JPH0154344B2 - - Google Patents
Info
- Publication number
- JPH0154344B2 JPH0154344B2 JP56078532A JP7853281A JPH0154344B2 JP H0154344 B2 JPH0154344 B2 JP H0154344B2 JP 56078532 A JP56078532 A JP 56078532A JP 7853281 A JP7853281 A JP 7853281A JP H0154344 B2 JPH0154344 B2 JP H0154344B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- reaction
- general formula
- acid
- piperazinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 72
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 35
- 239000002904 solvent Substances 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 25
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- 239000002253 acid Substances 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 19
- 239000013078 crystal Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- -1 etc. Substances 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 235000010288 sodium nitrite Nutrition 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 10
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 150000007514 bases Chemical class 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 7
- 229960001413 acetanilide Drugs 0.000 description 7
- 150000004820 halides Chemical class 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000008065 acid anhydrides Chemical class 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 5
- 239000004323 potassium nitrate Substances 0.000 description 5
- 235000010333 potassium nitrate Nutrition 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 150000003248 quinolines Chemical class 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006481 deamination reaction Methods 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 230000000802 nitrating effect Effects 0.000 description 3
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 2
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 2
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 2
- IQGRLFTWIPYMON-UHFFFAOYSA-N 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC(N)=C([N+]([O-])=O)C=C1F IQGRLFTWIPYMON-UHFFFAOYSA-N 0.000 description 2
- KCSLKTQEGORTAD-UHFFFAOYSA-N 5-bromo-6-chloro-2-methyl-8-nitroquinoline Chemical compound BrC1=C(Cl)C=C([N+]([O-])=O)C2=NC(C)=CC=C21 KCSLKTQEGORTAD-UHFFFAOYSA-N 0.000 description 2
- KRECUOJIUBUXRY-UHFFFAOYSA-N 5-bromo-6-fluoro-2-methyl-8-nitroquinoline Chemical compound BrC1=C(F)C=C([N+]([O-])=O)C2=NC(C)=CC=C21 KRECUOJIUBUXRY-UHFFFAOYSA-N 0.000 description 2
- BHUPYRLIWHVGNS-UHFFFAOYSA-N 6-fluoro-2-methyl-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinoline Chemical compound CN1CCN(CC1)C1=C2CCC(NC2=CC=C1F)C BHUPYRLIWHVGNS-UHFFFAOYSA-N 0.000 description 2
- AOOKRANOZZTGDH-UHFFFAOYSA-N 6-fluoro-2-methyl-5-(4-methylpiperazin-1-yl)quinoline Chemical compound CN1CCN(CC1)C1=C2C=CC(=NC2=CC=C1F)C AOOKRANOZZTGDH-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- QAWBXZYPFCFQLA-UHFFFAOYSA-N butanoyl bromide Chemical compound CCCC(Br)=O QAWBXZYPFCFQLA-UHFFFAOYSA-N 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000002736 metal compounds Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- ALPHMTFVUKDBGJ-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(F)C(Cl)=C1 ALPHMTFVUKDBGJ-UHFFFAOYSA-N 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000001119 stannous chloride Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PUWHABROFQJWSY-UHFFFAOYSA-N 1-fluoro-2-methyl-3,4-dihydro-2H-quinoline Chemical compound FN1C(CCC2=CC=CC=C12)C PUWHABROFQJWSY-UHFFFAOYSA-N 0.000 description 1
- MWFFNNKFHNIXCB-UHFFFAOYSA-N 2-(chloromethyl)-8-nitroquinoline Chemical compound C1=C(CCl)N=C2C([N+](=O)[O-])=CC=CC2=C1 MWFFNNKFHNIXCB-UHFFFAOYSA-N 0.000 description 1
- DDEAEWMDOSXKBX-UHFFFAOYSA-N 2-(chloromethyl)quinoline Chemical compound C1=CC=CC2=NC(CCl)=CC=C21 DDEAEWMDOSXKBX-UHFFFAOYSA-N 0.000 description 1
- SIQRLWJNWZCECZ-UHFFFAOYSA-N 2-(nitromethyl)quinoline Chemical compound C1=CC=CC2=NC(C[N+](=O)[O-])=CC=C21 SIQRLWJNWZCECZ-UHFFFAOYSA-N 0.000 description 1
- QEZGRWSAUJTDEZ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(piperidine-1-carbonyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)C(=O)N1CCCCC1 QEZGRWSAUJTDEZ-UHFFFAOYSA-N 0.000 description 1
- DJDDYWYYTKNZPM-UHFFFAOYSA-N 2-amino-1,3-dioxane-4,6-dione Chemical compound NC1OC(=O)CC(=O)O1 DJDDYWYYTKNZPM-UHFFFAOYSA-N 0.000 description 1
- DGFVAZGNENIKHY-UHFFFAOYSA-N 2-bromo-4-fluoro-5-(4-methylpiperazin-1-yl)aniline Chemical compound BrC1=C(N)C=C(C(=C1)F)N1CCN(CC1)C DGFVAZGNENIKHY-UHFFFAOYSA-N 0.000 description 1
- JZICUKPOZUKZLL-UHFFFAOYSA-N 2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2NC(C)CCC2=C1 JZICUKPOZUKZLL-UHFFFAOYSA-N 0.000 description 1
- AFRCIAQUASVGNF-UHFFFAOYSA-N 5-bromo-6-chloro-2-methylquinoline Chemical compound BrC1=C(Cl)C=CC2=NC(C)=CC=C21 AFRCIAQUASVGNF-UHFFFAOYSA-N 0.000 description 1
- XLZHFJXJPRVQPI-UHFFFAOYSA-N 5-bromo-6-fluoro-2-methylquinoline Chemical compound BrC1=C(F)C=CC2=NC(C)=CC=C21 XLZHFJXJPRVQPI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910001963 alkali metal nitrate Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 1
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- QFXZANXYUCUTQH-UHFFFAOYSA-N ethynol Chemical compound OC#C QFXZANXYUCUTQH-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- LJRGBERXYNQPJI-UHFFFAOYSA-M sodium;3-nitrobenzenesulfonate Chemical compound [Na+].[O-][N+](=O)C1=CC=CC(S([O-])(=O)=O)=C1 LJRGBERXYNQPJI-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Landscapes
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
本発明は新規なキノリン誘導体に関する。
本発明のキノリン誘導体は文献未載の新規化合
物であつて、下記一般式(1)で表わされる。
〔式中R1は水素原子、ニトロ基、アミノ基又
はハロゲン原子を、R2はハロゲン原子を、R3は
水素原子、低級アルキル基又は低級アルカノイル
基を、R4は低級アルキル基をそれぞれ示す。ま
たキノリン骨格の１位と２位及び３位と４位の炭
素間結合は共に二重結合又は一重結合を示す。但
しキノリン骨格の１位と２位及び３位と４位の炭
素間結合が共に一重結合である場合には、キノリ
ン骨格の１位の窒素原子に水素原子が結合するも
のとし、またR1がニトロ基、アミノ基又はハロ
ゲン原子であつてはならない。〕
上記一般式(1)で表わされる本発明の化合物は、
後記に示す通り抗菌作用を有するベンゾ〔ij〕キ
ノリジン−２−カルボン酸誘導体を合成するため
の中間体として有用であると共に、それ自身抗菌
作用を有し医薬用及び農園芸用の抗菌剤として有
用である。
上記一般式(1)において、R1〜R4で示される各
基としては具体的には次の通りである。
ハロゲン原子……弗素、塩素、臭素及び沃素原
子。
低級アルキル基……メチル、エチル、プロピ
ル、イソプロピル、ブチル、tert−ブチル基等。
低級アルカノイル基……ホルミル、アセチル、
プロピオニル、ブチリル、tert−ブチルカルボニ
ル、ペンタノイル、ヘキサノイル基等。
本発明の化合物は種々の方法により製造される
が、その好ましい例を挙げれば下記反応行程式−
１〜４に示す方法により製造される。
〔式中Ｘはハロゲン原子を示す。R2，R3及び
R4は前記に同じ。〕
反応行程式−１において、一般式(2)の化合物を
ニトロ化する反応には、通常のニトロ化剤をいず
れも使用でき、具体的には発煙硝酸、濃硝酸、混
酸（硫酸、発煙硝酸、リン酸又は無水酢酸と硝
酸）、硝酸カリウム、硝酸ナトリウム等のアルカ
リ金属硝酸塩と硫酸等で例示できる。使用される
ニトロ化剤の使用量としては、一般式(2)の化合物
に対して通常少なくとも等モル量程度、好ましく
は１〜1.5倍モル量を用いるのがよい。反応温度
は通常−20〜50℃、好ましくは−10℃〜室温とす
るのがよく、一般に１〜７時間程度で反応は終了
する。
一般式(3)の化合物と一般式(4)のピペラジン誘導
体との反応は、溶媒の存在下行うことが出来る。
使用される溶媒としては、例えばベンゼン、トル
エン、キシレン等の芳香族炭化水素類、メタノー
ル、エタノール、イソプロパノール、等の低級ア
ルコール類、ジオキサン、テトラヒドロフラン
（THF）、エチレングリコールジメチルエーテル、
ジエチルエーテル等のエーテル類、Ｎ−メチルピ
ロリドン、ジメチルホルムアミド（DMF）、ジメ
チルスルホキシド（DMSO）、ヘキサメチルリン
酸トリアミド等の極性溶剤を挙げることが出来
る。上記反応は、より有利には塩基性化合物を脱
酸剤として用いて行つてもよい。該塩基性化合物
としては、例えば炭酸カリウム、炭酸ナトリウ
ム、水酸化ナトリウム、炭酸水素ナトリウム、ナ
トリウムアミド、水素化ナトリウム、トリエチル
アミン、トリプロピルアミン等の第三級アミン、
ピリジン、キノリン等を例示できる。一般式(4)の
ピペラジン誘導体の使用量としては、一般式(3)の
化合物に対して通常１〜10倍モル量、好ましくは
３〜７倍モル量使用するのがよい。反応温度は通
常50〜150℃、好ましくは50〜100℃とするのがよ
く、一般に1.5〜10時間程度で反応は終了する。
一般式（1a）の化合物の還元には、通常のニ
トロ基の還元反応を利用出来、例えば酸化白
金、パラジウム黒、パラジウム炭素、等の還元触
媒を用いて、水、メタノール、エタノール、イソ
プロパノール、テトラヒドロフラン、エチルエー
テル等の溶媒中通常１〜10気圧、好ましくは１〜
３気圧の水素雰囲気中、一般に−30℃〜溶媒の沸
点範囲、好ましくは０℃〜室温付近にて接触還元
する方法、水素化リチウムアルミニウムを還元
剤として用い、エチルエーテル、テトラヒドロフ
ラン等の無水溶媒中還元する方法、鉄、亜鉛、
錫、塩化第一錫等の金属化合物と塩酸、酢酸、等
の酸とを用いて水、エタノール、メタノール、酢
酸等の溶媒中、還元する方法等を利用出来る。こ
れらの方法のうち好ましくは上記の方法を利用
するのがよい。該反応の反応温度は、通常０〜
100℃、好ましくは10〜50℃とするのがよく、一
般に該反応は10分〜３時間程度で終了する。使用
される金属化合物の使用量としては、一般式
（1a）の化合物に対して、通常少なくとも等モル
量程度、好ましくは２〜５倍モル量使用するのが
よい。
一般式（1b）の化合物の脱アミノ化反応は、
水等の溶媒中、硫酸、塩酸、臭酸、弗化ホウ素酸
等の酸と亜硝酸ナトリウムを用いてジアゾニウム
塩とし、ついでエタノール等のアルコール類、ア
ルカリ性ホルムアルデヒド等のアルデヒド類、亜
鉛、銅等の金属類又は次亜リン酸等の水素化剤と
反応させることにより行なうことが出来る。ここ
で使用される亜硝酸ナトリウムの使用量として
は、一般式（1b）の化合物に対して通常１〜２
倍モル量、好ましくは１〜1.5倍モル量とするの
がよい。また水素化剤の使用量としては、一般式
（1b）の化合物に対して通常大過剰量、好ましく
は５〜15倍モル量とするのがよい。該反応は通常
−20〜室温付近、好ましくは−５〜５℃付近で行
うのがよく、反応時間は一般に５〜24時間程度で
ある。
一般式（1c）の化合物の還元反応には通常の接
触還元を利用出来る。ここで使用される還元触媒
としては、例えば酸化白金、白金−炭素、パラジ
ウム黒、パラジウム炭素、ラネ−ニツケル等を挙
げることが出来る。使用される溶媒としては、例
えば水、メタノール、エタノール、イソプロパノ
ール等の低級アルコール類、テトラヒドロフラ
ン、エチルエーテル等のエーテル類、酢酸、無水
酢酸等を挙げることが出来る。反応は、通常１〜
10気圧、好ましくは２〜５気圧の水素雰囲気中、
一般に−30℃〜溶媒の沸点範囲、好ましくは０℃
〜室温付近にて行うことが出来る。還元触媒の使
用としては、一般式（1c）の化合物に対して通常
５〜15重量％、好ましくは５〜10重量％用いるの
がよい。
反応行程式 ２
〔式中X1はハロゲン原子を示す。R2，R3及び
R4は前記に同じ。〕
反応行程式−２において、一般式（1b）の化
合物のハロゲン化反応は、水等の溶媒中、硫酸、
塩酸、臭化水素酸、弗化ホウ素酸等の酸と亜硝酸
ナトリウムを用いてジアゾニウム塩とし、次いで
ハロゲン化水素酸（例えば臭化水素酸、塩酸等）
の存在下、銅粉又はハロゲン化銅（例えば臭化第
一銅、塩化第一銅、塩化第二銅等）等と反応させ
るか、或いは銅粉の存在下又は不存在下沃化カリ
ウムと反応させることにより（好ましくはハロゲ
ン化水素酸の存在下銅粉と反応させることによ
り）行うことができる。ここで使用される亜硝酸
ナトリウムの使用量としては、一般式（1b）の
化合物に対して通常１〜２倍モル量、好ましくは
１〜1.5倍モル量とするのがよい。また銅粉の使
用量としては、一般式（1b）の化合物に対して
通常１〜３倍モル量、好ましくは１〜２倍モル量
とするのがよい。反応は、通常−20℃〜室温付
近、好ましくは−５〜５℃付近で行うのがよく、
反応時間は一般に10分〜５時間程度である。
一般式（1e）の化合物を還元して一般式（1d）
の化合物を得る反応には、前記一般式（1c）の化
合物を還元して一般式（1d）の化合物を得る反
応の反応条件をいずれも適用できる。
〔式中R5は水素原子、R6は低級アルカノイル
基を示す。またこのR5とR6とはこれらが結合す
る窒素原子と共に互いに結合して基
The present invention relates to novel quinoline derivatives. The quinoline derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R 1 represents a hydrogen atom, a nitro group, an amino group, or a halogen atom, R 2 represents a halogen atom, R 3 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, and R 4 represents a lower alkyl group. . Further, the carbon bonds at the 1st and 2nd positions and the 3rd and 4th positions of the quinoline skeleton both represent a double bond or a single bond. However, if the carbon bonds at the 1st and 2nd positions and the 3rd and 4th positions of the quinoline skeleton are both single bonds, a hydrogen atom is bonded to the nitrogen atom at the 1st position of the quinoline skeleton, and R 1 is It must not be a nitro group, an amino group, or a halogen atom. ] The compound of the present invention represented by the above general formula (1) is
As shown below, it is useful as an intermediate for synthesizing benzo[ij]quinolidine-2-carboxylic acid derivatives that have antibacterial activity, and also has antibacterial activity itself and is useful as an antibacterial agent for pharmaceutical and agricultural and horticultural purposes. It is. In the above general formula (1), the groups represented by R 1 to R 4 are specifically as follows. Halogen atoms: fluorine, chlorine, bromine and iodine atoms. Lower alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl groups, etc. Lower alkanoyl group...formyl, acetyl,
Propionyl, butyryl, tert-butylcarbonyl, pentanoyl, hexanoyl groups, etc. The compound of the present invention can be produced by various methods, but a preferred example is the following reaction scheme -
It is manufactured by the methods shown in 1 to 4. [In the formula, X represents a halogen atom. R 2 , R 3 and
R 4 is the same as above. ] In Reaction Scheme-1, any ordinary nitrating agent can be used for the reaction of nitrating the compound of general formula (2), and specifically, fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, fuming nitric acid, , phosphoric acid or acetic anhydride and nitric acid), alkali metal nitrates such as potassium nitrate and sodium nitrate, and sulfuric acid. The amount of the nitrating agent to be used is usually at least equimolar, preferably 1 to 1.5 times the molar amount of the compound of general formula (2). The reaction temperature is usually -20 to 50°C, preferably -10°C to room temperature, and the reaction is generally completed in about 1 to 7 hours. The reaction between the compound of general formula (3) and the piperazine derivative of general formula (4) can be carried out in the presence of a solvent.
Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether,
Examples include ethers such as diethyl ether, polar solvents such as N-methylpyrrolidone, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and hexamethylphosphoric triamide. The above reaction may be carried out more advantageously using a basic compound as a deoxidizing agent. Examples of the basic compound include tertiary amines such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, triethylamine, and tripropylamine;
Examples include pyridine and quinoline. The amount of the piperazine derivative of general formula (4) to be used is usually 1 to 10 times the molar amount, preferably 3 to 7 times the molar amount of the compound of general formula (3). The reaction temperature is usually 50 to 150°C, preferably 50 to 100°C, and the reaction is generally completed in about 1.5 to 10 hours. For the reduction of the compound of general formula (1a), a normal nitro group reduction reaction can be used. For example, using a reduction catalyst such as platinum oxide, palladium black, palladium carbon, etc., water, methanol, ethanol, isopropanol, tetrahydrofuran, etc. , in a solvent such as ethyl ether, usually from 1 to 10 atm, preferably from 1 to 10 atm.
A method of catalytic reduction in a hydrogen atmosphere of 3 atm, generally at -30°C to the boiling point range of the solvent, preferably around 0°C to room temperature, using lithium aluminum hydride as a reducing agent, in an anhydrous solvent such as ethyl ether or tetrahydrofuran. How to reduce iron, zinc,
A method of reduction using a metal compound such as tin or stannous chloride and an acid such as hydrochloric acid or acetic acid in a solvent such as water, ethanol, methanol, or acetic acid can be used. Among these methods, the above-mentioned method is preferably used. The reaction temperature of this reaction is usually 0 to
The temperature is preferably 100°C, preferably 10 to 50°C, and the reaction is generally completed in about 10 minutes to 3 hours. The amount of the metal compound to be used is usually at least an equimolar amount, preferably 2 to 5 times the molar amount of the compound of general formula (1a). The deamination reaction of the compound of general formula (1b) is
A diazonium salt is prepared using an acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, or fluoroboric acid and sodium nitrite in a solvent such as water, and then alcohols such as ethanol, aldehydes such as alkaline formaldehyde, zinc, copper, etc. This can be carried out by reacting with metals or a hydrogenating agent such as hypophosphorous acid. The amount of sodium nitrite used here is usually 1 to 2
It is preferable to use twice the molar amount, preferably 1 to 1.5 times the molar amount. The amount of the hydrogenating agent to be used is usually a large excess amount, preferably 5 to 15 times the amount of the compound of general formula (1b). The reaction is usually carried out at around -20 to room temperature, preferably around -5 to 5°C, and the reaction time is generally about 5 to 24 hours. Conventional catalytic reduction can be used for the reduction reaction of the compound of general formula (1c). Examples of the reduction catalyst used here include platinum oxide, platinum-carbon, palladium black, palladium carbon, and Raney-nickel. Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran and ethyl ether, acetic acid, and acetic anhydride. The reaction is usually 1~
In a hydrogen atmosphere of 10 atmospheres, preferably 2 to 5 atmospheres,
Generally -30°C to the boiling point of the solvent, preferably 0°C
~ Can be carried out at around room temperature. The reduction catalyst is usually used in an amount of 5 to 15% by weight, preferably 5 to 10% by weight, based on the compound of general formula (1c). Reaction equation 2 [In the formula, X 1 represents a halogen atom. R 2 , R 3 and
R 4 is the same as above. ] In Reaction Scheme-2, the halogenation reaction of the compound of general formula (1b) is carried out using sulfuric acid,
A diazonium salt is prepared using an acid such as hydrochloric acid, hydrobromic acid, or fluoroboric acid and sodium nitrite, and then a hydrohalic acid (e.g., hydrobromic acid, hydrochloric acid, etc.)
or with potassium iodide in the presence or absence of copper powder. (preferably by reacting with copper powder in the presence of a hydrohalic acid). The amount of sodium nitrite used here is usually 1 to 2 times the molar amount, preferably 1 to 1.5 times the molar amount of the compound of general formula (1b). The amount of copper powder to be used is usually 1 to 3 times, preferably 1 to 2 times, the amount of the compound of general formula (1b). The reaction is usually carried out at around -20°C to room temperature, preferably around -5 to 5°C,
The reaction time is generally about 10 minutes to 5 hours. General formula (1d) is obtained by reducing the compound of general formula (1e).
Any of the reaction conditions for the reaction for reducing the compound of general formula (1c) to obtain the compound of general formula (1d) can be applied to the reaction to obtain the compound of formula (1d). [In the formula, R 5 represents a hydrogen atom, and R 6 represents a lower alkanoyl group. In addition, R 5 and R 6 are bonded together with the nitrogen atom to which they are bonded to form a group.
【式】を形成してもよい。R2，R3及
びR4は前記に同じ。〕
一般式(5)の化合物の加水分解は、適当な溶媒中
塩基性化合物の存在下に行うことが出来る。使用
される溶媒としては、例えば水、メタノール、エ
タノール、イソプロパノール等を挙げることが出
来る。使用される塩基性化合物としては、例えば
水酸化カリウム、水酸化ナトリウム、炭酸カリウ
ム、炭酸ナトリウム、炭酸水素ナトリウム等を挙
げることが出来る。使用される塩基性化合物の使
用量としては、一般式(5)の化合物に対して通常大
過剰量、好ましくは４〜８倍モル量とするのがよ
い。反応温度としては、通常室温〜150℃程度、
好ましくは50〜100℃程度とするのがよく、一般
に10分〜５時間程度で反応は終了する。
一般式(6)の化合物と一般式(7)の化合物との反応
は、無溶媒下縮合剤の存在下にて行なわれる。用
いられる縮合剤としては例えば五酸化リン、ポリ
リン酸等のリン酸類、硫酸等の酸類、オキシ塩化
リン、五塩化リン、三塩化リン等のリン化合物等
を挙げることができる。斯かる縮合剤の使用量と
しては、一般式(6)の化合物に対して通常大過剰量
とするのがよい。一般式(6)の化合物と一般式(7)の
化合物との使用割合としては、通常前者に対して
後者を少くとも等モル量、好ましくは１〜1.5倍
モル量使用するのがよい。該反応は通常70〜150
℃程度にて行なわれ、一般に数分〜１時間程度で
反応は終了する。
〔式中R3′は低級アルカノイル基を示す。R1，
R2，R4及び、キノリン骨格の１位と２位及び３
位と４位の炭素間結合は前記に同じ。〕
反応行程式−４において、一般式（1g）の化
合物のアシル化反応は、塩基性化合物の存在下又
は不存在下酸ハライド又は酸無水物等のアシル化
剤と反応させることにより行うことが出来る。こ
こで使用される酸ハライド又は酸無水物として
は、例えばアセチルクロライド、プロピオニルク
ロライド、ブチリルブロマイド等の酸ハロゲン化
物、無水酢酸等の酸無水物を挙げることが出来
る。塩基性化合物としては、公知のものを広く使
用出来、例えば水酸化ナトリウム、水酸化カリウ
ム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナ
トリウム等の無機塩基、ナトリウムメチラート、
ナトリウムエチラート等のアルコラート、トリエ
チルアミン、ピリジン、Ｎ，Ｎ−ジメチルアニリ
ン等の有機塩基が挙げられる。該反応は無溶媒で
もあるいは溶媒の存在下でも行なわれる。溶媒と
しては反応に悪影響を与えない不活性のものがす
べて用いられ、例えばメタノール、エタノール、
プロパノール、ブタノール、エチレングリコール
等のアルコール類、ジメチルエーテル、テトラヒ
ドロフラン、ジオキサン、モノグライム、ジグラ
イム等のエーテル類、アセトン、メチルエチルケ
トン等のケトン類、ベンゼン、トルエン、キシレ
ン等の芳香族炭化水素類、酢酸メチル、酢酸エチ
ル等のエステル類、Ｎ，Ｎ−ジメチルホルムアミ
ド、ジメチルスルホキサイド、ヘキサメチルリン
酸トリアミド等の非プロトン性極性溶媒等が挙げ
られる。上記方法における化合物（1g）に対す
るアシル化剤の使用割合はとくに限定されず、広
い範囲の中から選宜に選択されるが、反応を無溶
媒下に行なう場合には前者に対して後者を通常大
過剰量、溶媒中で行なう場合には通常前者に対し
て後者を等モル〜５倍モル、好ましくは等モル〜
３倍モル量にて用いるのが望ましい。また、その
反応温度もとくに限定されないが、通常室温〜
200℃、好ましくは50〜160℃で行なわれる。反応
時間は通常１〜30時間である。
また得られた化合物（1h）は、これをメタノ
ール、エタノール等のアルコール中水酸化カリウ
ム、水酸化ナトリウム等の無機塩基を脱酸剤とし
て用いて又は臭化水素酸、塩酸等の酸を用いて加
水分解することにより化合物（1g）に導くこと
もできる。
上記反応行程式−３において、出発原料として
用いられる一般式(5)の化合物は例えば下記反応行
程式−５に示す方法により製造される。
〔式中R2，R3，R5，R6，Ｘ及びX1は前記に同
じ。〕
反応行程式−５において、一般式(8)のアニリン
誘導体を一般式(9)のアニリン誘導体に導く反応
は、適当な溶媒中一般式(8)の化合物と酸無水物又
は酸ハロゲン化物とを反応させることにより行う
ことが出来る。使用される溶媒としては、例えば
メタノール、エチノール、イソプロパノール等の
低級アルコール類、ジオキサン、THF等のエー
テル類、酢酸、ピリジン、DMF，DMSO等を挙
げることが出来る。酸無水物としては、例えば無
水酢酸、無水フタール酸等を挙げることができ、
また酸ハロゲン化物としては、例えばアセチルク
ロライド、プロピオニルクロライド、ブチリルブ
ロマイド等を挙げることが出来る。酸無水物又は
酸ハロゲン化物の使用量としては、一般式(8)のア
ニリン誘導体に対して通常少なくとも等モル量程
度、好ましくは１〜３倍モル量とするのがよい。
反応温度としては、通常室温〜200℃、好ましく
は室温〜160℃程度で行うのがよく、反応は一般
に0.5〜５時間で終了する。
一般式(9)の化合物のニトロ化は、前記一般式(2)
の化合物のニトロ化と同様の反応条件下に行うこ
とができる。一般式(10)の化合物と一般式(4)の化合
物との反応は、前記一般式(3)の化合物と一般式(4)
の化合物との反応と同様の反応条件下に行うこと
ができる。一般式（5a）の化合物の還元は、前
記一般式（1a）の化合物の還元と同様の反応条
件下に行うことができる。一般式（5a）の化合
物の脱アミノ化は、前記一般式（1b）の化合物
の脱アミノ化と同様の反応条件下に行うことがで
きる。また一般式（5b）の化合物のハロゲン化
は、前記一般式（1b）の化合物のハロゲン化と
同様の反応条件下に行うことができる。また一般
式（5d）の化合物は一般式（5c）の化合物に塩
素、臭素等のハロゲン化物を反応させることによ
つても製造される。
本発明の化合物は例えば下記反応行程式−６又
は７に従い抗菌剤として有用な一般式（13）の化
合物に誘導され得る。
反応行程式 ６
〔式中R10及びR11はそれぞれ低級アルキル基
を示す。R2，R3及びR4は前記に同じ。〕
一般式（1d）の化合物と一般式（11）の化合
物との反応は、無溶媒下又は適当な溶媒中にて行
なわれる。溶媒としては例えばメタノール、エタ
ノール、イソプロパノール等のアルコール類、ベ
ンゼン、トルエン等の芳香族炭化水素類、アセト
ニトリル、ジメチルホルムアミド、ジメチルスル
ホキシド、ヘキサメチルリン酸トリアミド等を挙
げることができる。該反応を無溶媒下にて行なう
のが好適である。一般式（1d）の化合物に対す
る一般式（11）の化合物の使用割合は通常等モル
以上、好ましくは等モル〜1.5倍モル量とされる。
反応温度は通常室温〜150℃程度、好ましくは60
〜120℃であり、反応は通常0.5〜６時間で完了
し、容易に一般式（12）で表わされる化合物を収
得できる。
一般式（1d）の化合物と一般式（14）の化合
物との反応は、上記一般式（1d）の化合物と一
般式（11）の化合物との反応と同様の条件下に行
なうことができ、斯くして一般式（15）で表わさ
れる化合物を容易に収得できる。
一般式（12）で表わされる化合物又は一般式
（15）で表わされる化合物の環化反応は、従来公
知の各種環化反応例えば加熱による方法、オキシ
塩化リン、五塩化リン、三塩化リン、チオニルク
ロライド、濃硫酸、ポリリン酸等の酸性物質を用
いる環化法等に従い行ない得る。加熱による環化
法を採用する場合、高沸点炭化水素類及び高沸点
エーテル類例えばテトラリン、ジフエニルエーテ
ル、ジエチレングリコールジメチルエーテル等の
溶媒を用い、通常100〜250℃、好ましくは150〜
200℃の加熱条件を採用できる。又酸性物質を用
いる酸化法を採用する場合該酸性物質を化合物
（12）又は（15）に対して等モル量〜大過剰量好
ましくは10〜20倍量用い、通常100〜150℃で0.5
〜６時間程度反応させればよい。一般式（12）の
化合物を原料化合物とした場合には、上記環化反
応により目的とする一般式（13）の化合物を収得
し得る。また一般式（15）の化合物を原料化合物
とした場合には、上記環化反応により一般式
（16）の化合物を収得でき、これを単離して又は
単離することなく次の加水分解反応に供される。
一般式（16）の化合物の加水分解反応は、常法
に従い、例えば水酸化ナトリウム、水酸化カリウ
ム、水酸化バリウム等の塩基性化合物、硫酸、塩
酸、硝酸等の鉱酸、酢酸、芳香族スルホン酸等の
有機酸等の慣用の触媒の存在下に行なわれる。該
反応は一般には水、メタノール、エタノール、イ
ソプロパノール、ジオキサン、エチレングリコー
ル、アセトン、メチルエチルケトン、酢酸等の通
常の溶媒中で実施される。反応温度は通常室温〜
200℃、好ましくは50〜150℃である。斯くして一
般式（13）の化合物が収得される。
かくして得られる本発明のキノリン誘導体は、
慣用の単離手段、例えば過、再結晶、カラムク
ロマトグラフイー、プレパラテイブ薄層クロマト
グラフイー等により反応混合物から容易に単離精
製される。
以上の如くして得られる本発明の一般式(1)で表
わされるキノリン誘導体は、医薬的に許容される
酸を作用させることにより容易に酸付加塩とする
ことができ、本発明はこの酸付加塩をも包含す
る。上記において酸としては例えば、塩酸、硫
酸、リン酸、臭化水素酸等の無機酸、酢酸、シユ
ウ酸、コハク酸、マレイン酸、フマール酸、リン
ゴ酸、酒石酸、クエン酸、マロン酸、メタンスル
ホン酸、安息香酸等の有機酸を使用できる。
以下に参考例及び実施例を挙げる。
参考例 １
３−クロロ−４−フルオロアニリン50ｇを酢酸
150mlに溶かし、それに無水酢酸70.2ｇを滴下す
る。室温で30分撹拌後、反応混合物を水の中に注
入し、析出固体を取する。析出固体を水洗後、
酢酸エチルに溶解し、酢酸エチル層を希炭酸カリ
ウム水溶液で洗浄、硫酸マグネシウムで乾燥し、
溶媒を留去する。62ｇの３−クロロ−４−フルオ
ロアセトアニリドを得る。
mp.116〜117℃
参考例 ２
３−クロロ−４−フルオロアニリン10ｇを無水
フタル酸10.2ｇを30mlのDMFに溶かし、２時間
加熱還流する。反応混合物に水を加え、析出晶を
取する。析出晶を酢酸エチルに溶かし、炭酸水
素ナトリウム水溶液で洗浄後、硫酸マグネシウム
で乾燥して、14.4ｇのＮ−（３−クロロ−４−フ
ルオロ−１−フエニル）フタルイミドを得る。
mp.192〜193℃
参考例 ３
３−クロロ−４−フルオロアセトアニリド10ｇ
を濃硫酸35mlに溶かし、０℃で6.5ｇの硝酸カリ
ウムの25ml濃硫酸溶液を30分間で滴下する。滴下
後０℃で1.5時間撹拌する。反応混合物を400mlの
氷水中に注入し、析出晶を取し、水洗、乾燥
後、12.3ｇの２−ニトロ−４−フルオロ−５−ク
ロロ−アセトアニリドを得る。
mp.111〜112℃
参考例 ４
15〜20℃に保つてＮ−（３−クロロ−４−フル
オロ−１−フエニル）フタルイミド14ｇを濃硫酸
75mlに溶かし、−５℃で5.6ｇの硝酸カリウムの20
ml濃硫酸溶液を30分間で滴下する。−５〜０℃で
１時間撹拌後、反応混合物を1.5の氷水中に注
入し、析出晶を取する。水洗後、ジクロロメタ
ンに溶解し、硫酸マグネシウムで乾燥する。溶媒
を留去して、15.4ｇのＮ−（２−ニトロ−４−フ
ルオロ−５−クロロ−１−フエニル）フタルイミ
ドを得る。
mp.222〜224℃
参考例 ５
２−ニトロ−４−フルオロ−５−クロロ−アセ
トアニリド12ｇをメチルピペラジン25.8ｇを120
mlのDMFに溶解し、70℃で２時間撹拌する。過
剰のメチルピペラジン及びDMFを減圧留去し、
残渣に50mlの水を加え、析出晶を取する。水洗
後、メタノール−水で再結晶し、つづいてイソプ
ロパノールより再結晶して、14.3ｇの２−ニトロ
−４−フルオロ−５−（４−メチル−１−ピペラ
ジニル）アセトアニリドを得る。
mp.133〜135℃
参考例 ６
２−ニトロ−４−フルオロ−５−（４−メチル
−１−ピペラジニル）アセトアニリド10ｇと9.5
ｇの水酸化カリウムの８ml水溶液を100mlのメタ
ノールに溶かし、30分間還流する。冷却後、50ml
の水を反応混合物に加え析出固体を取し、水洗
後、イソプロパノールより再結晶して、8.0ｇの
２−ニトロ−４−フルオロ−５−（４−メチル−
１−ピペラジニル）アニリンを得る。
mp.151〜153℃
参考例 ７
２−ニトロ−４−フルオロ−５−（４−メチル
−１−ピペラジニル）アセトアニリド25ｇを濃塩
酸250mlに溶かし、この中に塩化第一錫・２水和
物57.2ｇの濃塩酸250ml溶液を一度に加える。反
応温度が40℃まで上昇する。１時間放冷撹拌後、
析出固体を取し、少量の水に溶解して、氷冷下
水酸化ナトリウム水溶液でアルカリ性にし、ジク
ロロメタン抽出する。炭酸カリウム乾燥後、溶媒
を留去する。残渣にｎ−ヘキサンを加えて結晶化
し、結晶を取、乾燥して、15.7ｇの２−アミノ
−４−フルオロ−５−（４−メチル−１−ピペラ
ジニル）アセトアニリドを得る。
mp.168〜169℃
参考例 ８
２−アミノ−４−フルオロ−５−（４−メチル
−１−ピペラジニル）アセトアニリド3.0ｇを水
10mlと濃塩酸30mlに溶かし、０℃で亜硝酸ナトリ
ウム水溶液（亜硝酸ナトリウム0.77ｇを水５mlに
とかしたもの）を滴下し、２分間撹拌し、ｎ−オ
クタノール２滴を加え、銅粉0.96ｇを一度に加え
る。30分間撹拌後、反応液を水に注入し、水酸化
ナトリウム水溶液でアルカリ性とし、ジクロロメ
タンで抽出し、硫酸マグネシウムで乾燥する。溶
媒留去後残渣をシリカゲルカラムクロマトグラフ
イー（クロロホルム−メタノール＝４：１）で精
製して、0.90ｇの３−（４−メチル−１−ピペラ
ジニル）−４−フルオロアセトアニリドを得る。
mp.175〜176℃
参考例 ９
0.60ｇの硫酸銀を10mlの濃硫酸に溶解し、撹拌
下、この溶液に３−（４−メチル−１−ピペラジ
ニル）−４−フルオロ−アセトアニリド0.80ｇを
加える。臭素0.61ｇを加え、内温30〜40℃で１時
間撹拌する。反応液を水に注入して不溶物を去
し、液に水酸化ナトリウム水溶液を加えてアル
カリ性とする。ジクロロメタンで抽出し、濃縮
後、シリカゲルカラムクロマトグラフイー（クロ
ロホルム−メタノール＝８：１）で精製して、
0.21ｇの２−ブロム−４−フルオロ−５−（４−
メチル−１−ピペラジニル）アセトアニリドを得
る。
mp.126〜127℃
参考例 10
２−ブロム−４−フルオロ−５−（４−メチル
−１−ピペラジニル）アセトアニリド0.10ｇを47
％臭化水素酸５mlに加え、１時間還流する。47％
臭化水素酸を留去し、残渣に水酸化ナトリウム水
溶液を加えてアルカリ性とし、析出する不溶の白
色固体を取し、乾燥して、0.08ｇの２−ブロム
−４−フルオロ−５−（４−メチル−１−ピペラ
ジニル）アニリンを得る。
mp.122〜124℃
参考例 11
５−ブロム−６−フルオロキナルジン21.0ｇを
濃硫酸117mlに溶解し、−５℃で11.5ｇの硝酸カリ
ウムの30ml濃硫酸溶液を滴下する。室温で５時間
撹拌後、反応混合物を２の氷水中に注入し、析
出固体を取する。液をアルカリ性にして、さ
らに少量の固体を得る。前記の析出固体とあわせ
て、ジクロロメタンに溶解し、硫酸ナトリウムで
乾燥する。溶媒を留去後イソプロパノールより再
結晶して、22.9ｇの５−ブロム−６−フルオロ−
８−ニトロキナルジンを得る。
mp.135〜137℃
参考例 12
５−ブロム−６−クロロ−キナルジン40ｇを濃
硫酸220mlに溶かし、０℃に冷却して、硝酸カリ
ウム20.5ｇの濃硫酸60ml溶液を30分間を要して滴
下する。その後室温で2.5時間撹拌する。反応液
を1.5の氷水中に注入し、析出晶を取する。
液をアルカリ性にして、さらに少量の固体を得
る。前記の析出固体とあわせて、イソプロパノー
ルより再結晶して、42.3ｇの５−ブロム−６−ク
ロロ−８−ニトロ−キナルジンを得る。
mp.141〜142℃
参考例 13
(a) ５−（４−メチル−１−ピペラジニル）−６−
フルオロ−１，２，３，４−テトラヒドロキナ
ルジン10ｇ及びイソプロピリデニルメトキシメ
チレンマロネート８ｇを室温下で混合し、次い
で100℃で30分加熱撹拌すると固化する。クロ
ロホルム−ｎ−ヘキサンより再結晶して環式イ
ソプロピリデニルＮ−〔５−（４−メチル−１−
ピペラジニル）−６−フルオロ−１，２，３，
４−テトラヒドロ−１−キナルジニル〕−アミ
ノメチレンマロネート14.6ｇ（92％）を得る。
白色結晶
元素分析値（C22H28O4N3Fとして）
Ｃ Ｈ Ｎ
分析値(%) 63.42 6.59 10.05
計算値(%) 63.29 6.76 10.07
(b) 五酸化リン25ｇとリン酸25ｇから調製される
ポリリン酸及び上記(a)で得られる環式イソプロ
ピリデニルＮ−〔５−（４−メチル−１−ピペラ
ジニル）−６−フルオロ−１，２，３，４−テ
トラヒドロ−１−キナルジニル）−アミノメチ
レンマロネート14.0ｇを100℃にて１時間加熱
撹拌し、80℃に冷却後、水60mlを加え溶解し、
20％水酸化ナトリウム水溶液で中和した後、ク
ロロホルム200mlで２回抽出する。クロロホル
ム層を無水硫酸マグネシウムで脱水乾燥後濃縮
乾固し、得られた結晶にメタノール40mlと活性
炭0.5ｇを加えて加熱溶解し、活性炭を去後
冷却し、析出した結晶を取し、８−（４−メ
チル−１−ピペラジニル）−９−フルオロ−５
−メチル−６，７−ジヒドロ−１−オキソ−
1H，5H−ベンゾ〔ij〕キノリジン−２−カル
ボン酸10.2ｇを得る。（84.6％）
白色稜状晶 融点 262〜263℃
実施例 １
２−ニトロ−４−フルオロ−５−（４−メチル
−１−ピペラジニル）アニリン20ｇを60％硫酸
（濃硫酸40mlと水48ml）に加え、さらにｍ−ニト
ロベンゼンスルホン酸ナトリウム13.2ｇを加え
る。110℃まで加熱溶解し、クロトンアルデヒド
6.6ｇを10分間で滴下する。５分後、反応混合物
を30mlの氷水中に注入する。得られた５−（４−
メチル−１−ピペラジニル）−６−フルオロ−８
−ニトロ−キナルジンを取り出すことなく、この
中に、71ｇの塩化第１錫・２水和物の140ml濃塩
酸溶液を加え、30分間撹拌する。活性炭処理後、
水酸化ナトリウム水溶液でアルカリ性とし、析出
物をジクロロメタンで抽出し、溶媒留去後、残渣
にイソプロパノールを加えて溶解し、濃塩酸を加
え塩酸塩とし、アセトンでよく洗浄後、水に溶か
し、水酸化ナトリウム水溶液でアルカリ性とす
る。析出固体を取し、ｎ−ヘキサンで再結晶し
て、8.7ｇの５−（４−メチル−１−ピペラジニ
ル）−６−フルオロ−８−アミノキナルジンを得
る。
黄色針状晶 mp.149〜151℃
実施例 ２
５−（４−メチル−１−ピペラジニル）−６−フ
ルオロ−８−アミノキナルジン1.5ｇに濃塩酸10
ml及び水３mlを加え、−20℃で0.39ｇの亜硝酸ナ
トリウムの２ml水溶液を滴下する。３分後ｎ−オ
クタノール（消包剤）１滴を加え、予め０℃に冷
却しておいた次亜リン酸（50％溶液）5.7ｇを−
２℃で滴下する。その後０〜５℃で７時間撹拌す
る。反応液を水にあけ、水酸化ナトリウム水溶液
でアルカリ性とする。ジクロロメタンで抽出し、
硫酸ナトリウムで乾燥する。溶媒を留去して、ｎ
−ヘキサンで再結晶して、0.71ｇの５−（４−メ
チル−１−ピペラジニル）−６フルオロキナルジ
ンを得る。
微黄色結晶 mp.87〜89.5℃
実施例 ３
５−（４−メチル−１−ピペラジニル）−６−フ
ルオロ−８−アミノキナルジン2.0ｇを７mlの水
と20mlの濃塩酸に溶解し、０℃で0.53ｇの亜硝酸
ナトリウムの３mlの水溶液を滴下する。５分後、
ｎ−オクタノール（消泡剤）１滴を加え、つづい
て銅粉0.46ｇを一度に加える。直ちに起泡し、起
泡がおさまつた後、さらに３分間、０〜５℃で撹
拌する。水で希釈し、水酸化ナトリウム水溶液で
アルカリ性とし、析出固体を取する。メタノー
ル−クロロホルム混合溶媒に溶かして、不溶物を
除き、濃縮後残渣をカラムクロマトグラフイー
（シリカゲル、クロロホルム：メタノール＝５：
１）で精製して1.65ｇの５−（４−メチル−１−
ピペラジニル）−６−フルオロ−８−クロロキナ
ジンを得る。
mp.108〜110℃
実施例 ４
５−ブロム−６−フルオロ−８−ニトロキナル
ジン9.0ｇをＮ−メチルピペラジン15.8ｇを
DMF90mlに溶解し、内温70℃で6.5時間撹拌す
る。過剰のＮ−メチルピペラジン及びDMFを減
圧留去し、残渣にｎ−ヘキサンを加えてよく撹拌
後、イソプロパノールを加えて析出した固体を
取する。析出固体を水に溶解し、水酸化ナトリウ
ム水溶液でアルカリ性とし、析出固体を取す
る。イソプロパノールより再結晶して、3.8ｇの
５−（４−メチル−１−ピペラジニル）−６−フル
オロ−８−ニトロキナルジンを得る。
mp.115〜117℃
実施例 ５
５−（４−メチル−１−ピペラジニル）−６−フ
ルオロ−８−ニトロキナルジン1.9ｇを30mlの酢
酸に溶わし、該溶液に塩化第１錫・２水和物5.7
ｇを加え、撹拌下、濃塩酸20mlを滴下する。滴下
後１時間室温で撹拌する。水で希釈して水酸化ナ
トリウム水溶液でアルカリ性とし、析出物をジク
ロロメタンで抽出する。硫酸マグネシウム乾燥
後、溶媒を留去し、ｎ−ヘキサンで再結晶して、
1.37ｇの５−（４−メチル−１−ピペラジニル）−
６−フルオロ−８−アミノキナルジンを得る。
mp.149〜151℃
実施例 ６
５−（４−メチル−１−ピペラジニル）−６−フ
ルオロキナルジン3.7ｇを酢酸100ml、酢酸エチル
10mlの混合溶媒に溶解し、５％パラジウム−炭素
１ｇを加え、ガラス性オートクレーブ中に入れ
る。水素圧５Kg／cm2を加え、室温下で３時間撹拌
する。水素を除いた後内容液を取り出し、触媒を
除去後、内容物を濃縮乾固し、次いでクロロホル
ム100mlを加え溶解後５％水酸化ナトリウム水溶
液50mlを加えて中和し、分液後100mlの水で２回
水洗する。クロロホルム層を乾燥後、濃縮乾固
し、これにヘキサン20ml、活性炭0.5ｇを加えて
加熱溶解する。活性炭を去後ヘキサン層を冷却
し析出晶を取し５−（４−メチル−１−ピペラ
ジニル）−６−フルオロ−１，２，３，４−テト
ラヒドロキナルジン3.5ｇを得る。
微黄色結晶 mp.64.5〜65.5℃
実施例 ７
実施例６と同様にして、５−（４−メチル−１
−ピペラジニル）−６−フルオロ−８−クロロ−
１，２，３，４−テトラヒドロキナルジンから、
５−（４−メチル−１−ピペラジニル）−６−フル
オロ−１，２，３，４−テトラヒドロキナルジン
を得る。
微黄色結晶 mp.64.5〜65.5℃
実施例 ８
５−（４−メチル−１−ピペラジニル）−６−フ
ルオロ−８−アミノキナルジン20.0ｇを水60mlと
47％臭酸200mlに溶解し、０℃冷却下亜硝酸ナト
リウム水溶液（亜硝酸ナトリウム6.55ｇを水32ml
に溶かしたもの）を滴下し、０℃で30分間撹拌す
る。ｎ−オクタノール２滴を加え、銅粉6.95ｇを
一度に加える。その後０℃で２時間撹拌する。反
応液を１の水にあけ、析出結晶を取、析出結
晶を水に懸濁して、水酸化ナトリウム水溶液でア
ルカリ性にし、固体を取する。固体をジクロロ
メタンに溶かし、不溶物を去後、炭酸カリウム
で乾燥する。溶媒を留去し、残渣をシリカゲルカ
ラムクロマトグラフイーで分離（クロロホルム−
メタノール＝８：１）し、13.5の５−（４−メチ
ル−１−ピペラジニル））−６−フルオロ−８−ブ
ロム−キナルジンを得る。
mp.123〜124℃
実施例 ９
５−ブロム−６−クロロ−８−ニトロ−キナル
ジン20.0ｇ及びピペラジン28.6ｇをＮ−メチルピ
ロリドン200mlに溶解し、内温50〜60℃で3.5時間
撹拌する。過剰のピペラジン及びＮ−メチルピロ
リドンを減圧留去し、残渣にヘキサンを加えて、
結晶化し、析出固体を取、析出固体を多量の臭
酸酸性の水に溶解し、水酸化ナトリウムを加え
て、アルカリ性とする。析出固体を取水洗し、
80〜90℃で一夜乾燥して、19.1ｇの５−ピペラジ
ニル−６−クロロ−９−ニトロキナルジンを得
る。
mp.151〜152℃
実施例 10
５−ピペラジニル−６−クロロ−８−ニトロキ
ナルジン16ｇを無水酢酸16.0ｇを酢酸100mlに溶
かし、外温60℃で1.5時間撹拌する。反応液に水
を加えて析出固体を取後、水に懸濁して、水酸
化ナトリウム水溶液に加えてアルカリ性とする。
黄色固体を取し、水洗後、80℃で１夜乾燥す
る。イソプロパノールより再結晶して、14.4ｇの
５−（４−アセチル−１−ピペラジニル）−６−ク
ロロ−８−ニトロキナルジンを得る。
黄色針状晶 mp.201〜202℃
実施例 11
５−（４−アセチル−１−ピペラジニル）−６−
クロロ−８−ニトロキナルジン13.7ｇを濃塩酸
137mlに溶解し、これに塩化第１錫・２水和物
35.5ｇの濃塩酸137ml溶液を一度に加える。温度
が40℃まで上昇する。１時間放冷撹拌後、析出固
体を取、氷水及びジクロロメタンを加えて撹拌
下、水酸化ナトリウム水溶液を加えてアルカリ性
とし、ジクロロメタン層を分離し、炭酸カリウム
で乾燥して、溶媒を留去する。イソプロパノール
より再結晶して、11.3ｇの５−（４−アセチル−
１−ピペラジニル）−６−クロロ−８−アミノ−
キナルジンを得る。
mp.195〜196℃
実施例 12
５−（４−アセチル−１−ピペラジニル）−６−
クロロ−８−アミノキナルジン5.0ｇを水10mlと
濃塩酸35mlに溶かす。０℃冷却下、亜硝酸ナトリ
ウム水溶液（亜硝酸ナトリウム1.41ｇを水５mlに
とかしたもの）を滴下する。ｎ−オクタノール２
滴を加え、予め０℃に冷却しておいた次亜リン酸
水溶液（50％溶液）16.6ｇを内温０℃で３〜５分
間で滴下する。その後０℃で４時間撹拌する。反
応液を氷水にあけ、水酸化ナトリウム水溶液でア
ルカリ性とし、ジクロロメタン抽出し、濃縮後、
シリカゲルカラムクロマトグラフイー（クロロホ
ルム：メタノール＝20：１）で精製し、ヘキサン
−イソプロパノールで再結晶して、0.93ｇの５−
（４−アセチル−１−ピペラジニル）−６−クロロ
−キナルジンを得る。
mp.164〜166℃
実施例 13
５−（４−アセチル−１−ピペラジニル）−６−
クロロ−キナルジン0.92ｇと５％Pt−C0.092ｇを
酢酸100mlに懸濁し、60〜70℃で、初期圧３気圧
で、５時間接触還元する。触媒過後、酢酸を濃
縮して、残渣に水を加えてアルカリ性とし、ジク
ロロメタンで抽出し、濃縮後、残渣をシリカゲル
カラムクロマトグラフイー（クロロホルム：メタ
ノール＝60：１）で精製して、0.47ｇの５−（４
−アセチル−１−ピペラジニル）−６−クロロ−
１，２，３，４−テトラヒドロキナルジンを得
る。
mp.192〜193℃
実施例 14
２−ブロム−４−フルオロ−５−（４−メチル
−１−ピペラジニル）アニリンを出発原料として
用い、実施例１と同様にして５−（４−メチル−
１−ピペラジニル）−６−フルオロ−８−ブロム
−キナルジンを得る。
mp.123〜124℃[Formula] may also be formed. R 2 , R 3 and R 4 are the same as above. ] Hydrolysis of the compound of general formula (5) can be carried out in an appropriate solvent in the presence of a basic compound. Examples of the solvent used include water, methanol, ethanol, and isopropanol. Examples of the basic compound used include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, and sodium hydrogen carbonate. The amount of the basic compound to be used is usually in large excess, preferably 4 to 8 times the molar amount, relative to the compound of general formula (5). The reaction temperature is usually about room temperature to 150℃,
The temperature is preferably about 50 to 100°C, and the reaction is generally completed in about 10 minutes to 5 hours. The reaction between the compound of general formula (6) and the compound of general formula (7) is carried out in the absence of a solvent and in the presence of a condensing agent. Examples of the condensing agent used include phosphorus pentoxide, phosphoric acids such as polyphosphoric acid, acids such as sulfuric acid, and phosphorus compounds such as phosphorus oxychloride, phosphorus pentachloride, and phosphorus trichloride. The amount of such a condensing agent to be used is usually a large excess amount relative to the compound of general formula (6). The ratio of the compound of general formula (6) and the compound of general formula (7) to be used is usually at least an equimolar amount, preferably 1 to 1.5 times the molar amount of the latter to the former. The reaction is usually 70-150
The reaction is carried out at a temperature of about 0.degree. C. and generally completes in about a few minutes to an hour. [In the formula, R 3 ' represents a lower alkanoyl group. R1 ,
R 2 , R 4 and positions 1, 2 and 3 of the quinoline skeleton
The carbon-carbon bond at position and 4-position is the same as above. ] In Reaction Scheme-4, the acylation reaction of the compound of general formula (1g) can be carried out by reacting it with an acylating agent such as an acid halide or an acid anhydride in the presence or absence of a basic compound. I can do it. Examples of the acid halide or acid anhydride used here include acid halides such as acetyl chloride, propionyl chloride, and butyryl bromide, and acid anhydrides such as acetic anhydride. As the basic compound, a wide variety of known compounds can be used, such as inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, sodium methylate,
Examples include alcoholates such as sodium ethylate, and organic bases such as triethylamine, pyridine, and N,N-dimethylaniline. The reaction may be carried out without a solvent or in the presence of a solvent. All inert solvents that do not adversely affect the reaction are used as solvents, such as methanol, ethanol,
Alcohols such as propanol, butanol, and ethylene glycol; ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene, toluene, and xylene; methyl acetate, and acetic acid. Examples include esters such as ethyl, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The ratio of the acylating agent to the compound (1g) in the above method is not particularly limited and may be selected from a wide range; however, when the reaction is carried out without a solvent, the former is usually used in proportion to the latter. In a large excess amount, when carrying out in a solvent, the latter is usually equimolar to 5 times the former, preferably equimolar to 5 times the former.
It is desirable to use 3 times the molar amount. Further, the reaction temperature is not particularly limited, but is usually room temperature to
It is carried out at 200°C, preferably 50-160°C. The reaction time is usually 1 to 30 hours. The obtained compound (1h) can also be obtained by diluting it in an alcohol such as methanol or ethanol using an inorganic base such as potassium hydroxide or sodium hydroxide as a deoxidizing agent or using an acid such as hydrobromic acid or hydrochloric acid. The compound (1g) can also be obtained by hydrolysis. In the above reaction scheme-3, the compound of general formula (5) used as a starting material is produced, for example, by the method shown in the following reaction scheme-5. [In the formula, R 2 , R 3 , R 5 , R 6 , X and X 1 are the same as above. ] In Reaction Scheme-5, the reaction that leads the aniline derivative of general formula (8) to the aniline derivative of general formula (9) is carried out by combining the compound of general formula (8) with an acid anhydride or an acid halide in an appropriate solvent. This can be done by reacting. Examples of the solvent used include lower alcohols such as methanol, ethynol, and isopropanol, ethers such as dioxane and THF, acetic acid, pyridine, DMF, and DMSO. Examples of acid anhydrides include acetic anhydride, phthalic anhydride, etc.
Examples of acid halides include acetyl chloride, propionyl chloride, butyryl bromide, and the like. The amount of acid anhydride or acid halide to be used is usually at least an equimolar amount, preferably 1 to 3 times the molar amount of the aniline derivative of general formula (8).
The reaction temperature is usually room temperature to 200°C, preferably room temperature to 160°C, and the reaction is generally completed in 0.5 to 5 hours. The nitration of the compound of general formula (9) is carried out using the above general formula (2).
can be carried out under similar reaction conditions to the nitration of compounds. The reaction between the compound of general formula (10) and the compound of general formula (4) is the reaction between the compound of general formula (3) and the compound of general formula (4).
It can be carried out under the same reaction conditions as the reaction with the compound. The reduction of the compound of general formula (5a) can be carried out under the same reaction conditions as the reduction of the compound of general formula (1a). Deamination of the compound of general formula (5a) can be carried out under the same reaction conditions as for deamination of the compound of general formula (1b). Further, the halogenation of the compound of general formula (5b) can be carried out under the same reaction conditions as for the halogenation of the compound of general formula (1b). The compound of general formula (5d) can also be produced by reacting the compound of general formula (5c) with a halide such as chlorine or bromine. The compound of the present invention can be derived into a compound of general formula (13) useful as an antibacterial agent, for example, according to Reaction Scheme-6 or 7 below. Reaction equation 6 [In the formula, R 10 and R 11 each represent a lower alkyl group. R 2 , R 3 and R 4 are the same as above. ] The reaction between the compound of general formula (1d) and the compound of general formula (11) is carried out without a solvent or in an appropriate solvent. Examples of the solvent include alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene and toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. It is preferable to carry out the reaction without a solvent. The ratio of the compound of general formula (11) to the compound of general formula (1d) is usually at least equimolar, preferably from equimolar to 1.5 times the molar amount.
The reaction temperature is usually room temperature to about 150℃, preferably 60℃.
~120°C, the reaction is usually completed in 0.5 to 6 hours, and the compound represented by general formula (12) can be easily obtained. The reaction between the compound of general formula (1d) and the compound of general formula (14) can be carried out under the same conditions as the reaction between the compound of general formula (1d) and the compound of general formula (11), In this way, the compound represented by general formula (15) can be easily obtained. The cyclization reaction of the compound represented by the general formula (12) or the compound represented by the general formula (15) can be carried out using various conventional cyclization reactions such as heating, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl This can be carried out by a cyclization method using an acidic substance such as chloride, concentrated sulfuric acid, or polyphosphoric acid. When a cyclization method by heating is employed, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetralin, diphenyl ether, and diethylene glycol dimethyl ether is used, and the temperature is usually 100 to 250°C, preferably 150 to 250°C.
Heating conditions of 200℃ can be adopted. In addition, when an oxidation method using an acidic substance is employed, the acidic substance is used in an equimolar amount to a large excess, preferably 10 to 20 times the amount of the compound (12) or (15), and is usually 0.5 times the amount at 100 to 150°C.
The reaction may be carried out for about 6 hours. When the compound of general formula (12) is used as a raw material compound, the target compound of general formula (13) can be obtained by the above cyclization reaction. In addition, when the compound of general formula (15) is used as a raw material compound, the compound of general formula (16) can be obtained by the above cyclization reaction, and it can be used in the next hydrolysis reaction with or without isolation. Served. The hydrolysis reaction of the compound of general formula (16) is carried out according to a conventional method, for example, using basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, acetic acid, aromatic sulfone, etc. It is carried out in the presence of conventional catalysts such as organic acids such as acids. The reaction is generally carried out in conventional solvents such as water, methanol, ethanol, isopropanol, dioxane, ethylene glycol, acetone, methyl ethyl ketone, acetic acid and the like. Reaction temperature is usually room temperature ~
The temperature is 200°C, preferably 50-150°C. In this way, a compound of general formula (13) is obtained. The quinoline derivative of the present invention thus obtained is
It is easily isolated and purified from the reaction mixture by conventional isolation means such as filtration, recrystallization, column chromatography, preparative thin layer chromatography, etc. The quinoline derivative represented by the general formula (1) of the present invention obtained as described above can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid. Also includes addition salts. Examples of acids in the above include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, and methanesulfonic acid. Organic acids such as acid and benzoic acid can be used. Reference examples and examples are listed below. Reference example 1 50g of 3-chloro-4-fluoroaniline was dissolved in acetic acid.
Dissolve in 150 ml and add 70.2 g of acetic anhydride dropwise. After stirring for 30 minutes at room temperature, the reaction mixture was poured into water and the precipitated solid was collected. After washing the precipitated solid with water,
Dissolve in ethyl acetate, wash the ethyl acetate layer with dilute aqueous potassium carbonate solution, dry with magnesium sulfate,
The solvent is distilled off. 62 g of 3-chloro-4-fluoroacetanilide are obtained. mp.116-117°C Reference Example 2 10 g of 3-chloro-4-fluoroaniline and 10.2 g of phthalic anhydride are dissolved in 30 ml of DMF and heated under reflux for 2 hours. Add water to the reaction mixture and collect the precipitated crystals. The precipitated crystals are dissolved in ethyl acetate, washed with an aqueous sodium bicarbonate solution, and then dried over magnesium sulfate to obtain 14.4 g of N-(3-chloro-4-fluoro-1-phenyl)phthalimide. mp.192-193℃ Reference example 3 3-chloro-4-fluoroacetanilide 10g
was dissolved in 35 ml of concentrated sulfuric acid, and a solution of 6.5 g of potassium nitrate in 25 ml of concentrated sulfuric acid was added dropwise at 0°C over 30 minutes. After dropping, stir at 0°C for 1.5 hours. The reaction mixture was poured into 400 ml of ice water, and the precipitated crystals were collected, washed with water, and dried to obtain 12.3 g of 2-nitro-4-fluoro-5-chloro-acetanilide. mp.111~112℃ Reference Example 4 14g of N-(3-chloro-4-fluoro-1-phenyl)phthalimide was dissolved in concentrated sulfuric acid while maintaining the temperature at 15~20℃.
20 of 5.6 g potassium nitrate dissolved in 75 ml at -5 °C.
ml concentrated sulfuric acid solution dropwise over 30 minutes. After stirring for 1 hour at -5 to 0°C, the reaction mixture was poured into 1.5 liters of ice water and the precipitated crystals were collected. After washing with water, dissolve in dichloromethane and dry with magnesium sulfate. The solvent is distilled off to obtain 15.4 g of N-(2-nitro-4-fluoro-5-chloro-1-phenyl)phthalimide. mp.222-224℃ Reference Example 5 12g of 2-nitro-4-fluoro-5-chloro-acetanilide and 25.8g of methylpiperazine were added to 120g of 2-nitro-4-fluoro-5-chloro-acetanilide
Dissolve in ml of DMF and stir at 70°C for 2 hours. Excess methylpiperazine and DMF were distilled off under reduced pressure,
Add 50ml of water to the residue and collect the precipitated crystals. After washing with water, it is recrystallized from methanol-water and then from isopropanol to obtain 14.3 g of 2-nitro-4-fluoro-5-(4-methyl-1-piperazinyl)acetanilide. mp.133-135℃ Reference example 6 2-nitro-4-fluoro-5-(4-methyl-1-piperazinyl)acetanilide 10g and 9.5
Dissolve 8 ml of an aqueous solution of g potassium hydroxide in 100 ml of methanol and reflux for 30 minutes. After cooling, 50ml
of water was added to the reaction mixture to collect the precipitated solid, which was washed with water and recrystallized from isopropanol to give 8.0 g of 2-nitro-4-fluoro-5-(4-methyl-
1-piperazinyl)aniline is obtained. mp.151-153℃ Reference Example 7 Dissolve 25 g of 2-nitro-4-fluoro-5-(4-methyl-1-piperazinyl)acetanilide in 250 ml of concentrated hydrochloric acid, and add 57.2 g of stannous chloride dihydrate. Add 250 ml of concentrated hydrochloric acid solution at once. The reaction temperature rises to 40°C. After cooling and stirring for 1 hour,
The precipitated solid was collected, dissolved in a small amount of water, made alkaline with an aqueous sodium hydroxide solution under ice cooling, and extracted with dichloromethane. After drying the potassium carbonate, the solvent is distilled off. The residue is crystallized by adding n-hexane, and the crystals are collected and dried to obtain 15.7 g of 2-amino-4-fluoro-5-(4-methyl-1-piperazinyl)acetanilide. mp.168-169℃ Reference example 8 3.0g of 2-amino-4-fluoro-5-(4-methyl-1-piperazinyl)acetanilide in water
Dissolve 10 ml and 30 ml of concentrated hydrochloric acid, dropwise add sodium nitrite aqueous solution (0.77 g of sodium nitrite dissolved in 5 ml of water) at 0°C, stir for 2 minutes, add 2 drops of n-octanol, and add 0.96 g of copper powder. Add at once. After stirring for 30 minutes, the reaction solution is poured into water, made alkaline with aqueous sodium hydroxide solution, extracted with dichloromethane, and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform-methanol = 4:1) to obtain 0.90 g of 3-(4-methyl-1-piperazinyl)-4-fluoroacetanilide. mp.175-176℃ Reference Example 9 Dissolve 0.60g of silver sulfate in 10ml of concentrated sulfuric acid, and add 0.80g of 3-(4-methyl-1-piperazinyl)-4-fluoro-acetanilide to this solution while stirring. . Add 0.61 g of bromine and stir at an internal temperature of 30 to 40°C for 1 hour. The reaction solution is poured into water to remove insoluble matter, and an aqueous sodium hydroxide solution is added to the solution to make it alkaline. Extracted with dichloromethane, concentrated, and purified with silica gel column chromatography (chloroform-methanol = 8:1).
0.21 g of 2-bromo-4-fluoro-5-(4-
Methyl-1-piperazinyl)acetanilide is obtained. mp.126-127℃ Reference example 10 0.10 g of 2-bromo-4-fluoro-5-(4-methyl-1-piperazinyl)acetanilide was added to 47
% hydrobromic acid and reflux for 1 hour. 47%
Hydrobromic acid was distilled off, the residue was made alkaline by adding an aqueous sodium hydroxide solution, and the precipitated insoluble white solid was collected and dried to give 0.08 g of 2-bromo-4-fluoro-5-(4 -methyl-1-piperazinyl)aniline is obtained. mp.122-124°C Reference Example 11 21.0 g of 5-bromo-6-fluoroquinaldine is dissolved in 117 ml of concentrated sulfuric acid, and a solution of 11.5 g of potassium nitrate in 30 ml of concentrated sulfuric acid is added dropwise at -5°C. After stirring at room temperature for 5 hours, the reaction mixture was poured into ice water in Step 2, and the precipitated solid was collected. The liquid is made alkaline and a small amount of solid is obtained. Together with the precipitated solid described above, it is dissolved in dichloromethane and dried over sodium sulfate. After distilling off the solvent, recrystallization from isopropanol yielded 22.9 g of 5-bromo-6-fluoro-
8-Nitroquinaldine is obtained. mp.135-137℃ Reference Example 12 Dissolve 40g of 5-bromo-6-chloro-quinaldine in 220ml of concentrated sulfuric acid, cool to 0℃, and dropwise add a solution of 20.5g of potassium nitrate in 60ml of concentrated sulfuric acid over 30 minutes. . Then stir at room temperature for 2.5 hours. Pour the reaction solution into 1.5 ml of ice water and collect the precipitated crystals.
The liquid is made alkaline and a small amount of solid is obtained. The mixture was combined with the precipitated solid and recrystallized from isopropanol to obtain 42.3 g of 5-bromo-6-chloro-8-nitro-quinaldine. mp.141-142℃ Reference example 13 (a) 5-(4-methyl-1-piperazinyl)-6-
10 g of fluoro-1,2,3,4-tetrahydroquinaldine and 8 g of isopropylidenyl methoxymethylene malonate are mixed at room temperature, and then heated and stirred at 100° C. for 30 minutes to solidify. Recrystallization from chloroform-n-hexane gave cyclic isopropylidenyl N-[5-(4-methyl-1-
piperazinyl)-6-fluoro-1,2,3,
14.6 g (92%) of 4-tetrahydro-1-quinaldinyl]-aminomethylene malonate are obtained. White crystals Elemental analysis (as C 22 H 28 O 4 N 3 F) C H N Analysis (%) 63.42 6.59 10.05 Calculated (%) 63.29 6.76 10.07 (b) Prepared from 25 g of phosphorus pentoxide and 25 g of phosphoric acid. and the cyclic isopropylidenyl N-[5-(4-methyl-1-piperazinyl)-6-fluoro-1,2,3,4-tetrahydro-1-quinaldinyl)- obtained in (a) above. 14.0g of aminomethylene malonate was heated and stirred at 100℃ for 1 hour, cooled to 80℃, and 60ml of water was added and dissolved.
After neutralizing with 20% aqueous sodium hydroxide solution, extract twice with 200 ml of chloroform. The chloroform layer was dehydrated and dried over anhydrous magnesium sulfate, concentrated to dryness, and 40 ml of methanol and 0.5 g of activated carbon were added to the obtained crystals and dissolved by heating. After removing the activated carbon, the precipitated crystals were collected and 8-( 4-Methyl-1-piperazinyl)-9-fluoro-5
-Methyl-6,7-dihydro-1-oxo-
10.2 g of 1H,5H-benzo[ij]quinolidine-2-carboxylic acid are obtained. (84.6%) White edge-shaped crystals Melting point 262-263℃ Example 1 20g of 2-nitro-4-fluoro-5-(4-methyl-1-piperazinyl)aniline was dissolved in 60% sulfuric acid (40ml of concentrated sulfuric acid and 48ml of water). Additionally, 13.2 g of sodium m-nitrobenzenesulfonate is added. Heat to 110℃ and dissolve crotonaldehyde.
Drop 6.6g over 10 minutes. After 5 minutes, the reaction mixture is poured into 30 ml of ice water. The obtained 5-(4-
Methyl-1-piperazinyl)-6-fluoro-8
Without removing the nitro-quinaldine, a solution of 71 g of stannous chloride dihydrate in 140 ml of concentrated hydrochloric acid is added thereto and stirred for 30 minutes. After activated carbon treatment,
The precipitate was made alkaline with an aqueous sodium hydroxide solution, the precipitate was extracted with dichloromethane, the solvent was distilled off, the residue was dissolved in isopropanol, the hydrochloride was added with concentrated hydrochloric acid, and after thorough washing with acetone, the precipitate was dissolved in water and hydroxylated. Make alkaline with sodium aqueous solution. The precipitated solid was collected and recrystallized from n-hexane to obtain 8.7 g of 5-(4-methyl-1-piperazinyl)-6-fluoro-8-aminoquinaldine. Yellow needle crystals mp.149-151℃ Example 2 1.5 g of 5-(4-methyl-1-piperazinyl)-6-fluoro-8-aminoquinaldine and 10 g of concentrated hydrochloric acid
ml and 3 ml of water are added, and at -20°C a 2 ml aqueous solution of 0.39 g of sodium nitrite is added dropwise. After 3 minutes, 1 drop of n-octanol (antipackaging agent) was added, and 5.7 g of hypophosphorous acid (50% solution), which had been cooled to 0°C, was added to -
Add dropwise at 2°C. Thereafter, the mixture is stirred at 0-5°C for 7 hours. Pour the reaction solution into water and make alkaline with an aqueous sodium hydroxide solution. Extract with dichloromethane,
Dry with sodium sulfate. The solvent was distilled off and n
- Recrystallization from hexane gives 0.71 g of 5-(4-methyl-1-piperazinyl)-6 fluoroquinaldine. Pale yellow crystals mp.87-89.5°C Example 3 2.0 g of 5-(4-methyl-1-piperazinyl)-6-fluoro-8-aminoquinaldine was dissolved in 7 ml of water and 20 ml of concentrated hydrochloric acid, and the mixture was heated at 0°C. 3 ml of an aqueous solution of 0.53 g of sodium nitrite is added dropwise. 5 minutes later,
Add 1 drop of n-octanol (antifoaming agent), followed by 0.46 g of copper powder all at once. It foams immediately, and after the foaming subsides, it is stirred for an additional 3 minutes at 0-5°C. Dilute with water, make alkaline with aqueous sodium hydroxide solution, and collect the precipitated solid. Dissolve in a methanol-chloroform mixed solvent, remove insoluble materials, concentrate, and then subject the residue to column chromatography (silica gel, chloroform:methanol = 5:
1) to produce 1.65 g of 5-(4-methyl-1-
piperazinyl)-6-fluoro-8-chloroquinazine is obtained. mp.108-110℃ Example 4 9.0g of 5-bromo-6-fluoro-8-nitroquinaldine and 15.8g of N-methylpiperazine
Dissolve in 90 ml of DMF and stir at an internal temperature of 70°C for 6.5 hours. Excess N-methylpiperazine and DMF are distilled off under reduced pressure, n-hexane is added to the residue, and after stirring well, isopropanol is added to collect the precipitated solid. Dissolve the precipitated solid in water, make alkaline with an aqueous sodium hydroxide solution, and collect the precipitated solid. Recrystallization from isopropanol gives 3.8 g of 5-(4-methyl-1-piperazinyl)-6-fluoro-8-nitroquinaldine. mp.115-117℃ Example 5 Dissolve 1.9 g of 5-(4-methyl-1-piperazinyl)-6-fluoro-8-nitroquinaldine in 30 ml of acetic acid, and add stannous chloride diwater to the solution. Japanese 5.7
g, and 20 ml of concentrated hydrochloric acid was added dropwise while stirring. After dropping, stir at room temperature for 1 hour. Dilute with water, make alkaline with aqueous sodium hydroxide solution, and extract the precipitate with dichloromethane. After drying magnesium sulfate, the solvent was distilled off and recrystallized from n-hexane.
1.37 g of 5-(4-methyl-1-piperazinyl)-
6-fluoro-8-aminoquinaldine is obtained. mp.149-151℃ Example 6 3.7g of 5-(4-methyl-1-piperazinyl)-6-fluoroquinaldine was added to 100ml of acetic acid and ethyl acetate.
Dissolve in 10 ml of mixed solvent, add 1 g of 5% palladium-carbon, and place in a glass autoclave. Add hydrogen pressure of 5 kg/cm 2 and stir at room temperature for 3 hours. After removing hydrogen, take out the contents, remove the catalyst, concentrate the contents to dryness, add 100 ml of chloroform to dissolve, neutralize by adding 50 ml of 5% aqueous sodium hydroxide solution, and after separating, add 100 ml of water. Wash twice with water. After drying the chloroform layer, it is concentrated to dryness, and 20 ml of hexane and 0.5 g of activated carbon are added thereto and dissolved by heating. After removing the activated carbon, the hexane layer was cooled and the precipitated crystals were collected to obtain 3.5 g of 5-(4-methyl-1-piperazinyl)-6-fluoro-1,2,3,4-tetrahydroquinaldine. Pale yellow crystals mp.64.5-65.5℃ Example 7 In the same manner as in Example 6, 5-(4-methyl-1
-piperazinyl)-6-fluoro-8-chloro-
From 1,2,3,4-tetrahydroquinaldine,
5-(4-methyl-1-piperazinyl)-6-fluoro-1,2,3,4-tetrahydroquinaldine is obtained. Pale yellow crystals mp.64.5-65.5℃ Example 8 20.0g of 5-(4-methyl-1-piperazinyl)-6-fluoro-8-aminoquinaldine and 60ml of water.
Dissolve in 200ml of 47% hydrochloric acid, cool at 0°C, and add sodium nitrite aqueous solution (6.55g of sodium nitrite to 32ml of water.
(dissolved in ) was added dropwise and stirred at 0°C for 30 minutes. Add 2 drops of n-octanol and 6.95g of copper powder all at once. Then stir at 0°C for 2 hours. Pour the reaction solution into 1 water, collect the precipitated crystals, suspend the precipitated crystals in water, make alkaline with an aqueous sodium hydroxide solution, and collect the solid. The solid is dissolved in dichloromethane, and after removing insoluble materials, it is dried over potassium carbonate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (chloroform-
methanol=8:1) to obtain 13.5 of 5-(4-methyl-1-piperazinyl))-6-fluoro-8-bromo-quinaldine. mp.123-124°C Example 9 20.0 g of 5-bromo-6-chloro-8-nitro-quinaldine and 28.6 g of piperazine are dissolved in 200 ml of N-methylpyrrolidone and stirred at an internal temperature of 50-60°C for 3.5 hours. Excess piperazine and N-methylpyrrolidone were distilled off under reduced pressure, and hexane was added to the residue.
After crystallization, the precipitated solid is taken, and the precipitated solid is dissolved in a large amount of water acidified with hydrochloric acid, and sodium hydroxide is added to make it alkaline. Remove the precipitated solid and wash it with water.
Drying at 80-90° C. overnight yields 19.1 g of 5-piperazinyl-6-chloro-9-nitroquinaldine. mp.151-152°C Example 10 16 g of 5-piperazinyl-6-chloro-8-nitroquinaldine and 16.0 g of acetic anhydride are dissolved in 100 ml of acetic acid, and the mixture is stirred at an external temperature of 60°C for 1.5 hours. Water is added to the reaction solution to remove the precipitated solid, which is then suspended in water and made alkaline by adding to an aqueous sodium hydroxide solution.
The yellow solid was collected, washed with water, and dried at 80°C overnight. Recrystallization from isopropanol yields 14.4 g of 5-(4-acetyl-1-piperazinyl)-6-chloro-8-nitroquinaldine. Yellow needle crystals mp.201-202℃ Example 11 5-(4-acetyl-1-piperazinyl)-6-
13.7 g of chloro-8-nitroquinaldine was dissolved in concentrated hydrochloric acid.
Dissolve in 137ml and add stannous chloride dihydrate to this.
Add a solution of 35.5 g of concentrated hydrochloric acid in 137 ml all at once. Temperature rises to 40°C. After cooling and stirring for 1 hour, the precipitated solid is collected, ice water and dichloromethane are added, and while stirring, an aqueous sodium hydroxide solution is added to make it alkaline. The dichloromethane layer is separated, dried over potassium carbonate, and the solvent is distilled off. Recrystallized from isopropanol to obtain 11.3 g of 5-(4-acetyl-
1-piperazinyl)-6-chloro-8-amino-
Get Quinaldine. mp.195-196℃ Example 12 5-(4-acetyl-1-piperazinyl)-6-
Dissolve 5.0 g of chloro-8-aminoquinaldine in 10 ml of water and 35 ml of concentrated hydrochloric acid. While cooling at 0°C, a sodium nitrite aqueous solution (1.41 g of sodium nitrite dissolved in 5 ml of water) was added dropwise. n-octanol 2
16.6 g of hypophosphorous acid aqueous solution (50% solution), which had been cooled in advance to 0°C, was added dropwise over 3 to 5 minutes at an internal temperature of 0°C. Thereafter, the mixture was stirred at 0°C for 4 hours. The reaction solution was poured into ice water, made alkaline with an aqueous sodium hydroxide solution, extracted with dichloromethane, and concentrated.
It was purified by silica gel column chromatography (chloroform:methanol = 20:1), recrystallized from hexane-isopropanol, and 0.93 g of 5-
(4-acetyl-1-piperazinyl)-6-chloro-quinaldine is obtained. mp.164-166℃ Example 13 5-(4-acetyl-1-piperazinyl)-6-
0.92 g of chloroquinaldine and 0.092 g of 5% Pt-C are suspended in 100 ml of acetic acid and catalytically reduced at 60-70°C and an initial pressure of 3 atm for 5 hours. After filtering the catalyst, acetic acid was concentrated, water was added to the residue to make it alkaline, extracted with dichloromethane, and after concentration, the residue was purified by silica gel column chromatography (chloroform:methanol = 60:1) to give 0.47g of 5-(4
-acetyl-1-piperazinyl)-6-chloro-
1,2,3,4-tetrahydroquinaldine is obtained. mp.192-193℃ Example 14 5-(4-Methyl-
1-piperazinyl)-6-fluoro-8-bromo-quinaldine is obtained. mp.123~124℃
Claims (1)
はハロゲン原子と、R2はハロゲン原子を、R3は
水素原子、低級アルキル基又は低級アルカノイル
基を、R4は低級アルキル基をそれぞれ示す。ま
たキノリン骨格の１位と２位及び３位と４位の炭
素間結合は共に二重結合又は一重結合を示す。但
しキノリン骨格の１位と２位及び３位と４位の炭
素間結合が共に一重結合である場合には、キノリ
ン骨格の１位の窒素原子に水素原子が結合するも
のとし、またR1がニトロ基、アミノ基又はハロ
ゲン原子であつてはならない。〕 で表わされるキノリン誘導体及びその塩。[Claims] 1. General formula [In the formula, R 1 represents a hydrogen atom, a nitro group, an amino group, or a halogen atom, R 2 represents a halogen atom, R 3 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, and R 4 represents a lower alkyl group. . Further, the carbon bonds at the 1st and 2nd positions and the 3rd and 4th positions of the quinoline skeleton both represent a double bond or a single bond. However, if the carbon bonds at the 1st and 2nd positions and the 3rd and 4th positions of the quinoline skeleton are both single bonds, a hydrogen atom is bonded to the nitrogen atom at the 1st position of the quinoline skeleton, and R 1 is It must not be a nitro group, an amino group, or a halogen atom. ] A quinoline derivative represented by these and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7853281A JPS57193459A (en) | 1981-05-22 | 1981-05-22 | Quinoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7853281A JPS57193459A (en) | 1981-05-22 | 1981-05-22 | Quinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57193459A JPS57193459A (en) | 1982-11-27 |
| JPH0154344B2 true JPH0154344B2 (en) | 1989-11-17 |
Family
ID=13664515
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7853281A Granted JPS57193459A (en) | 1981-05-22 | 1981-05-22 | Quinoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57193459A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129342A (en) * | 2016-11-30 | 2018-06-08 | 浙江九洲药物科技有限公司 | It is a kind of difficult to understand uncommon for Buddhist nun's intermediate and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55118485A (en) * | 1979-10-11 | 1980-09-11 | Otsuka Pharmaceut Co Ltd | Benzo ij quinolizine-2-carboxylic acid derivative |
| JPS5655371A (en) * | 1979-10-11 | 1981-05-15 | Otsuka Pharmaceut Co Ltd | Quinoline derivative |
-
1981
- 1981-05-22 JP JP7853281A patent/JPS57193459A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55118485A (en) * | 1979-10-11 | 1980-09-11 | Otsuka Pharmaceut Co Ltd | Benzo ij quinolizine-2-carboxylic acid derivative |
| JPS5655371A (en) * | 1979-10-11 | 1981-05-15 | Otsuka Pharmaceut Co Ltd | Quinoline derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57193459A (en) | 1982-11-27 |
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