CN103373955A - Multivalent azasugar derivatives and synthetic method thereof - Google Patents
Multivalent azasugar derivatives and synthetic method thereof Download PDFInfo
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- CN103373955A CN103373955A CN2012101207471A CN201210120747A CN103373955A CN 103373955 A CN103373955 A CN 103373955A CN 2012101207471 A CN2012101207471 A CN 2012101207471A CN 201210120747 A CN201210120747 A CN 201210120747A CN 103373955 A CN103373955 A CN 103373955A
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- azasugar
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000002253 acid Substances 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims description 212
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 147
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- 238000003756 stirring Methods 0.000 claims description 77
- 238000006243 chemical reaction Methods 0.000 claims description 39
- -1 substituted-phenyl Chemical group 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 26
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001263 acyl chlorides Chemical class 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims description 15
- 239000005457 ice water Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 11
- 239000012153 distilled water Substances 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 229910004373 HOAc Inorganic materials 0.000 claims description 8
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000001345 alkine derivatives Chemical class 0.000 claims description 6
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 5
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 5
- 229960005055 sodium ascorbate Drugs 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- UWCPYKQBIPYOLX-UHFFFAOYSA-N benzene-1,3,5-tricarbonyl chloride Chemical compound ClC(=O)C1=CC(C(Cl)=O)=CC(C(Cl)=O)=C1 UWCPYKQBIPYOLX-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 4
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 239000001384 succinic acid Substances 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 3
- 238000012650 click reaction Methods 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 3
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- KFCUPNHUPHDVJC-UHFFFAOYSA-N bromine azide Chemical compound BrN=[N+]=[N-] KFCUPNHUPHDVJC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims 1
- 108010006519 Molecular Chaperones Proteins 0.000 abstract description 8
- 102000005431 Molecular Chaperones Human genes 0.000 abstract description 7
- 239000000178 monomer Substances 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 2
- 208000015872 Gaucher disease Diseases 0.000 abstract 1
- 238000009126 molecular therapy Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 150000005846 sugar alcohols Polymers 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 124
- 239000003921 oil Substances 0.000 description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- 239000003480 eluent Substances 0.000 description 35
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 239000002994 raw material Substances 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 238000013375 chromatographic separation Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000012230 colorless oil Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- QRYWJFOBXFDERP-UHFFFAOYSA-N n-[(2-amino-6-methylpyridin-3-yl)methyl]-3,4,5-trimethoxybenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NCC=2C(=NC(C)=CC=2)N)=C1 QRYWJFOBXFDERP-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 6
- 150000001470 diamides Chemical class 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 102000004856 Lectins Human genes 0.000 description 5
- 108090001090 Lectins Proteins 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
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- 239000000706 filtrate Substances 0.000 description 4
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- 229920001542 oligosaccharide Polymers 0.000 description 4
- 150000002482 oligosaccharides Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 210000003712 lysosome Anatomy 0.000 description 3
- 230000001868 lysosomic effect Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- FFVPQWXBEUUBMF-UHFFFAOYSA-N 4-[[2-[1-[(2-fluorophenyl)methyl]-5,6-dihydro-4h-cyclopenta[c]pyrazol-3-yl]-5-(2-methylsulfonylethoxy)pyrimidin-4-yl]amino]pyridine-3-carboxamide Chemical compound CS(=O)(=O)CCOC1=CN=C(C=2C=3CCCC=3N(CC=3C(=CC=CC=3)F)N=2)N=C1NC1=CC=NC=C1C(N)=O FFVPQWXBEUUBMF-UHFFFAOYSA-N 0.000 description 2
- HDLPONLLJOSAIM-UHFFFAOYSA-N 5-[2-(dimethylamino)ethoxy]-2-[1-[(4-ethoxy-2,6-difluorophenyl)methyl]-5,6-dihydro-4h-cyclopenta[c]pyrazol-3-yl]-n-pyridin-4-ylpyrimidin-4-amine Chemical compound FC1=CC(OCC)=CC(F)=C1CN1C(CCC2)=C2C(C=2N=C(NC=3C=CN=CC=3)C(OCCN(C)C)=CN=2)=N1 HDLPONLLJOSAIM-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
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- 230000002950 deficient Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
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- UERNRFHISLXQFU-DFWYDOINSA-N (2S)-5-oxopyrrolidine-2-carboxylic acid pyridine Chemical compound c1ccncc1.OC(=O)[C@@H]1CCC(=O)N1 UERNRFHISLXQFU-DFWYDOINSA-N 0.000 description 1
- RWLALWYNXFYRGW-UHFFFAOYSA-N 2-Ethyl-1,3-hexanediol Chemical compound CCCC(O)C(CC)CO RWLALWYNXFYRGW-UHFFFAOYSA-N 0.000 description 1
- UJORPFQWUKFXIE-UHFFFAOYSA-N 2-[1-[(4-ethoxy-2,6-difluorophenyl)methyl]-5,6-dihydro-4h-cyclopenta[c]pyrazol-3-yl]-5-methoxy-n-pyridin-4-ylpyrimidin-4-amine Chemical compound FC1=CC(OCC)=CC(F)=C1CN1C(CCC2)=C2C(C=2N=C(NC=3C=CN=CC=3)C(OC)=CN=2)=N1 UJORPFQWUKFXIE-UHFFFAOYSA-N 0.000 description 1
- HRDCVMSNCBAMAM-UHFFFAOYSA-N 3-prop-2-ynoxyprop-1-yne Chemical class C#CCOCC#C HRDCVMSNCBAMAM-UHFFFAOYSA-N 0.000 description 1
- WDCOJSGXSPGNFK-UHFFFAOYSA-N 8-aminooctan-1-ol Chemical compound NCCCCCCCCO WDCOJSGXSPGNFK-UHFFFAOYSA-N 0.000 description 1
- GMXIEASXPUEOTG-UHFFFAOYSA-N 8-bromooctan-1-ol Chemical compound OCCCCCCCCBr GMXIEASXPUEOTG-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- IUEMWGVESHKMBN-UHFFFAOYSA-N C#CCC1(C=CC(C(NCC#C)=O)=CC1)C(N)=O Chemical compound C#CCC1(C=CC(C(NCC#C)=O)=CC1)C(N)=O IUEMWGVESHKMBN-UHFFFAOYSA-N 0.000 description 1
- GHKOMOBXLGYHOO-UHFFFAOYSA-N C#CCC1(C=CC=CC1C(NCC#C)=O)C(N)=O Chemical compound C#CCC1(C=CC=CC1C(NCC#C)=O)C(N)=O GHKOMOBXLGYHOO-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 229960005082 etohexadiol Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
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- 230000006674 lysosomal degradation Effects 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides derivatives of multivalent azasugar of 3,4,5-trihydroxyl-1-octylpiperidine-2-ketone having a general formula (I), and a synthetic method of the derivatives. According to the derivatives and the preparation method thereof provided by the invention, multivalent azasugar is formed by connecting (3S,4R,5S)-3,4,5-trihydroxyl-1-(8-aminooctyl)piperidine-2-ketone as a monomer with a polyatomic acid or polyacyl chloride, or connecting (3S,4R,5S)-3,4,5-trihydroxyl-1-(8-azidooctyl)piperidine-2-ketone as a monomer with a derivative of a polyatomic acid, polyhydric alcohol or polyacyl chloride The multivalent azasugar synthesized by the method provided by the invention has the potential of serving as a pharmacological molecular chaperone in CMT (Pharmacological Chaperone Molecular therapy) for treating Gaucher disease, and thereby having a high application value.
Description
Technical field
The present invention relates generally to Azasugar, relates in particular to (3S, 4R, 5S)-3,4, and multiple multivalence derivative and synthetic method thereof that 5-trihydroxy--1-octyl group-piperidines-2-ketone and multivalence parent nucleus are connected to form belong to biomedicine field.
Background technology
Sugar sheath ester is the important composition composition of cytolemma, and it relates in lysosomal degradation process and surpasses 50 kinds of lytic enzymes and the multiple protein factor.Any one albumen in the degradation pathway or the defective of protein factor all will cause sugared sheath ester degraded to be obstructed, and substrate is accumulated in the lysosome, cause lysosome to accumulate disease.Lysosome is accumulated modal Gaucher in the disease (dagger-axe Xie Shi or high Xue Shi) disease and is namely caused by the GC enzyme defect.
The sick methods for the treatment of of Gaucher mainly contains ERT (enzyme replacement treatment), SRT (substrate minimizing therapy) at present.CMT is too expensive and can't alleviate central nervous system symptom.As the SRT that ERT replenishes, then can only short application use owing to Side effects of pharmaceutical drugs.And up-to-date CMT (pharmacology molecular chaperones therapy) has brought hope to patient.At present the researchist filtered out several potential pharmacology molecular chaperoneses (expert opinion on pharmacotherapy 2007,8,427-435).
(3S, 4R, 5S)-3,4,5-trihydroxy--1-octyl group-piperidines-2-ketone is a kind of azasugar that has pharmacology molecular chaperones potentiality, its activation to sudden change GC enzyme has reached 6.2 times, has entered clinical the second stage of azasugar IFG (its activation to sudden change GC enzyme is three times) before the superorder far away.
Because bonding force is on the low side between interior some acceptor of body and the part, so there is the mechanism of some compensation avidity in the body, for example, between oligosaccharides and the lectin, by the aglucon polyvalency, make the interaction (Chem.Rev.2002.102,555.) between more saccharide residue participation oligosaccharides and the lectin.Interaction between the lectin of multivalence oligosaccharides and bunch collection is compared with the interaction between the lectin with monose, and strong ten times to thousand times of avidity, this phenomenon are called concerted effect or sugar (glycosides) cluster effect cui.And the application of concerted effect has exceeded the category of oligosaccharides and lectin already, by a large amount of pharmacologically actives that should be used for increasing lead compound, a large amount of successful precedents has been arranged.
Therefore the present invention namely is with (3S, 4R, 5S)-3,4, and 5-trihydroxy--1-octyl group-piperidines-2-ketone is monomer, synthetic its multivalence derivative, thus increase it to the activation of sudden change GC enzyme.
Summary of the invention
Problem to be solved by this invention mainly is to overcome the pharmacology molecular chaperones to the low defective of active activation of sudden change GC enzyme, synthetic new multivalence azasugar, thus the new pharmacology molecular chaperones that can increase better sudden change GC enzymic activity is provided.
Technical problem to be solved by this invention is achieved through the following technical solutions:
A kind of multivalence azasugar and derivative thereof have the structure shown in the general formula (I):
In the formula:
N is selected from arbitrary integer of 2 to 15, and preferred n is 8;
M is selected from 2 to 8 arbitrary integer, and preferred m is 2,3,4;
R
1Be selected from polynary substituted-phenyl, C
1-C
6Straight chain or with alkylidene group or the nitrogen-atoms of side chain; Preferred R
1Be benzene-1,2-base, benzene-1,3-base, benzene-Isosorbide-5-Nitrae-Ji, benzene-1,3,5-base, methylene radical, 1,1-dimethylene, 1,2,3-, three substituted propyls;
R
2Be selected from formamyl, 4-methoxyl group-1H-1,2,3-triazole-Isosorbide-5-Nitrae-Ji, N-((1H-1,2,3-triazole-Isosorbide-5-Nitrae base)-methyl)-carbamyl or 4-methylene radical-1H-1,2,3-triazole-Isosorbide-5-Nitrae-Ji.
A kind of shown in general formula (I) the multivalence azasugar and the synthetic method of derivative, can be selected from following two kinds of methods any:
Method 1: may further comprise the steps:
(1) dibasic alcohol is protected hydroxyl and azido reaction by bromo, azide, hydro-reduction, introducing tertbutyloxycarbonyl protection amino, introducing p-toluenesulfonyl successively, obtain compound 2-7;
(2) remove the tertbutyloxycarbonyl protecting group of compound 2-7 after, obtain compound 2-8, make itself and compound 2-9 that linked reaction occur after, obtain compound 2-10;
(3) compound 2-10 is reduced to compound 2-11;
(4) with compound 2-11 and polyprotonic acid or polynary acyl chlorides generation condensation reaction, then hydrogenation removes benzyl protecting group, obtains general formula (I) compound;
Method 2: may further comprise the steps:
(1) with propargyl amine and polyprotonic acid, polynary acyl chlorides or polyvalent alcohol generation condensation reaction, obtains N-propargyl amide derivatives or the polyvalent alcohol alkynes propyl ether of polyprotonic acid, polynary acyl chlorides;
(2) with N-propargyl amide derivatives or polyvalent alcohol alkynes propyl ether and the compound 2-10 generation click reaction of above-mentioned polyprotonic acid, polynary acyl chlorides, further hydrogenation removes benzyl, obtains general formula (I) compound.
Wherein, described polyprotonic acid is aliphatics polyprotonic acid or aromatic series polyprotonic acid; The preferred propanedioic acid of described aliphatics polyprotonic acid or Succinic Acid; Described aromatic series polyprotonic acid preferred m-phthalic acid, terephthalic acid or phthalic acid.
Wherein, described polynary acyl chlorides is trimesoyl chloride.
Wherein, described polyvalent alcohol is glycerol.
Preferably, the bromo-reaction in the step of described method 1 (1) is that dibasic alcohol is dissolved in the toluene, adds 40%HBr to reaction system, and 70 ℃ of backflows obtain compound 2-2;
Preferably, the azido reaction in the step of described method 1 (1) is that compound 2-2 is dissolved among the dry DMF, adds sodiumazide, is transferred to stir about 10h in 70 ℃ of oil baths after stirring under the room temperature, obtains compound 2-3;
Preferably, the hydro-reduction reaction in the step of described method 1 (1) is with compound 2-3 dissolve with methanol, adds 10%Pd/C, and catalytic hydrogenation under 0.4MPa obtains compound 2-4;
Preferably, the amino reaction of introducing tertbutyloxycarbonyl protection in the step of described method 1 (1) is that compound 2-4 is dissolved in the mixed solvent, adds (Boc)
2O regulates pH=8 with triethylamine, stirs under the room temperature, obtains compound 2-5; Wherein, THF: H in the described mixed solvent
2O=1: 1;
Preferably, the introducing p-toluenesulfonyl protection hydroxyl reaction in the step of described method 1 (1) is that compound 2-5 is dissolved in the chloroform, adds pyridine, p-TsCl under the ice-water bath, rises to after stirring and continues under the room temperature to stir, and obtains compound 2-6;
Preferably, the azido reaction in the step of described method 1 (1) is that compound 2-6 is dissolved among the dry DMF, adds sodiumazide, is transferred to stir about 10h in 70 ℃ of oil baths after stirring under the room temperature, obtains compound 2-7.
Preferably, the reaction that removes the tertbutyloxycarbonyl protecting group in the step of described method 1 (2) is in ice-water bath, and compound 2-7 is dissolved in the methylene dichloride, adds trifluoroacetic acid, rise to room temperature under the ice bath behind the stir about 10min and continue to stir, obtain compound 2-8;
Preferably, the linked reaction in the step of described method 1 (2) is with compound (3S, 4R, 5S, 6S)-3,4, and 5-three-O-phenmethyl-6-methoxyl group lactone is dissolved in the methyl alcohol, adds successively compound 2-8 crude product, NaCNBH
3, ZnCl
2, be transferred to stir about 3h in 60 ℃ of oil baths after stirring under the room temperature, obtain compound 2-10.
Preferably, the reduction reaction in the step of described method 1 (3) is that compound 2-10, Nickel dichloride hexahydrate are dissolved in the anhydrous methanol, stirs under the room temperature, then system is transferred in the ice-water bath, add sodium borohydride, stir until the solution becomes clarification obtains compound 2-11 crude product.
Preferably, condensation reaction in the step of described method 1 (4) is with polyprotonic acid, the logical nitrogen protection of HBTU, add methylene dichloride, after stirring under the room temperature, add successively DIPEA, compound 2-11 crude product, stir about 10h or compound 2-11 crude product passed into nitrogen protection under the room temperature, add methylene dichloride, the rear adding triethylamine that stirs, polynary acyl chlorides, stir about 10h under the room temperature obtains the multivalence azasugar that benzyloxy replaces;
Preferably, it is to add 10%Pd/C in the multivalence azasugar that above-mentioned benzyloxy is replaced that the hydrogenation in the step of described method 1 (4) removes benzyl reaction, and catalytic hydrogenation under 0.4MPa obtains general formula (I) compound.
Preferably, condensation reaction in the step of described method 2 (1) is with polyprotonic acid, HBTU, add DMF, under the room temperature behind the stir about 20min, add successively DIPEA, propargyl amine, stir about 10h under the room temperature, obtain the N-propargyl amide derivatives of polyprotonic acid or add methylene dichloride, propargyl amine, DIPEA, polynary acyl chlorides, stir about 24h under the room temperature, obtain under the N-propargyl amide derivatives of polynary acyl chlorides or the ice-water bath condition 60% sodium hydride being dissolved among the DMF, after stirring, add glycerol, propargyl bromide, be warming up to the about 5h of stirring at room, obtain polyvalent alcohol alkynes propyl ether;
Preferably, click reaction in the step of described method 2 (2) is the N-propargyl amide derivatives with above-mentioned polyprotonic acid, the N-propargyl amide derivatives of polynary acyl chlorides, pass into nitrogen protection among in polyvalent alcohol alkynes propyl ether compound or the three propargyl amine any and the compound 2-10, then after adding the dioxane dissolving, again with sodium ascorbate, cupric sulfate pentahydrate adds above-mentioned reaction system after with dissolved in distilled water, be transferred in 50 ℃ of oil baths after stirring at room is even and stir 24h, be down to and continue under the room temperature to stir, obtain the multivalence azasugar that benzyloxy replaces;
Preferably, to remove benzyl reaction be the multivalence azasugar HOAc/THF/H that above-mentioned benzyloxy is replaced to the hydrogenation in the step of described method 2 (2)
2After the dissolving of O mixed solvent, add 5% catalytic amount palladium hydroxide, hydrogenation is 5 days under 0.4MPa pressure, obtains general formula (I) compound; Wherein, HOAc: THF: H in the described mixed solvent
2O=4: 2: 1.
The multivalence Azasugar that the present invention synthesizes has the potentiality as pharmacology molecular chaperones among the treatment sick CMT of Gaucher (pharmacology molecular chaperones therapy), have very high using value, research of the present invention is that further pharmacological research and application lay the foundation.
Description of drawings
The structural formula of Fig. 1,2,3 part multivalence azasugars of the present invention;
The synthetic route of Fig. 4 the compounds of this invention precursor 2-7; (a) HBr, Toluene; (b) NaN
3, Dry DMF; (c) H
2, Pd/C, MeOH; (d) (Boc)
2O, N Et
3, THF, H
2O; (e) TsCl, Pyr, CHCl
3(f) NaN
3, dry DMF;
The synthetic route of Fig. 5 the compounds of this invention precursor 2-10; (a) TFA, CH
2Cl
2; (b) NaCNBH
3, ZnCl
2, MeOH;
Fig. 6 the compounds of this invention 2-18 is to the synthetic route of 2-23; (a) NiCl
2.6H
2O, NaBH
4, MeOH; (b) HBTU, DIPEA, Dry CH
2Cl
2(c) H
2, Pd/C, THF/H
2O; (d) NEt
3, Dry CH
2Cl
2
Fig. 7 the compounds of this invention 2-24 is to the synthetic route of 2-28 and 2-41; (a) HBTU, DIPEA, Dry DMF; (b) NEt
3, Dry CH
2Cl
2(c) CHCCH
2Br, NaH, DMF;
Fig. 8 the compounds of this invention 2-35 is to the synthetic route of 2-40 and 2-43; (a) Sodium Ascorbate, CuSO
4.5H
2O, Dioxane: H
2O=4: 1; (b) Pd (OH)
2, HOAc: THF: H
2O=4: 2: 1.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not consisted of any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can make amendment or replace the details of technical solution of the present invention and form, but these modifications and replacing all fall within the scope of protection of the present invention.
List of abbreviations
The present invention disclosed herein uses following chemical name:
The DMF DMF
The HBr hydrogen bromide
The Boc tertbutyloxycarbonyl
NaCNBH
3Sodium cyanoborohydride
The DIPEA DIPEA
HBTU benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
The THF tetrahydrofuran (THF)
NaN
3Sodiumazide
MeOH methyl alcohol
TsCl is to Methyl benzenesulfonyl base chlorine
The Pyr pyridine
CHCl
3Chloroform
The TFA trifluoroacetic acid
CH
2Cl
2Methylene dichloride
NiCl
2.6H
2The O Nickel dichloride hexahydrate
NaBH
4Sodium borohydride
NEt
3Triethylamine
CHCCH
2The Br propargyl bromide
The Bn benzyl
HOAc acetic acid
Embodiment 1 N
1, N
3-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1, synthetic (the compound 2-18-1) of 3-Malonamide
8-bromo-1-octanol (compound 2-2-1)
Compound 2-1-1 (ethohexadiol) (1.01g, 6.91mmol) is dissolved in the 20ml toluene, and room temperature downhill reaction system adds 40%HBr (aq) (1.12ml, 7.81mmol), is transferred in 70 ℃ of oil baths and refluxes.TLC monitoring behind the 72h, raw material still has residue, adds 40%HBr (aq) (0.5ml, 3.49mmol), continues backflow 24h.System is cooled to room temperature, the ether dilution, and saturated sodium bicarbonate solution, saturated nacl aqueous solution are respectively washed once, and dried over sodium sulfate is filtered after half an hour approximately, steams except ether.Residue normal pressure silica gel column chromatographic separation purifying, eluent: sherwood oil: ethyl acetate=6: 1, get oily product 1.21g, productive rate is 84.3%.
8-nitrine-1-octanol (compound 2-3-1)
Compound 2-2-1 (4.32g, 20.7mmol) is dissolved among the dry DMF, adds sodiumazide (2.02g, 30.9mmol), is transferred to stir about 10h in 70 ℃ of oil baths after stirring under the room temperature.TLC monitoring raw material is cooled to room temperature with reaction system after disappearing, the ether dilution, and distilled water, saturated sodium-chloride respectively wash twice, and water is with ether extracting twice again, and organic phase merges, and dried over sodium sulfate is filtered after half an hour approximately, steams except ether.Residue normal pressure silica gel column chromatographic separation purifying, eluent: sherwood oil: ethyl acetate=6: 1, get oily product 3.41g, productive rate is 96.3%.
8-amino-1-octanol (compound 2-4-1)
Compound 2-3-1 (3.95g, 23.1mmol) is added the hydrogenation pipe, use the 10ml dissolve with methanol, add 10%Pd/C (0.52g, 0.489mmol), catalytic hydrogenation under 0.4MPa.The TLC monitoring shows the rear diatomite filtration of raw material disappearance, directly throws next step after filtrate is concentrated.
N-(8-hydroxyl-octyl group)-t-butyl carbamate (compound 2-5-1)
Compound 2-4-1 (3.35g, 23.1mmol) is dissolved in 30ml mixed solvent (THF: H
2O=1: 1), add (Boc)
2O (5.04g, 23.1mmol) regulates pH=8 with triethylamine, stirs under the room temperature.After TLC monitoring shows that raw material disappears, the ethyl acetate dilution, saturated sodium-chloride washes twice, and water is with ethyl acetate extracting twice again, and organic phase merges, and dried over sodium sulfate is filtered after half an hour approximately, steams except ethyl acetate.Residue normal pressure silica gel column chromatographic separation purifying, eluent: sherwood oil: ethyl acetate=5: 1, get white solid compound 3.74g, two step productive rates are 66.2%.
4-methyl-sulfonic acid-8-(N-tert-butoxycarbonyl-amino)-monooctyl ester (compound 2-6-1)
Compound 2-5-1 (3.18g, 13.0mmol) is dissolved in the 20ml chloroform, adds pyridine (6.30ml, 77.8mmol), p-TsCl (9.20g, 48.3mmol) under the ice-water bath, rise to after stirring and continue under the room temperature to stir.After the TLC monitoring shows that raw material disappears, add distilled water, each 20ml of ethyl acetate, behind the stir about 20min, respectively wash 1 time with 1N HCl, saturated sodium bicarbonate solution, saturated nacl aqueous solution, water is with ethyl acetate extracting twice again, organic phase merges, and dried over sodium sulfate is filtered after half an hour approximately, steams except ethyl acetate.Residue normal pressure silica gel column chromatographic separation purifying, eluent: sherwood oil: ethyl acetate=10: 1, get colorless oil compound 5.90g, yield is 92.6%.
N-(8-nitrine-octyl group)-t-butyl carbamate (compound 2-7-1)
Compound 2-6-1 (5.90g, 14.8mmol) is dissolved among the dry DMF of 30ml, adds sodiumazide (1.25g, 19.2mmol), is transferred to stir about 10h in 70 ℃ of oil baths after stirring under the room temperature.TLC monitoring raw material is cooled to room temperature with reaction system after disappearing, the ether dilution, and distilled water, saturated sodium-chloride wash twice, and water is with ether extracting twice again, and organic phase merges, and dried over sodium sulfate is filtered after half an hour approximately, steams except ether.Residue normal pressure silica gel column chromatographic separation purifying, eluent: sherwood oil: ethyl acetate=20: 1, get oily product 3.66g, productive rate is 91.8%.
8-nitrine-1-octylame (compound 2-8-1)
In ice-water bath, compound 2-7-1 (120mg, 0.444mmol) is dissolved in the 2ml methylene dichloride, add the 0.5ml trifluoroacetic acid.Rising to room temperature under the ice bath behind the stir about 10min continues to stir.The TLC monitoring shows when raw material disappears, and reaction system is transferred in the ice-water bath, slowly adds saturated NaOH solution to pH＞9, with distilled water wash twice, water merges with methylene dichloride extracting twice again, organic phase, dried over sodium sulfate is filtered after half an hour approximately, steams except methylene dichloride.Crude product is removed with toluene dissolving steaming, repeat once to take away moisture content residual in the crude product.
(3S, 4R, 5S)-3,4,5-three (benzyloxy)-1-(8-nitrine octyl group) piperidines-2-ketone (compound 2-10-1)
Compound 2-9-1 ((3S, 4R, 5S, 6S)-3,4,5-three-O-phenmethyl-6-methoxyl group lactone) (165.8mg, 0.370mmol) is dissolved in the dry methyl alcohol of 10ml, adds successively compound 2-8-1 crude product, NaCNBH
3(46.2mg, 0.739mmol), ZnCl
2(10.1mg, 0.0741mol) is transferred to stir about 3h in 60 ℃ of oil baths after stirring under the room temperature.After TLC monitoring raw material disappears, reaction system is transferred in the ice-water bath, adds an amount of saturated sodium bicarbonate solution cancellation reaction, remove methyl alcohol under reduced pressure.The residue acetic acid ethyl dissolution, distilled water, saturated nacl aqueous solution are respectively washed once, and water merges with ethyl acetate extracting twice again, organic phase, and dried over sodium sulfate is filtered after half an hour approximately, steams except ethyl acetate.Residue normal pressure silica gel column chromatographic separation purifying, eluent: sherwood oil: acetone=9: 1, get colorless oil compound 189.5mg, yield is 89.9%.
(3S, 4R, 5S)-3,4,5-three (benzyloxy)-1-(the amino octyl group of 8-) piperidines-2-ketone (compound 2-11-1)
Compound 2-10-1 (50.6mg, 0.0888mmol), Nickel dichloride hexahydrate (21.5mg, 0.0905mmol) are dissolved in the 2ml anhydrous methanol, stir under the room temperature.Then system is transferred in the ice-water bath, adds sodium borohydride (3.4mg, 0.0899mmol), stir until the solution becomes clarification.Steam except methyl alcohol, with dichloromethane extraction five times, organic phase is steamed except methylene dichloride with anhydrous sodium sulfate drying about half an hour.Crude product steamed with toluene dissolving again remove, repeat once, take away moisture content residual in the crude product.
N
1, N
3-two (8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl groups)-1,3-Malonamide (compound 2-12-1)
Propanedioic acid (3.1mg, 0.0296mmol), HBTU (33.7mg, 0.0889mmol) are added reaction flask, and oil pump is drained, logical nitrogen protection.Add the 2ml dry methylene chloride, behind the stir about 20min, add successively DIPEA (14.7 μ l, 0.0889mmol), 2-11-1 crude product, stir about 10h under the room temperature under the room temperature.Steam except methylene dichloride residue normal pressure silica gel column chromatographic separation purifying.Successively with following eluent each minute once: sherwood oil: ethyl acetate: triethylamine=10: 100: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=70: 1.Get colorless oil compound 20.0mg, productive rate is 58.3%
N
1, N
3-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1,3-Malonamide (compound 2-18-1)
Compound 2-12-1 (59.3mg, 0.0513mmol) is advanced the hydrogenation pipe with the 4mlTHF solution transfer, add 10%Pd/C (2.5mg, 0.00235mmol), add again 2ml distilled water, catalytic hydrogenation under 0.4MPa.The TLC monitoring shows the rear diatomite filtration of raw material disappearance, and residue separates eluent after concentrating with reversed-phase column: methyl alcohol: water=2: 1, get white solid 19.1mg, and productive rate is 60.4%.
1H?NMR(400MHz，MeOD)δ3.77-3.83(m，4H)，3.47-3.56(m，4H)，3.36(t，J＝7.2Hz，4H)，3.13-3.21(m，8H)，1.53(m，8H)，1.34(br?s，16H)；
13C?NMR(100MHz，MeOD)δ171.81，169.55，76.83，73.64，69.40，51.71，49.21，48.07，40.52，30.25，30.20，27.90，27.79，27.69；HRMS：found?617.3747[M+H]
+，calcd?for?[C
29H
52N
4O
10+H]
+617.3756.
Embodiment 2 N
1, N
4Synthetic (the compound 2-19-1) of-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-Isosorbide-5-Nitrae-succinic diamides
N
1, N
4-two (8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl group)-Isosorbide-5-Nitrae-succinic diamides (compound 2-13-1)
Synthetic take compound 2-11 and Succinic Acid as raw material.Synthesis step is with compound 2-12-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: ethyl acetate: triethylamine=10: 100: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=70: 1.Product is the colorless oil compound, and productive rate is 64.6%.
N
1, N
4-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-Isosorbide-5-Nitrae-succinic diamides (compound 2-19-1)
Take compound 2-13-1 as raw material, synthesis step is identical with compound 2-18-1.Reversed-phase column separates, and eluent is CH
3OH: H
2O=1.8: 1.Product is white solid, and productive rate is 55.2%.
1H?NMR(400MHz，MeOD)δ3.75-3.85(m，4H)，3.46-3.56(m，4H)，3.36(td，J＝7.2，2.0Hz，4H)，3.12-3.19(m，6H)，2.45(s，4H)，1.52-1.60(m，4H)，1.44-1.52(m，4H)，1.28-1.36(m，16H)；
13C?NMR(100MHz，MeOD)δ174.51，171.92，76.85，73.70，69.46，51.73，48.11，40.41，32.46，30.33，30.28，30.24，27.92，27.84，27.71；HRMS：found?1171.6728[M+H]
+，calcd?for[C
71H
88N
4O
10+H]
+1171.6730.
Embodiment 3 N
1, N
3-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1, synthetic (the compound 2-20-1) of 3-benzenedicarboxamide
N
1, N
3-two (8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl groups)-1,3-benzenedicarboxamide (compound 2-14-1)
Compound 2-14 is that raw material is synthetic by compound 2-11-1 and m-phthalic acid.Synthesis step is with compound 2-12-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: ethyl acetate: triethylamine=10: 100: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=70: 1.Product is the colorless oil compound, and productive rate is 58.1%.
N
1, N
3-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1,3-benzenedicarboxamide (compound 2-20-1)
Take compound 2-14-1 as raw material, synthesis step is identical with compound 2-18-1.Reversed-phase column separates, and eluent is CH
3OH: H
2O=1.5: 1.Product is white solid, and productive rate is 50.5%
1H?NMR(400MHz，DMSO-d6)δ8.53(t，J＝5.6Hz，2H)，8.27(s，1H)，7.93(dd，J＝7.6，1.6Hz，2H)，7.53(t，J＝7.6Hz，1H)，5.24(d，J＝4.4Hz，2H)，5.18(d，J＝4.4Hz，2H)，4.98(d，J＝4.4Hz，2H)，3.54-3.64(m，4H)，3.30-3.38(m，4H)，3.15-3.30(m，8H)，3.01(dd，J＝12.4，7.6Hz，2H)，1.48-1.58(m，4H)，1.38-1.48(m，4H)，1.16-1.34(m，16H)；
13C?NMR(100MHz，DMSO-d6)δ169.77，165.73，134.90，129.49，128.22，126.13，75.56，72.30，68.11，50.08，45.97，39.31，29.07，28.73，26.54，?26.46，26.19；HRMS：found?679.3907[M+H]
+，calcd?for[C
34H
54N
4O
10+H]
+679.3913.
Embodiment 4 N
1, N
4Synthetic (the compound 2-21-1) of-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-Isosorbide-5-Nitrae-benzenedicarboxamides
N
1, N
4-two (8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl group)-Isosorbide-5-Nitrae-benzenedicarboxamides (compound 2-15-1)
Compound 2-15-1 is that raw material is synthetic by compound 2-11-1 and terephthalic acid.Synthesis step is with compound 2-12-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: ethyl acetate: triethylamine=10: 100: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=70: 1.Product is the colorless oil compound, and productive rate is 67.7%.
N
1, N
4-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-Isosorbide-5-Nitrae-benzenedicarboxamides (compound 2-21-1)
Compound 2-15-1 (58.1mg, 0.0477mmol) is added the hydrogenation pipe with the 4mlTHF dissolving, add 10%Pd/C (2.5mg, 0.00234mmol), add again 2ml distilled water, catalytic hydrogenation under 0.4MPa.The TLC monitoring shows the rear diatomite filtration of raw material disappearance, residue methanol/ethyl acetate recrystallization after concentrating.Obtain pure white solid 22.1mg, productive rate is 61.9%.
1H?NMR(400MHz，DMSO-d6)δ8.53(t，J＝5.6Hz，2H)，7.89(s，4H)，5.24(d，J＝4.4Hz，2H)，5.17(d，J＝4.4Hz，2H)，4.97(d，J＝4.4Hz，2H)，3.56-3.63(m，4H)，3.29-3.36(m，4H)，3.16-3.29(m，8H)，3.01(dd，J＝12.4，7.2Hz，2H)，1.47-1.51(m，4H)，1.38-1.47(m，4H)，1.18-1.33(m，16H)；
13C?NMR(100MHz，DMSO-d6)δ169.75，165.41，136.75，127.04，75.55，72.29，68.10，50.07，45.96，40.15，29.03，28.70，26.53，26.45，26.17；HRMS：found?679.3906[M+H]
+，calcd?for[C
34H
54N
4O
10+H]
+679.3913.
Embodiment 5 N
1, N
2-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1, synthetic (the compound 2-22-1) of 2-benzenedicarboxamide
N
1, N
2-two (8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl groups)-1,2-benzenedicarboxamide (compound 2-16-1)
Synthetic take compound 2-11-1 and phthalic acid as raw material.Synthesis step is with compound 2-12-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: ethyl acetate: triethylamine=10: 100: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=70: 1.Product is the colorless oil compound, and productive rate is 56.9%.
N
1, N
2-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1, synthetic (the compound 2-22-1) of 2-benzenedicarboxamide
Take compound 2-16-1 as raw material, synthesis step is identical with compound 2-18-1.Reversed-phase column separates, and eluent is CH
3OH: H
2O=1.5: 1.Product is white solid, and productive rate is 74.3%.
1H?NMR(600MHz，DMSO-d6)δ8.19(t，J＝3.6Hz，2H)，7.44-7.50(m，2H)，7.39-7.44(m，2H)，5.25(d，J＝4.2Hz，2H)，5.18(d，J＝4.2Hz，2H)，4.98(d，J＝4.8Hz，2H)，3.55-3.65(m，4H)，3.29-3.39(m，4H)，3.18-3.29(m，4H)，3.16(dd，J＝12.6，7.2Hz，4H)，3.02(dd，J＝12.6，7.2Hz，2H)，1.40-1.51(m，8H)，1.18-1.35(m，16H)；?
13C?NMR(150MHz，DMSO-d6)δ169.77，168.03，136.27，129.17，127.62，75.54，72.29，68.09，50.09，46.00，40.03，39.08，28.97，28.79，28.77，26.58，26.42，26.23；HRMS：found?679.3906[M+H]
+，calcd?for[C
34H
54N
4O
10+H]
+679.3913.
Embodiment 6 N
1, N
3, N
5-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1,3, synthetic (the compound 2-23-1) of 5-benzene trimethamide
N
1, N
3, N
5-two (8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl groups)-1,3, synthetic (the compound 2-17-1) of 5-benzene trimethamide
Compound 2-11-1 (55.3mg; 0.102mmol) crude product drains with oil pump; pass into nitrogen protection; add the 2ml dry methylene chloride; the rear adding triethylamine (16.4 μ l, 0.127mmol) that stirs, trimesoyl chloride (4.5 μ l; 0.0252mmol), stir about 10h under the room temperature.Evaporate to dryness methylene dichloride, residue normal pressure silica gel column chromatographic separation purifying.Successively with following eluent each minute once: sherwood oil: ethyl acetate: triethylamine=10: 100: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=70: 1.Get colorless oil compound 33.1mg, productive rate is 73.3%.
N
1, N
3, N
5-two (8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl groups)-1,3, synthetic (the compound 2-23-1) of 5-benzene trimethamide
Take compound 2-17-1 as raw material, synthesis step is identical with compound 2-18-1.Reversed-phase column separates, eluent: sodium methylate: water=1.8: 1.Product is oily liquids, and productive rate is 78.6%.
1H?NMR(600MHz，MeOD)δ8.39(s，3H)，3.77-3.84(m，6H)，3.54(t，J＝7.8?Hz，3H)，3.49(dd，J＝12.6，4.8Hz，3H)，3.40(t，J＝7.2Hz，6H)，3.35(td，J＝14.4，3.0Hz，6H)，3.16(dd，J＝12.6，7.8Hz，3H)，1.60-1.67(m，6H)，1.52-1.59(m，6H)，1.34-1.44(m，18H)，1.27-1.34(m，6H)；
13C?NMR(100MHz，MeOD)δ171.82，168.62，136.84，129.78，76.83，73.65，69.39，51.71，48.06，41.17，30.39，30.28，27.95，27.91，27.71；HRMS：found?979.5583[M+H]
+，calcd?for[C
48H
78N
6O
15+H]
+979.5598.
Embodiment 7 N
1, N
2-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,2-benzenedicarboxamide (compound 2-35-1)
N
1, N
2-dipropargyl-phthalic diamide (compound 2-24-1)
With phthalic acid (20.1mg; 0.121mmol), HBTU (101.0mg; 0.266mmol) adding reaction flask, logical nitrogen protection adds the dry DMF of 2ml; under the room temperature behind the stir about 20min; add successively DIPEA (79.6 μ l, 0.483mmol), propargyl amine (30.9 μ l; 0.482mmol), stir about 10h under the room temperature.Oil pump evaporate to dryness DMF, residue dissolve with methanol, silica gel mixed sample, dry column-packing, normal pressure column chromatography for separation.Eluent: methylene dichloride: methyl alcohol=40: 1.Get white solid compound 18.8mg, productive rate is 61.6%.
N
1, N
2-two ((1-(8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,2-benzenedicarboxamide (compound 2-29-1)
Compound 2-10-1 (89.7mg, 0.157mmol), compound 2-24-1 (12.6mg, 0.0524mmol) add reaction flask, drain with oil pump, pass into nitrogen protection, then add the dissolving of 8ml dioxane.Sodium ascorbate (Sodium Ascorbate) (30.2mg, 0.152mmol), cupric sulfate pentahydrate (26.2mg, 0.105mmol) with adding reaction system behind the 2ml dissolved in distilled water, be transferred in 50 ℃ of oil baths after stirring at room is even and stir 24h, be down to and continue under the room temperature to stir.The TLC monitoring shows when reaction system no longer changes, the ethyl acetate dilution, and saturated ammonium chloride solution, distilled water, saturated nacl aqueous solution are respectively washed twice, water is with ethyl acetate extracting twice again, organic phase merges, and dried over sodium sulfate is filtered after half an hour approximately, and filtrate is steamed except ethyl acetate.Residue normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: acetone: triethylamine=50: 50: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=30: 1 → 20: 1.Get colorless oil compound 51.1mg, productive rate is 70.6%.
N
1, N
2-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,2-benzenedicarboxamide (compound 2-35-1)
Compound 2-29-1 (51.1mg, 0.0370mmol) 14ml HOAc/THF/H
2O mixed solvent (HOAc: THF: H
2O=4: 2: 1) the hydrogenation pipe is advanced in solution transfer, adds 5% catalytic amount palladium hydroxide, and hydrogenation is 5 days under 0.4MPa pressure.Diatomite filtration, residue separated with reversed-phase column after filtrate was concentrated, and eluent is methyl alcohol: water=1.2: 1, get white solid 20.1mg, productive rate is 64.6%.
1H?NMR(600MHz，DMSO-d6)δ8.89(t，J＝6.0Hz，2H)，8.00(s，2H)，7.50(s，4H)，5.25(d，J＝4.8Hz，2H)，5.17(d，J＝4.2Hz，2H)，4.98(d，J＝4.2Hz，2H)，4.44(d，J＝6.0Hz，4H)，4.24(t，J＝7.2Hz，4H)，3.56-3.63(m，4H)，3.28-3.34(m，4H)，3.15-3.26(m，4H)，3.00(dd，J＝12.6，7.2Hz，2H)，1.69-1.77(m，4H)，1.36-1.45(m，4H)，1.13-1.27(m，16H)；
13C?NMR(100MHz，DMSO-d6)δ169.75，168.35，145.18，136.17，129.42，127.56，122.61，75.55，72.28，68.11，50.06，49.22，45.93，35.11，29.54，28.52，28.26，26.47，26.08，25.77；HRMS：found?841.4556[M+H]
+，calcd?for[C
40H
60N
10O
10+H]
+841.4567.
Embodiment 8 N
1, N
3-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1, synthetic (the compound 2-36-1) of 3-benzenedicarboxamide
N
1, N
3-dipropargyl-isophthaloyl amine (compound 2-25-1)
Take m-phthalic acid and propargyl amine as raw material, synthesis step is identical with compound 2-24-1.Dry column-packing, the normal pressure column chromatographic isolation and purification.Eluent: methylene dichloride: methyl alcohol=40: 1 → 30: 1, product are the white solid compound, and productive rate is 100%.
N
1, N
3-two ((1-(8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,3-benzenedicarboxamide (compound 2-30-1)
Take compound 2-10-1 and compound 2-25-1 as raw material, synthesis step is with compound 2-29-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: acetone: triethylamine=50: 50: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=30: 1 → 20: 1.Get the colorless oil compound, productive rate is 70.2%.
N
1, N
3-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,3-benzenedicarboxamide (compound 2-36-1)
Take compound 2-30-1 as raw material, operation steps is with compound 2-35-1.Separate eluent: methyl alcohol with reversed-phase column: water=1.5: 1, get the white solid compound, productive rate is 49.3%.
1H?NMR(400MHz，DMSO-d6)δ9.10(t，J＝5.6Hz，2H)，8.37(s，1H)，8.00(d，J＝7.6Hz，2H)，7.97(s，2H)，7.56(t，J＝7.6Hz，1H)，4.73-5.60(m，5H)，4.52(d，J＝5.2Hz，2H)，4.30(t，J＝6.8Hz，1H)，3.55-3.64(m，4H)，3.28-3.36(m，4H)，3.14-3.26(m，4H)，3.00(dd，J＝12.4，7.6Hz，2H)，1.72-1.82(m，4H)，1.36-1.46(m，4H)，1.13-1.29(m，16H)；
13C?NMR(100MHz，DMSO-d6)δ169.79，165.70，144.80，134.36，129.94，128.40，126.52，122.88，75.55，72.30，68.09，50.07，49.24，45.92，34.95，29.76，28.58，28.30，26.49，26.10，25.82；HRMS：found?1381.7353[M+H]
+，calcd?for[C
82H
96N
10O
10+H]
+1107.64084.
Embodiment 9 N
1, N
4Synthetic (the compound 2-37-1) of-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-Isosorbide-5-Nitrae-benzenedicarboxamides
N
1, N
4-dipropargyl-terephthalamide (compound 2-26-1)
Take terephthalic acid and propargyl amine as raw material, synthesis step is identical with compound 2-24-1.Dry column-packing, the normal pressure column chromatographic isolation and purification.Eluent: methylene dichloride: methyl alcohol=35: 1 → 30: 1, product are the white solid compound, and productive rate is 75.9%.
N
1, N
4-two ((1-(8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-Isosorbide-5-Nitrae-benzenedicarboxamides (compound 2-31-1)
Take compound 2-10-1 and compound 2-26-1 as raw material, synthesis step is with compound 2-29-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: acetone: triethylamine=50: 50: 1, sherwood oil: ethyl acetate: acetone: triethylamine=10: 80: 10: 1, methylene dichloride: methyl alcohol=30: 1 → 20: 1.Get the colorless oil compound, productive rate is 77.2%.
N
1, N
4-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-Isosorbide-5-Nitrae-benzenedicarboxamides (compound 2-37-1)
Take compound 2-31-1 (80.9mg, 0.0586mmol) as raw material, operation steps is with compound 2-35-1.Crude product methanol/ethyl acetate recrystallization.Obtain pure white solid 18.1mg, productive rate is 36.7%.
1H?NMR(600MHz，DMSO-d6)δ9.14(t，J＝6.0Hz，2H)，7.98(s，2H)，7.95(s，4H)，4.80-5.50(m，6H)，4.51(d，J＝6.0Hz，4H)，4.30(t，J＝7.2Hz，4H)，3.56-3.63(m，4H)，3.28-3.40(m，4H)3.16-3.26(m，4H)，3.00(dd，J＝12.0，7.8Hz，2H)，1.74-1.81(m，4H)，1.36-1.45(m，4H)，1.12-1.30(m，16H)；
13C?NMR(100MHz，DMSO-d6)δ169.76，165.44，144.74，136.44，127.25，122.85，75.55，72.28，68.11，50.05，49.22，45.90，34.93，29.70，28.53，28.25，26.46，26.05，25.77；MS(ESI)m/z?863[M+Na
+]；HRMS：found?841.4555[M+H]
+，calcd?for[C
40H
60N
10O
10+H]
+841.4567.
Embodiment 10 N
1, N
4Synthetic (the compound 2-38-1) of-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-Isosorbide-5-Nitrae-succinic diamides
N
1, N
4-dipropargyl-succinic diamide (compound 2-27-1)
Take Succinic Acid and propargyl amine as raw material, synthesis step is identical with compound 2-24-1.Silica gel mixed sample, dry column-packing, normal pressure column chromatographic isolation and purification.Eluent: methylene dichloride: methyl alcohol=30: 1.Product is the white solid compound, and productive rate is 80.3%.
N
1, N
4-two ((1-(8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-Isosorbide-5-Nitrae-succinic diamides (compound 2-32-1)
Take compound 2-10-1 and compound 2-27-1 as raw material, synthesis step is with compound 2-29-1.The normal pressure silica gel column chromatographic separation, successively with following eluent each minute once: sherwood oil: acetone: triethylamine=E40: 60: 1, sherwood oil: ethyl acetate: acetone: methyl alcohol: triethylamine=10: 80: 10: 4: 1, methylene dichloride: methyl alcohol=20: 1 → 15: 1.Get the colorless oil compound, productive rate is 33.7%.
N
1, N
4-two ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-Isosorbide-5-Nitrae-succinic diamides (compound 2-38-1)
Take compound 2-32-1 as raw material, operation steps is with compound 2-35-1.Separate eluent: methyl alcohol with reversed-phase column: water=1.8: 1, get the white solid compound, productive rate is 79.0%.
1H?NMR(600MHz，DMSO-d6)δ8.32(t，J＝5.6Hz，2H)，7.88(s，2H)，5.26(d，J＝4.4Hz，2H)，5.19(d，J＝4.4Hz，2H)，5.00(d，J＝4.4Hz，2H)，4.28(t，J＝6.8Hz，8H)，3.54-3.65(m，4H)，3.27-3.35(m，4H)，3.15-3.27(m，4H)，3.01(dd，J＝12.4，7.6Hz，2H)，2.36(s，4H)，1.70-1.82(m，4H)，1.36-1.47(m，4H)，1.13-1.30(m，16H)；?
13C?NMR(100MHz，DMSO-d6)δ171.34，169.78，144.96，122.57，75.56，72.29，68.11，50.07，49.22，45.92，34.27，30.49，29.69，28.55，28.29，26.48，26.08，25.79；MS(ESI)m/z?815[M+Na
+]，HRMS：found?793.4551[M+H]
+，calcd?for[C
36H
60N
10O
10+H]
+793.4567.
Embodiment 11 N
1, N
3, N
5-three ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,3, synthetic (the compound 2-39-1) of 5-benzene trimethamide
N
1, N
3, N
5-three propargyls-equal benzene trimethamide (compound 2-28-1)
Reaction flask is drained with oil pump; pass into nitrogen protection; add the 2ml dry methylene chloride; add propargyl amine (27 μ l; 0.422mmol), rear adding DIPEA (138.5 μ l, 0.840mmol), trimesoyl chloride (15.0 μ l stir; 0.0840mmol), stir about 24h under the room temperature.The evaporate to dryness methylene dichloride, residue dissolve with methanol, silica gel mixed sample, dry column-packing, normal pressure column chromatographic isolation and purification.Eluent: methylene dichloride: methyl alcohol=40: 1 → 30: 1.Get white solid compound 27.2mg, productive rate is 100%.
N
1, N
3, N
5-three ((1-(8-((3S, 4R, 5S)-3,4,5-three (benzyloxy)-2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,3,5-benzene trimethamide (compound 2-33-1)
Take compound 2-10-1 and compound 2-28-1 as raw material, synthesis step is with compound 2-29-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: acetone: triethylamine=54: 46: 1, sherwood oil: ethyl acetate: acetone: methyl alcohol: triethylamine=8: 8: 80: 4: 1, methylene dichloride: methyl alcohol=20: 1 → 15: 1.Get the colorless oil compound, productive rate is 66.7%.
N
1, N
3, N
5-three ((1-(8-((3S, 4R, 5S)-3,4,5-trihydroxy--2-carbonyl piperidin-1-yl) octyl group)-1H-1,2,3-triazole-4-yl)-methyl)-1,3,5-benzene trimethamide (compound 2-39-1)
Take compound 2-33-1 as raw material, operation steps is with compound 2-35-1.Crude product methanol/ethyl acetate recrystallization.Obtain the pure white solid, productive rate is 33.5%.
1H?NMR(600MHz，DMSO-d6)δ9.16(t，J＝6.0Hz，3H)，8.46(s，3H)，7.98(s，3H)，5.25(d，J＝4.2Hz，3H)，5.18(d，J＝4.2Hz，3H)，4.99(d，J＝4.2Hz，3H)，4.53(d，J＝5.4Hz，6H)，4.30(t，J＝7.2Hz，6H)，3.55-3.63(m，6H)，3.28-3.33(m，6H)，3.16-3.26(m，6H)，3.01(dd，J＝12.6，7.8Hz，3H)，1.74-1.81(m，6H)，1.37-1.45(m，6H)，1.15-1.28(m，24H)；
13C?NMR(100MHz，DMSO-d6)δ169.75，165.29，144.54，134.61，122.87，75.54，72.27，68.09，50.54，49.22，45.90，34.96，29.72，28.53，28.26，26.46，26.06，25.79；HRMS：found?1222.6565[M+H]
+，calcd?for[C
57H
87N
15O
15+H]
+1222.6579.
Embodiment 12 (3S, 3 ' S, 3 " S, 4R; 4 ' R, 4 " R, 5S, 5 ' S, S)-1,15 " ', 1 " (8,8 ', 8 " (4,4 ', 4 " nitrilo three (methylene radical) three (1H-1,2,3-triazole-4, the 1-yl)) three (hot-8, the 1-yl)) synthetic (the compound 2-40-1) of three (3,4,5-trihydroxy--piperidines-2-ketone)
(3S, 3 ' S, 3 " S, 4R; 4 ' R, 4 " R, 5S, 5 ' S, S)-1,15 " ', 1 " (8,8 ', 8 " (4,4 ', 4 " nitrilo three (methylene radical) three (1H-1,2,3-triazole-Isosorbide-5-Nitrae-yl)) three (hot-8, the 1-yl)) three (3,4,5-three (benzyloxy)-piperidines-2-ketone) (compound 2-34-1)
Be raw material by three propargyl amine and compound 2-10-1, synthesis step is with compound 2-29-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: acetone: triethylamine=54: 46: 1; Sherwood oil: ethyl acetate: acetone: methyl alcohol: triethylamine=8: 8: 80: 4: 1; Methylene dichloride: methyl alcohol=20: 1 → 15: 1.Get the colorless oil compound, productive rate is 51.6%.
(3S, 3 ' S, 3 " S, 4R; 4 ' R, 4 " R, 5S, 5 ' S, S)-1,15 " ', 1 " (8,8 ', 8 " (4,4 ', 4 " nitrilo three (methylene radical) three (1H-1,2,3-triazole-4, the 1-yl)) three (hot-8, the 1-yl)) synthetic (the compound 2-40-1) of three (3,4,5-trihydroxy--piperidines-2-ketone)
Take compound 2-34-1 as raw material, operation steps is with compound 2-35-1.Separate eluent: methyl alcohol: water=1.8: 1 with reversed-phase column.Get the white solid compound, productive rate is 41.8%.
1H?NMR(600MHz，MeOD)δ8.02(s，3H)，4.40(t，J＝7.2Hz，6H)，3.76-3.85(m，6H)，3.74(s，6H)，3.54(t，J＝7.8Hz，3H)，3.49(dd，J＝12.6，4.8Hz，3H)，3.33(td，J＝7.8，3.0Hz，6H)，3.16(dd，J＝12.6，7.8Hz，3H)，1.86-1.95(m，6H)，1.51-1.57(m，6H)，1.22-1.39(m，24H)；
13C?NMR(100MHz，MeOD)δ171.81，145.27，125.48，76.84，73.65，69.41，51.71，51.33，48.79，48.00，31.16，30.09，29.84，27.85，27.57，27.32；HRMS：found?1054.6012[M+Na]
+，calcd?for[C
48H
81N
13O
12+Na]
+1054.6020.
(((1-(2 for 4-for 8-for embodiment 13 (3S, 4R, 5S)-1-, 3-two (1-(1-(8-((3 ' S, 3 " S, 4 ' R; 4 " R, 5 ' S, 5 " S)-3; 4,5-trihydroxy--piperidines-2-ketone-1-yl)-octyl group)-1H-1,2; the methoxyl group of 3-triazole-Isosorbide-5-Nitrae-yl))-propoxy-)-methyl)-1H-1,2; 3-triazole-1-yl)-octyl group)-3,4, synthetic (the compound 2-43-1) of 5-trihydroxy--piperidines-2-ketone
Glycerol three propargyl ethers (compound 2-41-1)
Under the ice-water bath condition 60% sodium hydride (85.4mg, 2.14mmol) is dissolved among the dry DMF of 4ml, after stirring, add glycerol (43.7mg, 0.475mmol), propargyl bromide (317.2 μ l, 2.85mmol) is warming up to the about 5h of stirring at room.Then ethyl acetate dilution slowly adds ice and removes unnecessary sodium hydride under the ice-water bath condition, saturated nacl aqueous solution washs once, and the water ethyl acetate is in extracting twice, and organic phase merges, and anhydrous sodium sulfate drying filters after half an hour approximately.Filtrate is steamed except ethyl acetate, residue normal pressure silica gel column chromatographic separation purifying, and eluent: sherwood oil: ethyl acetate=9: 1, get the colorless oil compound, productive rate is 52.3%.
(((1-(2 for 4-for 8-for (3S, 4R, 5S)-1-, 3-two (1-(1-(8-((3 ' S, 3 " S, 4 ' R; 4 " R, 5 ' S, 5 " S)-3; 4,5-three (benzyloxy)-piperidines-2-ketone-1-yl)-octyl group)-1H-1,2; the methoxyl group of 3-triazole-Isosorbide-5-Nitrae-yl))-propoxy-)-methyl)-1H-1,2; 3-triazole-1-yl)-octyl group)-3,4,5-three (benzyloxy)-piperidines-2-ketone (compound 2-42-1)
Take compound 2-10-1 and compound 2-41-1 as raw material, synthesis step is with compound 2-29-1.Normal pressure silica gel column chromatographic separation purifying, successively with following eluent each minute once: sherwood oil: acetone: triethylamine=50: 50: 1, sherwood oil: ethyl acetate: acetone: methyl alcohol: triethylamine=8: 8: 80: 4: 1, methylene dichloride: methyl alcohol=30: 1 → 20: 1.Get the colorless oil compound, productive rate is 41.6%.
(((1-(2 for 4-for 8-for (3S, 4R, 5S)-1-, 3-two (1-(1-(8-((3 ' S, 3 " S, 4 ' R; 4 " R, 5 ' S, 5 " S)-3; 4,5-trihydroxy--piperidines-2-ketone-1-yl)-octyl group)-1H-1,2; the methoxyl group of 3-triazole-Isosorbide-5-Nitrae-yl))-propoxy-)-methyl)-1H-1,2; 3-triazole-1-yl)-octyl group)-3,4,5-trihydroxy--piperidines-2-ketone (compound 2-43-1)
Take compound 2-42-1 as raw material, operation steps is with compound 2-35-1.Separate with reversed-phase column, eluent is methyl alcohol: water=1.2: 1, get the white solid compound, and productive rate is 78.3%.
1H?NMR(400MHz，DMSO-d6)δ8.08(s，2H)，8.05(s，1H)，5.26(d，J＝4.8Hz，3H)，5.19(d，J＝4.4Hz，3H)，4.99(d，J＝4.4Hz，3H)，4.60(s，2H)，4.50(s，4H)，4.28-4.34(m，6H)，3.68-3.73(m，1H)，3.55-3.61(m，6H)，3.52(dd，J＝10.4，4.4Hz，3H)，3.47(dd，J＝10.4，5.6Hz，3H)，3.28-3.33(m，6H)，3.15-3.27(m，6H)，3.00(dd，J＝12.4，7.6Hz，3H)，1.74-1.81(m，6H)，1.37-1.43(m，6H)，1.20-1.30(m，24H)。HRMS：found?1107.6411[M+H]
+，calcd?for[C
51H
86N
12O
15+H]
+1107.6408.。
Claims (10)
1. a multivalence azasugar and derivative thereof have the structure shown in the general formula (I):
In the formula:
N is selected from arbitrary integer of 2 to 15, and preferred n is 8;
M is selected from 2 to 8 arbitrary integer, and preferred m is 2,3,4;
R
1Be selected from polynary substituted-phenyl, C
1-C
6Straight chain or with alkylidene group or the nitrogen-atoms of the replacement of side chain; Preferred R
1Be benzene-1,2-base, benzene-1,3-base, benzene-Isosorbide-5-Nitrae-Ji, benzene-1,3,5-base, methylene radical, 1,1-dimethylene, 1,2,3-, three substituted propyls;
R
2Be selected from formamyl, 4-methoxyl group-1H-1,2,3-triazole-Isosorbide-5-Nitrae-Ji, N-((1H-1,2,3-triazole-Isosorbide-5-Nitrae base)-methyl)-carbamyl or 4-methylene radical-1H-1,2,3-triazole-Isosorbide-5-Nitrae-Ji.
2. the synthetic method of multivalence azasugar as claimed in claim 1 and derivative thereof can be selected from following two kinds of methods any:
Method 1: may further comprise the steps:
(1) dibasic alcohol is protected amino, as to introduce p-toluenesulfonyl protection hydroxyl and azide reaction by bromo, azide, hydro-reduction, introducing tertbutyloxycarbonyl successively, obtain compound 2-7;
(2) remove the tertbutyloxycarbonyl protecting group of compound 2-7 after, obtain compound 2-8, make itself and compound 2-9 that linked reaction occur, obtain compound 2-10;
(4) with compound 2-11 and polyprotonic acid or polynary acyl chlorides generation condensation reaction, then hydrogenation removes benzyl protecting group, obtains general formula (I) compound;
Method 2: may further comprise the steps:
(1) with propargyl amine and polyprotonic acid, polynary acyl chlorides or polyvalent alcohol generation condensation reaction, obtains N-propargyl amide derivatives or the polyvalent alcohol alkynes propyl ether of polyprotonic acid, polynary acyl chlorides;
(2) with N-propargyl amide derivatives or polyvalent alcohol alkynes propyl ether and the compound 2-10 generation click reaction of above-mentioned polyprotonic acid, polynary acyl chlorides, further hydrogenation removes benzyl, obtains general formula (I) compound.
3. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof is characterized in that, described polyprotonic acid is aliphatics polyprotonic acid or aromatic series polyprotonic acid; Wherein, the preferred propanedioic acid of described aliphatics polyprotonic acid or Succinic Acid; Described aromatic series polyprotonic acid preferred m-phthalic acid, terephthalic acid or phthalic acid.
4. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof is characterized in that, described polynary acyl chlorides is trimesoyl chloride.
5. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof is characterized in that, described polyvalent alcohol is glycerol.
6. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof, it is characterized in that the bromo-reaction in the step of described method 1 (1) is that dibasic alcohol is dissolved in the toluene, add 40%HBr to reaction system, 70 ℃ of backflows obtain compound 2-2;
Azido reaction in the step of described method 1 (1) is that compound 2-2 is dissolved among the dry DMF, adds sodiumazide, is transferred to stir about 10h in 70 ℃ of oil baths after stirring under the room temperature, obtains compound 2-3;
Hydro-reduction reaction in the step of described method 1 (1) is with compound 2-3 dissolve with methanol, adds 10%Pd/C, and catalytic hydrogenation under 0.4MPa obtains compound 2-4;
The amino reaction of introducing tertbutyloxycarbonyl protection in the step of described method 1 (1) is that compound 2-4 is dissolved in the mixed solvent, adds (Boc)
2O regulates pH=8 with triethylamine, stirs under the room temperature, obtains compound 2-5; Wherein, THF: H in the described mixed solvent
2O=1: 1;
Introducing p-toluenesulfonyl protection hydroxyl reaction in the step of described method 1 (1) is that compound 2-5 is dissolved in the chloroform, adds pyridine, p-TsCl under the ice-water bath, rises to after stirring and continues under the room temperature to stir, and obtains compound 2-6;
Azido reaction in the step of described method 1 (1) is that compound 2-6 is dissolved among the dry DMF, adds sodiumazide, is transferred to stir about 10h in 70 ℃ of oil baths after stirring under the room temperature, obtains compound 2-7.
7. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof, it is characterized in that, the reaction that removes the tertbutyloxycarbonyl protecting group in the step of described method 1 (2) is in ice-water bath, compound 2-7 is dissolved in the methylene dichloride, add trifluoroacetic acid, rise to room temperature under the ice bath behind the stir about 10min and continue to stir, obtain compound 2-8;
Linked reaction in the step of described method 1 (2) is with compound (3S, 4R, 5S, 6S)-3,4, and 5-three-O-phenmethyl-6-methoxyl group lactone is dissolved in the methyl alcohol, adds successively compound 2-8 crude product, NaCNBH
3, ZnCl
2, be transferred to stir about 3h in 60 ℃ of oil baths after stirring under the room temperature, obtain compound 2-10.
8. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof, it is characterized in that, reduction reaction in the step of described method 1 (3) is that compound 2-10, Nickel dichloride hexahydrate are dissolved in the anhydrous methanol, stir under the room temperature, then system is transferred in the ice-water bath, add sodium borohydride, stir until the solution becomes clarification obtains compound 2-11 crude product.
9. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof, it is characterized in that, condensation reaction in the step of described method 1 (4) is with polyprotonic acid, the logical nitrogen protection of HBTU, add methylene dichloride, after stirring under the room temperature, add successively DIPEA, compound 2-11 crude product, stir about 10h or compound 2-11 crude product passed into nitrogen protection under the room temperature, add methylene dichloride, rear adding triethylamine stirs, polynary acyl chlorides, stir about 10h under the room temperature obtains the multivalence azasugar that benzyloxy replaces;
It is to add 10%Pd/C in the multivalence azasugar that above-mentioned benzyloxy is replaced that hydrogenation in the step of described method 1 (4) removes benzyl reaction, and catalytic hydrogenation under 0.4MPa obtains general formula (I) compound.
10. the synthetic method of multivalence azasugar as claimed in claim 2 and derivative thereof, it is characterized in that, condensation reaction in the step of described method 2 (1) is with polyprotonic acid, HBTU, add DMF, under the room temperature behind the stir about 20min, add successively DIPEA, propargyl amine, stir about 10h under the room temperature obtains the N-propargyl amide derivatives of polyprotonic acid or adds methylene dichloride, propargyl amine, DIPEA, polynary acyl chlorides, stir about 24h under the room temperature obtains under the N-propargyl amide derivatives of polynary acyl chlorides or the ice-water bath condition 60% sodium hydride being dissolved among the DMF, after stirring, add glycerol, propargyl bromide is warming up to the about 5h of stirring at room, obtains polyvalent alcohol alkynes propyl ether;
Click in the step of described method 2 (2) reaction is to pass into nitrogen protection among any and the compound 2-10 in N-propargyl amide derivatives, polyvalent alcohol alkynes propyl ether compound or the three propargyl amine of the N-propargyl amide derivatives of above-mentioned polyprotonic acid, polynary acyl chlorides, then after adding the dioxane dissolving, again sodium ascorbate, cupric sulfate pentahydrate are added above-mentioned reaction system after with dissolved in distilled water, be transferred in 50 ℃ of oil baths after stirring at room is even and stir 24h, be down to and continue under the room temperature to stir, obtain the multivalence azasugar that benzyloxy replaces;
It is the multivalence azasugar HOAc/THF/H that above-mentioned benzyloxy is replaced that hydrogenation in the step of described method 2 (2) removes the benzyl reaction
2After the dissolving of O mixed solvent, add 5% catalytic amount palladium hydroxide, hydrogenation is 5 days under 0.4MPa pressure, obtains general formula (I) compound; Wherein, HOAc: THF: H in the described mixed solvent
2O=4: 2: 1.
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| CN106800519A (en) * | 2017-02-08 | 2017-06-06 | 中南民族大学 | Ultrasonic radiation method Fast back-projection algorithm bridging type pair, the universal method of three, four amide derivatives and application |
| WO2020046132A1 (en) | 2018-08-31 | 2020-03-05 | Leiden University | Pharmacological chaperones for enzyme treatment therapy |
| NL2021840B1 (en) | 2018-10-19 | 2020-05-13 | Univ Leiden | Pharmacological Chaperones For Enzyme Treatment Therapy |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004039373A1 (en) * | 2002-10-29 | 2004-05-13 | Ranbaxy Laboratories Limited | Iminosugar derivatives as glucosidase inhibitors |
| US20080269285A1 (en) * | 2005-06-23 | 2008-10-30 | Centre National De La Recherche Scientifique | Novel Compounds of the Family of Iminosugars, Uses Thereof for Trewating Lysosomal Diseases, and Method for Preparing Same |
| CN101508671A (en) * | 2009-03-24 | 2009-08-19 | 北京大学 | Aza saccharide compounds, synthesis and uses thereof |
| CN101747259A (en) * | 2008-12-18 | 2010-06-23 | 北京大学 | Azasugars compounds, synthesis method and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004039373A1 (en) * | 2002-10-29 | 2004-05-13 | Ranbaxy Laboratories Limited | Iminosugar derivatives as glucosidase inhibitors |
| US20080269285A1 (en) * | 2005-06-23 | 2008-10-30 | Centre National De La Recherche Scientifique | Novel Compounds of the Family of Iminosugars, Uses Thereof for Trewating Lysosomal Diseases, and Method for Preparing Same |
| CN101747259A (en) * | 2008-12-18 | 2010-06-23 | 北京大学 | Azasugars compounds, synthesis method and applications thereof |
| CN101508671A (en) * | 2009-03-24 | 2009-08-19 | 北京大学 | Aza saccharide compounds, synthesis and uses thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106800519A (en) * | 2017-02-08 | 2017-06-06 | 中南民族大学 | Ultrasonic radiation method Fast back-projection algorithm bridging type pair, the universal method of three, four amide derivatives and application |
| CN106800519B (en) * | 2017-02-08 | 2019-03-12 | 中南民族大学 | Ultrasonic radiation method rapid synthesis bridging type pair, the universal method and application of three, four amide derivatives |
| WO2020046132A1 (en) | 2018-08-31 | 2020-03-05 | Leiden University | Pharmacological chaperones for enzyme treatment therapy |
| NL2021840B1 (en) | 2018-10-19 | 2020-05-13 | Univ Leiden | Pharmacological Chaperones For Enzyme Treatment Therapy |
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