JP2000500444A - 3−フェニル−1−メチレンジオキシフェニル−インダン−2−カルボン酸誘導体の製造プロセス - Google Patents
3−フェニル−1−メチレンジオキシフェニル−インダン−2−カルボン酸誘導体の製造プロセスInfo
- Publication number
- JP2000500444A JP2000500444A JP9518416A JP51841697A JP2000500444A JP 2000500444 A JP2000500444 A JP 2000500444A JP 9518416 A JP9518416 A JP 9518416A JP 51841697 A JP51841697 A JP 51841697A JP 2000500444 A JP2000500444 A JP 2000500444A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- product
- defined above
- reacting
- 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.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims description 27
- 230000008569 process Effects 0.000 title claims description 17
- RAEQPWKIDMNAFS-UHFFFAOYSA-N 1-(7-phenyl-7ah-1,3-benzodioxol-3a-yl)-2,3-dihydro-1h-indene-2-carboxylic acid Chemical class OC(=O)C1CC2=CC=CC=C2C1C1(C=CC=2)OCOC1C=2C1=CC=CC=C1 RAEQPWKIDMNAFS-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 199
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 239000000047 product Substances 0.000 claims description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 125000004432 carbon atom Chemical group C* 0.000 claims description 38
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 32
- 229910052794 bromium Inorganic materials 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 238000007127 saponification reaction Methods 0.000 claims description 9
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 7
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 7
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000006345 epimerization reaction Methods 0.000 claims description 5
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 5
- KLRLIDQAFFVFCV-UHFFFAOYSA-M magnesium;5h-1,3-benzodioxol-5-ide;bromide Chemical compound [Mg+2].[Br-].C1=[C-]C=C2OCOC2=C1 KLRLIDQAFFVFCV-UHFFFAOYSA-M 0.000 claims description 3
- 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 claims description 2
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 8
- 230000002378 acidificating effect Effects 0.000 claims 6
- 150000004699 copper complex Chemical class 0.000 claims 6
- 239000012467 final product Substances 0.000 claims 6
- 229910052763 palladium Inorganic materials 0.000 claims 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 2
- 150000004682 monohydrates Chemical class 0.000 claims 2
- 238000010626 work up procedure Methods 0.000 claims 2
- OMMGAHDTAKZKRS-UHFFFAOYSA-N [Mg]C1=CC=C2OCOC2=C1 Chemical compound [Mg]C1=CC=C2OCOC2=C1 OMMGAHDTAKZKRS-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 33
- JBQMFBWTKWOSQX-UHFFFAOYSA-N 2,3-dihydro-1h-indene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)CCC2=C1 JBQMFBWTKWOSQX-UHFFFAOYSA-N 0.000 abstract description 26
- 150000003222 pyridines Chemical class 0.000 abstract description 23
- 125000003118 aryl group Chemical group 0.000 abstract description 7
- UUAVCCWBNUITBB-UPRLRBBYSA-N (1s,2r,3s)-1-(1,3-benzodioxol-5-yl)-3-[2-(carboxymethoxy)-4-methoxyphenyl]-5-propoxy-2,3-dihydro-1h-indene-2-carboxylic acid Chemical compound C1([C@H]2[C@@H]([C@H](C3=CC=C(C=C32)OCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1OCC(O)=O UUAVCCWBNUITBB-UPRLRBBYSA-N 0.000 abstract description 2
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract 1
- GLCKXJLCYIJMRB-UPRLRBBYSA-N enrasentan Chemical compound C1([C@H]2[C@@H]([C@H](C3=CC=C(C=C32)OCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1OCCO GLCKXJLCYIJMRB-UPRLRBBYSA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- -1 (+) (1S, 2R, 3S) -3- [2- (2-Hydroxyethyl-1-yloxy) -4-methoxyphenyl] -1- (3 , 4-Methylenedioxyphenyl) -5- (prop-1-yloxy) indane -2-carboxylic acid Chemical class 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 230000002194 synthesizing effect Effects 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000007858 starting material Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- XUDCMQBOWOLYCF-UHFFFAOYSA-N 2,3-dihydro-1h-indene-2-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)CC2=C1 XUDCMQBOWOLYCF-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 150000001940 cyclopentanes Chemical class 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 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
- 239000012141 concentrate Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N dimethylsulfide Substances CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- KHGMUWBYGFWGCZ-UHFFFAOYSA-N 2-bromo-5-methoxyphenol Chemical class COC1=CC=C(Br)C(O)=C1 KHGMUWBYGFWGCZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical class C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 239000000138 intercalating agent Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- CLWAXFZCVYJLLM-UHFFFAOYSA-N 1-chlorohexadecane Chemical compound CCCCCCCCCCCCCCCCCl CLWAXFZCVYJLLM-UHFFFAOYSA-N 0.000 description 1
- FQYHNQZECWZUON-UHFFFAOYSA-N 1-propoxy-2,3-dihydro-1h-indene-2-carboxylic acid Chemical compound C1=CC=C2C(OCCC)C(C(O)=O)CC2=C1 FQYHNQZECWZUON-UHFFFAOYSA-N 0.000 description 1
- MWGATWIBSKHFMR-UHFFFAOYSA-N 2-anilinoethanol Chemical compound OCCNC1=CC=CC=C1 MWGATWIBSKHFMR-UHFFFAOYSA-N 0.000 description 1
- IJFXRHURBJZNAO-UHFFFAOYSA-M 3-hydroxybenzoate Chemical compound OC1=CC=CC(C([O-])=O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-M 0.000 description 1
- WTQIZFCJMGWUGZ-UHFFFAOYSA-N 5-methyl-2-(2-phenylpropan-2-yl)cyclohexan-1-ol Chemical compound OC1CC(C)CCC1C(C)(C)C1=CC=CC=C1 WTQIZFCJMGWUGZ-UHFFFAOYSA-N 0.000 description 1
- QGOISSZAFDUIJP-UHFFFAOYSA-N 5-propoxy-2,3-dihydro-1h-indene-2-carboxylic acid Chemical compound CCCOC1=CC=C2CC(C(O)=O)CC2=C1 QGOISSZAFDUIJP-UHFFFAOYSA-N 0.000 description 1
- 101150108397 Abcd2 gene Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical class [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- BALXUFOVQVENIU-GNAZCLTHSA-N Ephedrine hydrochloride Chemical compound Cl.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GNAZCLTHSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000004789 Rosa xanthina Nutrition 0.000 description 1
- 241000109329 Rosa xanthina Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- NTHNFFZUMONUII-UHFFFAOYSA-L [Na+].[Na+].C(CC)OC1C(CC2=CC=CC=C12)C(=O)[O-].C(CC)OC1C(CC2=CC=CC=C12)C(=O)[O-] Chemical compound [Na+].[Na+].C(CC)OC1C(CC2=CC=CC=C12)C(=O)[O-].C(CC)OC1C(CC2=CC=CC=C12)C(=O)[O-] NTHNFFZUMONUII-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- PMHQVHHXPFUNSP-UHFFFAOYSA-M copper(1+);methylsulfanylmethane;bromide Chemical compound Br[Cu].CSC PMHQVHHXPFUNSP-UHFFFAOYSA-M 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- UWCHSDIUMBNDLT-UHFFFAOYSA-L copper;methylsulfanylmethane;dibromide Chemical compound CSC.Br[Cu]Br UWCHSDIUMBNDLT-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- QGFRSPMTVBPWNK-UHFFFAOYSA-N dilithium;oxygen(2-);hydrate Chemical compound [Li+].[Li+].O.[O-2] QGFRSPMTVBPWNK-UHFFFAOYSA-N 0.000 description 1
- XYSXGUSQSGEZTE-UHFFFAOYSA-L disodium;2,3-dihydro-1h-indene-2-carboxylate Chemical compound [Na+].[Na+].C1=CC=C2CC(C(=O)[O-])CC2=C1.C1=CC=C2CC(C(=O)[O-])CC2=C1 XYSXGUSQSGEZTE-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000010954 inorganic particle Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- FUJCRWPEOMXPAD-UHFFFAOYSA-N lithium oxide Chemical compound [Li+].[Li+].[O-2] FUJCRWPEOMXPAD-UHFFFAOYSA-N 0.000 description 1
- 229910001947 lithium oxide Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- WCNLCIJMFAJCPX-UHFFFAOYSA-N pethidine hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 WCNLCIJMFAJCPX-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C305/00—Esters of sulfuric acids
- C07C305/26—Halogenosulfates, i.e. monoesters of halogenosulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US634595P | 1995-11-08 | 1995-11-08 | |
| US60/006,345 | 1995-11-08 | ||
| PCT/US1996/018846 WO1997017342A1 (en) | 1995-11-08 | 1996-11-08 | A process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2000500444A true JP2000500444A (ja) | 2000-01-18 |
Family
ID=21720444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9518416A Ceased JP2000500444A (ja) | 1995-11-08 | 1996-11-08 | 3−フェニル−1−メチレンジオキシフェニル−インダン−2−カルボン酸誘導体の製造プロセス |
Country Status (22)
| Country | Link |
|---|---|
| US (3) | US6147232A (enExample) |
| EP (1) | EP0880518B1 (enExample) |
| JP (1) | JP2000500444A (enExample) |
| KR (1) | KR19990067376A (enExample) |
| CN (1) | CN1084742C (enExample) |
| AR (1) | AR005237A1 (enExample) |
| AT (1) | ATE236151T1 (enExample) |
| AU (1) | AU711450B2 (enExample) |
| BR (1) | BR9611540A (enExample) |
| CO (1) | CO4761056A1 (enExample) |
| CZ (1) | CZ141598A3 (enExample) |
| DE (1) | DE69627199T2 (enExample) |
| ES (1) | ES2191121T3 (enExample) |
| HU (1) | HUP9901985A2 (enExample) |
| IL (1) | IL124312A0 (enExample) |
| NO (1) | NO982090L (enExample) |
| NZ (1) | NZ323790A (enExample) |
| PL (1) | PL326699A1 (enExample) |
| TR (1) | TR199800839T2 (enExample) |
| TW (1) | TW466236B (enExample) |
| WO (1) | WO1997017342A1 (enExample) |
| ZA (1) | ZA969408B (enExample) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU711936B2 (en) * | 1996-08-09 | 1999-10-28 | Banyu Pharmaceutical Co., Ltd. | Stereoselective deoxygenation reaction |
| US20060281723A1 (en) * | 1999-04-16 | 2006-12-14 | Kafrissen Michael E | Folic acid-containing pharmaceutical compositions, and related methods and delivery systems |
| CN102887808B (zh) * | 2012-10-26 | 2014-12-10 | 华东师范大学 | 一种多取代茚醇衍生物的制备方法 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3997540A (en) * | 1975-07-21 | 1976-12-14 | Burroughs Wellcome Co. | O [(O-piperazinocarbonyl-phenyl)-thio]-benzoates |
| US4073912A (en) * | 1976-10-12 | 1978-02-14 | Smithkline Corporation | Piperidylidene derivatives of benzo-fused xanthenes, thioxanthenes and dibenzoxepins and antipsychotic use thereof |
| EP0612244B1 (en) * | 1991-11-05 | 2001-09-19 | Smithkline Beecham Corporation | Endothelin receptor antagonists |
| US5389620A (en) * | 1993-08-18 | 1995-02-14 | Banyu Pharmaceutical Co., Ltd. | Endothelin antagonistic heteroaromatic ring-fused cyclopentene derivatives |
| ZA969363B (en) * | 1995-11-08 | 1997-11-18 | Smithkline Beecham Corp | An improved process for preparing aromatic ring-fused cyclopentane derivatives. |
| AU1054297A (en) * | 1995-11-08 | 1997-05-29 | Smithkline Beecham Corporation | A process of making 3-phenyl-1-methylenedioxyphenyl-indane-2-carboxylic acid derivatives |
| US6022972A (en) * | 1997-08-08 | 2000-02-08 | Merck & Co., Inc. | Pyridine propanoic acid derivatives |
| US6172231B1 (en) * | 1998-04-09 | 2001-01-09 | Merck & Co., Inc. | Oxidation process using periodic acid |
| US6031101A (en) * | 1998-04-09 | 2000-02-29 | Merck & Co., Inc. | Oxidation process using tempo |
-
1996
- 1996-11-08 TR TR1998/00839T patent/TR199800839T2/xx unknown
- 1996-11-08 HU HU9901985A patent/HUP9901985A2/hu unknown
- 1996-11-08 CO CO96059112A patent/CO4761056A1/es unknown
- 1996-11-08 DE DE69627199T patent/DE69627199T2/de not_active Expired - Fee Related
- 1996-11-08 CN CN96199421A patent/CN1084742C/zh not_active Expired - Fee Related
- 1996-11-08 NZ NZ323790A patent/NZ323790A/en unknown
- 1996-11-08 ZA ZA969408A patent/ZA969408B/xx unknown
- 1996-11-08 KR KR1019980703386A patent/KR19990067376A/ko not_active Ceased
- 1996-11-08 CZ CZ981415A patent/CZ141598A3/cs unknown
- 1996-11-08 ES ES96940864T patent/ES2191121T3/es not_active Expired - Lifetime
- 1996-11-08 AU AU10820/97A patent/AU711450B2/en not_active Ceased
- 1996-11-08 AR ARP960105121A patent/AR005237A1/es unknown
- 1996-11-08 WO PCT/US1996/018846 patent/WO1997017342A1/en not_active Ceased
- 1996-11-08 EP EP96940864A patent/EP0880518B1/en not_active Expired - Lifetime
- 1996-11-08 AT AT96940864T patent/ATE236151T1/de not_active IP Right Cessation
- 1996-11-08 IL IL12431296A patent/IL124312A0/xx unknown
- 1996-11-08 JP JP9518416A patent/JP2000500444A/ja not_active Ceased
- 1996-11-08 PL PL96326699A patent/PL326699A1/xx unknown
- 1996-11-08 BR BR9611540A patent/BR9611540A/pt not_active Application Discontinuation
- 1996-11-08 US US09/068,581 patent/US6147232A/en not_active Expired - Fee Related
-
1997
- 1997-01-23 TW TW086100704A patent/TW466236B/zh not_active IP Right Cessation
-
1998
- 1998-05-07 NO NO982090A patent/NO982090L/no unknown
-
2000
- 2000-03-08 US US09/521,172 patent/US6288247B1/en not_active Expired - Fee Related
-
2001
- 2001-09-10 US US09/949,577 patent/US6479659B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1084742C (zh) | 2002-05-15 |
| EP0880518A1 (en) | 1998-12-02 |
| DE69627199T2 (de) | 2004-01-29 |
| ZA969408B (en) | 1997-06-10 |
| CZ141598A3 (cs) | 1998-11-11 |
| NZ323790A (en) | 2000-02-28 |
| IL124312A0 (en) | 1998-12-06 |
| BR9611540A (pt) | 1999-03-02 |
| US20020087011A1 (en) | 2002-07-04 |
| NO982090L (no) | 1998-07-07 |
| AU711450B2 (en) | 1999-10-14 |
| MX9803646A (es) | 1998-10-31 |
| CO4761056A1 (es) | 1999-04-27 |
| PL326699A1 (en) | 1998-10-26 |
| KR19990067376A (ko) | 1999-08-16 |
| ATE236151T1 (de) | 2003-04-15 |
| EP0880518B1 (en) | 2003-04-02 |
| DE69627199D1 (de) | 2003-05-08 |
| WO1997017342A1 (en) | 1997-05-15 |
| US6479659B2 (en) | 2002-11-12 |
| TW466236B (en) | 2001-12-01 |
| HK1016588A1 (en) | 1999-11-05 |
| EP0880518A4 (en) | 1999-07-28 |
| HUP9901985A2 (hu) | 1999-09-28 |
| CN1206415A (zh) | 1999-01-27 |
| US6147232A (en) | 2000-11-14 |
| ES2191121T3 (es) | 2003-09-01 |
| AR005237A1 (es) | 1999-04-28 |
| US6288247B1 (en) | 2001-09-11 |
| NO982090D0 (no) | 1998-05-07 |
| AU1082097A (en) | 1997-05-29 |
| TR199800839T2 (enExample) | 1998-08-21 |
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