CN1237968A - 苯并噻吩类化合物的合成方法 - Google Patents
苯并噻吩类化合物的合成方法 Download PDFInfo
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- CN1237968A CN1237968A CN97199842A CN97199842A CN1237968A CN 1237968 A CN1237968 A CN 1237968A CN 97199842 A CN97199842 A CN 97199842A CN 97199842 A CN97199842 A CN 97199842A CN 1237968 A CN1237968 A CN 1237968A
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- compound
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- reaction
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- 238000000034 method Methods 0.000 title claims abstract description 25
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title abstract description 35
- 230000008569 process Effects 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 230000015572 biosynthetic process Effects 0.000 title description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
- -1 pyrrolidyl Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 19
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 7
- 238000010520 demethylation reaction Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 230000017858 demethylation Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical group BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000008707 rearrangement Effects 0.000 description 3
- 238000006462 rearrangement reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical class OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- QDAWXRKTSATEOP-UHFFFAOYSA-N 2-acetylbenzoic acid Chemical group CC(=O)C1=CC=CC=C1C(O)=O QDAWXRKTSATEOP-UHFFFAOYSA-N 0.000 description 1
- IVHKZCSZELZKSJ-UHFFFAOYSA-N 2-hydroxyethyl sulfonate Chemical compound OCCOS(=O)=O IVHKZCSZELZKSJ-UHFFFAOYSA-N 0.000 description 1
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical class CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical class CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KCFJAAFTSDUPIE-UHFFFAOYSA-N C(CCC)NCCOC1=CC=C(C(=O)C=2C3=C(SC2C2=CC=C(C=C2)O)C=CC(=C3)O)C=C1 Chemical compound C(CCC)NCCOC1=CC=C(C(=O)C=2C3=C(SC2C2=CC=C(C=C2)O)C=CC(=C3)O)C=C1 KCFJAAFTSDUPIE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- GVHFVTLDHBPKOF-UHFFFAOYSA-N [4-[2-(dimethylamino)ethoxy]phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(OCCN(C)C)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 GVHFVTLDHBPKOF-UHFFFAOYSA-N 0.000 description 1
- CRPBGTFXFYXYBH-UHFFFAOYSA-N [4-[2-(ethoxymethylamino)ethoxy]phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(OCCNCOCC)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 CRPBGTFXFYXYBH-UHFFFAOYSA-N 0.000 description 1
- SEPMRKANBJYIOT-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-[3-methyl-2-(methylamino)pentoxy]phenyl]methanone Chemical compound C1=CC(OCC(C(C)CC)NC)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 SEPMRKANBJYIOT-UHFFFAOYSA-N 0.000 description 1
- JCHQKERCGIFPRD-UHFFFAOYSA-K [B+3].[I-].[I-].[I-] Chemical compound [B+3].[I-].[I-].[I-] JCHQKERCGIFPRD-UHFFFAOYSA-K 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229950002314 closilate Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-N dithionous acid Chemical compound OS(=O)S(O)=O GRWZHXKQBITJKP-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000000434 field desorption mass spectrometry Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000005342 methoxybenzoic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 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
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
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- 229940116351 sebacate Drugs 0.000 description 1
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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- C—CHEMISTRY; METALLURGY
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
本发明提供了用甲磺酸制备苯并噻吩类化合物的改进方法。
Description
本发明涉及化学制药领域，提供了由二烷氧基苯乙酮制备一组苯并噻吩化合物的有利方法。通过该方法可在大规模生产时以优异产率得到目标化合物。
U.S.4,380,635公开了由二烷氧基苯并噻吩中间体制备苯并噻吩类化合物的方法，它是在多磷酸(PPA)的存在下，通过α-(3-甲氧基苯硫基)-4-甲氧基苯乙酮的分子内环化实现的。将苯乙酮原料化合物在PPA中加热至约85℃保持约1小时，得到约3∶1两种异构体，6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩和4-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩的混合物。但是，当反应在生产规模进行时，由于苯并噻吩异构体沉淀而产生粘稠的糊状物，在常规的生产设备中不能充分的搅拌。
有尝试不同的反应使用溶剂来解决糊状物的问题，Guy等，Synthesis,222(1980)。但是，当用于工业生产时，另外加入的溶剂导致苯乙酮原料的不完全结晶，6-甲氧基-3-(4-甲氧基苯基)苯并[b]噻吩的不完全重排以及极大延长了反应时间。
这样，需要开发出更好的方法，以使由二烷氧基苯乙酮衍生物生成苯并噻吩类化合物获得适宜的收率和可接受的反应时间。
本发明提供了利用甲磺酸制备苯并噻吩的方法。该方法是通过二烷氧基苯乙酮衍生物的分子内环化反应制备苯并噻吩。
本发明提供了制备式Ⅰb所示化合物的方法，该方法包括在甲磺酸的存在下，将式Ⅱ化合物环化；
其中，R相同或不同地表示C1-C6烷基；
其中，R的定义同上。
苯并噻吩在雷洛昔芬(式Ⅲ所示化合物，其中R1和R2一起形成1-哌啶基)的合成中是一重要中间体，其中雷洛昔芬是选择性雌激素受体调节剂或SERM。除了提供制备该中间体的方法外，本发明还提供了制备式Ⅲ化合物或其药学可接受盐或其溶剂化物的方法；
其中，R1和R2独立地表示C1-C6烷基，或与和它们连接的氮原子一起表示哌啶基、吡咯烷基、甲基吡咯烷基、二甲基吡咯烷基或六亚甲基亚氨基；
该方法包括在甲磺酸存在下，将式Ⅱ化合物环化；
其中，R相同或不同地表示C1-C6烷基。
本方法中的许多起始原料和化合物详细参见U.S.4,133,814和U.S.4,380,635，其公开的内容并入本发明作为参考。
本发明中，所有温度表示摄氏温度。所有数量，比例，浓度，比率等除溶剂比率以体积单位表示外，若无另外说明，均以重量单位表示。
“C1-C6烷基”表示C1-C6的直链或支链烷基。具体的C1-C6烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、2-甲基戊基等。“C1-C4烷基”表示C1-C4的直链或支链烷基，包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
本发明的制备式Ⅰ化合物的方法示于下述方案Ⅰ；
方案Ⅰ
全部的反应过程包括第一步的环化反应步骤和后续的重排步骤。式Ⅰ化合物是目标化合物。本发明中的起始化合物(式Ⅱ化合物)物)可按照U.S.4,133,814和U.S.4,380,653公开的路线制得。
本发明实践中所用的含有溶剂混合物和助溶剂的溶剂可以影响全部反应，包括反应产物和总收率。具体的，选择的溶剂是非常弱的碱。本发明的优选的碱是芳香族溶剂，而使用脂肪族和氯化了的溶剂也可得到适宜的结果。溶剂的具体例有甲苯、庚烷、二甲苯、氯苯、二甲氧基乙烷和四氯乙烷，但本发明并不限于前述例。本发明中优选的溶剂是甲苯。
第一步的环化反应在甲磺酸的存在下进行，通常约比后续重排反应快约50-100倍。
环化反应速率可通过增加反应混合物中甲磺酸的量来提高。反应通常在共沸除水的回流条性下进行。
本发明中，环化反应的温度为约50℃-约110℃，优选为约75℃-110℃，最优选为约80℃-110℃。
将起始化合物苯乙酮(式Ⅱ化合物)在甲磺酸和甲苯的存在下加热至少30分钟，优选约60-300分钟。这样，苯乙酮在约90℃进行环化和重排约3-5小时。此时可选择性地加入庚烷，可提高收率。加入庚烷后，优选保持反应温度为约90℃。
在环化和重排反应中会生成许多脱甲基(desmethyl)副产物。四种结构不同的脱甲基副产物示于图2。图Ⅱ
异构体A和B是由化合物Ⅰa衍生的，而异构体C和D是由化合物Ⅰ衍生的。异构体A∶B∶C∶D在具体反应混合物中的比率大概是1∶1∶9∶9。异构体通常由HPLC检测。异构体的比率和最终产率取决于动力学控制的环化反应。在甲苯中使用甲磺酸，在环化反应中可得到适宜的异构体比率75∶25-80∶20(Ⅰ/Ⅰa′)，而在环化步骤中使用多磷酸得到的异构体的比率为75∶25。此过程中未观察到邻位和对位异构体的平衡。
重排反应是热力学控制的反应。所述反应的平衡常数为K1＞100,K2约为7-9。使用甲磺酸和甲苯/庚烷作为溶剂系统，式Ⅰa化合物在反应混合物中生成沉淀，使反应终止。非目的异构体化合物Ⅰb′的重排速度是所需异构体化合物Ⅰb的3-5倍。
庚烷是优选的附加溶剂，可影响苯乙酮产物的结晶化。结晶导致溶解度的降低，使反应平衡移动。最好在反应混合物达到平衡前加入庚烷。
在重排的最后阶段可进一步将适宜的溶剂或溶剂混合物加入到反应混合物中。适宜溶剂的例子包括但不限于异丙醇(IPA)等。该溶剂的加入降低了产物的溶解度，同时也提高了纯度。
全部反应可以“一罐”合成，分批，半连续，连续等方式进行。本领域人员可以理解这些反应模式的区别，包括哪种反应可用于不同的目的。例如，在半连续或连续反应中，将起始化合物和溶剂进料到固体酸树脂的填充柱。过量的溶剂和产物的回收和分离可通过蒸馏完成。另外，反应可选择性地在有机溶剂存在下进行，所述有机溶剂可与水形成共沸溶剂，这样可促进在反应过程中通过共沸蒸馏除去副产物。这样的溶剂的例子包括芳香烃类，例如苯，甲苯，二甲苯等。
苯乙酮产物可用通常的萃取方法分离，加入水，分层，选择性的再次用有机溶剂萃取水层，合并有机层，浓缩合并的有机层。当起始化合物是甲氧基衍生物时，目的产物6-烷氧基化合物在浓缩的溶剂时结晶，而4-烷氧基异构体留在溶剂中。目的产物6-烷氧基化合物可通过过滤收集。
本发明的优选的环化方法是，起始化合物是α-(3-甲氧基苯硫基)-4-甲氧基苯乙酮，经环化和重排后，得到6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩。该产物可接着被转化为式Ⅲ化合物，例如6-羟基-2-(4-羟基苯基)-3-[4-(2-氨基乙氧基)基)苯甲酰基]苯并[b]噻吩。化合物6-烷氧基-2-(4-烷氧基苯基)苯并[b]噻吩向式Ⅲ化合物的转变可参照U.S.4,380,635。
在本领域中，适宜的活泼酯基团(R)是已知的。很多形成和消除保护基的反应在许多标准著作中均有记载，包括，有机合成中的保护基，Plenum Press(London and New York,1973)；Green,T.W.，有机合成中的保护基，Wiley,(New York,1981)；肽，Vol.I,Schrooder and Lubke,Academic Press(London and New York,1965)。有关羟基的保护基，特别是甲基的非部位选择性消除也是已知的。已被在6-和4′-位用甲氧基预先保护的式Ⅲ化合物可被选择性地消除以生成带有4′-位甲氧基的式Ⅲ化合物。通常，消除4′-位甲氧基的过程包括将6-,4′-二甲氧基反应物与去甲基化剂混合，该去甲基化剂选自三溴化硼，三氯化硼和三碘化硼；或将其与AlCl3和各种硫醇试剂例如EtSH混合。反应在惰性气体如氮气中进行，相对于每摩尔消除的甲氧基加入一或多摩尔试剂。
适宜的用于脱保护反应的溶剂是在整个去甲基反应中保持惰性的溶剂或溶剂混合物。优选卤代溶剂例如二氯甲烷，1,2-二氯乙烷和氯仿，或芳香族溶剂例如苯或甲苯。反应温度应足以将去甲基反应进行完全。但是，将反应温度保持在0℃以下是有利的，这样可使4-甲氧基的消除选择性最大，且避免不希望的副产物尤其是过度去甲基化导致的6-,4′-二羟基类似物的产生。在优选的反应条件下，在搅拌约1-24小时后生成选择性的去烷基产物。优选的各种条件包括在二氯甲烷中，氮气下，使用相对于1摩尔6-,4′-二甲氧基反应物约1.5摩尔三溴化硼在-20℃反应1-4小时。
式Ⅲ化合物经常以其酸加成盐的形式给药。酸加成盐可象在有机化学中，通过将本发明合成的化合物与适宜的酸反应容易地合成。酸加成盐在适宜的温度下迅速生成，收率很高，通常在反应的最后步骤从适宜的酸性洗剂中分离化合物而制得。例如，可利用有机酸或无机酸生成盐。
用来生成这样的盐的无机酸具体包括，盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸或连二磷酸等。与有机酸生成盐的例子有，脂肪族一或二羧酸盐，苯基取代的烷酸，羟基烷酸和羟基烷双酸，芳酸，脂肪族和芳香族磺酸。其药学可接受盐包括乙酸盐，苯乙酸盐，三氟乙酸盐，丙烯酸盐，抗坏血酸盐，苯甲酸盐，氯苯甲酸盐，二硝基苯甲酸盐，羟基苯甲酸盐，甲氧基苯甲酸盐，甲基苯甲酸盐，邻乙酰基苯甲酸盐，萘基-2-苯甲酸盐，溴化物，异丁酸盐，苯基丁酸盐，β-羟基丁酸盐，丁炔-1,4-二羧酸盐，己炔-1,4-二羧酸盐，癸酸盐，辛酸盐，氯化物，桂皮酸盐，柠檬酸盐，甲酸盐，富马酸盐，羟基乙酸盐，庚酸盐，马脲酸盐，乳酸盐，苹果酸盐，马来酸盐，羟基马来酸盐，丙二酸盐，扁桃酸盐，甲磺酸盐，烟酸盐，异烟酸盐，硝酸盐，草酸盐，邻苯二甲酸盐，对苯二甲酸盐，磷酸盐，磷酸一氢盐，磷酸二氢盐，偏磷酸盐，焦磷酸盐，丙炔酸盐，丙酸盐，苯基丙酸盐，水扬酸盐，癸二酸盐，琥珀酸盐，辛二酸盐，硫酸盐，硫酸氢盐，焦硫酸盐，亚硫酸盐，亚硫酸氢盐，磺酸盐，苯磺酸盐，对溴苯磺酸盐，氯苯磺酸盐，乙基磺酸盐，2-羟基乙基磺酸盐，甲磺酸盐，萘基-1-磺酸盐，萘基-2-磺酸盐，对甲苯磺酸盐，二甲苯磺酸盐，酒石酸盐等。优选的盐是盐酸盐。
用如下式Ⅲ化合物进一步说明本文所公开的全部方法：
6-羟基-2-(4-羟基苯基)-3-[4-(2-二甲基氨基乙氧基)苯甲酰基]苯并[b]噻吩，
3-[4-(2-乙氧基甲基氨基乙氧基)苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩，
3-[4-(2-乙氧基异丙基氨基乙氧基)苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩，
3-[4-(2-丁基氨基乙氧基)苯甲酰基]-5-羟基-2-(4-羟基苯基)苯并[b]噻吩，
3-[4-(2-(1-甲基丙基)甲基氨基乙氧基)-苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩，
6-羟基-2-(4-羟基苯基)-3-[4-[2-二(2-甲基丙基)氨基乙氧基]苯甲酰基]苯并[b]噻吩，
6-羟基-2-(4-羟基苯基)-3-[4-(2-吡咯烷基乙氧基)苯甲酰基]苯并[b]噻吩，
6-羟基-2-(4-羟基苯基)-3-[4-(2-哌啶子基乙氧基)苯甲酰基]苯并[b]噻吩，
6-羟基-2-(4-羟基苯基)-3-[4-(2-吗啉代基乙氧基)苯甲酰基]苯并[b]噻吩，
3-[4-(2-六亚甲基亚氨基乙氧基)苯甲酰基]-6-羟基-2-(4-羟基苯基)苯并[b]噻吩。
下述实施例将对本发明作进一步的说明，但本发明范围并不受下述实施例的限制。本领域的技术人员会想到作多种修改，但并没有超出本发明的范围。本说明书中所提到的所有出版物和专利申请均以本领域技术人员所能清楚的标准进行阐述。实施例
所有试验均在干燥氮气的正压力下进行。所有使用的溶剂和试剂均直接使用。百分数通常表示重量百分数(w/w)，除了高效液相色谱(HPLC)溶剂是按体积百分数(V/V)计算的。质子核磁共振光谱(1H NMR)和13C核磁共振光谱(13C NMR)是用Bruker AC-300 FTNMR波谱仪在300.135MHz或用GE QE-300波谱仪在300.15MHz得到的。硅胶快速色谱可按Still等，用硅胶60(230-400目，E.Merk),Still等，J.Org.Chem.,43,2923(1978)所记载的进行。碳原子，氢原子和氮原子的元素分析是在Control EquipmentCorporation440元素分析仪进行的。硫元素的分析是在Brinkman比色元素分析仪上进行的。熔点是用开口毛细玻璃管在Gallenkamp热空气浴熔点仪或在Mettler FP62自动测定仪上测定的。场解吸质谱(FDMS)是用Varian Instrument VG70-SE或VG ZAB-3F质谱仪得到的。高分辨率自由原子轰击质谱(FABMS)是在VarianInstruments VG ZAB-2SE质谱仪上进行的。
6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩的收率可用高效液相色谱法以按常规方法例如，按美国专利No.4,133,814制得的可信样品作为对照进行测定。
实施例1
将40克α-(3-甲氧基苯硫基)-4-甲氧基苯乙酮，5克甲磺酸和120ml甲苯(Drum Stock)加入到1升装有回流冷凝器和迪安-斯达克榻分水器的三颈园底烧瓶中。或者在分水器中预先装入甲苯或者向反应器中加入额外的溶剂。将混合物加热至回流并搅拌2小时共沸除去水。冷却反应混合物至90℃。另外将9克甲磺酸加入到反应混合物中，在90℃搅拌3-5小时。在5-20分钟内加入56ml庚烷Stock)。将反应混合物在90℃下搅拌1小时，然后在80℃下搅拌3-4小时。在5-20分钟内加入98ml异丙醇(IPA)(Drum Stock)，然后在约83℃回流30分钟。将反应混合物以不超过每小时50℃的速度冷却至0℃。然后在0℃搅拌至少1小时，过滤，用75ml 70/30(甲苯/IPA)洗涤两次，在60℃下真空干燥过夜。收率70％，效力100％，去甲基0.4％。
Claims (11)
1．制备式Ⅰb所示化合物的方法，包括在甲磺酸存在下，将式Ⅱ二烷氧基化合物环化，其中，R相同或不同地表示C1-C6烷基。
2．根据权利要求1的制备方法，其特征在于进一步包括通过将式Ⅰb所示化合物重排制备式Ⅰ化合物，其中，R相同或不同地表示C1-C6烷基。
3．根据权利要求1的制备方法，其中R是甲基。
4．根据权利要求1的制备方法，其特征在于进一步包括加入甲苯。
5．根据权利要求4的制备方法，其特征在于进一步包括加入庚烷。
6．根据权利要求5的制备方法，其特征在于进一步包括加入异丙醇。
7．根据权利要求1的制备方法，其中所述环化反应在约70℃-约90℃进行。
8．根据权利要求1的制备方法，其中所述方法是分批操作的。
9．根据权利要求1的制备方法，其中所述方法是连续进行的。
10．制备式Ⅲ化合物或其药学可接受盐或其溶剂化物的方法；
其中，R1和R2独立地表示C1-C6烷基，或与和它们连接的氮原子一起表示哌啶基、吡咯烷基、甲基吡咯烷基、二甲基吡咯烷基或六亚甲基亚氨基；
该方法包括在甲磺酸存在下，将式Ⅱ化合物环化；其中，R相同或不同地表示C1-C6烷基。
11．根据权利要求10的制备方法，其中R是甲基。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3118196P | 1996-11-19 | 1996-11-19 | |
| US60/031181 | 1996-11-19 |
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| CN1237968A true CN1237968A (zh) | 1999-12-08 |
| CN1130357C CN1130357C (zh) | 2003-12-10 |
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| US (1) | US5969157A (zh) |
| EP (1) | EP0842930B1 (zh) |
| JP (1) | JP2001504497A (zh) |
| KR (1) | KR20000053333A (zh) |
| CN (1) | CN1130357C (zh) |
| AR (1) | AR010615A1 (zh) |
| AT (1) | ATE217620T1 (zh) |
| AU (1) | AU726401B2 (zh) |
| BR (1) | BR9712773A (zh) |
| CA (1) | CA2271922A1 (zh) |
| CO (1) | CO4920247A1 (zh) |
| DE (1) | DE69712590T2 (zh) |
| DK (1) | DK0842930T3 (zh) |
| ES (1) | ES2173399T3 (zh) |
| HU (1) | HUP9904510A3 (zh) |
| ID (1) | ID18917A (zh) |
| IL (1) | IL129868A (zh) |
| PE (1) | PE16799A1 (zh) |
| PT (1) | PT842930E (zh) |
| SI (1) | SI0842930T1 (zh) |
| TW (1) | TW461888B (zh) |
| WO (1) | WO1998022456A1 (zh) |
| ZA (1) | ZA9710262B (zh) |
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| WO2001009116A2 (en) * | 1999-07-29 | 2001-02-08 | Eli Lilly And Company | A NOVEL CRYSTALLINE FORM OF 6-HYDROXY-3- (4-[2-(PIPERIDIN-1-YL) ETHOXY]PHENOXY)- 2-(4-METHOXYPHENYL)BENZO[b]THIOPHENE HYDROCHLORIDE |
| AU2002230409A1 (en) * | 2000-11-27 | 2002-06-03 | Eli Lilly And Company | Process for preparing 3-aryl-benzo(b)thiophenes |
| US20050069962A1 (en) * | 2001-10-12 | 2005-03-31 | Archer Robert M | Antibody complexes and methods for immunolabeling |
| US8323903B2 (en) | 2001-10-12 | 2012-12-04 | Life Technologies Corporation | Antibody complexes and methods for immunolabeling |
| NZ537328A (en) * | 2002-05-31 | 2008-04-30 | Genetic Technologies Ltd | Maternal antibodies as fetal cell markers to identify and enrich fetal cells from maternal blood |
| AU2003266940B2 (en) | 2002-09-30 | 2007-02-08 | A/S Gea Farmaceutisk Fabrik | Novel raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these |
| US8394582B2 (en) * | 2003-03-05 | 2013-03-12 | Genetic Technologies, Inc | Identification of fetal DNA and fetal cell markers in maternal plasma or serum |
| WO2008047105A1 (en) | 2006-10-17 | 2008-04-24 | Cipla Limited | Crystalline form of benzothiophene compound and process for preparation thereof |
| US9447467B2 (en) | 2009-04-21 | 2016-09-20 | Genetic Technologies Limited | Methods for obtaining fetal genetic material |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU509682B2 (en) * | 1975-10-28 | 1980-05-22 | Eli Lilly And Company | 2-Aroyl-3-Phenylbenzothiophene Derivatives |
| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| AT364852B (de) * | 1977-11-05 | 1981-11-25 | Thomae Gmbh Dr K | Verfahren zur herstellung von kondensierten isothiazol-3(2h)-on-1,1-dioxiden und von deren salzen |
| US4436748A (en) * | 1980-10-20 | 1984-03-13 | Hoechst-Roussel Pharmaceuticals Inc. | Benzo[b]thiophenes |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
| IL65378A (en) * | 1981-04-03 | 1986-02-28 | Lilly Co Eli | Process for preparing 3-(4-aminoethoxybenzoyl)benzo-(b)thiophenes |
| US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
| US4544746A (en) * | 1982-05-17 | 1985-10-01 | Ciba-Geigy Corporation | Process for preparing 2-anilinoacridone |
| JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
| DE4204969A1 (de) * | 1992-02-19 | 1993-08-26 | Basf Ag | Verfahren zur herstellung von benzo(b)thiophenen |
| US5466810A (en) * | 1994-06-10 | 1995-11-14 | Eli Lilly And Company | 2-amino-3-aroyl-benzo[β]thiophenes and methods for preparing and using same to produce 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)-benzoyl]benzo[β]thiophenes |
| DE4423893C2 (de) * | 1994-07-07 | 1996-09-05 | Freudenberg Carl Fa | Flachdichtung mit flexibler Leiterplatte |
| US5523416A (en) * | 1994-07-22 | 1996-06-04 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxy-benzoyl) benzo (B)-thiophenes |
| US5552401A (en) * | 1995-02-28 | 1996-09-03 | Eli Lilly And Company | 2-benzyl-3-arylbenzothiophenes |
| US5614639A (en) * | 1995-03-31 | 1997-03-25 | Eli Lilly And Company | Process for preparing 2-substituted benzo[b]thiophene compounds and intermediates thereof |
| US5606075A (en) * | 1995-06-07 | 1997-02-25 | Eli Lilly And Company | Process for the synthesis of benzo[b]thiophenes |
| US5606076A (en) * | 1995-06-07 | 1997-02-25 | Eli Lilly And Company | Process for the synthesis of benzo[b]thiophenes |
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- 1997-11-14 AT AT97309186T patent/ATE217620T1/de active
- 1997-11-14 DE DE69712590T patent/DE69712590T2/de not_active Expired - Lifetime
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Also Published As
| Publication number | Publication date |
|---|---|
| EP0842930B1 (en) | 2002-05-15 |
| WO1998022456A1 (en) | 1998-05-28 |
| DE69712590T2 (de) | 2002-10-31 |
| AR010615A1 (es) | 2000-06-28 |
| IL129868A0 (en) | 2000-02-29 |
| BR9712773A (pt) | 1999-10-26 |
| SI0842930T1 (en) | 2002-10-31 |
| PE16799A1 (es) | 1999-02-19 |
| TW461888B (en) | 2001-11-01 |
| DK0842930T3 (da) | 2002-07-15 |
| AU726401B2 (en) | 2000-11-09 |
| ID18917A (id) | 1998-05-20 |
| JP2001504497A (ja) | 2001-04-03 |
| EP0842930A1 (en) | 1998-05-20 |
| US5969157A (en) | 1999-10-19 |
| DE69712590D1 (de) | 2002-06-20 |
| KR20000053333A (ko) | 2000-08-25 |
| AU5462298A (en) | 1998-06-10 |
| ZA9710262B (en) | 1999-05-13 |
| CN1130357C (zh) | 2003-12-10 |
| ES2173399T3 (es) | 2002-10-16 |
| ATE217620T1 (de) | 2002-06-15 |
| HUP9904510A3 (en) | 2000-08-28 |
| PT842930E (pt) | 2002-08-30 |
| HUP9904510A2 (hu) | 2000-05-28 |
| CA2271922A1 (en) | 1998-05-28 |
| IL129868A (en) | 2002-09-12 |
| CO4920247A1 (es) | 2000-05-29 |
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