JP5282029B2 - キノロンカルボン酸誘導体の製法 - Google Patents
キノロンカルボン酸誘導体の製法 Download PDFInfo
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- JP5282029B2 JP5282029B2 JP2009508904A JP2009508904A JP5282029B2 JP 5282029 B2 JP5282029 B2 JP 5282029B2 JP 2009508904 A JP2009508904 A JP 2009508904A JP 2009508904 A JP2009508904 A JP 2009508904A JP 5282029 B2 JP5282029 B2 JP 5282029B2
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- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title abstract description 9
- -1 quinolone compound Chemical class 0.000 claims abstract description 57
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 114
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000005843 halogen group Chemical group 0.000 claims description 47
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 125000003277 amino group Chemical group 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 claims description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- 150000001924 cycloalkanes Chemical class 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims 1
- 150000001638 boron Chemical class 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000203 mixture Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 229910052731 fluorine Inorganic materials 0.000 description 18
- 125000001153 fluoro group Chemical group F* 0.000 description 18
- 238000000034 method Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 125000001309 chloro group Chemical group Cl* 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- XQFGVGNRDPFKFJ-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydropyrrolo[1,2-b]pyridazine Chemical compound N1CCC=C2CCCN21 XQFGVGNRDPFKFJ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- JUSOWTKVZJDEDG-IONNQARKSA-N 6,7-difluoro-1-[(1r,2s)-2-fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(F)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2[C@@H]1C[C@@H]1F JUSOWTKVZJDEDG-IONNQARKSA-N 0.000 description 2
- WGQJZAJLWWLKHN-BLWKPCCLSA-N 7-[(7s)-7-amino-7-methylspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid;dihydrate Chemical compound O.O.FC1=CC(C(C(C(O)=O)=CN2[C@H]3[C@H](C3)F)=O)=C2C(OC)=C1C(C[C@@]1(N)C)CC21CC2 WGQJZAJLWWLKHN-BLWKPCCLSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-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
- 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- UPXKVBIEOMMGLJ-XUIRIPPPSA-N (7s)-2-benzyl-7-methyl-5-azaspiro[2.4]heptan-7-amine;dihydrochloride Chemical compound Cl.Cl.C[C@@]1(N)CNCC11C(CC=2C=CC=CC=2)C1 UPXKVBIEOMMGLJ-XUIRIPPPSA-N 0.000 description 1
- BVLDJMARULEEGX-QYCVXMPOSA-N (7s)-7-methyl-5-azaspiro[2.4]heptan-7-amine;dihydrochloride Chemical compound Cl.Cl.C[C@@]1(N)CNCC11CC1 BVLDJMARULEEGX-QYCVXMPOSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- XLOLWBTYFFTMCW-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydroimidazo[1,5-a]pyridine Chemical compound C1CCN2CNCC2=C1 XLOLWBTYFFTMCW-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CSZSOJGIKUZIBL-DKSSEZFCSA-N 1-[(1r,2s)-2-fluorocyclopropyl]-8-methoxy-7-[(3r)-3-[1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopropyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(N2C[C@@H](CC2)C2(CC2)NC(=O)OC(C)(C)C)C=CC(C(C(C(O)=O)=C2)=O)=C1N2[C@@H]1C[C@@H]1F CSZSOJGIKUZIBL-DKSSEZFCSA-N 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- AILFRWRYZZVJTL-UHFFFAOYSA-N 1-methylpiperazin-1-ium;chloride;hydrochloride Chemical compound Cl.Cl.CN1CCNCC1 AILFRWRYZZVJTL-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- ANIMQFJMACSGNN-UHFFFAOYSA-N 2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13),11-tetraene-11-carboxylic acid Chemical group O1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=CC=C3 ANIMQFJMACSGNN-UHFFFAOYSA-N 0.000 description 1
- XMUWOBYBMGVFIU-UHFFFAOYSA-N 2-methylpiperazine;dihydrochloride Chemical compound Cl.Cl.CC1CNCCN1 XMUWOBYBMGVFIU-UHFFFAOYSA-N 0.000 description 1
- CGVCRJWKRVYOID-UHFFFAOYSA-N 2h-oxazine-6-carboxylic acid Chemical compound OC(=O)C1=CC=CNO1 CGVCRJWKRVYOID-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical compound OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YNDBCGZWBLQBKH-UHFFFAOYSA-N C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)OC)F)F)=O)C(=O)O.O Chemical compound C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)OC)F)F)=O)C(=O)O.O YNDBCGZWBLQBKH-UHFFFAOYSA-N 0.000 description 1
- BUPCRXULACKHSP-UHFFFAOYSA-N C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)OC)F)F)=O)C(=O)O.O.O.C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)OC)N1CC(CCC1)NC)F)=O)C(=O)O Chemical compound C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)OC)F)F)=O)C(=O)O.O.O.C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)OC)N1CC(CCC1)NC)F)=O)C(=O)O BUPCRXULACKHSP-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- LRCRQTQCDDWEKC-UHFFFAOYSA-N N,N-dimethylaniline 4-methylmorpholine Chemical compound CN1CCOCC1.CN(C1=CC=CC=C1)C LRCRQTQCDDWEKC-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- XUBOMFCQGDBHNK-UHFFFAOYSA-N gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCNC(C)C1 XUBOMFCQGDBHNK-UHFFFAOYSA-N 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- VEXIRMPBAHTVNL-UHFFFAOYSA-N n-methylpiperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.CNC1CCCNC1 VEXIRMPBAHTVNL-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Quinoline Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
で示される部分構造を意味する。]
で示される化合物に、溶媒中、塩基存在下、式(3):
(a)これらが結合する炭素原子を含んで、3員環から6員環の環状構造を形成してスピロ環構造を形成してもよく、スピロ環は、窒素原子、酸素原子または硫黄原子を環の構成原子として含んでいてもよく、このようにして形成された環には、ハロゲン原子、炭素数1から6のアルキル基またはアミノ基が置換していてもよく、さらにこのアルキル基はハロゲン原子、炭素数1から6のアルキル基、アルコキシ基からなる群から選ばれる基を置換基として有してもよい。あるいは、
(b)二重結合によって結合するエキソメチレン基を形成してもよく、さらにこのエキソメチレン基は、水酸基、アミノ基、ハロゲン原子、炭素数1から6のアルキルチオ基および炭素数1から6のアルコキシ基からなる群の置換基から選ばれる基1または2を有していてもよい。
Wは、−CHR5−、−O−、−NR6−を示し、ここでR5は、水素原子、ハロゲン原子、炭素数1から6のアルキル基、炭素数3から6のシクロアルキル基、炭素数2から6のアルケニル基、炭素数2から6のアルキニル基、または炭素数1から6のアルコキシ基を示すが、このうちシクロアルキル基の場合はアミノ基を置換基として有していてもよく、さらにアルキル基の場合は水酸基、アミノ基、ハロゲン原子、炭素数1から6のアルキルチオ基および炭素数1から6のアルコキシ基からなる群の置換基から選ばれる基1または2以上を置換基として有していてもよく、あるいはこのR5と上記R3またはR4は、これらが結合する炭素原子を含んで炭素数3〜6のシクロアルカンまたは5〜7員の飽和複素環を形成してもよく、このようにして形成されたシクロアルカンまたは飽和複素環は、炭素数1から6のアルキル基もしくはアミノ基を置換基として有していてもよい。
R6は、水素原子、炭素数1から6のアルキル基または炭素数3から6のシクロアルキル基を意味する。Yは、水素原子、飽和異項環上の任意の炭素原子に結合するアミノ基、炭素数1〜6のアルキル、炭素数1〜6のアルキルアミノ基、炭素数3から6のシクロアルキル基、化学的手段により容易にアミノ基もしくは炭素数1〜6のアルキルアミノ基に変換可能な基を示し、nは0〜2を示す。]
で示される化合物の塩、およびホウ素誘導体を反応させ、得られるホウ素キレート化合物からホウ素キレートを切断することを特徴とする、式(1):
で示される化合物、その塩、またはそれらの水和物の製造方法に関するものである。
で示される部分構造を意味する。]
で示される化合物(以下、化合物(2)と言う。)である。
化合物(3)の塩としては、薬学的に許容される塩であれば特に制限はなく、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、燐酸塩、硝酸塩及び硫酸塩等の鉱酸塩;安息香酸塩、メタンスルホン酸塩、2−ヒドロキシエタンスルホン酸塩及びp−トルエンスルホン酸塩等の有機スルホン酸塩;酢酸塩、プロピオン酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、グルタル酸塩、アジピン酸塩、酒石酸塩、マレイン酸塩、リンゴ酸塩及びマンデル酸塩等の有機カルボン酸塩を挙げることができる。
三級アミン塩は、置換基導入用の環状アミン化合物の塩化合物において、塩を形成している酸が弱酸であるようなときには添加することが好ましい。
以下に実施例をもって本願発明を具体的に説明するが、本発明はこれらに限定されるものではなく、またこれらは如何なる意味においても限定的に解釈してはならない。
6,7−ジフルオロ−1,4−ジヒドロ−1−[(1R,2S)−2−フルオロシクロプロピル]−8−メトキシ−4−オキソ−3−キノリンカルボン酸(90g)、ベンジル−(7S)−7−メチル−5−アザスピロ[2.4]ヘプタン−7−アミン二塩酸塩(90g)、トリエチルアミン(39.9ml)および三フッ化ホウ素−テトラヒドロフラン錯体(63.4ml)のアセトニトリル溶液(800ml)を室温にて30分攪拌後、さらに三フッ化ホウ素−テトラヒドロフラン錯体(6.3ml)を加え、そのままの温度にて1時間攪拌した。さらにまた、トリエチルアミン(159.5ml)を加え、室温で16時間攪拌した。溶媒を減圧留去した後、残渣にメタノール(900ml)を加え6時間加熱還流した。室温まで冷却後、5%Pd−C(4.5g)を加え、水素雰囲気下、40℃にて5時間攪拌した後、反応液にトリエチルアミン(90ml)および水(225ml)を加え、40℃にて1時間攪拌した。Pd−Cを濾去後、濾液を減圧濃縮し、得られた残渣へ水(720ml)およびメタノール(180ml)を加え、5N水酸化ナトリウム水溶液にてpH8に調整した。60℃にて40分間攪拌後、5N水酸化ナトリウム水溶液でpH7へ調整し、室温にて1時間攪拌した。得られた結晶を濾取・乾燥し、標題化合物を淡褐色結晶として120.9g(収率91%)得た。
1H−NMR(400MHz,0.1N−NaOD)δppm:0.48−0.56(2H,m),0.66−0.76(2H,m),1.12(3H,s),1.42−1.63(2H,m),3.55(3H,s),3.59−3.72(4H,m),3.98−4.03(1H,m),4.79−5.03(1H,m),7.65(1H,d,J=13.9Hz),8.44(1H,s)
元素分析:Calc.C;55.38%、H;5.93%、N;9.07%
Obsd.C;55.19%、H;5.98%、N;9.19%
6,7−ジフルオロ−1,4−ジヒドロ−1−[(1R,2S)−2−フルオロシクロプロピル]−8−メトキシ−4−オキソ−3−キノリンカルボン酸(3g)、(7S)−7−メチル−5−アザスピロ[2.4]ヘプタン−7−アミン二塩酸塩(3g)、トリエチルアミン(1.34ml)および三フッ化ホウ素−テトラヒドロフラン錯体(2.68g)のアセトニトリル溶液(24ml)を室温にて30分攪拌後、さらに三フッ化ホウ素−テトラヒドロフラン錯体(0.27g)を加え、そのままの温度にて1時間攪拌した。さらにまた、トリエチルアミン(5.37ml)を加え、室温で5時間攪拌した。溶媒を減圧留去した後、残渣にメタノール(30ml)を加え2時間加熱還流し、溶媒を留去した。残渣に90%含水メタノールを加え、5N水酸化ナトリウム水溶液にてpH8に調整した。60℃で40分間攪拌後、5N水酸化ナトリウム水溶液にてpH7へ調整後、5℃で16時間攪拌した.結晶を濾取・乾燥し,標題化合物を4.23g(収率93%)得た。各種スペクトルデータは、実施例1と一致した。
1−シクロプロピル−6,7−ジフルオロ−1,4−ジヒドロ−8−メトキシ−4−オキソ−3−キノリンカルボン酸(3g)、3−メチルアミノピペリジン二塩酸塩(2.1g)、トリエチルアミン(1.43ml)および三フッ化ホウ素−テトラヒドロフラン錯体(2.84g)のアセトニトリル溶液(30ml)を室温で2時間攪拌後、トリエチルアミン(5.71ml)を加え、さらに室温で24時間攪拌した。溶媒を減圧留去後,残渣にメタノール(30ml)を加え6時間加熱還流した。溶媒を減圧留去した後、80%含水メタノール30mlを加え、5N水酸化ナトリウム水溶液でpH8に調整した後、室温にて16時間攪拌した。得られた結晶を濾取して乾燥し、標題化合物を3.98g(収率92%)得た。
1H−NMR(400MHz,DMSO−d6)δppm:0.90−1.31(4H,m),1.31−2.12(4H,m),2.67−3.71(5H,m),3.77(3H,s),3.98−4.09(1H,m),7.85(1H,d,J=11.1Hz),8.78(1H,s)
元素分析:Calc.C;56.69%、H;6.62%、N;9.74%
Obsd.C;56.48%、H;6.63%、N;9.86%
1−シクロプロピル−6,7−ジフルオロ−1,4−ジヒドロ−8−メトキシ−4−オキソ−3−キノリンカルボン酸(3g)、2−メチルピペラジン二塩酸塩(1.93g)、トリエチルアミン(1.43ml)および三フッ化ホウ素−テトラヒドロフラン錯体(2.84g)のアセトニトリル溶液(30ml)を室温にて1時間攪拌後、トリエチルアミン(5.71ml)を加え、さらに室温で24時間攪拌した.溶媒を減圧留去後,残渣にメタノール(30ml)を加え5時間加熱還流した。溶媒を減圧留去した後、80%含水メタノール(30ml)を加え、5N水酸化ナトリウム水溶液でpH7に調整した後、室温にて16時間攪拌した。得られた結晶を濾取・乾燥し、標題化合物を3.55g(収率91%)得た。
1H−NMR(400MHz,CDCl3)δppm:1.02−1.31(7H,m),2.92−3.53(7H,m),3.77(3H,s),3.91−4.11(1H,m),7.85(1H,d,J=12.3Hz),8.79(1H,s)
元素分析:Calc.C;59.37%、H;6.03%、N;10.93%
Obsd.C;59.49%、H;5.77%、N;11.03%
9,10−ジフルオロ−(3S)−メチル−7−オキソ−2,3−ジヒドロ−7H−ピリド[1,2,3−de]−1,4−ベンゾオキサジン−6−カルボン酸(3g)、4−メチルピペラジン二塩酸塩(2.22g)、トリエチルアミン(1.43ml)および三フッ化ホウ素−テトラヒドロフラン錯体(2.84g)のアセトニトリル溶液(30ml)を室温にて30分間攪拌後、トリエチルアミン(5.71ml)を加え、さらに室温で24時間攪拌した。溶媒を減圧留去後,残渣にメタノール(30ml)を加え24時間加熱還流した。溶媒を減圧留去した後、エタノール(15ml)を加え、室温にて16時間攪拌した。得られた結晶を濾取・乾燥し、標題化合物を3.55g(収率92%)得た。
1H−NMR(400MHz,CDCl3)δppm:1.63(3H,d,J=7Hz),2.38(3H,s),2.54−2.60(4H,m),3.40−3.44(4H,m),4.35−4.52(3H,m),7.76(1H,d,J=11.8Hz),8.64(1H,s)
元素分析:Calc.C;59.82%、H;5.58%、N;11.63%
Obsd.C;60.01%、H;5.69%、N;11.53%
7−フルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−8−メトキシ−4−オキソ−1,4−ジヒドロ−3−キノリンカルボン酸(3g)、トリエチルアミン塩酸塩(2.8g)および三フッ化ホウ素−テトラヒドロフラン錯体(2.84g)のアセトニトリル溶液(45ml)を室温にて30分攪拌後、tert−ブチル{1−[(3R)−ピロリジン−3−イル]シクロプロピル}カルバメート・シュウ酸塩(3.54g)およびトリエチルアミン(5.71ml)を加え、そのままの温度にて10時間攪拌した。溶媒を減圧留去後,残渣にメタノール(30ml)を加え12時間加熱還流した。溶媒を減圧留去した後、80%含水メタノール(20ml)を加え、5N水酸化ナトリウム水溶液にてpH7に調整後、60℃にて30分攪拌後、室温にて16時間攪拌した。得られた結晶を濾取・乾燥し、標題化合物を4.79g(収率94%)得た。
1H−NMR(400MHz,CDCl3)δppm:0.68−0.95(4H,m),1.29−1.58(2H,m),1.42(3H,s),1.71−1.91(1H,m),2.03−2.15(1H,m),2.22−2.40(1H,m),3.36−3.71(4H,m),3.52(3H,s),3.79−3.90(1H,m),4.74−5.05(1H,m),4.99(1H,brs),6.94(1H,d,J=9.2Hz),8.06(1H,d,J=9.2Hz),8.65(1H,d,J=3.1Hz),15.18(1H,brs)
元素分析:Calc.C;62.26%、H;6.43%、N;8.38%
Obsd.C;62.14%、H;6.47%、N;8.43%
Claims (3)
- 式(2):
で示される部分構造を意味する。]
で示される化合物に、溶媒中、塩基存在下、式(3):
(a)これらが結合する炭素原子を含んで、3員環から6員環の環状構造を形成してスピロ環構造を形成してもよく、スピロ環は、窒素原子、酸素原子または硫黄原子を環の構成原子として含んでいてもよく、このようにして形成された環には、ハロゲン原子、炭素数1から6のアルキル基またはアミノ基が置換していてもよく、さらにこのアルキル基はハロゲン原子、炭素数1から6のアルキル基、アルコキシ基からなる群から選ばれる基を置換基として有してもよい。あるいは、
(b)二重結合によって結合するエキソメチレン基を形成してもよく、さらにこのエキソメチレン基は、水酸基、アミノ基、ハロゲン原子、炭素数1から6のアルキルチオ基および炭素数1から6のアルコキシ基からなる群の置換基から選ばれる基1または2を有していてもよい。
Wは、−CHR5−、−O−、−NR6−を示し、ここでR5は、水素原子、ハロゲン原子、炭素数1から6のアルキル基、炭素数3から6のシクロアルキル基、炭素数2から6のアルケニル基、炭素数2から6のアルキニル基、または炭素数1から6のアルコキシ基を示すが、このうちシクロアルキル基の場合はアミノ基を置換基として有していてもよく、さらにアルキル基の場合は水酸基、アミノ基、ハロゲン原子、炭素数1から6のアルキルチオ基および炭素数1から6のアルコキシ基からなる群の置換基から選ばれる基1または2以上を置換基として有していてもよく、あるいはこのR5と上記R3またはR4は、これらが結合する炭素原子を含んで炭素数3〜6のシクロアルカンまたは5〜7員の飽和複素環を形成してもよく、このようにして形成されたシクロアルカンまたは飽和複素環は、炭素数1から6のアルキル基もしくはアミノ基を置換基として有していてもよい。
R6は、水素原子、炭素数1から6のアルキル基または炭素数3から6のシクロアルキル基を意味する。Yは、水素原子、飽和異項環上の任意の炭素原子に結合するアミノ基、炭素数1〜6のアルキル、炭素数1〜6のアルキルアミノ基、炭素数3から6のシクロアルキル基、化学的手段により容易にアミノ基もしくは炭素数1〜6のアルキルアミノ基に変換可能な基を示し、nは0〜2を示す。]
で示される化合物の塩、およびトリフルオロホウ素化合物を反応させ、得られるホウ素キレート化合物からホウ素キレートを切断することを特徴とする、式(1):
で示される化合物、その塩、またはそれらの水和物の製造方法。 - トリフルオロホウ素化合物が、トリフルオロホウ素ジエチルエーテル錯体またはトリフルオロホウ素テトラヒドロフラン錯体である請求項1記載の製造方法。
- 反応混合物中にさらに三級アミン塩を存在させるものである請求項1又は2に記載の製造方法。
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JPH05294938A (ja) * | 1991-07-16 | 1993-11-09 | Chugai Pharmaceut Co Ltd | キノロンカルボン酸誘導体の製造方法 |
JPH07309864A (ja) * | 1993-08-27 | 1995-11-28 | Hokuriku Seiyaku Co Ltd | 5−アミノ−8−メチル−7−ピロリジニルキノリン−3−カルボン酸誘導体 |
WO2005047260A1 (en) * | 2003-11-13 | 2005-05-26 | Quimica Sintetica, S.A. | Process for preparing gatifloxacin |
WO2005097752A1 (en) * | 2004-03-31 | 2005-10-20 | Bayer Pharmaceuticals Corporation | Quinolone carboxylic acid derivatives for treatment of hyperproliferative conditions |
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JPH0784423B2 (ja) | 1987-06-18 | 1995-09-13 | 宇部興産株式会社 | 3−アミノ−2−置換ベンゾイルアクリル酸誘導体 |
DE68920773T2 (de) | 1988-05-19 | 1995-05-18 | Chugai Pharmaceutical Co Ltd | Chinoloncarbonsäure-Derivate. |
US5869661A (en) * | 1991-07-16 | 1999-02-09 | Chugai Seiyaku Kabushiki Kaisha | Method of producing a quinolonecarboxylic acid derivative |
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JPH05294938A (ja) * | 1991-07-16 | 1993-11-09 | Chugai Pharmaceut Co Ltd | キノロンカルボン酸誘導体の製造方法 |
JPH07309864A (ja) * | 1993-08-27 | 1995-11-28 | Hokuriku Seiyaku Co Ltd | 5−アミノ−8−メチル−7−ピロリジニルキノリン−3−カルボン酸誘導体 |
WO2005047260A1 (en) * | 2003-11-13 | 2005-05-26 | Quimica Sintetica, S.A. | Process for preparing gatifloxacin |
WO2005097752A1 (en) * | 2004-03-31 | 2005-10-20 | Bayer Pharmaceuticals Corporation | Quinolone carboxylic acid derivatives for treatment of hyperproliferative conditions |
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