CN1037147A - N-环丙基苯胺及其在制备1-环丙基喹诺酮羧酸和其衍生物中的应用 - Google Patents
N-环丙基苯胺及其在制备1-环丙基喹诺酮羧酸和其衍生物中的应用 Download PDFInfo
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- CN1037147A CN1037147A CN89103163A CN89103163A CN1037147A CN 1037147 A CN1037147 A CN 1037147A CN 89103163 A CN89103163 A CN 89103163A CN 89103163 A CN89103163 A CN 89103163A CN 1037147 A CN1037147 A CN 1037147A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- AOTWIFLKURJQGE-UHFFFAOYSA-N n-cyclopropylaniline Chemical compound C1CC1NC1=CC=CC=C1 AOTWIFLKURJQGE-UHFFFAOYSA-N 0.000 title claims description 8
- XPOANZUZZWFFKP-UHFFFAOYSA-N 1-cyclopropyl-2-oxoquinoline-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CC2=CC=CC=C2N1C1CC1 XPOANZUZZWFFKP-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 24
- -1 C 1~3Alkyl Chemical class 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 150000001942 cyclopropanes Chemical class 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- AXNUZKSSQHTNPZ-UHFFFAOYSA-N 3,4-difluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1 AXNUZKSSQHTNPZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BEECAQIHCYTZHC-UHFFFAOYSA-N 2,3,4,5-tetrafluoroaniline Chemical compound NC1=CC(F)=C(F)C(F)=C1F BEECAQIHCYTZHC-UHFFFAOYSA-N 0.000 description 1
- IDPFUSFISAHBPQ-UHFFFAOYSA-N 2,3,4-tris(fluoromethyl)aniline Chemical compound NC1=CC=C(CF)C(CF)=C1CF IDPFUSFISAHBPQ-UHFFFAOYSA-N 0.000 description 1
- JFJQMUQRTCGSFC-UHFFFAOYSA-N 2-(chloromethyl)aniline Chemical class NC1=CC=CC=C1CCl JFJQMUQRTCGSFC-UHFFFAOYSA-N 0.000 description 1
- XUPCRFCPXDLPAW-UHFFFAOYSA-N 2-(fluoromethyl)aniline Chemical class NC1=CC=CC=C1CF XUPCRFCPXDLPAW-UHFFFAOYSA-N 0.000 description 1
- ZGZURPPCPVPDMX-UHFFFAOYSA-N 2-bromo-3,4-difluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1Br ZGZURPPCPVPDMX-UHFFFAOYSA-N 0.000 description 1
- UKKFELITTUIEND-UHFFFAOYSA-N 2-chloro-3,4-difluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1Cl UKKFELITTUIEND-UHFFFAOYSA-N 0.000 description 1
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 1
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 1
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 1
- QUXLCYFNVNNRBE-UHFFFAOYSA-N 6-methylpyridin-2-amine Chemical compound CC1=CC=CC(N)=N1 QUXLCYFNVNNRBE-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
一种制备式(I)所示的喹诺酮羧酸衍生物的方
法,其中中间体(IV)是新化合物。
Description
本发明涉及适用于制备4-喹诺酮-3-羧酸的N-环丙基苯胺类化合物及其用N-环丙基苯胺类化合物制备喹诺酮羧酸衍生物的方法。
在7位上具有胺取代基的4-喹诺酮-3-羧酸类化合物由于它们的强抗菌作用而为人们所知,特别是,1-环丙基类化合物由于它们的高活性而更为突出。
在这些化合物中,1-环丙基-6-氟-1,4-二氢-7-(1-哌嗪基)-4-氧-3-喹啉羧酸(ciprofloxacin)可作为例子被提到。
根据本发明的方法可以制备1-环丙基喹诺酮羧酸类化合物或其衍生物,由于具有优良的作用,它们是有用的。
本发明涉及制备如式(Ⅰ)所示的喹诺酮羧酸衍生物的方法,
式中
R2表示氢、C1~3烷基或卤素,
X1表示氢、C1~3烷基、卤素或NR8R9,其中R8和R9及与它们键连的氮原子一起形成五员环或六员环,环还可以含有另外的原子或基团 NR10或O,并且可被C1~3烷基、羟基或C1~3烷氧基特别是甲氧基或NR11R12任意地单取代或双取代,其中R10和R11可以是相同的或不同的,并表示氢或C1~3烷基,R12表示氢、C1~3烷基、乙酰基或叔丁氧羰基,
X2和X3可以是相同的或不同的,并且表示氢、硝基或卤素,
A表示氮或基团C-X4,其中X4表示氢、C1~3烷基、含1~3个碳原子的烷氧基,含1~3个碳原子的烷硫基、卤素、硝基、氰基或醇部分最多含有3个碳原子的烷氧羰基,
Y表示腈基、酯基COOR5或酰胺基CONR6R7,其中R5表示C1~3烷基,R6和R7可以是相同的或不同的,并且表示氢或C1~3烷基,R6可以是任意取代的苯基,
所述方法的特征在于,第一步先使式(Ⅱ)的苯胺与式(Ⅲ)的环丙烷衍生物反应,经消除HX5而得到N-环丙基苯胺(Ⅳ),
式中X1、X2、X3和A具有上述意义,
式中X5表示卤素,
R1表示含1~3个碳原子的烷基,
R2具有上述意义,
Z表示氧或硫,
(Ⅳ)
将(Ⅳ)化合物还原成为式(Ⅴ)化合物,
接着按照下述反应式,使(Ⅴ)与式(Ⅵ)的烯衍生物反应,经消除R3OH和R4OH,得到喹诺酮羧酸衍生物(Ⅰ),
式中Y具有上述意义,
R3和R4是相同的或不同的,并且表示C1~3烷基,
如果需要,可通过消除先前引入的乙酰基或叔丁氧羰基保护基,来制备R11和R12都为氢或R11为氢而R12为C1~3烷基(反之亦然)的化合物。
一种较好地制备如式(Ⅰ)所示的喹诺酮羧酸衍生物的方法,
式中R2表示氢或卤素,
X1表示卤素或NR8R9,其中R8和R9以及与它们键连着的氮原子一起形成五员环或六员环,环还可以含有另外的原子或基团 NR10或O,并可被C1~3烷基、羟基、甲氧基或NR11R12任意地单取代或双取代,其中R10和R11可以是相同的或不同的,并表示氢或C1~3烷基,R12表示氢、C1~3烷基、乙酰基或叔丁氧羰基,
X2表示氟,
X3表示氢、硝基或卤素,
A表示氮或基团C-X4,其中X4表示氢、卤素或硝基,
Y表示腈基或酯基COOR5,其中R5表示C1~3烷基,
其特征在于,第一步,式(Ⅱ)的苯胺与式(Ⅲ)的环丙烷衍生物按下述反应式反应,消除HX5给出N-环丙基苯胺(Ⅳ),
式中X1、X2、X3和A具有上述意义,
式中X5表示氯或溴,
R1表示C1~3烷基,
R2具有上述意义,
Z表示氧或硫,
将式(Ⅳ)化合物还原成式(Ⅴ)化合物,
接着,再使式(Ⅴ)化合物与式(Ⅵ)的烯衍生物按照下式反应,消除R3OH和R4OH而得到喹诺酮羧酸衍生物(Ⅰ),
式中Y具有上述意义,
R3和R4可以是相同的或不同的,并且表示甲基或乙基,
一种特别好的制备式(Ⅰ)的喹诺酮羧酸衍生物的方法,
式中R2表示氟或氯,特别是表示氢,
X1表示氯、氟或NR8R9,其中R8和R9及其与它们键连着的氮原子一起形成五员环或六员环,环还可以另外含有基团 NR10作为环的成员,并且可被甲基、羟基、甲氧基或NR11R12任意地单取代或双取代,其中R10和R11可以是相同的或不同的,并且表示氢或甲基,R12表示氢、C1~3烷基、乙酰基或叔丁氧羰基,
X2表示氟,
X3表示氢或硝基,
A表示C-X4,其中X4表示氢、甲基、氟或氯,
Y表示酯基COOR5,其中R5表示甲基或乙基,
其特征在于,先使式(Ⅱ)的苯胺与式(Ⅲ)的环丙烷衍生物反应,经消除HX5而得到N-环丙基苯胺(Ⅳ),
式中X1、X2、X3和A具有上述意义,
式中X5表示溴,
R1表示乙基,
R2具有上述意义,
Z表示氧或硫,
(Ⅳ)
再将式(Ⅳ)化合物还原成式(Ⅴ)化合物,
接着,再使式(Ⅴ)化合物与式(Ⅵ)的烯衍生物按照下述反应式反应,消除R3OH和R4OH得到喹诺酮羧酸衍生物(Ⅰ),
式中Y具有上述意义,
R3表示甲基,
R4表示甲基或乙基,
在酸性或碱性条件下,可用已知方法将喹诺酮羧酸衍生物(Ⅰ)转化成具有抗菌活性的喹诺酮羧酸。
例如,如果用3,4-二氟苯胺和1-溴-1-乙氧基环丙烷作为第一步的起始原料,那么得到的是N-(1-乙氧基环丙基)-3,4-二氟苯胺。
将化合物(3)还原除去-OEt并与甲氧亚甲基丙二酸二乙酯(5)反应之后,就得到已知的1-环丙基-6,7-二氟-1,4-二氢-4-氧-喹啉羧酸乙酯(6)。
作为本发明方法的起始原料的苯胺(Ⅱ)是已知的,或者可用已知方法制备。
可被提及的例子有:3-氯-4-氟苯胺、3,4-二氟苯胺、2,3,4-三氟苯胺、3-氯-4-硝基苯胺、3,4-二氟-2-甲基苯胺、3,4-二氯-2-甲基苯胺、3,4-亚甲基二氧苯胺、2,3,4,5-四氟苯胺、2-氯-3,4-二氟苯胺、2-溴-3,4-二氟苯胺、2-氨基吡啶、2-氨基-6-甲基吡啶、2-氨基-5-氯吡啶、2-氨基-5-溴吡啶。
用作为起始原料的式(Ⅲ)环丙烷衍生物为已知的(J.Org.Chem.1985,3255;Recl.Trav.Chim.Pays-Bas 100,184)。
可被提及的例子有:1-氯-1-甲氧基环丙烷、1-溴-1-甲氧基环丙烷、1-溴-1-乙氧基环丙烷、1-溴-1-甲硫基环丙烷、1-氯-1-甲硫基环丙烷。
其它起始原料在Recl.Trav.Chim.Pays-Bas,100,184(1981)中有描述,例如:
作为起始原料的式(Ⅴ)的烯衍生物是已知的。
可被提及的例子有:甲氧亚甲基丙二酸二乙酯、甲氧亚甲基丙二酸二甲酯、甲氧亚甲基氰乙酸乙酯。
取代反应(Ⅱ)+(Ⅲ)→(Ⅳ)在20-120℃,最好在40-80℃温度范围内进行。
可用于此反应的稀释剂有:戊烷、己烷、庚烷、苯、甲苯、四氯化碳、氯仿、二氯甲烷或这些溶剂的混合物。
可用于此反应的酸夹带剂有:三乙胺、二氮杂双环〔2.2.2〕辛烷、1,8-二氮杂双环〔5.4.0〕十一烯-7、吡啶、碳酸钾、碳酸氢钠、二甲基苄胺。
用于还原反应(Ⅳ)→(Ⅴ)的还原剂有:氰基硼氢化钠、硼氢化钠、氢化铝锂,更好的为硼氢化钠和三氟化硼-乙醚复合物的1∶1混合物。
该反应可在稀释剂如二氧六环或四氢呋喃中进行。
反应(Ⅴ)+(Ⅳ)→(Ⅰ)在50-300℃,最好在100-250℃的温度范围内进行。
R3OH的消除反应可通过加热纯反应物或其与稀释剂如二苯醚、联苯或二者混合物的混合物来进行。
环化成(Ⅰ)的反应(消除R4OH的反应)在加入稀释剂如二苯醚、联苯或多磷酸的情况下进行。
(Ⅴ)和(Ⅵ)的反应可在加入碱如二氮杂双环〔5.3.0〕十一烯-7-、1,4-二氮杂双环〔2.2.2〕辛烷、氢化钠或叔丁醇钾的情况下进行。
该反应可在大气压下进行,但也可在升高的压力下进行。通常反应在大约1~100巴的压力范围内进行,1~10巴更好。
下述实施例用来说明本发明:
实施例1
将2.9g(20mmol)4-硝基苯胺,4.95g(30mmol)1-溴-1-乙氧基环丙烷和2g(30mmol)三乙胺在15ml二氯甲烷中的混合物加热回流3天。用水振摇提取混合物,用硫酸钠干燥并浓缩,残留物以二氯甲烷为洗脱剂进行硅胶柱层析。还原时,在无水和冰冷却下制备1.1g(30mmol)硼氢化钠和4g(30mmol)氟化硼-乙醚络合物在30ml无水四氢呋喃中的混合物,将混合物在冰冷却下搅拌1小时,加入得到的4-(1-乙氧环丙基氨基)硝基苯(3.2g),再将混合物加热回流1.5小时。浓缩之,残留物溶于30ml二氯甲烷中,用水洗涤溶液,硫酸钠干燥并浓缩,残留物用乙醇重结晶。将3.3g(15mmol)乙氧亚甲基丙二酸二乙酯加入得到的4-环丙基氨基硝基苯(2.1gm.p.134-6℃)在10ml二甲基甲酰胺中的溶液中,再在冰冷却和无水的条件下,在30分钟内加入375mg80%氢化钠。将混合物在冰冷却下搅拌30分钟,在室温下搅拌1小时,倒入25ml冰水和1.4ml乙酸的混合物中。将沉积的N-(4-硝基苯基)-N-环丙基氨基亚甲基丙二酸二乙酯抽吸滤出,用水和甲醇洗涤并干燥〔2.3g,m.p.116-120℃(异丙醇重结晶)〕。将该产物与9g多磷酸在145℃加热1小时,冷却并将混合物引入50ml冰水中。抽吸滤出所产生的暗色沉淀,经与二氯甲烷/甲醇(95∶5)搅拌,并用乙二醇单甲醚重结晶而纯化,得到1.2g1-环丙基-1,4-二氢-6-硝基-4-氧-3-喹啉羧酸乙酯,m.p.226-8℃(分解)。
将以该方式得到的酯在7.6ml乙酸、5.4ml水和0.9ml硫酸的混合物中加热回流1小时,并将悬浮液倒入40ml冰水中。抽吸滤出沉积的沉淀,用水洗涤并干燥。得到0.95g1-环丙基-1,4-二氢-6-硝基-4-氧-3-喹啉羧酸,m.p.256-262℃(分解)。
实施例2
按相似于实施例1的方法使3-氯-4-硝基苯胺反应,经过4-环丙基氨基-2-氯硝基苯(m.p.94-98℃),给出7-氯-1-环丙基-1,4-二氢-6-硝基-4-氧-3-喹啉羧酸,m.p.278-281℃(分解)。
实施例3
将4.37g3-氯-4-氟苯胺(30mmol)、7.4g1-溴-1-乙氧基环丙烷(45mmol)和4.5g三乙胺(45mmol)在30ml二氯甲烷中煮沸48小时。然后将混合物用水洗涤数次,硫酸钠干燥并浓缩。残留物以二氯甲烷为洗脱剂进行硅胶层析纯化。
还原时,在冰冷却下制备2.28g硼氢化钠(60mmol)和8.5g三氟化硼乙醚合物(60mmol)在60ml无水四氢呋喃中的混合物,并在冰冷却下搅拌1小时,再加入得到的3-氯-N-(1-乙氧基环丙基)-4-氟苯胺并加热回流1.5小时。然后浓缩反应混合物,并将残留物溶于二氯甲烷,用水洗涤,硫酸钠干燥并浓缩。
将得到的粗产物(5.4g)在50ml二苯基醚中与6.1g甲氧基亚甲基丙二酸二乙酯在240℃时加热30分钟,然后真空下除去溶剂。残留物用乙二醇单甲醚重结晶,得到5.6g7-氯-1-环丙基-6-氟-1,4-二氢-4-氧-3-喹啉羧酸乙酯,m.p.219-221℃,文献值:220℃(Liebigs Ann.Chem.1987,20)。
实施例4
以3,4-二氟苯胺为起始原料,按照与实施例3相似的方法得到了1-环丙基-6,7-二氟-1,4-二氢-4-氧-3-喹啉羧酸乙酯,m.p.225-7℃。
实施例5
以2,3,4-三氟苯胺为起始原料,按照相似于实施例3的方法得到了1-环丙基-6,7,8-三氟-1,4-二氢-4-氧-3-喹啉羧酸乙酯,m.p.167-8℃。
Claims (5)
1、制备如式(Ⅰ)所示的喹诺酮羧酸衍生物的方法,
式中R2表示氢、C1~3烷基或卤素,
X1表示氢、C1~3烷基、卤素或NR8R8,其中R8和R9及与它们链连着的氮原子一起形成五员环或六员环,环还可以含有另外的原子或基团 NR10或O作为环的成员,并且可被C1~3烷基、羟基、烷氧基或NR11R12任意地单取代或双取代,其中R10和R11可以是相同的或不同的,并且表示氢或C1~3烷基,R12表示氢、C1~3烷基、乙酰基或叔丁氧羰基,
X2和X3可以是相同或不同的,并且表示氢、硝基或卤素,
A表示氮或基团C-X4,其中X4表示氢,C1~3烷基、含1-3个碳原子的烷氧基、含1~3个碳原子的烷硫基、卤素、硝基、氰基或醇部分最多含有3个碳原子的烷氧羰基,
Y表示腈基、酯基COOR5或酰胺基CONR6R7,其中R5表示C1~3烷基、R6和R7可以是相同的或不同的,并且表示氢或C1~3烷基、R6可为任意取代的苯基,
所述方法的特征在于:第一步先使式(Ⅱ)的苯胺与式(Ⅲ)的环丙烷衍生物反应,消除HX5而得到N-环丙基苯胺(Ⅳ),
式中X1、X2、X3和A具有上述意义,
式中X5表示卤素,
R1表示含1~3个碳原子的烷基,
R2具有上述意义,
Z表示氧或硫,
将(Ⅳ)化合物还原转化成式(Ⅴ)化合物,
接着按照下述反应式使式(Ⅴ)化合物与式(Ⅵ)的烯衍生物反应,消除R3OH和R4OH,得到喹诺酮羧酸衍生物(Ⅰ),
式中Y具有上述意义,
R3和R4是相同的或不同的,并且表示C1~3烷基。
2、根据权利要求1的制备式(Ⅰ)的喹诺酮羧酸衍生物的方法,
式中R2表示氢或卤素,
X1表示卤素或NR8R9,其中R8和R9以及与它们键连着的氮原子一起形成五员环或六员环,环还可以含有另外的原子或基团 NR10或O作为环的成员,并可被C1~3烷基、羟基、甲氧基或NR11R12任意地单取代或双取代,其中R10和R11可以是相同的或不同的,并且表示氢或C1~3烷基,R12表示氢、C1~3烷基、乙酰基或叔丁氧羰基,
X2表示氟,
X3表示氢、硝基或卤素,
A表示氮或基团C-X4,其中X4表示氢、卤素或硝基,
Y表示腈基或酯基COOR5,其中R5表示C1~3烷基,其特征在于,先使式(Ⅱ)的苯胺与式(Ⅲ)的环丙烷衍生物按下述反应式反应,消除HX5给出N-环丙基苯胺(Ⅳ),
式中X1、X2、X3和A具有上述意义,
式中X5表示氯或溴,
R1表示C1~3烷基,
R2具有上述意义,
Z表示氧或硫,
将式(Ⅳ)化合物还原成式(Ⅴ)化合物,
接着,再使式(Ⅴ)化合物与式(Ⅵ)的烯衍生物反应,消除R3OH和R4OH而得到喹诺酮羧酸衍生物(Ⅰ),
式中Y具有上述意义,
R3和R4可以是相同的或不同的,并且表示甲基或乙基。
3、根据权利要求1制备如式(Ⅰ)所示的喹诺酮羧酸衍生物的方法,
式中R2表示氟或氯,特别是表示氢,
X1表示氯、氟或NR8R9,其中R8和R9及其它们键连着的氮原子一起形成五员环或六员环,环还可以另外含有基团 NR10作为环的成员,并且环可被甲基、羟基、甲氧基或NR11R12任意地单取代或双取代,其中R10和R11可以是相同的或不同的,并且表示氢或甲基,R12表示氢、C1~3烷基、乙酰基或叔丁氧羰基,
X2表示氟,
X3表示氢或硝基,
A表示C-X4,其中X4表示氢、甲基、氟或氯,
Y表示酯基COOR5,其中R5表示甲基或乙基,
其特征在于:先使式(Ⅱ)的苯胺与式(Ⅲ)的环丙烷衍生物按下述反应式反应,消除HX5而得到N-环丙基苯胺(Ⅳ),
式中X1、X2、X3和A具有上述意义,
式中X5表示溴,
R1表示乙基,
R2具有上述意义,
Z表示氧或硫,
再将式(Ⅳ)化合物还原成式(Ⅴ)化合物,
然后再使式(Ⅴ)化合物与式(Ⅵ)的烯衍生物反应,消除R3OH和R4OH得到喹诺酮羧酸衍生物(Ⅰ),
式中Y具有上述意义,
R3表示甲基,
R4表示甲基或乙基。
4、式(Ⅳ)所示的N-环丙基苯胺类化合物,
式中R2表示氢、C1~3烷基或卤素,
X1表示氢、C1~3烷基、卤素或NR8R9,其中R8和R9与及其它们键连着的氮原子一起形成五员环或六员环,环还可以含有另外的原子或基团 NR10或O作为环的成员,环可以被C1~3烷基、羟基、甲氧基或NR11R12任意地单取代或双取代,其中R10和R11可以相同或不同,并且表示氢或C1~3烷基,R12表示氢、C1~3烷基、乙酰基或叔丁氧羰基,
X2和X3可以是相同的或不同的,并且表示氢、硝基或卤素,
A表示氮或基团C-X4,其中X4表示氢、C1~3烷基、含1~3个碳原子的烷氧基、含1~3个碳原子的烷硫基、卤素硝基、氰基或醇部分最多含有3个碳原子的烷氧羰基,
R1表示含1~3个碳原子的烷基,
Z表示氧或硫。
5、权利要求4的式(Ⅳ)化合物在制备喹诺酮羧酸衍生物中的应用。
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HUT67395A (en) * | 1993-07-13 | 1995-04-28 | Somfai | Method for the n-cyclopropylation of primary and secondary aromatic amines |
DE19720541A1 (de) | 1997-05-16 | 1998-11-19 | Bayer Ag | Verfahren zur kontinuierlichen Herstellung von Dihydroxydiphenylalkanen |
DE19720540A1 (de) | 1997-05-16 | 1998-11-19 | Bayer Ag | Verfahren zur Aufarbeitung von Mutterlaugen aus der Bisphenolsynthese |
JP2000229946A (ja) * | 1998-12-10 | 2000-08-22 | Toyama Chem Co Ltd | キノロンカルボン酸の製造法およびその中間体 |
US20100074949A1 (en) | 2008-08-13 | 2010-03-25 | William Rowe | Pharmaceutical composition and administration thereof |
US8354427B2 (en) | 2004-06-24 | 2013-01-15 | Vertex Pharmaceutical Incorporated | Modulators of ATP-binding cassette transporters |
CN107501099B (zh) | 2004-06-24 | 2021-03-19 | 沃泰克斯药物股份有限公司 | Atp-结合弹夹转运蛋白的调控剂 |
PL1993360T3 (pl) | 2005-12-28 | 2017-08-31 | Vertex Pharmaceuticals Incorporated | Stałe postacie n-[2,4-bis(1,1-dimetyloetylo)-5-hydroksyfenylo]-1,4- dihydro-4-oksochinolino-3-karboksyamidu |
WO2010065905A2 (en) * | 2008-12-05 | 2010-06-10 | Oregon Health & Science University | Compounds having antiparasitic or anti-infectious activity |
US8598354B2 (en) | 2008-12-05 | 2013-12-03 | University Of South Florida | Compounds having antiparasitic or anti-infectious activity |
KR101955863B1 (ko) | 2009-03-20 | 2019-03-07 | 버텍스 파마슈티칼스 인코포레이티드 | 낭성 섬유증 막횡단 전도도 조절자의 조정자의 제조 방법 |
US8802700B2 (en) | 2010-12-10 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
IL265430B2 (en) | 2012-02-27 | 2024-08-01 | Vertex Pharma | Pharmaceutical preparations containing a solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and uses thereof |
AU2015330923B2 (en) | 2014-10-07 | 2020-03-12 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
-
1988
- 1988-03-11 DE DE3808117A patent/DE3808117A1/de not_active Withdrawn
-
1989
- 1989-03-01 EP EP89103547A patent/EP0332033A2/de not_active Withdrawn
- 1989-03-02 JP JP1048690A patent/JPH024778A/ja active Pending
- 1989-03-08 IL IL89534A patent/IL89534A0/xx unknown
- 1989-03-09 PT PT89955A patent/PT89955A/pt not_active Application Discontinuation
- 1989-03-09 FI FI891122A patent/FI891122A/fi not_active Application Discontinuation
- 1989-03-10 KR KR1019890002951A patent/KR890014486A/ko not_active IP Right Cessation
- 1989-03-10 HU HU891182A patent/HUT50781A/hu unknown
- 1989-03-11 CN CN89103163A patent/CN1037147A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
FI891122A (fi) | 1989-09-12 |
JPH024778A (ja) | 1990-01-09 |
HUT50781A (en) | 1990-03-28 |
PT89955A (pt) | 1989-11-10 |
KR890014486A (ko) | 1989-10-24 |
EP0332033A2 (de) | 1989-09-13 |
IL89534A0 (en) | 1989-09-10 |
FI891122A0 (fi) | 1989-03-09 |
DE3808117A1 (de) | 1989-09-21 |
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