CN109627270A - 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 - Google Patents
一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 Download PDFInfo
- Publication number
- CN109627270A CN109627270A CN201811551666.0A CN201811551666A CN109627270A CN 109627270 A CN109627270 A CN 109627270A CN 201811551666 A CN201811551666 A CN 201811551666A CN 109627270 A CN109627270 A CN 109627270A
- Authority
- CN
- China
- Prior art keywords
- building block
- compound
- group
- glucose
- pseudomonas aeruginosa
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 102000036639 antigens Human genes 0.000 title claims abstract description 33
- 108091007433 antigens Proteins 0.000 title claims abstract description 33
- 239000000427 antigen Substances 0.000 title claims abstract description 32
- 241000589517 Pseudomonas aeruginosa Species 0.000 title claims abstract description 29
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 20
- 229920001542 oligosaccharide Polymers 0.000 title abstract description 7
- 150000002482 oligosaccharides Chemical class 0.000 title abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 56
- -1 L-fucose amine Chemical class 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 45
- 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 abstract description 30
- 150000004043 trisaccharides Chemical class 0.000 claims abstract description 25
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 239000000126 substance Substances 0.000 claims abstract description 21
- TVTGZVYLUHVBAJ-GASJEMHNSA-N D-Fucosamine Chemical compound C[C@H]1OC(O)[C@H](N)[C@@H](O)[C@H]1O TVTGZVYLUHVBAJ-GASJEMHNSA-N 0.000 claims abstract description 18
- SHZGCJCMOBCMKK-PQMKYFCFSA-N L-Fucose Natural products C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 claims abstract description 17
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims abstract description 17
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- PNNNRSAQSRJVSB-DPYQTVNSSA-N aldehydo-D-fucose Chemical compound C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-DPYQTVNSSA-N 0.000 claims abstract description 10
- 239000012046 mixed solvent Substances 0.000 claims abstract description 10
- 229930192474 thiophene Natural products 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 4
- 229940079593 drug Drugs 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 51
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 239000011669 selenium Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000012634 fragment Substances 0.000 claims description 11
- 235000000346 sugar Nutrition 0.000 claims description 11
- 239000008103 glucose Substances 0.000 claims description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 241000894006 Bacteria Species 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- 229960005486 vaccine Drugs 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052711 selenium Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 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 claims description 3
- 208000032536 Pseudomonas Infections Diseases 0.000 claims description 3
- 230000008901 benefit Effects 0.000 claims description 3
- 235000009508 confectionery Nutrition 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 241000195493 Cryptophyta Species 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical group 0.000 claims description 2
- 239000011435 rock Substances 0.000 claims description 2
- NTBYIQWZAVDRHA-KCDKBNATSA-N (2s,3s,4r,5s)-2-amino-3,4,5-trihydroxyhexanal Chemical compound C[C@H](O)[C@@H](O)[C@@H](O)[C@H](N)C=O NTBYIQWZAVDRHA-KCDKBNATSA-N 0.000 claims 1
- TVTGZVYLUHVBAJ-ZZWDRFIYSA-N (3s,4s,5s,6s)-3-amino-6-methyloxane-2,4,5-triol Chemical compound C[C@@H]1OC(O)[C@@H](N)[C@H](O)[C@@H]1O TVTGZVYLUHVBAJ-ZZWDRFIYSA-N 0.000 claims 1
- GZCGUPFRVQAUEE-KVTDHHQDSA-N aldehydo-D-mannose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O GZCGUPFRVQAUEE-KVTDHHQDSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 62
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 239000011734 sodium Substances 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 229960001866 silicon dioxide Drugs 0.000 description 23
- 238000000746 purification Methods 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 11
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 239000007789 gas Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001720 carbohydrates Chemical group 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 150000002772 monosaccharides Chemical class 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000002158 endotoxin Substances 0.000 description 7
- 229920006008 lipopolysaccharide Polymers 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 206010035664 Pneumonia Diseases 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 6
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 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 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 5
- 244000052616 bacterial pathogen Species 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229940126543 compound 14 Drugs 0.000 description 5
- 229940126142 compound 16 Drugs 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 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 4
- 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
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 4
- 208000009470 Ventilator-Associated Pneumonia Diseases 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940126086 compound 21 Drugs 0.000 description 4
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 4
- 150000002016 disaccharides Chemical class 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- DUKURNFHYQXCJG-UHFFFAOYSA-N Lewis A pentasaccharide Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(CO)O2)O)C(NC(C)=O)C(OC2C(C(OC3C(OC(O)C(O)C3O)CO)OC(CO)C2O)O)OC1CO DUKURNFHYQXCJG-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 3
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229930182478 glucoside Natural products 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 229950006780 n-acetylglucosamine Drugs 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- 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
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- RZJGKPNCYQZFGR-UHFFFAOYSA-N 1-(bromomethyl)naphthalene Chemical compound C1=CC=C2C(CBr)=CC=CC2=C1 RZJGKPNCYQZFGR-UHFFFAOYSA-N 0.000 description 2
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 2
- 206010061926 Purulence Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229960004821 amikacin Drugs 0.000 description 2
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000000386 donor Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000008131 glucosides Chemical class 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 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
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- BBDNZMUIQBRBJH-UHFFFAOYSA-N sulfurochloridic acid;toluene Chemical compound OS(Cl)(=O)=O.CC1=CC=CC=C1 BBDNZMUIQBRBJH-UHFFFAOYSA-N 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- PTFZMXAQQHCHMG-RJYAGPCLSA-N (2S)-2-amino-N-(1-diphenoxyphosphorylethyl)-3-methylpentanamide Chemical compound C=1C=CC=CC=1OP(=O)(C(C)NC(=O)[C@@H](N)C(C)CC)OC1=CC=CC=C1 PTFZMXAQQHCHMG-RJYAGPCLSA-N 0.000 description 1
- NNGITUHFLCZEKQ-UHFFFAOYSA-N 2,4-dichloro-3,6-dioxocyclohexa-1,4-diene-1-carbonitrile Chemical compound ClC1=CC(=O)C(C#N)=C(Cl)C1=O NNGITUHFLCZEKQ-UHFFFAOYSA-N 0.000 description 1
- YDZYREHHCRHTRZ-UHFFFAOYSA-N 4-methylbenzenesulfonyl iodide Chemical group CC1=CC=C(S(I)(=O)=O)C=C1 YDZYREHHCRHTRZ-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 208000031729 Bacteremia Diseases 0.000 description 1
- LVAFXZPABJCMJK-UHFFFAOYSA-N COClCC1=CC=CC=C1 Chemical compound COClCC1=CC=CC=C1 LVAFXZPABJCMJK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 125000002353 D-glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- WQAXJVYXCKNYCB-UHFFFAOYSA-N [Se].C1=CC=CC=C1 Chemical compound [Se].C1=CC=CC=C1 WQAXJVYXCKNYCB-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical class C(C)(=O)* 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- SHZGCJCMOBCMKK-PHYPRBDBSA-N alpha-D-fucose Chemical compound C[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O SHZGCJCMOBCMKK-PHYPRBDBSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000007924 bacterial virulence factor Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000003495 flagella Anatomy 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 239000000937 glycosyl acceptor Substances 0.000 description 1
- 239000000348 glycosyl donor Substances 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229940041153 polymyxins Drugs 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Chemical class 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002277 temperature effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- RJFSDTDWWBECIL-UHFFFAOYSA-N trifluoro(methyl)-$l^{4}-sulfane Chemical compound CS(F)(F)F RJFSDTDWWBECIL-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/104—Pseudomonadales, e.g. Pseudomonas
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/738—Cross-linked polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Communicable Diseases (AREA)
- Crystallography & Structural Chemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种绿脓假单胞菌O11血清型O抗原寡糖的化学合成方法,属于化学领域。本发明利用D‑葡萄糖砌块、L‑岩藻糖胺砌块、D‑岩藻糖胺砌块构建O抗原三糖;其中,D‑葡萄糖砌块或L‑岩藻糖胺砌块与D‑岩藻糖胺砌块通过1,2‑α‑顺式‑糖苷键连接,D‑葡萄糖砌块与L‑岩藻糖胺砌块通过1,2‑β‑反式糖苷键连接,所述1,2‑α‑顺式‑糖苷键的构建是在混合溶剂中进行的;所述混合溶剂包括二氯甲烷、乙醚、噻吩中的两种或两种以上。本发明方法利用D‑甘露糖为原料,简便高效的得到D‑岩藻糖,并且依赖适宜的混合溶剂,实现了其顺式糖苷键的均一构建,立体选择性可达100%,在开发抗绿脓假单胞菌的新型药物和疫苗开发等方面具有很好的应用前景。
Description
技术领域
本发明涉及一种绿脓假单胞菌O11血清型O抗原寡糖的化学合成方法,属于化学领域。
背景技术
绿脓假单胞菌是一类需氧的、杆状的革兰氏阴性菌,一般栖息于土壤和水环境中。特别的,绿脓假单胞菌也是一类广泛存在于医院环境中的机会主义致病菌,引发菌血症,尿路感染以及肺炎等疾病。绿脓假单胞菌的易感人群包括烧伤病人、ICU中的病人、手术后病人以及免疫系统缺陷病人例如癌症、糖尿病和先天性囊泡纤维症患者。在我国大陆地区的呼吸机相关性肺炎(VAP)和医院获得性肺炎(HAP)中绿脓假单胞菌的流行性研究发现,在VAP 中,绿脓假单胞菌占所有分离株的19.4%((95%置信区间(CI)17.6-21.2%)),HAP的比例比较相似,为17.8%(95%CI 14.6-21.6%)。此外,该研究还发现从VAP中分离到的绿脓假单胞菌对庆大霉素(51.1%,95%CI 37.7–64.4%)和阿米卡星(22.5%,95%CI 14.3–33.6%)具有较高的耐药性,而从HAP中分离得到的绿脓假单胞菌对阿米卡星(22.2%(95%CI 13.8–33.6%))和头孢哌酮(50.0%(95%CI 30.2–69.8%))具有较高的耐药性。
在全球范围内,临床上发现绿脓假单胞菌对包括多粘菌素、氟喹诺酮类、碳青霉烯类等抗生具有一定的耐药性。2016年,世界卫生组织将绿脓假单胞菌列为目前最急需研究和发展新型抗生素或者疫苗的致病菌之一。截至目前,市场上还没有针对该致病菌的疫苗问世。有关绿脓假单胞菌的疫苗研究始于1980年代,研究领域集中于该致病菌的脂多糖、糖-蛋白缀合物、鞭毛、灭活或者减毒全菌以及该菌的DNA序列等方面。绿脓假单胞菌的脂多糖由一些在人体上不常见的单糖以及糖苷键连接方式构成,是一种重要的毒力因素。根据单糖种类的和糖苷键连接方式的不同,绿脓假单胞菌共有20种不同的血清型抗原。其中具体结构为 [-3)-α-L-N-乙酰岩藻糖胺-(1-3)-α-D-N-乙酰岩藻糖胺-(1-2)-β-D-葡萄糖-(1-]n的O11血清型抗原,这是一个由三糖重复片段收尾相接而成的一个长链抗原,具体的重复单元数n受该致病菌的基因所调控。
目前,针对该结构化合物都是从含有该脂多糖结构的野生治病菌或者含有编码该结构的基因工程菌中提取得,包括LPS高表达菌株的构建和培养,蛋白酶k的降解,石炭酸热萃取, Tricine-SDS-polyacrylamide gel electrophoresis(PAGE)分析和Westernimmunoblot检测等一系列步骤。此外,使用生物提取方法得到的脂多糖还存在化学结构不均一的问题,同时还存在着安全性的问题,因为是从菌体中直接提取的脂多糖,很有可能会掺杂其他细菌毒力因子,不仅不能够对人体产生免疫保护,反而会使人体受到菌体毒力因子的直接感染而致病,这样会产生严重的副作用。为了避免这样的问题,我们决定利用化学合成的方法来直接合成该脂多糖多糖,这样就避免了化学结构不均一以及掺杂其他未知毒力因子的问题,合成出的脂多糖具有明确的化学结构,并且可以保证仅有此种荚膜多糖参与疫苗的组成,不会掺杂其他物质。
然而,在复杂寡糖合成过程中,糖苷键的构建是寡糖合成中最基本但是也最为棘手和关键的问题,由于糖类化合物结构的多样性,立体化学的复杂性,因此与其他结构的有机化合物不同,寡糖的合成的方法学依然是不成熟和不完善的,被认为是有机化学领域中唯一存在众多方法(数十种之多)但又有没有一个具有普适性的方法为大家公认的领域。因为糖模块的结构复杂、顺式糖苷键选择性低,导致难以该结构合成构建,目前还没有报道利用化学合成的方法来构建该化合物,从而制约了该结构化解无的化学合成方法的研究。
发明内容
为了解决上述问题,本发明通过三种糖砌块化学方法合成绿脓假单胞菌的O11血清型O 抗原三糖片段,主要包括葡萄糖砌块、L-岩藻糖胺砌块、D-岩藻糖胺砌块以及1,2--顺式- 糖苷键和1,2-β-反式糖苷键。其中D-岩藻糖胺的合成和1,2-α-顺式-糖苷键的构建是该目标三糖的关键步骤。本发明开发了一条由D-葡萄糖合成D-岩藻糖胺的方法,并且通过溶剂效应,温度效应和添加剂效应的协同作用成功解决了构建1,2-α-顺式-糖苷键的立体选择性问题。利用合成的三个糖基砌块合成了保护目标三糖,最后脱去保护得到的目标三糖如式1。同时,三糖的还原端组装有带有氨基的连接臂,为下一步的缀合蛋白作准备。
本发明的第一个目的是提供一种绿脓假单胞菌的O11血清型O抗原三糖的合成方法,所述方法包括:利用D-葡萄糖砌块、L-岩藻糖胺砌块、D-岩藻糖胺砌块构建O抗原三糖;其中, D-葡萄糖砌块或L-岩藻糖胺砌块与D-岩藻糖胺砌块通过1,2-α-顺式-糖苷键连接,D-葡萄糖砌块与L-岩藻糖胺砌块通过1,2-β-反式糖苷键连接,所述1,2-α-顺式-糖苷键的构建是在混合溶剂中进行的;所述混合溶剂包括二氯甲烷、乙醚、噻吩中的两种或两种以上。
在本发明的一种实施方式中,所述D-葡萄糖砌块的化学结构如式II所示,L-岩藻糖胺砌块的化学结构式如式III所示,D-岩藻糖胺砌块的化学结构式如式IV所示,
其中,linker包括-(CH2)n-N-Y1Y2,或者O-(CH2)n-SY1(Y2),或者O-(CH2)n-N3,n=1~10; Y1为氢(H)或者苄基(Bn);Y2为氢(H)或者苄甲氧羰基(Cbz);R1包括但不限定于氢 (H)、酯基、乙酰基(Ac)、苯甲酰基(Bz)、新戊酰基(Piv)、氯乙酰基(ClAc)、乙酰丙酰基(Lev)、烯丙羰酰基(Alloc);R2,R3,R4为氢(H)或者酯基、醚基包括但不限于乙酰基(Ac)、苯甲酰基(Bz)、新戊酰基(Piv)、氯乙酰基(ClAc)、乙酰丙酰基(Lev)、烯丙羰酰基(Alloc)以及苄基(Bn)、对甲氧基苄基(pMBn)、烯丙基(All)、三苯甲基(Tr)、单甲氧基三苯甲基(Mmt)和硅醚类基团基团;R5,R6包括但不限于氢(H)、醚类基团、苄基 (Bn)、对甲氧基苄基(pMBn)、烯丙基(All)、三苯甲基(Tr)、单甲氧基三苯甲基(Mmt) 和硅醚类基团基团;R7,R8,R9,R10包括氢(H)、氮(N)或者乙酰基(Ac)。
在本发明的一种实施方式中,所述方法包括利用D-葡萄糖砌块和L-岩藻糖胺砌块合成二糖片段,其化学结构如式V所示,
在本发明的一种实施方式中,所述D-葡萄糖砌块与L-岩藻糖胺砌块的1,2-β-反式糖苷键连接是在TMSOTf促进作用下,以二氯甲烷作为溶剂中进行的。
在本发明的一种实施方式中,所述方法包括利用二糖片段与D-岩藻糖胺砌块合成三糖片段,其化学结构式如式I所示,
在本发明的一种实施方式中,所述方法包括预先合成O抗原三糖前体,还原记得O抗原三糖,所述O抗原三糖前体的化学结构式包括如下通式:
在本发明的一种实施方式中,所述D-葡萄糖砌块(式II)的端基位是三氯乙酰亚胺酯,为离去基团,其余取代基Rn参见式II。
在本发明的一种实施方式中,所述D-葡萄糖砌块的合成方法包括:以为1,2,3,4,6-五-O- 乙酰基葡萄糖起始原料,利用干燥N、N-二甲基甲酰胺和乙酸肼脱去1号位乙酰基裸漏出-OH,裸露的-OH与三氯乙腈(Cl3CN)反应得到化合物D-葡萄糖砌块。
在本发明的一种实施方式中,所述L-岩藻糖砌块(式III)端基位为烯丙基(OAll)保护,其余位置取代基Rn参见式III。
在本发明的一种实施方式中,所述L-岩藻糖砌块是以烯丙基2-脱氧-2叠氮基-L-岩藻糖苷为起始原料,用二丁基氧化锡(Bu2SnO)和2-溴甲基萘的作用下选择性保护4号位的羟基得到4-Nap岩藻糖;然后用苄基保护剩余的3号位羟基,再在二氯二氰基苯醌的作用下脱去4 号位的Nap基团得到最终糖砌块B。
在本发明的一种实施方式中,所述D-岩藻糖胺砌块的端基位为linker,如式IV所示。
在本发明的一种实施方式中,所述D-岩藻糖胺砌块的合成方法利用葡萄糖构建得到D- 岩藻糖胺,包括:以3,4,6-O-三乙酰基甘露糖烯为原料,经过叠氮化物、硒试剂得到1-硒苯-2 叠氮葡萄糖,脱除乙酰基,然后6-C进行甲基化,最终得到D-岩藻糖胺类化合物。
在本发明的一种实施方式中,所述方法具体包括:以3,4,6-O-三乙酰基甘露糖烯为原料,在二乙酸碘苯(PhI(OAc)2)作用下,与叠氮基三甲基硅烷(TMS-N3)和二苯基二硒(Ph2Se2) 生成1-硒苯-2叠氮葡萄糖,然后碱性条件下脱除乙酰基,加入4-甲苯磺酰氯实现6-C甲基化,得到D-岩藻糖胺化合物。
在本发明的一种实施方式中,所述方法还包括将D-岩藻糖胺化合物的3、4-C进行保护,然后脱去4-C的Nap基团,用乙酰基保护起来,四丁基溴化铵(NBS)水解D-岩藻糖的1号位硒苯基,用Cl3CN和DBU将岩藻糖做成糖基三氯乙酰亚胺酯,随后在路易斯酸的促进下组装上氨基连接臂,最后脱去D-岩藻糖3号位上的乙酰基得到D-岩藻糖胺砌块。
在本发明的一种实施方式中,所述3-C的保护试剂包括甲氧基苄氯(PMBCl)和氧化二丁基锡(Bu2SnO)。
在本发明的一种实施方式中,所述4-C的保护试剂包括苄基。
在本发明的一种实施方式中,所述4-C的Nap基团的脱除去利用DDQ实现的。
在本发明的一种实施方式中,所述路易斯酸包括三氟甲磺酸三甲基硅脂。
本发明的第二个目的是提供一种组装有氨基连接臂的绿脓假单胞菌的O11血清型O抗原三糖,所述抗原三糖是利用上述方法制备得到的。
本发明的第三个目的是提供一种糖-蛋白缀合物的制备方法,所述方法是利用上述的组装有氨基连接臂的绿脓假单胞菌的O11血清型O抗原三糖。
本发明的第四个目的是提供一种糖-蛋白缀合物的制备方法,所述方法是包含绿脓假单胞菌的O11血清型O抗原三糖,所述绿脓假单胞菌的O11血清型O抗原三糖的制备方法为上述方法。
本发明的第五个目的是将上述的组装有氨基连接臂的绿脓假单胞菌的O11血清型O抗原三糖应用于在开发或制备绿脓假单胞菌疫苗或者绿脓假单胞菌感染导致的疾病的药物中的应用。
本发明有益效果:
1、本发明是通过化学方法合成得到绿脓假单胞菌O11血清型O-抗原三糖片段。本发明中开发了一种由D-甘露糖转变为D-岩藻糖的方法,方法简便高效,除了6-C甲基化约50左右,其余都可在80%以上;然后所得糖基砌块用于合成绿脓假单胞菌O11血清型O-抗原三糖片段。
2、常用糖苷键的构建是利用糖环C-2位酰基辅助下的邻基参与效应,高效率的构建1,2- 反式糖苷键,2-位乙酰基作为糖化学保护策略中最易得、最有效的保护剂,如本发明中反式糖苷键的构建。然而对于1,2-顺式反应,由于反应方法是没有普适性的,各反应条件对反应影响较大,其中有设计糖砌块的时候选择性在C-6用大空间位阻的保护基保护和在特别的针对半乳糖的在C-4位引入酰基形成类似长程邻基辅助效应的机制的报道,本发明方法采用一种适宜的混合溶剂,实现了顺式糖苷键的均一构建,立体选择性可达100%。
3、本发明通过保护基团的选择和优化以及糖苷化反应的策略,成功完成了O11三糖重复单元的制备。本发明方法合成的绿脓假单胞菌O11血清型O-抗原三糖片段组装有氨基连接臂,可以和抗原蛋白相连制成糖缀合物,对发展治疗和预防绿脓假单胞菌疫苗具有重要作用。
附图说明
图1:单糖砌块3(D-葡萄糖砌块)的合成路线图;
图2:单糖砌块7(L-岩藻糖砌块)的合成路线图;
图3:单糖砌块17(D-岩藻糖胺砌块)的合成路线图;
图4:单糖砌块17构建方法一的合成路线图;
图5:单糖砌块17构建方法二的合成路线图;
图6:二糖20的合成路线图;
图7:三糖24的合成路线图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或者制造商建议的条件进行,所用的试剂或者仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
本发明的产率计算方法为“产物(mol)/反应底物(mol)*100%”。本发明中化合物结构鉴定的方法为核磁共振图谱的测定(400M),高分辨质谱测定,旋光值测定,结果在每个化合物的具体合成中列出。
实施例1
糖砌块3(D-葡萄糖砌块)的合成如图1:
如图1所示,以全乙酰葡萄糖1作为起始原料,在干燥的N,N-二甲基甲酰胺中利用乙酸肼(NH2-NH2-AcOH)选择性的水解掉1号位上的乙酰基。得到的1-OH葡萄糖2在然后无水二氯甲烷中利用三氯乙腈(Cl3CN)和1,8-二氮杂二环十一碳-7-烯(DBU)生成葡萄糖基三氯乙酰亚胺酯3。
具体试验操作和步骤:
化合物2:全乙酰葡萄糖1(5.0g,12.8mmol)溶解在无水DMF(65ml)中,加入醋酸肼(1.45g,15.6mmol)。反应在40℃下搅拌6h,用TLC监测反应物消失。反应液冷却到室温,用饱和NaCI溶液洗涤,分离有机相,用无水Na2SO4干燥,浓缩后用硅胶柱纯化(石油醚/乙酸乙酯,2:1)得化合物2(3.9g,11.2mmol)。该化合物的鉴定数据已有相关文献报道。
化合物3:化合物2(1.1g,3.16mmol)溶解在无水DCM(30ml)并且冷却到0℃。依次往反应液里面加入Cl3CN(3.2ml,31.6mmol)和DBU(0.45ml,0.3mmol),该反应在冰浴下搅拌4h,用TLC监测反应原料消失。反应液恢复到室温,用饱和NaHCO3萃取,分离有机相,用无水Na2SO4干燥,浓缩后用硅胶柱纯化(石油醚/乙酸乙酯,4:1)得化合物3(1.3 g,2.8mmol)。该化合物的鉴定数据已有相关文献报道。
实施例2:
糖砌块7(L-岩藻糖砌块)的合成路线为图2。
如图2所示,以烯丙基2-脱氧-2叠氮基-L-岩藻糖苷4为起始原料,先在含有甲醇钠的碱性环境下脱去3,4号位的乙酰基,得到的二羟基化合物在二丁基氧化锡和溴甲基萘的作用下在4号位选择性的用Nap基保护起来得到化合物5,3-Nap化合物5的羟基用苄基保护生成化合物6。最后用DDQ脱去6的Nap基得到化合物3-OH化合物7。
具体试验操作和步骤:
化合物5:烯丙基2-脱氧-2叠氮基-L-岩藻糖苷4(500mg,2.2mmol)容易无水甲苯(22 ml),然后加入二丁基氧化锡(814mg,3.3mmol)。将反应液加热到110℃搅拌1h。随后反应液冷却到40℃,加入溴甲基萘(814mg,3.3mmol)和四丁基溴化铵(1.05g,3.3mmol),继续反应20h。反应完全后加入乙酸乙酯(30ml)稀释,用饱和食盐水洗涤。分离有机相,浓缩后用硅胶柱纯化(石油醚/乙酸乙酯,5:1)得化合物5(527mg,1.7mmol,79%)。[α]D 20=34.0°(c=1.00,CHCl3);1H NMR(400MHz,Chloroform-d)δ7.85(dt,J=10.5,7.7Hz,4H, Ar-H),7.59–7.45(m,3H,Ar-H),5.94(ddt,J=16.8,10.9,5.6Hz,1H,Ally-H),5.33(dd,J=17.2,1.7Hz,1H,Ally-CH2a),5.21(dd,J=10.5,1.5Hz,1H,Ally-CH2b),4.88(s,2H,2Nap-H),4.12(dd, J=12.9,6.2Hz,1H,Ally-H),4.23(d,J=8.1Hz,1H,1-H),4.12(dd,J=12.9,6.2Hz,1H, Ally-OCH2b),3.74(d,J=3.3Hz,1H,4-H),3.66(dd,J=10.0,8.0Hz,1H,2-H),3.47(q,J=6.5 Hz,1H,5-H),3.35(dd,J=10.0,3.3Hz,1H,3-H),2.32(s,1H,4-OH),1.34(d,J=6.4Hz,6-CH3). 13C NMR(101MHz,CDCl3)δ134.65,133.65,133.20,128.55,127.93,127.77,126.98,126.33, 126.22,125.75,117.61,100.75,79.41,77.33,77.22,77.01,76.70,72.19,70.19,69.97,68.34,62.57, 16.33.HRMS(ESI)m/z calcd for C20H23N3O4Na[M+Na]+391.1581,found 391.1564。
化合物6:将化合物5(527mg,1.7mmol)溶于无水DMF(17ml)中,冷却至0℃,冰浴30min。往反应瓶中加入NaH(140mg,3.4mmol),继续在0℃下搅拌30min,加入溴化苄(0.5ml,3.4mmol)。反应液恢复到室温,继续搅拌4h,待反应原料全部消失之后加入 DCM(20ml)稀释,用冰水淬灭反应。用饱和NaHCO3洗涤三次,合并有机相,浓缩后经硅胶柱纯化(石油醚/乙酸乙酯,25:1)得到化合物6(531mg,1.2mmol,68%)[α]D 20=50.3°(c =1.00,CHCl3)。1HNMR(400MHz,Chloroform-d)δ7.90–7.77(m,4H,Ar-H),7.57–7.45(m, 3H,Ar-H),7.38–7.21(m,6H,Ar-H),5.94(dddd,J=16.9,10.8,6.1,5.0Hz,1H,Ally-H),5.32(dt, J=17.2,1.7Hz,1H,Ally-H),5.19(dq,J=10.5,1.5Hz,1H,Ally-H),4.97(d,J=11.7Hz,1H, PhCH),4.87(s,2H,2Nap-H)4.71(d,J=11.7Hz,1H,PhCH-H),4.39(ddt,J=12.9,5.0,1.6Hz, 1H,Ally-H),4.22(d,J=8.0Hz,1H,1-H),4.10(ddt,J=12.9,6.1,1.4Hz,1H,Ally-H),3.87(dd,J =10.4,8.0Hz,1H,2-H),3.55(d,J=2.8Hz,1H,4-H),3.42-3.38(m,1H,5-H),3.36(dd,J= 10.4,2.8Hz,1H,3-H),1.20(d,J=6.4Hz,3H,6-CH3).
13C NMR(101MHz,Chloroform-d)δ138.38,135.34,133.93,133.38,133.23,128.55,128.48, 128.36,128.07,127.89,127.83,126.79,126.38,126.21,125.90,117.58,101.11,81.07(C-1), 75.17,74.85,72.87,70.74,70.07,63.31,17.02.HRMS(ESI)m/z calcd for C27H29N3O4Na[M+Na]+482.2050,found 482.2041。
化合物7:将化合物6(531mg,1.16mmol)溶于二氯甲烷(50ml)和水(5ml)的混合溶剂中,反应液冷却至0℃,加入DDQ(540mg,2.32mmol)。反应液在室温下搅拌2h,待TLC监测原料全部反应完全后,用10%Na2S2O3洗涤反应液,分离有机相,用无水硫酸钠干燥后浓缩,经硅胶柱纯化(石油醚/乙酸乙酯,3:1)得到化合物7(325mg,0.96mmol, 85%)。[α]D 20=-3.6°(c=1.00,CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.42–7.28(m,5H, Ar-H),5.94(dddd,J=16.7,10.4,6.1,5.1Hz,1H,Ally-H),5.33(dq,J=17.2,1.6Hz,1H,Ally-H), 5.21(dq,J=10.5,1.4Hz,1H,Ally-H),4.81(d,J=11.6Hz,1H,Bn-H),4.72(d,J=11.6Hz,1H, Bn-H),4.41(ddt,J=12.9,5.1,1.6Hz,1H,Ally-H),4.26(d,J=7.7Hz,1H,1-H),4.11(ddt,J=12.9,6.1,1.4Hz,1H,Ally-H),3.58–3.49(m,3H,2-H,4-H,5-H),3.45(dd,J=10.4,3.3Hz,1H, 3-H),2.14(s,1H,-OH),1.31(d,J=6.5Hz,3H,6-Me)。13C NMR(101MHz,Chloroform-d)δ138.02,133.75,128.68,128.30,128.18,117.63,101.11,78.60,76.04,73.12,70.95,70.17, 64.73,17.01。HRMS(ESI)m/z calcd for C16H21N3O4Na[M+Na]+342.1424,found342.1430。
实施例3:
糖砌块17的合成路线为图3。
如图3所示,以3,4,6-O-三乙酰基甘露糖糖烯8为起始原料,与二乙酸碘苯(PhI(OAc)2)、叠氮基三甲基硅烷(TMS-N3)和二苯基二硒(Ph2Se2)加成反应得到1-硒苯基-2-叠氮基化合物9。用甲醇和甲醇钠脱去9的三个乙酰基,然后利用接着用4-甲苯磺酰氯(TsCl)选择性保护6号位羟基得到化合物10。接下来,6-Ts葡萄糖10的Ts基团用碘化钠碘代,紧接着用氰基硼氢化钠(NaCNBH3)把6号位还原成甲基,得到D-岩藻糖化合物11。用对甲氧基苄氯(PMBCl)和氧化二丁基锡(Bu2SnO)选择性保护D-岩藻糖化合物的3号位得到化合物 12,随后用苄基保护4号位羟基得到化合物13。13的4号位Nap用DDQ脱去,随后用乙酰基保护起来得到化合物14。用四丁基溴化铵(NBS)水解化合物14的1号位硒苯基,紧接着用Cl3CN和DBU将1-OH岩藻糖做成糖基三氯乙酰亚胺酯供体15。随后在三氟甲磺酸三甲基硅脂的促进下化合物15与一个三碳连接臂反应,得到一个组装有连接臂的岩藻糖化合物 16。最后在甲醇和甲醇钠的碱性环境下脱去化合物16的乙酰基得到糖砌块17。
具体试验操作和步骤:
化合物9:将半乳糖烯化合物8(2.0g,7.35mmol)溶于无水二氯甲烷(35ml)中,然后冷却到-30℃。在氩气保护下加入二乙酸碘苯(2.4g,7.35mmol)和叠氮三甲基硅烷(1.8ml,14.7mmol),继续在-30℃下搅拌0.5h,然后缓慢恢复到室温,继续搅拌3h之后经TLC监测原料反应完全能。反应液用饱和NaHCO3洗涤(20ml)3次,分离有机相用无水硫酸钠干燥,过滤,滤液旋干后经由硅胶柱纯化(石油醚/乙酸乙酯,6:1),得到化合物9(2.4g,5.15mmol,70%)。[α]D 20=931.7°(c=1.00,CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.78-7.11(m,5H, Ar-H),6.01(d,J=5.4Hz,1H,H-1),5.47(dd,J=3.4,1.4Hz,1H,4-H),5.12(dd,J=10.9,3.3Hz, 1H,3-H),4.67(ddd,J=7.1,5.8,1.3Hz,1H,5-H),4.26(dd,J=10.9,5.4Hz,1H,2-H),4.08(dd,J =11.5,5.9Hz,1H,6a-H),4.02(dd,J=11.4,7.1Hz,1H,6b-H),2.15(s,3H,COCH3),2.07(s,3H, COCH3),1.98(s,3H,COCH3).13C NMR(101MHz,Chloroform-d):δ169.93,137.08,135.12, 129.91,129.19,128.56,128.23,128.04,127.97,84.44,77.22,75.34,73.68,73.44,70.09, 67.05,58.99,21.67,20.83。HRMS(ESI)m/z calcd forC18H21N3NaO7Se[M+Na]+494.0442。
化合物10:将化合物9(0.5g,1.1mmol)溶解在甲醇(2.2ml)里,加入甲醇钠(29mg,0.5mmol)。反应液在室温下搅拌2h,TLC检测显示原料反应完全。用氢型Amberlite IR120树脂中和反应液至~7。过滤树脂,将溶剂旋干。
将上一步的粗产物溶解在无水吡啶(8ml)里,在氩气保护下加入TsCl(253mg,1.3mmol)。反应液在室温下搅拌12h,TLC检测原料反应完全。用DCM稀释反应液,用1M盐酸洗涤,然后用饱和碳酸氢钠萃取。合并有机相,用无水硫酸钠干燥,浓缩后用硅胶柱纯化(二氯甲烷/甲醇,200:1)得到化合物10(384mg,077mmol,70%)。[α]D 20=133.6°(c=1.00,CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.3Hz,2H,Ar-H),7.58(dt,J=6.7,1.6Hz,2H, Ar-H),7.36-7.23(m,6H,Ar-H),5.86(d,J=5.3Hz,1H,H-1),4.57-4.50(m,1H,5-H),4.29(dd, J=10.6,6.0Hz,1H,6a),4.10–3.93(m,3H,H-2,H-4,6b-H),3.78(ddd,J=9.8,6.0,3.3Hz,1H, H-3),2.68(dd,J=6.5,4.8Hz,2H,3-OH,4-OH),2.44(s,3H,PhCH3)。13CNMR(101MHz, CDCl3)δ145.20,135.04,132.36,132.11,132.01,129.94,129.24,128.78,128.66,128.24,128.00, 127.67,84.62,77.34,77.22,77.02,76.70,70.62,69.97,67.87,67.55,61.57,21.68。HRMS(ESI)m/z calcd for C19H21N3NaO5SSe[M+Na]+506.0265。
化合物11:在氩气保护下,将化合物10(380mg,0.76mmol)溶于2-丁酮(9.6ml)中,加入碘化钠(568mg,3.8mmol)。反应液在80℃下搅拌12h,TLC检测原料反应完全。反应液恢复到室温,加入乙酸乙酯(10ml)稀释,用10%硫代硫酸钠洗涤两次,水洗涤两次,合并有机相,用无水硫酸钠干燥。浓缩后经由硅胶柱纯化(石油醚/乙酸乙酯,4:1)得到新化合物(259mg,0.57mmol,75%)。[α]D 20=317.6°(c=1.00,CHCl3)。1H NMR(400MHz, Chloroform-d)δ7.61–7.43(m,4H,Ar-H),7.39–7.12(m,6H,Ar-H),5.96(d,J=5.3Hz,1H, 1-H),4.44–4.33(m,1H,5-H),4.22(d,J=3.7Hz,1H,4-H),4.09(dd,J=10.2,5.3Hz,1H,2-H), 3.79(ddd,J=9.9,6.1,3.3Hz,1H,3-H),3.17(dd,J=12.7,8.2Hz,1H,6-Ha),3.06(dd,J=12.7,6.0Hz,1H,6-Hb),2.75(d,J=6.2Hz,1H,3-OH),2.45(d,J=3.9Hz,1H,4-OH)。13C NMR(101MHz,CDCl3)δ134.58,132.92,132.87,132.81,129.49,129.32,129.28,129.18,128.19,127.97, 127.46,85.04,84.62,77.36,77.25,77.04,76.73,72.32,71.32,68.93,61.71,26.94。HRMS(ESI)m/z calcd for C12H14IN3NaO3Se[M+Na]+477.9143。
在氩气的保护下将新化合物溶解在DMF(2ml)中,加入氰基硼氢化钠(48mg,0.75mmol)。反应在95℃下搅拌12h,TLC检测原料反应完全。反应液恢复到室温,用水和乙酸乙酯洗涤反应液,合并有机相,用无水硫酸钠干燥,浓缩后用硅胶柱纯化(石油醚/乙酸乙酯2:1)得到化合物11(35mg,0.1mmol,70%)。[α]D 20=259.4°(c=1.00,CHCl3)。1HNMR(400MHz,Chloroform-d)δ7.73-7.45(m,2H,Ar-H),7.40-6.93(m,3H,Ar-H),5.92(d,J=5.3Hz,1H,H-1),4.39(dt,J=7.4,6.0Hz,1H,5-H),4.05(dd,J=10.0,5.3Hz,1H,2-H),3.91–3.74(m,2H, H-3.4-H),2.60(d,J=6.3Hz,1H,3-OH),2.26(d,J=4.0Hz,1H,4-OH),1.27(d,J=6.6Hz,3H, 6-CH3).13C NMR(101MHz,Chloroform-d)δ134.48,129.15,127.90,85.00,77.22,71.46, 71.29,68.69,61.88,15.98。HRMS(ESI)m/z calcd for C12H15N3NaO3Se[M+Na]+346.0230,found 346.0226。
化合物12:将化合物11(3.0g,9.1mmol)溶于无水甲苯(54ml)中,在氩气保护下加入Bu2SnO(3.5g,13.7mmol)。反应液加热到118℃搅拌下回流1.5h。随后将反应液冷却至 60℃,加入PMBCl(1.9ml,13.7mmol)和TBAI(5.1g,13.7mmol),继续搅拌2h。反应液冷却到室温,加入乙酸乙酯(80ml)稀释,用水(100ml)洗涤2次,分离有机相,用无水硫酸钠干燥,滤液浓缩后用硅胶柱纯化(石油醚/乙酸乙酯,6:1)得到化合物12(2.7g,6 mmol,66%)。[α]D 20=137.9°(c=1.00,CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.26(s, 11H,Ar-H),5.88(d,J=5.4Hz,1H,H-1),4.70(d,J=11.0Hz,1H,Bn-H),4.63(d,J=11.0Hz,1H, Bn-H),4.36-4.24(m,1H,5-H),4.15(dd,J=10.2,5.3Hz,1H,2-H),3.86(dt,J=3.2,1.5Hz,1H, 4-H),3.82(s,3H,Me-H),3.69(dd,J=10.2,3.2Hz,1H,3-H),2.35(t,J=1.6Hz,1H,4-OH),1.26(d,J=6.6Hz,3H,6-Me).13C NMR(101MHz,Chloroform-d)δ159.74,134.40,129.75,129.10,129.08,127.75,114.14,85.28,78.85,71.84,68.61,68.55,60.18,55.31,16.05。 HRMS(ESI)m/z calcd for C20H23N3O4SeNa[M+Na]+472.0751,found 472.0725。
化合物13:用将化合物12(2.2g,4.9mmol)溶于DMF(30ml)中,0℃下搅拌30min,在氩气保护下缓慢划入氢化那(396mg,9.8mmol)。冰浴下继续搅拌30min,往反应液中逐滴加入溴化苄(1.2ml,9.8mmol)。继续搅拌反应2h,TLC检测原料全部反应完全,加入冰水淬灭反应,用DCM稀释反应液,萃取后由无水硫酸钠干燥,浓缩液使用硅胶柱纯化(石油醚/乙酸乙酯,30:1)得到化合物13(1.9g,3.6mmol,74%)。[α]D 20=71.5°(c=1.00,CHCl3)。1HNMR(400MHz,Chloroform-d)δ7.57-7.55(m,2H,Ar-H),7.36-7.25(m,10H,Ar-H),6.94- 6.91(m,2H,Ar-H),5.92(d,J=5.3Hz,1H,H-1),4.94(d,J=11.4Hz,1H,PhCH),4.77-4.66(m,2H,PhCH2),4.60(d,J=11.5Hz,1H,PhCH),4.33(dd,J=10.2,5.3Hz,1H,H-2),4.21(q,J=6.5Hz,1H,H-5),3.83(s,3H,OCH3),3.71(dd,J=10.3,2.7Hz,1H,H-3),3.68(dd,J=2.8,1.1Hz, 1H,H-4),1.12(d,J=6.4Hz,3H,6-CH3)。13C NMR(101MHz,CDCl3)δ159.63,138.33,134.48, 129.72,129.16,128.90,128.44,128.32,127.90,127.77,114.14,85.79,80.47,77.16,76.01,75.13, 72.40,69.56,61.03,55.46,16.69。HRMS(ESI)m/z calcd forC27H29N3NaO4Se[M+Na]+562.1221, found 562.1209。
化合物14:将化合物13(900mg,1.67mmol)溶解于DCM(84ml)中,在氩气保护下加入2,3-二氯-5,6-二氰基-1,4-苯醌(564mg,2.5mmol)和水(4.2ml)。反应在室温下搅拌7 h,用TLC检测反应完全。加入DCM(50ml)稀释,用10%硫代硫酸钠(100ml)洗涤反应液两次。分离有机相,经由无水硫酸钠,浓缩后用硅胶柱纯化(石油醚/乙酸乙酯,10:1)得到新产物(573mg,1.4mmol,82%)。把新产物溶解在干燥的吡啶(3.2ml)中,冷却至0℃, 30min后缓慢加入乙酸酐(0.5ml,5.12mmol),反应液恢复到室温继续搅拌5h,TLC检测原料反应完全。用1M的盐酸洗涤反应液,接着用饱和碳酸氢钠和饱和食盐水萃取。分离有机相,浓缩后用硅胶柱纯化(石油醚/乙酸乙酯=20:1)得到化合物14(598mg,1.3mmol,quant)。1H NMR(400MHz,Chloroform-d)δ7.68-7.21(m,9H,Ar-H),5.91(d,J=5.3Hz,1H,H-1), 5.46(dd,J=3.3,1.2Hz,1H,H-4),4.75(d,J=10.7Hz,1H,PhCH2),4.53(d,J=10.7Hz,1H, PhCH),4.48-4.37(m,1H,H-5),4.12(dd,J=10.3,5.4Hz,1H,H-2),3.78(dd,J=10.4,3.3Hz, 1H,H-3),2.15(s,3H,COCH3),1.12(d,J=6.5Hz,3H,6-CH3)。13C NMR(101MHz,Chloroform-d) δ170.52,136.90,134.53,129.12,128.50,128.34,128.07,127.88,85.08,71.68,68.89, 67.77,60.36,20.76,16.07。HRMS(ESI)m/z calcd for C21H23N3NaO4Se[M+Na]+484.0751, found484.0749。
化合物15:将化合物14(580mg/1.3mmol)溶于四氢呋喃(6ml)和水(6ml)的混合溶液,并且冷却至0℃。加入四丁基溴化铵(538mmol,3mmol),反应液回复到室温继续搅拌5h,TLC检测显示原料反应完全。反应液用10%硫代硫酸钠洗涤,用DCM和水萃取,分离有机相,用无水硫酸钠干燥,浓缩后用硅胶柱纯化(石油醚/乙酸乙酯,4:1)得到新化合物(417mmol,1.3mmol,quant.)[α]D 20=54.9°(c=1.00,CHCl3)。1H NMR(400MHz, Chloroform-d)δ7.43–7.30(m,8H,Ar-H),5.47(dd,J=3.3,1.3Hz,1H,1a-H),5.34(dd,J=3.4, 1.1Hz,0.8H,4b-H),5.32(d,J=3.6Hz,1H,4a-H),4.77(d,J=10.8Hz,1H,PhCH),4.75(d,J= 11.1Hz,0.8H,PhCH),4.54(d,J=7.9Hz,1H,1b-H),4.53(d,J=10.8Hz,1H,PhCH),4.53(d,J= 11.1Hz,0.8H,PhCH),4.32(qd,J=6.6,1.3Hz,1H,5-H),4.03(dd,J=10.5,3.2Hz,1H,2a-H), 3.74(dd,J=10.5,3.5Hz,1H,3a-H),3.69(td,J=6.4,1.1Hz,0.8H,5b-H),3.58(dd,J=10.2,7.9 Hz,0.8H,2b-H),3.45(dd,J=10.3,3.4Hz,0.8H,3b-H),2.19(s,2.4H,COCH3),2.18(s,3H, COCH3),1.25(d,J=6.5Hz,2.4H,6b-CH3),1.19(d,J=6.5Hz,3H,6a-CH3).。13C NMR(101MHz,CDCl3)δ170.90,170.88,137.15,137.04,128.63,128.52,128.40,128.22,128.17,96.20, 92.46,77.91,77.48,77.36,77.16,77.16,76.84,74.36,71.91,71.67,69.69,69.46,68.39,65.21, 64.03,59.82,20.95,20.93,16.55,16.42。HRMS(ESI)m/z calcd forC15H19N3O5Na[M+Na]+ 344.1217,found 344.1208。
将新化合物(417mmol,1.3mmol)溶于无水二氯甲烷(14ml),冷却至0℃。依次加入三氯乙腈(0.4ml,3.78mmol)和DBU(23μL,0.13mmol),反应液继续搅拌5h,TLC 检测原料反应完全。直接将反应液在室温下浓缩,经由硅胶柱纯化(石油醚/乙酸乙酯,10:1) 得到化合物15(518mg,1.1mmol,88%)。
化合物16:糖基三氯乙酰亚胺酯15(518mg,1.1mmol)和氮-苄基-氮-甲酸苄酯-丙醇(500 mg,1.7mmol)溶于无水DCM中,加入分子筛,室温下搅拌半小时。然后将反应液冷却至-40℃,在氩气下加入缓缓加入TMSOTf(0.3ml,1.3mmol)。反应液在-40℃下继续搅拌4h,用TLC监测原料反应完全,用三乙胺(1ml)淬灭反应。反应液用饱和NaHCO3萃取,分离有机相,用无水Na2SO4干燥后经由硅胶柱纯化得到化合物16(396mg,0.44mmol,60%)。 [α]D 20=-10.8°(c=1.00,CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.45–7.16(m,15H,Ar-H),5.23–5.12(m,2H,PhCH),4.74–4.59(m,3H,3-H,2PhCH),4.61–4.38(m,2H,2NPhCH),4.21(dd,J=33.3,8.0Hz,1H,1-H),4.02–3.87(m,1H,linker-OCH),3.79(t,J=9.5Hz,1H 2-H),3.67 (d,J=3.0Hz,1H,4-H),3.63–3.27(m,4H,5-H linker-OCH,linker-NCH2),2.07(s,3H,COCH3), 2.01–1.76(m,2H,linker-CH2),1.24(d,J=6.4Hz,3H,6-CH3).13C NMR(101MHz,CDCl3)δ 170.38,137.95,137.70,128.52,128.46,128.40,128.32,127.97,127.92,127.87,127.27,101.99, 77.37,77.25,77.05,76.74,76.19,75.59,74.23,70.48,67.40,67.19,61.11,50.90,44.67,43.62, 28.48,28.03,20.89,16.57.HRMS(ESI)m/zcalcd for C33H38N4O7Na[M+Na]+625.2633,found 625.2650。
化合物17:将化合物16(262mg,0.42mmol)溶于甲醇(4ml)中,加入甲醇钠(40mg)。反应液在室温下搅拌2h,待原料全部反应完全之后,用甲醇稀释反应液,用氢型AmberliteIR120树脂中和反应液至pH~7。滤去树脂,滤液浓缩后经由硅胶柱纯化(石油醚/乙酸乙酯,3:1)得到化合物17(244mg,0.42mmol,quant.)。[α]D 20=-24.1°(c=1.00,CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.76–6.87(m,15H,Ar-H),5.22(d,J=9.4Hz,2H,PhCH),4.83(d,J=11.6Hz,1H,PhCH),4.78(d,J=11.6Hz,1H,PhCH),4.58(d,J=14.0Hz,2H,PhCH),4.25–4.08(m,1H,1-H),4.05–3.86(m,1H,linker-OCH),3.62–3.34(m,7H,2-H,3-H,4-H,5-H,linker-OCH,linker-NCH2),2.46(s,1H,-OH),2.02–1.80(m,2H,linker-CH2),1.31(d,J=6.4Hz, 3H,6-CH3).13C NMR(101MHz,Chloroform-d)δ138.00,128.58,128.56,128.50,128.26, 128.08,127.95,127.89,102.12(1-C),78.48,77.36,75.94,72.96,70.84,67.24,64.70,50.94, 43.74,28.58,16.91。HRMS(ESI)m/z calcd for C31H36N4NaO6[M+Na]+583.2527,found 583.2531。
实施例4:D-岩藻糖砌块合成方法的考察
方法一:
根据已有文献报道的类似化合物合成方法中总结得到合成D-岩藻糖砌块的方法1,如图 4所示。以半乳糖烯糖S1作为起始原料,在二苯基二硒醚、三甲基硅烷基叠氮和二乙酰基碘苯的共同作用下,在其一号二号位分别引入硒苯基和叠氮基,得到重要的中间体S2,在甲醇甲醇钠作用下,脱去三四六号位的乙酰基得到化合S3,接着在四六位引入苄叉基得到化合物 S4,再将三号位用乙酰基暂时保护起来得到化合物S5,然后在三甲基硅三氟甲磺酸和硼烷的共同作用下,将苄叉基选择性打开,将苄基引入到四号位,得到化合物S6,然后在裸露的六号位在对甲苯化酰氯和吡啶的作用下引入对甲苯磺酰基,得到化合物S7,然而在将六号位的对甲苯磺酰基用碘原子取代时,反应无法顺利进行。
发明人尝试了不同条件,包括:乙腈和TBAI在分别在100℃,80℃条件下以及丁酮和碘化钠在80℃的条件下进行反应,均未能在六号位引入碘,得到相应的产物S8,进而无法继续沿路线合成目标合成D-岩藻糖砌块。
方法二:
对方法一进行改进,改进之后的合成路线如图5所示。以全乙酰葡萄糖烯糖S9为起始原料,利用自由基加成反应,在一号二号位分别引入硒苯基和叠氮基,得到化合物S10,然后脱乙酰后得到化合物S11,紧接着四六位用苄叉基同时保护得到化合物S12,然后将三号位暂时用乙酰基保护后得到化合物S13,接下来在80%醋酸溶液中打开苄叉基得到化合物S14,在六号位在对甲苯磺酸和吡啶的条件下引入对甲苯磺酰基,得到化合物S15,然后在2-丁酮的回流溶液中与碘化钠反应,六号位引入碘,得到化合物S16。用氰基硼氢化钠还原的方法还原化合物S16的六号位羟基,使之还原成甲基,得化合物S17,然后在四号位先引入三氟甲磺酰基,得到化合物S18,再用亚硝酸钾还原,得到四号位竖直羟基的化合物S19,即成功将四号位平伏的羟基转变为竖直键的羟基,从而转变成D-岩藻糖构型,而后在氧化银的中性条件下,在四号位的羟基上引入苄基,得到化合物S20。
这种方法尽管能够得到所需的化合物S20,但是实用性不高,主要体现在路线步骤太长,共计有11个反应模块,尤其是在4-OH转位和最后一步利用Ag2O上OBn基团两步反应产率都不足50%上,以至于该路线总产率不足2%。
实施例5:
二糖20的合成路线为图6。
如图6所示,二糖18的合成依靠先前由图1路线合成的葡萄糖化合物3和由图2路线合成的L-岩藻糖化合物7在路易斯酸TMSOTf的催化下完成。随后在甲醇溶液中利用氯化钯水解掉二糖18还原端的烯丙基得到1-OH二糖化合物19。最后用2,2,2-三氟-N-苯基亚氨代乙酰氯将19做成含有N-苯基-三氟乙酰亚胺酯的二糖供体20。
具体试验操作和步骤:
化合物18:在氮气保护下将单糖供体3(500mg,1.0mmol)和糖基受体7(165mg,0.52mmol)溶于无水DCM(10ml),加入分子筛。反应液在室温下搅拌30min,然后冷却至0℃,加入TMSOTf(36μL,0.2mmol)。反应液缓慢回复到室温并继续搅拌5h,TLC检测发现原料反应完全。反应液用三乙胺淬灭,用饱和碳酸氢钠溶液萃取,浓缩液经硅胶柱纯化(石油醚/乙酸乙酯,2:1)得到化合物18(300mg,0.46mmol,88%)。[α]D 20=2.3°(c=1.00, CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.52–6.73(m,6H,Ar-H),5.84(ddt,J=16.4,10.8, 5.6Hz,1H,Ally-H),5.23(d,J=17.3Hz,1H,Ally-H),5.17–5.05(m,3H,Ally-H,3’-H,4’-H), 5.03(t,J=8.2Hz,1H,2’-H),4.80(d,J=11.3Hz,1H,Bn-H),4.77(d,J=7.7Hz,1H,1’-H),4.46 (d,J=11.4Hz,1H,Bn-H),4.29(dd,J=13.0,5.0Hz,1H,Ally-H),4.20(dd,J=12.3,4.4Hz,1H,6’-Ha),4.17–4.08(m,2H,6’-Hb,1-H),4.00(dd,J=13.0,6.2Hz,1H,Ally-H),3.66(qd,J=10.3, 4.9Hz,3H,5’-H,2-H,3-H),3.43(d,J=2.5Hz,1H,4-H),3.35(d,J=6.4Hz,1H,5-H),1.99(s, 3H,CH3CO),1.95(s,3H,CH3CO),1.92(s,3H,CH3CO),1.79(s,3H,CH3CO),1.10(d,J=6.3 Hz,3H,6-CH3)。13C NMR(101MHz,Chloroform-d)δ170.38,170.08,169.04,168.88,137.76, 133.47,128.04,127.91,127.52,117.24,100.54,98.46,79.37,77.03,75.44,74.68,72.99, 71.87,71.34,70.06,69.76,68.00,61.87,61.62,20.46,20.32,16.50。HRMS(ESI)m/z calcd for C30H39N3NaO13[M+Na]+672.2375,found 672.2377。
化合物19:将化合物18(300mg,0.46mmol)溶于无水甲醇(23ml),随后将反应液加热到40℃。加入氯化钯(16mg),继续搅拌1h,TLC检测原料反应完全。反应液用DCM 稀释并用饱和碳酸氢钠萃取,分离有机相,浓缩后经硅胶柱(石油醚/乙酸乙酯,1:1)纯化得到化合物19(256mg,0.40mmol,88%)。[α]D 20=-7.1°(c=1.00,CHCl3)。1H NMR(400MHz, Chloroform-d)。-anomerδ7.35–7.22(m,5H,Ar-H),5.23(d,J=3.5Hz,1H,1-H),5.22–5.00 (m,3H,2’-H,3’-H,4’-H),4.86–4.72(m,2H,1’-H,Bn-H),4.43(d,J=11.0Hz,1H,Bn-H),4.38 (d,J=7.8Hz,1H,1’-H),4.28(dd,J=10.6,2.7Hz,1H,3-H),4.25–4.11(m,2H,6’-Hab),4.11–4.02(m,1H,5-H),3.75–3.65(m,2H,2-H,5’-H),3.61(d,J=2.8Hz,1H,4-H),2.01(s,3H,OAc-Me),1.97(s,3H,OAc-Me),1.93(s,3H,OAc-Me),1.72(s,3H,OAc-Me),1.10(d,J=6.4Hz, 3H,6-Me)。-anomerδ7.35–7.22(m,5H,Ar-H),5.22–5.00(m,3H,2’-H,3’-H,4’-H),4.80(d, J=11.5Hz,1H,Bn-H),4.47(d,J=11.3Hz,1H,Bn-H),4.38(d,J=7.8Hz,1H,1’-H),4.22– 4.03(m,4H,6ab-H,1’-H,3-H),3.74–3.58(m,3H,2-H,4-H,5’-H),3.51–3.41(m,1H,5-H), 2.01(s,3H,OAc-Me),1.97(s,3H,OAc-Me),1.94(s,3H,OAc-Me),1.72(s,3H,OAc-Me),1.10 (d,J=6.4Hz,3H,6-Me)。13C NMR(101MHz,CDCl3)δ170.79,170.69,170.43,170.38,169.33, 169.29,169.15,169.05,137.87,128.44,128.39,128.36,128.32,128.24,128.14,128.12,128.00, 127.93,102.18,101.52,98.74,98.67,98.65,96.22,92.72,79.54,79.42,79.37,77.37,77.25,77.14, 77.05,76.87,76.73,76.48,75.73,75.52,75.17,75.03,75.00,74.96,74.06,73.33,73.23,73.20, 72.13,72.10,71.97,71.82,71.56,70.69,70.62,70.40,68.25,68.20,66.62,63.71,63.53,62.05, 61.99,61.78,58.93,43.75,29.68,20.71,20.69,20.66,20.58,20.56,20.54,16.78,16.67,16.61, 16.57。HRMS(ESI)m/z calcd for C27H35N3NaO13[M+Na]+632.2062,found 632.2039。
化合物20:将化合物19(86mg,0.14mmol)溶于无水DCM中并冷却到0℃。在氩气保护下加入2,2,2-三氟-N-苯基亚氨代乙酰氯(0.1ml)和DBU(30μL)。反应液恢复到室温继续搅拌20h。在室温下浓缩后经由硅胶柱纯化(石油醚/乙酸乙酯,2.5:1)得到化合物20 (67mg)。
实施例6:
三糖24的合成路线为图7。
如图7所示,二糖供体20和单糖受体17在二氯甲烷,乙醚和噻吩等溶剂的共同作用下由路易斯酸TMSOTf催化得到1,2-cis连接的三糖21。用硫代乙酸和吡啶在零度下将21的叠氮基还原成乙酰氨基化合物22。22葡萄糖基上的4个乙酰基在碱性条件下脱除得到化合物 23。最后,用钯碳和氢气脱去所有的芳香基团得到组装有氨基连接臂的绿脓假单胞菌O11血清型O抗原三糖。
具体试验操作和步骤:
化合物21:在氩气保护下将二糖供体20(35mg)和单糖受体17(45mg)溶于无水DCM(0.9ml)、乙醚(0.9ml)和噻吩(0.9ml)的混合溶剂中,加入分子筛,在室温下搅拌30min,随后冷却至0℃。加入TMSOTf,继续搅拌8h,TLC检测显示糖基供体全部反应完毕。用三乙胺淬灭反应,用饱和碳酸氢钠萃取,有机相浓缩后经硅胶柱(石油醚/乙酸乙酯, 3:1)和Sephadex LH-20凝胶柱(DCM/MeOH,1:1)纯化得到化合物21(37mg)。[α]D 20=-44.5°(c =1.00,CHCl3)。1H NMR(400MHz,Chloroform-d)δ7.41–7.19(m,20H,Ar-H),5.30–5.04(m, 6H,2PhCH,1’-H,2”-H,3”-H,4”-H),4.83(d,J=11.1Hz,1H,PhCH),4.77-4.75(m,3H,2PhCH,1”-H),4.55-4.50(m,2H,NPhCH),4.42(d,J=11.0Hz,1H,PhCH),4.33–4.21(m,1H,6”-H),4.18(d,J=7.0Hz,1H,1-H),4.07(m,2H,3’-H,6”-H),4.00–3.88(m,1H,linker-OCH),3.81(t,J =9.0Hz,1H,2-H),3.79–3.67(m,2H,5’-H,5”-H),3.62(dd,J=10.7,3.7Hz,1H,2’-H),3.53- 3.26(m,6H,linker-OCH,linker-NCH2,3-H,4H,4’-H),2.04(s,1H,COCH3),2.00(s,1H,COCH3), 1.96–1.81(m,2H,linker-CH2),1.80(s,1H,COCH3),1.30(d,J=6.7,3H,6-CH3),1.10(d,J=6.4 Hz,3H,6’-CH3)。13C NMR(101MHz,CDCl3)δ170.70,170.41,169.22,168.95,138.47,137.94, 137.78,128.50,128.44,128.38,127.99,127.96,127.89,127.86,127.77,127.62,127.25,102.44, 100.52,99.60,79.20,79.11,77.34,77.22,77.02,76.70,75.31,75.26,73.29,72.29,71.96,70.71, 68.03,67.50,67.18,63.61,61.76,58.26,50.90,49.78,44.76,43.68,29.69,28.52,28.09,23.42, 20.66,20.59,16.95,16.54。HRMS(ESI)m/z calcd for C58H69N7NaO18[M+Na]+1174.4591,found1174.4626。
化合物22:将化合物21(30mg)溶于干燥吡啶(0.5ml)和硫代乙酸(0.5ml)里。0℃下搅拌12h,用TLC检测原料反应完全,用甲苯与反应液共沸三次后用硅胶柱纯化(二氯甲烷/甲醇,50:1)得到化合物21(30mg)。[α]D 20=49.5°(c=1.00,CHCl3).1H NMR(400MHz,Chloroform-d)δ7.80–6.90(m,20H,Ar-H),6.83(d,J=8.1Hz,1H,NHAc-H),6.18(d,J=9.2Hz, 1H,NHAc-H),5.27–5.13(m,3H,3”-H,2Cbz-H),5.10–4.99(m,2H,1’-H,4”-H),4.96(t,J= 8.7Hz,1H,2”-H),4.88(d,J=11.1Hz,1H,Bn-H),4.84–4.79(m,1H,Bn-H),4.74(d,J=15.5 Hz,2H,Bn-H),4.63(d,J=8.0Hz,3H,1”-H,3-H,2’-H),4.41(d,J=10.9Hz,1H,Bn-H),4.34– 4.25(m,2H,6”-H,1-H),4.25–4.13(m,1H,2-H),4.09(t,J=9.0Hz,1H,6”-H),3.86(dtt,J= 34.7,10.8,6.0Hz,3H,5’-H,4-H,3’-H),3.66(dd,J=9.7,6.0Hz,1H,5”-H),3.60–3.52(m,1H, 3-H),3.44(d,J=7.3Hz,2H,5-H,4’-H),3.34–3.08(m,1H,linker-OCH2-H),2.87(dt,J=14.3, 5.0Hz,1H,linker-NH2-H),2.14(s,3H,OAc-Me),2.09(s,3H,NHAc-Me),2.06(s,3H,OAc-Me), 2.00(s,3H,OAc-Me),1.89(s,3H,NHAc-Me),1.80(s,3H,OAc-Me),1.68(d,J=9.6Hz,1H), 1.32(d,J=6.3Hz,3H,6’-Me),1.17(d,J=6.5Hz,3H,6-Me).13C NMR(101MHz,Chloroform-d) δ171.62,171.05,170.77,170.42,169.28,168.83,156.56,138.81,138.17,137.98,137.35,136.86, 128.66,128.55,128.51,128.47,128.36,128.17,128.09,127.96,127.91,127.80,127.76,127.71, 127.65,127.50,127.28,127.19,126.35,101.24,100.77,99.67,80.00,79.66,78.94,77.83,77.23, 75.05(d,J=13.2Hz),73.18,72.20,72.07,70.73,68.21,67.52,67.33,65.76,61.95,52.22,49.70, 47.60,42.47,31.92,29.69,26.87,23.33,20.84,20.58,20.56,17.24,16.73。
HRMS(ESI)m/z calcd for C58H69N7NaO18[M+Na]+1206.4998。
化合物23:将化合物22(22mg)溶解于甲醇中(5ml)并加入甲醇钠(10mg)。反应液在室温下搅拌2h,用TLC检测原料反应完全,用氢型Amberlite IR120树脂中和反应和至~7。过滤树脂,反应液浓缩后经硅胶柱纯化(二氯甲烷:甲醇,10:1)得到化合物23(18mg)。[α]D 20=-16.3°。1H NMR(400MHz,Chloroform-d)δ7.60–7.13(m,20H),7.12(d,J=7.3Hz,1H, NHAc-H),6.69(d,J=9.8Hz,1H,NHAc-H),5.23(d,J=12.6Hz,1H,Cbz-H),5.15(d,J=12.4 Hz,1H,Bn-H),5.05(d,J=12.3Hz,1H,Cbz-H),4.96–4.83(m,2H,1’-H,Bn-H),4.79(d,J= 15.7Hz,1H,Bn-H),4.72(d,J=12.2Hz,1H,Bn-H),4.66–4.49(m,2H,Bn-H,2’-H),4.36(s, 1H,OH-H),4.28(d,J=9.5Hz,1H,2A-H),4.22(d,J=16.0Hz,1H,Bn-H),4.03(d,J=7.3Hz, 2H,1”-H,NCH2-H),4.00–3.84(m,4H,3’-H,1-H,6”-H,OCH2-H),3.72(dd,J=12.5,6.1Hz,1H, 6”-H),3.64(q,J=6.7Hz,1H,5-H),3.42(ddd,J=26.0,12.9,5.7Hz,4H,5-H,2”-H,3”-H,4”-C), 3.33(d,J=4.6Hz,1H,3-H),3.31–3.19(m,2H,4’-H,5”-C),3.15(td,J=9.7,4.0Hz,1H, OCH2-H),2.88–2.74(m,2H,NH2-H),2.09(s,3H,NHAc-Me),1.96(s,3H,NHAc-Me),1.72– 1.57(m,2H,linker-CH2),1.32(s,J=6.4,3H,6-Me),1.03(s,J=6.3,3H,6-Me)。13C NMR(101 MHz,CDCl3)δ172.97,172.65,156.77,138.85,138.64,137.11,136.82,128.75,128.60,128.38, 128.14,128.05,127.64,127.50,127.34,127.26,127.07,101.41,99.87,82.13,79.54,77.36,77.04, 76.72,76.31,75.31,74.62,74.34,74.14,72.82,71.70,70.92,67.67,67.56,65.55,62.61,52.00, 49.50,48.11,42.01,29.72,26.65,23.53,17.50,16.75。HRMS(ESI)m/z calcd for C62H77N3NaO20[M+Na]+1038.4570,found 1038.4538。
化合物24:将化合物23(12mg)溶于甲醇(3ml)、二氯甲烷(1ml)和水(1ml)的混合溶剂,并加入两滴冰乙酸,随后加入钯碳(10mg)。反应在BLT-2000中压氢化仪中进行,氢气压力为0.4MPa,反应时间12h。待反应结束后反应液用硅藻土过滤,浓缩后经 CHROMAFIX C18ec纯的得到化合物24(7mg)。1H NMR(400MHz,Deuterium Oxide)δ5.03 (s,1H,1’-H),4.51(d,J=7.9Hz,1H,1”-H),4.37(d,J=8.4Hz,1H,1-H),4.17(s,1H,2’-H),4.07 (q,J=6.6Hz,1H,5’-H),4.02(s,1H,3’-H),3.99–3.86(m,4H,2-H,4’-H,6”-H,OCH2-H),3.80– 3.75(m,1H,5-H),3.67(ddt,J=16.6,10.9,6.0Hz,3H,3-H,6”-H,OCH2-H),3.46(m,2H,3”-H, 5”-H),3.34(t,J=9.3Hz,1H,4”-H),3.26(t,J=8.6Hz,1H,2”-H),3.05(t,J=6.9Hz,2H,NCH2-H),2.00(s,3H,NHAc-Me),1.98(s,3H,NHAc-Me),1.91(t,J=6.4Hz,2H,CH2-H),1.23(d,J=6.9Hz,3H,6-Me),1.21(d,J=6.8Hz,3H,6’-Me)。13C NMR(101MHz,Deuterium Oxide)δ 174.35,101.49,100.22,98.89,76.54,76.00,75.46,74.78,72.81,71.31,70.63,70.33,69.63, 69.60,68.39,67.88,66.88,60.84,51.31,47.88,37.60,26.64,,22.20,22.17,15.39,15.29。 HRMS(ESI)m/z calcd for C25H45N3NaO14[M+Na]+634.2794,found 634.2789。
实施例7:考察溶剂对三糖24中顺式糖苷键构建的影响
利用糖环C-2位酰基辅助下的邻基参与效应,高效率的构建1,2-反式糖苷键已成为糖化学中较为成熟的方法,而2-位乙酰基作为糖化学保护策略中最易得、最有效的保护剂,一般被优先考虑,例如在本专利中化合物18的合成。然而对于1,2-顺式反应,目前还没有成熟的方法。
参照实施例6,其他条件不变,改变溶剂组分,产物构型结果见表1。
由表1可知,1,2-顺式糖苷键构建受溶剂影响很大,其中以无水二氯甲烷/乙醚/噻吩混合溶剂效果最佳,可以达到均一α构型产物,反应立体选择性可达100%。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.一种绿脓假单胞菌O11血清型O抗原三糖的合成方法,其特征在于,所述方法包括:利用D-葡萄糖砌块、L-岩藻糖胺砌块、D-岩藻糖胺砌块构建O抗原三糖;其中,D-葡萄糖砌块或L-岩藻糖胺砌块与D-岩藻糖胺砌块通过1,2-α-顺式-糖苷键连接,D-葡萄糖砌块与L-岩藻糖胺砌块通过1,2-β-反式糖苷键连接,所述1,2-α-顺式-糖苷键的构建是在混合溶剂中进行的;所述混合溶剂包括二氯甲烷、乙醚、噻吩中的两种或两种以上。
2.根据权利要求1所述的方法,其特征在于,所述D-葡萄糖砌块的化学结构如式II所示,L-岩藻糖胺砌块的化学结构式如式III所示,D-岩藻糖胺砌块的化学结构式如式IV所示,
其中,linker包括-(CH2)n-N-Y1Y2,或者O-(CH2)n-SY1(Y2),或者O-(CH2)n-N3,n=1~10;Y1为氢(H)或者苄基(Bn);Y2为氢(H)或者苄甲氧羰基(Cbz);
R1包括但不限定于氢(H)、酯基、乙酰基(Ac)、苯甲酰基(Bz)、新戊酰基(Piv)、氯乙酰基(ClAc)、乙酰丙酰基(Lev)、烯丙羰酰基(Alloc);
R2,R3,R4为氢(H)或者酯基、醚基包括但不限于乙酰基(Ac)、苯甲酰基(Bz)、新戊酰基(Piv)、氯乙酰基(ClAc)、乙酰丙酰基(Lev)、烯丙羰酰基(Alloc)以及苄基(Bn)、对甲氧基苄基(pMBn)、烯丙基(All)、三苯甲基(Tr)、单甲氧基三苯甲基(Mmt)和硅醚类基团基团;
R5,R6包括但不限于氢(H)、醚类基团、苄基(Bn)、对甲氧基苄基(pMBn)、烯丙基(All)、三苯甲基(Tr)、单甲氧基三苯甲基(Mmt)和硅醚类基团基团;
R7,R8,R9,R10包括氢(H)、氮(N)或者乙酰基(Ac)。
3.根据权利要求1或2所述的方法,其特征在于,所述方法包括利用D-葡萄糖砌块和L-岩藻糖胺砌块合成二糖片段,其化学结构如式V所示,
4.根据权利要求3所述的方法,其特征在于,所述方法包括利用二糖片段与D-岩藻糖胺砌块合成三糖片段,其化学结构式如式I所示,
5.根据权利要求1所述的方法,其特征在于,所述方法包括预先合成O抗原三糖前体,还原即得O抗原三糖,所述O抗原三糖前体的化学结构式为式VI,
6.根据权利要求1-5任一所述的方法,其特征在于,所述方法是利用葡萄糖合成得到D-岩藻糖胺,包括:以3,4,6-O-三乙酰基甘露糖烯为原料,经过叠氮化物、硒试剂得到1-硒苯-2叠氮葡萄糖,脱除乙酰基,然后6-C进行甲基化,最终得到D-岩藻糖胺类化合物。
7.一种组装有氨基连接臂的绿脓假单胞菌的O11血清型O抗原三糖化合物,其特征在于,所述化合物是利用权利要求1-6任一所述方法制备得到的。
8.一种糖-蛋白缀合物的制备方法,其特征在于,所述方法是包含绿脓假单胞菌的O11血清型O抗原三糖,所述绿脓假单胞菌的O11血清型O抗原三糖的制备方法为权利要求1-6任一所述的方法。
9.权利要求1-6所述合成方法在开发或制备绿脓假单胞菌疫苗或者绿脓假单胞菌感染导致的疾病的药物中的应用。
10.权利要求7所述化合物或者权利要求8所述的糖-蛋白缀合物的制备方法在开发或制备绿脓假单胞菌疫苗或者绿脓假单胞菌感染导致的疾病的药物中的应用。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811551666.0A CN109627270B (zh) | 2018-12-18 | 2018-12-18 | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 |
PCT/CN2019/119584 WO2020125307A1 (zh) | 2018-12-18 | 2019-11-20 | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 |
JP2021512705A JP7209815B2 (ja) | 2018-12-18 | 2019-11-20 | 緑膿菌o11血清型o抗原オリゴ糖の化学合成方法 |
US17/017,896 US20200405840A1 (en) | 2018-12-18 | 2020-09-11 | Chemical Synthesis of Oligosaccharides of Pseudomonas aeruginosa Serotype O11 O-antigen |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811551666.0A CN109627270B (zh) | 2018-12-18 | 2018-12-18 | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109627270A true CN109627270A (zh) | 2019-04-16 |
CN109627270B CN109627270B (zh) | 2020-12-29 |
Family
ID=66075319
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811551666.0A Active CN109627270B (zh) | 2018-12-18 | 2018-12-18 | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20200405840A1 (zh) |
JP (1) | JP7209815B2 (zh) |
CN (1) | CN109627270B (zh) |
WO (1) | WO2020125307A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020125307A1 (zh) * | 2018-12-18 | 2020-06-25 | 江南大学 | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 |
CN115677800A (zh) * | 2022-10-28 | 2023-02-03 | 山东大学 | 一种铜绿假单胞菌o10血清型o-抗原三糖及其合成方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108329362A (zh) * | 2018-03-20 | 2018-07-27 | 江南大学 | 一种革兰氏阳性菌表面荚膜多糖结构衍生物的制备方法 |
CN108558961A (zh) * | 2018-01-29 | 2018-09-21 | 江南大学 | 类志贺邻单胞菌o51血清型o抗原寡糖化学合成方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10596272B2 (en) * | 2015-06-08 | 2020-03-24 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Vaccines against Streptococcus pneumoniae serotype 5 |
CN109627270B (zh) * | 2018-12-18 | 2020-12-29 | 江南大学 | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 |
-
2018
- 2018-12-18 CN CN201811551666.0A patent/CN109627270B/zh active Active
-
2019
- 2019-11-20 JP JP2021512705A patent/JP7209815B2/ja active Active
- 2019-11-20 WO PCT/CN2019/119584 patent/WO2020125307A1/zh active Application Filing
-
2020
- 2020-09-11 US US17/017,896 patent/US20200405840A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108558961A (zh) * | 2018-01-29 | 2018-09-21 | 江南大学 | 类志贺邻单胞菌o51血清型o抗原寡糖化学合成方法 |
CN108329362A (zh) * | 2018-03-20 | 2018-07-27 | 江南大学 | 一种革兰氏阳性菌表面荚膜多糖结构衍生物的制备方法 |
Non-Patent Citations (3)
Title |
---|
ANELLO J. D"AMBRA,等: "Analysis by the reductive-cleavage method of a polysaccharide containing 2-acetamido-2,6-dideoxy-D and -L-galactopyranosyl residues", 《CARBOHYDRATE RESEARCH》 * |
CHARLES R. DEAN,等: "WbjA Adds Glucose To Complete the O-Antigen Trisaccharide Repeating Unit of the Lipopolysaccharide of Pseudomonas aeruginosa Serogroup O11", 《JOURNAL OF BACTERIOLOGY》 * |
CHUNJUN QIN,等: "Total Synthesis of a Densely Functionalized Plesiomonas shigelloides Serotype 51 Aminoglycoside Trisaccharide Antigen", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020125307A1 (zh) * | 2018-12-18 | 2020-06-25 | 江南大学 | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 |
CN115677800A (zh) * | 2022-10-28 | 2023-02-03 | 山东大学 | 一种铜绿假单胞菌o10血清型o-抗原三糖及其合成方法 |
CN115677800B (zh) * | 2022-10-28 | 2023-08-08 | 山东大学 | 一种铜绿假单胞菌o10血清型o-抗原三糖及其合成方法 |
Also Published As
Publication number | Publication date |
---|---|
WO2020125307A1 (zh) | 2020-06-25 |
CN109627270B (zh) | 2020-12-29 |
JP2022511591A (ja) | 2022-02-01 |
JP7209815B2 (ja) | 2023-01-20 |
US20200405840A1 (en) | 2020-12-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108558961B (zh) | 类志贺邻单胞菌o51血清型o抗原寡糖化学合成方法 | |
Emmadi et al. | Expeditious synthesis of bacterial, rare sugar building blocks to access the prokaryotic glycome | |
Gening et al. | Synthesis of β-(1→ 6)-linked glucosamine oligosaccharides corresponding to fragments of the bacterial surface polysaccharide poly-N-acetylglucosamine | |
CN107955082B (zh) | 幽门螺旋杆菌脂多糖外核心八糖的制备方法 | |
CN109627270A (zh) | 一种绿脓假单胞菌o11血清型o抗原寡糖的化学合成方法 | |
Zhang et al. | Total Synthesis of β-d-ido-Heptopyranosides Related to Capsular Polysaccharides of Campylobacter jejuni HS: 4 | |
Fujiwara et al. | Synthesis of the neoglycoconjugates of phenolic glycolipid-related trisaccharides for the serodiagnosis of leprosy | |
CN109776634A (zh) | 一种幽门螺旋杆菌o2血清型o抗原寡糖类化合物的合成 | |
Zhu et al. | A facile and effective synthesis of α-(1→ 6)-linked mannose di-, tri-, tetra-, hexa-, octa-, and dodecasaccharides, and β-(1→ 6)-linked glucose di-, tri-, tetra-, hexa-, and octasaccharides using sugar trichloroacetimidates as the donors and unprotected or partially protected glycosides as the acceptors | |
Gouin et al. | Direct azidation of unprotected carbohydrates with PPh3/CBr4/NaN3. Modulation of the degree of substitution | |
Yamada et al. | Lactotriaose-containing carbosilane dendrimers: syntheses and lectin-binding activities | |
Pinto et al. | Synthesis of oligosaccharides corresponding to biological repeating units of Shigella flexneri variant Y polysaccharide. Part 1. Overall strategy, synthesis of a key trisaccharide intermediate, and synthesis of a pentasaccharide | |
Miyagawa et al. | Synthesis of glycoconjugate polymer carrying globotriaose as artificial multivalent ligand for Shiga toxin-producing Escherichia coli O157: H7 | |
Zong et al. | Facile syntheses of the disaccharide repeating unit of the O-antigenic polysaccharide of Burkholderia pseudomallei strain 304b and its dimer and trimer | |
CN114085255B (zh) | 一种苏黎世克罗诺杆菌5型脂多糖o-抗原寡糖片段及其制备方法与应用 | |
Dhara et al. | Convergent synthesis of a pentasaccharide repeating unit corresponding to the cell wall O-antigen of Salmonella enterica O44 | |
Boutet et al. | Synthesis of branched tri-to pentasaccharides representative of fragments of Shigella flexneri serotypes 3a and/or X O-antigens | |
Mandal et al. | Concise synthesis of two pentasaccharides corresponding to the α-chain oligosaccharides of Neisseria gonorrhoeae and Neisseria meningitidis | |
US10851130B2 (en) | Chemical synthesis method of Plesiomonas shigelloides serotype O51 O-antigen oligosaccharide | |
Mulard et al. | Total synthesis of a tetra-and two pentasaccharide fragments of the O-specific polysaccharide of Shigella flexneri serotype 2a | |
Nishida et al. | Syntheses and 1H-NMR Studies of Methyl 4, 6-Di-O-glucopyranosyl-β-d-glucopyranosides Chirally Deuterated at the (l→ 6)-Linkage Moiety | |
Chaudhury et al. | A target oriented expeditious approach towards synthesis of certain bacterial rare sugar derivatives | |
CN115232177B (zh) | 一种痢疾志贺氏菌10型o-抗原寡糖的化学合成方法 | |
CN111228478A (zh) | 三糖重复单元寡糖链在制备金黄色葡萄球菌疫苗中的应用 | |
Zhang et al. | Synthesis of an xylosylated rhamnose pentasaccharide, the repeating unit of the O-chain polysaccharide of the lipopolysaccharide of Xanthomonas campestris pv. begoniae GSPB 525 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |