CN101033238B - Preparation method and use for purine compounds double amino acid ester - Google Patents
Preparation method and use for purine compounds double amino acid ester Download PDFInfo
- Publication number
- CN101033238B CN101033238B CN2006100244016A CN200610024401A CN101033238B CN 101033238 B CN101033238 B CN 101033238B CN 2006100244016 A CN2006100244016 A CN 2006100244016A CN 200610024401 A CN200610024401 A CN 200610024401A CN 101033238 B CN101033238 B CN 101033238B
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- China
- Prior art keywords
- ethyl
- vitamin
- amino
- acid
- phosphonium mesitoyl
- 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.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 92
- -1 amino acid ester Chemical class 0.000 title claims abstract description 78
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 title claims 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 194
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 29
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 201
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 123
- 235000013343 vitamin Nutrition 0.000 claims description 122
- 239000011782 vitamin Substances 0.000 claims description 122
- 229940088594 vitamin Drugs 0.000 claims description 122
- 229930003231 vitamin Natural products 0.000 claims description 122
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 101
- 238000006243 chemical reaction Methods 0.000 claims description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- 239000002585 base Substances 0.000 claims description 34
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 29
- 239000005864 Sulphur Substances 0.000 claims description 29
- 125000004423 acyloxy group Chemical group 0.000 claims description 27
- 235000001014 amino acid Nutrition 0.000 claims description 25
- 229940024606 amino acid Drugs 0.000 claims description 24
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 16
- 241000700721 Hepatitis B virus Species 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 11
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 10
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012346 acetyl chloride Substances 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- NWIHXVIQPGSBAM-UHFFFAOYSA-N 1-O-amino 3-O-tert-butyl 2-propan-2-ylpropanedioate Chemical compound CC(C)C(C(=O)ON)C(=O)OC(C)(C)C NWIHXVIQPGSBAM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012454 non-polar solvent Substances 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- GNVMUORYQLCPJZ-UHFFFAOYSA-N carbamothioic s-acid Chemical compound NC(S)=O GNVMUORYQLCPJZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 7
- 239000011707 mineral Substances 0.000 claims description 7
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 7
- 150000003222 pyridines Chemical class 0.000 claims description 7
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 6
- ISDSOPJFXRDHCF-UHFFFAOYSA-N CC(C)C(N)C([O])=O Chemical compound CC(C)C(N)C([O])=O ISDSOPJFXRDHCF-UHFFFAOYSA-N 0.000 claims description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 5
- 239000005977 Ethylene Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000000010 aprotic solvent Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- JPQQOHOMPDKBDL-UHFFFAOYSA-N C(C)(C)(C)OC(=O)C(C(=O)SN)CC1=CC=CC=C1 Chemical compound C(C)(C)(C)OC(=O)C(C(=O)SN)CC1=CC=CC=C1 JPQQOHOMPDKBDL-UHFFFAOYSA-N 0.000 claims description 4
- MQHMYPUFYARQMN-UHFFFAOYSA-N ClOP(=O)OCl Chemical compound ClOP(=O)OCl MQHMYPUFYARQMN-UHFFFAOYSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- LJXAOMAKPYUYBO-UHFFFAOYSA-N NC(C(=O)[S])CC1=CC=CC=C1 Chemical compound NC(C(=O)[S])CC1=CC=CC=C1 LJXAOMAKPYUYBO-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 claims description 2
- 150000002169 ethanolamines Chemical class 0.000 claims description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000003947 ethylamines Chemical class 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002989 glutamic acid Drugs 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- 150000003956 methylamines Chemical class 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
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- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims 1
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
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- 239000002243 precursor Substances 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 abstract description 6
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- 208000015181 infectious disease Diseases 0.000 abstract description 2
- 239000011149 active material Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
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- YTRQFSDWAXHJCC-UHFFFAOYSA-N chloroform;phenol Chemical compound ClC(Cl)Cl.OC1=CC=CC=C1 YTRQFSDWAXHJCC-UHFFFAOYSA-N 0.000 description 1
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- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
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- 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 1
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- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 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 1
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- 239000002609 medium Substances 0.000 description 1
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- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- ABMDIECEEGFXNC-UHFFFAOYSA-N n-ethylpropanamide Chemical compound CCNC(=O)CC ABMDIECEEGFXNC-UHFFFAOYSA-N 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
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- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- 229960001179 penciclovir Drugs 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
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- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- A61P31/12—Antivirals
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention provides a kind of purine compound diplo-amino acid ester shown as formula (I), and the acceptance of inorganic or organic salt in pharmacology, in which, R1 is amino, R2 is the free L-amino amino acid or with the protection of amino, n is 0 or 1, X is O or S. The invention also provides the preparation method of this compound and its application in medicine for the treatment of viral infectious disease as active materials.
Description
Technical field
The present invention relates to pharmaceutical chemistry and anti-virus infection therapeutics field, be specifically related to purine compound and the purposes in the preparation antiviral thereof.
Background technology
Hepatitis B is the disease of a kind of serious harm human health of being caused by hepatitis B virus (HBV).According to statistics, nearly in the world 3.5 hundred million Chronic HBV carrier, annual nearly 1,000,000 people die from the disease that HBV causes.In China 1.2 hundred million people being arranged approximately is hepatitis B virus carrierss, hepatitis B patient 2,800 ten thousand, and 1/3rd people can develop into chronic hepatitis, liver cirrhosis or primary hepatocarcinoma (HCC) in the hepatitis B patient.The main medicine of chronic hepatitis B treatment comprises Interferon, rabbit, ucleosides antiviral and immunomodulator.The ucleosides antiviral is the inhibitor of viral DNA polymerase or reversed transcriptive enzyme, and they can stop the synthetic of viral DNA chain, thereby suppresses virus replication.In the anti-HBV medicine of ucleosides, non-cyclic nucleoside phosphonate compound has vital role, its can be used as nucleosides 5 '-analogue of phosplate, can walk around the restrictive first phosphorylation reaction of speed in the nucleoside analog reactivation process, therefore inhibited equally for the dna virus of the viral thymidine kinase (TK) of can not encoding, has the more antiviral activity of wide spectrum (Erik De Clercq Nature Rev.2002,1,13).In addition because the structure of this compounds is different from the L-nucleoside medicine, thereby and the anti-HBV medicine of L-ucleosides of clinical application such as lamivudine between do not produce cross resistance.(Doo?E?Gastroenterology?2001,120:1000;Das,K?J?Virol?2001,75:4771)。Because these characteristics make the acyclonucleosides phosphonic acid ester represent the extremely promising antiviral of a class.
Adefovir dipivoxil (bis (POM) PMEA; be called for short ADV) be 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 Adefovir (PMEA; Adefovir) two pivaloyl oxygen methyl ester prodrugs; going on the market through the FDA approval in September, 2003, is the anti-HBV medicine of second ucleosides small molecules that goes on the market behind lamivudine.ADV all has very strong antiviral activity (Yuen MF.Expert Opin Pharmacother.2004,5 (11): 2361-7) to hepatitis B virus (HBV), dhbv dna (DHBV) and to the variation hepatitis B virus (YMDD) of lamivudine tolerance in vitro and in vivo.Clinical study shows that this medicine can obviously improve patient's liver histological character, reduce serum HBV-DNA and transaminase level, increase e antigen (HBeAg) transformation efficiency, and the no matter state of HBeAg, genotype, people's species diversity or not existing variant viral to lamivudine resistance all not influence ADV brings into play anti-HBV activity (Anneke KRaney.Expert Opin.Investig Drugs 2003,12 (8): 1281-1295).But during using, ADV also has following major defect: (1) unstable chemcial property, its hydrolysis reaction for the seroenzyme mediation is extremely sensitive, can not effectively increase site of action drug level (PieterAnnaert, Pharmaceutical Research.1997,14 (4): 492-496); (2) nucleic acid of transhipment a part need discharge two normal formaldehyde and trimethylacetic acid (Jae-Taeg Hwang.Drugs ofthe Future 2004,29 (2) with genotoxic potential; 163-177).A new generation's Adefovir prodrug purpose of design is intended to increase the metabolic stability of medicine, prolongs action time, increases drug bioavailability, reduces drug toxicity simultaneously.
Human peptide transporter (Human peptide transporters) is a kind of integration endochylema membranin that mediation two in the human body, tripeptides absorb, and it belongs to proton according to patience oligopeptides transporter family.Present two kinds of human peptide transporter (PepT1 with transport activity, PepT2) cloned and the function assessment conclusive evidence, wherein PepT1 is called as enteron aisle peptide transporter, it mainly is present on the intestinal epithelial cell pectination film, substrate-the proton of the contrary concentration gradient of the mediation process that cotransports, natural L-amino acid is its suitable transhipment substrate (Isabel Rubio-Aliaga TRENDS in Pharmacological Sciences, 2002,23 (9): 434-440).Because illustrating of this mechanism, recently the amino acid ester modifying method is used to antiviral nucleoside derivatives and improves bioavailability and strengthen in the design of drug effect, respectively the bioavailability of former medicine is brought up to 63%, 61% (Birger Brodin.Pharmacology ﹠amp from 6%, 20% as L-valine ester prodrug L-Valaciclovir, the L-Valganciclovir of acyclovir (Acyclovir) and ganciclovir (Ganciclovir); Toxicology.2002,90:285-29; Raymund R Razonable, Expert Rev.Anti-infect.Ther.2004,2 (1): 27-42).Two L-Xie Ansuans of the Penciclovir of MEDIVIR AB company development and the Isoleucine ester derivative all can obviously improve the bioavailability of former medicine and make medicine have potent anti-varicella virus, parotid gland virus and EB-virus function (Per Engelhardt, US 0020188125); The L-L-valine ester derivative BRL 44385 of 9-(3-hydroxypropyl-1-oxygen) guanine of Smithline Beecham company development can be when improving former medicine bioavailability, make medicine have potent restraining effect (Harnden to dna virus (the simple virus 1/2 of the parotid gland, varicella virus, cytomegalovirus, hepatitis B virus etc.), Michael, WO9509855).Above result of study has shown that the amino acid ester modifying method is in the advantage of improving aspect the ucleosides antiviral pharmacokinetics.
Summary of the invention
An object of the present invention is to provide and have particularly acceptable salt on the novel purine compounds of resistance of hepatitis B (HBV) and acquired immune deficiency syndrome (AIDS) (HIV) virus activity and the pharmacology thereof of antiviral activity.
Another object of the present invention provides the above-mentioned particularly preparation method of acceptable salt on the novel purine compounds of resistance of hepatitis B and HIV virus activity and the pharmacology thereof of antiviral activity that has.
A further object of the present invention provide this compounds and salt thereof as active substance in the particularly application in the medicine of the infectious diseases that causes of HBV and HIV virus of preparation treatment disease of viral infection.
The invention provides on purine compounds double amino acid ester shown in the formula (I) and the pharmacology thereof and can accept inorganic or organic salt:
In the formula (I),
R
1Be amino;
R
2For amido protecting or free L-type amino acid;
N is 0 or 1;
X is O or S.
The present invention also provides purine compounds double amino acid ester with above-mentioned formula (I) structure and two kinds of preparation methods of salt thereof.
Method one: undertaken by following flow process I
Flow process I
Illustration: bromoethanol a.2-, N, N-Dimethylamino pyridine, dicyclohexylcarbodiimide, 0~25 ℃, 6~24 hours; B. isobutyl chloroformate, N-methylmorpholine, hydrogen sulfide ,-20~-10 ℃, 1~4 hour; C.1,2-ethylene dibromide, sodium hydride ,-20~0 ℃, 1~5 hour; Chloromethyl chlorsulfonic acid ester, 4-n-butyl ammonium hydrogen sulfate, 0~25 ℃, 6~12 hours; D.N, N '-dicyclohexyl-4-morpholinyl-amidine (DCMC), 1,8-diazabicyclo [5,4,0] undecane-7-alkene (DBU) is alkali, 25~90 ℃, 4-48 hour; E. hydrogenchloride saturated/1,4-dioxane or Acetyl Chloride 98Min./methyl alcohol ,-10~25 ℃, 0.5-6 hour.
Method one may further comprise the steps:
(1) preparation of N-tertbutyloxycarbonyl (BOC) L-amino acid ester
N-tertbutyloxycarbonyl L-amino acid and ethylene bromohyrin are in aprotic solvent, at dicyclohexyl carbodiimide (DCC) and N, N dimethylamine yl pyridines (DMAP) exists down, in 0~25 ℃ of reaction 6~24 hours, obtains N-tertbutyloxycarbonyl L-amino acid bromo-ethyl ester; Or
N-tertbutyloxycarbonyl L-amino acid is at isobutyl chloroformate, N-methylmorpholine, hydrogen sulfide reaction 1~4 hour in low temperature-20~-10 ℃, obtain the amino thiocarboxylic acid of N-tertbutyloxycarbonyl L-, and then with 1, the 2-ethylene dibromide is in non-protonic solvent, in the presence of highly basic,, obtain the amino thiocarboxylic acid of N-tertbutyloxycarbonyl L--2-bromo-ethyl ester low temperature-20~0 ℃ reaction 1~5 hour;
Bromochloromethane and chlorsulfonic acid reaction obtain chloromethyl chlorsulfonic acid ester, chloromethyl chlorsulfonic acid ester and N-tertbutyloxycarbonyl L-amino acid are in inert solvent-water two-phase system, at phase-transfer catalyst, 4-n-butyl ammonium hydrogen sulfate exists down, 0~25 ℃ of reaction 6~12 hours, obtain the amino acid whose chloromethyl ester of N-tertbutyloxycarbonyl L-.
(2) amino carbothioic acid ester of various N-tertbutyloxycarbonyl L-amino acid esters or L-and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is in polar aprotic solvent; with N; N '-dicyclohexyl-4-morpholinyl-amidine (DCMC) or 1; 8-diazabicyclo [5; 4; 0] undecane-7-alkene (DBU) is alkali, 25~90 ℃ of reactions 4-48 hour, obtains product.
(3) product for preparing in the step 2 in the above is in polarity or non-polar solvent, hydrogenchloride saturated 1,4-dioxane or Acetyl Chloride 98Min./methyl alcohol exists down, in-10~25 ℃, reacts and obtains the product compound in 0.5~6 hour.
(4) as required, be prepared into acceptable salt on the corresponding pharmacology.For example, the purine compound tri hydrochloride is prepared into pharmacology on acceptable salt with three times of normal mineral acids such as formation vitriol, phosphoric acid salt, Citrate trianion and maleate etc. such as sulfuric acid, phosphoric acid and organic acid such as citric acid, toxilic acid by method well known in the prior art with free back such as sodium bicarbonate, yellow soda ash.
Method two: undertaken by following flow process II
Flow process II
A. oxalyl chloride, N, N '-diethylformamide (DEF), 0~50 ℃, 0.5~4.5 hour; B.N, N-Dimethylamino pyridine (DMAP), dicyclohexylcarbodiimide (DCC), 0~25 ℃, 6~24 hours; C. pyridine, triethylamine, 0~25 ℃, 1~10 hour; D. saturated hydrogenchloride/1,4-dioxane or Acetyl Chloride 98Min./methyl alcohol ,-10~25 ℃, 0.5~6 hour.
Method two may further comprise the steps:
(1) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is in inert solvent, at halogenating agent oxalyl chloride and catalyzer, N; N '-diethylformamide exists down; in 0~50 ℃, reacted, obtain 9-[2-(phosphonium mesitoyl methoxy) ethyl 0.5~4.5 hour] the dichloro-phosphonic acid ester of VITAMIN B4.
(2) N-tertbutyloxycarbonyl L-amino acid and ethylene glycol are in aprotic solvent, and at dicyclohexyl carbodiimide and N, the N dimethylamine yl pyridines exists down, in 0~25 ℃ of reaction 6~24 hours, obtains N-tertbutyloxycarbonyl L-amino acid-hydroxyethyl ester.
(3) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the dichloro-phosphonic acid ester of VITAMIN B4 and N-tertbutyloxycarbonyl L-amino acid-hydroxyethyl ester in inert solvent, in the presence of pyridine and triethylamine,, obtain the product compound 0~25 ℃ of reaction 1~10 hour.
(4) the product compound that obtains in the step (3) above in polarity or non-polar solvent, hydrogenchloride saturated 1, in the presence of 4-dioxane or the Acetyl Chloride 98Min./methyl alcohol,, react and obtained the product compound in 0.5~6 hour in-10~25 ℃.
(5) as required, be prepared into acceptable salt on the corresponding pharmacology.For example, the purine compound tri hydrochloride is prepared into pharmacology on acceptable salt with three times of normal mineral acids such as formation vitriol, phosphoric acid salt, Citrate trianion and maleate etc. such as sulfuric acid, phosphoric acid and organic acid such as citric acid, toxilic acid by method well known in the prior art with free back such as sodium bicarbonate, yellow soda ash.
The present invention further provides Adefovir bisphosphonate compounds shown in the formula (I) and salt thereof in the particularly application on the medicine of the infectious diseases that causes of hepatitis B virus of preparation treatment disease of viral infection.
Acceptable salt can be enumerated and hydrochloric acid particularly on the pharmacology of compound of the present invention, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, the salt of mineral acids such as phosphoric acid, with formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, organic acid and aspartic acids such as ethyl sulfonic acid, the acid salt of acidic amino acids such as L-glutamic acid, or the salt that forms with alkali, as sodium, potassium, calcium, the salt of mineral alkalis such as aluminium, ammonium salt, methylamine salt, ethylamine salt, ethanolamine salt etc., or and Methionin, arginine, the salt that basic aminoacidss such as ornithine form.
The representative example of compound is as follows shown in the formula of the present invention (I):
(1) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(2) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-acetoxyl group) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(3) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl base sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(4) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-phenyl propionyl sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(5) (2S, 2 ' S)-9-{2-[O, O '-two [(1-tertbutyloxycarbonyl-2-Pyrrolizidine base formyl radical sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(6) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(7) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(8) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(9) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(10) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(11) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(12) (2S, 2 ' S)-9-{2-[O, O '-two [(2-glycyl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(13) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl base sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(14) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-phenyl propionyl sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(15) (2S, 2 ' S)-9-{2-[O, O '-two [(2-Pyrrolizidine formyl radical sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(16) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(17) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } the VITAMIN B4 tri hydrochloride;
(18) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl oxygen base) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(19) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(20) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(21) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(22) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-phenyl propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(23) (2S, 2 ' S)-9-{2-[O, O '-two [(1-tertbutyloxycarbonyl-2-Pyrrolizidine base methanoyl) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(24) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(25) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(26) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(27) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-phenyl propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(28) (2S, 2 ' S)-9-{2-[O, O '-two [(2-Pyrrolizidine base methanoyl) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(29) (2S, 2 ' S)-9-{2-[O, O '-two [(the amino propionyloxy of 2-) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(30) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride.
The structure of above compound sees Table-1
Table-1 compound number and structure
Numbering | n? | X? | R 1 | R 2 |
1? | 1? | O? | -NH 2 | BOC-L-Ile? |
2? | 1? | O? | -NH 2 | BOC-Gly? |
3? | 1? | S? | -NH 2 | BOC-L-Val? |
4? | 1? | S? | -NH 2 | BOC-L-Phe? |
5? | 1? | S? | -NH 2 | BOC-L-Pro? |
6? | 1? | S? | -NH 2 | BOC-L-Leu? |
7? | 1? | S? | -NH 2 | BOC-L-Ile? |
8? | 0? | O? | -NH 2 | BOC-L-Val? |
9? | 0? | O? | -NH 2 | BOC-L-Leu? |
10? | 0? | O? | -NH 2 | BOC-L-Ile? |
11? | 1? | O? | -NH 2 | L-Ile? |
12? | 1? | O? | -NH 2 | Gly? |
13? | 1? | S? | -NH 2 | L-Val? |
14? | 1? | S? | -NH 2 | L-Phe? |
15? | 1? | S? | -NH 2 | L-Pro? |
16? | 1? | S? | -NH 2 | L-Leu? |
17? | 1? | S? | -NH 2 | L-Ile? |
18? | 0? | O? | -NH 2 | L-Val? |
19? | 0? | O? | -NH 2 | L-Leu? |
20? | 0? | O? | -NH 2 | L-Ile? |
21? | 1? | O? | -NH 2 | BOC-L-Val? |
22? | 1? | O? | -NH 2 | BOC-L-Phe? |
23? | 1? | O? | -NH 2 | BOC-L-Pro? |
24? | 1? | O? | -NH 2 | BOC-L-Ala? |
25? | 1? | O? | -NH 2 | BOC-L-Leu? |
26? | 1? | O? | -NH 2 | L-Val? |
27? | 1? | O? | -NH 2 | L-Phe? |
28? | 1? | O? | -NH 2 | L-Pro? |
29? | 1? | O? | -NH 2 | L-Ala? |
30? | 1? | O? | -NH 2 | L-Leu? |
Acceptable salt has the particularly function of the infectious diseases that causes of HBV and HIV virus of treatment disease of viral infection on the present invention's purine compounds double amino acid ester required for protection and the pharmacology thereof.
Acceptable salt has the activity of the treatment disease of viral infection similar or stronger to the Adefovir of the anti-HBV medicine of ucleosides small molecules in the prior art on the present invention's purine compounds double amino acid ester required for protection and the pharmacology thereof; so these compounds can be used for preparing the medicine of the infectious diseases that novel therapeutic disease of viral infection, particularly HBV and HIV virus causes.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment never are any limitation of the invention.Among all embodiment, fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct; 1H-NMR Varian Mercury 400 nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm); Separate with the undeclared 200-300 order that is of silica gel.
Compound of the present invention can be by two kinds of method preparations.
Prepare compound of the present invention according to method one:
1, with 1, the 3-dioxolane is a starting raw material, presses currently known methods (Nucleoside ﹠amp; Nucleotide 1996,15, and 1771) through some step reaction synthetic intermediate 9-[2-(phosphonium mesitoyl methoxy) ethyls] purine derivative.
2, N-tertbutyloxycarbonyl (BOC) L-amino acid and ethylene bromohyrin are in non-polar solvents such as toluene, methylene dichloride, chloroform, tetrahydrofuran (THF), at N, the N-Dimethylamino pyridine, dicyclohexylcarbodiimide exists down in 0~25 ℃ of reaction 6~24 hours, top condition for the methylene dichloride be solvent in 10~25 ℃ of reactions 12~24 hours, obtain N-tertbutyloxycarbonyl (BOC) L-amino acid-bromo-ethyl ester.
3, N-tertbutyloxycarbonyl L-amino acid and isobutyl chloroformate (IBCF) and hydrogen sulfide obtain the amino thiocarboxylic acid of N-tertbutyloxycarbonyl L-toluene, methylene dichloride, chloroform, tetrahydrofuran (THF) low temperature-30~10 ℃ reaction 1~10 hour.Top condition was that tetrahydrofuran (THF) is a solvent ,-20~10 reactions 2~4 hours.Products therefrom and glycol dibromide are in non-protonic solvents such as toluene, methylene dichloride, chloroform, tetrahydrofuran (THF), in the presence of sodium hydride, sodium tert-butoxide, trimethyl carbinol lithium, sodium ethylate etc. ,-40~10 ℃ of reactions 0.5~10 hour.Optimum reaction condition reacted 2~5 hours in-20~0 ℃ in the presence of sodium hydride for being solvent with the tetrahydrofuran (THF).Obtain the amino thiocarboxylic acid of N-tertbutyloxycarbonyl L--2-bromo-ethyl ester.
4, the reaction of N-tertbutyloxycarbonyl (BOC) L-amino acid and bromochloromethane and chlorsulfonic acid obtains chloromethyl chlorsulfonic acid ester, in inert solvent-water two-phase system (methylene dichloride-water, chloroform-water, dithiocarbonic anhydride-water, tetracol phenixin-water etc.), at phase-transfer catalyst, 4-n-butyl ammonium hydrogen sulfate, tetra-n-butyl ammonium bromide exist down,-20~25 ℃ of reactions 0.5~24 hour, obtain the amino acid whose chloromethyl ester of N-tertbutyloxycarbonyl L-.Optimum reaction condition was phase-transfer catalyst with the 4-n-butyl ammonium hydrogen sulfate for being reaction system with methylene dichloride-water, in 0~15 ℃ of reaction 6~12 hours.
5, the amino thiocarboxylic acid of N-tertbutyloxycarbonyl L-amino acid-bromo-ethyl ester, N-tertbutyloxycarbonyl L--2-bromo-ethyl ester, the amino acid whose chloromethyl ester of N-tertbutyloxycarbonyl L-and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is at N, in dinethylformamide, methyl-sulphoxide, the pyridine isopolarity aprotic solvent, at N, N '-dicyclohexyl-4-morpholinyl-amidine or 1,8-diazabicyclo [5,4,0] undecane-7-alkene exists down, 25~90 ℃ of reactions 4~48 hours, obtain compound 1~10; Optimum reaction condition is for being solvent with N, dinethylformamide, and at N, N '-dicyclohexyl-4-morpholinyl-amidine and 1,8-diazabicyclo [5,4,0] undecane-7-alkene (DBU) exist down, 40~80 ℃ of reactions, and 6~24 hours.
6, compound 1~10 is at ethyl acetate, isopropyl acetate, 1, in the Semi-polarity solvents such as 4-dioxane, hydrogenchloride saturated 1,4-dioxane or Acetyl Chloride 98Min./methyl alcohol exists down, obtains compound 11~20 in 0.5-12 hour in-20~25 ℃ of reactions.Optimum reaction condition is with 1, and the 4-dioxane is a reaction solvent, hydrogenchloride saturated 1, the 4-dioxane exists down in 0~10 ℃ of reaction 3~6 hours.
7, as required, be prepared into corresponding salt.The purine compound tri hydrochloride is prepared into acceptable salt on the pharmacology with free back such as sodium bicarbonate, yellow soda ash according to a conventional method with three times of normal mineral acids such as formation vitriol, phosphoric acid salt, Citrate trianion and maleate etc. such as sulfuric acid, phosphoric acid and organic acid such as citric acid, toxilic acid.
Prepare compound of the present invention according to method two:
1,9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is raw material, by with perception method (Mark D.Erion.et al J.Am.Chem.Soc.2004,126,5154-5163) preparation dichloro-9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4.
2, N-tertbutyloxycarbonyl L-amino acid and ethylene glycol are in non-polar solvents such as toluene, methylene dichloride, chloroform, tetrahydrofuran (THF), at N, the N-Dimethylamino pyridine, dicyclohexylcarbodiimide exists down in 0~25 ℃ of reaction 6~24 hours, top condition for the methylene dichloride be solvent in 10~25 ℃ of reactions 12~24 hours, obtain N-tertbutyloxycarbonyl L-amino acid-hydroxyethyl ester.
3,9-[2-(phosphonium mesitoyl methoxy) ethyl] dichloro-of VITAMIN B4 sees acid esters and N-tertbutyloxycarbonyl L-amino acid-hydroxyethyl ester in non-polar solvents such as toluene, methylene dichloride, chloroform, tetrahydrofuran (THF); in the presence of pyridine and triethylamine; 0~25 ℃ of reaction 1~10 hour; optimum reaction condition is for being solvent with the methylene dichloride; at 0~10 ℃, react and obtained compound 21~25 in 2~6 hours.
4, compound 21~25 is 1, in the non-polar solvent such as 4-dioxane, ethyl acetate, isopropyl acetate, methylene dichloride, in the presence of saturated 1 at hydrogenchloride, the 4-dioxane or Acetyl Chloride 98Min./methyl alcohol, in-10~100 ℃, reacted 0.5~6 hour, optimum reaction condition for 1, that the 4-dioxane is a solvent is saturated 1 at hydrogenchloride, under the 4-dioxane condition, obtained compound 26~30 in 2~4 hours 0~10 ℃ of reaction.
5,, be prepared into corresponding salt according to needs.The purine compound tri hydrochloride is prepared into acceptable salt on the pharmacology with free back such as sodium bicarbonate, yellow soda ash according to a conventional method with three times of normal mineral acids such as formation vitriol, phosphoric acid salt, Citrate trianion and maleate etc. such as sulfuric acid, phosphoric acid and organic acid such as citric acid, toxilic acid.
Embodiment 1:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 1)
1.1 (1S)-and the tertiary butyl-1-[(2-bromine oxethyl) carbonyl]-preparation of 2-methyl butyl carbamate (a)
With the N-tert-butoxy-oxo-L-isoleucine (5.00g, 0.02mol), ethylene bromohyrin (2.98g 0.024mol) is dissolved in the 200ml dry methylene chloride, is cooled to 10 ℃ with ice-water-bath, and gradation adds N, the N dimethylamine yl pyridines (2.92g, 0.023mol).Finish, architecture heat preservation stirred 15 minutes.Then slowly drip dicyclohexylcarbodiimide (4.53g, 30ml dichloromethane solution 0.022mol).Finish, temperature of reaction was risen to room temperature reaction 12 hours naturally.Insolubles in the system is filtered, and steaming desolventizes.In the gained resistates, add the 100ml ethyl acetate, made the abundant sedimentation of solid in the system in static 6 hours at low temperature (10 ℃).Filter, filtrate is with 100 * 2ml washing, and the 200ml saturated common salt is washed, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, get crude product 8.65g.With sherwood oil: ethyl acetate=10: 1 is an eluent, and silica gel column chromatography is got colorless oil tertiary butyl 1-[(2-bromine oxethyl) carbonyl]-2-methyl butyl carbamate (a) 4.86g, yield 68.39%.
1HNMR(CDCl
3):4.99(d,J=8.15Hz,1H),4.48-4.37(m,2H),4.28(m,1H),3.52-3.47(m,2H),1.87(m,1H),1.42(s,9H),1.22-1.17(m,2H),0.94-0.87(m,6H);EI-MS(m/e):323,M+
1.2:(2S, 2 ' S)-9-{2-[O O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] and ethyl } preparation of VITAMIN B4 (compound 1)
Under the room temperature condition; with tertiary butyl 1-[(2-bromine oxethyl) carbonyl]-2-methyl butyl carbamate (a) (0.63g; 1.8mmol); 9-[2-(phosphonium mesitoyl methoxy) ethyl] and VITAMIN B4 (0.10g, 0.36mnol) and N, N '-dicyclohexyl-4-morpholinyl-amidine (0.21g; 0.72mmol) be suspended in the dry N of 10ml; in the dinethylformamide, room temperature reaction 24 hours is then 80 ℃ of reactions 4 hours.With the reaction solvent evaporated under reduced pressure, add the 20ml ethyl acetate in the resistates,-5~0 ℃ of sedimentation 6 hours, filtering insolubles, filtrate are respectively with 1% citric acid, and water and saturated common salt are washed, anhydrous sodium sulfate drying, filter, filtrate concentrates, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=25: 1) get white vacuolar membrane shape solid chemical compound 43mg.Productive rate: 15.17%.
1HNMR(CDCl
3):δ=8.32(s,1H),7.96(s,1H),5.87(brs,2H),5.21-5.40(m,2H),4.39(t,J=5.32Hz,2H),4.10-4.37(m,10H),3.93(m,2H),3.81(d,J=8.41Hz,2H),1.84(m,2H),1.42(s,18H),1.05-1.26(m,4H),0.85-0.91(m,12H).EI-MS(m/e):787,M+
Embodiment 2:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-acetoxyl group) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 2)
2.1: the carbonyl tertiary butyl-1-[(2-bromine oxethyl)] preparation of methyl carbamate (a)
With N-tertbutyloxycarbonyl-glycine (3.70g, 0.021mol), ethylene bromohyrin (3.47g 0.028mol) is dissolved in the 200ml dry methylene chloride, is cooled to 10 ℃ with ice-water-bath, and gradation adds N, the N dimethylamine yl pyridines (3.10g, 0.025mol).Finish, architecture heat preservation stirred 15 minutes.Then slowly drip dicyclohexylcarbodiimide (4.53g, 30ml dichloromethane solution 0.022mol).Subsequent process is similar to the synthetic of compound 1.1. get colorless oil (a) 3.21g, yield 54.39%.
2.2:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-acetoxyl group) ethyl] phosphonium mesitoyl methoxy] and ethyl } preparation of VITAMIN B4 (compound 2)
Under the room temperature condition; with (a) (0.99g; 3.55mmol); 9-[2-(phosphonium mesitoyl methoxy) ethyl] and VITAMIN B4 (0.16g, 0.59mnol) and N, N '-dicyclohexyl-4-morpholinyl-amidine (0.33g; 1.13mmol) be suspended in the dry N of 10ml; in the dinethylformamide, room temperature reaction 24 hours, the back was 80 ℃ of reactions 4 hours.With the reaction solvent evaporated under reduced pressure, add the 20ml ethyl acetate in the resistates,-5~0 ℃ of sedimentation 6 hours, filtering insolubles, filtrate are respectively with 1% citric acid, and water and saturated common salt are washed, anhydrous sodium sulfate drying, filter, filtrate concentrates, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=25: 1) get bacalite shape compound 52.4mg.Productive rate: 13.15%.
1HNMR(CDCl
3):δ=8.26(s,1H),8.11(s,1H),5.44(brs,2H),4.38-4.45(m,2H),4.23-4.31(m,8H),3.93-4.01(m,6H),3.84(d,J=8.52Hz,2H),1.43(s,18H).EI-MS(m/e):675,M+.
Embodiment 3:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl base sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 3)
3.1:(S the preparation of)-2-t-butoxycarbonyl amino-3-methyl list Thiobutyric acid (a)
(2.50g 0.0115mol) is dissolved in the 25ml dry tetrahydrofuran, is cooled to-15 ℃ with ice-salt bath with N-tertbutyloxycarbonyl-L-Xie Ansuan, add N-methylmorpholine (11.54g, 0.0575mol) and isobutyl chloroformate (1.74g, 0.0126mol), architecture heat preservation stirring 30 minutes.Temperature remains on below-15 ℃ in reaction system, feeds the self-control hydrogen sulfide, and aeration time continues 1.5-2 hour, and the stink damp bulk absorption is after saturated to the system, and insulation reaction made reaction carry out fully in 2 hours again.Add the 40ml anhydrous diethyl ether, with 0.1M hydrochloric acid regulation system pH to 3, divide and get organic layer, with 2 * 20ml water, the water washing of 2 * 20ml saturated common salt, anhydrous sodium sulfate drying, filter, solvent evaporated gets faint yellow oily thing (S)-2-t-butoxycarbonyl amino-3-methyl list Thiobutyric acid (a) 2.22g, yield 82.85%.
1HNMR(CDCl
3):5.06(m,1H),4.24(m,1H),2.27(m,1H),1.43(s,9H),0.93-0.89(m,6H).
3.2:(1S the carbonyl)-tertiary butyl-1-[(2-bromotrifluoromethane sulphur)]-preparation of 2-methyl-propyl carbamate (b)
(0.17g 4.29mmol) adds in the 10ml tetrahydrofuran (THF), stirs and is cooled to-15 ℃ with ice-salt bath with sodium hydride, slowly be added dropwise to (S)-2-t-butoxycarbonyl amino-3-methyl list Thiobutyric acid (a) (1.00g, 4.29mmol) the 2ml tetrahydrofuran solution, drip to finish insulation reaction 1.5 hours, room temperature reaction 2 hours, slowly be added dropwise to glycol dibromide (1.60g, 5ml tetrahydrofuran solution 8.58mol), drip and finish system room temperature reaction 12 hours.System is filtered, filtrate is with 2 * 20ml water, the water washing of 2 * 20ml saturated common salt, anhydrous sodium sulfate drying, filter, filtrate concentrates, residue column chromatography for separation (eluent: sherwood oil: ethyl acetate=20: 1), get faint yellow oily thing (S)-2-t-butoxycarbonyl amino-3-methyl list Thiobutyric acid-2-bromo-ethyl ester (b) 0.59g, yield 40.52%.
1HNMR(CDCl
3):4.95(d,J=8.95Hz,1H),4.26(m,1H),3.42(t,J=7.34Hz,2H),3.29(t?J=6.6Hz,2H)2.31-2.25(m,1H),1.46(s,18H),0.99(d,J=6.78Hz,3H),0.86(d,J=6.96Hz,3H).
3.3:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl base sulphur) ethyl] phosphonium mesitoyl methoxy] and ethyl } preparation of VITAMIN B4 (compound 3)
With (S)-2-t-butoxycarbonyl amino-3-methyl list Thiobutyric acid-2-bromo-ethyl ester (b) (0.44g; 1.3mmol) and 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 (0.08g; 0.26mmol) and N; N '-dicyclohexyl-4-morpholinyl-amidine (0.15g; 0.26mmol) be suspended in the dry N of 10ml; in the dinethylformamide, room temperature reaction 24 hours, the back was 80 ℃ of reactions 5 hours.With the reaction solvent evaporated under reduced pressure, add the 20ml ethyl acetate in the resistates,-5~0 ℃ of sedimentation, filtering insolubles, filtrate are respectively with 10 * 2ml, 1% citric acid, and water and saturated common salt are washed, anhydrous sodium sulfate drying, filter, filtrate concentrates, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=25: 1) get colourless amber shape compound 58mg.Productive rate: 13.09%.
1HNMR(CDCl
3):δ=8.27(s,1H),8.05(s,1H),6.18(brs,2H),5.21-5.39(m,2H),3.97-4.41(m,8H),3.91(t,J=4.89Hz,2H),3.79(d,J=8.41Hz,2H),3.04-3.21(m,4H),2.24(m,2H),1.42(S,18H),0.96(d,J=6.84Hz,6H),0.83(d,J=6.65Hz,6H).ESI-MS(m/e):792.2,(M+H)+.
Embodiment 4:(2S, 2 ' S)-9-{2-[O O '-two [(2-t-butoxycarbonyl amino-3-phenyl propionyl sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 4)
N-tertbutyloxycarbonyl-L-phenylalanine is a starting raw material; to be similar to the method preparation of embodiment 3; off-white color amber shape compound (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-phenyl propionyl sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl VITAMIN B4 61mg.Productive rate: 12.67%.
1HNMR(CDCl
3):δ=8.31(s,1H),8.01(s,1H),7.11-7.26(m,10H),6.12(brs,2H),5.44-5.37(m,2H),4.09-4.45(m,8H),3.81-3.90(m,4H),3.14-3.31(m,4H),2.88-3.13(m,4H),1.42(S,18H)。
Embodiment 5:(2S, 2 ' S)-9-{2-[O, O '-two [(1-tertbutyloxycarbonyl-2-Pyrrolizidine base formyl radical sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 5)
N-tertbutyloxycarbonyl-L-proline(Pro) is a starting raw material; to be similar to the method preparation of embodiment 3; get sundown oily compound (2S; 2 ' S)-9-{2-[O; O '-two [(1-tertbutyloxycarbonyl-2-Pyrrolizidine base formyl radical sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4 55mg, productive rate: 18.61%.
1HNMR(CDCl
3):δ=8.35(s,1H),8.07(s,1H),5.84(brs,2H),4.47(m,2H),4.36-4.24(m,6H),3.83-3.96(m,4H),3.38-3.57(m,4H),3.14-3.26(m,4H),1.42(S,18H),2.13-2.24(m,4H),1.91-2.02(m,4H),1.43(d,J=16.67Hz,18H)。
Embodiment 6:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 6)
N-tertbutyloxycarbonyl-L-proline(Pro) is a starting raw material; to be similar to the method preparation of embodiment 3; get white foam shape compound (2S; 2 ' S)-9-{2-[O; O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4 67mg, productive rate: 31.38%.
1HNMR(CDCl
3):δ=8.31(s,1H),7.97(s,1H),5.97(brs,2H),5.24-5.41(m,2H),4.51-4.28(m,8H),3.91-4.02(m,4H),3.23-3.41(m,4H),1.72-1.80(m,4H),1.07(brs,12H)。
Embodiment 7:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 7)
The N-tert-butoxy-oxo-L-isoleucine is a starting raw material; to be similar to the method preparation of embodiment 3; get off-white color foam-like compound (2S; 2 ' S)-9-{2-[O; O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4; 81mg, productive rate: 35.23%.
1HNMR(CDCl
3):δ=8.36(s,1H),8.04(s,1H),5.87(brs,2H),5.18-5.34(m,2H),4.32-4.42(m,4H),4.08-4.11(m,4H),3.92(m,2H),3.81(d,J=8.66Hz?2H),3.02-3.18(m,4H),1.92-1.99(m,2H),1.42(s,18H),1.11-1.17(m,4H),0.79-0.98(m,12H)。
Embodiment 8:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) methylene radical] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 8)
8.1: chloromethyl chlorsulfonic acid ester (a)
(100ml, 1.5mol), (50ml 0.75mol) places in the reaction flask bromochloromethane altogether, slowly reaction system is heated to backflow, reacts 3 hours with chlorsulfonic acid.Reaction is finished, system is cooled to room temperature, after with in its slow impouring 500g trash ice, treat behind the ice-out with methylene dichloride (400 * 2ml) extraction, organic layer is told, anhydrous sodium sulfate drying filters, and filtrate is steamed under normal pressure and desolventized, 45-50 ℃/9-10mmHg cut is collected in the resistates underpressure distillation.Get product 30.25g, productive rate: 24.4%.
1HNMR(CDCl
3):5.96(s,2H)
8.2:(1S the carbonyl)-tertiary butyl-1-[(chlorine methoxyl group)]-preparation of 2-methyl-propyl carbamate (b)
With N-tertbutyloxycarbonyl-L-Xie Ansuan (3.00g, 0.0138mol), sodium bicarbonate (4.59g, 0.0546mol) and four-normal-butyl monoammonium sulfate (0.47g, 0.00138mol) in the system as for 50ml water and 50ml methylene dichloride, cryosel is bathed and is cooled to 0 ℃, slowly be added dropwise to chloromethyl chlorsulfonic acid ester (a) (2.78g under the vigorous stirring, 0.0167mol) the 14ml dichloromethane solution, drip to finish, system rises to room temperature naturally and reacted 12 hours.Organic layer is told, and with the washing of 2 * 10ml saturated common salt, anhydrous sodium sulfate drying filters, and filtrate concentrates, residue column chromatography for separation (eluent: sherwood oil: ethyl acetate=15: 1) get colorless oil 2.96g.Productive rate: 80.77%.
1HNMR(CDCl
3):5.83(d,J=5.86Hz,1H),5.58(d,J=5.37Hz,1H),4.97(dJ=8.3Hz,1H),4.23-4.21(m,1H),2.15(m,1H),1.41(s,9H),0.96(d,J=6.83Hz,3H),0.89(d,J=6.84Hz,3H)。
8.3:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) methylene radical] phosphonium mesitoyl methoxy] and ethyl } preparation of VITAMIN B4 (compound 8)
With 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 (0.10g; 0.36mmol); tertiary butyl 1-[(chlorine methoxyl group) carbonyl]-2-methyl-propyl carbamate (b) (0.48g; 1.8mmol); N, (0.21g 0.72mmol) is suspended in the 10ml exsiccant N-N-methyl-2-2-pyrrolidone N-N '-dicyclohexyl-4-morpholinyl-amidine; behind the room temperature reaction 24 hours, 80 ℃ were reacted 5 hours.In system impouring 5ml 1% citric acid and 5ml ethyl acetate, extraction, tell organic phase, water is continuous with 2 * 5ml ethyl acetate extraction, and ester is also laminated, continuous with 2 * 5ml1% citric acid, water and saturated common salt water washing, anhydrous sodium sulfate drying filters, filtrate concentrates, residue column chromatography for separation (eluent: methylene dichloride: methyl alcohol=25: 1) get colourless amber shape thing 55mg.Productive rate: 20.8%.
1HNMR(CDCl
3):δ=8.28(s,1H),7.97(s,1H),6.18(brs,2H),5.66-5.72(m,4H),5.21-5.36(m,2H),4.41(m,2H),4.27-4.31(m,2H),3.91(m,2H),3.85(d,J=5.09Hz,2H),2.13-2.18(m,2H),1.42(s,18H),0.96(d,J=6.32Hz,6H),0.84(d,J=6.78Hz,6H)。
Embodiment 9:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 9)
N-tertbutyloxycarbonyl-L-leucine is a starting raw material; to be similar to the method preparation of embodiment 8; get off-white color foam-like compound (2S; 2 ' S)-9-{2-[O; O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4 26mg, productive rate: 9.56%.
1HNMR(CDCl
3):δ=8.34(s,1H),8.06(s,1H),6.21(brs,2H),5.76-5.91(m,4H),5.18-5.29(m,2H),4.52-4.36(m,4H),3.94(m,2H),3.91(d,J=5.97Hz,2H),1.71-1.93(m,6H),1.42(s,18H),0.91(t,J=5.5Hz,12H)。
Embodiment 10:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 10)
The N-tert-butoxy-oxo-L-isoleucine is a starting raw material; to be similar to the method preparation of embodiment 8; get white foam shape compound (2S; 2 ' S)-9-{2-[O; O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4 85mg, productive rate: 15.56%.
1HNMR(CDCl
3):δ=8.28(s,1H),7.96(s,1H),6.09(brs,2H),5.59-5.72(m,4H),5.08-5.21(m,2H),4.38(m,2H),4.23-4.31(m,2H),3.89(m,2H),3.82(d,J=7.33Hz,2H),1.84(m,2H),1.41(s,18H),1.07-1.16(m,4H),0.81-0.95(m,12H)。
Embodiment 11:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 11)
Compound (0.21g with preparation among the embodiment 1; 0.267mmol) be dissolved in 1ml drying 1; in the 4-dioxane; with the cryosel bath system is cooled to 0 ℃ under the nitrogen protection; stir slowly drip down 15% hydrogenchloride 1,4-dioxane solution (1ml; 4mmol), insulation reaction 1 hour, back room temperature reaction transformed abundant in 3 hours to product.Left standstill 30 minutes, and supernatant liquor in the system was inhaled abandoned, solids is abandoned the solvent suction with the washing of 5 * 2ml ethyl acetate, sedimentation 5 times, gets white foam shape solid 0.176g, productive rate: 95.24% after the resistates thorough drying.
1HNMR(CD
3OD):δ=8.43(s,1H),8.39(s,1H),4.55(t,J=5.08Hz,2H),4.38-4.53(m,4H)4.21-4.36(m,4H),4.06-4.11(m,2H),3.98-4.02(m,4H),1.98-2.01(m,2H),1.34-1.57(m,4H),0.96-1.03(m,12H).ESI-MS:588.2(M+H)+。
Embodiment 12:(2S, 2 ' S)-9-{2-[O, O '-two [(2-glycyl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 12)
Compound with preparation among the embodiment 2 is a raw material, to be similar to the method preparation of embodiment 11, gets white powder thing 22mg, productive rate: 87.76%.
1HNMR(CD
3OD):δ=8.54(brs,4H),8.49(s,1H),8.42(s,1H),4.44(m,2H),4.31(m,4H)4.16(m,4H),3.97(d,J=7.82Hz,2H),3.92(m,2H),3.85(s,4H).EI-MS(m/e):475M+。
Embodiment 13:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl base sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 13)
With Acetyl Chloride 98Min. (0.077ml, 1.06mmol), methyl alcohol (0.058ml, 1.36mmol) place the dry ethyl acetate of 1.6ml, system is bathed with cryosel and is cooled to-5~0 ℃, reacts 30 minutes, slowly is added dropwise to the compound (30mg of preparation among the embodiment 3,0.0379mmol) the dry ethyl acetate solution of 1.6ml, drip and finish, insulation reaction 2 hours, the back rises to room temperature reaction naturally and transformed abundant to product in 6 hours.Left standstill 30 minutes, and supernatant liquor in the system was inhaled abandoned, solids is abandoned the solvent suction with the washing of 5 * 2ml ethyl acetate, sedimentation 5 times, gets white semi-solid 13mg, productive rate: 58.03% after the resistates thorough drying.
1HNMR(CD
3OD):δ=8.43(s,1H),8.39(s,1H),,4.58(t,J=4.69Hz,2H),4.14-4.22(m,6H),3.98-4.02(m,4H),3.31(t,J=6.26Hz,4H),2.26-2.41(m,2H),1.12(d,J=6.85,6H),1.04(d,J=7.04Hz,6H).ESI-MS:592.1(M+H)+。
Embodiment 14:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-phenyl propionyl sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 14)
Compound with preparation among the embodiment 4 is a raw material, to be similar to the method preparation of embodiment 13, gets white powder thing 14mg, productive rate: 84.46%.
1HNMR(CD
3OD):δ=8.38(s,1H),8.35(s,1H),7.28-7.38(m,10H),4.56(m,4H),4.05-4.18(m,4H),3.96(t,J=4.59Hz),3.91(d,J=8.25Hz,2H),3.24(m,4H),3.13-3.19(m,4H)。
Embodiment 15:(2S, 2 ' S)-9-{2-[O, O '-two [(2-Pyrrolizidine formyl radical sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 15)
Compound with preparation among the embodiment 5 is a raw material, to be similar to the method preparation of embodiment 13, gets off-white color spumescence solid 10mg, productive rate: 41.55%.
1HNMR(CD
3OD):δ=8.44(s,1H),8.40(s,1H),4.68(m,2H),4.56(m,2H),4.17-4.19(m,4H),3.97-4.01(m,4H),3.39(t,J=6.96Hz,4H),3.33(m,4H),2.50-2.56(m,2H),2.07-2.16(m,6H).ESI-MS:588.1(M+H)+。
Embodiment 16:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 16)
Compound with preparation among the embodiment 6 is a raw material, to be similar to the method preparation of embodiment 13, gets colourless gelatinous semi-solid 7mg, productive rate: 46.34%.
1HNMR(CD
3OD):δ=8.42(s,1H),8.37(s,1H),4.55(m,2H),4.18-4.26(m,6H),4.01(m,4H),3.31(m,4H),1.72-1.81(m,4H),1.02(m,12H).ESI-MS:620.2(M+H)+。
Embodiment 17:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 17)
Compound with preparation among the embodiment 7 is a raw material, to be similar to the method preparation of embodiment 13, gets white fluffy solid 14mg, productive rate: 50.26%.
1HNMR(CD
3OD):δ=8.41(s,1H),8.36(s,1H),4.56(t,J=5.12Hz,2H),4.18-4.25(m,6H),3.91-4.01(m,4H),3.24(m,4H),2.07(m,2H),1.24-1.61(m,4H),0.97-1.08(m,12H)ESI-MS:620.2(M+H)+。
Embodiment 18:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl oxygen base) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 18)
Compound with preparation among the embodiment 8 is a raw material, to be similar to the method preparation of embodiment 11, gets white foam shape solid 18mg, productive rate, 57.45%.
1HNMR(CD
3OD):δ=8.42(s,1H),8.37(s,1H),5.65-5.91(m,4H),4.57(t,J=4.89Hz,2H),4.11(m,2H),4.08(d,J=8.22Hz,2H),4.02(t,J=4.89Hz,2H),2.14-2.21(m,2H),1.02-1.16(m,12H).ESI-MS:532.1(M+H)+。
Embodiment 19:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 19)
Compound with preparation among the embodiment 9 is a raw material, to be similar to the method preparation of embodiment 11, gets white foam shape solid 14mg, productive rate: 90.74%.
1HNMR(CD
3OD):δ=8.42(s,1H),8.38(s,1H),5.85-5.73(m,4H),4.56(t,J=5.13Hz,2H),4.18(m,2H),4.09(d,J=8.43Hz,2H),4.02(t,J=4.76Hz,2H),1.71-1.86(m,6H),1.01(m,12H)。
Embodiment 20:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 20)
Compound with preparation among the embodiment 10 is a raw material, to be similar to the method preparation of embodiment 11, gets off-white color spumescence solid 15mg, productive rate: 78.26%.
1HNMR(CD
3OD):δ=8.41(s,1H),8.36(s,1H),5.73-5.89(m,4H),4.56(t,J=5.13Hz,2H),4.18(m,2H),4.08(d,J=8.07Hz,2H),4.01(t,J=5.14Hz,2H),2.05(m,2H),1.32-1.61(m,4H),0.97-1.06(m,12H)。
Embodiment 21:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 21)
21.1:(1S the carbonyl)-tertiary butyl-1-[(2-hydroxy ethoxy)]-preparation of 2-methyl-propyl carbamate (a)
With N-tertbutyloxycarbonyl L-Xie Ansuan (0.22g, 1mmol), ethylene glycol (0.06g, 1mmol), place the 15ml dry methylene chloride, be cooled to 10 ℃ with ice-water-bath, gradation adds N, the N dimethylamine yl pyridines (0.122g, 1mmol), architecture heat preservation stirred 15 minutes, slowly be added dropwise to dicyclohexylcarbodiimide (0.22g, 1.1mmol) the 10ml dichloromethane solution, finish, temperature of reaction was risen to room temperature reaction 24 hours naturally.Insolubles in the system is filtered, steaming desolventizes, and resistates is dissolved in the 10ml ethyl acetate, and low temperature (10 ℃) leaves standstill, filter, with 2 * 5ml 1M sal enixum, water and the washing of 5% sodium carbonate solution, anhydrous magnesium sulfate drying filters filtrate respectively, solvent removes under reduced pressure, resistates is with sherwood oil: ethyl acetate=4: 1 is an eluent, and silica gel column chromatography is got colorless oil tertiary butyl 1-[(2-hydroxy ethoxy) carbonyl]-2-methyl-propyl carbamate (a) 0.167g, yield: 76.95%.
1HNMR(CDCl
3):5.15(d,J=8.43Hz,1H),4.20-4.27(m,3H),3.77(t,J=4.59Hz,2H),3.24(brs,1H)1.81(m,1H),1.41(s,9H),1.21-1.13(m,2H),0.85-0.91(m,6H)。
21.2: dichloro-9-[2-(phosphonium mesitoyl methoxy) ethyl] preparation of VITAMIN B4 (b)
With oxalyl chloride (0.54ml; 6.28mmol) slowly be added dropwise to contain 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 (0.50g; 1.8mmol); N; the N-diethylformamide (0.20ml, in 14ml methylene dichloride 1.9mmol), system refluxed 3 hours; extract reaction solution and use the methyl alcohol cancellation, detect two chloro things to TLC and transform fully.System is chilled to room temperature, and concentrating under reduced pressure is with yellow foam dichloro-9-[2-(phosphonium mesitoyl methoxy) ethyl of remnants] VITAMIN B4 (b) 0.37g, thick yield 66.95%.Gains are dissolved in the 2ml dry methylene chloride, and cryosel is bathed and is cooled to 0 ℃, slowly adds the 0.3ml pyridine, low temperature (preserving standby below 0 ℃).
21.3:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) ethyl] phosphonium mesitoyl methoxy] and ethyl } preparation of VITAMIN B4 (compound 21)
With tertiary butyl 1-[(2-hydroxy ethoxy) carbonyl]-2-methyl-propyl carbamate (a) (0.94g; 3.6mmol); triethylamine (1.50ml; 10.78mmol) be dissolved in the 6ml dry methylene chloride; system is bathed with cryosel and is cooled to 0 ℃, slowly is added dropwise to dichloro-9-[2-(phosphonium mesitoyl methoxy) ethyl] dichloromethane solution of VITAMIN B4 (b), drip and finish; insulation reaction 1 hour, after slowly rose to room temperature reaction 4 hours.Solution is used 3 * 1ml water, 2 * 1ml, 1% citric acid and saturated common salt water washing respectively, and anhydrous magnesium sulfate drying filters, filtrate concentrates, resistates is with methylene dichloride: methyl alcohol=15: 1 is eluent, and silica gel column chromatography is got faint yellow semi-solid 0.22g, yield: 15.53%.
1HNMR(CDCl
3):8.36(s,1H),8.09(s,1H),6.21(brs,2H),5.25-5.41(m,2H),4.45(t,J=6.25Hz,2H),4.11-4.36(m,10H),3.97(t,J=5.51Hz,2H),3.82(d,J=9.35Hz,2H),2.02-2.18(m,2H),1.42(s,18H),0.96(d,J=6.41Hz,6H),0.82(d,J=6.59Hz,6H).EI-MS(m/e):759,M+。
Embodiment 22:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-phenyl) propionyloxy] ethyl] phosphonium mesitoyl methoxy } ethyl } preparation of VITAMIN B4 (compound 22)
N-tertbutyloxycarbonyl L-phenylalanine is a starting raw material, to be similar to the method preparation of embodiment 21, gets light yellow spumescence solid 43mg, yield: 13.97%.
1HNMR(CDCl
3):8.31(s,1H),8.01(s,1H),7.14-7.26(m,10H),6.01(brs,2H),5.37-5.44(m,2H),4.75(m,2H),4.21-4.27(m,10H),3.91(m,2H),3.81(d,J=8.80Hz,2H),2.98-3.13(m,4H),1.38(s,18H).ESI-MS:856.2(M+H)+。
Embodiment 23:(2S, 2 ' S)-9-{2-[O, O '-two [(1-tertbutyloxycarbonyl-2-Pyrrolizidine base methanoyl) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 23)
N-tertbutyloxycarbonyl L-proline(Pro) is a starting raw material, to be similar to the method preparation of embodiment 21, gets light yellow amber shape thing 31mg, yield: 11.41%.
1HNMR(CDCl
3):8.34(s,1H),7.96(s,1H),5.76-5.84(m,2H),4.41(t,J=4.76Hz,2H),4.21-4.33(m,10H),3.95(m,2H),3.79-3.86(m,2H),3.35-3.53(m,4H),2.14-2.24(m,4H),1.91-2.02(m,4H),1.43(d,J=17.38Hz,18H).EI-MS(m/e):755,M+。
Embodiment 24:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 24)
N-tertbutyloxycarbonyl L-L-Ala is a starting raw material, to be similar to the method preparation of embodiment 21, gets the semi-solid 44mg of off-white color, yield: 22.4%.
1HNMR(CDCl
3):8.33(s,1H),7.98(s,1H),5.92(brs,2H),5.40-5.48(m,2H),4.23-4.42(m,12H),3.83-3.93(m,4H),1.37-1.43(m,24H)。
Embodiment 25:(2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } preparation of VITAMIN B4 (compound 25)
N-tertbutyloxycarbonyl L-leucine is a starting raw material, to be similar to the method preparation of embodiment 21, gets light yellow spumescence solid 24mg, yield: 8.47%.
1HNMR(CDCl
3):8.36(s,1H),8.04(s,1H),6.24(brs,2H),5.25-5.40(m,2H),4.24-4.42(m,12H),3.94(m,2H),3.85(d,J=8.47Hz,2H),1.44-1.59(m,6H),1.42(s,18H),0.91(t,J=6.59Hz,12H).EI-MS(m/e):787,M+。
Embodiment 26:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 26)
Compound with preparation among the embodiment 21 is a raw material, to be similar to the method preparation of embodiment 11, gets the semi-solid 13mg of off-white color, yield: 61.36%.
1HNMR(CD
3OD):8.41(s,1H),8.36(s,1H),4.54(t,J=4.76Hz,2H),4.40-4.47(m,4H),4.31(m,4H),3.98-4.02(m,6H),2.30-2.33(m,2H),1.04-1.16(m,12H).EI-MS(m/e):559,M+。
Embodiment 27:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-phenyl propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 27)
Compound with preparation among the embodiment 22 is a raw material, to be similar to the method preparation of embodiment 11, gets the semi-solid 0.106g of off-white color, yield: 91.51%.
1HNMR(CD
3OD):δ=8.37(s,1H),8.35(s,1H),7.25-7.36(m,10H),4.51(t,J=5.09Hz,2H),4.27-4.31(m,6H),4.22-4.26(m,4H),3.98-4.01(m,4H),3.16-3.28(m,4H),ESI-MS:656.3(M+H)+
Embodiment 28:(2S, 2 ' S)-9-{2-[O, O '-two [(2-Pyrrolizidine base methanoyl) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (skill compound 28)
Compound with preparation among the embodiment 23 is a raw material, to be similar to the method preparation of embodiment 11, gets the semi-solid 0.106g of off-white color, yield: 91.51%.
1HNMR(CD
3OD):δ=8.43(s,1H),8.39(s,1H),4.49-4.55(m,4H),4.52(m,2H),4.11(m,4H),3.99-4.01(m,4H),3.37-3.43(m,4H),2.41-2.45(m,2H),2.06-2.19(m,6H)。ESI-MS:556.2(M+H)+。
Embodiment 29:(2S, 2 ' S)-9-{2-[O, O '-two [(the amino propionyloxy of 2-) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 29)
Compound with preparation among the embodiment 24 is a raw material, to be similar to the method preparation of embodiment 11, gets the semi-solid 26mg of off-white color, yield: 77.65%.
1HNMR(CD
3OD):δ=8.42(s,1H),8.38(s,1H),4.55(t,J=5.08Hz,2H),4.43(t,J=4.41Hz,2H),4.29-4.32(m,4H),4.18(q,J=7.14Hz,2H),4.01(m,4H),1.56(d,J=7.28Hz,6H)。EI-MS(m/e):503,M+。
Embodiment 30:(2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. the preparation of tri hydrochloride (compound 30)
Compound with preparation among the embodiment 25 is a raw material, to be similar to the method preparation of embodiment 11, gets light yellow semi-solid 46mg, yield: 81.45%.
1HNMR(CD
3OD):δ=8.44(s,1H),8.41(s,1H),4.57(m,2H),4.31(m,4H),4.11(m,4H),4.08-4.11(m,4H),4.02(d,J=7.42Hz,2H),1.71-1.85(m,6H),0.98(t,J=5.76Hz,12H),EI-MS(m/e):587,M+。
Embodiment 31: the extracorporeal antivirus effect determination of activity
1, test method:
(1) cell toxicity test
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay MTT) detection of drugs is to the restraining effect of HepG 2215 growths to adopt the tetrazole reduction method.Get one bottle in HepG 2215 cells, with being prepared into single cell suspension after the trysinization, cell concn to 2 * 104cell/ml is adjusted in the counting back, adds in 96 well culture plates.Place cell culture incubator, 37 ℃, 5%CO2 overnight incubation.Suction goes to add the DMEM substratum (5% foetal calf serum) that contains the different concns medicine behind the supernatant.After acting on 9 days, add the MTT of 10 μ l in each hole and continue cultivation 4 hours.The careful suction goes supernatant, every hole to add 150 μ l DMSO, after the vibration, detects the OD value at 570nm place with microplate reader gently.
(2) to the inhibition test of hepatitis B virus-DNA (HBV-DNA)
A) cell drug is handled
Get one bottle in HepG 2215 cells,, regulate cell concn to 2 * 104cell/ml, add in the 24 porocyte culture plates (1ml/well) with being prepared into single cell suspension after the trysinization.37 ℃, 5%CO2 overnight incubation.Take out 24 porocyte culture plates, add 55 times of weaker concn medicines behind the sucking-off supernatant successively, and the positive control medicine.Continue to cultivate, changed the substratum that contains medicine in per 3 days, and collected in the 9th day each hole supernatant liquor to centrifuge tube-20 ℃ frozen standby.
B) quantitative fluorescent PCR reaction
Serum specimen (100ul) place lysate (1mmol/L Tris-Hcl, pH 8.0,10mmol/LNacl, 0.1mmol/L EDTA, 0.5%SDS, 0.8mg/ml Proteinase K) 37 ℃ of hatching 5h, with phenol chloroform and chloroform extracting twice respectively, use ethanol sedimentation more then.Be dissolved in the 50 μ l water in order to making pcr amplification.
The 2ul viral DNA is put into the reaction mixture of 48 μ l, comprises the Gold Taq polymerase of 5mmol/L Mgcl2, every kind of dNTP0.2mmol/L, 2.5U, the UNG enzyme of 0.2U and each 0.4mmol/L of primer, probe 0.15mmol/L.Behind 37 ℃ of 5min, 95 ℃ of sex change 3min30s, 94 ℃ of 20s, 60 ℃ of 40s (fluorescent signal detection) circulate last 4 ℃ of preservations 41 times.Detect used Taqman probe sequence: 5 ' FAM-CCAGCAGCGCCTCCTCCTGC-3 ' TAMARA; Primer sequence: Forward primer:5 '-CCC TCAGGCTCAGGGCATA-3 ', Reverse primer:5 '-CTTCCTGACTGCCGATTGGT-3 '.
2. test clone:
HepG 2215 cells draw from university of Fudan University molecule virus laboratory.This cell strain is that the recombinant plasmid transfection recipient cell HepG2 with 2 full genes of HBV DNA from beginning to end forms, can be at external stable secretion HBsAg, and HBeAg and complete Dane particle can also produce a large amount of replicative intermediate (RI).Cell cultures is in the DMEM that contains 10% foetal calf serum.
3. positive controls is the two pivalates (Adefovir Dipivoxil) of Adefovir.
4, each compound suppresses EC to HBV-DNA in the HepG2.2.15 cell
50, cytotoxicity CC
50, and effect selectivity index SI value sees Table-2.
Table-2 test compounds are to the inhibition effect of HBV-DNA in the HepG2.2.15 cell
Compound number | aEC 50(Mm) | bCC 50(μM) | cSI? |
1? | 5.87? | 269? | 45.93? |
5? | 0.25? | 818? | 3176.47? |
6? | 6.63? | 3583? | 540.57? |
7? | 11.59? | 2303? | 198.96? |
11? | 0.095? | 6636? | 69523.81? |
13? | 0.752? | 28712? | 38167.17? |
14? | 0.208? | 10984? | 52727.27? |
15? | 0.096? | 795? | 8203.12? |
16? | 0.946? | 18939? | 20000.00? |
17? | 0.211? | 3409? | 16129.03? |
18? | 0.304? | 3378? | 11094.52? |
19? | 0.0655? | 6318? | 96416.18? |
20? | 0.34? | 8560? | 25111.11? |
21? | 270? | 454? | 1.68? |
22? | 93.18? | 217? | 2.33? |
23? | 5.87? | 19393? | 3303.23? |
26? | 1.31? | 2587? | 1963.21? |
27? | 0.31? | 2590? | 8142.85? |
28? | 13.33? | 6242? | 468.18? |
29? | 12.57? | 1840? | 146.38? |
30? | 1.00? | 1128? | 1128? |
Adefovir | 0.517? | 540? | 1044.48? |
A.EC
50: medium effective concentration b.CC
50: half cytotoxicity concentration c .SI: effect selectivity index (CC
50/ EC
50)
Similar or more excellent to the two pivalates of positive control Adefovir in anti-HBV activity and effect selectivity index by table-2 claimed compounds of the present invention as can be known, this illustrates that they have the better therapeutic index.
Claims (7)
2. according to acceptable salt on the purine compounds double amino acid ester of claim 1 and the pharmacology thereof, it is characterized in that acceptable salt is selected from following compound on described purine compounds double amino acid ester and the pharmacology thereof:
(1) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(2) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-acetoxyl group) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(3) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl base sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(4) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-phenyl propionyl sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(5) (2S, 2 ' S)-9-{2-[O, O '-two [(1-tertbutyloxycarbonyl-2-Pyrrolizidine base formyl radical sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(6) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(7) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(8) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(9) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(10) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(11) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(12) (2S, 2 ' S)-9-{2-[O, O '-two [(2-glycyl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(13) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl base sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(14) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-phenyl propionyl sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(15) (2S, 2 ' S)-9-{2-[O, O '-two [(2-Pyrrolizidine formyl radical sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(16) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(17) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyl group sulphur) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(18) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl oxygen base) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(19) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(20) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylpent acyloxy) methylene radical] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(21) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-methylbutyryl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(22) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-3-phenyl propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(23) (2S, 2 ' S)-9-{2-[O, O '-two [(1-tertbutyloxycarbonyl-2-Pyrrolizidine base methanoyl) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(24) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(25) (2S, 2 ' S)-9-{2-[O, O '-two [(2-t-butoxycarbonyl amino-4-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4;
(26) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-methylbutyryl oxygen base) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(27) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-3-phenyl propionyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(28) (2S, 2 ' S)-9-{2-[O, O '-two [(2-Pyrrolizidine base methanoyl) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(29) (2S, 2 ' S)-9-{2-[O, O '-two [(the amino propionyloxy of 2-) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride;
(30) (2S, 2 ' S)-9-{2-[O, O '-two [(2-amino-4-methylpent acyloxy) ethyl] phosphonium mesitoyl methoxy] ethyl } VITAMIN B4. tri hydrochloride.
3. according to acceptable salt on the purine compounds double amino acid ester of claim 1 and the pharmacology thereof, it is characterized in that acceptable salt is on the described pharmacology: the inorganic acid salt that this purine compounds double amino acid ester and hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid form; Organic acid salt with formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid or ethyl sulfonic acid formation; The acid salt that forms with the acidic amino acid of aspartic acid or L-glutamic acid; Or the salt that forms with the mineral alkali of sodium, potassium or calcium; Ammonium salt, methylamine salt, ethylamine salt, ethanolamine salt; Or the salt that forms with the basic aminoacids of Methionin, arginine, ornithine.
4. the method for acceptable salt on purine compounds double amino acid ester for preparing claim 1 and the pharmacology thereof may further comprise the steps:
(1) N-tertbutyloxycarbonyl L-amino acid and ethylene bromohyrin are in aprotic solvent, and at dicyclohexyl carbodiimide and N, there is reaction down in the N dimethylamine yl pyridines, obtains N-tertbutyloxycarbonyl L-amino acid bromo-ethyl ester; Or
N-tertbutyloxycarbonyl L-amino acid and isobutyl chloroformate, N-methylmorpholine and stink damp precursor reactant, obtain the amino thiocarboxylic acid of N-tertbutyloxycarbonyl L-, and then with 1, the 2-ethylene dibromide is in non-protonic solvent, reaction in the presence of highly basic obtains the amino thiocarboxylic acid of N-tertbutyloxycarbonyl L--2-bromo-ethyl ester;
Chloromethyl chlorsulfonic acid ester and N-tertbutyloxycarbonyl L-amino acid are in two-phase system, and reaction obtains the amino acid whose chloromethyl ester of N-tertbutyloxycarbonyl L-in the presence of the phase-transfer catalyst 4-n-butyl ammonium hydrogen sulfate;
(2) the amino carbothioic acid ester of various N-tertbutyloxycarbonyl L-amino acid esters or L-respectively with 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is in polar aprotic solvent, with N, N '-dicyclohexyl-4-morpholinyl-amidine or 1,8-diazabicyclo [5,4,0] undecane-7-alkene is alkali reaction, obtains product;
(3) above in the step (2) products therefrom in polarity or non-polar solvent, hydrogenchloride saturated 1,4-dioxane or Acetyl Chloride 98Min./methyl alcohol exists down that reaction obtains product;
(4) as required, according to ordinary method the product that obtains in the step (3) is prepared into acceptable salt on the corresponding pharmacology.
5. the method for acceptable salt on purine compounds double amino acid ester for preparing claim 1 and the pharmacology thereof may further comprise the steps:
(1) 9-[2-(phosphonium mesitoyl methoxy) ethyl] VITAMIN B4 is in inert solvent, at halogenating agent oxalyl chloride and catalyst n, there is reaction down in N '-diethylformamide, obtains 9-[2-(phosphonium mesitoyl methoxy) ethyl] the dichloro-phosphonic acid ester of VITAMIN B4;
(2) N-tertbutyloxycarbonyl L-amino acid and ethylene glycol are in aprotic solvent, and at dicyclohexyl carbodiimide and N, there is reaction down in the N dimethylamine yl pyridines, obtains N-tertbutyloxycarbonyl L-amino acid-hydroxyethyl ester;
(3) 9-[2-(phosphonium mesitoyl methoxy) ethyl] the dichloro-phosphonic acid ester of VITAMIN B4 and N-tertbutyloxycarbonyl L-amino acid-hydroxyethyl ester are in inert solvent, and reaction obtains product in the presence of pyridine and triethylamine;
(4) product that obtains in the step (3) is in polarity or non-polar solvent, hydrogenchloride saturated 1,4-dioxane or Acetyl Chloride 98Min./methyl alcohol exists down that reaction obtains corresponding compounds;
(5) as required, according to ordinary method the product that obtains in the top step is prepared into acceptable salt on the corresponding pharmacology.
6. pharmaceutical composition, comprise at least aly as acceptable salt on each described purine compounds double amino acid ester and the pharmacology thereof in the claim 1 to 3 of effective constituent, described compound is in conjunction with acceptable vehicle or carrier at least a pharmacology.
7. be used for the treatment of application in the medicine of the infectious diseases that causes by hepatitis B virus according to the pharmaceutical composition of claim 6 in preparation.
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US5627165A (en) * | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
WO1997030051A1 (en) * | 1996-02-16 | 1997-08-21 | Medivir Ab | Acyclic nucleoside derivatives |
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US5627165A (en) * | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
WO1997030051A1 (en) * | 1996-02-16 | 1997-08-21 | Medivir Ab | Acyclic nucleoside derivatives |
Non-Patent Citations (1)
Title |
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Carlo Ballatore,et al.Synthesis and Evaluation of Novel Amidate Prodrugs of PMEA and PMPA.《Bioorganic & Medicinal Chemistry Letters》.2001,第11卷1053-1056. * |
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