JPS63316757A - 3-amino-2-substituted benzoylacrylic acid derivative - Google Patents
3-amino-2-substituted benzoylacrylic acid derivativeInfo
- Publication number
- JPS63316757A JPS63316757A JP62152099A JP15209987A JPS63316757A JP S63316757 A JPS63316757 A JP S63316757A JP 62152099 A JP62152099 A JP 62152099A JP 15209987 A JP15209987 A JP 15209987A JP S63316757 A JPS63316757 A JP S63316757A
- Authority
- JP
- Japan
- Prior art keywords
- group
- methoxy
- compound
- reaction
- formula
- 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.)
- Granted
Links
- -1 3-amino-2-substituted benzoylacrylic acid Chemical class 0.000 title claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract 2
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000002560 nitrile group Chemical class 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 27
- 150000001875 compounds Chemical class 0.000 abstract description 25
- 239000002904 solvent Substances 0.000 abstract description 12
- 239000002253 acid Substances 0.000 abstract description 10
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- YTLYLLTVENPWFT-UPHRSURJSA-N (Z)-3-aminoacrylic acid Chemical class N\C=C/C(O)=O YTLYLLTVENPWFT-UPHRSURJSA-N 0.000 abstract description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 150000002825 nitriles Chemical class 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000013522 chelant Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- YVJHZWWMKFQKDC-UHFFFAOYSA-N 2,4,5-trifluoro-3-methoxybenzoic acid Chemical compound COC1=C(F)C(F)=CC(C(O)=O)=C1F YVJHZWWMKFQKDC-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- ZKKBIZXAEDFPNL-HWKANZROSA-N (e)-3-(dimethylamino)prop-2-enenitrile Chemical compound CN(C)\C=C\C#N ZKKBIZXAEDFPNL-HWKANZROSA-N 0.000 description 1
- PLPDHGOODMBBGN-VOTSOKGWSA-N (e)-4-oxo-4-phenylbut-2-enoic acid Chemical class OC(=O)\C=C\C(=O)C1=CC=CC=C1 PLPDHGOODMBBGN-VOTSOKGWSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KTPHYLJFAZNALV-UHFFFAOYSA-N 2,3,4-trifluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(F)=C1F KTPHYLJFAZNALV-UHFFFAOYSA-N 0.000 description 1
- SESHQEGOVPUXAH-UHFFFAOYSA-N 2,4,5-trifluoro-3-methoxyaniline Chemical compound COC1=C(F)C(N)=CC(F)=C1F SESHQEGOVPUXAH-UHFFFAOYSA-N 0.000 description 1
- JVQSZTJTWSUJCR-UHFFFAOYSA-N 2,4,5-trifluoro-3-methoxybenzoyl chloride Chemical compound COC1=C(F)C(F)=CC(C(Cl)=O)=C1F JVQSZTJTWSUJCR-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000052583 Anaphase-Promoting Complex-Cyclosome Apc8 Subunit Human genes 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101000912124 Homo sapiens Cell division cycle protein 23 homolog Proteins 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000007824 aliphatic compounds Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MVUMJYQUKKUOHO-AATRIKPKSA-N ethyl (e)-3-(dimethylamino)prop-2-enoate Chemical compound CCOC(=O)\C=C\N(C)C MVUMJYQUKKUOHO-AATRIKPKSA-N 0.000 description 1
- HVJXUGXNDLCTGC-UHFFFAOYSA-N ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)prop-2-enoate Chemical compound C=1C(F)=C(F)C(OC)=C(F)C=1C(=O)C(C(=O)OCC)=CNC1CC1 HVJXUGXNDLCTGC-UHFFFAOYSA-N 0.000 description 1
- MVUMJYQUKKUOHO-UHFFFAOYSA-N ethyl 3-(dimethylamino)prop-2-enoate Chemical compound CCOC(=O)C=CN(C)C MVUMJYQUKKUOHO-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 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
- 239000007788 liquid Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- MVPDNJQLPITPIX-UHFFFAOYSA-N methyl 3-(dimethylamino)prop-2-enoate Chemical compound COC(=O)C=CN(C)C MVPDNJQLPITPIX-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
発明の目的
°本発明は、強力な抗菌活性を示す８−アルコキシキノ
ロンカルボン酸誘導体を合成するための有用な中間体で
ある、３−アミノ−２−置換ベンゾイルアクリル酸誘導
体に関する。DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention provides 3-amino-2-substituted benzoylacrylic acids, which are useful intermediates for the synthesis of 8-alkoxyquinolone carboxylic acid derivatives exhibiting strong antibacterial activity. Regarding derivatives.
発明の構成
本発明の３−アミノ−２−置換ベンゾイルアクリル酸霞
導体は、
一般式 。Structure of the Invention The 3-amino-2-substituted benzoylacrylic acid haze conductor of the present invention has the general formula.
で表わされる新規化合物である。This is a new compound represented by
上記式中、Ｒ１は低級アルキル基を示し Ｒ２およびＲ
５は四−または異なるアルキル基を示すかあるいはゼれ
らが結合している窒素原子とともに１さらに場合によっ
ては＆素原子、硫黄原子、スルフィニル基またはスルホ
ニル基と一緒になつて形成する環状アミノ基を示しても
よく、Ａはニトリル基または低級アルコキシカルゲニル
基を示す。In the above formula, R1 represents a lower alkyl group, R2 and R
5 represents a 4- or different alkyl group, or a cyclic amino group formed by combining 1 with the nitrogen atom to which they are bonded, and in some cases with an elemental atom, a sulfur atom, a sulfinyl group, or a sulfonyl group; and A represents a nitrile group or a lower alkoxycargenyl group.
前記一般式（１１において、好適にはＲ１は例えばメチ
ル、エチル、ｎ−プロピル、インゾロビルのような炭素
数１乃至３個を有する直鎖状若しくは分校鎖状のアルキ
ル基を示し、Ｒ２およびＲ５は同一または異なって例え
ばメチル、エチル、ｎ−プロピル、イソプロピル、ｎ−
ブチル、イソジチル、５ｅｃ−ブチル、ｎ−ペンチル、
ｎ−ヘキシルのような炭素数１乃至６個を有する直鎖状
若しくは分枝鎖状のアルキル基を示すが、゛ あるい
はそれらが結合している窒素原子とともに形成する例え
ばｌ−ピロリノニル、ピペリジ−Ｎ”３０２のよりな５
若しくは６員墳状アミノ基−Ｊ
を示してもよく、Ａはニトリル基または例えばメトキシ
カルテニル、エトキシカルボニル、ｎ−プロポキシカル
がニル、イソプロポキシカル−ニル、ｎ−ブトキシカル
がニル、イソブトキシカルテニルのような炭素数２乃至
５個を有するアルコキシカルゲニル基ｆ： 示ｔ。In the general formula (11), R1 preferably represents a linear or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, inzolobil, and R2 and R5 are Same or different, e.g. methyl, ethyl, n-propyl, isopropyl, n-
Butyl, isodityl, 5ec-butyl, n-pentyl,
It refers to a linear or branched alkyl group having 1 to 6 carbon atoms such as n-hexyl, or a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as n-hexyl, or a group formed with the nitrogen atom to which they are bonded, such as l-pyrrolinonyl, piperidi-N ``302 no Yorina 5
Alternatively, A may represent a 6-membered mounded amino group -J, where A is a nitrile group or, for example, methoxycartenyl, ethoxycarbonyl, n-propoxycarnyl, isopropoxycartenyl, n-butoxycarnyl, isobutoxycartenyl, or isobutoxycartenyl. Alkoxycargenyl group f having 2 to 5 carbon atoms such as nil: t.
前記一般式＋１１における特に好適な化合物としチルア
ミノ基、ジエチルアミノ基、１−ピロリジニル基、ピペ
リジノ基またはモルホリノ基を示１． 、Ａがニトリル
基、メトキシカルブニル基またはエトキシカルボニル基
を示す化合物を挙げることができる。Particularly preferred compounds in the above general formula +11 are thylamino group, diethylamino group, 1-pyrrolidinyl group, piperidino group or morpholino group.1. , A represents a nitrile group, a methoxycarbonyl group or an ethoxycarbonyl group.
本発明の前記一般式（１１ｔ−有する３−アミノ−２−
置換ベンゾイルアクリル酸誘導体は、一般式
（式中、Ｘは塩素、臭素のような］〜ロゲン原子を示し
、・Ｒ１は前述したものと同意義を示す。）で表わされ
る置換ベンゾイル−・ライド化合物と、一般式
％式％
（式中、Ｒ２、Ｒ５およびＡは前述したものと同意義を
示す。）
で表わされる３−アミノアクリル酸誘導体を不活性溶媒
中、塩基の存在下に反応させることによって製造するこ
とができる。The general formula (11t-3-amino-2-
The substituted benzoyl acrylic acid derivative is a substituted benzoyl-ride compound represented by the general formula (wherein, X represents a chlorine or bromine atom, and R1 has the same meaning as described above). and a 3-aminoacrylic acid derivative represented by the general formula % (wherein R2, R5 and A have the same meanings as described above) in an inert solvent in the presence of a base. It can be manufactured by
本反応に使用できる溶媒は、テトラヒドロフラン、ジエ
チルエーテル、ジオキサン、ジメトキシエタン等のエー
テル系化合物、ベンゼン、トルエン、キシレン等の芳香
族化合物又は塩化メチレン、クロロホルム等の塩素系化
合物が使用できるが、特にエーテル系溶媒が好ましい。The solvents that can be used in this reaction include ether compounds such as tetrahydrofuran, diethyl ether, dioxane, and dimethoxyethane, aromatic compounds such as benzene, toluene, and xylene, and chlorine compounds such as methylene chloride and chloroform. A system solvent is preferred.
反応温度は一３０〜１７０℃、好ましくは０〜８０℃の
範囲で行われる。通常、室温付近ですみやかに進行する
が、その後反応を完結させるため５（）〜８０℃に加熱
することが好ましい。反応時間は反応温度にも依るが、
１〜１５時間が範囲である。The reaction temperature is -30 to 170°C, preferably 0 to 80°C. Usually, the reaction proceeds quickly at around room temperature, but it is preferable to heat the reaction to 5() to 80°C to complete the reaction afterwards. The reaction time depends on the reaction temperature, but
The range is 1 to 15 hours.
使用できる塩基としては、ピリジン、トリエチルアミン
、Ｎ−メチルピペリジン等の３級ア・ ミンがあげられ
るが、トリエチルアミンが好ましい。Examples of bases that can be used include tertiary amines such as pyridine, triethylamine, and N-methylpiperidine, with triethylamine being preferred.
反応基質（Ｉｌｌおよび−の濃度はそれぞれＯ，１〜１
０Ｍの範囲で可能であるが、通常０．５〜１．２Ｍの範
囲で実施した方がよい。The concentrations of the reaction substrates (Ill and - are O, 1 to 1, respectively)
Although it is possible in the range of 0M, it is usually better to carry out in the range of 0.5 to 1.2M.
また、（■）と（２）とは１：１の化学量論量（モル比
）で反応させるのが好ましく、塩基は酸−・ライドＩＩ
ＤＫ対しテ０．８〜３．０等量、好ましくハ１．０〜１
．５等量用いるのがよい。Further, it is preferable that (■) and (2) are reacted in a stoichiometric amount (molar ratio) of 1:1, and the base is acid-Ride II.
Te 0.8 to 3.0 equivalent to DK, preferably Ha 1.0 to 1
．． It is best to use 5 equivalents.
反応終了後、生成物を得る方法としては、反応混合物を
濃縮後、又は濃縮せずに水に加え、生成した塩を除いた
後、非水溶性有機溶媒で抽出するという一般的方法が行
える。抽出液から溶媒を除くことにより目的物は高い純
度で得られるが、さらに精美する場合には、カラムクロ
マトグラ・フィーや再結晶により純品として単離できる
。After completion of the reaction, the product can be obtained by the general method of adding the reaction mixture to water after concentrating it or without concentrating it, removing the generated salt, and then extracting it with a water-insoluble organic solvent. The target product can be obtained in high purity by removing the solvent from the extract, but if it is to be purified further, it can be isolated as a pure product by column chromatography or recrystallization.
なお、上記反応において使用される置換ペン６２−７６
８９２号明絹書に記載されているが、本願明細書におい
て参考例として詳述する。In addition, substitution pens 62-76 used in the above reaction
Although it is described in Meishu No. 892, it will be described in detail in the present specification as a reference example.
本発明の化合物（１１は、抗菌剤を製造するための有用
な中間体であるが、例えば以下に示す反応径路に従って
、１位にシクロゾロピル基、８位にアルコキシ基を有す
る新規なキノロンカルチン酸系の抗菌剤に導くことがで
きる。The compound of the present invention (11 is a useful intermediate for producing antibacterial agents, for example, a novel quinolone carcinic acid having a cyclozolopyl group at the 1-position and an alkoxy group at the 8-position according to the reaction route shown below) This can lead to antibacterial agents in the system.
（１１Ｇｅ１）
上記式中、Ｒ１，Ｒ２およびＲ３は前述したものと同意
義を示し、Ｒは低級アルキル基を示し、一般式ＹＮ）Ｉ
を有するアミン化合物（■は、置換基として低級ア
ルキル基、低級アルコキシ基、水酸基またはアミノ基を
有していてもよいピロリジンまたはピペラジン誘導体を
示す。(11Ge1) In the above formula, R1, R2 and R3 have the same meanings as described above, R represents a lower alkyl group, and the general formula YN)I
(■ indicates a pyrrolidine or piperazine derivative which may have a lower alkyl group, lower alkoxy group, hydroxyl group or amino group as a substituent.
第１工程の反応は、化合ｍ１ｌ）とシクロプロピルアミ
ンを不活性溶媒中で反応させて、化合物（ＩＩＩ）を得
る反応である。The reaction in the first step is a reaction in which compound m1l) and cyclopropylamine are reacted in an inert solvent to obtain compound (III).
本反応において使用できる溶媒は、ジエチルエーテル、
テトラヒドロフラン、ジオキサン等のエーテル系化合物
、ヘキサン、シクロヘキサン等の脂肪族化合物、ベンゼ
ン、トルエン、キシレン等の芳香族化合物、塩化メチレ
ン、クロロホルム、四塩化炭素等の塩素系化合物又は酢
酸メチル、酢酸エチル等のエステル化合物が使用できる
０反応温度は一２０〜１００℃、好ましくは０〜５０℃
の範囲で行なわれる０反応時間は反応温度によっても異
なるが、数分〜１０時間、通常２時間以内である。Solvents that can be used in this reaction include diethyl ether,
Ether compounds such as tetrahydrofuran and dioxane, aliphatic compounds such as hexane and cyclohexane, aromatic compounds such as benzene, toluene and xylene, chlorine compounds such as methylene chloride, chloroform and carbon tetrachloride, or methyl acetate and ethyl acetate. The reaction temperature at which the ester compound can be used is -20 to 100°C, preferably 0 to 50°C.
The zero reaction time, which is carried out within the range of , varies depending on the reaction temperature, but is from several minutes to 10 hours, usually within 2 hours.
第２工程の反応は、化合物（２）を溶媒の存在下で脱酸
剤で処理して、化合物（Ｉｖ）ヲ得る反応である。The reaction in the second step is a reaction in which compound (2) is treated with a deoxidizing agent in the presence of a solvent to obtain compound (Iv).
本反応において使用できる溶媒は、ジエチルエーテル、
テトラヒドロフラン、ジオキサン等のエーテル系化合物
又はＮ、Ｎ−ジメチルホルムアミド、ジメチルスルホキ
シＰ、ヘキサメチルリン酸トリアミド、スルホラン、Ｎ
−メチルピロリドン等の非プロトン性極性溶媒が使用で
きる。使用できる脱酸剤としては、水素化す） ＩＪウ
ム、ブチルリチウム、ナトリウムメトキシド、カリウム
ｔ−ブトキシド、金属ナトリウム、炭酸ナトリウム、炭
酸カリウム又はフッ化カリウム等があげられるが、水素
化ナトリウムが好ましい。反応温度は使用される脱酸剤
の種類によっても異なるが、室温〜３００℃、好ましく
は室温〜１００℃の範囲で行なわれる０反応時間は反応
温度によっても異なるが、１〜２０時間、通常２〜６時
間である。Solvents that can be used in this reaction include diethyl ether,
Ether compounds such as tetrahydrofuran and dioxane, or N,N-dimethylformamide, dimethylsulfoxy P, hexamethylphosphoric acid triamide, sulfolane, N
- Aprotic polar solvents such as methylpyrrolidone can be used. Examples of the deoxidizing agent that can be used include sodium hydride, butyl lithium, sodium methoxide, potassium t-butoxide, metallic sodium, sodium carbonate, potassium carbonate, and potassium fluoride, with sodium hydride being preferred. The reaction temperature varies depending on the type of deoxidizing agent used, but the reaction time is 1 to 20 hours, usually 2 hours, although the reaction time varies depending on the reaction temperature. ~6 hours.
第３工程の反応は、ａｌ化合物（Ｍ ？ホウフッ化水素
酸と加熱して、そのフッ化ホウ素キレート（式中、Ｒ１
は前述したものと同意義を示す。）となし、ｂ）得られ
る化合物（■りとアミン化合物（Ｖｌとを脱酸剤の存在
下または非存在下で、必要に応じて溶媒中で反応させて
、化合物（至）を得る反応である。In the third step, the al compound (M?) is heated with borofluoric acid to form its boron fluoride chelate (in the formula,
has the same meaning as above. ) and b) The resulting compound (■) is reacted with the amine compound (Vl) in the presence or absence of a deoxidizing agent, if necessary in a solvent, to obtain the compound (to). be.
本反応において用いられる溶媒としては、ジメチルスル
ホキシド、ジメチルホルムアミド、ヘキサメチルリン醗
トリアミド、ジメチルアセトアミ）１１等の非プロトン
性極性溶媒が好適であるが、他にアセトン、メチルエチ
ルケトン等のケトン類、ジエチルエーテル、テトラヒド
ロフラン、ジオキサン等のエーテル類、酢酸エチル等の
エステル類、メタノール、エタノール、ｎ−プロΔノー
ル、インプロノ９ノール、ブタノール等のアルコール類
、アセトニトリル等のニトリル類を使用することもでき
る。脱酸剤としては、トリエチルアミン、トリブチルア
ミン、ピリジン、ピコリン、ルチジン、コリノン等の３
級アミン類または炭酸ナトリウム、炭酸カリウムのよう
な無機塩基を例示することができる。As the solvent used in this reaction, aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, and dimethylacetamide (11) are suitable; however, acetone, ketones such as methyl ethyl ketone, and diethyl Ethers such as ether, tetrahydrofuran, and dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-proΔnol, improno9ol, and butanol, and nitrites such as acetonitrile can also be used. As a deoxidizing agent, there are three types such as triethylamine, tributylamine, pyridine, picoline, lutidine, cholinone, etc.
Examples include class amines or inorganic bases such as sodium carbonate and potassium carbonate.
脱酸剤の使用量は化合物（Ｉｔ／’）に対゛して等モル
乃至５倍モルが好ましいが、前記アミン類の場合には溶
媒として大過剰用いることもできる。また、過剰のアミ
ン（■が脱酸剤として作用するため、他の脱酸剤を添加
しない場合でも反応は円滑に進行する０反応は室温から
２００℃の範囲で行われる。The amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of the compound (It/'), but in the case of the above-mentioned amines, it can be used in large excess as a solvent. Further, since the excess amine (■) acts as a deoxidizing agent, the reaction proceeds smoothly even when no other deoxidizing agent is added.The reaction is carried out at a temperature ranging from room temperature to 200°C.
本ｂ）工程の反応においては、まず目的物のキレート化
合物が得られるが、このものは含水アルコールまたは塩
基性含水アルコールと処理することＫより、それぞれ化
合物（至）・ＢＰ、付加物または（■に誘導することが
できる。化合物Ｍ・ＢＰ、付加物は塩基処理によって容
易に目的化合物Ｍに誘導される。In the reaction of this step b), the target chelate compound is first obtained, but this compound must be treated with a hydrous alcohol or a basic hydrous alcohol to form the compound (to), BP, adduct or (■), respectively. The compound M·BP and the adduct can be easily derived into the target compound M by treatment with a base.
本処理操作において使用される塩基としては、水酸化ナ
トリウム、水酸化カリウムのような水酸化アルカリ、炭
酸ナトリウム、炭酸カリウムのような炭酸アルカリまた
はトリエチルアミン、４−ジメチルアミノピリジンのよ
うな３級アミン類をあげることができる。Bases used in this treatment include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, or tertiary amines such as triethylamine and 4-dimethylaminopyridine. can be given.
このようにして得られる化合物（至）または（■・ＢＰ
、付加物は必要に応じて常法に従って所望の塩にされる
。The compound thus obtained (to) or (■・BP
If necessary, the adduct is converted into a desired salt according to conventional methods.
前記一般式Ｍを有するキノロンカル？ン酸誘導体および
七〇薬理上許容される塩は、すぐれた抗菌作用を示す、
その抗菌活性を寒天平板希釈法により測定したところ、
例えば黄色ブドウ状球菌、腸球菌などのダラム陽件菌お
よび大腸菌、赤痢菌、肺炎桿菌、変形菌、セラチア、エ
ンテロバクタ−、サルモネラ、緑膿菌などのダラム陰性
菌並びＫそれらの耐性菌を包含する広範囲な病原菌に対
して強力な抗菌活性を示した。Quinolonecal having the general formula M? Acid derivatives and 70 pharmacologically acceptable salts exhibit excellent antibacterial activity.
Its antibacterial activity was measured by the agar plate dilution method.
Examples include Durham-positive bacteria such as Staphylococcus aureus and Enterococcus, as well as Durham-negative bacteria such as Escherichia coli, Shigella, Klebsiella pneumoniae, Proteus protease, Serratia, Enterobacter, Salmonella, and Pseudomonas aeruginosa, as well as their resistant bacteria. It showed strong antibacterial activity against a wide range of pathogenic bacteria.
その試験結果をノルフロキサシンを対照化合物として第
−表に示す。The test results are shown in Table 1, using norfloxacin as a control compound.
次に実施例および参考例を挙げて、本発明をさらに具体
的に説明する。Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.
実施例 １
３−メトキシ−２，４，５−トリフルオロ安息香酸クロ
ライド２．Ｏｆ （８，９１ｍｍｏｔ）を無水Ｔ）ＩＦ
ｌｏ−に溶かし、氷水で５℃以下に冷却した。Example 1 3-methoxy-2,4,5-trifluorobenzoic acid chloride 2. Of (8,91mmot) anhydrous T) IF
The mixture was dissolved in lo- and cooled to below 5°C with ice water.
この溶液に３−ジメチルアミノアクリル駿メチルエステ
ル１．１５ ｔ （８，９１ｍｍｏｔ） １に無水ＴＥ
Ｆ’ ３紅に溶かして滴下し、さらに冷却下にトリエチ
ルアミン０．９４ ｆ （９，３１汽→をゆっくりと滴
下して室温で５時間攪拌した後、６０℃で５０分加熱し
た。反応液を濃縮後、水２０ａｌｔ−加えてｃＨ２Ｃ１
２２０ｍｌにて２回抽出して、水で洗浄後乾燥した。鏝
縮後、メタノール−水（６：４） １０屑ｌを加えて再
結晶を行い、３−ツメチルアミノ−２−（３−メトキシ
−２，４，５−トリフルオロベンゾイル）アクリル酸メ
チルエステル１．３６ｆを得た。収率４８幅
融点 ８７〜９０℃
ＮＭＲスペクトル（ＣＤＣｔ、）δｐｐｍ ：３．０７
（ｂｓ 、 ６ Ｈ、Ｎ（ＣＨ３）２）３− ！Ｓ
３ （ｓ −３Ｅ ＩＣ０ＯＣＩ（ｓ ）３．９９（ｓ
、フッ素とのカップリングがある、３Ｈ，Ａｒ０ＣＨ５
）７．０７（オクテツト、ＩＢ、芳香族プロトン）７．
７１（ｓ、１Ｂ、オレフィンプロトン）マススペクト／
ｌ／ ： ｍ／ｅ Ｍ” ３１７元素分析値係（Ｃ１４
Ｈ１４ＦｉＳＮＯ４として）理論値： Ｃ，５３，００
１，４，４５：Ｎ、４．４１分析値： Ｃ，５２，９４
：Ｈ，４，４３：Ｎ、４．３１実施例 ２
エステル
３−メトキシ−２，４，５−トリフルオロ安息香酸クロ
ライ）’ ３． Ｏｆ （１３，４ｍｍｏ／−）を無水
エーテル５Ｎに溶かし、氷水で５℃以下に冷却し、この
溶液にトリエチルアミン１．３！Ｍ（１３，４酬ｏｔ）
を無水エーテルｌＯ−に溶かした溶液を滴下した。さら
に冷却下に３−ジメチルアミノアクリル酸エチルエステ
ル１．９２９ （１３，４ｍｍｏｊ ） ｆ無水エーテ
ル２０ｍｇＫ溶かしゆっくりと滴下して室温で５時間攪
拌した後、−夜装置した０反応液を９縮後、水２０ｔｔ
ｒ＆を加えてＣＨ２Ｃｌ２２０屑ｌにて２回抽出して、
水で洗浄後乾燥した。この溶液をカラム精製して３−ジ
メチルアミノ−２−（３−メトキシ−２，４，５−）リ
フルオロペンソイル）アクリル酸エチルエステル１．３
０ｆｔ−得た。収率２９％、油状物。Add 1.15 t (8,91 mmot) of 3-dimethylaminoacrylic methyl ester to this solution and add 1 to anhydrous TE.
F' 3 was dissolved in red and added dropwise, and while cooling, 0.94 f triethylamine (9,31 steam) was slowly added dropwise, stirred at room temperature for 5 hours, and then heated at 60°C for 50 minutes.The reaction solution was stirred at room temperature for 5 hours. After concentration, add 20 alt of water and add cH2C1
It was extracted twice with 220 ml, washed with water, and then dried. After troweling, recrystallization was performed by adding 10 scraps of methanol-water (6:4) to obtain methyl 3-methylamino-2-(3-methoxy-2,4,5-trifluorobenzoyl)acrylate 1. I got 36f. Yield 48 Range Melting point 87-90°C NMR spectrum (CDCt,) δppm: 3.07
(bs, 6H, N(CH3)2)3-! S
3 (s −3E IC0OCI(s ) 3.99(s
, 3H,Ar0CH5 with coupling with fluorine
) 7.07 (octet, IB, aromatic proton) 7.
71 (s, 1B, olefin proton) mass spectrum/
l/: m/e M” 317 elemental analysis value section (C14
H14FiSNO4) Theoretical value: C,53,00
1,4,45:N, 4.41 Analysis value: C, 52,94
:H, 4,43:N, 4.31 Example 2 Ester 3-methoxy-2,4,5-trifluorobenzoic acid chloride)' 3. Of (13,4 mmo/-) was dissolved in 5N anhydrous ether, cooled to below 5°C with ice water, and 1.3 mmol of triethylamine was added to this solution. M (13,4 ot)
A solution of was dissolved in anhydrous ether lO- was added dropwise. Further, while cooling, 1.929 (13.4 mmoj) f of 3-dimethylaminoacrylic acid ethyl ester was dissolved in 20 mg of anhydrous ether, slowly added dropwise, and stirred at room temperature for 5 hours. 20t water
Add r& and extract twice with 20 liters of CH2Cl2,
After washing with water, it was dried. This solution was purified by column and 3-dimethylamino-2-(3-methoxy-2,4,5-)lifluoropensoyl)acrylic acid ethyl ester
0ft-obtained. Yield 29%, oil.
１ｉＭＲスペクトル（ＣＤＣｔ、）δｐｐｍ ：１．０
２（ｔ、３１１．ＣＨ，ＣｌＩ２０）３．１０ （ｂｓ
、 ６）１ 、 Ｎ（ＣＢ、）２）４．０２（ｑ、２
Ｈ，ＣＨ２Ｃｌ２０）実施例 ３
３−メトキシ−２，４，５−）リフルオロ安息香酸クロ
ライｌ’ ２．Ｏｆ （８，９１ｍｒｎｏｊ ）を無水
ＴＨＦ １０ｙｓｌに溶かし、氷水で５℃以下に冷却し
、この溶液に３−ジメチルアミノアクリロニトリル０．
８６ｆ （８，９１ｍｍｏｔ） ｆ無水Ｔ）ＩＦ ３１
１１７に溶かし、滴下した。さらに冷却下にトリエチル
アミン０．９４ｆ （９，３ｔｍｗ／） ’にゆっくり
と滴下して室温で４時間攪拌した後、６５℃で３．５時
間加熱した０反応液を濃縮後、水２０Ｍを加えてクロロ
ホルム２０Ｗ１１にて３回抽出して、水で洗浄後乾燥し
た。1iMR spectrum (CDCt,) δppm: 1.0
2(t, 311.CH, ClI20) 3.10 (bs
, 6) 1 , N(CB,) 2) 4.02(q, 2
H, CH2Cl20) Example 3 3-methoxy-2,4,5-)lifluorobenzoic acid chloride l' 2. Of (8,91 mrnoj) was dissolved in 10 ysl of anhydrous THF, cooled to below 5°C with ice water, and 0.0 ml of 3-dimethylaminoacrylonitrile was added to this solution.
86f (8,91mmot) f Anhydrous T) IF 31
117 and added dropwise. Furthermore, while cooling, it was slowly added dropwise to 0.94f (9,3tmw/)' of triethylamine, stirred at room temperature for 4 hours, and heated at 65°C for 3.5 hours. After concentrating the reaction solution, 20M of water was added. It was extracted three times with chloroform 20W11, washed with water, and then dried.
カラム精製して３−ツメチルアミノ−２−（３−メトキ
シ−２＝Ｌ５− ）リフルオロベンゾイル）アクリルニ
トリル２．０２ｆｔ−得た。収率８０％融点 ９７〜９
９℃
ＮＭＲスペクトル（ＣＤＣ２３）δｐｐｍ ：３．３３
（ｂａ、３Ｂ）
３．４７ （ｂｓ 、 ３１（、Ｎ（ＣＨ，）２）４．
０５（ｓ、フッ素とのカップリングがある、３）！、Ａ
ｒ０Ｃ’Ｉ（、）６．９７（オクテツト、ＩＦｌ、芳香
族プロトン）７．９０（ｓ、ｌＨ，オレフィンプロトン
）マススペクトル： ｍ／ｅ Ｍ” ２８４元素分析値
％（Ｃ１！５Ｈ１１Ｆ３”２０２として）理論値： Ｃ
，！’１４．９３：）１．３．９０：Ｎ、９．８６分析
値： Ｃ，５４，９３：）１，３．９０：Ｎ、９．８１
参考例 １
酸メチルエステル
実施例１で得た３−ジメチルアミノ−２−（３−メトキ
シ−２，４，５−）リフルオロペンソイル）アクリル酸
メチルエステル５．６４ｆ（１７，８膿ｏ１ ）ｋジク
ロルメタン６０ｍ１ｖｃ溶解、氷冷攪拌下、シクロプロ
ピルアミン１．２２ｆ（２１，４工ｏｔ）をゆっくりと
滴下し、更に室温で１（）分間攪拌した。Column purification gave 2.02 ft of 3-methylamino-2-(3-methoxy-2=L5-)lifluorobenzoyl)acrylonitrile. Yield 80% Melting point 97-9
9°C NMR spectrum (CDC23) δppm: 3.33
(ba, 3B) 3.47 (bs, 31(,N(CH,)2)4.
05 (s, there is a coupling with fluorine, 3)! ,A
r0C'I (,) 6.97 (octet, IFl, aromatic proton) 7.90 (s, lH, olefin proton) Mass spectrum: m/e M" 284 elemental analysis value % (as C1!5H11F3"202) Theoretical value: C
，! '14.93:) 1.3.90:N, 9.86 Analysis value: C, 54, 93:) 1, 3.90:N, 9.81
Reference Example 1 Acid Methyl Ester 3-dimethylamino-2-(3-methoxy-2,4,5-)lifluoropensoyl)acrylic acid methyl ester obtained in Example 1 5.64f (17,8 puso1) After dissolving 60ml of dichloromethane and stirring under ice cooling, 1.22f (21.4 tons) of cyclopropylamine was slowly added dropwise, and the mixture was further stirred at room temperature for 1 minute.
反応液を減圧乾固して残渣にメタノール−水（５：３）
８１１１／を加えて再結晶化を行い、３−シクロプロピ
ルアミノ−２−（３−メトキシ−２，４，５−トリフ・
ルオロペンゾイル）アクリル戯メチルエステル３．８４
９を得た。Ｆｆｉから同様の操作によって２欠品０．４
４ｔを得た。The reaction solution was dried under reduced pressure and the residue was mixed with methanol-water (5:3).
8111/ was added to perform recrystallization, and 3-cyclopropylamino-2-(3-methoxy-2,4,5-trif.
(fluoropenzoyl) acrylic methyl ester 3.84
I got a 9. 2 missing items 0.4 by the same operation from Ffi
Obtained 4t.
融点 ７８〜８１℃
同様にして、３−ジメチルアミノアクリル酸エチルを用
いることにより、３−シクロプロピルアミノ−２−（３
−メトキシ−２，４，５−）リフルオロベンゾイル）ア
クリル酸エチルエステルを得た。Melting point: 78-81°C Similarly, by using ethyl 3-dimethylaminoacrylate, 3-cyclopropylamino-2-(3
-Methoxy-2,4,5-)lifluorobenzoyl)acrylic acid ethyl ester was obtained.
参考例 ２
３−シクロプロピルアミノ−２−（３−メトキシ−２，
４，５−トリフルオロベンゾイル）アクリル酸エチルエ
ステル１．２０ ？ （０，００３５モル）を無水テト
ラヒドロフラン３０Ｍに溶解し、６０チ水素化ナトリウ
ム１５０ ｘｇ （０，００３５−Ｅ−ル）を加え室温
で３０分間攪拌し、ＩＮ塩酸で酸性とした後、酢酸エチ
ルで抽出した。酢酸エチル層を水洗、乾燥後、減圧ＩＩ
＃ｉｆし、１−シクロプロピル−６，７−ジフルオロ−
８−メトキシ−１，４−ジヒドロ−４−オキソキノリン
−３−カルチン酸エチルエステル０．８３ｆｔ無色針状
結晶として得た。Reference example 2 3-cyclopropylamino-2-(3-methoxy-2,
4,5-trifluorobenzoyl)acrylic acid ethyl ester 1.20 ? (0,0035 mol) was dissolved in 30 M of anhydrous tetrahydrofuran, 150 x g (0,0035-E-L) of sodium 60 thihydride was added, stirred at room temperature for 30 minutes, acidified with IN hydrochloric acid, and then dissolved with ethyl acetate. Extracted. After washing the ethyl acetate layer with water and drying, vacuum II
#if, 1-cyclopropyl-6,7-difluoro-
8-Methoxy-1,4-dihydro-4-oxoquinoline-3-carcinic acid ethyl ester was obtained as 0.83 ft colorless needle crystals.
融点 １８０−１８２℃
マススペクトル： ｍ／ｅ ３２３ （Ｍ”） ＋ ２
５１ （Ｍ”−ＣＯ２Ｅｔ） −４１（０３Ｈ５つ
参考例 ３
１−シクロプロピル−６，７−ジフルオロ−８−メトキ
シ−１，４−ノヒｒロー４−オキソキノリ参考例２で得
られた１−シクロプロピル−６，７−ジフルオロ−８−
メトキシ−１，４−ジヒＰロー４−オキソキノリン−３
−カルビン酸エチルエステル１． Ｏｆ （０，００３
モル）を４２チホウフツ化水素酸２０ｔｘｌ圧懸濁し、
９０−１００℃で３時間攪拌後、水に圧加し、析出する
結晶をＦ集して１−７クロプロビルー６．７−ジフルオ
ロ−８−メトキシ−１，４−ジヒドロ−４−オキソキノ
リン−３Ｐカルゲン酸・ＢＦ２−キレート１．１ｔを無
色粉末状結晶として得た。Melting point 180-182℃ Mass spectrum: m/e 323 (M”) + 2
51 (M"-CO2Et) -41 (03H 5 Reference Examples 3 1-Cyclopropyl-6,7-difluoro-8-methoxy-1,4-nohiro-4-oxoquinoli 1-Cyclopropyl obtained in Reference Example 2 Propyl-6,7-difluoro-8-
Methoxy-1,4-dihydro-4-oxoquinoline-3
-Carbic acid ethyl ester 1. Of (0,003
mol) was suspended under pressure in 20 txl of 42-thioboric acid,
After stirring at 90-100°C for 3 hours, it was pressurized into water, and the precipitated crystals were collected in F to give 1-7 cloprobyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3P. 1.1 t of calgenic acid BF2-chelate was obtained as colorless powdery crystals.
融点 ２２４−２２６℃
元素分析値慢（Ｃ１４Ｈ１゜ＢＦ４ＮＯ４として）理論
値： Ｃ，４９，０１：Ｈ，２，９４：１１１，４．０
８分析値： Ｃ’、４９．２４：Ｈ，３，０１：Ｎ、３
．７９参考例 ４
酸塩
参考例３で得られたキレート化合物０．１１ ？（０，
ｏ００３２モル）をジメチルスルホキシｒｏ、ｓ。Melting point 224-226℃ Elemental analysis value (as C14H1゜BF4NO4) Theoretical value: C, 49,01:H, 2,94:111,4.0
8 analysis value: C', 49.24:H, 3,01:N, 3
．． 79 Reference Example 4 Chelate Compound Obtained in Acid Acid Reference Example 3 0.11 ? (0,
o0032 mol) to dimethylsulfoxyro,s.
ｍｌに溶解し、無水ピペラジンｏ、１１ｆ（０，００１
２モル）を添加し、室温に一夜放置した。反応混合物を
ジエチルエーテル５（ｌεに圧加し、析出するキレート
化合物の黄色結晶をＦ果し、これを８０−エタノール３
Ｑｍｌとトリエチルアミン５ゴの混合液に溶解せしめ、
４時間加熱還流した０反応液を熱時濾過して不溶物を除
去、ｐ液を減圧濃縮して得られる結晶をエタノールで洗
浄し、１−シクロプロピル−６−フルオロ−８−メトキ
シ−７−（１−ピペラジニル） −１，４−ジヒド四−
４−オキソキノリン−３−カルーン酸０．０７ ｆを無
色粉末状結晶として得た。ml of anhydrous piperazine o, 11f (0,001
2 mol) was added and left at room temperature overnight. The reaction mixture was pressurized with diethyl ether 5 (lε), and the precipitated yellow crystals of the chelate compound were separated.
Dissolved in a mixture of Qml and triethylamine 5g,
The 0 reaction solution heated under reflux for 4 hours was filtered while hot to remove insoluble matter, the p solution was concentrated under reduced pressure, the resulting crystals were washed with ethanol, and 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-piperazinyl) -1,4-dihydro4-
0.07 f of 4-oxoquinoline-3-carunic acid was obtained as colorless powdery crystals.
融点 １７７−１７８℃
この結晶をエタノール３０１に懸濁し、濃塩酸１ ｒｎ
ｒ、を溢加後、溶媒を減圧濃縮、残渣をエタノールで洗
浄１−で目的化合物の塩酸塩０．０６Ｆを無色粉床とし
て得た。Melting point: 177-178°C The crystals were suspended in ethanol 301 and concentrated hydrochloric acid 1 rn
After adding r, the solvent was concentrated under reduced pressure, and the residue was washed with ethanol to obtain 0.06F hydrochloride of the target compound as a colorless powder bed.
融点 ２４６−２４８℃（分解）
元素分析値チ（Ｃ１８Ｈ２゜僅、０４・ＥＣｔ−捧Ｂ２
０として）理論値： Ｃ，５３，１４：Ｈ，５，４５：
Ｎ、１０．３３分析値： ｃ、５３．３１：Ｈ，５，４
７：Ｎ、１０．３６参考例４と同様にして下記の化合物
を合成した。Melting point 246-248℃ (decomposition) Elemental analysis value Chi (C18H2゜slight, 04・ECt-B2
0) Theoretical value: C, 53, 14: H, 5, 45:
N, 10.33 analysis value: c, 53.31: H, 5,4
7:N, 10.36 The following compound was synthesized in the same manner as in Reference Example 4.
参考例 Ｙ Ｎ−ｍｐ（℃） 備
考参考例 １０
３−メトキシ−２，４，５−トリフルオロ安息香酸訃よ
びその酸クロリド
ペンタフルオロベンゾニトリル１６０．Ｏｆ（０，８３
モル）をメタノール２．５！に溶解、攪拌下室温でナト
リウムメトキシｒ４４．８ｆ（０，８３モル）のメタノ
ール溶液１．６ Ｊ １ｆ１滴下した０滴下終了後室温
で一夜放置、溶媒を減圧留去、残渣をトルエン−水で振
とうし、トルエン層を水洗、無水硫酸す） ＩＪウムで
乾燥後、減圧留去し、残った固形物をｎ−ヘキサンで洗
浄して４−メトキシ−２，３，５，６−チトラフルオロ
ペンゾニトリル１６０．７ｔｆ無色針状結晶として得た
。Reference example Y N-mp (℃)
Reference Example 10 3-methoxy-2,4,5-trifluorobenzoic acid and its acid chloride pentafluorobenzonitrile 160. Of(0,83
mole) to methanol 2.5! A methanol solution of sodium methoxy r44.8f (0.83 mol) was added dropwise at room temperature under stirring. Wash the toluene layer with water and anhydrous sulfuric acid) After drying with IJum, evaporate under reduced pressure, and wash the remaining solid with n-hexane to obtain 4-methoxy-2,3,5,6-titrafluoropene. Zonitrile 160.7tf was obtained as colorless needle crystals.
マススペクトル： ｍ／ｅ ２０５（Ｍ”） 、 １９
０（Ｍ”−ＣＨ５）。Mass spectrum: m/e 205 (M”), 19
0(M''-CH5).
１６２ （Ｍ”−ＣＨ３−Ｃｏ）
オートクレーブ中に液体アンモニア１５０―と上記のよ
うにして得た４−メトキシ−２，３，５，６−チトラフ
ルオロベンゾニトリル１００．０ｆ（０，４９モル）を
詰め、室温で一夜放置した。アンモニアを除去後、残っ
た固形物を水洗し、２−アミノ−４−メトキシ−３，５
，６−ドリフルオロペンゾニトリル８４．４ｔ’ｉ無色
粉末として得た。162 (M"-CH3-Co) In an autoclave, 150- of liquid ammonia and 100.0 f (0.49 mol) of 4-methoxy-2,3,5,6-titrafluorobenzonitrile obtained as above were added. Packed and left overnight at room temperature. After removing ammonia, the remaining solid was washed with water and 2-amino-4-methoxy-3,5
, 6-dolifluoropenzonitrile 84.4t'i was obtained as a colorless powder.
マススペクトル： ｍ／ｅ ２０２ （Ｍつ、 １７２
（Ｍ”−ＣＨ２−０）。Mass spectrum: m/e 202 (M, 172
(M''-CH2-0).
１５９ （Ｍ”−ＣＨ５−Ｃｏ ）
次いでこの２−アミノ−４−メトキシ−３，５，６−ド
リフルオロペンゾニトリル８４．４Ｆ（０，４２モル）
Ｋ水５０―と濃硫酸２００−を添加、１００℃で１時間
攪拌俵、水１５０１ｊを加え、更に２時間１１０−１２
０℃で攪拌した。室温にまで放冷後、氷水を圧加し、炭
酸カリウムで中和した。159 (M”-CH5-Co) Then this 2-amino-4-methoxy-3,5,6-dolifluoropenzonitrile 84.4F (0.42 mol)
Add 50% of K water and 200% of concentrated sulfuric acid, stir at 100°C for 1 hour, add 1501j of water, and keep at 110% for another 2 hours.
Stirred at 0°C. After cooling to room temperature, ice water was added under pressure and neutralized with potassium carbonate.
析出する結晶を酢酸エチルで抽出、有機層を水洗、無水
硫酸ナトリウムで乾燥後、減圧留去し、３−メトキシ−
２，４，５−）リフルオロアニリン５７．６ｔｆ：無色
針状結晶として得た。The precipitated crystals were extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 3-methoxy-
2,4,5-)Refluoroaniline 57.6tf: Obtained as colorless needle crystals.
融点 ４５−４７℃
マススペクトＡ／ ： ｍ／ｅ １７７ （Ｍ”） 、
１４７ （Ｍ”−ＣＩ（２−Ｏ）ＮＭＲスペクトル（Ｃ
’ＤＣｔ３）δｐｐｍ ：３．６５ （ｂｒ １２１１
１− ＮＨ２）４．０１（ｓ 、 ３Ｂ、 −０ＣＲ，
）６゜２２〜６．３６（ｍ、ＩＨ，ａｒｏｍＨ）このよ
うにして得た３−メトキシ−２，４，５−トリフルオロ
アニリン１．０１Ｆ（０，００５６モル）を酢酸３縮、
水２５−１癖硫酸１．６８ｒ（０，０１６８モル）の混
液に溶解し、０℃に冷却後、亜硝酸ナトリウム０．４６
Ｐ（０，００６６モル）を含む水溶液ｌ ａｔを攪拌下
、０−３℃で滴下した。滴下終了後、同温度で３０分間
攪拌し、ジアゾニウム塩溶液を得た。Melting point 45-47℃ Mass spectrum A/: m/e 177 (M”),
147 (M”-CI(2-O) NMR spectrum (C
'DCt3) δppm: 3.65 (br 1211
1-NH2)4.01(s, 3B, -0CR,
) 6°22-6.36 (m, IH, aromaH) 1.01F (0,0056 mol) of 3-methoxy-2,4,5-trifluoroaniline thus obtained was tricondensed with acetic acid,
Dissolved in a mixture of 25-1 water and 1.68 r (0,0168 mol) of sulfuric acid, cooled to 0°C, and then added 0.46 mol of sodium nitrite.
An aqueous solution containing P (0,0066 mol) was added dropwise at 0-3° C. with stirring. After the dropwise addition was completed, the mixture was stirred at the same temperature for 30 minutes to obtain a diazonium salt solution.
一方、硫酸銅５水和物１．８Ｏｒ（ｏ、ｎ０７２モル）
を水ＩＱｍｌに溶解し、これにシアン化カリウム１．９
５９ （０，０３モル）を含む水溶液５紅を攪拌下、２
０℃以下で滴下、得られた褐色透明溶液に炭酸水素ナト
リウム４．０２ｆ（０，０４８モル）を添加後、ベンゼ
ン３０ｍ１を添加した。On the other hand, copper sulfate pentahydrate 1.8Or (o, n072 mol)
was dissolved in IQml of water, and 1.9 mL of potassium cyanide was added to it.
59 (0.03 mol) with stirring,
The mixture was added dropwise at 0° C. or below, and 4.02 f (0,048 mol) of sodium hydrogen carbonate was added to the resulting brown transparent solution, followed by 30 ml of benzene.
この２層になった溶液に、激しく攪拌しつつ前記のジア
ゾニウム塩溶液を３０〜４５℃で滴下し、滴下終了後、
反応ｆｊｌ−液ｔ−６５℃まで加熱した。室温に冷却後
、ベンゼン膚を分取し、水洗、乾燥後、減圧留云し、残
渣をシリカゲルカラムクロマトグラフィー（溶媒：トル
エン）に付し、３−メトキシ−２，４，５−トリフルオ
ロベンゾニ）１フル０．７７ｔを赤色油状物として得た
。The above-mentioned diazonium salt solution was added dropwise to this two-layered solution at 30 to 45°C while stirring vigorously, and after the addition was completed,
Reaction fjl-liquid t-heated to 65°C. After cooling to room temperature, the benzene skin was collected, washed with water, dried, and distilled under reduced pressure. The residue was subjected to silica gel column chromatography (solvent: toluene) to obtain 3-methoxy-2,4,5-trifluorobenzoni. ) 0.77 t of 1ful was obtained as a red oil.
ＩＲスペクトル（フィルム法、シｒｎａＰ−１）：２２
５０．１６２０．１５００，１４８０，１１２０．１０
８０上記のようにして得た３−メトキシ−２，４，５−
トリフルオロベンゾニトリル１．２４Ｐ（０，００７モ
ル）に濃硫酸５１と水１．２ ｍを添加し、１００−１
４０℃で３０分間加熱後、氷水に圧加し、酢酸エチルで
抽出した。酢酸エチル層を水洗し乾燥後、減圧乾固し、
３−メトキシ−２ｓＣ５−）リフルオロベンズアミｒ１
．１ｏｒを淡褐色粉末として得た。IR spectrum (film method, SirnaP-1): 22
50.1620.1500, 1480, 1120.10
80 3-Methoxy-2,4,5- obtained as above
Add 51 m of concentrated sulfuric acid and 1.2 m of water to 1.24 P (0,007 mol) of trifluorobenzonitrile to make 100-1
After heating at 40°C for 30 minutes, the mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and dried under reduced pressure.
3-Methoxy-2sC5-)lifluorobenzami r1
．． 1or was obtained as a light brown powder.
融点 １３１−１３３℃
マススペクトル： ｍ／ｅ ２０５ （Ｍ”） 、 １
８９ （Ｍ”−Ｎ）１２）次にこの３−メトキシ−２１
４，５−トリフルオロベンズアミド４６．４ｆ（０，２
２６モル）を水９００νに懸濁し、ＩＮ水酸化ナトリウ
ム２２６Ｍ（０，２２６モル）を加えて攪拌下２時間加
熱還流した。室但にまで放冷後、酢酸エチルで抽出して
未反応物を除去し、水層を塩酸で酸性とした。Melting point: 131-133°C Mass spectrum: m/e 205 (M”), 1
89 (M”-N)12) Next, this 3-methoxy-21
4,5-trifluorobenzamide 46.4f (0,2
26 mol) was suspended in 900 ν of water, 226 M (0,226 mol) of IN sodium hydroxide was added, and the mixture was heated under reflux for 2 hours with stirring. After cooling to room temperature, unreacted substances were removed by extraction with ethyl acetate, and the aqueous layer was made acidic with hydrochloric acid.
析出する結晶全酢酸エチルで抽出、有機層を水洗し乾燥
後、減圧留去して３−メトキシ−２，４，５−トリフル
オロ安息香酸３７．１ ｆを無色針状結晶として得た。The precipitated crystals were all extracted with ethyl acetate, the organic layer was washed with water, dried, and then evaporated under reduced pressure to obtain 37.1 f of 3-methoxy-2,4,5-trifluorobenzoic acid as colorless needle crystals.
融点 １１５−１１７℃
マススペクトル： ｍ／ｅ ２０６ （Ｍ”） 、 １
８９ （Ｍ”−０１１） 。Melting point: 115-117°C Mass spectrum: m/e 206 (M”), 1
89 (M”-011).
１６１ （Ｍ”−ＣＯＯＥ）
ＮＭＲスペクトル（ｃＤｃｚ、）δｐｐｘ１１＝４．０
９（５，３Ｅ、ＯＣＲ，）
７．５０〜７．６２ （ｍ 、 Ｉ Ｂ 、 ａｒｏｍ
Ｅ ）８．０〜１０．０ （ｂｒ 、 １１１ 、 Ｃ
００Ｅ ）次いで、３−メトキシ−２，４，５−）リフ
ルオロ安息香ｉ１１．１４Ｆ（０，００５５モル）ｔ［
ｉｌぺ／セン１０継に溶解し、塩化チオニル５１を加え
て１時間加熱還流した。反応後、ベンゼンおよび過剰の
塩化チオニルを完全に留去し、３−メトキシ−２，４，
５−トリフルオロ安息香酸クロリドを得九。161 (M”-COOE) NMR spectrum (cDcz,) δppx11=4.0
9 (5,3E, OCR,) 7.50-7.62 (m, IB, arom
E) 8.0-10.0 (br, 111, C
00E) Then 3-methoxy-2,4,5-)lifluorobenzoic i11.14F (0,0055 mol) t[
The mixture was dissolved in ilpe/sen 10th grade, added with thionyl chloride 51, and heated under reflux for 1 hour. After the reaction, benzene and excess thionyl chloride were completely distilled off, and 3-methoxy-2,4,
9. 5-Trifluorobenzoic acid chloride was obtained.
Claims (1)
Ｒ＾３は同一または異なるアルキル基を示すかあるいは
それらが結合している窒素原子とともに、さらに場合に
よつては酸素原子、硫黄原子、スルフイニル基またはス
ルホニル基と一緒になつて形成する環状アミノ基を示し
てもよく、Ａはニトリル基または低級アルコキシカルボ
ニル基を示す。） で表わされる３−アミノ−２−置換ベンゾイルアクリル
酸誘導体。[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 represents a lower alkyl group, and R^2 and R^3 represent the same or different alkyl group or a cyclic amino group formed together with the nitrogen atom to which they are bonded, and optionally an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group, and A is a nitrile group or A 3-amino-2-substituted benzoyl acrylic acid derivative represented by (representing a lower alkoxycarbonyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62152099A JPH0784423B2 (en) | 1987-06-18 | 1987-06-18 | 3-Amino-2-substituted benzoyl acrylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62152099A JPH0784423B2 (en) | 1987-06-18 | 1987-06-18 | 3-Amino-2-substituted benzoyl acrylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63316757A true JPS63316757A (en) | 1988-12-26 |
| JPH0784423B2 JPH0784423B2 (en) | 1995-09-13 |
Family
ID=15533029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62152099A Expired - Lifetime JPH0784423B2 (en) | 1987-06-18 | 1987-06-18 | 3-Amino-2-substituted benzoyl acrylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0784423B2 (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6416746A (en) * | 1987-07-09 | 1989-01-20 | Kyorin Seiyaku Kk | Anisole derivative and production thereof |
| JPH0269474A (en) * | 1988-07-15 | 1990-03-08 | Bayer Ag | 7-(1-pyrrolidinyl)-3-quinolone-and-naphthylidone -carboxylic acid derivative, production thereof, antibacterial agent and feed additive |
| FR2649699A1 (en) * | 1989-07-13 | 1991-01-18 | Rhone Poulenc Agrochimie | Fungicidal 4-phenylpyrimidines |
| EP0418175A2 (en) * | 1989-09-11 | 1991-03-20 | Rhone Poulenc Agriculture Ltd. | Isoxazoles herbicides |
| US5011971A (en) * | 1988-06-09 | 1991-04-30 | Chemie Linz Gesellschaft M.B.H. | Process for the preparation of substituted 3-amino-2 (benzoyl)-acrylic acid esters, and a process for the preparation of intermediates for antibacterial active compounds from these compounds |
| EP0605259A2 (en) * | 1993-01-01 | 1994-07-06 | Canon Kabushiki Kaisha | Image reading apparatus and image processing apparatus |
| WO2004108680A1 (en) * | 2003-06-06 | 2004-12-16 | Daiichi Pharmaceutical Co., Ltd. | Intermediates and process for thr production of optically active quinolonecarboxylic acid derivatives |
| WO2008126384A1 (en) | 2007-03-30 | 2008-10-23 | Daiichi Sankyo Company, Limited | Method for producing quinolone carboxylic acid derivative |
| JP4751557B2 (en) * | 2000-03-07 | 2011-08-17 | 富山化学工業株式会社 | One-pot synthesis of alkyl 3-cyclopropylamino-2- [2,4-dibromo-3- (difluoromethoxy) benzoyl] -2-propenoate as a useful intermediate for antimicrobial quinolone drugs |
| CN108088930A (en) * | 2017-12-29 | 2018-05-29 | 成都百裕制药股份有限公司 | A kind of quinoline carboxylic acid ethyl ester or/and its detection method in relation to substance |
| CN110357816A (en) * | 2019-08-08 | 2019-10-22 | 内蒙古源宏精细化工有限公司 | A kind of synthetic method of gatifloxacin cyclized ester |
-
1987
- 1987-06-18 JP JP62152099A patent/JPH0784423B2/en not_active Expired - Lifetime
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6416746A (en) * | 1987-07-09 | 1989-01-20 | Kyorin Seiyaku Kk | Anisole derivative and production thereof |
| US5011971A (en) * | 1988-06-09 | 1991-04-30 | Chemie Linz Gesellschaft M.B.H. | Process for the preparation of substituted 3-amino-2 (benzoyl)-acrylic acid esters, and a process for the preparation of intermediates for antibacterial active compounds from these compounds |
| JPH0269474A (en) * | 1988-07-15 | 1990-03-08 | Bayer Ag | 7-(1-pyrrolidinyl)-3-quinolone-and-naphthylidone -carboxylic acid derivative, production thereof, antibacterial agent and feed additive |
| FR2649699A1 (en) * | 1989-07-13 | 1991-01-18 | Rhone Poulenc Agrochimie | Fungicidal 4-phenylpyrimidines |
| EP0418175A2 (en) * | 1989-09-11 | 1991-03-20 | Rhone Poulenc Agriculture Ltd. | Isoxazoles herbicides |
| TR25897A (en) * | 1989-09-11 | 1993-11-01 | Rhone Poulenc Agriculture | 4-BENZOIL ISOXAZOLE DERIVATIVES, COMPOSITIONS AND THEIR USE AS A HAZARDOUS KILLER |
| EP0605259A2 (en) * | 1993-01-01 | 1994-07-06 | Canon Kabushiki Kaisha | Image reading apparatus and image processing apparatus |
| EP0605259A3 (en) * | 1993-01-01 | 1995-02-08 | Canon Kk | Image reading apparatus and image processing apparatus. |
| JP4751557B2 (en) * | 2000-03-07 | 2011-08-17 | 富山化学工業株式会社 | One-pot synthesis of alkyl 3-cyclopropylamino-2- [2,4-dibromo-3- (difluoromethoxy) benzoyl] -2-propenoate as a useful intermediate for antimicrobial quinolone drugs |
| WO2004108680A1 (en) * | 2003-06-06 | 2004-12-16 | Daiichi Pharmaceutical Co., Ltd. | Intermediates and process for thr production of optically active quinolonecarboxylic acid derivatives |
| US7915418B2 (en) | 2003-06-06 | 2011-03-29 | Daiichi Pharmaceutical Co., Ltd. | Intermediates and process for the production of optically active quinolonecarboxylic acid derivatives |
| JPWO2004108680A1 (en) * | 2003-06-06 | 2006-07-20 | 第一製薬株式会社 | Intermediate for producing optically active quinolonecarboxylic acid derivative and process for producing the same |
| WO2008126384A1 (en) | 2007-03-30 | 2008-10-23 | Daiichi Sankyo Company, Limited | Method for producing quinolone carboxylic acid derivative |
| US7875722B2 (en) | 2007-03-30 | 2011-01-25 | Daiichi Sankyo Company, Limited | Method for producing quinolone carboxylic acid derivative |
| CN108088930A (en) * | 2017-12-29 | 2018-05-29 | 成都百裕制药股份有限公司 | A kind of quinoline carboxylic acid ethyl ester or/and its detection method in relation to substance |
| CN110357816A (en) * | 2019-08-08 | 2019-10-22 | 内蒙古源宏精细化工有限公司 | A kind of synthetic method of gatifloxacin cyclized ester |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0784423B2 (en) | 1995-09-13 |
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