US20100305364A1 - Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate - Google Patents
Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate Download PDFInfo
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- US20100305364A1 US20100305364A1 US12/853,440 US85344010A US2010305364A1 US 20100305364 A1 US20100305364 A1 US 20100305364A1 US 85344010 A US85344010 A US 85344010A US 2010305364 A1 US2010305364 A1 US 2010305364A1
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- HHZZOQSDZBZQFK-UHFFFAOYSA-N [1-[di(propan-2-yloxy)phosphorylmethoxy]cyclopropyl]methanol Chemical compound CC(C)OP(=O)(OC(C)C)COC1(CO)CC1 HHZZOQSDZBZQFK-UHFFFAOYSA-N 0.000 title abstract description 19
- 238000004519 manufacturing process Methods 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 239000000543 intermediate Substances 0.000 abstract description 10
- 229940127073 nucleoside analogue Drugs 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 230000000840 anti-viral effect Effects 0.000 abstract description 4
- 241000700721 Hepatitis B virus Species 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- ZANNOFHADGWOLI-UHFFFAOYSA-N ethyl 2-hydroxyacetate Chemical compound CCOC(=O)CO ZANNOFHADGWOLI-UHFFFAOYSA-N 0.000 description 7
- QJTROUHNWPQATP-UHFFFAOYSA-N 1-(trityloxymethyl)cyclopropan-1-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OCC1(O)CC1 QJTROUHNWPQATP-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- KLPTYUXPTXPKDQ-UHFFFAOYSA-N [[1-[di(propan-2-yloxy)phosphorylmethoxy]cyclopropyl]methoxy-diphenylmethyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OCC1(OCP(=O)(OC(C)C)OC(C)C)CC1 KLPTYUXPTXPKDQ-UHFFFAOYSA-N 0.000 description 5
- -1 cyclopropyl alcohol compound Chemical class 0.000 description 5
- KOMSQTMQKWSQDW-UHFFFAOYSA-N ethyl 5-methyl-1,2-oxazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NOC=1C KOMSQTMQKWSQDW-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 0 *CC1(OCP(=O)(OC(C)C)OC(C)C)CC1 Chemical compound *CC1(OCP(=O)(OC(C)C)OC(C)C)CC1 0.000 description 1
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- XMRMBJKJUHEXCT-UHFFFAOYSA-N C.CCOC(=O)CC Chemical compound C.CCOC(=O)CC XMRMBJKJUHEXCT-UHFFFAOYSA-N 0.000 description 1
- WWGXLBKEHHXCGH-UHFFFAOYSA-N C1CCOC1.CC(C)(C)[Si](OCC1(O)CC1)(C1=CC=CC=C1)C1=CC=CC=C1.CC(C)OP(=O)(COC1(CO)CC1)OC(C)C.CC(C)OP(=O)(COC1(CO[Si](C2=CC=CC=C2)(C2=CC=CC=C2)C(C)(C)C)CC1)OC(C)C.CCOC(=O)CO.CCOC(=O)CO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C.CO.F.N Chemical compound C1CCOC1.CC(C)(C)[Si](OCC1(O)CC1)(C1=CC=CC=C1)C1=CC=CC=C1.CC(C)OP(=O)(COC1(CO)CC1)OC(C)C.CC(C)OP(=O)(COC1(CO[Si](C2=CC=CC=C2)(C2=CC=CC=C2)C(C)(C)C)CC1)OC(C)C.CCOC(=O)CO.CCOC(=O)CO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C.CO.F.N WWGXLBKEHHXCGH-UHFFFAOYSA-N 0.000 description 1
- LUEHUNRAXTYSTP-UHFFFAOYSA-N C1CCOC1.CC(C)OP(=O)(COC1(CO)CC1)OC(C)C.CCC1(O)CC1.CCC1(OCP(=O)(OC(C)C)OC(C)C)CC1.CCOC(=O)CC.CCOC(=O)CO Chemical compound C1CCOC1.CC(C)OP(=O)(COC1(CO)CC1)OC(C)C.CCC1(O)CC1.CCC1(OCP(=O)(OC(C)C)OC(C)C)CC1.CCOC(=O)CC.CCOC(=O)CO LUEHUNRAXTYSTP-UHFFFAOYSA-N 0.000 description 1
- JLKJXDOWBVVABZ-UHFFFAOYSA-N CC(C)(C)C(=O)OCOP(=O)(COC1(CN2C=NC3=C2N=C(N)N=C3)CC1)OCOC(=O)C(C)(C)C Chemical compound CC(C)(C)C(=O)OCOP(=O)(COC1(CN2C=NC3=C2N=C(N)N=C3)CC1)OCOC(=O)C(C)(C)C JLKJXDOWBVVABZ-UHFFFAOYSA-N 0.000 description 1
- AFWWNHLDHNSVSD-UHFFFAOYSA-N CC1=C2N=CNC2=NC(N)=N1 Chemical compound CC1=C2N=CNC2=NC(N)=N1 AFWWNHLDHNSVSD-UHFFFAOYSA-N 0.000 description 1
- WAVXBPQEVHGKPB-UHFFFAOYSA-N CC1=NC(N)=NC2=C1N=CN2CC1(OCP(=O)(O)O)CC1 Chemical compound CC1=NC(N)=NC2=C1N=CN2CC1(OCP(=O)(O)O)CC1 WAVXBPQEVHGKPB-UHFFFAOYSA-N 0.000 description 1
- DHJJMKFTVYRUSG-UHFFFAOYSA-N CC1=NC(N)=NC2=C1N=CN2CC1(OCP(=O)(OC(C)C)OC(C)C)CC1 Chemical compound CC1=NC(N)=NC2=C1N=CN2CC1(OCP(=O)(OC(C)C)OC(C)C)CC1 DHJJMKFTVYRUSG-UHFFFAOYSA-N 0.000 description 1
- CXYUCHDVLWUDNS-UHFFFAOYSA-N CCC1(C)CC1 Chemical compound CCC1(C)CC1 CXYUCHDVLWUDNS-UHFFFAOYSA-N 0.000 description 1
- 238000006129 Kulinkovich cyclopropane synthesis reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
-
- 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
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Definitions
- the present invention relates to a new process for preparing a compound of the following formula (2):
- the present invention also relates to new intermediates, and a process for preparing the compound of formula (1) [compound (1), below] from the compound of formula (2) [compound (2), below] prepared according to the present invention.
- the compound (1) is a therapeutic agent against hepatitis B (Korean Patent Application No. 2002-0003051, WO 02/057288), and the compound (2) can be used as an important reactant together with a compound of the following formula (3):
- X represents fluorine, chlorine, bromine, or iodine, for preparing the compound (1).
- Such purine derivatives as the compound (1) are known to have anticancer and antiviral activities, and ten (10) or more kinds of such derivatives including AZT, 3TC, ACV, etc. are already commercially available.
- the present inventors thus extensively studied to improve the process for preparing the compound (2), and as a result found that the problems of the earlier process as mentioned above can be overcome by use of trityl chloride instead of t-butyl(diphenyl)silyl chloride as a reactant to give the compound (2) in high purity.
- the inventors also found that the compound (1) can be obtained in high yield by use of highly pure compound (2) thus obtained, and then completed the present invention.
- an object of the present invention is to provide a new process for preparing the compound (2).
- the present invention provides a process for preparing the compound (2) comprising the steps of reacting the compound of formula (4) with trityl chloride to prepare trityloxy-acetic acid ethyl ester of the following formula (8):
- N-methylpyrrolidone can be more preferably selected as a solvent for the combination step of the cyclopropyloxy group of formula (9) with the phosphonate group to give the compound (2) in better yield and purity.
- X represents fluorine, chlorine, bromine, or iodine.
- the preferable amount of each reactant and reaction conditions including reaction temperature and purification process may be specifically explained below.
- NMP N-methyl pyrrolidone
- ethyl magnesium halide preferably, ethyl magnesium chloride or ethyl magnesium bromide
- Kulinkovich reaction J. Am. Chem. Soc., 1995, 117, 9919-9920
- aqueous citric acid solution is added thereto, and the reaction mixture is stirred and extracted to give the compound of formula (9).
- the compound of formula (9) is dissolved in a solvent, particularly preferably in NMP, 1.3 ⁇ 1.7 equiv. of DBMP and 1.5 ⁇ 2.0 equiv.
- the compound of formula (10) thus obtained is converted into a solid form by treatment with heptane under a low temperature.
- To the compound of formula (10) are added 1.5 ⁇ 2.5 equiv. of TFA and 0.1 ⁇ 0.5 ml/g of H 2 O, and the mixture is stirred at room temperature.
- an acid-base treatment filtration of thus produced solid, and extraction give the compound (2).
- the acid-base treatment is carried out with sodium hydroxide, and the extraction with methylene chloride.
- the process of the present invention produces the compound (2) in high purity running into 98 to 100%.
- the compounds of formulae (9) and (10) obtained as intermediates for the process of the present invention are themselves novel compounds. Therefore, the present invention further provides these novel intermediate compounds.
- the compound (2) prepared by the above process is a key intermediate for synthesizing the nucleoside analogue of formula (1) as mentioned above.
- the compound (1) can be prepared by a process comprising the steps of introducing a leaving group into the compound (2) to prepare a compound of the following formula (11):
- L represents a leaving group, preferably, methanesulfonyloxy, para-toluenesulfonyloxy, or halogen
- the present invention provides a process for preparing the compound (1) from the compound (2) prepared by a process depicted in Reaction Scheme 2.
- Trityl chloride (279 g, 1.0 mol) was dissolved in EDC (680 ml, 5 ml/g with respect to ethyl glycolate), and ethyl glycolate (135 g, 1.3 mol) was added to the mixture. Pyridine (99 g, 1.25 mol) was added thereto, and the mixture was stirred for 19 hours at 40° C. After completion of the reaction was confirmed by HPLC, 0.5 N aqueous hydrochloric acid solution (270 ml, 2 ml/g with respect to ethyl glycolate) was added to make the reaction solution a two-phase solution, which was then extracted. After the extraction was performed once again, EDC was distilled under reduced pressure. In order to obtain the compound of formula (8) as a solid form, hexane (680 ml) was added to the concentrated compound, the temperature was lowered to 0° C., and the mixture was stirred for about 3 hours and filtered.
- TrCl TrCl Compound (8) RT: 5.38 8.58 Area %: 2.39 83.93
- Tetrahydrofuran [1040 ml, 3 ml/g with respect to the compound of formula (8)] was added to the compound of formula (8) prepared in Example 1 on the premise that the yield of Example 1 is 100%, and the mixture was cooled to 0° C. Titanium tetraisopropoxide (113.8 g, 0.4 mol) was added thereto, and ethyl magnesium bromide (1500 ml, 3.0 mol, 1 M concentration) was added thereto dropwise at 5 ⁇ 15° C. over 3 ⁇ 6 hours.
- TrOH TrOH Compound (9) RT: 5.40 6.23 Area %: 5.07 78.54
- the compound of formula (10) obtained in Example 3 (59.15 g, 116.3 mmol) was dissolved in acetone [59.2 ml, 1 ml/g with respect to the compound of formula (10)], H 2 O (5.9 ml, 327.8 mmol) and TFA (26.52 g, 232.6 mmol) were added, and the mixture was stirred at room temperature. After the portion of the compound of formula (10) was confirmed 7% or less by HPLC, 3N aqueous NaOH solution [75 ml, 2.6 ml/g with respect to the compound of formula (10)] was added thereto, and acetone was removed therefrom by distillation under reduced pressure.
- the intermediate compound of formula (10) can be obtained as a solid, which solves the problem of the prior art that diisopropylbromomethyl phosphonate is not removed but retained in the compound (2) to lower the purity thereof.
- N-methylpyrrolidone is selected instead of dimethylformamide as a solvent for preparing the compound of formula (10)
- stability of the compound of formula (9) against lithium t-butoxide is highly improved to affect the purity and yield of the compound (2) in a favorable manner.
- the compound (1) useful as an antiviral agent can be advantageously prepared with high yield by using the highly pure compound (2) obtained according to the present invention.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention relates to a new process for preparing diisopropyl {[1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate (2), which is a key intermediate for synthesizing an antiviral (particularly, against hepatitis B virus) nucleoside analogue. The present invention also relates to new intermediates, and a process for preparing the antiviral nucleoside analogue from the compound (2) prepared according to the present invention.
Description
- This application is a Divisional of co-pending application Ser. No. 11/631,263 filed on Dec. 29, 2006 and for which priority is claimed under 35 U.S.C. §120. Application Ser. No. 11/631,263 is the national phase of PCT International Application No. PCT/KR05/002007 filed on Jun. 27, 2005 under 35 U.S.C. §371. This application also claims priority under 35 U.S.C. §119 to Application No. 10-2004-0051558, filed on Jul. 2, 2004 in the Republic of Korea. The entire contents of each of the above-identified applications are hereby incorporated by reference.
- The present invention relates to a new process for preparing a compound of the following formula (2):
- which is a key intermediate for synthesizing an antiviral (particularly, against hepatitis B virus) nucleoside analogue of the following formula (1):
- The present invention also relates to new intermediates, and a process for preparing the compound of formula (1) [compound (1), below] from the compound of formula (2) [compound (2), below] prepared according to the present invention.
- The compound (1) is a therapeutic agent against hepatitis B (Korean Patent Application No. 2002-0003051, WO 02/057288), and the compound (2) can be used as an important reactant together with a compound of the following formula (3):
- in which X represents fluorine, chlorine, bromine, or iodine, for preparing the compound (1).
- Such purine derivatives as the compound (1) are known to have anticancer and antiviral activities, and ten (10) or more kinds of such derivatives including AZT, 3TC, ACV, etc. are already commercially available.
- The compound (2) used as an important intermediate for preparing the compound (1) has been prepared according to the process depicted in the following Reaction Scheme 1:
- The above process of Scheme 1 uses ethyl glycolate of the following formula (4):
- as a starting material.
- In the process of Scheme 1, ethyl glycolate of formula (4) is combined with t-butyl(diphenyl)silyl chloride to give the compound of formula (5), which is reacted with ethyl magnesium bromide and titanium tetraisopropoxide according to the process (Syn. Lett, 07, 1053-1054, 1999) known in the art to give the cyclopropyl alcohol compound of formula (6), which is then obtained as a solid from heptane. Thus obtained compound of formula (6) is dissolved in dimethylformamide and reacted with lithium t-butoxide and diisopropylbromomethyl phosphonate to give the compound of formula (7). This compound of formula (7) is refluxed with ammonium fluoride in methanol to give the compound (2).
- The above process, however, has the demerit of giving an impure form of compound (2) because diisopropylbromomethyl phosphonate used in the step of synthesizing the compound of formula (7) is remained in the reaction solution, and so always included in the finally obtained compound (2) in an amount of 7˜15%. Further, poor stability of the compound of formula (6) against lithium t-butoxide during the step of synthesizing the compound of formula (7) are responsible for varied yield and difficult handling.
- Therefore, it has been desired for those skilled in the art to raise purity of the compound (2) and to improve stability of the compound of formula (6) during synthesis of the compound of formula (7).
- The present inventors thus extensively studied to improve the process for preparing the compound (2), and as a result found that the problems of the earlier process as mentioned above can be overcome by use of trityl chloride instead of t-butyl(diphenyl)silyl chloride as a reactant to give the compound (2) in high purity. The inventors also found that the compound (1) can be obtained in high yield by use of highly pure compound (2) thus obtained, and then completed the present invention.
- Therefore, an object of the present invention is to provide a new process for preparing the compound (2).
- It is another object of the present invention to provide new intermediates obtained during the process of preparing the compound (2).
- It is a further object of the present invention to provide a process for preparing the nucleoside analogue of formula (1) useful as an antiviral agent using the compound (2) obtained by the process according to the present invention.
- The present invention provides a process for preparing the compound (2) comprising the steps of reacting the compound of formula (4) with trityl chloride to prepare trityloxy-acetic acid ethyl ester of the following formula (8):
- reacting the compound of formula (8) with ethyl magnesium halide to prepare 1-trityloxymethyl-cyclopropanol of the following formula (9):
- combining the 1-trityloxymethyl-cyclopropanol of formula (9) with diisopropylbromo-methylphosphonate in a solvent in the presence of a base to prepare (1-trityloxymethyl-cyclopropoxymethyl)-phosphonic acid diisopropyl ester of the following formula (10):
- as a solid form, and converting the trityl group of the compound of formula (10) into hydroxyl group.
- When carrying out the process of the present invention, N-methylpyrrolidone (NMP) can be more preferably selected as a solvent for the combination step of the cyclopropyloxy group of formula (9) with the phosphonate group to give the compound (2) in better yield and purity.
- The process of the present invention can be depicted as the following Reaction Scheme 2.
- in which X represents fluorine, chlorine, bromine, or iodine.
- The preferable amount of each reactant and reaction conditions including reaction temperature and purification process may be specifically explained below.
- First, the abbreviations used in the present specification are defined as follows:
- Tr: Trityl
- Et: Ethyl
- EDC: 1,2-Dichloro ethane
- THF: Tetrahydrofuran
- EA: Ethyl acetate
- iPr: Isopropyl
- LTB: Lithium t-butoxide
- NMP: N-methyl pyrrolidone
- DBMP: Diisopropylbromomethyl phosphonate
- MTBE: Methyl t-butyl ether
- TFA: Trifluoroacetic acid
- MDC: Methylene chloride
- AN: Acetonitrile
- Min: Minute
- In the first reaction step of ethyl glycolate of formula (4) with trityl chloride, 1.0 equiv. of trityl chloride (TrCl) and 1˜1.3 equiv. of pyridine are added to 1.0˜1.5 equiv. of the compound of formula (4), and the mixture is stirred in the presence of EDC at about 30˜60° C. After the stirring, an acid-base treatment to the mixture gives the compound of formula (8), which is then treated with hexane to be converted into a solid form, or used in the next reaction without further purification. To the compound of formula (8) are introduced 2.1˜3.1 equiv. of ethyl magnesium halide, preferably, ethyl magnesium chloride or ethyl magnesium bromide, and 0.2˜0.6 equiv. of titanium tetraisopropoxide, and Kulinkovich reaction (J. Am. Chem. Soc., 1995, 117, 9919-9920) is performed at 5˜15° C. Then, aqueous citric acid solution is added thereto, and the reaction mixture is stirred and extracted to give the compound of formula (9). The compound of formula (9) is dissolved in a solvent, particularly preferably in NMP, 1.3˜1.7 equiv. of DBMP and 1.5˜2.0 equiv. of LTB are added thereto, and the mixture is stirred over 6 to 19 hours under the condition of not exceeding 45° C. and subjected to an acid-base treatment to give the compound of formula (10). The compound of formula (10) thus obtained is converted into a solid form by treatment with heptane under a low temperature. To the compound of formula (10) are added 1.5˜2.5 equiv. of TFA and 0.1˜0.5 ml/g of H2O, and the mixture is stirred at room temperature. After the stirring, an acid-base treatment, filtration of thus produced solid, and extraction give the compound (2). Here, preferably, the acid-base treatment is carried out with sodium hydroxide, and the extraction with methylene chloride.
- The process of the present invention produces the compound (2) in high purity running into 98 to 100%.
- Also, the compounds of formulae (9) and (10) obtained as intermediates for the process of the present invention are themselves novel compounds. Therefore, the present invention further provides these novel intermediate compounds.
- The compound (2) prepared by the above process is a key intermediate for synthesizing the nucleoside analogue of formula (1) as mentioned above. Specifically, the compound (1) can be prepared by a process comprising the steps of introducing a leaving group into the compound (2) to prepare a compound of the following formula (11):
- in which L represents a leaving group, preferably, methanesulfonyloxy, para-toluenesulfonyloxy, or halogen, coupling the compound of formula (11) with the compound of formula (3) to prepare a compound of the following formula (12):
- in which X is defined as above, hydrolyzing the compound of formula (12) to prepare a compound of the following formula (13):
- in which X is defined as above, removing the group X from the compound of formula (13) and concurrently introducing t-butylcarbonyloxymethyl group into the phosphonic acid moiety.
- The detailed reaction conditions of the above process are described in the applicant's prior application (Korean Patent Application No. 2002-0003051, WO 02/057288). Therefore, the present invention provides a process for preparing the compound (1) from the compound (2) prepared by a process depicted in Reaction Scheme 2.
- The present invention will be more specifically explained by the following examples. However, it should be understood that these examples are intended to illustrate the present invention but not in any manner to limit the scope of the present invention.
- In the examples below, the HPLC conditions for determining the completion of reaction are as follows:
- [HPLC Conditions]
- Column: Capcell pak C18 (Type: MG 5 μm; Size: 4.6 mm I.D×250 mm)
- Wavelength (λ): 254 nm
- Flow rate: 1.0 ml/min
- Gradient condition: Start: 20/80 (H2O/AN, 0.1% TFA), 5 min: 20/80, 7 min: 0/100, 10 min: 0/100, 12 min: 20/80
- Trityl chloride (279 g, 1.0 mol) was dissolved in EDC (680 ml, 5 ml/g with respect to ethyl glycolate), and ethyl glycolate (135 g, 1.3 mol) was added to the mixture. Pyridine (99 g, 1.25 mol) was added thereto, and the mixture was stirred for 19 hours at 40° C. After completion of the reaction was confirmed by HPLC, 0.5 N aqueous hydrochloric acid solution (270 ml, 2 ml/g with respect to ethyl glycolate) was added to make the reaction solution a two-phase solution, which was then extracted. After the extraction was performed once again, EDC was distilled under reduced pressure. In order to obtain the compound of formula (8) as a solid form, hexane (680 ml) was added to the concentrated compound, the temperature was lowered to 0° C., and the mixture was stirred for about 3 hours and filtered.
- [HPLC]
-
Compound: TrCl Compound (8) RT: 5.38 8.58 Area %: 2.39 83.93 - 1H NMR (400 MHz, CDCl3) δ 1.23 (t, 3H, J=8 Hz), 3.78 (s, 2H), 4.14 (q, 2H, J=8 Hz), 7.26˜7.22 (m, 3H), 7.33˜7.29 (m, 6H), 7.50˜7.47 (m, 6H)
- 13C NMR (400 MHz, CDCl3) δ 10.8, 57.3, 59.3, 84.0, 123.9, 124.6, 125.3, 140.0, 166.7
- Tetrahydrofuran [1040 ml, 3 ml/g with respect to the compound of formula (8)] was added to the compound of formula (8) prepared in Example 1 on the premise that the yield of Example 1 is 100%, and the mixture was cooled to 0° C. Titanium tetraisopropoxide (113.8 g, 0.4 mol) was added thereto, and ethyl magnesium bromide (1500 ml, 3.0 mol, 1 M concentration) was added thereto dropwise at 5˜15° C. over 3˜6 hours. After completion of the reaction was confirmed by HPLC, 20% aqueous citric acid solution [1790 ml, 5 ml/g with respect to the compound of formula (8)] was added to the reaction solution under the condition of not exceeding 35° C., which was stirred for about 1 hour. After the stirring, tetrahydrofuran therein was distilled under reduced pressure, and the residue was extracted twice, first with 1390 ml [4 ml/g with respect to the compound of formula (8)] of ethyl acetate and second with 690 ml [2 ml/g with respect to the compound of formula (8)] of the same. Thus resulted organic layer was washed with saturated aqueous NaHCO3 solution [690 ml, 2 ml/g with respect to the compound of formula (8)], and concentrated under reduced pressure to give the title compound of formula (9).
- [HPLC]
-
Compound: TrOH Compound (9) RT: 5.40 6.23 Area %: 5.07 78.54 - 1H NMR (400 MHz, CDCl3) δ 0.45 (dd, 2H, J=8 Hz), 0.80 (dd, 2H, J=8 Hz), 2.59 (s, 1H), 3.18 (s, 2H), 7.23˜7.32 (m, 9H), 7.45˜7.47 (m, 6H)
- 13C NMR (400 MHz, CDCl3) δ 8.4, 51.9, 63.9, 83.0, 123.7, 124.6, 125.3, 140.5
- To the compound of formula (9) (261.25 g, 0.79 mol) obtained by concentration under reduced pressure in Example 2 (it was assumed that the compound of formula (9) was obtained in a yield of 79% starting from Example 1, since the peak area by HPLC was 78.54%) were added NMP [1050 ml, 4 ml/g with respect to the compound of formula (9)] and DBMP (307 g, 1.2 mol). To the reaction mixture was added LTB (107 g, 1.3 mol), which was then stirred under the condition of not exceeding 45° C. After about 6˜19 hours, completion of the reaction was confirmed by HPLC, and 14% aqueous NH4Cl solution [1830 ml, 7 ml/g with respect to the compound of formula (9)] was added thereto to stop the reaction. MTBE [first: 1050 ml, 4 ml/g with respect to the compound of formula (9); second: 520 ml, 2 ml/g with respect to the compound of formula (9)] was added thereto twice for phase-separation. Thus obtained organic layers were combined and washed with 21% aqueous NaCl solution [1650 ml, 6.3 ml/g with respect to the compound of formula (9)]. The remaining organic layer was concentrated under reduced pressure, and heptane [1300 ml, 5 ml/g with respect to the compound of formula (8)] was added thereto. The mixture was cooled to −10° C., and filtered after about 3 hours to give the title compound of formula (10) (586 g, Purity 96.23%, Yield 71.3%) as a solid.
- [HPLC]
-
Compound: TrOH Compound (9) Compound (10) RT: 5.24 6.02 9.26 Area %: 0.10 0.09 96.23 - [NMR] No other peaks were observed besides the peak for the compound of formula (10).
- 1H NMR (400 MHz, CDCl3) δ 0.54 (dd, 2H, J=8 Hz), 0.80 (dd, 2H, J=8 Hz), 1.33˜1.29 (m, 12H), 3.22 (s, 2H), 3.92 (d, 2H, J=8 Hz), 4.67˜4.76 (m, 2H), 7.21˜7.31 (m, 9H), 7.43˜7.46 (m, 6H)
- 13C NMR (400 MHz, CDCl3) δ 11.9, 24.4, 24.4, 24.5, 24.6, 63.5, 63.8, 64.0, 65.1, 67.3, 71.3, 71.4, 86.9, 127.4, 128.3, 129.1, 144.3
- The compound of formula (10) obtained in Example 3 (59.15 g, 116.3 mmol) was dissolved in acetone [59.2 ml, 1 ml/g with respect to the compound of formula (10)], H2O (5.9 ml, 327.8 mmol) and TFA (26.52 g, 232.6 mmol) were added, and the mixture was stirred at room temperature. After the portion of the compound of formula (10) was confirmed 7% or less by HPLC, 3N aqueous NaOH solution [75 ml, 2.6 ml/g with respect to the compound of formula (10)] was added thereto, and acetone was removed therefrom by distillation under reduced pressure. The solid produced during the reaction was filtered off, and the filtrate was extracted twice with methylene chloride [118.3 ml×2, 2 ml/g with respect to the compound of formula (10)]. Thus obtained organic layer was concentrated under reduced pressure to give the title compound (2) [31.71 g, Purity 98%, Yield with respect to the compound of formula (10) 102.4%].
- [HPLC]
-
Compound: TrOH Compound (10) RT: 5.14 9.20 Area %: 93.58 5.07 - [NMR] Only the peak for methylene chloride, the solvent, besides the peak for the compound (2) was observed.
- 1H NMR (400 MHz, DMSO) δ 0.55 (dd, 2H, j=8 Hz), 0.72 (dd, 2H, J=8 Hz), 1.22˜1.24 (m, 12H), 3.32 (s, 2H), 3.53 (d, 2H, J=4 Hz), 3.81 (d, 2H, J=8 Hz), 4.53˜4.72 (m, 2H), 4.73 (t, 1H)
- 13C NMR (400 MHz, DMSO) δ 7.44, 20.7, 20.75, 20.85, 20.88, 58.81, 60.47, 60.69, 61.62, 61.77, 67.12, 67.18
- As explained above, when trityl chloride is used according to the present invention, the intermediate compound of formula (10) can be obtained as a solid, which solves the problem of the prior art that diisopropylbromomethyl phosphonate is not removed but retained in the compound (2) to lower the purity thereof. Particularly, if N-methylpyrrolidone is selected instead of dimethylformamide as a solvent for preparing the compound of formula (10), stability of the compound of formula (9) against lithium t-butoxide is highly improved to affect the purity and yield of the compound (2) in a favorable manner. Also, the compound (1) useful as an antiviral agent can be advantageously prepared with high yield by using the highly pure compound (2) obtained according to the present invention.
Claims (1)
Priority Applications (1)
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US12/853,440 US20100305364A1 (en) | 2004-07-02 | 2010-08-10 | Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate |
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KR10-2004-0051558 | 2004-07-02 | ||
KR1020040051558A KR101033290B1 (en) | 2004-07-02 | 2004-07-02 | New process for preparing diisopropyl 1-hydroxymethyl-cyclopropyloxymethylphosphonate |
PCT/KR2005/002007 WO2006004330A1 (en) | 2004-07-02 | 2005-06-27 | Process for preparing di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate |
US63126307A | 2007-03-27 | 2007-03-27 | |
US12/853,440 US20100305364A1 (en) | 2004-07-02 | 2010-08-10 | Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate |
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PCT/KR2005/002007 Division WO2006004330A1 (en) | 2004-07-02 | 2005-06-27 | Process for preparing di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate |
US63126307A Division | 2004-07-02 | 2007-03-27 |
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US11/631,263 Expired - Fee Related US7795463B2 (en) | 2004-07-02 | 2005-06-27 | Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate |
US12/853,440 Abandoned US20100305364A1 (en) | 2004-07-02 | 2010-08-10 | Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate |
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CL2008000070A1 (en) * | 2007-01-17 | 2008-07-25 | Lg Life Sciences Ltd | MALEIC ACID MONOSAL (3 - [({1 - [(2-AMINO-9H-PURIN-9-IL) METHYL] CICLOPROPIL} OXI) METHYL] -8,8-DIMETHYL-3,7-DIOXO-2,4 , 6-TRIOXA-3 LAMBDA 5-PHOSPHANON-1-IL-PIVALATE; PHARMACEUTICAL COMPOSITION THAT INCLUDES THE SUCH MONOSAL; AND USE FOR THE TREATMENT OF VIRUS H |
CN106432330B (en) * | 2015-08-11 | 2019-02-01 | 天津科伦药物研究有限公司 | The midbody compound and its preparation method and application of LB80380 drug |
KR20180014903A (en) | 2016-08-01 | 2018-02-12 | 삼성디스플레이 주식회사 | Electronic device, mounting method of the same, and method of manufacturing display apparatus having the same |
CN108997429B (en) * | 2018-07-27 | 2020-10-30 | 广州粤美医药科技有限公司 | Method for preparing Beciclovir |
CN115181013B (en) * | 2022-07-22 | 2023-08-08 | 北京先通国际医药科技股份有限公司 | Preparation method and application of key intermediate of modified fatty acid type PET reagent precursor |
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2004
- 2004-07-02 KR KR1020040051558A patent/KR101033290B1/en active Protection Beyond IP Right Term
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2005
- 2005-06-27 RU RU2007104036/04A patent/RU2326885C1/en not_active IP Right Cessation
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- 2005-06-27 TW TW094121379A patent/TWI326685B/en not_active IP Right Cessation
- 2005-06-27 BR BRPI0512886-2A patent/BRPI0512886A/en not_active IP Right Cessation
- 2005-06-27 WO PCT/KR2005/002007 patent/WO2006004330A1/en active Application Filing
- 2005-06-27 EP EP05765985A patent/EP1765838A4/en not_active Withdrawn
- 2005-06-27 JP JP2007519120A patent/JP4422183B2/en active Active
- 2005-06-27 CA CA2571592A patent/CA2571592C/en not_active Expired - Fee Related
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- 2005-06-27 AU AU2005260375A patent/AU2005260375B8/en not_active Ceased
- 2005-06-27 US US11/631,263 patent/US7795463B2/en not_active Expired - Fee Related
- 2005-07-01 AR ARP050102748A patent/AR049566A1/en active IP Right Grant
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TW200606170A (en) | 2006-02-16 |
RU2007104036A (en) | 2008-08-10 |
CA2571592A1 (en) | 2006-01-12 |
AU2005260375A1 (en) | 2006-01-12 |
CN101061128B (en) | 2010-10-06 |
US20090187019A1 (en) | 2009-07-23 |
US7795463B2 (en) | 2010-09-14 |
TWI326685B (en) | 2010-07-01 |
NZ552246A (en) | 2009-07-31 |
ZA200610744B (en) | 2008-05-28 |
EP1765838A1 (en) | 2007-03-28 |
MXPA06015262A (en) | 2007-03-21 |
CA2571592C (en) | 2010-02-09 |
KR101033290B1 (en) | 2011-05-09 |
AU2005260375B8 (en) | 2011-01-20 |
BRPI0512886A (en) | 2008-04-15 |
JP2008505066A (en) | 2008-02-21 |
CN101061128A (en) | 2007-10-24 |
AU2005260375B2 (en) | 2010-12-09 |
AR049566A1 (en) | 2006-08-16 |
KR20060002501A (en) | 2006-01-09 |
WO2006004330A1 (en) | 2006-01-12 |
EP1765838A4 (en) | 2009-05-27 |
JP4422183B2 (en) | 2010-02-24 |
RU2326885C1 (en) | 2008-06-20 |
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