度为0.1mol/L),在Blue LED的照射下室温搅拌4h,即得硫苷化合物S-d。
本发明上述合成路线不限于以化合物3-1为原料,采用相同的方法,将原料化合物3-1替换为本发明上述制得的任一烯丙基砜类糖基供体,可以得到对应的硫苷化合物。
以下为本发明具体硫苷化合物的合成实施例。
实施例17、本发明硫苷化合物S-1~S-17、S-22的合成
采用上述路线1相同的方法,制得本发明各硫苷化合物S-1~S-17、S-22。结构及表征如下:
甲基N-苯甲酰基-S-(2,3,4,6-四氧乙酰基-l-α-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=92%)
1H NMR(400MHz,Chloroform-d)δ7.83(m,2H),7.58-7.49(m,1H),7.43(m,3H),5.64(d,J=5.8Hz,1H),5.32-5.20(m,2H),5.07-4.94(m,2H),4.37(ddd,J=10.3,5.0,2.2Hz,1H),4.25(dd,J=12.6,5.0Hz,1H),4.16(dd,J=10.6,2.2Hz,1H),3.80(s,2H),3.35(dd,J=14.6Hz,J=3.5Hz,1H),3.13(dd,J=
14.6,3.5Hz,1H),2.07(s,3H),2.02(s,3H),2.02(s,3H),1.99(s,3H).
甲基N-苯甲酰基-S-(2,3,4,6-四氧乙酰基-2-去氧氨基-α-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=70%)
1H NMR(400MHz,Chloroform-d)δ7.89-7.84(m,2H),7.57-7.50(m,2H),7.43(m,2H),5.80(d,J=8.8Hz,1H),5.41(d,J=5.3Hz,1H),5.35-5.29(m,1H),5.14-5.07(t,J=9.6Hz,1H),4.98(dd,J=11.3,9.3Hz,1H),4.54(ddd,J=11.3,8.8,5.3Hz,1H),4.32(dt,J=10.1,3.6Hz,1H),4.20(d,J=3.7Hz,2H),3.80(s,3H),3.41(dd,J=14.7,4.7Hz,1H),3.17(dd,J=14.6,3.3Hz,1H),2.04(s,3H),2.03(s,3H),1.97(s,3H),1.96(s,3H).
甲基N-苯甲酰基-S-(2,3,4,6-四氧乙酰基-l-α-D-甘露糖基)-L-半胱氨酸(纯度大于90%,Yield=88%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.85(m,2H),7.57-7.50(m,1H),7.43(m,2H),5.38(dd,J=3.3,1.7Hz,1H),5.32-5.24(m,3H),5.18(dd,J=10.0,3.3Hz,1H),4.33(d,J=4.4Hz,1H),4.26-4.15(m,2H),3.80(s,3H),3.38(dd,J=14.5,4.9Hz,1H),3.22(dd,J=14.5,3.6Hz,1H),2.14(s,3H),2.05(s,3H),1.99(s,3H),1.95(s,3H).
甲基N-苯甲酰基-S-(2,3,4-三氧乙酰基-l-α-D-鼠李糖基)-L-半胱氨酸(纯度大于90%,Yield=87%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.50(m,1H),7.43(m,2H),5.34(dd,J=3.4,1.6Hz,1H),5.22(d,J=1.6Hz,1H),5.18(dd,J=10.0,3.4Hz,1H),5.11-5.04(m,2H),4.21-4.07(m,1H),3.35(dd,J=13.9,5.0Hz,1H),3.16(dd,J=13.9,4.9Hz,1H),2.09(s,3H),2.05(s,3H),1.97(s,3H),1.23(d,J=6.2Hz,3H).
甲基N-苯甲酰基-S-(3,4,6-三氧乙酰基-2-去氧-α-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=72%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.50(m,1H),7.43(m,2H),5.43-5.39(m,d,J=5.1Hz,1H),5.29-5.23(m,1H),5.21-5.13(m,1H),4.96(t,J=9.6Hz,1H),4.33(ddd,J=9.8,5.3,2.0Hz,1H),4.27(dd,J=12.3,5.3Hz,1H),4.13(dd,J=12.3,2.0Hz,1H),3.79(s,3H),3.35(dd,J=14.6,5.0Hz,1H),3.16(dd,J=14.6,3.6Hz,1H),2.35(ddd,J=13.4,5.2,1.4Hz,1H),2.25-2.14(m,1H),2.04(s,3H),2.00(s,3H),1.97(s,3H).
甲基N-苯甲酰基-S-(2’,3’,6’,2,3,4,6-七氧乙酰基-α-D麦芽糖基)-L-半胱氨酸(纯度大于90%,Yield=75%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.50(m,1H),7.43(m,2H),5.50(d,J=5.7Hz,1H),5.42-5.32(m,2H),5.30-5.21(m,2H),5.12-5.04(t,J=9.8Hz,1H),4.91(m,2H),4.51(d,J=2.3Hz,1H),4.31(ddd,J=9.8,5.2,2.2Hz,1H),4.24(dd,J=12.4,3.8Hz,1H),4.15(dd,J=12.3,5.3Hz,1H),4.07(dd,J=12.5,2.4Hz,1H),4.03-3.97(m,1H),3.87(dd,J=9.8,7.9Hz,1H),3.83(s,3H),3.34(dd,J=14.6,4.7Hz,1H),3.16(dd,J=14.6,3.6Hz,1H),2.10(s,3H),2.06(s,3H),2.05(s,2H),2.04(s,3H),2.03(s,3H),2.01(s,2H),2.00(s,3H).
甲基N-苯甲酰基-S-(2’,3’,6’,2,3,4,6-七氧乙酰基-α-D乳糖基)-L-半胱氨酸(纯度大于90%,Yield=80%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.51(m,1H),7.42(m,2H),5.56(d,J=5.7Hz,1H),5.35(d,J=3.4Hz,1H),5.27(t,J=9.5Hz,1H),5.22(m,1H),5.10(dd,J=10.4,7.9Hz,1H),4.99-4.93(m,2H),4.54-4.47(m,2H),4.27(ddd,J=10.1,5.4,1.9Hz,1H),4.18-4.05(m,3H),3.89(t,J=6.9Hz,1H),3.78(s,3H),3.75-3.70(t,J=9.4Hz,1H),3.30(dd,J=14.5,5.0Hz,1H),3.11(dd,J=14.5,3.6Hz,1H),2.14(s,3H),2.06(s,3H),2.05(s,6H),2.04(s,3H),2.01(s,3H),1.96(s,3H).
甲基N-苯甲酰基-S-(2,3,4-三氧乙酰基-α-L-来苏糖基)-L-半胱氨酸(纯度大于90%,Yield=63%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.51(m,1H),7.42(m,2H),5.29(dd,J=4.5,3.3Hz,1H),5.22(dd,J=8.1,3.3Hz,1H),5.15(dt,J=8.3,4.3Hz,1H),5.13-5.06(m,1H),5.05-5.02(m,1H),3.86(d,J=2.3Hz,1H),3.80(s,3H),3.79(d,J=2.8Hz,1H),3.41(dd,J=14.5,4.7Hz,1H),3.15(dd,J=14.5,3.9Hz,1H),2.09(s,3H),2.07(s,3H),2.04(s,3H).
甲基N-苯甲酰基-S-(2,3,4-三氧乙酰基-α-D-***糖基)-L-半胱氨酸(纯度大于90%,Yield=76%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.51(m,1H),7.42(m,2H),5.72(d,J=5.3Hz,1H),5.30-5.27(m,1H),5.23(dd,J=10.1,5.1Hz,1H),5.17-5.13(m,1H),5.08-5.03(m,1H),4.21-4.15(dd,J=13.2,1.5Hz,1H),3.80(s,3H),3.35(dd,J=14.1,4.6Hz,1H),3.05(dd,J=14.1,5.3Hz,1H),2.11(s,3H),2.05(s,2H),2.00(s,3H).
甲基N-苯甲酰基-S-(2,3,5-三氧乙酰基-α-D-核糖基)-L-半胱氨酸(纯度大于90%,Yield=78%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.51(m,1H),7.42(m,2H),5.48(t,J=3.2Hz,1H),4.92(d,J=7.7Hz,1H),5.02(m,3H),3.97(dd,J=11.6,4.4Hz,1H),3.80(s,3H),3.71(dd,J=11.6,8.3Hz,1H),3.34(dd,J=14.3,4.7Hz,1H),3.20(dd,J=14.3,5.3Hz,1H),2.05(s,3H),2.04(s,3H),2.03(s,3H).
甲基N-苯甲酰基-S-(2,3,4,6-四氧乙酰基-α-D-半乳糖基)-L-半胱氨酸(纯度大于90%,Yield=63%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.51(m,1H),7.42(m,2H),5.72(d,J=5.6Hz,1H),5.44(d,J=3.3,1H),5.27(dd,J=11.1,5.6Hz,1H),5.20(m,1H),5.14(dd,J=11.0,3.3Hz,1H),4.56(t,J=6.4Hz,1H),4.17(dd,J=11.4,5.2Hz,1H),4.03(dd,J=11.4,7.4Hz,1H),3.80(s,3H),3.34(dd,J=14.5,4.9Hz,1H),3.13(dd,J=14.4,3.8Hz,1H),2.15(s,3H),2.07(s,3H),1.99(s,3H),1.91(s,3H).
甲基N-苯甲酰基-S-(2,3,4-三氧乙酰基-α-L-岩藻糖基)-L-半胱氨酸(纯度大于90%,Yield=71%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.57-7.51(m,1H),7.42(m,2H),5.82(d,J=5.1Hz,1H),5.26(m,1H),5.22-5.16(m,2H),5.08(m,1H),4.40(q,J=6.5Hz,1H),3.81(s,3H),3.28(dd,J=14.0,4.6Hz,1H),3.05(dd,J=14.0,5.2Hz,1H),2.15(s,3H),2.04(s,3H),1.98(s,3H),1.15(d,J=6.5Hz,3H).
甲基N-苯甲酰基-S-(2,3,4-三氧乙酰基-α-L-木糖基)-L-半胱氨酸(纯度大于90%,Yield=73%)
1H NMR(400MHz,Chloroform-d)δ5.50(d,J=5.3Hz,1H),5.23(t,J=9.2Hz,1H),5.17(m,1H),5.05(m,1H),4.99-4.87(m,4H),4.54(d,J=9.2Hz,1H),4.10(dd,J=11.6,5.3Hz,1H),3.98-3.89(m,1H),3.80(s,3H),3.38(s,3H),3.38-3.30(m,2H),3.20(dd,J=14.4,5.3Hz,1H),3.11(dd,J=14.5,3.8Hz,1H),2.07(s,3H),2.04(s,3H),2.03(s,6H),1.99(s,6H).
甲基N-(N-叔丁氧基-L-缬氨酸基)-S-(2,3,4,6-四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=70%)
1H NMR(400MHz,Chloroform-d)δ5.60(d,J=5.8Hz,1H),5.25(d,J=9.8Hz,1H),5.17-5.07(m,1H),5.02-4.96(m,1H),4.91(m,1H),4.35-4.28(m,2H),4.26-4.20(m,1H),4.01(m,1H),3.78(s,3H),3.16-3.03(m,2H),2.22-2.15(m,1H),2.11(s,3H),2.06(s,2H),2.04(s,3H),2.01(s,3H),1.46(s,9H),1.00-0.97(d,J=6.9Hz,3H),0.93(d,J=6.9Hz,3H).
甲基N-(N-叔丁氧基-L-苏氨酸基)-S-(2,3,4,6-四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=90%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.65(t,J=7.4Hz,1H),7.59-7.52(m,2H),7.48(d,J=7.9Hz,1H),5.67(d,J=5.7Hz,1H),5.54(d,J=7.7Hz,1H),5.27(t,J=9.8Hz,1H),5.08-5.01(m,1H),4.96(dd,J=10.4,5.8Hz,1H),4.94-4.88(m,1H),4.40(dd,J=6.6,2.4Hz,1H),4.33(dt,J=10.1,3.6Hz,1H),4.25(d,J=2.6Hz,2H),4.19-4.14(m,1H),3.76(s,3H),3.08(d,J=4.8Hz,2H),2.12(s,3H),2.06(s,3H),2.04(s,3H),2.01(s,3H),1.48(s,9H),1.21(d,J=6.3Hz,3H)
甲基N-(N-叔丁氧基-L-酪氨酸基)-S-(2,3,4,6-四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=70%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.86(m,2H),7.65(t,J=7.4Hz,1H),7.59-7.52(m,2H),5.42(d,J=5.7Hz,1H),5.27(d,J=10.0Hz,1H),5.14-5.03(m,1H),4.96(dd,J=10.4,5.7Hz,1H),4.87-4.72(m,2H),4.38(m,1H),4.34-4.25(m,2H),4.19(d,J=10.5Hz,1H),3.77(s,3H),3.11(dd,J=14.0,6.0Hz,1H),3.04m,2H),2.94(dd,J=14.0,6.4Hz,1H),2.10(s,3H),2.05(s,3H),2.05(s,3H),2.03(s,3H),1.44(s,9H).
甲基N-(N-叔丁氧基-L-色氨酸基)-S-(2,3,4,6-四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=81%)
1H NMR(400MHz,Chloroform-d)δ8.81(s,1H),7.63(d,J=7.9Hz,1H),7.38(d,J=8.0Hz,1H),7.22-7.15(m,1H),7.15-7.08(m,2H),6.93(d,J=7.9Hz,1H),5.23-5.14(t,J=9.8Hz,1H),5.09(m,2H),4.89(dd,J=10.3,5.8Hz,2H),4.85-4.79(m,1H),4.58(s,1H),4.24(dt,J=10.2,3.7Hz,1H),4.17(s,1H),3.68(s,3H),3.47(dd,J=14.6,4.7Hz,1H),3.15(dd,J=14.6,6.1Hz,1H),2.95(dd,J=14.3,5.6Hz,2H),2.78(m,1H),2.07(s,3H),2.04(s,3H),2.04(s,3H),2.02(s,3H),1.46(s,9H).
(2,3,4,6-四乙酰基-1-α-D-吡喃葡萄糖基)-L-半胱氨酸甲酯(纯度大于90%,Yield=28%)
1H NMR(400MHz,Chloroform-d)δ5.71(d,J=5.8Hz,1H),5.34(t,J=9.8Hz,1H),5.07-4.98(m,2H),4.41(ddd,J=10.1,4.8,2.2Hz,1H),4.29(dd,J=12.4,5.1Hz,1H),4.14-4.10(m,1H),3.74(s,3H),3.71(m,1H),2.92(d,J=5.9Hz,2H),2.10(s,3H),2.07(s,3H),2.04(s,3H),2.01(s,3H).
实施例18、本发明硫苷化合物S-18的合成
采用与上述路线1相同的方法,制得本发明硫苷化合物S18,路线如下:
甲基N-(N-叔丁氧基-L-蛋氨酸基)-S-(2,3,4,6-四氧乙酰基-D-葡萄糖基)-L-半胱氨酸(纯度大于90%,Yield=80%)
1H NMR(400MHz,Chloroform-d)δ7.90-7.87(m,2H),7.67-7.62(m,1H),7.55(m,2H),5.68(d,J=5.8Hz,1H),5.48(d,J=8.2Hz,1H),5.34-5.28(m,1H),5.08-5.00(m,2H),4.68(m,1H),4.39(ddd,J=10.0,4.5,2.5Hz,1H),4.33(dd,J=12.3,4.5Hz,1H),4.16(dd,J=12.3,2.5Hz,0H),3.77(s,3H),3.12(dd,J=14.1,6.7Hz,1H),2.93(dd,J=14.0,5.1Hz,1H),2.52(t,J=7.4Hz,2H),2.22-2.13(m,2H),2.10(s,3H),2.09(s,3H),2.07(s,3H),2.03(s,3H),2.01(s,3H),1.46(s,9H).
实施例19、本发明硫苷化合物S-19~S-21的合成
采用上述路线2相同的方法,制得本发明各硫苷化合物S-19~S-21。结构及表征如下:
苯基-2,3,4,6-四乙酰基-1-硫-α-D-吡喃葡萄糖(纯度大于90%,Yield=84%)
1H NMR(400MHz,Chloroform-d)δ7.46-7.42(m,2H),7.33-7.27(m,3H),5.92(d,J=5.7Hz,0H),5.48-5.40(t,J=10.0Hz,1H),5.09(m,1H),4.57(ddd,J=10.3,5.2,2.2Hz,1H),4.28(dd,J=12.4,5.2Hz,1H),4.04(dd,J=12.3,2.3Hz,1H),2.11(s,3H),2.06(s,1H),2.04(s,3H),2.03(s,3H).
2-吡啶基-2,3,4,6-四乙酰基-1-硫-α-D-吡喃葡萄糖(纯度大于90%,Yield=82%)1H NMR(400MHz,Chloroform-d)δ7.78(m,1H),7.30(m,1H),7.08(m,1H),6.68(d,J=5.7Hz,1H),5.41(t,J=9.8Hz,1H),5.26(dd,J=10.3,5.7Hz,1H),5.13(t,J=9.8Hz,1H),4.38(ddd,J=10.2,4.5,2.3Hz,1H),4.27(dd,J=12.4,4.6Hz,1H),4.01(dd,J=12.4,2.3Hz,1H),2.04(s,3H),2.04(s,3H),2.02(s,3H),1.98(s,3H).
甲基-2,3,4,6-四乙酰基-1-硫-α-D-吡喃葡萄糖(纯度大于90%,Yield=75%)
1H NMR(400MHz,Chloroform-d)δ5.55(d,J=5.8Hz,1H),5.42-5.36(t,J=9.8Hz,1H),5.09-5.01(m,2H),4.39(ddd,J=10.2,4.9,2.3Hz,1H),4.30(dd,J=12.3,4.9Hz,1H),4.09(dd,J=12.3,2.3Hz,1H),2.09(s,3H),2.06(s,3H),2.06(s,3H),2.03(s,3H),2.01(s,3H).
实施例20、本发明硫苷化合物S-23的合成
采用上述路线4相同的方法,制得本发明各硫苷化合物S-23。结构及表征如下:
(2,3,4,6-四氧乙酰基-α-D-葡萄糖基)-2,3,4,6-四氧乙酰基-1-硫-β-D-葡萄糖苷(纯度大于90%,Yield=74%)
1H NMR(400MHz,Chloroform-d)δ5.94(d,J=5.6Hz,1H),5.30(t,J=9.9Hz,1H),5.20-4.97(m,5H),4.56(d,J=9.9Hz,1H),4.41-4.38(m,2H),4.20-4.08(m,3H),3.74-3.72(m,1H),2.11,2.10,2.03,2.02,2.00(5x s,24H,8x CH3)
实施例21、本发明硫苷化合物S-24的合成
采用以下合成路线,制得本发明各硫苷化合物S-24。结构及表征如下:
5-三氟甲基吡啶-1-硫-(2,3,4,6-四氧乙酰基-β-D-葡萄糖基)二硫化物1H NMR(400MHz,Chloroform-d)δ8.74-8.51(s,1H),8.02(d,J=8.5Hz,1H),7.83(dd,J=8.6,2.3Hz,1H),5.31-5.20(m,2H),5.10-5.02(m,1H),4.73-4.64(m,1H),4.10-3.95(m,2H),3.70(ddd,J=10.1,4.4,2.8Hz,1H),2.09(s,3H),2.01(s,6H),1.87(s,3H).
具体制备方法为:
0℃下,将10mmol的Ⅰ-24溶于二氯甲烷(30mL)中,先后缓慢滴加硫代乙酸(1.7mL,24mmol)和三氟化硼***(3.7mL,30mmol),随后升至室温搅拌过夜。原料反应完全后,用冰水淬灭,二氯甲烷萃取,饱和碳酸氢钠水溶液、饱和食盐水洗涤,无水硫酸钠干燥有机相,抽滤并旋干滤液,得到产物Ⅱ-24。
Ⅱ-24和半胱氨酸甲酯盐酸盐(2.05g,12mmol)溶于DMF(10mL)中,加入三乙胺(1.7mL,12mmol)室温搅拌8小时。TLC监测Ⅱ反应完全后,经乙酸乙酯萃取,半饱和食盐水洗涤后,用无水硫酸钠干燥有机相,抽滤并旋干滤液,采用柱层析法纯化得到产物Ⅲ-24。
Ⅲ-24(1.82g,5mmol)和2,2’-双(5-三氟甲基吡啶基)二硫(3.6g,10mmol)溶于二氯甲烷(20mL)中,室温搅拌1小时,旋干溶剂后,采用柱层析法纯化得到产物S-24,纯度大于90%,三步产率57%。
综上所述,本发明提供了一种式I所示的糖基供体及其制备方法,以及式I所示的糖基供体在制备式III所示的硫苷类化合物中的用途。本发明提供的糖基供体结构新颖,制备方法简单;本发明以上述糖基供体为原料,利用自由基反应,制备得到了硫苷类化合物,其中大部分具有特殊的α构型,该制备方法简单、反应条件温和、收率高,具有非常好的应用前景。
Claims (12)
1.一种制备硫苷化合物的方法,其特征在于,所述方法为:将糖基供体与糖基受体反应,得到硫苷化合物;
其中,所述硫苷化合物的结构如式III所示:
所述糖基受体的结构为
R5s选自
R10选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、肽链去掉一个氢原子后剩下的基团,所述取代基选自卤素、卤代烷基;上述m表示1-5的整数;
上述Y选自无、NH或O;R1a、R2a选自各自独立地选自H、Boc、Bz、C1-6烷基、C1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、其中m1、m2各自独立地选自0-5的整数;Ra1选自取代或未取代的C1-6烷基,所述取代基选自卤素、羟基;Ra3选自取代或未取代的C1-6烷基、芳基、杂芳基,所述取代基选自卤素、羟基;
所述糖基供体的结构如式I所示:
A环选自R1、R2、R3、R4各自独立地选自H、C1-6烷基、M1OH、M1NHAc、M1OAc、M1选自0-3个亚甲基;
R5选自C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基、H、苯基;
R6、R7、R8、R9为H;
所述糖基供体不为
2.根据权利要求1所述的方法,其特征在于,所述糖基供体的结构如式II-1或II-2所示:
其中,R1、R2、R3、R4各自独立地选自H、甲基、M1OH、M1NHAc、M1OAc、M1选自0-3个亚甲基;
R5选自C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基、H、苯基;
R6、R7、R8、R9为H。
3.一种制备硫苷化合物的方法,其特征在于,所述方法为:将糖基供体与糖基受体反应,得到硫苷化合物;
其中,所述糖基受体的结构为
R5s选自
R10选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、肽链去掉一个氢原子后剩下的基团,所述取代基选自卤素、卤代烷基;上述m表示1-5的整数;
上述Y选自无、NH或O;R1a、R2a选自各自独立地选自H、Boc、Bz、C1-6烷基、C1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、其中m1、m2各自独立地选自0-5的整数;Ra1选自取代或未取代的C1-6烷基,所述取代基选自卤素、羟基;Ra3选自取代或未取代的C1-6烷基、芳基、杂芳基,所述取代基选自卤素、羟基;
所述糖基供体的结构如式I所示:
其中,A环选自R1、R2、R3、R4各自独立地选自H、C1-6烷基、M1OH、M1NHAc、M1OAc、M1选自0-3个亚甲基;
R5为C7烷基、C8烷基、C9烷基、C10烷基;
R6、R7、R8、R9为H;
所述糖基供体不为
4.根据权利要求3所述的方法,其特征在于,所述糖基供体的结构如式II-1或II-2所示:
其中,R1、R2、R3、R4各自独立地选自H、甲基、M1OH、M1NHAc、M1OAc、M1选自0-3个亚甲基;
R5为C7烷基、C8烷基、C9烷基、C10烷基;
R6、R7、R8、R9为H。
5.一种制备硫苷化合物的方法,其特征在于,所述方法为:将糖基供体与糖基受体反应,得到硫苷化合物;
其中,所述糖基受体的结构为
R5s选自
R10选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、肽链去掉一个氢原子后剩下的基团,所述取代基选自卤素、卤代烷基;上述m表示1-5的整数;
上述Y选自无、NH或O;R1a、R2a选自各自独立地选自H、Boc、Bz、C1-6烷基、C1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、其中m1、m2各自独立地选自0-5的整数;Ra1选自取代或未取代的C1-6烷基,所述取代基选自卤素、羟基;Ra3选自取代或未取代的C1-6烷基、芳基、杂芳基,所述取代基选自卤素、羟基;
所述糖基供体的结构如式I所示:
其中,A环选自
R1选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R2、R3、R4各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
R2选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R1、R3、R4各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
R3选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R1、R2、R4各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
R4选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R1、R2、R3各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
M1选自0-3个亚甲基;
R5选自C1-10烷基、H、苯基;
R6、R7、R8、R9为H。
6.根据权利要求5所述的方法,其特征在于,所述糖基供体的结构如式II-1或II-2所示:
其中,R1选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R2、R3、R4各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
R2选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R1、R3、R4各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
R3选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R1、R2、R4各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
R4选自C2-3烯基、M1OBz、M1OBn、M1N3、M1OTBS时,R1、R2、R3各自独立地选自H、C1-6烷基、C2-3烯基、M1OH、M1NHAc、M1OAc、M1OBz、M1OBn、M1N3、M1OTBS、
M1选自0-3个亚甲基;
R5选自C1-8烷基、H、苯基;
R6、R7、R8、R9为H。
7.一种制备硫苷化合物的方法,其特征在于,所述方法为:将糖基供体与糖基受体反应,得到硫苷化合物;
其中,所述糖基受体的结构为
R5s选自
R10选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、肽链去掉一个氢原子后剩下的基团,所述取代基选自卤素、卤代烷基;上述m表示1-5的整数;
上述Y选自无、NH或O;R1a、R2a选自各自独立地选自H、Boc、Bz、C1-6烷基、C1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、其中m1、m2各自独立地选自0-5的整数;Ra1选自取代或未取代的C1-6烷基,所述取代基选自卤素、羟基;Ra3选自取代或未取代的C1-6烷基、芳基、杂芳基,所述取代基选自卤素、羟基;
所述糖基供体的结构选自:
8.一种制备硫苷化合物的方法,其特征在于,所述方法为:将糖基供体与糖基受体反应,得到硫苷化合物;
其中,所述糖基受体的结构为
R5s选自
R10选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、肽链去掉一个氢原子后剩下的基团,所述取代基选自卤素、卤代烷基;上述m表示1-5的整数;
上述Y选自无、NH或O;R1a、R2a选自各自独立地选自H、Boc、Bz、C1-6烷基、C1-6烷氧基、芳基、杂芳基、肽链去掉一个氢原子后剩下的基团、其中m1、m2各自独立地选自0-5的整数;Ra1选自取代或未取代的C1-6烷基,所述取代基选自卤素、羟基;Ra3选自取代或未取代的C1-6烷基、芳基、杂芳基,所述取代基选自卤素、羟基;
所述糖基供体的结构选自:
其中,表示或二者的任意比例混合物。
9.根据权利要求1-8任一项所述的方法,其特征在于,所述R5s选自
所述糖基供体与糖基受体的摩尔比为1:(1.1~2.5),优选为1:(1.2~2);
所述反应是在氮气氛围中、蓝色LED的照射下进行的;
所述反应的温度为20~45℃,优选为室温~45℃;反应时间为1.5~5小时,优选为2~4小时;
所述反应是在光敏剂的作用下进行的,光敏剂选自
Ir[dF(CF3)(ppy)2](dtbbpy)PF6,优选为Ir[dF(CF3)(ppy)2](dtbbpy)PF6,更优选为Ir[dF(CF3)(ppy)2](dtbbpy)PF6;
所述反应的溶剂选自水或者1,2-DCE、DMSO、EtOAc、glyme、1,4-dioxane、THF、MeOH、DMF、MeCN、MeCN中的一种或多种与水在任意比例下组成的混合溶液。
10.根据权利要求1-9任一项所述的方法,其特征在于,所述硫苷化合物的结构如式III-1、III-2、III-3或III-4所示:
式III-1和式III-3中:当Y选自O时,R1a选自甲基,R2a选自Bz、H、当Y选自NH时,R1a选自R2a选自Boc;当Y选自无时,R1a选自甲氧基,R2a选自Bz;
式III-2和式III-4中:R10选自取代或未取代的苯环、取代或未取代的氮杂芳环、甲基、所述取代基选自卤素、卤代烷基。
11.根据权利要求10所述的方法,其特征在于:所述硫苷化合物的结构选自:
12.根据权利要求11所述的方法,其特征在于:所述硫苷化合物的结构选自:
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