CS270577B2 - Method of quinoline carboxylic acids production - Google Patents
Method of quinoline carboxylic acids production Download PDFInfo
- Publication number
- CS270577B2 CS270577B2 CS878688A CS868887A CS270577B2 CS 270577 B2 CS270577 B2 CS 270577B2 CS 878688 A CS878688 A CS 878688A CS 868887 A CS868887 A CS 868887A CS 270577 B2 CS270577 B2 CS 270577B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- group
- oxo
- cyclopropyl
- dihydro
- fluoro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 24
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- -1 methoxy, amino, methylamino Chemical group 0.000 claims description 71
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000011541 reaction mixture Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052801 chlorine Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- ISPVACVJFUIDPD-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ISPVACVJFUIDPD-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- KNEXGVPHPGXAGF-UHFFFAOYSA-N 1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 KNEXGVPHPGXAGF-UHFFFAOYSA-N 0.000 claims description 3
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 3
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 208000024780 Urticaria Diseases 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 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 4
- 238000001816 cooling Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- PCSAPCNEJUEIGU-UHFFFAOYSA-N 2,4-dichloro-5-fluoro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(Cl)C([N+]([O-])=O)=C1Cl PCSAPCNEJUEIGU-UHFFFAOYSA-N 0.000 description 3
- BWQMAOINYNKMSK-UHFFFAOYSA-N 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=C(Cl)C(F)=CC(C(Cl)=O)=C1Cl BWQMAOINYNKMSK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- NMASXYCNDJMMFR-UHFFFAOYSA-N 1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 NMASXYCNDJMMFR-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- ZYEWNAMVVRPNJX-UHFFFAOYSA-N 2,3,4,5-tetrafluorobenzoyl fluoride Chemical compound FC(=O)C1=CC(F)=C(F)C(F)=C1F ZYEWNAMVVRPNJX-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- VZQWDTRNBPDEGB-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C([N+]([O-])=O)C(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 VZQWDTRNBPDEGB-UHFFFAOYSA-N 0.000 description 2
- ZHFGWIOLVRSZNQ-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(Cl)C(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ZHFGWIOLVRSZNQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000011775 sodium fluoride Substances 0.000 description 2
- 235000013024 sodium fluoride Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- NSMWYRLQHIXVAP-OLQVQODUSA-N (2r,5s)-2,5-dimethylpiperazine Chemical compound C[C@H]1CN[C@H](C)CN1 NSMWYRLQHIXVAP-OLQVQODUSA-N 0.000 description 1
- IFNWESYYDINUHV-PHDIDXHHSA-N (2r,6r)-2,6-dimethylpiperazine Chemical compound C[C@@H]1CNC[C@@H](C)N1 IFNWESYYDINUHV-PHDIDXHHSA-N 0.000 description 1
- NSMWYRLQHIXVAP-WDSKDSINSA-N (2s,5s)-2,5-dimethylpiperazine Chemical compound C[C@H]1CN[C@@H](C)CN1 NSMWYRLQHIXVAP-WDSKDSINSA-N 0.000 description 1
- IFNWESYYDINUHV-OLQVQODUSA-N (2s,6r)-2,6-dimethylpiperazine Chemical compound C[C@H]1CNC[C@@H](C)N1 IFNWESYYDINUHV-OLQVQODUSA-N 0.000 description 1
- ARHYWWAJZDAYDJ-UHFFFAOYSA-N 1,2-dimethylpiperazine Chemical compound CC1CNCCN1C ARHYWWAJZDAYDJ-UHFFFAOYSA-N 0.000 description 1
- BDGJUVBOIQSLOE-UHFFFAOYSA-N 1,3-dichloro-2,4-difluoro-5-(fluoromethyl)benzene Chemical compound FCC1=CC(Cl)=C(F)C(Cl)=C1F BDGJUVBOIQSLOE-UHFFFAOYSA-N 0.000 description 1
- JXWCOCIEGOAZOG-UHFFFAOYSA-N 1,5-dichloro-2-fluoro-4-methylbenzene Chemical compound CC1=CC(F)=C(Cl)C=C1Cl JXWCOCIEGOAZOG-UHFFFAOYSA-N 0.000 description 1
- ANHDTIZJXXMRCV-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC=CC=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1F ANHDTIZJXXMRCV-UHFFFAOYSA-N 0.000 description 1
- MSSDTZLYNMFTKN-UHFFFAOYSA-N 1-Piperazinecarboxaldehyde Chemical compound O=CN1CCNCC1 MSSDTZLYNMFTKN-UHFFFAOYSA-N 0.000 description 1
- ITXLERDKFZOJPO-UHFFFAOYSA-N 1-cyclopropyl-6,8-difluoro-7-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound CN1CC2CC1CN2C(C=1F)=C(F)C=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 ITXLERDKFZOJPO-UHFFFAOYSA-N 0.000 description 1
- JNUTUHAUMNUZAG-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-(5-prop-2-ynyl-2,5-diazabicyclo[2.2.2]octan-2-yl)quinoline-3-carboxylic acid Chemical compound C12=CC(N3C4CCC(N(C4)CC#C)C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 JNUTUHAUMNUZAG-UHFFFAOYSA-N 0.000 description 1
- QMLVECGLEOSESV-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-7-(5-methyl-2-aza-5-azoniabicyclo[2.2.1]heptan-2-yl)-4-oxoquinoline-3-carboxylate Chemical compound CN1CC2CC1CN2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-UHFFFAOYSA-N 0.000 description 1
- WBAZKXNBWFVTFI-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-7-(5-methyl-2-aza-5-azoniabicyclo[2.2.2]octan-2-yl)-4-oxoquinoline-3-carboxylate Chemical compound CN1CC2CCC1CN2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 WBAZKXNBWFVTFI-UHFFFAOYSA-N 0.000 description 1
- BDXOBBWCDGYVPB-UHFFFAOYSA-N 1-cyclopropyl-7-(1,4-diazabicyclo[3.2.1]octan-4-yl)-6-fluoro-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)C)N1CCN2CCC1C2)F)=O)C(=O)O BDXOBBWCDGYVPB-UHFFFAOYSA-N 0.000 description 1
- YEGBYBZWOAXYLK-UHFFFAOYSA-N 1-cyclopropyl-7-(2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(N3C4CCC(NC4)C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 YEGBYBZWOAXYLK-UHFFFAOYSA-N 0.000 description 1
- JGNYZYABUWGSJV-UHFFFAOYSA-N 1-cyclopropyl-7-(2,5-diazabicyclo[2.2.2]octan-2-yl)-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(N3C4CCC(NC4)C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 JGNYZYABUWGSJV-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-ZIEKVONGSA-N 1-ethylpiperazine Chemical class CCN1CCN[13CH2][13CH2]1 WGCYRFWNGRMRJA-ZIEKVONGSA-N 0.000 description 1
- SFKRXQKJTIYUAG-UHFFFAOYSA-N 2,3,4,5-tetrafluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(F)=C1F SFKRXQKJTIYUAG-UHFFFAOYSA-N 0.000 description 1
- XWCKIXLTBNGIHV-UHFFFAOYSA-N 2,3,4,5-tetrafluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(F)C(F)=C1F XWCKIXLTBNGIHV-UHFFFAOYSA-N 0.000 description 1
- RIZUCYSQUWMQLX-UHFFFAOYSA-N 2,3-dimethylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1C RIZUCYSQUWMQLX-UHFFFAOYSA-N 0.000 description 1
- KZCWJHUTTSVCRO-UHFFFAOYSA-N 2,4-dichloro-5-fluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(Cl)C=C1Cl KZCWJHUTTSVCRO-UHFFFAOYSA-N 0.000 description 1
- RPZXUSJCSDQNTE-UHFFFAOYSA-N 2,4-dichloro-5-fluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(Cl)C=C1Cl RPZXUSJCSDQNTE-UHFFFAOYSA-N 0.000 description 1
- IFNWESYYDINUHV-UHFFFAOYSA-N 2,6-dimethylpiperazine Chemical compound CC1CNCC(C)N1 IFNWESYYDINUHV-UHFFFAOYSA-N 0.000 description 1
- BYYCSTYYULCJLQ-UHFFFAOYSA-N 2-(2-methylpropyl)piperazine Chemical compound CC(C)CC1CNCCN1 BYYCSTYYULCJLQ-UHFFFAOYSA-N 0.000 description 1
- DXOHZOPKNFZZAD-UHFFFAOYSA-N 2-ethylpiperazine Chemical compound CCC1CNCCN1 DXOHZOPKNFZZAD-UHFFFAOYSA-N 0.000 description 1
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 1
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 1
- HJBIXRKZHZQGKZ-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 HJBIXRKZHZQGKZ-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- HBCSNWKQNPKIHK-UHFFFAOYSA-N 2-propan-2-ylpiperazine Chemical compound CC(C)C1CNCCN1 HBCSNWKQNPKIHK-UHFFFAOYSA-N 0.000 description 1
- FNJWLOHHZVGUIX-UHFFFAOYSA-N 2-propylpiperazine Chemical compound CCCC1CNCCN1 FNJWLOHHZVGUIX-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- MHTQOWXOYVNDMH-UHFFFAOYSA-N 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoic acid Chemical compound OC(=O)CC(=O)C1=CC(F)=C(F)C(Cl)=C1F MHTQOWXOYVNDMH-UHFFFAOYSA-N 0.000 description 1
- RMBZGFRPRFOSCD-UHFFFAOYSA-N 3-(cyclopropylamino)prop-2-enoic acid Chemical compound OC(=O)C=CNC1CC1 RMBZGFRPRFOSCD-UHFFFAOYSA-N 0.000 description 1
- IEDMMCZBIKXEJP-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(F)C(Cl)=C1F IEDMMCZBIKXEJP-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- UJSLOZAVHMSQNG-UHFFFAOYSA-N 4-oxo-3h-quinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C(=O)O)C=NC2=C1 UJSLOZAVHMSQNG-UHFFFAOYSA-N 0.000 description 1
- PTHNNGVSMMURMJ-UHFFFAOYSA-N 5,6-dihydrobenzo[h]quinoline-2-carboxylic acid Chemical compound N1=C(C=CC=2CCC3=C(C1=2)C=CC=C3)C(=O)O PTHNNGVSMMURMJ-UHFFFAOYSA-N 0.000 description 1
- HDPODBQAFOAFJY-UHFFFAOYSA-N 5-chloro-2,3,4-trifluorobenzoyl fluoride Chemical compound FC(=O)C1=CC(Cl)=C(F)C(F)=C1F HDPODBQAFOAFJY-UHFFFAOYSA-N 0.000 description 1
- YDCABRFIMRVMGF-UHFFFAOYSA-N 6,8-dichloro-1-cyclopropyl-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid Chemical compound C12=C(Cl)C(N3CCNCC3)=C(Cl)C=C2C(=O)C(C(=O)O)=CN1C1CC1 YDCABRFIMRVMGF-UHFFFAOYSA-N 0.000 description 1
- UMJMPQGMWKLZEC-UHFFFAOYSA-N 6,8-dichloro-1-cyclopropyl-7-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(Cl)C(F)=C(Cl)C=C2C(=O)C(C(=O)O)=CN1C1CC1 UMJMPQGMWKLZEC-UHFFFAOYSA-N 0.000 description 1
- KWJDQEWXENHGMW-UHFFFAOYSA-N 6-chloro-1-cyclopropyl-7,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(F)=C(Cl)C=C2C(=O)C(C(=O)O)=CN1C1CC1 KWJDQEWXENHGMW-UHFFFAOYSA-N 0.000 description 1
- RQBLLVJGAAWYEN-UHFFFAOYSA-N 6-chloro-1-cyclopropyl-8-fluoro-4-oxo-7-(4-propan-2-ylpiperazin-1-yl)quinoline-3-carboxylic acid Chemical compound C1CN(C(C)C)CCN1C1=C(Cl)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F RQBLLVJGAAWYEN-UHFFFAOYSA-N 0.000 description 1
- URLFJCGEAZUVFK-UHFFFAOYSA-N 6-chloro-1-cyclopropyl-8-fluoro-7-[3-(4-methoxyphenyl)piperazin-1-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1NCCN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=CC=2Cl)F)C1 URLFJCGEAZUVFK-UHFFFAOYSA-N 0.000 description 1
- LHZDPJRHQVYKPA-UHFFFAOYSA-N 7-(2-aza-5-azoniabicyclo[2.2.1]heptan-2-yl)-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(N3C4CC(NC4)C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 LHZDPJRHQVYKPA-UHFFFAOYSA-N 0.000 description 1
- DFACKXMBSZDJTQ-UHFFFAOYSA-N 7-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(N3C4CC(N(C4)CC=4C=CC=CC=4)C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DFACKXMBSZDJTQ-UHFFFAOYSA-N 0.000 description 1
- SUVHVMBUDRXNKI-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-6-fluoro-4-oxo-7-(3-phenylpiperazin-1-yl)quinoline-3-carboxylic acid Chemical compound C12=C(Cl)C(N3CC(NCC3)C=3C=CC=CC=3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 SUVHVMBUDRXNKI-UHFFFAOYSA-N 0.000 description 1
- MVXLDPRRAAVKTB-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-6-fluoro-4-oxo-7-piperidin-1-ylquinoline-3-carboxylic acid Chemical compound C12=C(Cl)C(N3CCCCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MVXLDPRRAAVKTB-UHFFFAOYSA-N 0.000 description 1
- FZMLPRJNWFWIIK-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-7-(4-ethyl-3-oxopiperazin-1-yl)-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1C(=O)N(CC)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl FZMLPRJNWFWIIK-UHFFFAOYSA-N 0.000 description 1
- OASCSOIVISTYGS-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-7-[3-(3,4-dimethoxyphenyl)piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(OC)C(OC)=CC=C1C1NCCN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=CC=2F)Cl)C1 OASCSOIVISTYGS-UHFFFAOYSA-N 0.000 description 1
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 1
- CCKMPJCQCAUMLM-UHFFFAOYSA-N C12=C(Cl)C(N3C4CN(C4)CC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 Chemical compound C12=C(Cl)C(N3C4CN(C4)CC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 CCKMPJCQCAUMLM-UHFFFAOYSA-N 0.000 description 1
- OGYCESUAAKCZKZ-UHFFFAOYSA-N C1C(N2)CC(O)CC2CN1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 Chemical compound C1C(N2)CC(O)CC2CN1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 OGYCESUAAKCZKZ-UHFFFAOYSA-N 0.000 description 1
- ISOXNKJOELNAKZ-UHFFFAOYSA-N CC(CCCCC)C1=NC2=CC=CC=C2C=C1C(=O)O Chemical compound CC(CCCCC)C1=NC2=CC=CC=C2C=C1C(=O)O ISOXNKJOELNAKZ-UHFFFAOYSA-N 0.000 description 1
- UIUMVYUNAMACHR-UHFFFAOYSA-N CCC(CCCCC)C=1N(C2=CC=C(C=C2C(C1C(=O)O)=O)F)C1CC1 Chemical compound CCC(CCCCC)C=1N(C2=CC=C(C=C2C(C1C(=O)O)=O)F)C1CC1 UIUMVYUNAMACHR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- MOVMCBGQQLGROS-UHFFFAOYSA-N Cl.C1(CC1)N1C=C(C(C2=CC(=C(C=C12)N1CCN2CCC1C2)F)=O)C(=O)O Chemical compound Cl.C1(CC1)N1C=C(C(C2=CC(=C(C=C12)N1CCN2CCC1C2)F)=O)C(=O)O MOVMCBGQQLGROS-UHFFFAOYSA-N 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical class CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- GYIWFHXWLCXGQO-UHFFFAOYSA-N barium(2+);ethanolate Chemical compound [Ba+2].CC[O-].CC[O-] GYIWFHXWLCXGQO-UHFFFAOYSA-N 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 description 1
- 230000004665 defense response Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- ZKBBUZRGPULIRN-UHFFFAOYSA-N diethyl 2,2-diethylpropanedioate Chemical compound CCOC(=O)C(CC)(CC)C(=O)OCC ZKBBUZRGPULIRN-UHFFFAOYSA-N 0.000 description 1
- UMCIIIXCSXZJNZ-UHFFFAOYSA-N diethyl 2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C(=O)C1=CC(F)=C(Cl)C([N+]([O-])=O)=C1Cl UMCIIIXCSXZJNZ-UHFFFAOYSA-N 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- GCJYPXZGQIYKRF-UHFFFAOYSA-N ethyl 2-(3,5-dichloro-2,4-difluorobenzoyl)-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=CC(Cl)=C(F)C(Cl)=C1F GCJYPXZGQIYKRF-UHFFFAOYSA-N 0.000 description 1
- BNEXAOCXYOUGIB-UHFFFAOYSA-N ethyl 2-(5-chloro-2,3,4-trifluorobenzoyl)-3-(cyclopropylamino)prop-2-enoate Chemical compound C=1C(Cl)=C(F)C(F)=C(F)C=1C(=O)C(C(=O)OCC)=CNC1CC1 BNEXAOCXYOUGIB-UHFFFAOYSA-N 0.000 description 1
- KOPFQNRNKNWYHK-UHFFFAOYSA-N ethyl 2-(5-chloro-2,3,4-trifluorobenzoyl)-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=CC(Cl)=C(F)C(F)=C1F KOPFQNRNKNWYHK-UHFFFAOYSA-N 0.000 description 1
- JIVWQBJMHFWMKG-UHFFFAOYSA-N ethyl 3-(2,4-dichloro-5-fluoro-3-nitrophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(Cl)C([N+]([O-])=O)=C1Cl JIVWQBJMHFWMKG-UHFFFAOYSA-N 0.000 description 1
- VIAZYLXGWMAOOA-UHFFFAOYSA-N ethyl 3-(3,5-dichloro-2,4-difluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(Cl)=C(F)C(Cl)=C1F VIAZYLXGWMAOOA-UHFFFAOYSA-N 0.000 description 1
- UCFRMVIODHQKQP-UHFFFAOYSA-N ethyl 3-(cyclopropylamino)-2-(3,5-dichloro-2,4-difluorobenzoyl)prop-2-enoate Chemical compound C=1C(Cl)=C(F)C(Cl)=C(F)C=1C(=O)C(C(=O)OCC)=CNC1CC1 UCFRMVIODHQKQP-UHFFFAOYSA-N 0.000 description 1
- ITQFPVUDTFABDH-UHFFFAOYSA-N ethyl 3-ethoxyprop-2-enoate Chemical compound CCOC=CC(=O)OCC ITQFPVUDTFABDH-UHFFFAOYSA-N 0.000 description 1
- FCGILORQEAHNMB-UHFFFAOYSA-N ethyl 6,8-dichloro-1-cyclopropyl-7-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Cl)C(F)=C(Cl)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 FCGILORQEAHNMB-UHFFFAOYSA-N 0.000 description 1
- UUAYWVOLZVLIAX-UHFFFAOYSA-N ethyl 6-chloro-1-cyclopropyl-7,8-difluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(Cl)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 UUAYWVOLZVLIAX-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- OQCUGPQOZNYIMV-UHFFFAOYSA-N pyrrolidin-3-ylmethanamine Chemical compound NCC1CCNC1 OQCUGPQOZNYIMV-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- CESKLHVYGRFMFP-UHFFFAOYSA-N sulfonmethane Chemical compound CCS(=O)(=O)C(C)(C)S(=O)(=O)CC CESKLHVYGRFMFP-UHFFFAOYSA-N 0.000 description 1
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Optical Fibers, Optical Fiber Cores, And Optical Fiber Bundles (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
Description
(57) ZpúSOti výroby sloučenin obecného vzorce I, vc kterém R1 znamená methyl, ethyl, propyl, isopropyl, cyklopropyl, vinyl, 2-hydroxyethyl, 2-fluor-ethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, fenyl, 4-fluorfenyl, ,2,4-difluorfenyl, znamená CN nebo COOR^, kde R^ znamená vodík,(57) PU SO the production of compounds of formula I, VC wherein R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, is CN or COOR 4, wherein R 4 is hydrogen,
C, . -alkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)- methyl·, dále R znamená CON(Cj_4-alkyl)2, R znamená cyklickou aminoskupinu vzorce (a) nebo (b), X znamená halogen, A znamená N nebo C-R^^, kde R^ znamená vodík, halogen, methyl nebo nitroskupinu, spočívající v tom, že se nechají reagovat sloučeniny vzorce II a aminy odpovídající skupinám (a) a (b) bez použití rozpouštědel při teplotách mezi 20 a 200°C, popřípadě za tlaku 0,1 až 20,0 MPa. Vyráběné sloučeniny mají antibakteriální vlastnosti a mohou se používat jako léčiva.C,. -alkyl, (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl, furthermore R represents CON (C 1-4 -alkyl) 2 , R represents a cyclic amino group of formula (a) or (b) X is halogen, A is N or CR 1, wherein R 1 is hydrogen, halogen, methyl or nitro, by reacting compounds of formula II and amines corresponding to groups (a) and (b) without using solvents at temperatures between 20 and 200 ° C, optionally at a pressure of 0.1 to 20.0 MPa. The compounds produced have antibacterial properties and can be used as medicaments.
ϊϊ
Vynález sc týká nového způsobu výroby chinolinkarboxylových kyselin, které se mohou . používat jako takové nebo vo formě svých esterů, solí, prekursorů atd. Jako antlbakteriálnč účinné prostřodky v humánní a veterinární medicině, jakož i jako prostředky stimulující obrannou reakci.The invention relates to a novel process for the preparation of quinolinecarboxylic acids which can be used. used as such or in the form of its esters, salts, precursors, etc. As antibacterial agents in human and veterinary medicine as well as as a means of stimulating a defense response.
Předmětem předloženého vynálezu je způsob výroby sloučenin obecného vzorce I ,The present invention provides a process for the preparation of compounds of formula I,
(X) ve kterém(X) in which
R^ znamená methylovou skupinu, ethylovou skupinu, propylovou skupinu, isopropylovou skupinu, cyklopropylovou skupinu, vinylovou skupinu, 2-hydroxyethylovou skupinu, 2-fluorethylovou skupinu, methoxyskupinu, aminoskupinu, methylaminoskupinu, dimethylaminoskupinu, ethylaminoskupinu, fenylovou skupinu, 4-fluorfenylovou skupinu, 2,4-difluorfenylovou skupinu,R ^ is methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl, 2 , 4-difluorophenyl,
2 *2 *
R znamená skupinu CN nebo skupinu COOR , kde *R is CN or COOR where *
R znamená atom vodíku, alkylovou skupinu s 1 až 4 atomy uhlíku, (5-methyl-2-oxo-l,3-dioxol-4-yl)methylovou skupinu, · dále znamená skupinu C0N(alkyl)2, kde alkyl obsahuje 1 až 4 atomy uhlíku, znamená cyklickou aminoskupinu zvolenou ze skupiny tvořené skupinami vzorcůR is hydrogen, C 1 -C 4 alkyl, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, · C0N (alkyl) 2 , wherein alkyl contains 1 C 4-C, represents a cyclic amino group selected from the group consisting of formulas
přičemž 'whereas '
R znamená atom vodíku, alkylovou skupinu s 1 až 4 atomy uhlíku, 2-hydroxyethylovou skupinu, allylovou skupinu, propargylovou skupinu, 2-oxopropylovou skupinu, 3-oxobutylovou skupinu, fenacylovou skupinu, formylovou skupinu, skupinu CFC12-S-,skupinu CFC12-SO2-, skupinu CH^O-CO-S-, benzylovou skupinu, 4-aminobenzylovou skupinu, skupinu vzorceR is hydrogen, C1-C4alkyl, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, formyl, CFC1 2 -S-, CFC1 2 -SO 2 -, CH 2 O-CO-S-, benzyl, 4-aminobenzyl, formula
К** znamená vodík nebo methylovou skupinu, znamená vodík nebo alkylovou skupinu β 1 až 4 atomy uhlíku,K ** represents hydrogen or a methyl group, represents hydrogen or an alkyl group having 1 to 4 carbon atoms,
R znamená atom vodíku, aminoskupinu, methylaminoskupinu, ethylaminoskupinu, aminomethylovou skupinu, methylaminomethylovou skupinu, ethylaminomethylovou skupinu, dimethylaminomethylovou skupinu, hydroxyskupinu nebo hydroxymethylovou skupinu, gR is hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxy or hydroxymethyl, g
R znamená vodík, methylovou skupinu, ethylovou skupinu nebo atom chloru,R is hydrogen, methyl, ethyl or chlorine,
X znamená atom halogenu, zejména atom fluoru a chloru aX is halogen, especially fluorine and chlorine; and
A znamená atom dusíku N nsbo skupinu C-R11, kdeA represents a nitrogen atom N nsbo CR 11, wherein
R11 znamená atom vodíku, atom halogenu, jako atom fluoru, atom bromu nebo chloru, methylovou skupinu nsbo nitroskupinu, a symboly R6 společně s R1 mohou tvořit můstek vzorceR 11 represents a hydrogen atom, a halogen atom such as a fluorine atom, a bromine or chlorine atom, a methyl group or a nitro group, and R 6 together with R 1 may form a bridge of the formula
-0-CH2-CH^CHr -S-CH2-CH-CH3 nebo-0-CH 2 -CH = CH r -S-CH 2 -CH-CH 3 or
-ch2-ch2-ch-ch3, který spočívá v tom, Že se na sloučeniny obecného vzorce II-ch 2 -ch 2 -ch-ch 3 , characterized in that the compounds of the general formula (II) are treated
OO
ve kterémin which
22
R , R , А а X mají shora uvedený význam, aR, R, A, and X are as defined above, and
Y znamená atom halogenu, zejména fluoru a chloru, nebo znamená nitroskupinu, alkylsulfonylovou skupinu s 1 až 4 atomy uhlíku nebo alkyl• sulfonyloxyskupinu s 1 až 4 atomy uhlíku, působí aminy zvolenými ze skupiny tvořené aminy vzorceY represents a halogen atom, in particular fluorine and chlorine atom, or represents a nitro group, an alkylsulfonyl group having 1 to 4 carbon atoms or an alkylsulfonyloxy group having 1 to 4 carbon atoms, acting with amines selected from the group consisting of amines of the formula
ve kterých , .in which , .
r\ R5, R6, R7 a R° mají shora uvedený význam, .R 1 , R 5 , R 6 , R 7 and R 0 are as defined above,.
’ bez použití rozpouštědel při teplotách mezi 20 θθ a 200 °C, popřípadě za tlaku, výhodně při ? 0,1 až 20,0 MPa.without the use of solvents at temperatures between 20 ° C and 200 ° C, optionally under pressure, preferably at ? 0.1 to 20.0 MPa.
‘ Uvedené aminy jsou při postupu podle vynálezu reakční složkou a současně rozpouštěd* lem. Jsou-li takové aminy při teplotě místnosti pevnými látkami, pak se roztaví a reakce se sloučeninou vzorce II se provádí v tavenině,The amines are a reactant and a solvent in the process according to the invention. If such amines are solids at room temperature, they are melted and the reaction with the compound of formula II is carried out in the melt,
Nutno označit za vysloveně překvapující skutečnost, žeIt should be described as a surprising fact that
a) reakce sloučenin vzorce ’ΓΙ 8 aminy probíhá mnohem vyšší rychlostí, že při použití přídavného rozpouštědla,(a) the reaction of the compounds of formula ’8 amines proceeds at a much higher rate than that when using an additional solvent;
b) reakce probíhá při nižších teplotách, čímž vzniká menší množství vedlejších produktů a(b) the reaction proceeds at lower temperatures, resulting in less by - products; and
c) navzdory nadbytku aminu nedochází к žádné další substituci skupiny X.c) despite the excess of the amine, there is no further substitution of group X.
Posléze zjištěná skutečnost je o to překvapivější, vzhledem к tomu, že když se slouCenina vzorce II dávkuje do aminu, je přítomen alespoň na začátku téměř nekonečně vysoký nadbytek aminu, . Výhody postupu podle vynálezu jsou tudíž následujíoíi , · - Čistší produkt (menší množství vedlejšíoh produktů) v důsledku nižší reakční teploty ' - úspora Času v důsledku vyšší reakční rychlostiThe latter is all the more surprising since, when the compound of formula (II) is dosed into the amine, an almost infinitely high excess of amine is present at least initially. Thus, the advantages of the process of the invention are as follows: - cleaner product (less by-products) due to lower reaction temperature - time savings due to higher reaction rate
- ekonomická výhoda v důsledku odpadnutí přídavného rozpouštědla. ,- economical advantage due to the absence of additional solvent. ,
Poměr sloučenin obecného vzorce II a aminů se může pohybovat v rozmezí od 1 ι 1 do X i 50, výhodně od 1 i 2 do 1 i 10» zoela zvláště výhodně od 1 i 3 do 1 ι 5.The ratio of the compounds of the formula (II) to the amines can range from 1 to 1 to 15, preferably from 1 to 2 to 10, particularly preferably from 1 to 3 to 5.
Reakční teplota se pohybuje v rozmezí od 20 do 200 °C, výhodnš v rozmezí od 80 do 180 °C a zoela zvláště výhodně od 120 do 160 °C«The reaction temperature is between 20 and 200 ° C, preferably between 80 and 180 ° C, and particularly preferably between 120 and 160 ° C.
Při postupu podle vynálezu se jako aminů výhodně používá pyrrolidinu, piperazinu, N-methylpiperazinu, N-ethylpiperazinu, N-(2-hydroxyethyl)-piperazinu, N-formylpiperazinu, 2-methylpiperazinu, 1,2-dimethylpiperazinu, cis- a trans-2,5-dimethylpiperazinu, cis- a trans-2,6-dimethylpiperazinu, 2-ethylpiperazinu, 2-propylpiperazinu, 2-isopropylpiperazinu, 2-isobutylpiperazinu, 3-aminopyrrolidinu a 3-aminomethylpyrrolidinu.In the process according to the invention, the amines are preferably pyrrolidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N- (2-hydroxyethyl) -piperazine, N-formylpiperazine, 2-methylpiperazine, 1,2-dimethylpiperazine, cis- and trans- 2,5-dimethylpiperazine, cis- and trans-2,6-dimethylpiperazine, 2-ethylpiperazine, 2-propylpiperazine, 2-isopropylpiperazine, 2-isobutylpiperazine, 3-aminopyrrolidine and 3-aminomethylpyrrolidine.
Chinolinkarboxylové kyseliny vzorce II se vyrábějí dále popsaným způsobem.The quinolinecarboxylic acids of formula II are prepared as described below.
Příklad AExample A
6-chlor-l~cyklopropyl-7,8-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
COOHCOOH
CS 270677 02CS 270677 02
15,7 g (0,65 mol) hořčíkových třísek se rozmíchá ve 40 ml ethanolu a 2 ml tetrachlor-., methanu a po zahájení reakce se při teplotě 50 až 60 °C přikape 103 g (0,64 mol) diethylesteru malonové kyseliny v 80 ml ethanolu a 250 ml toluenu. Reakční směs se míchá 1 hodinu při této teplotě, potom se ochladí na teplotu -5 až -10 °C, přikape se roztok 138 g (0,65 mol) · 5-chlor-2,3,4-třifluorbenzoylfluoridu v 63 ml toluenu, reakční směs se míchá ještě 1 hodinu při teplotě 0 °C a poté se ponechá přes noc v klidu. Poté se reakční směs zahřívá ještě 2 hodiny na teplotu 40 až 50 °C, potom se ochladí a přidá se к ní 250 ml ledové vody a 38,5 ml koncentrované kyseliny sírové. Organická fáze se oddělí, vodná fáze se dvakrát extrahuje 150 ml toluenu, spojené organické fáze se promyjí nasyceným roztokem chloridu sodného, vysuší se síranem sodným a zahustí se.15.7 g (0.65 mol) of magnesium chips are slurried in 40 ml of ethanol and 2 ml of carbon tetrachloride and after the start of the reaction, 103 g (0.64 mol) of diethyl malonate are added dropwise at 50-60 ° C. in 80 ml of ethanol and 250 ml of toluene. The reaction mixture is stirred at this temperature for 1 hour, then cooled to -5 to -10 ° C, a solution of 138 g (0.65 mol) of 5-chloro-2,3,4-trifluorobenzoyl fluoride in 63 ml of toluene is added dropwise. The reaction mixture was stirred at 0 ° C for 1 h and then left to stand overnight. The reaction mixture was then heated at 40-50 ° C for 2 hours, then cooled and 250 ml of ice water and 38.5 ml of concentrated sulfuric acid were added. The organic phase is separated, the aqueous phase is extracted twice with 150 ml of toluene, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated.
Ke zbytku se přidá 200 ml vody (výhodný je zde přídavek 0,4 g 4-toluensulfonové kyseliny) a reakční směs se zahřívá za účelem desethoxykarboxylace po dobu 5 hodin к varu pod zpětným chladičem. Potom se reakční směs třikrát extrahuje 200 ml dichlormethanu, dichlormethanový extrakt se promyje nasyceným roztokem chloridu sodného, vysuší se síranem sodným, zahustí se a zbytek se destiluje za sníženého tlaku. Získá se 103 g (56,5 S teorie ethylesteru) (5-chlor-2,3,4-trifluorbenzoyl)octové kyseliny o teplotě varu 110 °C/120 Pa.200 ml of water are added to the residue (0.4 g of 4-toluenesulfonic acid is preferred) and the reaction mixture is heated under reflux for 10 hours for 10-carboxylation. The reaction mixture is then extracted three times with 200 ml of dichloromethane, the dichloromethane extract is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and the residue is distilled under reduced pressure. 103 g (56.5% of ethyl ester) of (5-chloro-2,3,4-trifluorobenzoyl) -acetic acid are obtained, b.p. 110 DEG C./120 mbar.
103 g (0,37 mol) získaného esteru a 83 g (0,56 mol) triethylesteru orthomravenčí kyseliny se spolu s 95 g acetanhydridu zahřívá 2 hodiny na teplotu 150 až 160 °C a potom se zahustí při teplotě 120 až 130 °C za atmosférického tlaku a nakonec se v zahušťování pokračuje ve vysokém vakuu. Získá se 115 g (92 \ teorie) ethylesteru 2-(5-chlor-2,3,4-trifluorbenzoyl)-3-ethoxyakrylové kyseliny ve formě oleje.103 g (0.37 mol) of the ester obtained and 83 g (0.56 mol) of orthoformic acid triethyl ester, together with 95 g of acetic anhydride, are heated at 150 to 160 ° C for 2 hours and then concentrated at 120 to 130 ° C. atmospheric pressure and finally the concentration is continued under high vacuum. 115 g (92% of theory) of 2- (5-chloro-2,3,4-trifluorobenzoyl) -3-ethoxyacrylic acid ethyl ester are obtained in the form of an oil.
К 84,1 g (0,25 mol) této sloučeniny ve 170 ml ethanolu se za chlazení ledem přikapeTo 84.1 g (0.25 mol) of this compound in 170 ml of ethanol was added dropwise under ice-cooling
14,8 g (0,26 mol) cyklopropylaminu a reakční směs se míchá 2 hodiny při této teplotě. Potom se reakční směs rozmíchá se 170 ml vody, ochladí se v ledové lázni, vyloučená sraženina se odfiltruje, promyje se vodou a malým množstvím methanolu a vysuší se. Získá se 47 g (54 S teorie) ethylesteru 2-(5-chlor-2,3,4-trifluorbenzoyl)-3-cyklopropylaminoakrylové kyseliny o teplotě tání 71 až 73 °C. Podle ^H-NMR spektra je produkt přítomen ve formě směsi s cis-trans-konfigurací. · g (0,14 mol) této sloučeniny se zahřívá ve 230 ml dimethylformamidu s 0,7 g (0,23 mol) fluoridu sodného po dobu 2 hodin na teplotu 160 až 170 °C. Reakční smés se potom vylije do 400 ml ledové vody, sraženina se odfiltruje, promyje se vodou a vysuší se. Izoluje se 44 g (99 4 teorie) ethylesteru 6-chlor-l-cyklopropyl-7,8-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 169 až 172 °C.14.8 g (0.26 mol) of cyclopropylamine and the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture is stirred with 170 ml of water, cooled in an ice bath, the precipitate formed is filtered off, washed with water and a small amount of methanol and dried. 47 g (54% of theory) of 2- (5-chloro-2,3,4-trifluorobenzoyl) -3-cyclopropylaminoacrylic acid ethyl ester of melting point 71-73 ° C are obtained. According to 1 H-NMR spectrum, the product is present in the form of a mixture with the cis-trans configuration. G (0.14 mol) of this compound was heated in 230 ml of dimethylformamide with 0.7 g (0.23 mol) of sodium fluoride at 160-170 ° C for 2 hours. The reaction mixture is then poured into 400 ml of ice-water, the precipitate is filtered off, washed with water and dried. 44 g (99% of theory) of 6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester of melting point 169 DEG-172 DEG C. are isolated.
К 44 g (0,13 mol) esteru chinolonkarboxylové kyseliny ve 300 ml ledové kyseliny octové a 179 ml vody se přidá33 ml koncentrované kyseliny sírové a reakční směs se zahřívá po dobu 2 hodin na teplotu 150 °C. Poté se reakční směs vmíchá do 400 ml ledové vody, sraženina se odfiltruje, promyje se vodou a vysuší se. Získá se 37 g (95 A teorie) 6-chlor-l-cyklopropyl-7,θ-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 200 až 204 °C.To 44 g (0.13 mol) of the quinolonecarboxylic acid ester in 300 ml of glacial acetic acid and 179 ml of water was added33 ml of concentrated sulfuric acid and the reaction mixture was heated at 150 ° C for 2 hours. The reaction mixture is then stirred into 400 ml of ice water, the precipitate is filtered off, washed with water and dried. 37 g (95 A of theory) of 6-chloro-1-cyclopropyl-7, 6-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 200 DEG-204 DEG C. are obtained.
Příklad ВExample В
8-chlor-l-cyklopropyl-6,7-difluor-l,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
OO
COOHCOOH
CS 270577 82CS 270577 82
3-chlor-2,4,5-trifluorbenzoylchlorid se nechá reagovat analogickým postupem jako v příkladu A, přičemž reakce probíhá přes následující stupně: .3-Chloro-2,4,5-trifluorobenzoyl chloride is reacted in an analogous manner to that described in Example A, the reaction proceeding through the following steps:.
ethyleeter (3-chlor-2,4,5-trlfluorbenzoyl)octové kyseliny ve formé enolu (výtěžeki 52 teorie; teplota tání 72 až 75 °C)j ethylester 2-(2-chlor-2,4,5-trifluorbenzoyl)-3-ethoxyakrylové kyseliny (výtěžek surového produktu: 95 4 teorie; olej);(3-chloro-2,4,5-trifluorobenzoyl) acetic acid ethyl ether (52 theory yield; mp 72-75 ° C) 2- (2-chloro-2,4,5-trifluorobenzoyl) ethyl ester - 3-ethoxyacrylic acid (crude product yield: 95% of theory; oil);
ethylester 2-(3-chlor-2,4,5-trifluorbenzyl)-3-cyklopropylaminoakrylové kyseliny (výtěžek:2- (3-chloro-2,4,5-trifluorobenzyl) -3-cyclopropylaminoacrylic acid ethyl ester (yield:
4 teorie; teplota tání 78 až 80 °C); * ethylester 8-chlor-l-cyklopropy1-6,7-difluor-1,4-dihydro-4-oxo-3-phinolInkarboxylové kyseliny (výtěžek: 85 * teorie; teplota tání 154 ař 157 °C);4 theory; mp 78-80 ° C); * 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-phinolinecarboxylic acid ethyl ester (yield: 85 * theory; mp 154-157 ° C);
8-chlor-l-cyklopropy1-6,7-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxyΙονή kyselina (výtěžek:8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (yield:
97,6 % teorie; teplota tání 189 až 192 °C).97.6% of theory; mp 189-192 ° C).
Příklade .Example.
·. 6,8-dichlor-l-cyklopropyl-7-fluor-1,4-dihýdro-4-oxo-3-chinolinkarboxylová kyselina·. 6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
ClCl
COOHCOOH
3,5-dichlor-2,4-difluorbenzylfluorid se nechá reagovat analogickým postupem jako je popsán v příkladu A, přičemž reakce probíhá přes následující stupně:The 3,5-dichloro-2,4-difluorobenzyl fluoride is reacted in an analogous manner to that described in Example A, the reaction proceeding through the following steps:
ethylester (3,5-dichlor-2,4-dlfluorbenzoyl)octové kyseliny (výtěžek: 43 4; teplota varu(3,5-dichloro-2,4-difluorobenzoyl) acetic acid ethyl ester (yield: 43 4; boiling point)
133 °C/333 Pa)| ethylester 2-(3,5-dichlor-2,4-difluorbenzoyl)-3-ethoxyakrylové kyseliny (výtěžek surového produktu: 91 4 teorie; olej);133 ° C / 333 Pa) 2- (3,5-dichloro-2,4-difluorobenzoyl) -3-ethoxyacrylic acid ethyl ester (crude product yield: 91% of theory; oil);
éthylester 2-(3,5-dichlor-2,4-difluorbenzoyl)-3-cyklopropylaminoakrylové kyseliny (výtěžek: 96 4 teorie; teplota tání 71 až 74 °C);2- (3,5-dichloro-2,4-difluorobenzoyl) -3-cyclopropylaminoacrylic acid ethyl ester (yield: 96%); mp 71-74 ° C);
ethylester 6,8-dichlor-l-cyklopropyl-7-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny (výtěžek: 97 4 teorie; teplota tání 215 až 217 °C za rozkladu); .6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (yield: 97 4 theory; mp 215-217 ° C dec.); .
6,8-dichlor-l-cyklopropyl-7-fluor-1,4-dihydro-4-oxo-4-chinolinkarboxylová kyselina (výtěžek: 93 «í teorie; teplota tání 204 až 206 °C).6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-4-quinolinecarboxylic acid (yield: 93%; mp 204-206 ° C).
Oalší chinolinkarboxylové kyseliny, zejména cyklopropyl-6,7,8-trifluor-1,4-dihydro-4αχα-3-chinolinkarboxylové kyseliny se mohou vyrábět podle následujícího reakčního schématu:Other quinolinecarboxylic acids, in particular cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4α-α-3-quinolinecarboxylic acids, can be prepared according to the following reaction scheme:
(3)(3)
ОО
2Н52 Н 5
(б)(б)
Podle toho se diethylester malonové kyseliny vzorce (2) acyluje v přítomnosti ethoxidu hořefinatého působením 2,3,4,5-tetrefluorbenzoylchlorldu vzorce (1) na ester aroylmalonové kyseliny vzorce (3) (srov. Organicum, 3. vydání, 1964, str. 438).Accordingly, the malonic acid diethyl ester of formula (2) is acylated in the presence of a barium ethoxide by treating 2,3,4,5-tetrefluorobenzoyl chloride of formula (1) with an aroyl malonic ester of formula (3) (cf. Organicum, 3rd edition, 1964, p. 438).
Místo sloučeniny vzorce (1) lze použít také fluoridu 2,3,4,5-tetrafluorbenzoové kyseliny.2,3,4,5-Tetrafluorobenzoic acid fluoride can also be used in place of the compound of formula (1).
Parciálním zmýdelněním a dekarboxylací sloučeniny vzorce (3) ve vodném prostředí katalytickým množstvím kyseliny sírové nebo kyseliny p-toluensulfonové se v dobrém výtěžku získá ethylester aroyloctové kyseliny vzorce (4), který působením smésl triethylesteru orthomravenčí kyseliny a acetanhydridu přechází na ethylester 2-(2,3,4,5-tetrařluorbenzoyl)-3-ethoxyakrylové kyseliny vzorce (5). Reakce sloučeniny vzorce (5) s cyklopropylaminem v rozpouštědle, jako například v methylenchloridu, alkoholu, chloroformu, cyklohexanu nebo toluenu vede při mírné exothermním průběhu к žádanému meziproduktu vzorce (6).Partial saponification and decarboxylation of the compound of formula (3) in aqueous medium with a catalytic amount of sulfuric acid or p-toluenesulfonic acid affords ethyl aroylacetic acid of formula (4) in good yield, which is converted to ethyl 2- (2, 2) by treatment with triethyl orthoformate and acetic anhydride. 3,4,5-Tetrafluorobenzoyl) -3-ethoxyacrylic acid of formula (5). Reaction of the compound of formula (5) with cyclopropylamine in a solvent such as methylene chloride, alcohol, chloroform, cyclohexane or toluene leads to the desired intermediate of formula (6) with a slight exothermic course.
Cyklizační reakce sloučeniny vzorce (6) na sloučeninu vzorce (7) se provádí v rozmezí teplot od asi 60 do 300 °C, výhodně od 80 do 160 °C.The cyclization reaction of the compound of formula (6) to the compound of formula (7) is carried out in a temperature range of about 60 to 300 ° C, preferably 80 to 160 ° C.
Jako ředidla se mohou používat dioxan, dimethylsulfoxid, N-methylpyrrolidon, eulfolan, hexamethyltriamid fosforečné kyseliny a výhodné N,N-dimethylformamid.Diluents which may be used are dioxane, dimethylsulfoxide, N-methylpyrrolidone, eulfolane, hexamethylphosphoric triamide, and preferably N, N-dimethylformamide.
Jako činidla vázající kyselinu přiohézejíoí pro tento reakční stupeň v úvahu terč, butoxid draselný, butyllithium, fenyllithium, fenylmagnesiumbromld, methoxid sodný, hydrid sodný, uhličitan sodný nebo uhličitan draselný a zvláště výhodně fluorid draselný nebo fluorid sodný. Může býti výhodné používat nadbytku 10 molérních procent báze.Suitable acid binding agents for this reaction step include a target, potassium butoxide, butyllithium, phenyllithium, phenylmagnesium bromide, sodium methoxide, sodium hydride, sodium carbonate or potassium carbonate, and particularly preferably potassium fluoride or sodium fluoride. It may be advantageous to use an excess of 10 mole percent base.
Hydrolýza esteru sloučeniny vzorce (7) probíhající v posledním stupni za bázických nebo kyselých podmínek vede к l-cyklopropyl-6,7,8-trifluor-l,4-dihydro-4-oxo-3-chinolinkarboxylové kyselině.Hydrolysis of the ester of the compound of formula (7), carried out in the last step under basic or acidic conditions, yields 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
2,3,4,5-tetrafluorbenzoylchlorid vzorce (1) používaný jako výchozí látka pro tento způsob syntézy se získá obvyklým způsobem z 2,3,4,5-tetrafluorbenzoové kyseliny, která Je známá z literatury (srov. 0. G. Yakobson, V.N. Odinokov a N.N. Vorozhtsov Jr., Žurnál obščij chimii 36, 139 (1966) a thionylchloridu. Získaný produkt má teplotu varu 75 až 80 °C/1700 Pa.The 2,3,4,5-tetrafluorobenzoyl chloride of formula (1) used as the starting material for this synthesis process is obtained in a conventional manner from 2,3,4,5-tetrafluorobenzoic acid which is known in the literature (cf. G. Yakobson) , VN Odinokov and NN Vorozhtsov Jr., Journal obshchij chimii 36, 139 (1966) and thionyl chloride, and the product obtained has a boiling point of 75-80 ° C / 1700 Pa.
2,3,4,5-tetrafluorbsnzoylfluorid má teplotu varu od 46 do 47 °C/2000 Pa (ηθθ » 1,4375).2,3,4,5-tetrafluorobenzoyl fluoride has a boiling point of from 46 to 47 ° C / 2000 Pa (ηθθ »1.4375).
Další chinolln-karboxylové kyseliny se mohou vyrábět následujícím způsobem:Other quinoline carboxylic acids can be prepared as follows:
CH2 CH 2
COOC2H5 (VII)COOC 2 H 5
(VIII)(VIII)
(IX)(IX)
(X)(X)
Podle toho se diethylester malonové kyseliny vzorce VII acyluje sloučeninou vzorce IV v přítomnosti alkoxidu hořečnatého na ester acylmalonové kyseliny vzorce VIII (Organicum,Accordingly, the diethyl malonic ester of formula VII is acylated with a compound of formula IV in the presence of magnesium alkoxide to give an acylmalonic acid ester of formula VIII (Organicum,
3. vydání, 1964, str. 438).3rd edition, 1964, p. 438).
Parciálním zmýdelněním a dekarboxylací sloučeniny vzorce VIII ve vodném prostředí katalytickým množstvím p-toluensulfonové kyseliny se získá v dobrém výtěžku ethyloster aroyloctové kyseliny vzorce IX, který se působením směsi triethylesteru orthomravěnčí кувеИпу a acetanhydridu převede na ethylester 2-(2,4-dichlor-5-fluorbenzoyl)-3-ethoxyakrylové kyseliny vzorce X. Reakce sloučeniny vzorce X s cyklopropylaminem v rozpouštědle, jako například v methylenchloridu, alkoholu, chloroformu, cyklohexanu nebo toluenu vede při mírně exothermním průběhu к žádanému meziproduktu vzorce VI.Partial saponification and decarboxylation of a compound of formula VIII in aqueous medium with a catalytic amount of p-toluenesulfonic acid affords a good yield of ethyl aroylacetic acid of formula IX, which is converted to 2- (2,4-dichloro-5- ethyl ester) by treatment with triethyl orthoformate and acetic anhydride. The reaction of a compound of formula X with cyclopropylamine in a solvent such as methylene chloride, alcohol, chloroform, cyclohexane or toluene results in a slightly exothermic course to the desired intermediate of formula VI.
Cyklizační reakce sloučeniny vzorce VI na sloučeninu vzorce II (R1 c alkyl) se provádí v rozsahu teplot od asi 60 do 280 °C, výhodně od 80 do 180 °C·The cyclization reaction of the compound of formula VI to the compound of formula II (R 1c alkyl) is carried out in a temperature range of from about 60 to 280 ° C, preferably from 80 to 180 ° C.
Jako ředidla se mohou používat dioxan, dimethylsulfoxid, N-methylpyrrolidon, sulfonal, hexamethyltriamid fosforečné kyseliny a výhodně N,N-dimethylformamid.Diluents which may be used are dioxane, dimethylsulfoxide, N-methylpyrrolidone, sulfonal, hexamethylphosphoric triamide and preferably N, N-dimethylformamide.
Jako činidla vázající kyselinu přicházejí v úvahu pro tento účel reakce terč, butoxid draselný, butyllithium, fenyllithium, fenylmagnesiumbromid, ethoxid Bodný a zvláště výhodně hydrid sodný nebo uhličitan draselný. Může být také‘výhodné použít nadbytku báze ve výši 10 molárních procent.Suitable acid-binding agents are, for this purpose, a target, potassium butoxide, butyllithium, phenyllithium, phenylmagnesium bromide, stannous ethoxide, and particularly preferably sodium hydride or potassium carbonate. It may also be advantageous to use an excess of base at 10 mole percent.
2,4-dichlor-5-fluorbenzoylchlorid vzorce IV, který se používá jako výchozí látka pro tento způsob syntézy, jakož i odpovídající karboxylové kyselina a 3-fluor-4,6-dichlortoluen vzorce XI, potřebný pro výrobu sloučeniny vzorce IV, jsou známy z EP-A 2-0 078 362.The 2,4-dichloro-5-fluorobenzoyl chloride of formula IV, which is used as the starting material for this synthesis process, as well as the corresponding carboxylic acid and 3-fluoro-4,6-dichlorotoluene of formula XI required for the preparation of the compound of formula IV from EP-A 2-0 078 362.
Výhodnými sloučeninami, které se mohou vyrábět postupem podle vynálezu jsou sloučeniny poopsané v EP-A2-0 078 362, str. 4, řádky 10 až 16, EP-A-1 0049 355, příklady 1 až 19, DE-OS 3 420 743, str. 35, řádek 20 až str. 37, řádek 11 a OE-OS 3 318 145, str. 31, řádek 1 až str. 32, řádek 13. 'Preferred compounds which can be prepared by the process according to the invention are those described in EP-A2-0 078 362, page 4, lines 10 to 16, EP-A-1 0049 355, examples 1 to 19, DE-OS 3 420 743 page 35, line 20 to page 37, line 11 and OE-OS 3 318 145, page 31, line 1 to page 32, line 13. '
Dalšími sloučeninami, které lze vyrábět postupem podle vynálezu jsou:Other compounds which can be produced by the process of the invention are:
6-chlor-1-cyklopropy1-7-(1,4-diazabicyklo β,2,1] -okt-4-yl)-l,4-dihydro-4-oxo-3-chinolinkarbo106-chloro-1-cyclopropyl-7- (1,4-diazabicyclo [b, 2,1] oct-4-yl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
CS 270577 82 xylová kyselina, „*·CS 270577 82 xylic acid, '* ·
1-cyklopropy1-7-(1,4-diazabicyklo[3,2,13okt-4-yl)-6-fluor-1,4-dihydro-8-methyl-4-oxo-3-chino1inkarboxy1ová kyselina,1-Cyclopropyl-7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid,
7-(l,4-diazabicyklo (з,2,1J okt-4-y1)-6-fluor-1-(2-fluorethy1)-l,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, . ·7- (1,4-diazabicyclo (η, 2,1J oct-4-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;
7-(1,4-diazabicyklo £з,2,1] okt-4-yl)-6-f luor-1-(4-f luorfeny 1)-1,4-dihydro-4-oxo-3-c'hinolinkarboxylová kyselina,7- (1,4-diazabicyclo [2.2.1] oct-4-yl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-3-c quinolinecarboxylic acid,
1-cyklopropy1-7-(1,4-diazabicyklo |S,2,1J okt-4-yl)-6-fluor-1,4-dihydro-4-oxo-l,8-naftyridin-3-karboxylová kyselina,1-cyclopropyl-7- (1,4-diazabicyclo [5.1.1] oct-4-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
7~(1,4-diazabicyklo ^3,2,1] okt-4-yl)-l-ethyl-6-fluor-1,4-dihydro-4-oxo-l,θ-naftyridin-3-кагboxylová kyselina, .7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1, 6-naphthyridine-3-carboxylic acid ,.
7-(l,4-diazabicyklo[j,2,lJ okt-4-yl)-l-ethyl-6-fluor-l,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, *7- (1,4-diazabicyclo [1,2.1] oct-4-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, *
7-(l,4-diazabicyklo [з,2,lJokt-4-yl)-9-fluor-6,7-dihydro-5-methyl-l-oxo-lH,5H-benzo i,j chinolin-2-karboxylová kyselina,7- (1,4-diazabicyclo [2.2.1] oct-4-yl) -9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H, 5H-benzoquinoline-2- carboxylic acid,
7- (l,4-diazabicyklo{3,2,lJ okt-4-yl)-6-fluor-1-(4-fluórfeny1)-1,4-dihydro-4-oxo-l,θ-naftyridin-3-karboxylová kyselina, ethylester l-cyklopropyl-7-(l,4-dlazabicyklo[3,2,l| -okt-4-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, (5-methy1-2-oxo-1,3-dioxol-4-ylmethyl)ester 1-cyklopropy1-7-(1,4-diazabicyklo {S ,2,ljokt-4-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny ,7- (1,4-diazabicyclo {3,2,1J oct-4-yl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1, 6-naphthyridin-3 -carboxylic acid, 1-cyclopropyl-7- (1,4-palzabicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 1-Cyclopropyl-7- (1,4-diazabicyclo {S, 2,1-oct-4-yl) -6-fluoro-1, (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) ester 4-dihydro-4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-7-(1,4-diazabicyklo[з,1,1] hept-4-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, l-cyklopropyl-7-(l,4-diazabicyklo[3,l,1[ hept-4-yl)-6,8-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina,1-Cyclopropyl-7- (1,4-diazabicyclo [з, 1,1] hept-4-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7 - (1,4-diazabicyclo [3.1.1 [hept-4-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
8- chlor-l-cyklopropy 1-7-(1,4-diazabicyklo[*3,1,]J -hept-4-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, l-cyklopropyl-7-(l,4-diazabicyklo [з,1,1] hept-4-yl)-6-fluor-1,4-dihydro-8-methyl-4-охо-З-chlnolinkarboxylová kyselina,8-Chloro-1-cyclopropyl-7- (1,4-diazabicyclo [3.1.1] hept-4-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1-cyclopropyl-7- (1,4-diazabicyclo [з, 1,1] hept-4-yl) -6-fluoro-1,4-dihydro-8-methyl-4-fluoro-2-quinolinecarboxylic acid ,
1-cyklopropy1-7-(1,4-diazabicyklo [з,1,1] hept-4-yl)-6-fluor-1,4-dihydro-4-oxo-l,8-naftyridin-3-karboxylová kyselina, methylester l-cyklopropyl-7-(l,4-diazabicyklo{3,l,1] -hept-4-yl)-6-fluor-1,4-dihydro-4-oxo-1-Cyclopropyl-7- (1,4-diazabicyclo [з, 1,1] hept-4-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid , 1-cyclopropyl-7- (1,4-diazabicyclo {3,1,1] -hept-4-yl) -6-fluoro-1,4-dihydro-4-oxo-methyl ester
3-chinolinkarboxylové kseliny, ’ l-cyklopropyl-6,8-difluor-1,4-dihydro-7-(8-methyl-3,8-diazabicyklo[3,2,3 okt-3-yl)-4-oxo-3-chinolinkarboxylová kyselina,3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (8-methyl-3,8-diazabicyclo [3.2.3 oct-3-yl) -4-oxo -3-quinolinecarboxylic acid,
8-chlor-1-cyklopropy1-6-fluor-1,4-dihydro-7-(8-methy1-3,B-diazabicyklo[з,2, 3 okt-3-yl)-4-oxo-3-chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (8-methyl-3, β-diazabicyclo [η 2, 3 oct-3-yl) -4-oxo-3-quinolinecarboxylic acid acid,
1-cyklopropy1-8-fluor-1,4-dihydro-7-(8-methy1-3,8-diazabicyklo |з,2,1] okt-3-yl)-4-oxo-l,8-nařtyridin-3-karboxylová kyselina,’1-cyclopropyl-8-fluoro-1,4-dihydro-7- (8-methyl-3,8-diazabicyclo [2.2.1] oct-3-yl) -4-oxo-1,8-naphthyridine- 3-carboxylic acid
1-cyklop гору1-6-fluor-1,4-dihydro-7-(3-methy1-3,8-diazabicyklo^3,2,13 okt-8-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (3-methyl-3,8-diazabicyclo [3,2,13] oct-8-yl) -4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-6,8-difluor-1,4-dihydro-7-(3-methy1-3,8-diazgbicyklo ,2,1J okt-8-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-methyl-3,8-diazbicyclo, 2,1J oct-8-yl) -4-oxo-3-quinolinecarboxylic acid,
8-chlor-1-cyklopropy1-6-fluor-1,4-dihydro-7-(3-methy1-3,8-diazabicyklo {з, 2,1J okt-8-yl)-8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (3-methyl-3-,8-diazabicyclo {з, 2,1J-oct-8-yl) -
-4 oxo-3-chinolinkarboxylová kyselina,-4 oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-7-(2,5-diazabicyklo [2,2,1]hept-2-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, l-cyklopropyl-7-(2,5-diazabicyklo [2,2,1] hept-2-yl)-6,8-difluor-1,A-dlhydro-A-oxo^-chino^ linkarboxylová kyselina, ·*1-Cyclopropyl-7- (2,5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7 - (2,5-diazabicyclo [2.2.1] hept-2-yl) -6,8-difluoro-1,1'-dlhydro-N-oxo-4-quinolinecarboxylic acid;
8-chlor-l-cyklopropyl-7-(2,5-diazabicyklo ^2,2,1]-hept-2-yl)-7-fluor-1,4-dihydro-4-oxo-3chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-7- (2,5-diazabicyclo [2.2.1] hept-2-yl) -7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy 1-7-(2,5-diazabicyklo (2,2,l]hept-2-yl)-6-fluor-1,4-dihydro-4-oxo-l,8-naftyridin-3-karboxylová kyselina, .1-cyclopropyl 1-7- (2,5-diazabicyclo (2,2,1] hept-2-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid acid,.
1-cyklopropy1-6-fluor-1,4-dihydro-7- 5-(2-hydroxyethyl)-2,5-diazabicyklo [2,2,1] hept-2-yl)-4-oxo-3-chinolinkarboxylová kyselina, l-cyklopropyl-6-fluor-l,4-dihydro-4-oxo-7- 5-(2-oxopropyl)-2,5-diazabioyklo [2,2,1] hept-2-yl -3-chinolinkarboxylová kyselina,1-Cyclopropyl-6-fluoro-1,4-dihydro-7- 5- (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -4-oxo-3-quinolinecarboxylic acid 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- 5- (2-oxopropyl) -2,5-diazabioyklo [2.2.1] hept-2-yl-3- quinolinecarboxylic acid,
1-cyklopropy1-6-fluor-1,4-dihydro-7-(5-methy1-2,5-diazabicyklo[2,2,1] hept-2-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-cyclopropyl-6-fluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-6,8-difluor-1,4-dihydro-7-(5-methy1-2,5-diazabicyklo[2,2,1] hept-2-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -4-oxo-3-quinolinecarboxylic acid ,
8-chlor-l-cykloproPyl-6-tluor-l,4-dthydro-7-(5-methyl-2,5-diazabicyklo[2,2,1| hept-2-yl)-4-oxo-3-chinolinkarboxylová kyselina,8-chloro-l-cyclopropyl-6-yl P-fluoro-l, 4-dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.1 | hept-2-yl) -4-oxo- 3-quinolinecarboxylic acid,
1-cyklopropy1-7-(8-ethy1-3,8-diazabicyklo[з,2,1}-okt-3-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, , l-cyklopropyl-6-fludr-l,4-dihydro-4-oxo-7- 8-(3-oxobutyl)-3,8-diazabicyklo [з,2,1] okt-3-yl -1-cyclopropyl-7- (8-ethyl-3,8-diazabicyclo [2.2.1] oct-3-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1,1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- 8- (3-oxobutyl) -3,8-diazabicyclo [з, 2.1] oct-3-yl-
3-chinolinkarboxylová kyselina,3-quinolinecarboxylic acid,
7- 8-(4-aminobenzyl)-3,8-diazabicyklo^,2,l] okt-3-yl -l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina, l-cyklopropyl-7-(2,5-diazabicykloJ2,2,2] okt-2-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina,7- 8- (4-aminobenzyl) -3,8-diazabicyclo [2.2.1] oct-3-yl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7- (2,5-diazabicyclo [2.2.2] oct-2-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-7-(2,5-diazabicyklo [2,2,2]okt-2-yl)-6,8-difluor-1,4-dihydro-4- oxo-3-chinolinkarboxylová kyselina,1-Cyclopropyl-7- (2,5-diazabicyclo [2.2.2] oct-2-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
8- chlor-1-cyklopropyl-7-(2,5-diazabicyklo [2,2,2]-jOkt-2-yl)-7-fluor-1,4-dihydro-4-oxo-3chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-7- (2,5-diazabicyclo [2.2.2] oct-2-yl) -7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
1-ucyklopropy1-7-(2,5-diazabicyklo [2,2,2] okt-2-yl)-6-fluor-1,4-dihydro-4-oxo-l,O-naftyridin-3-karboxylová kyselina,1-cyclopropyl-7- (2,5-diazabicyclo [2.2.2] oct-2-yl) -6-fluoro-1,4-dihydro-4-oxo-1,0-naphthyridine-3-carboxylic acid ,
1-cyklopropy1-6-fluor-1,4-dihydro-7-(5-methy1-2,5-diazabicyklo [2,2,2] okt-2-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-cyclopropyl-6-fluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-6,8-difluor-1,4-dihydro-7-(5-methyl-2,5-diazabicyklo Q,2,2]okt-2-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo Q, 2,2] oct-2-yl) -4-oxo-3-quinolinecarboxylic acid,
B-chlor-l-cyklopropyl-6-fluor-l,4-dihydro-7-(5-methyl-2,5-diazabicyklo [2,2,2] okt-2-yl)-4-oxo-3-chinolinkarboxylová kyselina,B-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -4-oxo-3- quinolinecarboxylic acid,
1-cyklopropy1-7-(3,9-diazabicyklo [5,3,1] non-3-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina,1-Cyclopropyl-7- (3,9-diazabicyclo [5.3.1] non-3-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-6-fluor-1,4-dihydro-7-(7-hydroxy-3,9-diazabicyklo [3,3,1] non-3-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-cyclopropyl-6-fluoro-1,4-dihydro-7- (7-hydroxy-3,9-diazabicyclo [3.3.1] non-3-yl) -4-oxo-3-quinolinecarboxylic acid,
1-cyklopropy1-6-fluor-1,4-dihydro-7-(3-oxa-7,9-diazabicyklo [з,3,1] non-7-yl)-4-oxo-3-chinolinkarboxylová kyselina,1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (3-oxa-7,9-diazabicyclo [3.1.1] non-7-yl) -4-oxo-3-quinolinecarboxylic acid,
7-(5-ally1-2,5-diazabicyklo [2,2,1]hept-2-yl)-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-3- .7- (5-allyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-.
-chinolinkarboxylová kyselina,- quinolinecarboxylic acid,
1-cyklopropy1-6-fluor-1,4-dihydro-4-oxo-7-(5-propargy1-2,5-diazabicyklo [2,2,2] okt-2-yl)-3-chinolinkarboxylová kyselina,1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (5-propargyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -3-quinolinecarboxylic acid,
CS 270577 82 hydrochlorid l-cyklopropyl-7-(l,4-diazabicyklo [3,2,1J-okt-4-yl)-6-fluor-1,4-dihydro-4-oxo- · ' -3-chinolinkarboxylové kyseliny o teplotě tání 322 °C, hemiembonát l-cyklopropyl-7-(l,4-diazablcyklo [3,2,1] -okt-4-yl)-6-fluor-1,4-dlhydro-4-oxo-3-chinolinkarboxylové kyseliny od 271 °C, hydrát hydrochloridu B-chlor-l-cyklopropyl-7-(l,4-diazabicyklo[з,2,1] okt-4-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 310 °C,.CS 270577 82 1-Cyclopropyl-7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride m.p. 322 DEG C. 1-cyclopropyl-7- (1,4-diazablicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dlhydro-4-oxo- hemiembonate 3-quinolinecarboxylic acid from 271 ° C, B-chloro-1-cyclopropyl-7- (1,4-diazabicyclo [з, 2,1] oct-4-yl) -6-fluoro-1,4-dihydro hydrochloride -4-oxo-3-quinolinecarboxylic acid, m.p. 310 DEG C .;
1-cyklopropy1-7-(1, 4-diazabicyklo ,2,1] okt-4-yl )-6,8-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina o teplotě tání 275 až 282 °C,’ hydrochlorid l-cyklopropyl-7-(l,4-diazabicyklo [3,2,lf-okt-4-yl)-l,4-dihydro-6-nitro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 303 až,307 °C,.1-Cyclopropyl-7- (1,4-diazabicyclo, 2,1] oct-4-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 275-282 ° C, 1-Cyclopropyl-7- (1,4-diazabicyclo [3.2.1f-oct-4-yl) -1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid hydrochloride o mp 303-307 ° C.
hydrochlorid l-cyklopropyl-7-(l,4-diazabicyklo[з,2,1| -okt-4-yl)-6-fluor-1,4-dihydro-4-oxo-1,8-naftyridin-3-karboxylové kyseliny o teplotě tání nad 300 °C, hydrochlorid 7-(1,4-diazabicyklo[3,2,1] okt-4-yl)-l-ethyl-6,8-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 308 až 312 °C, hydrochlorid 10-(1, 4-diazabicyklo |з,2,1] okt-4-yl)-9-fluor-2,3-dihydro-3-methyl-7-oxo-7H-pyrido 1,2,3-del 1,4 benzoxacin-6-karboxylové kyseliny o teplotě tání 355 °C, hydrochlorid 7-(1,4-diazabicyklo J3,2,1Jokt-4-yl)-6, 8-difluor-1-(4-fluorfenyl)-l,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 310 až 314 °C,1-cyclopropyl-7- (1,4-diazabicyclo [2.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- hydrochloride above 300 ° C, 7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -1-ethyl-6,8-difluoro-1,4-dihydro-4 hydrochloride -oxo-3-quinolinecarboxylic acid, m.p. 308 DEG-312 DEG C., 10- (1,4-diazabicyclo [2.2.1] oct-4-yl) -9-fluoro-2,3-dihydro-3 hydrochloride methyl-7-oxo-7H-pyrido 1,2,3-del 1,4 benzoxacin-6-carboxylic acid, m.p. 355 ° C, 7- (1,4-diazabicyclo [3,2,2] oct-4-yl) hydrochloride yl) -6,8-difluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 310 DEG-314 DEG C .;
1-cyklopropy1-7-(1,4-diazabicyklo jT,2,lJokt-4-yl)-6-fluor-1,4-dihydro-8-nitro-4-oxo-3-ohinolinkarboxylová kyselina o teplotě tání 215 až 232 °C.1-Cyclopropyl-7- (1,4-diazabicyclo [1,2.1] oct-4-yl) -6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid, m.p. 232 DEG.
7-chloř-1-cyklopropy1-6-fluor-1, 4-dihydro-8-nitro-4-oxo-3-chinolinkarboxylová kyselina,7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid,
* Za chlazení ledem a za míchání se к 34 ml koncentrovaná kyseliny sírové přikape 40 ml koncentrované kyseliny dusičné, Do této nitrační směsi os po čéeteoh přidá 20,9 g 2,4-dichior-5-fluorbenzoové kyseliny, přičemž se teplota zvýší na 45 až 50 °C, Potom se reakční směs zahřívá ještě 3 hodiny na teplotu 90 až 100 °C, ochlazená směs se potom vylije na 350 ml ledové vody, sraženina so odfiltruje a promyje ee vodou. Vlhký eurový produkt se za horka rozpustí ve 30 ml methanolu а к získanému roztoku se přidá 150 ml vody.* While cooling with ice and stirring, 40 ml of concentrated nitric acid are added dropwise to 34 ml of concentrated sulfuric acid. To this nitration mixture is added 20.9 g of 2,4-dichloro-5-fluorobenzoic acid to the nitration mixture, increasing the temperature to 45 ml. The reaction mixture is then heated at 90-100 ° C for 3 hours, the cooled mixture is then poured onto 350 ml of ice-water, the precipitate is filtered off and washed with water. The wet euro product is dissolved hot in 30 ml of methanol and 150 ml of water are added to the obtained solution.
Sraženina se za studená odfiltruje, promyje se směsí methanolu a vody a vysuší se za sníženého tlaku při teplotě 80 °C. Získá se 21,2 g surové 2,4-dichlor-5-fluor-3-nitrobenzoové kyseliny. Získaná kyselina je dostatečně čistá pro další reakce. Vzorek překrystalovaný ze směsi toluenu a petroletheru skýtá krystaly o teplotě tání 192 °C.The precipitate is filtered off cold, washed with a mixture of methanol and water and dried under reduced pressure at 80 ° C. 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitrobenzoic acid are obtained. The acid obtained is sufficiently pure for further reactions. A sample recrystallized from a mixture of toluene and petroleum ether yields crystals of m.p. 192 ° C.
b) 2,4-dichlor-5-fluor-3-nitrobenzoylchloridb) 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride
106,6 g 2,4-dichlor-5-fluor-3-nitrobenzoové kyseliny se zahřívá s 250 ml thionylchloridu po dobu 2 hodin к varu pod zpětným chladičem. Nadbytečný thionylchlorid se potom oddestiluje při atmosférickém tlaku a zbytek ee frakcionuje ve vakuu. Při teplotě 110 až 115 °C / 8 až 9 Pa přechází 104,7 g 2,4-dichlor-5-fluor-3-nitrobenzoylchloriduг Stáním se vytvoří krystaly o teplotě tání 55 až 37 °C.106.6 g of 2,4-dichloro-5-fluoro-3-nitrobenzoic acid are heated to reflux with 250 ml of thionyl chloride for 2 hours. Excess thionyl chloride is then distilled off at atmospheric pressure and the residue is fractionated in vacuo. 104.7 g of 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride are passed over at 110 to 115 ° C / 8 to 9 Pa. On standing, crystals of melting point 55-37 ° C are formed.
c) Ethylester (2,4-dichlor-5-fluor-3-nitrobenzoyl)-octové kyseliny(c) (2,4-Dichloro-5-fluoro-3-nitrobenzoyl) -acetic acid ethyl ester
К 10,1 g hořčíkových třísek v 21 ml ethanolu se přidá 2,1 g tetrachlormethanu a po začátku vývoje vodíku se přikape směs sestávající z 66,6 g diethylesteru malonové kyseliny, 4Ό ml ethanolu a 150 ml toluenu při teplotě 50 až 60 °C. Reakční'směs se dále míchá při té- . to teplotě po dobu 1 hodiny, potom se ochladí na teplotu -5 až -10 °C a pozvolna se к ní přikape roztok 109,2 g 2,4-dichlor-5-fluor-3-nitrobenzoylchloridu v 50 ml toluenu. Poté se reakční směs míchá 1 hodinu při teplotě 0 °C, přes noc se nechá teplota vystoupit na teplotu místnosti a potom se ještě 2 hodiny zahřívá na teplotu 40 až 50 °C. К reakční směsi se za chlazení ledem přidá směs sestávající z 160 ml vody a 10,4 ml konoentrované kyseliny sírové a organické fáze se oddělí. Vodná fáze se extrahuje toluenem a spojené organické extrakty se promyjí nasyceným roztokem chloridu sodného, vysuší se síranem sodným a rozpouštědlo se odpaří. Ve formě surového produktu se získá 144,5 g diethylesteru (2,4-dichlor-5-fluor-3-nitrobenzoy1)malonové kyseliny. Tento produkt se po přidání 200 ml vody a 0,6 g 4-toluensulfonové kyseliny zahřívá к varu pod zpětným chladičem, směs se extrahuje methylenchloridem, extrakt se vysuší síranem sodným a rozpouštědlo se oddestiluje ve vakuu. Získá se 110 g ethylesteru substituované benzoyloctové kyseliny ve formě surového produktu. Získaný produkt Je pro další reakce dostatečně čistý.To 10.1 g of magnesium chips in 21 ml of ethanol, 2.1 g of carbon tetrachloride are added, and after the start of hydrogen evolution, a mixture consisting of 66.6 g of diethyl malonate, 4Ό ml of ethanol and 150 ml of toluene is added dropwise at 50 to 60 ° C. . The reaction mixture was further stirred at room temperature. The reaction mixture is cooled to -5 to -10 ° C and a solution of 109.2 g of 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride in 50 ml of toluene is slowly added dropwise. The reaction mixture was stirred at 0 ° C for 1 hour, allowed to warm to room temperature overnight and then heated to 40-50 ° C for 2 hours. A mixture consisting of 160 ml of water and 10.4 ml of concentrated sulfuric acid is added to the reaction mixture under ice-cooling, and the organic phases are separated. The aqueous phase is extracted with toluene and the combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated. 144.5 g of (2,4-dichloro-5-fluoro-3-nitrobenzoyl) malonic acid diethyl ester is obtained as a crude product. This product is heated to reflux after addition of 200 ml of water and 0.6 g of 4-toluenesulfonic acid, the mixture is extracted with methylene chloride, the extract is dried over sodium sulfate and the solvent is distilled off in vacuo. 110 g of substituted benzoylacetic acid ethyl ester are obtained in the form of a crude product. The product obtained is sufficiently pure for further reactions.
d) 7-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-8-nitro-4-oxo-3-chinolinkarboxylová kyselinad) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid
СООНСООН
244,8 g ethylesteru (2,4-dlchlor-5-fluor-3-nitrobenzoýl)octové kyseliny se zahřívá s 166 g triethylesteru orthomravenčí kyseliny a 185 g acetanhydridu po dobu 3 hodin na teplotu 150 až 160 °C. Reakční směs se poté zahustí za sníženého tlaku a ve formě olejovitého zbytku se získá 270 g ethylesteru 2-(2,4-dlchlor-5*fluor-3-nltrobenzoyl)*3-ethoxyakrylovó kyseliny,244.8 g (2,4-dlchloro-5-fluoro-3-nitrobenzoyl) acetic acid ethyl ester was heated with 166 g triethyl orthoformate and 185 g acetic anhydride for 3 hours at 150-160 ° C. The reaction mixture is then concentrated under reduced pressure to give 270 g of 2- (2,4-dlchloro-5 * fluoro-3-nitrobenzoyl) * 3-ethoxyacrylic acid ethyl ester as an oily residue,
К 38 g tohoto meziproduktu v 80 ml ethanolu se za chlazení ledem přikope 5,9 g cyklopropylaminu a reakční směs ae míchá 1 hodinu při teplotě 20 °C. Vyloučený produkt se po přidání 100 ml vody odfiltruje, promyje se směsí ethanolu a vody v poměru 1:1a pak se vysuší, Získá se 32,8 g ethylesteru 2-(2,4-dichlor-5*fluor-3-nitrobenzoyl)-3-cyklopropylaminoakrylové kyseliny o teplotě tání 143 až 146 °C,5.9 g of cyclopropylamine and the reaction mixture were added dropwise to 38 g of this intermediate in 80 ml of ethanol and stirred for 1 hour at 20 ° C. The precipitated product is filtered off after addition of 100 ml of water, washed with a 1: 1 mixture of ethanol and water and then dried to give 32.8 g of 2- (2,4-dichloro-5 * fluoro-3-nitrobenzoyl) ethyl ester - 143 DEG -146 DEG C. 3-cyclopropylaminoacrylic acid,
К 7,8 g shora uvedené sloučeniny ve 30 ml bezvodého dioxanu se přidá 3,1 g 1,8-diazabicyklo [5,4,oJundec-7-enu a reakční směs se zahřívá 4 hodiny na teplotu 100 °C. Rozpouštědlo se oddestiluje za sníženého tlaku, zbytek se vyjme směsí methylenchloridu a vody, methylenchlorldová fáze se oddělí, vysuší se síranem sodným a methylenchlorid se oddestiluje, Získá se 7,2 g ethylesteru 7-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-8-nitro-4-oxo-3-chinolinkarboxylové kyseliny ve formě surového produktu. Po překrystalování s acetonitrilu tají světle hnědé krystaly při teplotě 174 až 175 °C. Výtěžek 6 g.To 7.8 g of the above compound in 30 ml of anhydrous dioxane, 3.1 g of 1,8-diazabicyclo [5.4.0] undec-7-ene was added and the reaction mixture was heated at 100 ° C for 4 hours. The solvent is distilled off under reduced pressure, the residue is taken up in a mixture of methylene chloride and water, the methylene chloride phase is separated, dried over sodium sulphate and the methylene chloride is distilled off to give 7.2 g of 7-chloro-1-cyclopropyl-6-fluoro-1 ethyl ester. 4-Dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid as a crude product. After recrystallization from acetonitrile, the light brown crystals melted at 174-175 ° C. Yield 6 g.
Analogickým způsobem se vyrobí následující sloučeniny:The following compounds were prepared in an analogous manner:
7-(5-benzyl-2,5-diazabicyklo [2,2,1J hept-2-yl)-l-cyklopropyl-6-f luor-1 ,'4-dihydro-4-oxo-3-chinolinkarboxylová kyselina o teplotě tání 205 až 214 °C,7- (5-benzyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid o mp 205-214 ° C,
1-cyklopropyl-6-fluor-1,4-dihydro-7-(8-methy1*3,B-diazabicyklo{j ,2,1]okt-3-yl)-4-oxo-3-chinolinkarboxylová kyselina o teplotě tání 273 až 278 °C, hydrochlorid l-cyklopropyl-6-fluor-1,4-dihydro-7-(5-methyl-l,4-diazabicyklo [j,2,1]okt-4-yl)-4-oxo-3-chinolinkarboxylové kyseliny o těplotě tání nad 300 °C, ethylester 1-cyklopropy1-7-(1,4-diazabicyklo [3,2,1] -okt-4-yl)-6,8-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 196 až 199 °C, hydrochlorid 7-(1,4-diazabicyklo [3,2,1]okt-4-yl)*6,8-difluor-l*(2,4-difluorfenyl)-l,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny o teplotě tání 329 až 331 °C, hydrochlorid 7-(l,4-diazabicyklo [з ,2,1]okt-4-yl)-6,8-difluor-1,4-dihydro-l-methylamino-4oxo-3-chinolinkarboxylové kyseliny o teplotě tání 300 až 305 °C.1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (8-methyl-3, β-diazabicyclo [j, 2,1] oct-3-yl) -4-oxo-3-quinolinecarboxylic acid at temperature m.p. 273-278 ° C, 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (5-methyl-1,4-diazabicyclo [j, 2,1] oct-4-yl) -4- oxo-3-quinolinecarboxylic acid of melting point above 300 ° C, 1-cyclopropyl-7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -6,8-difluoro-1 ethyl ester, 196 DEG-199 DEG C., 7- (1,4-diazabicyclo [3.2.1] oct-4-yl) *, 6,8-difluoro-, 4-dihydro-4-oxo-3-quinolinecarboxylic acid. 1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 329-331 ° C, 7- (1,4-diazabicyclo [з, 2,1] oct) hydrochloride -4-yl) -6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid, m.p. 300-305 ° C.
Dalšími účinnými látkami, které se mohou vyrobit postupem podle vynálezu,jsou:Other active substances which can be produced by the process according to the invention are:
6-chlor-7-[з- (4-chlorfenyl)-1-piperazinyl]-l-cyklopropyl-8-fluor-1,4-dihydro-4-oxo-3-chi nolinkarboxylová kyselina,6-chloro-7- [α- (4-chlorophenyl) -1-piperazinyl] -1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
6-chlor-l-cyklopropyl-8-fluor-7- jj-(4~fluorfenyl)-l-piperazinylj-l,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina,6-chloro-1-cyclopropyl-8-fluoro-7- [4- (4-fluorophenyl) -1-piperazinyl] -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
CS 270577 82CS 270577 82
7-Q-(4-bromfenyl)-l-piporaziny Г]-6-chlor-l-cyklopropу1-tí-fluor-1,4-dihydro-4-oxo-3-chino1inkarboxylová kyselina,7-Q- (4-Bromo-phenyl) -1-piperazinyl-6-chloro-1-cyclopropol-1-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
6-chlor-l-cyklopropyl-8-fluor-1,4-dihydro-8-[3-(4-methylfenyl)-l nolinkarboxylová kyselina,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-8- [3- (4-methylphenyl) -1-nolinecarboxylic acid,
7- j3-(4-bifenylyl)-l-plperaziny1J-6-chlor-l-cyklopropyl-8-fluor-1,4-dihydro-4-oxo-3-Chino-7- [3- (4-Biphenylyl) -1-plperazinyl] -6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quino-
1inkarboxylová kyselina,1-carboxylic acid,
6- chlor-l-cyklopropyl-8-fluor-1,4-dihydro-7- [3-(4-methoxyfenyl)-l-piperazinylJ-4-oxo-3-chinolinkarboxylová kyselina, * ó-chlor-l-cyklopropyl-S-fluor-ls 4-dihydro-7-js-(4-hydroxyfenyl)-1-р1регаз1пуГ)-4-oxo-3~6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7- [3- (4-methoxyphenyl) -1-piperazinyl] -4-oxo-3-quinolinecarboxylic acid, * 6-chloro-1-cyclopropyl -S-fluoro-1 with 4-dihydro-7-iso- (4-hydroxyphenyl) -1-nitro-4-oxo-3-
-chinolinkaboxylová kyselina, ·-quinoline carboxylic acid, ·
8- chlor-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7-(3-feny1-1-piperazinyl)-3-chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-phenyl-1-piperazinyl) -3-quinolinecarboxylic acid,
8-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7-^(4-nitrofenyl)-1-piperazinyf] -3-chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-nitrophenyl) -1-piperazinyl-3-quinolinecarboxylic acid,
8-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7- Qí-(4-piperidinofenyl)-l-piperazinylJ-3-chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- N - (4-piperidinophenyl) -1-piperazinyl-3-quinolinecarboxylic acid,
8-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7- |3-(3,4-dimethoxyfenyl)-l-piperazínyf) -3-chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [3- (3,4-dimethoxyphenyl) -1-piperazinyl] -3-quinolinecarboxylic acid,
8-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7- [}-(3,4,5-trimethoxyfenyl)-l-piperazinyÍ]-3-chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [} - (3,4,5-trimethoxyphenyl) -1-piperazinyl] -3-quinolinecarboxylic acid,
8-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7- [j-(2-thienyl)-l-piperazinylJ-3-^chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [1- (2-thienyl) -1-piperazinyl] -3-quinolinecarboxylic acid,
8-chlor-1-cyklopropy1-6-fluor-1,4-dihydro-4-oxo-7-piperidino-3-chinolinkarboxylová kyselina,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperidino-3-quinolinecarboxylic acid,
7- (3-amino-l-pyrrolidinyl)-8-chlor-l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-J-chinolinkarboxylová kyselina,7- (3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
6,8-dichlor-l-cyklopropyl-l,4-dlhydro-4-oxo-7-(l-piperazinyl)-3-chinolinkarboxylová kyselina , ,.6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid;
7-(4-acetуl-l-piperazínyl)-6,8-dichlor-1-cyklopropy1-1,4-dihydro-4-oxo-J-chinolinkarboxylová · . , kyselina,7- (4-acetol-1-piperazinyl) -6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1-quinolinecarboxylic acid. , acid,
7- (4-acetyl-l-piperazinyl)-6-chlor-l-cyklopropyl-8-řluor-l,4-dihydro-4-oxo-3-chinolinkorboxylová kyselina,7- (4-acetyl-1-piperazinyl) -6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecorboxylic acid,
6-chlor-l-cyklopropyl-8-fluor-1,4-dihydro-7-(4-isopropyl-l-piperazinyl)-4-oxo-3-chinolinkarboxylová kyselina,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7- (4-isopropyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid,
6-chlor-l-cyklopropyl-8-fluor-l,4-dlhydro-4-oxo-7-morfolino-3-chinolinkarboxylová kyselina,6-chloro-1-cyclopropyl-8-fluoro-1,4-dlhydro-4-oxo-7-morpholino-3-quinolinecarboxylic acid,
6-chlor-l-cyklopropyl-8-fluor-1,4-dihydro-4-oxo-7-thiomorfolino-J-chinolinkarboxylová kyselina,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-β-quinolinecarboxylic acid,
8- chlor-l-cyklopropy1-7-(4-ethyl-3-oxo-l-piperazinyl)-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina.8-Chloro-1-cyclopropyl-7- (4-ethyl-3-oxo-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Postupem podle vynálezu se zpravidla získají nejdříve volné karboxylové kyseliny, které se poté mohou převádět na soli, estery, prekursory atd. podle známých metod.As a rule, free carboxylic acids are obtained first by the process according to the invention, which can then be converted into salts, esters, precursors, etc. according to known methods.
Zcela zvláště výhodně se postupem podle vynálezu vyrábí Ciprofloxacin a odpovídajícíVery particularly preferably, Ciprofloxacin and the corresponding are produced by the process according to the invention
1-ethylpiperazinderivát.1-ethylpiperazine derivative.
Příklady provedeníExamples
CS 270577 0202
PřikladlHe did
606 dílů hmotnostních l-cyklopropyl-7-chlor-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxyluvd kyoollny u 575 dílů hmotnostníoh piperazinu so zahřívá ve vhodném reaktoru 30 minut na teplotu 150 až 160 °C. Poté ee reakční směs zředí vodou, přičemž se v 71¾ výtěžku získá l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7-(l-piperazinyl)-3-chinolinkarboxylová kyselina и ob π a Iichii Čistě látky asi 90 4.606 parts by weight of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid for 575 parts by weight of piperazine are heated at 150-160 ° C for 30 minutes in a suitable reactor. Thereafter, the reaction mixture is diluted with water to give 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid in both 2 and 7 yields. about 90 4.
Příklad 2Example 2
133 dílů hmotnostních l-cyklopropyl-6,7-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny a 129 dílů hmotnostních piperazinu se nechá reagovat stejným způsobem jako v příkladu 1. V 70¾ výtěžku se získá l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-(l-piperazinyl)-3-chinolinkarboxylová kyselina s obsahem čisté látky 90,5 4.133 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 129 parts by weight of piperazine were reacted in the same manner as in Example 1. In 70¾ yield, 1-cyclopropyl was obtained. -6-fluoro-1,4-dihydro-4-oxo- (1-piperazinyl) -3-quinolinecarboxylic acid with a pure substance content of 90.5 4.
Příklad 3 .Example 3.
143 dílů hmotnostních piperazinu se zahřeje na teplotu 140 až 150 °C. Do této taveniny se během 20 minut přidá 94 dílů hmotnostních l-cyklopropyl-7-chlor-6-fluor-1,4 dihydro-4-oxo-3-chinolinkarboxylové kyseliny. Reakční směs se ochladí na 100 °C a přidá se voda. Přitom vykrystaluje l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7-(l-piperazinyl)-3-chinolinkarboxylová kyselina v 78¾ výtěžku. Čistota produktu činí 97,2 %.143 parts by weight of piperazine were heated to 140-150 ° C. 94 parts by weight of 1-cyclopropyl-7-chloro-6-fluoro-1,4 dihydro-4-oxo-3-quinolinecarboxylic acid are added to the melt over 20 minutes. The reaction mixture was cooled to 100 ° C and water was added. 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid crystallizes in 78 ' yield. The purity of the product was 97.2%.
P ř í к 1 a d 4 .Example 1 a d 4.
150 dílů hmotnostních piperazinu se nechá reagovat se 102 díly hmotnostními 1-cyklopropyl-6,7-difluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny způsobem popsaným v příkladu 3. Získá se l-cyklopropyl-6-fluor-1,4-dihydro-4-oxo-7-(l-piperazinyl)-3-chinolinkarboxylová kyselina ve výtěžku 76 4. Čistota produktu činí 97,5 4.150 parts by weight of piperazine were reacted with 102 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as described in Example 3. 1-Cyclopropyl-6-fluoro was obtained. -1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid in 76% yield.
P ř í к 1 a d 5Example 1 a d 5
Ke 122 dílům hmotnostním 1-ethylpiperazinu, zahřátém na teplotu 140 až 150 °C, se během 30 minut přidá 60 dílů hmotnostních l-cyklopropyl-7-chlor-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny. Po ochlazení na teplotu 100 °C se přidá voda, přičemž vykrystaluje 1-cyklopropy1-6-fluor-1,4-dihydro-4-oxo-7-(4-ethyl-l-piperazinyl)-3-chinolinkarboxylová kyselina v 76¾ výtěžku. Čistota produktu činí 98,2To 122 parts by weight of 1-ethylpiperazine heated to 140-150 ° C was added 60 parts by weight of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid over 30 minutes acid. After cooling to 100 ° C, water is added to crystallize 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-ethyl-1-piperazinyl) -3-quinolinecarboxylic acid in 76¾ yield. . The purity of the product is 98.2
P ř í к 1 a d 6Example 1 a d 6
Ke 135 dílům hmotnostním 3-aminopyrrolidinu se při teplotě 140 až 150 °C přidá 100 dílů hmotnostních 1-cyklopropy1-7,8-dichlor-6-fluor-l,4-dihydro-4-oxo-3-chinolinkarboxylové kyseliny. Reakční směs se ochladí, přidá se к ní voda v 60¾ výtěžku se izoluje 7-(3-amino-l-pyrrol idiny1)-8-chlor-1-cyklopropy1-6-fluor-1,4-dihydro-4-oxo-3-chinolinkarboxylová kyselina.100 parts by weight of 1-cyclopropyl-7,8-dichloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are added to 135 parts by weight of 3-aminopyrrolidine at 140-150 ° C. The reaction mixture is cooled, water is added thereto in 60¾ yield, and 7- (3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo is isolated. 3-quinolinecarboxylic acid.
.Příklad 7..Example 7.
Ke 174 dílům hmotnostním 3,5-dimethylpiperazinu se při teplotě 140 až 150 °C přidá 300 dílů hmotnostních l-cyklopropyl-6,7,8-trifluor-l,4-dihydro-4-oxoi-3-chinolinkarboxylové kyseliny. Reakční směs se ochladí, přidá se к ní voda a v 74¾ výtěžku ss izoluje 1-cyklopropyl-6,8-difluor-l,4-dihydro-7-(3,5-dimethyl-l-piperazinyl)-4-oxo-3-chinolinkarboxylová kyselina .300 parts by weight of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are added to 174 parts by weight of 3,5-dimethylpiperazine at 140-150 ° C. The reaction mixture was cooled, water was added and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3,5-dimethyl-1-piperazinyl) -4-oxo was isolated in 74¾ yield. 3-quinolinecarboxylic acid.
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863641312 DE3641312A1 (en) | 1986-12-03 | 1986-12-03 | METHOD FOR PRODUCING CHINOLINE CARBONIC ACIDS |
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| Publication Number | Publication Date |
|---|---|
| CS868887A2 CS868887A2 (en) | 1989-11-14 |
| CS270577B2 true CS270577B2 (en) | 1990-07-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CS878688A CS270577B2 (en) | 1986-12-03 | 1987-11-30 | Method of quinoline carboxylic acids production |
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| EP (1) | EP0274033B1 (en) |
| JP (1) | JPS63145268A (en) |
| KR (1) | KR970005191B1 (en) |
| CN (1) | CN87107230A (en) |
| AT (1) | ATE73446T1 (en) |
| AU (1) | AU593961B2 (en) |
| CS (1) | CS270577B2 (en) |
| DD (1) | DD270904A5 (en) |
| DE (2) | DE3641312A1 (en) |
| DK (1) | DK174929B1 (en) |
| ES (1) | ES2038156T3 (en) |
| FI (1) | FI875289A7 (en) |
| GR (1) | GR3004301T3 (en) |
| HU (1) | HU199823B (en) |
| IE (1) | IE64261B1 (en) |
| IL (1) | IL84627A (en) |
| NO (1) | NO174199C (en) |
| NZ (1) | NZ222736A (en) |
| PH (1) | PH24489A (en) |
| PL (1) | PL158614B1 (en) |
| PT (1) | PT86252B (en) |
| SU (1) | SU1482526A3 (en) |
| UA (1) | UA8017A1 (en) |
| YU (1) | YU45049B (en) |
| ZA (1) | ZA879040B (en) |
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| IN166416B (en) * | 1985-09-18 | 1990-05-05 | Pfizer | |
| AU5449590A (en) * | 1989-04-28 | 1990-11-29 | Daiichi Pharmaceutical Co., Ltd. | Anti-hiv drug |
| WO1991004972A1 (en) * | 1989-10-06 | 1991-04-18 | Pfizer Inc. | 1,4-dihydro-4-oxo-3-quinoline derivatives as selectively toxic mammalian antibacterial agents |
| US5385913A (en) * | 1989-10-06 | 1995-01-31 | Pfizer Inc. | 1,4-dihydro-4-oxo-3-quinoline derivatives as selectively toxic mammalian antibacterial agents |
| JP2613139B2 (en) * | 1990-07-19 | 1997-05-21 | エスエス製薬 株式会社 | Quinolonecarboxylic acid derivatives |
| ES2050613B1 (en) * | 1992-10-16 | 1996-03-16 | Iteve S A | NEW PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF THE ACID 1-CICLOPROPIL-3-QUINOLINCARBOXILICO. |
| US6034100A (en) * | 1993-03-10 | 2000-03-07 | Otsuka Pharmaceutical Co., Ltd. | Method for inhibiting cytokine secretion |
| WO1998042341A1 (en) * | 1997-03-25 | 1998-10-01 | Sankyo Company, Limited | Anti-fiv agent |
| KR100454750B1 (en) * | 2002-06-20 | 2004-11-03 | 삼성에스디아이 주식회사 | Blue light-emitting compound for organic electroluminescent device and organic electroluminescent device using the same |
| PT1666477E (en) | 2003-09-10 | 2013-08-28 | Kyorin Seiyaku Kk | 7-(4-substituted 3- cyclopropylaminomethyl-1- pyrrolidinyl) q uinolonecarboxylic acid derivative |
| CA2688008A1 (en) | 2007-05-24 | 2008-11-27 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
| CN101671302B (en) * | 2008-12-30 | 2011-03-30 | 广东海康兽药有限公司 | Production process of enrofloxacin antibacterial drug for fowl and livestock |
| CN101899044B (en) * | 2010-08-16 | 2012-07-18 | 常州市勇毅生物药业有限公司 | Method for synthesizing Gemifloxacin main ring compound |
| CN113912540A (en) * | 2021-12-15 | 2022-01-11 | 山东国邦药业有限公司 | Synthesis method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS5365887A (en) * | 1976-11-22 | 1978-06-12 | Kyorin Seiyaku Kk | Substituted quinoline*arboxylate and process for preparing same |
| DE2656574A1 (en) * | 1976-12-10 | 1978-06-15 | Schering Ag | 1-Alkyl-4-oxo-1,4-di:hydro-1,6-naphthyridine-3-carboxylic acid derivs. - with antibacterial activity esp. effective in the urinary tract |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| JPS5845426B2 (en) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | Substituted quinoline carboxylic acid derivatives |
| DE3142854A1 (en) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-CHINOLINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| DE3318145A1 (en) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-6,8-DIFLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| AU553415B2 (en) * | 1983-09-19 | 1986-07-17 | Abbott Japan Co., Ltd. | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
| IL74244A (en) * | 1984-02-17 | 1988-06-30 | Warner Lambert Co | Quinoline derivatives,their preparation and pharmaceutical compositions containing them |
| DE3420743A1 (en) * | 1984-06-04 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-6,8-DIHALOGEN-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| JPS61205258A (en) * | 1985-03-08 | 1986-09-11 | Kyorin Pharmaceut Co Ltd | Quinolonecarboxylic acid derivative and production thereof |
-
1986
- 1986-12-03 DE DE19863641312 patent/DE3641312A1/en not_active Withdrawn
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1987
- 1987-11-17 NO NO874788A patent/NO174199C/en not_active IP Right Cessation
- 1987-11-20 ES ES198787117130T patent/ES2038156T3/en not_active Expired - Lifetime
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- 1987-11-20 AT AT87117130T patent/ATE73446T1/en not_active IP Right Cessation
- 1987-11-20 EP EP87117130A patent/EP0274033B1/en not_active Expired - Lifetime
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- 1987-12-01 FI FI875289A patent/FI875289A7/en not_active Application Discontinuation
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- 1987-12-01 JP JP62301624A patent/JPS63145268A/en active Pending
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- 1987-12-02 CN CN198787107230A patent/CN87107230A/en active Pending
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- 1987-12-03 AU AU82177/87A patent/AU593961B2/en not_active Expired
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|---|---|---|---|
| IF00 | In force as of 2000-06-30 in czech republic | ||
| MK4A | Patent expired |
Effective date: 20071130 |