CN1156725A - 制备4-氯-2-噻吩甲酸的中间体及其制备方法 - Google Patents
制备4-氯-2-噻吩甲酸的中间体及其制备方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 27
- JWQMRBBWZUKWFJ-UHFFFAOYSA-N 4-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=CS1 JWQMRBBWZUKWFJ-UHFFFAOYSA-N 0.000 title abstract description 12
- 239000000543 intermediate Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 19
- 239000003513 alkali Substances 0.000 claims description 12
- QUBJDMPBDURTJT-UHFFFAOYSA-N 3-chlorothiophene Chemical compound ClC=1C=CSC=1 QUBJDMPBDURTJT-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000001569 carbon dioxide Substances 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 230000005595 deprotonation Effects 0.000 claims description 3
- 238000010537 deprotonation reaction Methods 0.000 claims description 3
- 150000007520 diprotic acids Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 claims 1
- 230000009466 transformation Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 31
- 239000000243 solution Substances 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- -1 silyl compound Chemical class 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- PVMBAVARWKNHCX-UHFFFAOYSA-N 3-silylthiophene-2-carboxylic acid Chemical compound [SiH3]C1=C(SC=C1)C(=O)O PVMBAVARWKNHCX-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- LDDQLRUQCUTJBB-UHFFFAOYSA-N ammonium fluoride Chemical compound [NH4+].[F-] LDDQLRUQCUTJBB-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- MYECGOOHWUKLCY-UHFFFAOYSA-N (3-chlorothiophen-2-yl)-trimethylsilane Chemical compound C[Si](C)(C)C=1SC=CC=1Cl MYECGOOHWUKLCY-UHFFFAOYSA-N 0.000 description 2
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- PYHXGXCGESYPCW-UHFFFAOYSA-N alpha-phenylbenzeneacetic acid Natural products C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical group ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LNRFCDWBAPPUPY-UHFFFAOYSA-N C(=O)OCC.ClC=1C=CSC1 Chemical compound C(=O)OCC.ClC=1C=CSC1 LNRFCDWBAPPUPY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LVNHFSCFGLADLP-UHFFFAOYSA-N [N].CCCCCC Chemical compound [N].CCCCCC LVNHFSCFGLADLP-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910001618 alkaline earth metal fluoride Inorganic materials 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- 229910001634 calcium fluoride Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JZGZKRJVTIRPOK-UHFFFAOYSA-N ethyl thiophene-2-carboxylate Chemical compound CCOC(=O)C1=CC=CS1 JZGZKRJVTIRPOK-UHFFFAOYSA-N 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002641 lithium Chemical class 0.000 description 1
- QSPAEUKIWTXLSC-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li+].CC(C)NC(C)C QSPAEUKIWTXLSC-UHFFFAOYSA-N 0.000 description 1
- ORUIBWPALBXDOA-UHFFFAOYSA-L magnesium fluoride Chemical compound [F-].[F-].[Mg+2] ORUIBWPALBXDOA-UHFFFAOYSA-L 0.000 description 1
- 229910001635 magnesium fluoride Inorganic materials 0.000 description 1
- 229910001512 metal fluoride Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 150000007518 monoprotic acids Chemical class 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- VYGSFTVYZHNGBU-UHFFFAOYSA-N trichloromethanesulfonic acid Chemical group OS(=O)(=O)C(Cl)(Cl)Cl VYGSFTVYZHNGBU-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Seasonings (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Catalysts (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Paper (AREA)
Abstract
本发明公开了制备4-氯-2-噻吩甲酸的新中间体，即下列IVb的化合物，及其制备方法，其中每个R选自C1-C6烷基、苯基和苄基。
Description
4-氯-2-噻吩甲酸的结构为：
它是合成药物化合物的重要中间体，例如，Ehrgott等人在美国专利5,047,554实施例72中公开的5-氟-6-氯-3-(4-氯-2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺。
J.Iriarte等人在J.Heterocyclic Chem.，13 393(1976)上，发表了4-氯-2-噻吩甲酸(这里，为了方便简写为“CTCA”)的合成。该文报导了用氧化银氧化相应的2-醛得到定量产率CTCA的粗品。报导了粗品酸熔点(mp)为124-126℃。进一步指出此产物“用甲醇或二氯甲烷反复结晶”熔点为131-132℃。Iriarte等人在同一篇文章中又报导了用4-氯噻吩-2-甲酸乙酯在氢氧化钾甲醇溶液中皂化，这里的甲酸酯是在三氯化铝存在下，由噻吩-2-甲酸乙酯直接氯代得到的，制备的CTCA熔点为125-126℃。
Lemaire等人在J.Electroanal.Chem.，281，293，(1990)中特别报导了采用格氏试剂方法制备3-氯-2-三甲基甲硅烷基噻吩，产物用于电聚合以制备聚(3-氯噻吩)。不论是CTCA还是任何合成它的方法均未被公开。
现在，本发明者已经确定用温度控制的区域选择性方法可以制备出CTCA，这种方法将潜在的反应位置保护起来，因此阻止了副产物生成。
从最广泛的方面来看，本发明提供了一个制备4-氯-2-噻吩甲酸的方法，它包括从式IV a化合物中脱去甲硅烷基-SiR3，其中每个R基独立地选自(C1-C6)烷基、苄基和苯基。
上面制备4-氯-2-噻吩甲酸方法的一种变异方法包括从式IVb化合物中脱去甲硅烷基-SiR2-
其中R的定义如前面所述。
更详细地，制备4-氯-2-噻吩甲酸的方法包括下列步骤：
1)在温度低于约-50℃条件下，用碱处理3-氯噻吩，随后用式为R3SiX甲硅烷基化合物处理，其中X代表离去基，每个R基独立地选自(C1-C6)烷基、苄基和苯基，结果生成式Ia化合物
2)在温度低于约-50℃条件下，用足够量的碱处理步骤(1)的产物，使氯代噻吩环5位去质子，因此相应地生成式IIa的负离子
3)在温度低于-50℃条件下，用二氧化碳处理步骤(2)的产物，相应地生成式IIIa的一元羧酸盐
4)将步骤(3)的产物转变为相应的酸(即式IVa的酸)；和
5)脱去硅烷基-SiR3。
紧接上述制备4-氯-2-噻吩甲酸的另一种方法包括下列步骤：
1)在温度低于约-50℃条件下，用碱处理3-氯噻吩，随后用式R2SiX2甲硅烷化合物处理，其中X和R如产面所述，因此生成式Ib化合物
2)在温度低于约-50℃条件下，用足够量碱处理步骤(1)的产物，使二噻吩环的5位和5′位去质子，因此相应地生成式IIb的二负离子
3)在温度低于-50℃条件下，用二氧化碳处理步骤(2)的产物，生成式IIIb相应的二元羧酸盐
4)将步骤(3)的式IIIb产物转变成相应的二元酸(即化学式IVb化合物)；和
5)脱去甲硅烷基-SiR2-。
作为离去基“X”常用的是卤基(包括氯、溴和碘)、三氟甲磺酸酯基、三氟乙酸酯基、乙酰胺基、三氟乙酰胺基、1，2，4-三唑基和咪唑基，以及本领域已知的其它基团。优选氯和三氯甲烷磺酸酯基，由于它们是容易得到的商品。
作为C1-C6烷基的R的具体实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和正己基。
用上述方法制备的CTCA是相当纯的，熔点为138℃，表明了这种方法比先有技术方法制备出的产品纯度高得多，先有技术方法即使经过反复重结晶，熔点仅为131-132℃。
本发明进一步提供了制备5-氟-6-氯-3-(4-氯-2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺(反应路线1下方结构式VIII)的多种方法(它们是变异方法)，它们包括：在碱存在下，将5-氟-6-氯-2-羟基吲哚-1-甲酰胺(反应路线中结构式VII)与按照上面描述的任一方法制备的4-氯-2-噻吩甲酸的活化形式(例如其酰氯、酰基咪唑或甲酯)进行反应。最好应用由CTCA与羰基二咪唑反应制备的活化酰基咪唑或者由CTCA与亚硫酰氯反应制得的酰氯。这两种优选的活化的衍生物都可以用常规的方法制得。
制备5-氟-6-氯-3-(4-氯-2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的再一方法包括下面步骤：
(1)在碱存在下，将5-氟-6-氯-2-羟基吲哚-1-甲酰胺与式IVc的活化的一元羧酸反应(其中Y代表氯、1-咪唑基或甲基)，因此相应地生成式Va的5-氟-6-氯-3-(4-氯-3-三取代的甲硅烷基-2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺
(2)脱去甲硅烷基-SiR3。
紧接上述方法的一种变异方法包括下面步骤：
(1)碱存在下，将5-氟-6-氯-2-羟基吲哚-1-甲酰胺与式IVd的活性二元羧酸反应(其中Y如前面所述)，因此相应地生成式Vb化合物
(2)脱去甲硅烷基-SiR2-。
化学式IVa和IVb化合物也是新化合物，因此它提供了本发明的又一个特征。
以式R3SiX为例，本发明的化学反应可以概述成总反应路线如下：
反应路线I
本领域的技术人员知道：在反应路线I中，应用式R2SiX2甲硅烷化合物来替代式R3SiX的甲硅烷化合物时，其相应的结果是：用前述的化学式Ib的二聚的3-氯噻吩来替代式Ia的一元衍生物，用前述的式IVb的二元酸来替代式IVa的一元酸和用前述的式Vb的二元衍生物来替代式Va的一元衍生物。
首先，值得注意的是所有下面说明的反应必须在惰性气氛中进行，优先选用氩气或氮气。为了方便起见，下面把甲硅烷保护基R3Si-(和-R2Si-)简称为“保护基”，把该甲硅烷基化合物简称为“保护试剂”。还要注意当指定温度为低于约-50℃，优选低于-70℃时，最好选用温度-78℃，因为它用干冰/丙酮浴很容易实现。更低温度也是做得到的，例如用液氮冷却己烷浴，可以达到-94℃温度，但是没有显著的优越性。
2位保护物3-氯噻吩可以这样制备：首先用等量的强碱(如烷基锂)，处理3-氯噻吩，温度低于-50℃，优选低于-70℃，这样去质子作用是区域选择性的且有利于2位。碱优先选用正丁基锂，由于它已经商品化。将3-氯噻吩和碱分别溶于惰性溶剂(“惰性”是相对于所应用的反应条件而言)中，如四氢呋喃(THF)和己烷。把反应混合物进行搅拌，时间的范围由半小时到数小时。这时可以加入等量或略微过量(10％)的保护试剂。经几分钟到数小时后，将反应混合物加热到室温左右或小于室温，加入水和/或盐水终止反应。然后把保护的产物萃取到一个适当的有机溶剂中，通常情况下为乙酸乙酯，然后干燥、和用传统蒸发方法分离。
然后在一个适当的无水溶剂[如四氢呋喃(THF)]中，将2-保护的-3-氯噻吩与碱(等量或略过量)反应，温度低于-50℃，优选低于-70℃，使噻吩的硫原子邻近的未保护的那个碳原子上选择性脱去质子。在保持温度低于-50℃的同时，用二氧化碳处理脱去质子的中间体。因此使中间体捕捉二氧化碳产生式IIIa或IIIb的4-氯-5-保护的-2-噻吩羧酸盐。专业人员知道：应选用适当的碱，这个碱具有比保护基较弱的亲核性，因此它不进攻或取代已连接在噻吩环上的保护基。这个步骤有用的碱的实例包括二烷基胺化锂类，它们可以直接用二烷基与烷基锂化合物反应非常方便地制得。例如，在前述步骤生成的2-保护的-3-氯噻吩引入之前，把正丁基锂在四氢呋喃中于0℃与等量的二烷基胺(如二异丙基胺)反应，因此生成二异丙基胺化锂。然后将温度适当降到低于-50℃，进行二氧化碳捕捉。用酸性水溶液(例如盐酸水溶液)终止反应，把该羧酸盐转变成酸。然后分离出有机层、萃取水溶液部分(例如，用乙酸乙酯)，并分离出该酸。
这时，用氟化物处理产物，可以脱去保护基生成4-氯-2-噻吩甲酸。此酸可被活化，而且与5-氟-6-氯-2-羟基吲哚-1-甲酰胺(本文也称为甲酰胺母体)反应，生成药物5-氟-6-氯-3-(4-氯-2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺。
另外，保护基不需要脱去，使保护的酸活化，直接地与甲酰胺母体反应，生成相应的保护的药物(Va)或(Vb)。
如上所述，在两种情况下，都是用氟化物负离子处理脱去保护基，用酸水溶液(如盐酸)终止反应，分离出最终的药物。氟化物离子源要求并不苛刻，可以使用相当广泛围的含氟化物试剂，其中包括：碱金属氟化物(例如，氟化钠、氟化钾、氟化锂和氟化铯)；碱土金属氟化物(例如，氟化镁和氟化钙)；氟化氢(包括自由形式(HF)和结合形式例如，氟化氢吡啶鎓)和四(低级烷基)氟化铵。优选四(低级烷基)氟化铵，其中四(正丁基)氟化铵特别优选，由于它已商品化。可以使用过量氟化物(即2-3倍相当的量)以加速反应。
应用5-氟-6-氯-3-(4-氯-2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的方法在Ehrgott的美国专利No 5,047,554中提出过。
下述实施例解释本发明的各个方面，但决不是以任何形式限制本发明范围。在这些实施例中，NMR数据是用Brooker AM250和AM300仪器得到的。1H(质子)核磁共振谱应用的频率为250MHz或300MHz。13C核磁共振谱是在62.5MHz或75MHz下得到的。
实施例1a
2-三甲基甲硅烷基-3-氯噻吩
在不断搅拌和-72℃(丙酮/干冰浴)的条件下，向溶于50ml四氢呋喃的3-氯噻吩(5.0g，42.16mmol)中，在15分钟内，加入16.8ml 2，5M的正丁基锂的己烷溶液。加入期间，反应温度保持低于-70℃。当全部加入正丁基锂溶液后不久，生成白色沉淀。在低于-70℃下搅拌40分钟后，慢慢地在5分钟内加入5.88ml的氯代三甲基甲硅烷。加入后，溶液瞬息间变清，随后生成氯化锂付产物，溶液又转为浑浊。10分钟后，将反应溶液温度加热到0℃。在0℃条件下，加入5ml水，随后再加入25ml盐水，以终止反应。然后用乙酸乙酯(2×30ml)萃取水溶液。有机萃取物用硫酸钠干燥、过滤和蒸发得到8.0g清油状标题化合物。
物理性质：质谱(EIMS)m/z＝192(M++2，14％)，190(M+，36％)，177(M++2-CH3，41％)，和175(M+-CH3，100％)；1HNMR(CDCl3)δ7.49(1H，d，J＝4.7Hz)，7.07(1H，d，J＝4.7Hz)，和0.46(9H，s)；13CNMR(CDCl3)δ132.0，130.2，130.1，129.8，和-0.7。
实施例1b
4-氯-5-三甲基甲硅烷基-2-噻吩甲酸
将少量(4mg)的二苯基乙酸样品溶于50ml四氢呋喃中，并在室温下搅拌。向这个溶液中慢慢滴加2.5M正丁基锂的己烷溶液，直到生成二苯基乙酸二负离子，溶液变为浅黄色。这个方法必需保证溶液是无水的。这里将溶液冷却到-72℃(丙酮/干冰浴)。在这个温度条件下，加入462ml(11.542mmol)2.5M正丁基锂的己烷溶液，随后再加入1.76ml(12.592mmol)的二异丙基胺，为了生成二异丙基铵锂，把反应溶液温度升到0℃(冰浴)，20分钟后，再降到-72℃。在20分钟时间内，向这个冷却的反应溶液中加入2.0g(10.493mmol)2-三甲基甲硅烷基-3-氯噻吩溶于5ml四氢呋喃的溶液。反应釜温度保持低于-70℃，以便保证区域选择性去质子作用。反应30分钟后，使二氧化碳气体以汽泡通过黄色溶液。鼓泡时，反应温度维持低于-55℃。二氧化碳处理延续10分钟。二氧二碳的加入，溶液温度逐渐升到0℃，此时用50ml 1N盐酸终止反应，有部分气体逸出。在加入酸性溶液时，反应温度升至室温。再加入50ml的盐水。分离出有机层，水溶液层用乙酸乙酯(2×50ml)萃取。合并有机萃取物，用盐水洗涤(1×50ml)，干燥(硫酸钠)，过滤，蒸发得到2.38克的白色固体。粗产物用庚烷重结晶得到1.67g纯的白色小针状标题化合物，熔点mp＝206-210℃。
物理性质：质谱(LSIMS)m/z＝237(M+H++2，12％)，和235(M+H+，10％)；1HNMR(CDCl3)δ7.74(1H，s)和0.41(9H，s)；13CNMR(CDCl3+CD3OD)δ163.1，141.2，137.8，134.7，131.6和-1.4。
实例1c
4-氯-2-噻吩甲酸
把300mg(1.278mmol)的4-氯-5-三甲基甲硅烷基-2-噻吩甲酸的样品溶于10ml四氢呋喃和0.3ml水中，并冷却到-5℃(冰/盐水浴)。将2.6ml的1M四正丁基氟化铵的四氢呋喃溶液慢慢地加入到反应溶液中。四小时后，把反应物倒入50ml 5％的碳酸氢钠水溶液中。将全部反应溶液转移到分液漏斗中，并用乙酸乙酯(2×25ml)洗涤。碱性水溶液用浓盐酸酸化到pH＝2，然后用乙酸乙酯(3×30ml)萃取，有机萃取物用硫酸钠干燥，过滤和蒸发得到216mg白色固体产物。用热的正庚烷重结晶得到85mg纯的结晶状产物，熔点mp＝138℃。
物理性质：质谱(EIMS)m/z 164(M++2，30％)，和162(M++，100％)；1HNMR(CDCl3)δ10.9(1H，br s，可交换的)，7.74(1H，d，J＝1.5Hz)，和7.43(1H，d，J＝1.5Hz)；13CNMR(CDCl3)δ166.1，134.6，133.2，128.3，和126.5。
实例2a
5-氟-6-氯-2，3-二氢-3-[羟基-2-(4-氧-5-三甲基甲硅烷基噻吩基)亚甲基]-2-氧代-1H-吲哚-1-甲酰胺
把375mg(1.60mmol)的4-氯-5-三甲基甲硅烷基-2-噻吩甲酸的样品与5ml亚硫酰氯混合，并加热回流。1.5小时后，反应完全。把烧瓶慢慢地冷却到室温。蒸出过量的亚硫酰氯，得到预期的棕色油状酰氯。将棕色油状物溶于5ml的N，N-二甲基甲酰胺中，并把它慢慢地加入到5-氟-6-氯-2，3-二氢-2-氧代-1H-吲哚-1-甲酰胺(500mg，2.24mmol)和4-(N，N-二甲基氨基)吡啶(708mg，5.80mmol)的15ml N，N-二甲基甲酰胺溶液中，于0℃时搅拌1小时后，把反应物倒入30ml 1N盐酸溶液中，使产物沉淀为红褐色固体。将粗产物过滤和用热乙酸重结晶，得到307mg(0.69mmol)纯的黄色结晶状固体标题化合物，熔点mp＝200℃。
物理性质：质谱(LSIMS)m/z 470(M-H++Na++4，4％)，468(M-H++Na+2，16％)，466(M-H++Na+，21％)，448(M++4，17％)，446(M++2，74％)，444(M+，100％)，405(M+-CONH+4，8％)，403(M+-CONH+2，28％)和401(M+-CONH，39％)；1HNMR(DMSO-d5)δ8.97(1H，可交换的)，8.51(1H，s)，8.11(1H，d，JH-F＝7.3Hz)，7.96(1H，d，JH-F＝1，1.0Hz)，7.30(1H，可交换的)，6.21(1H，可交换的)，和0.37(9H，s)。
实例2b5-氟-6-氯-2，3-二氢-3-[羟基-2-(4-氯噻吩基)亚甲基]-2-氧代-1H-吲哚-1-甲酰胺
把50mg(0.11mmol)5-氟-6-氯-2，3-二氢-3-[羟基-2-(4-氯-5-三甲基甲硅烷基噻吩基)亚甲基]-2-氧代-1H-吲哚-1-甲酰胺的样品溶于2ml四氢呋喃中，并冷却到5℃。用针筒取0.56ml的1M四正丁基氟化铵的四氢呋喃溶液注入到搅拌着的冷却的吲哚底物的溶液中。1小时后，向这个反应物中加入0.25ml的水。再过30分钟后，加入5ml 1N盐酸溶液终止反应，然后将反应物倾入到15ml的水中。这引起沉淀出产物，过滤得到25mg预期的黄色固体标题化合物，将它用乙酸重结晶得产物晶体，熔点mp＝234-237℃。
物理性质：1HNMR(DMSO-d6)δ9.10(1H，可交换的)，8.69(1H，d，J＝1.5Hz)，8.10(1H，d，JH-F＝7.4Hz)，8.06(1H，d，JH-F＝11.4Hz)，7.65(1H，d，J＝1.5Hz)，和7.26(1H，可交换的)。
Claims (3)
1.下式IVb的化合物其中每个R基独立地选自C1-C6烷基、苄基和苯基。
2.制备权利要求1的式IVb化合物的方法，它包括下列步骤：
(1)在温度低于-50℃的条件下，用碱处理3-氯噻吩，然后用式R2SiX2的甲硅烷化合物处理，其中X是离去基团，每个R基独立地选自C1-C6烷基、苄基和苯基，从而生成式Ib化合物
(2)在温度低于-50℃的条件下，用足够量的碱处理步骤(1)的产物，使二个噻吩环上的5和5′位去质子，从而相应地生成式IIb的二负离子
(3)在温度低于-50℃条件下，用二氧化碳处理步骤(2)的产物，生成相应的IIIb二元羧酸盐
(4)转变式IIIb的产物为相应的二元酸。
3.权利2所述的方法，其中R是甲基，X是氯或是三氟甲烷磺酸酯基，而且步骤(1)至(3)的每个步骤的温度均低于-70℃。
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Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
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| CN96114452A Pending CN1158853A (zh) | 1992-11-23 | 1996-11-08 | 制备5-氟-6-氯-3-(4-氯-2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的方法 |
| CN96114451A Pending CN1158851A (zh) | 1992-11-23 | 1996-11-08 | 4-氯-2-噻吩甲酸的制备方法 |
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| US (1) | US5648502A (zh) |
| EP (1) | EP0669924B1 (zh) |
| JP (2) | JP2706573B2 (zh) |
| KR (1) | KR950704727A (zh) |
| CN (4) | CN1036001C (zh) |
| AT (1) | ATE146181T1 (zh) |
| AU (1) | AU670454B2 (zh) |
| BR (1) | BR9307503A (zh) |
| CA (1) | CA2148616C (zh) |
| CZ (1) | CZ131695A3 (zh) |
| DE (1) | DE69306595T2 (zh) |
| DK (1) | DK0669924T3 (zh) |
| EG (1) | EG20200A (zh) |
| ES (1) | ES2095080T3 (zh) |
| FI (1) | FI935168A (zh) |
| GR (1) | GR3022396T3 (zh) |
| HU (1) | HUT68757A (zh) |
| IL (2) | IL107612A0 (zh) |
| MX (1) | MX9307292A (zh) |
| MY (1) | MY109037A (zh) |
| NO (1) | NO952021D0 (zh) |
| NZ (1) | NZ256279A (zh) |
| PL (1) | PL174312B1 (zh) |
| RU (1) | RU2114854C1 (zh) |
| WO (1) | WO1994012505A1 (zh) |
| ZA (1) | ZA938705B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100413861C (zh) * | 2002-12-10 | 2008-08-27 | 维勒凯姆制药股份有限公司 | 用于治疗或预防黄病毒感染的化合物 |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998045282A1 (en) * | 1997-04-04 | 1998-10-15 | Pfizer Inc. | Processes and intermediates for preparing 2-fluorothiophene derivatives |
| US7560551B2 (en) | 2006-01-23 | 2009-07-14 | Amgen Inc. | Aurora kinase modulators and method of use |
| CN101854933A (zh) | 2007-09-10 | 2010-10-06 | 钙医学公司 | 调节细胞内钙的化合物 |
| ITMI20071971A1 (it) * | 2007-10-10 | 2009-04-11 | Altergon Sa | Composizione farmaceutica per la somministrazione sublinguale di progesterone, e metodo per la sua preparazione |
| WO2009076454A2 (en) | 2007-12-12 | 2009-06-18 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
| JP5782377B2 (ja) | 2008-08-27 | 2015-09-24 | カルシメディカ，インク． | 細胞内カルシウムを調節する化合物 |
| US8524763B2 (en) | 2008-09-22 | 2013-09-03 | Calcimedica, Inc. | Inhibitors of store operated calcium release |
| US8143269B2 (en) | 2008-10-03 | 2012-03-27 | Calcimedica, Inc. | Inhibitors of store operated calcium release |
| CN101987842A (zh) * | 2009-07-31 | 2011-03-23 | 上海开拓者医药发展有限公司 | 一种2-甲基噻吩衍生物的制备方法 |
| WO2011034962A2 (en) | 2009-09-16 | 2011-03-24 | Calcimedica Inc. | Compounds that modulate intracellular calcium |
| WO2012027710A2 (en) | 2010-08-27 | 2012-03-01 | Calcimedica Inc. | Compounds that modulate intracellular calcium |
| US9512116B2 (en) | 2012-10-12 | 2016-12-06 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
| CN109096245A (zh) * | 2018-09-27 | 2018-12-28 | 上海雅本化学有限公司 | 一种5-氯噻吩-2-甲酸的制备方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4432974A (en) * | 1982-03-04 | 1984-02-21 | E. I. Du Pont De Nemours And Company | Antiinflammatory and/or analgesic 2,3-diaryl-5-silyl thiophenes |
| DE3534286A1 (de) * | 1985-09-26 | 1987-04-02 | Hoechst Ag | Verfahren zur herstellung von halogenthiophen-2-carbonsaeuren |
| HU208421B (en) * | 1988-10-18 | 1993-10-28 | Pfizer | Process for producing starting materials for producing 3-acyl-2-oxindol-carboxamides ofantiphlogistic activity |
| US5047554A (en) * | 1989-04-18 | 1991-09-10 | Pfizer Inc. | 3-substituted-2-oxindole derivatives |
| FR2655655A1 (fr) * | 1989-12-07 | 1991-06-14 | Rhone Poulenc Chimie | Procede de preparation de polysilthiophenediyle et polymeres obtenus a l'issue de ce procede. |
| CA2119155C (en) * | 1991-10-18 | 1999-06-15 | Dennis Paul Phillion | Fungicides for the control of take-all disease of plants |
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1993
- 1993-09-17 PL PL93309048A patent/PL174312B1/pl unknown
- 1993-09-17 AU AU48587/93A patent/AU670454B2/en not_active Ceased
- 1993-09-17 DK DK93921527.3T patent/DK0669924T3/da active
- 1993-09-17 AT AT93921527T patent/ATE146181T1/de not_active IP Right Cessation
- 1993-09-17 RU RU95112836A patent/RU2114854C1/ru active
- 1993-09-17 CZ CZ951316A patent/CZ131695A3/cs unknown
- 1993-09-17 DE DE69306595T patent/DE69306595T2/de not_active Expired - Fee Related
- 1993-09-17 BR BR9307503A patent/BR9307503A/pt not_active Application Discontinuation
- 1993-09-17 CA CA002148616A patent/CA2148616C/en not_active Expired - Fee Related
- 1993-09-17 NZ NZ256279A patent/NZ256279A/en unknown
- 1993-09-17 ES ES93921527T patent/ES2095080T3/es not_active Expired - Lifetime
- 1993-09-17 US US08/436,415 patent/US5648502A/en not_active Expired - Fee Related
- 1993-09-17 WO PCT/US1993/008613 patent/WO1994012505A1/en not_active Application Discontinuation
- 1993-09-17 JP JP6513105A patent/JP2706573B2/ja not_active Expired - Lifetime
- 1993-09-17 KR KR1019950702059A patent/KR950704727A/ko active IP Right Grant
- 1993-09-17 EP EP93921527A patent/EP0669924B1/en not_active Expired - Lifetime
- 1993-11-15 IL IL10761293A patent/IL107612A0/xx unknown
- 1993-11-19 MY MYPI93002430A patent/MY109037A/en unknown
- 1993-11-21 ZA ZA938705A patent/ZA938705B/xx unknown
- 1993-11-21 EG EG73493A patent/EG20200A/xx active
- 1993-11-22 FI FI935168A patent/FI935168A/fi not_active Application Discontinuation
- 1993-11-22 MX MX9307292A patent/MX9307292A/es not_active IP Right Cessation
- 1993-11-22 CN CN93114714A patent/CN1036001C/zh not_active Expired - Fee Related
- 1993-11-22 HU HU9303311A patent/HUT68757A/hu unknown
-
1995
- 1995-05-22 NO NO952021A patent/NO952021D0/no unknown
-
1996
- 1996-11-08 CN CN96114450A patent/CN1156725A/zh active Pending
- 1996-11-08 CN CN96114452A patent/CN1158853A/zh active Pending
- 1996-11-08 CN CN96114451A patent/CN1158851A/zh active Pending
-
1997
- 1997-01-29 GR GR960403453T patent/GR3022396T3/el unknown
- 1997-03-17 IL IL12046197A patent/IL120461A0/xx unknown
- 1997-07-02 JP JP9176977A patent/JP2795642B2/ja not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100413861C (zh) * | 2002-12-10 | 2008-08-27 | 维勒凯姆制药股份有限公司 | 用于治疗或预防黄病毒感染的化合物 |
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