NO174199B - Fremgangsm}te til fremstilling av kinolinkarboksylsyrer - Google Patents
Fremgangsm}te til fremstilling av kinolinkarboksylsyrer Download PDFInfo
- Publication number
- NO174199B NO174199B NO874788A NO874788A NO174199B NO 174199 B NO174199 B NO 174199B NO 874788 A NO874788 A NO 874788A NO 874788 A NO874788 A NO 874788A NO 174199 B NO174199 B NO 174199B
- Authority
- NO
- Norway
- Prior art keywords
- cyclopropyl
- dihydro
- oxo
- fluoro
- acid
- Prior art date
Links
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000004519 manufacturing process Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 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 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- -1 amino, methylamino, ethylamino, aminomethyl Chemical group 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 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
- 239000007858 starting material Substances 0.000 claims description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 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
- 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 9
- 239000000651 prodrug Substances 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000004936 stimulating effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000002844 melting Methods 0.000 description 27
- 230000008018 melting Effects 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 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
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 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
- 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 5
- 238000001816 cooling Methods 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 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 4
- 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000013078 crystal Substances 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
- 239000011541 reaction mixture Substances 0.000 description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-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
- 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 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring 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
- 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
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 2
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 239000006227 byproduct Substances 0.000 description 2
- 229950005499 carbon tetrachloride Drugs 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 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 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 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
- 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
- 238000007363 ring formation reaction Methods 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
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 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
- 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
- MSSDTZLYNMFTKN-UHFFFAOYSA-N 1-Piperazinecarboxaldehyde Chemical compound O=CN1CCNCC1 MSSDTZLYNMFTKN-UHFFFAOYSA-N 0.000 description 1
- ALRZZABRVIYCNY-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-7-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound CN1C(C2)CCC1CN2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 ALRZZABRVIYCNY-UHFFFAOYSA-N 0.000 description 1
- ZWLNNJUVRYMXIQ-UHFFFAOYSA-N 1-cyclopropyl-7-(1,4-diazabicyclo[3.2.1]octan-4-yl)-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(N3C4CCN(C4)CC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ZWLNNJUVRYMXIQ-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
- 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
- BYYCSTYYULCJLQ-UHFFFAOYSA-N 2-(2-methylpropyl)piperazine Chemical compound CC(C)CC1CNCCN1 BYYCSTYYULCJLQ-UHFFFAOYSA-N 0.000 description 1
- SZZIGSBHEDAVBX-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)piperazine Chemical compound COC1=C(OC)C(OC)=CC(C2NCCNC2)=C1 SZZIGSBHEDAVBX-UHFFFAOYSA-N 0.000 description 1
- XMTDOVQYBQWJAL-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)piperazine Chemical compound C1=C(OC)C(OC)=CC=C1C1NCCNC1 XMTDOVQYBQWJAL-UHFFFAOYSA-N 0.000 description 1
- VGANTLKDSNLDDD-UHFFFAOYSA-N 2-(3-nitrophenyl)piperazine Chemical compound [O-][N+](=O)C1=CC=CC(C2NCCNC2)=C1 VGANTLKDSNLDDD-UHFFFAOYSA-N 0.000 description 1
- ZXWFFOCOSVMOPB-UHFFFAOYSA-N 2-(4-bromophenyl)piperazine Chemical compound C1=CC(Br)=CC=C1C1NCCNC1 ZXWFFOCOSVMOPB-UHFFFAOYSA-N 0.000 description 1
- OTOVNNDSINVUBR-UHFFFAOYSA-N 2-(4-chlorophenyl)piperazine Chemical compound C1=CC(Cl)=CC=C1C1NCCNC1 OTOVNNDSINVUBR-UHFFFAOYSA-N 0.000 description 1
- NZAKSEMIIIZYEM-UHFFFAOYSA-N 2-(4-fluorophenyl)piperazine Chemical compound C1=CC(F)=CC=C1C1NCCNC1 NZAKSEMIIIZYEM-UHFFFAOYSA-N 0.000 description 1
- INKLSJITWMAFRT-UHFFFAOYSA-N 2-(4-methoxyphenyl)piperazine Chemical compound C1=CC(OC)=CC=C1C1NCCNC1 INKLSJITWMAFRT-UHFFFAOYSA-N 0.000 description 1
- FCNXNUWTNOYQME-UHFFFAOYSA-N 2-(4-methylphenyl)piperazine Chemical compound C1=CC(C)=CC=C1C1NCCNC1 FCNXNUWTNOYQME-UHFFFAOYSA-N 0.000 description 1
- MUECOXPJCJWOTK-UHFFFAOYSA-N 2-(4-phenylmethoxyphenyl)piperazine Chemical compound C=1C=CC=CC=1COC(C=C1)=CC=C1C1CNCCN1 MUECOXPJCJWOTK-UHFFFAOYSA-N 0.000 description 1
- HIEDNYNFVIKPKN-UHFFFAOYSA-N 2-(4-piperidin-1-ylphenyl)piperazine Chemical compound C1CCCCN1C1=CC=C(C2NCCNC2)C=C1 HIEDNYNFVIKPKN-UHFFFAOYSA-N 0.000 description 1
- WWYFHDNQGVTJJJ-UHFFFAOYSA-N 2-cyclohexylpiperazine Chemical compound C1CCCCC1C1NCCNC1 WWYFHDNQGVTJJJ-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
- RIMRLBGNCLMSNH-UHFFFAOYSA-N 2-phenylpiperazine Chemical compound C1NCCNC1C1=CC=CC=C1 RIMRLBGNCLMSNH-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
- BFVCDPJJFUPNAQ-UHFFFAOYSA-N 2-thiophen-2-ylpiperazine Chemical compound C1NCCNC1C1=CC=CS1 BFVCDPJJFUPNAQ-UHFFFAOYSA-N 0.000 description 1
- VWNMVYACOKCDLR-UHFFFAOYSA-N 3,5-dichloro-2,4-difluorobenzoyl fluoride Chemical compound FC(=O)C1=CC(Cl)=C(F)C(Cl)=C1F VWNMVYACOKCDLR-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
- SASIFHOHGBPKMK-UHFFFAOYSA-N 4-piperazin-2-ylphenol Chemical compound C1=CC(O)=CC=C1C1NCCNC1 SASIFHOHGBPKMK-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
- 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
- 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
- ZKKQMUZJOIZCTF-UHFFFAOYSA-N C(C)OC(C(=C(C1CC1)N)C(C1=C(C(=C(C(=C1)Cl)F)Cl)F)=O)=O Chemical compound C(C)OC(C(=C(C1CC1)N)C(C1=C(C(=C(C(=C1)Cl)F)Cl)F)=O)=O ZKKQMUZJOIZCTF-UHFFFAOYSA-N 0.000 description 1
- DAPHBLIFIBVHJT-UHFFFAOYSA-N C(C)OC(C(=C(C1CC1)N)C(C1=C(C(=C(C(=C1)F)Cl)[N+](=O)[O-])Cl)=O)=O Chemical compound C(C)OC(C(=C(C1CC1)N)C(C1=C(C(=C(C(=C1)F)Cl)[N+](=O)[O-])Cl)=O)=O DAPHBLIFIBVHJT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VXDTVXDDIQTAGY-UHFFFAOYSA-N Cl.C1(CC1)N1C=C(C(C2=CC(=C(C=C12)N1CCN2CCC1(C2)C)F)=O)C(=O)O Chemical compound Cl.C1(CC1)N1C=C(C(C2=CC(=C(C=C12)N1CCN2CCC1(C2)C)F)=O)C(=O)O VXDTVXDDIQTAGY-UHFFFAOYSA-N 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
- PVVKJTVLUGWIAW-UHFFFAOYSA-N Cl.C1(CC1)N1C=C(C(C2=CC(=C(C=C12)N1CCN2CCC1C2)[N+](=O)[O-])=O)C(=O)O Chemical compound Cl.C1(CC1)N1C=C(C(C2=CC(=C(C=C12)N1CCN2CCC1C2)[N+](=O)[O-])=O)C(=O)O PVVKJTVLUGWIAW-UHFFFAOYSA-N 0.000 description 1
- DTPSYDGUVCDBJP-UHFFFAOYSA-N Cl.C1(CC1)N1C=C(C(C2=CC(=C(N=C12)N1CCN2CCC1C2)F)=O)C(=O)O Chemical compound Cl.C1(CC1)N1C=C(C(C2=CC(=C(N=C12)N1CCN2CCC1C2)F)=O)C(=O)O DTPSYDGUVCDBJP-UHFFFAOYSA-N 0.000 description 1
- ZFFBYTYCWQWVCE-UHFFFAOYSA-N Cl.N12CCN(C(CC1)C2)C2=C(C=C1C(C(=CN(C1=C2F)C2=C(C=C(C=C2)F)F)C(=O)O)=O)F Chemical compound Cl.N12CCN(C(CC1)C2)C2=C(C=C1C(C(=CN(C1=C2F)C2=C(C=C(C=C2)F)F)C(=O)O)=O)F ZFFBYTYCWQWVCE-UHFFFAOYSA-N 0.000 description 1
- DOBJVLQCTICURS-UHFFFAOYSA-N Cl.N12CCN(C(CC1)C2)C2=C(C=C1C(C(=CN(C1=C2F)CC)C(=O)O)=O)F Chemical compound Cl.N12CCN(C(CC1)C2)C2=C(C=C1C(C(=CN(C1=C2F)CC)C(=O)O)=O)F DOBJVLQCTICURS-UHFFFAOYSA-N 0.000 description 1
- OQXUWOBTQLIULS-UHFFFAOYSA-N Cl.N12CCN(C(CC1)C2)C2=C(C=C1C(C(=CN(C1=C2F)NC)C(=O)O)=O)F Chemical compound Cl.N12CCN(C(CC1)C2)C2=C(C=C1C(C(=CN(C1=C2F)NC)C(=O)O)=O)F OQXUWOBTQLIULS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 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
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- JABCVSYKXWKZLZ-UHFFFAOYSA-N ethyl 2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=CC(F)=C(Cl)C([N+]([O-])=O)=C1Cl JABCVSYKXWKZLZ-UHFFFAOYSA-N 0.000 description 1
- LYOAKSDOTROZEF-UHFFFAOYSA-N ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=CC(F)=C(Cl)C=C1Cl LYOAKSDOTROZEF-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
- VOLUOOYGRKDBSQ-UHFFFAOYSA-N ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=CC(F)=C(F)C(Cl)=C1F VOLUOOYGRKDBSQ-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
- 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
- LZMXLCPYJNRWNQ-UHFFFAOYSA-N ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(F)C(Cl)=C1F LZMXLCPYJNRWNQ-UHFFFAOYSA-N 0.000 description 1
- PZHBCYPIIDMQIW-UHFFFAOYSA-N ethyl 3-(5-chloro-2,3,4-trifluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(Cl)=C(F)C(F)=C1F PZHBCYPIIDMQIW-UHFFFAOYSA-N 0.000 description 1
- SXMREQZRBBCOLI-UHFFFAOYSA-N ethyl 3-amino-2-[(3-chloro-2,4,5-trifluorophenyl)methyl]-3-cyclopropylprop-2-enoate Chemical compound C(C)OC(C(=C(C1CC1)N)CC1=C(C(=C(C(=C1)F)F)Cl)F)=O SXMREQZRBBCOLI-UHFFFAOYSA-N 0.000 description 1
- UCKBRIDVNDEKNN-UHFFFAOYSA-N ethyl 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)prop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=CC(F)=C(F)C(F)=C1F UCKBRIDVNDEKNN-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
- UIQJDECRSCNKCH-UHFFFAOYSA-N ethyl 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate Chemical compound C12=C([N+]([O-])=O)C(Cl)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 UIQJDECRSCNKCH-UHFFFAOYSA-N 0.000 description 1
- NUBFPWXUKJGZNA-UHFFFAOYSA-N ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Cl)C(F)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 NUBFPWXUKJGZNA-UHFFFAOYSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XDKQUSKHRIUJEO-UHFFFAOYSA-N magnesium;ethanolate Chemical compound [Mg+2].CC[O-].CC[O-] XDKQUSKHRIUJEO-UHFFFAOYSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Inorganic materials [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 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)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Optical Fibers, Optical Fiber Cores, And Optical Fiber Bundles (AREA)
Description
Foreliggende oppfinnelse angår en ny fremgangsmåte for fremstilling av kinolinkarboksylsyrer med den nedenfor angitte formel.
Forbindelsene med den nedenfor angitte formel I har inte-ressante egenskaper og finner anvendelse som sådanne eller i form av deres estere, salter, prodrugs eller lignende som antibakterielle midler i human- og animalmedisinen samt som middel som stimulerer immunforsvaret.
Fra DE-A-28 04 097, EP-A-0 195 841, US-PS 4 448 962, DE-A-0 078 362, EP-A-0 167 763 samt EP-A-0 126 355 er det allerede kjent en fremgangsmåte for fremstilling av kinolon karboksyl-syrederivater som er substituert i 7-posisjon med cykliske aminer. Ved denne fremgangsmåte anvendes de cykliske aminer dog ikke i ren form, altså uten oppløsningsmiddel eller hydratvann. De oppnådde utbytter og produktrenheter ved denne metode er ikke tilfredsstillende.
Overraskende er det nu funnet at man fullstendig kan gi avkall på ytterligere oppløsningsmidler og anvende det rene hydrat- eller krystallvannfrie amin og allikevel oppnå diverse fordeler.
Gjenstand for oppfinnelsen er i henhold til dette en fremgangsmåte for fremstilling av forbindelser med formel I
der
R<1> betyr metyl, etyl, propyl, isopropyl, cyklopropyl, 2-hydroksyetyl, 2-fluoretyl, 4-fluorfenyl, 2,4-difluorfenyl;
R<2> betyr CN eller C00R<2>' der R<2>' har betydningen hydrogen
eller C^_4alkyl;
R<3> betyr en cyklisk aminogruppe som
der
R<4> betyr hydrogen, C^_4alkyl, 2-hydroksyetyl eller 2-oksy-propyl;
R<5> betyr hydrogen eller metyl;
R^ betyr hydrogen eller Cj^alkyl;
R<7> betyr hydrogen, amino, metylamino, etylamino, aminometyl,
metylaminometyl, etylaminometyl, dimetylaminometyl,
hydroksy eller hydroksymetyl;
R<8> betyr hydrogen, metyl, etyl eller klor;
X betyr halogen og fortrinnsvis fluor og klor, og
A betyr C-R-H der R-H betyr hydrogen eller halogen,
og denne fremgangsmåte karakteriseres ved at forbindelser med den generelle formel II
der
R<1>, R<2>, A og X har den ovenfor angitte betydning, og
Y betyr halogen, fortrinnsvis fluor eller klor, omsettes med oppløsningsmiddelfrie aminer med formelen
der
R4, R5, R6, R<7>, R<8> og R<9> har den ovenfor angitte betydning, uten anvendelse av oppløsningsmidler ved temperaturer fra 20 til 200°C.
De nevnte aminer er, ved fremgangsmåten ifølge oppfinnelsen, samtidig både reaksjonsdeltagere og oppløsningsmiddel. Er aminene faste ved romtemperatur, smeltes de, reaksjonen med (II) gjennomføres derefter i smeiten.
Det må betegnes som meget overraskende at a) reaksjonen mellom (II) og aminene forløper meget raskere enn ved anvendelse av et ekstra oppløsningsmiddel, at b) reaksjonen forløper ved lavere temperaturer hvorved det dannes mindre biprodukter og at c) det på tross av overskuddet av amin ikke finner sted noen ytterligere substitusjon av X.
Det sistnevnte er desto mere overraskende, fordi nemlig, når (II) inndoseres i aminet foreligger i det minste ved begynnelsen et omtrent uendelig stort overskudd av amin. Fordelene ved fremgangsmåten ifølge oppfinnelsen er følgelig: - Renere produkt (mindre biprodukter) ved den lavere reaksj onstemperatur
Tidsbesparelse ved den høyere reaksjonshastighet Økonomisk fordel ved bortfall av et ekstra oppløsningsmid-del .
Forholdet forbindelsene (II):aminene kan være 1:1 til 1:50, fortrinnsvis 1:2 til 1:10 og helst 1:3 til 1:5. Reaksjons-temperaturen ligger ved 20 til 200°C, foretrukket blir området på 80 til 180°C, og helst 120 til 160°C.
Spesielt foretrukket er for fremgangsmåten ifølge oppfinnelsen cykliske aminer som morfolin, piperidin, tiomorfolin, pyrrolidin, piperazin, N-metylpiperazin, N-etylpiperazin, N-(2-hydroksyetyl )-piperazin, N-formylpiperazin, 2-metylpiperazin, 1,2-dimetylpiperazin, cis- og trans-2,5-dimetylpiperazin, cis- og trans-2,6-dimetylpiperazin, 2-etylpiperazin, 2-propylpiperazin, 2-isopropylpiperazin, 2-isobutylpiperazin, 2-piperazinon, l-metyl-2-piperazinon, l-etyl-2-piperazinon, 2-cykloheksylpiperazin, 2-fenylpiperazin, 2-(4-klorfenyl)-piperazin, 2-(4-fluorfenyl)-piperazin, 2-(4-bromfenyl)-piperazin, 2-(4-metylfenyl)-piperazin, 2-(4-bifenyl )-piperazin, 2-(4-metoksyfenyl)-piperazin, 2-(4-benzyloksy-fenyl)-piperazin, 2-(4-hydroksyfenyl)-piperazin, 2-(4-nitrofenyl)-piperazln, 2-(3-nitrofenyl )-piperazin, 2-(4-piperidinofenyl )-piperazin, 2-(3,4-dimetoksyfenyl)-piperazin, 2-(3,4,5-trimetoksyfenyl)-piperazin,, 2-(3,4-dimetoksy-6-metyl)-piperazin, 2-(2-tienyl)-piperazin og 3-aminopyrrolidin og 3-aminometylpyrrolidin.
Kinolinkarboksylsyrene med formel II fremstilles som angitt i det følgende:
Eksempel A 6-klor-l-cyklopropyl-7,8-difluor-l, 4 - dihydro -4 -ok so - 3-kinolinkarboksylsyre
15,7 g (0,65 mol) magnesiumspon utrøres i 40 ml etanol og 20 ml tetraklormetan og blandes efter begynnende reaksjon ved 50 til 60°C dråpevis med 103 g (0,64 mol) malonsyredietylester i 80 ml etanol og 250 ml toluen. Man omrører i 1 time ved denne temperatur, avkjøler til -5 til -10°C, drypper til. en oppløsning av 138 g (0,65 mol) 5-klor-2,3,4-trifluor-benzoyl-fluorid i 63 ml toluen, omrører ennå i 1 time ved 0°C og lar det stå natten over ved romtemperatur. Derefter oppvarmes det hele ennå i 2 timer ved 40 til 50°C, avkjøles og blandes med 250 ml isvann og 38,5 ml konsentrert svovelsyre. Den organiske fase separeres, den vandige fase ekstraheres med 2 ganger 150 ml toluen, de forenede organiske faser vaskes med mettet natriumkloridoppløsning, tørkes med natriumsulfat og dampes inn.
Resten blandes med 200 ml vann (fordelaktig er her tilsetning av 0,4 g 4-toluensulfonsyre) og oppvarmes til desetoksykar-boksylering i 5 timer under tilbakeløp. Man ekstraherer med 3 ganger 200 ml diklormetan, vasker med mettet natriumklorid-oppløsning, tørker med natriumsulfat, damper inn og destille-rer under høyvakuum. Man får 103 g (56,5%) (5-klor-2,3,4-trif luorbenzoyl)-eddiksyre-etylester med kokepunkt på 110°C/0,9 Torr.
103 g (0,37 mol) av den dannede ester på 83 g (0,56 mol) ortomaursyretrietylester oppvarmes med 95 g eddiksyreanhydrid i 2 timer ved 150-160° C og dampes inn derefter ved 120 til 130° C under normalt trykk og derefter under høyvakuum. Man får 115 g (92$ av det teoretiske) 2-(5-klor-2,3,4-trifluor-benzoyl )-3-etoksy-acrylsyre-etylester som olje.
84,1 g (0,25 mol) av denne forbindelse blandes i 170 ml etanol under isavkjøling dråpevis med 14,8 g (0,26 mol) cyklopropylamin og omrøres i 2 timer ved romtemperatur. Derefter røres det hele ut med 170 ml vann, avkjøles i is, hvorefter den dannede utfelling suges fra, vaskes med vann og litt metanol og tørkes. Man får 47 g (54%) 2-(5-klor-2,3,4-trifluorbenzoyl)-3-cyklopropylamino-acrylsyreetylester av smeltepunkt 71-73°C. Ifølge ^H-NMR-spektrum foreligger en cis-trans-blanding.
47 g (0,14 mol) av denne forbindelse oppvarmes i 230 ml dimetylformamid med 9,7 g (0,23 mol) natriumfluorid i 2 timer ved 160 til 170°C. Reaksjonsblandingen helles i 400 ml isvann, utfellingen suges fra, vaskes med vann og tørkes. Man isolerer 44 g (99%) 6-klor-l-cyklopropyl-7,8-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester med smeltepunkt 169-172°C. 44 g (0,13 mol) av kinolonkarboksylsyreesteren blandes i 300 ml iseddik og 179 ml vann med 33 ml konsentrert svovelsyre og oppvarmes i 2 timer ved 150°C. Reaksjonsblandingen innrøres i 400 ml isvann, utfellingen suges fra, vaskes med vann og tørkes. Det isoleres 37 g (95% av det teoretiske) 6-klor-l-cyklopropyl-7 ,8-dif luor-1,4-dihydro-4-okso-3-kinol inkarboksylsyre med et smeltepunkt på 200 til 204°C. Eksempel B 8-klor-l-cyklopropyl-6,7-difluor-l,4 -dihydro-4-okso-3-kinolinkarboksylsyre
Man omsetter 3-klor-2,4,5-trifluorbenzoylklorid analogt eksempel A, i det følgende trinn passeres: (3-klor-2,4,5-trifluor-benzoyl)-eddiksyre-etylester som enol (Utbytte: 42%, smeltepunkt 72-75'C),
2-(3-klor-2 ,4 ,5-trifluor-benzoyl )- 3-etoksy-acrylsyre-etyl-ester
(Råutbytte: 95% olje),
2-( 3-klor-2,4,5-trifluor-benzyl)-3-cyklorpropyl-amino-acryl-syreetylester
(Utbytte: 67%, smeltepunkt 78-8C<T>C),
8-klor-l-cyklopropyl-6,7-difluor-l, 4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester
(Utbytte: 85%, smeltepunkt 154-157'C),
8-klor-l-cyklopropyl - 6 ,7-difluor-l , 4-dihydro-4-okso-3-kinolinkarboksylsyre
(Utbytte: 97,6%, smeltepunkt 189-192'C).
Eksempel C
6 ,8-diklor-l-cyklopropyl-7-fluor-l , 4 - dihydro-4 -okso-3-kinolinkarboksylsyre
Man omsetter 3,5-diklor-2,4-difluor-benzoylfluorid analogt eksempel A, i det følgende trinn passeres: (3,5-diklor-2,4-difluor-benzoyl)-eddiksyre-etylester (Utbytte: 43%, kokepunkt 133'C/2,5 Torr),
2 - ( 3 , 5-diklor-2 , 4-difluor-benzoyl )-3-etoksy-acrylsyre-etylester
(Råutbytte: 91% olje),
2-(3,5-diklor-2,4- di fluor-benzoyl ) -3-cyklopropy1-amino-acrylsyreetylester
(Utbytte: 96%, smeltepunkt 71-74'C),
6 ,8-diklor-l-cyklopropyl-7-fluor-l ,4 - dihydro-4 -okso-3-kinolinkarboksylsyre-etylester (Utbytte: 97%, smeltepunkt 215-217°C under spaltning), 6 ,8-diklor-l-cyklopropyl-7-fluor-l , 4 - dihydro-4 - okso-4 - kinolinkarboksylsyre
(Utbytte: 93%, smeltepunkt 204-206°C).
Ytterligere kinolinkarboksylsyrer, spesielt cyklopropyl-6,7,8-trifluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre kan fremstilles i henhold til følgende reaksjonsskjema: Derefter acyleres malonsyredietylester (2) i nærvær av magnesiumetylat med 2 ,3 ,4,5-tetrafluorbenzoylklorid (1) til aroylmalonester (3) ("Organicum", 3. oppi. 1964, side 438).
I stedet for (1) kan det også anvendes 2,3,4,5-tetrafluor-benzosyrefluorid.
Ved partiell forsåpning av dekarboksylering av (3) i vandig medium med katalytiske mengder svovelsyre eller p-toluensulfonsyre får man i godt utbytte aroyleddiksyreetylesteren (4), som med o-maursyretrietylester/acetanhydrid går over til 2-(2,3,4,5-tetrafluorbenzoyl)-3-etoksy-acrylsyreetylester (5). Omsetningen av (5) med cyklopropylamin i et oppløsningsmiddel som metylenklorid, alkohol, kloroform, cykloheksan eller toluen fører i svakt eksoterm reaksjon . til det ønskede mellomprodukt (6).
Ringslutningsreaksjonen (6) (7), gjennomføres i et temperaturområde på ca. 60 til SOO^, fortrinnsvis 80 til 180°C.
Som fortynningsmiddel kan det anvendes dioksan, dimetylsulf-oksyd, N-metylpyrrolidon, sulfolan, heksametylfosforsyretri-amid og fortrinnsvis N,N-dimetylformamid.
Som syrebinder kommer det for dette reaksjonstrinn i betrakt-ning kalium-tert.-butanolat, butyl-litium, litiumfenyl, fenylmagnesiumbromid, natriummetylat, natriumhydrid, natrium-eller kaliumkarbonat, og spesielt foretrukket kalium- eller natriumfluorid. Det kan være fordelaktig å anvende et overskudd på 10 mol-% av basen.
Den i siste trinn foretatte esterhydrolyse av (7) under basiske eller sure betingelser fører til l-cyklopropyl-6,7,8-trifluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre.
Det som utgangsmaterial for denne syntesemåte anvendte 2,3,4,5-tetrafluorbenzoylklorid (1) ble på vanlig måte dannet ut fra den litteraturkjente 2 ,3,4,5-tetrafluor-benzosyre (G.G. Yakobson, V.N. Odinokov og N.N. Vorozhtosov Jr., "Zn. Obsh. Khim." 36, 139 (1966)) med tlonylklorid. Det har et kokepunkt på 65-80°C/17 mbar. 2,3,4,5-tetrafluorbenzoylfluo-ridet har et kokepunkt på 46 til 47°C/20 mbar (nD<20>: 1,4375 ).
Ytterligere kinolinkarboksylsyrer kan fremstilles som følger:
Derefter acyleres malonsyredietylesteren (VII) med IV i nærvær av magnesiumalkoholat til acylmalonester VII ("Organicum", 3. oppi. 1964, side 438).
Ved partiell forsåpning av dekarboksylering av VIII i vandig medium med katalytiske mengder p-toluensulfonsyre får man i godt utbytte aroyleddiksyreetylesteren IX, som med o-maur-syretrietylester/acetanhydrid går over til 2-(2 ,4-diklor-5-fluor-benzoyl)-3-etoksy-acrylsyreetylester X. Omsetningen av X med cyklopropylamin i et oppløsningsmiddel som metylenklorid, alkohol, kloroform, cykloheksan eller toluen fører i svakt eksoterm reaksjon til det ønskede mellomprodukt VI.
Ringslutningsreaksjonen VI -* II (R<1> = alkyl) gjennomføres i et temperaturområde på ca. 60 til 280°C, fortrinnsvis 80° til 180°C.
Som fortynningsmiddel kan det anvendes dioksan, dimetylsulf-oksyd, N-metyl-pyrrolidon, sulfolan, heksametylfosforsyre-triamid og fortrinnsvis N,N-dimetylformamid.
Som syrebinder kommer det for dette reaksjonstrinn i betrakt-ning kalium-t-butanolat, butyllitium, fenyllitium, fenylmagnesiumbromid, natriummetylat og spesielt foretrukket natriumhydrid eller kaliumkarbonat. Det kan være fordelaktig å anvende et overskudd på 10 mol-% av base.
Det som utgangsmaterial for denne syntesemetode anvendte 2,4-diklor-5-fluor-benzoylklorid IV og den tilsvarende karboksyl-syre samt det for fremstilling av IV nødvendige 3-fluor-4,6-diklortoluen XI er kjent fra EP-A2-0 078 362.
Foretrukne forbindelser som kan fremstilles ved fremgangsmåten ifølge oppfinnelsen er omtalt i EP-A2-0 078 362, side 4, linje 10 til 16, EP-A-1 0049 355, eksempler 1 til 19, DE-OS 3 420 743, side 35, linje 20 til 37, linje 11 og DE-0S 3 318 145, side 31, linje 1 til side 32, linje 13.
Ytterligere forbindelser som er fremstillbare ved fremgangsmåten ifølge oppfinnelsen er: 1-cyklopropyl - 7-( 1 , 4-diazabicyklo [3 , 2 , l] okt-4-yl)-6-f luor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-hydroklorid med smeltepunkt 322°C, l-cyklopropyl-7-( 1, 4-di azab i cyklo [3 , 2 , l] okt-4-yl )-6-fluor-1 ,4-dihydro-4-okso-3-kinol i nkar bok sy 1 syre-hemi embonat , smeltepunkt fra 271°C,
8-kl or-1 - cyklopropyl-7-(1,4-diazabicyklo[3,2,l]-okt-4-yl)-6-fluor-1 ,4-dihydro-4-okso-3-kinolinkarboksylsyre-hydroklorid-hydrat, smeltepunkt 310°C,
l-cyklopropyl-7-(l,4-diazabicyklo[3,2,l]okt-4-yl)-6,8-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre med smeltepunkt 275-282°C,
l-cyklopropyl-7-(l,4-diazabicyklo[3,2,l]okt-4-yl)-l,4-dihydro-6-nitro-4-okso-3-kinolinkarboksylsyre-hydroklorid med smeltepunkt 303-307°C,
1-cyklopropyl-7-(l,4-diazabicyklo[3,2, l]okt-4-yl)-6-f luor-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre-hydroklorid med smeltepunkt >300°C,
7-( 1 , 4-diazabicyklo [3 ,2 , l]okt-4-yl )-1-etyl-6,8-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-hydroklorid med smeltepunkt 308-312°C,
10- (1 , 4-diazabicyklo[3 , 2 ,l]okt-4-yl )-9-f luor-2 ,3-dihydro-3-metyl-7-okso-7H-pyrido[l,2,3-de][1,4]benzoksasin-6-karboksyl-syre-hydroklorid med smeltepunkt 355°C,
7-( 1, 4-diazabicyklo [3 , 2 , l]okt-4-yl)-6 ,8-dif luor-1-(4-f luor-
f enyl )-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-hydroklorid med smeltepunkt 310-314°C,
l-cyklopropyl-7-( 1 , 4-di azabicyklo[3 ,2 ,1] okt-4-6yl )-6-fluor-1,4-dihydro-8-nitro-4-okso-3-kinolinkarboksylsyre med smeltepunkt 215-232°C.
Den hertil nødvendige 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-8-nitro-4-okso-3-kinolinkarboksylsyre fås over følgende trinn:
a) 2,4-diklor-5-fluor-3-nitro-benzosyre
Under isavkjøling og omrøring blandes 34 ml konsentrert
svovelsyre dråpevis med 40 ml konsentrert saltpetersyre. I denne nitreringsblanding innfører man porsjonsvis 20,9 g 2,4-diklor-5-fluorbenzosyre i det temperaturen stiger til 45-50°C. Derefter oppvarmes ennå i 3 timer ved 90-100°C, den til romtemperatur avkjølte blanding helles i 350 ml isvann, utfellingen suges fra og vaskes med vann. Det fuktige råprodukt oppløses varmt i 30 ml metanol og oppløsningen blandes med 150 ml vann.
Utfellingen suges fra kaldt, vaskes med metanol/vann og tørkes i vakuum ved 80°C. Man får 21,2 g rå 2,4-diklor-5-fluor-3-nitro-benzosyre. Den er tilstrekkelig ren for de ytterligere omsetninger. En prøve, omkrystallisert fra toluen/petroleter, gir krystaller av smeltepunkt 192°C.
b) 2,4-diklor-5-fluor-3-nitro-benzoylklorid
106,6 g 2,4-diklor-5-fluor-3-nitro-benzosyre oppvarmes med 250 ml tienylklorid i 2 timer under tilbakeløpskoking. Overskytende tienylklorid destilleres derefter av ved normaltrykk og resten fraksjoneres under finvakuum. Ved 110-1156C/0,08-0,09 mbar går det over 104,7 g 2,4-diklor-5-fluor-3-nitro-benzoylklorid. Ved henstand danner -det seg krystaller med smeltepunkt 35-37°C. c) (2,4-diklor-5-fluor-3-nitro-benzoyl)-eddiksyreetylester
10,1 g magnesiumspon blandes i 21 ml etanol med 2,1 g
tetraklormetan og efter begynnelsen av hydrogenutviklingen tilsettes dråpevis en blanding av 66,6 g malonsyredietylester, 40 ml etanol og 150 ml toluen ved 50-60° C. Man omrører i 1 time ved denne temperatur, avkjøler til -5 til -10°C og drypper langsomt til en oppløsning av 109,2 g 2,4-diklor-5-fluor-3-nitro-benzoylklorid i 50 ml toluen. Derefter omrøres i 1 time ved 0°C, bringes natten over til romtemperatur og oppvarmes ennå i 2 timer ved 40-50°C. Reaksjonsblandingen blandes under isavkjøling med en blanding av 160 ml vann og 10,4 ml konsentrert svovelsyre og den organiske fase separeres. Den vandige fase ekstraheres med toluen og de forenede organiske ekstrakter
vaskes med mettet natriumkloridoppløsning, tørkes med natriumsulfat og oppløsningsmidlet fjernes. Man får 144,5 g (2,4-diklor-5-fluor-3-nitro-benzoyl)-malonsyredietylester som råprodukt. Dette oppvarmes efter tilsetning av 200 ml vann og 0,6 g 4-toluensulfonsyre i 3 timer under tilbakeløp, blandingen ekstraheres med metylenklorid, ekstraktet tørkes med natriumsulfat og oppløsningsmidlet destilleres av under vakuum. Det oppnås 118 g substituert benzoyleddikester som råprodukt. Det har en for de videre omsetninger tilstrekkelig renhet.
d) 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-8-nitro-4-okso-3-kinolinkarboksylsyre
244,8 g (2,4-diklor-5-fluor-3-nitro-benzoyl)-eddiksyre-etylester oppvarmes med 166 g ortomaursyretrietylester og 185 g eddiksyreanhydrid i 3 timer ved 150-160°C. Man damper inn under vakuum og får 270 g 2-(2,4-diklor-5-fluor-3-nitro-benzoyl)-3-etoksy-acrylsyre-etylester som oljeaktig rest.
38 g av denne mellomforbindelse blandes i 80 ml etanol
under isavkjøling dråpevis med 5,9 g cyklopropylamin og omrøres i 1 time ved 20°C. Det utfelte produkt suges fra efter tilsetning av 100 ml vann, vaskes med etanol/I^O (1:1) og tørkes. Man får 32,8 g 2-( 2,4-diklor-5-f luor-3-nitro-benzoyl)-3-cyklopropyl-amino-acrylsyreetylester av smeltepunkt 143-146°C.
7,8 g av ovennevnte forbindelse blandes i 30 ml vannfri dioksan med 3,1 g 1,8-diazabicyklo[5,4,0]undec-7-en (DBU)
og oppvarmes 4 timer ved 100°C. Oppløsningsmidlet destilleres av under vakuum, resten tas opp i metylenklorid/vann, metylenkloridfasen separeres, tørkes med natriumsulfat og metylenkloridet destilleres av. Det oppnås 7,2 g 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-8-nitro-4-okso-3-kinolinkarboksylsyreetylester som råprodukt. Efter omkrystallisering fra acetonitril smelter de lysebrune krystaller ved 174-175°C.
Utbytte: 6 g.
7-( 5-benzyl-2,5-diazabicyklo[2,2,l]hept-2-yl)-1-cyklopropyl-6- fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre av smeltepunkt 205-214°C,
1-cyklopropyl-6-fluor-1,4-dihydro-7-(8-metyl-3 ,8-diazabicyklo[3,2,1]okt-3-yl)-4-okso-3-kinolinkarboksylsyre av smeltepunkt 273-278"C.
l-cyklopropyl-6-fluor-l,4-dihydro-7-(5-metyl-l , 4-diazabicyklo[3,2,l]okt-4-yl)-4-okso-3-kinolinkarboksylsyre-hydroklorid med smeltepunkt > 300°C,
1,1 g l-cyklopropyl-7-(l,4-diazabicyklo[3,2,l]okt-4-yl)-6,8-d i fluor-1 ,4 - dihydro-4 -okso-3-kinol inkarboksyl syre-etylester med smeltepunkt 196-199°C,
7- (l,4-diazabicyklo[3,2,l]okt-4-yl )-6,8-difluor-1-(2,4-di fluorf enyl )-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-hydroklorid med smeltepunkt 329-331°C,
7-(1, 4-diazabicyklo[3,2,1]okt-4-yl)-6,8-difluor-1,4-dihydro-1-metylamino-4-okso-3-kinolinkarboksylsyre-hydrokiorid med smeltepunkt 300-305°C.
Ifølge oppfinnelsen oppnås vanligvis i første rekke de fri karboksylsyrer som derefter kan overføres i salter, estere, prodrugs ifølge kjente metoder.
De helt spesielt foretrukne ved fremgangsmåten ifølge oppfinnelsen fremstillbare forbindelser er ciprofloxacin og det tilsvarende 1-etyl-piperazinderivat.
EKSEMPELER
Eksempel 1
606 vektdeler 1-cyklopropyl-7-klor-6-fluor-1, 4-dihydro-4-okso-3-kinolinkarboksylsyre og 575 vektdeler piperazin oppvarmes i en egnet reaktor i 30 minutter ved 150 til 160°C. Reaksjonsblandingen fortynnes med vann, idet det i 71%-ig utbytte fås l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-kinolinkarboksylsyre med en renhet på -ca. 98%.
Eksempel 2
133 vektdeler l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre og 129 vektdeler piperazin omsettes som angitt i eksempel 1. Man får i 70%-ig utbytte 1-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-kinolinkarboksylsyre med en renhet på 98,5%.
Eksempel 3
143 vektdeler piperazin oppvarmes ved 140 til 150°C. I denne smelte inndoseres i løpet av 20 minutter 94 vektdeler 1-cyklopropyl - 7-klor-6-f luor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre. Man avkjøler til 100°C og tilsetter vann. Derved utkrystalliserer l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-kinolinkarboksylsyre i 78%-ig utbytte med en renhet på 97,2%.
Eksempel 4
150 vektdeler piperazin omsettes med 102 vektdeler l-cyklopropyl-6 , 7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre som angitt i eksempel 3. Man får l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-kinolinkarboksylsyre i et utbytte på 76% med en renhet på 97,5%.
Eksempel 5
Til 122 vektdeler 1-etyl-piperazin, som var blitt oppvarmet til 140 til 150°C, settes i løpet av 30 minutter 60 vektdeler l-cyklopropyl-7-klor-6-fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre. Efter avkjøling til 100°C tilsettes vann, og 1-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(4-etyl-1-piperazi-nyl )-3-kinol inkarboksylsyre krystalliserer ut i 76%-ig utbytte og 98,2%-ig renhet.
Claims (6)
1.
Fremgangsmåte for fremstilling av forbindelser med formel I
der
R<1> betyr metyl, etyl, propyl, isopropyl, cyklopropyl,'" 2-
hydroksyetyl, 2-fluoretyl, 4-fluorfenyl, 2,4-difluorfenyl;
R<2> betyr CN eller COOR<2>' der R<2>' har betydningen hydrogen
eller C^_4alkyl;
R<3> betyr en cyklisk aminogruppe som
der
R<4> betyr hydrogen, Ci_4alkyl, 2-hydroksyetyl eller 2-oksy-
propyl;
R<5> betyr hydrogen eller metyl;
r<6> betyr hydrogen eller C^_4alkyl;
R<7> betyr hydrogen, amino, metylamino, etylamino, aminometyl,
metylaminometyl, etylaminometyl, dimetylaminometyl, hydroksy eller hydroksymetyl;
R<8> betyr hydrogen, metyl, etyl eller klor;
X betyr halogen og fortrinnsvis fluor og klor, og A betyr C-R<*1> der R<1*> betyr hydrogen eller halogen, karakterisert ved forbindelser med den generelle formel II
der R<1>, R<2>, A og X har den ovenfor angitte betydning, og Y betyr halogen, fortrinnsvis fluor eller -klor, omsettes med oppløsningsmiddelfrie aminer med formelen
der
R4, R5, R<6>, R<7>, R<8> og R<9> har den ovenfor angitte betydning, uten anvendelse av oppløsningsmidler ved temperaturer fra 20 til 200°C.
2.
Fremgangsmåte ifølge krav 1, karakterisert ved at l-cyklopropyl-7-klor-6-fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre omsettes uten oppløsningsmiddel med piperazin ved 120 til 160°C.
3.
Fremgangsmåte ifølge krav log2, karakterisert ved at l-cyklopropyl-6,7-difluor-l, 4-dihydro-4-okso-3-kinolinkarboksylsyre omsettes uten oppløsningsmiddel med piperazin ved 120 til 160°C.
4. Fremgangsmåte ifølge krav 1 og 2, karakterisert ved at l-cyklopropyl-7-klor-6-fluor-1,4rdihydro-4-okso-3-kinolinkarboksylsyre inndoseres i piperazin som er oppvarmet til 140 til 150°C hvorefter det hele avkjøles, vann tilsettes og omsetningsproduktet krystalliseres ut.
5 .
Fremgangsmåte ifølge krav 4, karakterisert ved at man anvender l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre som utgangsmateriale.
6.
Fremgangsmåte ifølge krav 1, karakterisert ved at man omsetter l-cyklopropyl-7-klor-6-fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre med 1-etylpiperazin, 2-hydroksyetylpiperazin eller 1-metylpiperazin.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863641312 DE3641312A1 (de) | 1986-12-03 | 1986-12-03 | Verfahren zur herstellung von chinolincarbonsaeuren |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO874788D0 NO874788D0 (no) | 1987-11-17 |
| NO874788L NO874788L (no) | 1988-06-06 |
| NO174199B true NO174199B (no) | 1993-12-20 |
| NO174199C NO174199C (no) | 1994-04-06 |
Family
ID=6315377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO874788A NO174199C (no) | 1986-12-03 | 1987-11-17 | Fremgangsmåte til fremstilling av kinolinkarboksylsyrer |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0274033B1 (no) |
| JP (1) | JPS63145268A (no) |
| KR (1) | KR970005191B1 (no) |
| CN (1) | CN87107230A (no) |
| AT (1) | ATE73446T1 (no) |
| AU (1) | AU593961B2 (no) |
| CS (1) | CS270577B2 (no) |
| DD (1) | DD270904A5 (no) |
| DE (2) | DE3641312A1 (no) |
| DK (1) | DK174929B1 (no) |
| ES (1) | ES2038156T3 (no) |
| FI (1) | FI875289A (no) |
| GR (1) | GR3004301T3 (no) |
| HU (1) | HU199823B (no) |
| IE (1) | IE64261B1 (no) |
| IL (1) | IL84627A (no) |
| NO (1) | NO174199C (no) |
| NZ (1) | NZ222736A (no) |
| PH (1) | PH24489A (no) |
| PL (1) | PL158614B1 (no) |
| PT (1) | PT86252B (no) |
| SU (1) | SU1482526A3 (no) |
| UA (1) | UA8017A1 (no) |
| YU (1) | YU45049B (no) |
| ZA (1) | ZA879040B (no) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN166416B (no) * | 1985-09-18 | 1990-05-05 | Pfizer | |
| WO1990013542A1 (fr) * | 1989-04-28 | 1990-11-15 | Daiichi Pharmaceutical Co., Ltd. | Medicament anti-hiv |
| 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 (ja) * | 1990-07-19 | 1997-05-21 | エスエス製薬 株式会社 | キノロンカルボン酸誘導体 |
| ES2050613B1 (es) * | 1992-10-16 | 1996-03-16 | Iteve S A | Nuevo procedimiento para la preparacion de derivados del acido 1-ciclopropil-3-quinolincarboxilico. |
| US6034100A (en) * | 1993-03-10 | 2000-03-07 | Otsuka Pharmaceutical Co., Ltd. | Method for inhibiting cytokine secretion |
| AU6421898A (en) * | 1997-03-25 | 1998-10-20 | Sankyo Company Limited | Anti-fiv agent |
| KR100454750B1 (ko) * | 2002-06-20 | 2004-11-03 | 삼성에스디아이 주식회사 | 유기 전계 발광 소자용 청색 발광 화합물 및 이를 사용한유기 전계 발광 소자 |
| US7514451B2 (en) | 2003-09-10 | 2009-04-07 | Kyorin Pharmaceutical Co., Ltd. | 7-(4-Substituted-3-cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative |
| US8222407B2 (en) | 2007-05-24 | 2012-07-17 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
| CN101671302B (zh) * | 2008-12-30 | 2011-03-30 | 广东海康兽药有限公司 | 禽畜用抗菌药恩诺沙星的生产工艺 |
| CN101899044B (zh) * | 2010-08-16 | 2012-07-18 | 常州市勇毅生物药业有限公司 | 吉米沙星主环化合物的合成方法 |
| CN113912540A (zh) * | 2021-12-15 | 2022-01-11 | 山东国邦药业有限公司 | 一种1-环丙基-6,7-二氟-1,4-二氢-4-氧代-3-喹啉甲酸的合成方法 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5365887A (en) * | 1976-11-22 | 1978-06-12 | Kyorin Seiyaku Kk | Substituted quinoline*arboxylate and process for preparing same |
| DE2656574A1 (de) * | 1976-12-10 | 1978-06-15 | Schering Ag | Neue 1,6-naphthyridincarbonsaeurederivate und verfahren zu ihrer herstellung |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| JPS5845426B2 (ja) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | 置換キノリンカルボン酸誘導体 |
| DE3142854A1 (de) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-piperazino-chinolin-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| DE3318145A1 (de) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| 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 (de) * | 1984-06-04 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-6,8-dihalogen-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| JPS61205258A (ja) * | 1985-03-08 | 1986-09-11 | Kyorin Pharmaceut Co Ltd | キノロンカルボン酸誘導体及びその製造方法 |
-
1986
- 1986-12-03 DE DE19863641312 patent/DE3641312A1/de not_active Withdrawn
-
1987
- 1987-11-17 NO NO874788A patent/NO174199C/no not_active IP Right Cessation
- 1987-11-20 AT AT87117130T patent/ATE73446T1/de not_active IP Right Cessation
- 1987-11-20 DE DE8787117130T patent/DE3777370D1/de not_active Expired - Lifetime
- 1987-11-20 ES ES198787117130T patent/ES2038156T3/es not_active Expired - Lifetime
- 1987-11-20 EP EP87117130A patent/EP0274033B1/de not_active Expired - Lifetime
- 1987-11-26 YU YU2156/87A patent/YU45049B/xx unknown
- 1987-11-27 IL IL84627A patent/IL84627A/xx not_active IP Right Cessation
- 1987-11-30 CS CS878688A patent/CS270577B2/cs not_active IP Right Cessation
- 1987-11-30 NZ NZ222736A patent/NZ222736A/en unknown
- 1987-12-01 FI FI875289A patent/FI875289A/fi not_active Application Discontinuation
- 1987-12-01 JP JP62301624A patent/JPS63145268A/ja active Pending
- 1987-12-01 DD DD87309727A patent/DD270904A5/de not_active IP Right Cessation
- 1987-12-02 PT PT86252A patent/PT86252B/pt unknown
- 1987-12-02 SU SU87A patent/SU1482526A3/ru active
- 1987-12-02 KR KR1019870013716A patent/KR970005191B1/ko not_active IP Right Cessation
- 1987-12-02 HU HU875424A patent/HU199823B/hu unknown
- 1987-12-02 PL PL1987269185A patent/PL158614B1/pl unknown
- 1987-12-02 ZA ZA879040A patent/ZA879040B/xx unknown
- 1987-12-02 IE IE327987A patent/IE64261B1/en not_active IP Right Cessation
- 1987-12-02 CN CN198787107230A patent/CN87107230A/zh active Pending
- 1987-12-02 PH PH36159A patent/PH24489A/en unknown
- 1987-12-02 DK DK198706331A patent/DK174929B1/da not_active IP Right Cessation
- 1987-12-02 UA UA4203762A patent/UA8017A1/uk unknown
- 1987-12-03 AU AU82177/87A patent/AU593961B2/en not_active Expired
-
1992
- 1992-04-08 GR GR920400663T patent/GR3004301T3/el unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1K | Patent expired |