FI113652B - Uusia kinoloni- tai naftyridonikarboksyylihappojohdannaisia tai niiden suola - Google Patents

Info

Publication number

FI113652B

FI113652B FI970578A FI970578A FI113652B FI 113652 B FI113652 B FI 113652B FI 970578 A FI970578 A FI 970578A FI 970578 A FI970578 A FI 970578A FI 113652 B FI113652 B FI 113652B

Authority

FI

Finland

Prior art keywords

carboxylic acid

fluoro

dihydro

salt

isoindolin

Prior art date

1994-08-12

Links

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• Global Dossier
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• 150000003839 salts Chemical class 0.000 title claims abstract description 195
• LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims description 19
• 239000002253 acid Substances 0.000 title description 32
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
• 125000005843 halogen group Chemical group 0.000 claims abstract description 17
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
• 125000003277 amino group Chemical group 0.000 claims abstract description 5
• 239000003242 anti bacterial agent Substances 0.000 claims abstract description 5
• 125000001424 substituent group Chemical group 0.000 claims abstract description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
• -1 naphthyridone carboxylic acid derivative Chemical class 0.000 claims description 140
• ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 claims description 14
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 10
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 10
• 238000002360 preparation method Methods 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
• 239000002671 adjuvant Substances 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims description 2
• 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
• 125000004414 alkyl thio group Chemical group 0.000 abstract 1
• 125000001118 alkylidene group Chemical group 0.000 abstract 1
• 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
• 150000001875 compounds Chemical class 0.000 description 167
• 238000005481 NMR spectroscopy Methods 0.000 description 131
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 86
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 55
• 239000013078 crystal Substances 0.000 description 53
• 239000000203 mixture Substances 0.000 description 52
• 239000011541 reaction mixture Substances 0.000 description 52
• 239000002904 solvent Substances 0.000 description 51
• 230000002829 reductive effect Effects 0.000 description 49
• 238000006243 chemical reaction Methods 0.000 description 45
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 43
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 40
• 238000001914 filtration Methods 0.000 description 38
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
• 239000000243 solution Substances 0.000 description 32
• 238000004821 distillation Methods 0.000 description 29
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
• 239000000725 suspension Substances 0.000 description 28
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
• 239000003480 eluent Substances 0.000 description 21
• 238000000034 method Methods 0.000 description 20
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
• 239000012044 organic layer Substances 0.000 description 19
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
• 238000003756 stirring Methods 0.000 description 17
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 16
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 15
• 238000004440 column chromatography Methods 0.000 description 14
• 238000004519 manufacturing process Methods 0.000 description 14
• 125000006239 protecting group Chemical group 0.000 description 13
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
• 238000001816 cooling Methods 0.000 description 12
• 238000010992 reflux Methods 0.000 description 11
• 239000011877 solvent mixture Substances 0.000 description 11
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 10
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 8
• GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 8
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 7
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
• 230000002411 adverse Effects 0.000 description 7
• 150000001408 amides Chemical class 0.000 description 7
• 238000003818 flash chromatography Methods 0.000 description 7
• 239000005457 ice water Substances 0.000 description 7
• 230000003287 optical effect Effects 0.000 description 7
• 239000012453 solvate Substances 0.000 description 7
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 6
• 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 6
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
• 230000001580 bacterial effect Effects 0.000 description 6
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
• MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 6
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
• 239000000706 filtrate Substances 0.000 description 6
• 229910052763 palladium Inorganic materials 0.000 description 6
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
• 239000002244 precipitate Substances 0.000 description 6
• NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical class C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 5
• BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
• 230000000844 anti-bacterial effect Effects 0.000 description 5
• 239000001569 carbon dioxide Substances 0.000 description 5
• 229910002092 carbon dioxide Inorganic materials 0.000 description 5
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
• 239000003054 catalyst Substances 0.000 description 5
• 239000010410 layer Substances 0.000 description 5
• 150000002905 orthoesters Chemical class 0.000 description 5
• 235000017557 sodium bicarbonate Nutrition 0.000 description 5
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
• 239000007787 solid Substances 0.000 description 5
• UVIKJAKNMDKKFO-JTQLQIEISA-N (2S)-6-(2,3-dihydro-1H-isoindol-5-yl)-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid Chemical compound C1=C2CNCC2=CC(C2=C3OC[C@@H](N4C3=C(C(C(C(O)=O)=C4)=O)C=C2F)C)=C1 UVIKJAKNMDKKFO-JTQLQIEISA-N 0.000 description 4
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
• 241000894006 Bacteria Species 0.000 description 4
• 241000588724 Escherichia coli Species 0.000 description 4
• 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 4
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
• 101150003085 Pdcl gene Proteins 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 4
• 239000002585 base Substances 0.000 description 4
• 239000012267 brine Substances 0.000 description 4
• 230000000694 effects Effects 0.000 description 4
• 150000002170 ethers Chemical class 0.000 description 4
• 150000004673 fluoride salts Chemical class 0.000 description 4
• 239000007789 gas Substances 0.000 description 4
• 239000001257 hydrogen Substances 0.000 description 4
• 229910052739 hydrogen Inorganic materials 0.000 description 4
• 239000002198 insoluble material Substances 0.000 description 4
• 159000000003 magnesium salts Chemical class 0.000 description 4
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
• 239000012299 nitrogen atmosphere Substances 0.000 description 4
• 238000007363 ring formation reaction Methods 0.000 description 4
• 239000011734 sodium Substances 0.000 description 4
• 229910052708 sodium Inorganic materials 0.000 description 4
• 239000007858 starting material Substances 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
• 239000008096 xylene Substances 0.000 description 4
• VAYISIYCRRTUOV-UHFFFAOYSA-N 1-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1=CC=C2N(OC)C=C(C(O)=O)C(=O)C2=C1 VAYISIYCRRTUOV-UHFFFAOYSA-N 0.000 description 3
• WBHKMAPRABNYBR-UHFFFAOYSA-N 1-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound C1=CC=C2N(C)C=C(C(O)=O)C(=O)C2=C1 WBHKMAPRABNYBR-UHFFFAOYSA-N 0.000 description 3
• CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 description 3
• OSTUUSSBUJMYGX-UHFFFAOYSA-N 5-bromo-2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindole Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CC2=CC(Br)=CC=C2C1 OSTUUSSBUJMYGX-UHFFFAOYSA-N 0.000 description 3
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
• 239000007864 aqueous solution Substances 0.000 description 3
• 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
• 230000015572 biosynthetic process Effects 0.000 description 3
• 230000005587 bubbling Effects 0.000 description 3
• 150000007942 carboxylates Chemical class 0.000 description 3
• 238000002512 chemotherapy Methods 0.000 description 3
• 229910052801 chlorine Inorganic materials 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
• 238000005859 coupling reaction Methods 0.000 description 3
• 238000002425 crystallisation Methods 0.000 description 3
• 230000008025 crystallization Effects 0.000 description 3
• 239000003814 drug Substances 0.000 description 3
• NOKSGGAPKDVWKU-UHFFFAOYSA-N ethyl 3-(4-bromo-2,5-difluoro-3-methylphenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(Br)C(C)=C1F NOKSGGAPKDVWKU-UHFFFAOYSA-N 0.000 description 3
• 150000004820 halides Chemical class 0.000 description 3
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 3
• 229910052751 metal Inorganic materials 0.000 description 3
• 239000002184 metal Substances 0.000 description 3
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
• 229910000027 potassium carbonate Inorganic materials 0.000 description 3
• 235000019260 propionic acid Nutrition 0.000 description 3
• 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 3
• 229920006395 saturated elastomer Polymers 0.000 description 3
• 239000012312 sodium hydride Substances 0.000 description 3
• 229910000104 sodium hydride Inorganic materials 0.000 description 3
• 125000003003 spiro group Chemical group 0.000 description 3
• 150000003462 sulfoxides Chemical class 0.000 description 3
• 238000003786 synthesis reaction Methods 0.000 description 3
• 238000012360 testing method Methods 0.000 description 3
• GXTGJNPFAHSYJW-UHFFFAOYSA-N tributyl-[2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]stannane Chemical compound C1C2=CC([Sn](CCCC)(CCCC)CCCC)=CC=C2CN1S(=O)(=O)C1=CC=C(C)C=C1 GXTGJNPFAHSYJW-UHFFFAOYSA-N 0.000 description 3
• WORJEOGGNQDSOE-ASTXPPQBSA-N trichloro(deuterio)methane;trideuterio(deuteriooxy)methane Chemical compound [2H]C(Cl)(Cl)Cl.[2H]OC([2H])([2H])[2H] WORJEOGGNQDSOE-ASTXPPQBSA-N 0.000 description 3
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
• MWFXSHSEROFKDO-UHFFFAOYSA-N 1-cyclopropyl-6,8-difluoro-7-(2-methyl-1,3-dihydroisoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2CN(C)CC2=CC=C1C(C=1F)=C(F)C=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 MWFXSHSEROFKDO-UHFFFAOYSA-N 0.000 description 2
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• MPTRETZZNQDVMV-UHFFFAOYSA-N benzyl 5-tributylstannyl-1,3-dihydroisoindole-2-carboxylate Chemical compound C1C2=CC([Sn](CCCC)(CCCC)CCCC)=CC=C2CN1C(=O)OCC1=CC=CC=C1 MPTRETZZNQDVMV-UHFFFAOYSA-N 0.000 description 1
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
• 229910052794 bromium Inorganic materials 0.000 description 1
• YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• 239000002775 capsule Substances 0.000 description 1
• 150000001735 carboxylic acids Chemical class 0.000 description 1
• 239000003795 chemical substances by application Substances 0.000 description 1
• 239000000460 chlorine Substances 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 235000015165 citric acid Nutrition 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• 238000006114 decarboxylation reaction Methods 0.000 description 1
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
• IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
• 239000003085 diluting agent Substances 0.000 description 1
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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• 239000006185 dispersion Substances 0.000 description 1
• 229940079593 drug Drugs 0.000 description 1
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• HCJNGUXHEMZMCE-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-4-oxo-7-tributylstannyl-1,8-naphthyridine-3-carboxylate Chemical compound C1=C(C(=O)OCC)C(=O)C=2C=C(F)C([Sn](CCCC)(CCCC)CCCC)=NC=2N1C1CC1 HCJNGUXHEMZMCE-UHFFFAOYSA-N 0.000 description 1
• ZRTIFIJEZAKEOS-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-7-[2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(C=3C=C4CN(CC4=CC=3)S(=O)(=O)C=3C=CC(C)=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 ZRTIFIJEZAKEOS-UHFFFAOYSA-N 0.000 description 1
• WFRPIAWXZMJQFF-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-7-[3-methyl-2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(C=3C=C4C(C)N(CC4=CC=3)S(=O)(=O)C=3C=CC(C)=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 WFRPIAWXZMJQFF-UHFFFAOYSA-N 0.000 description 1
• SLMLSJOZQHIKNQ-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-8-(fluoromethoxy)-7-[2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]-4-oxoquinoline-3-carboxylate Chemical compound C12=C(OCF)C(C=3C=C4CN(CC4=CC=3)S(=O)(=O)C=3C=CC(C)=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 SLMLSJOZQHIKNQ-UHFFFAOYSA-N 0.000 description 1
• CKBOTNAPGMBWLF-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-8-(fluoromethyl)-4-oxo-7-(2-phenylmethoxycarbonyl-1,3-dihydroisoindol-5-yl)quinoline-3-carboxylate Chemical compound C12=C(CF)C(C=3C=C4CN(CC4=CC=3)C(=O)OCC=3C=CC=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 CKBOTNAPGMBWLF-UHFFFAOYSA-N 0.000 description 1
• VMEJPECFXVBDRQ-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-8-methoxy-7-[3-methyl-2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]-4-oxoquinoline-3-carboxylate Chemical compound C12=C(OC)C(C=3C=C4C(C)N(CC4=CC=3)S(=O)(=O)C=3C=CC(C)=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 VMEJPECFXVBDRQ-UHFFFAOYSA-N 0.000 description 1
• VXRBGAFSKVCCPM-UHFFFAOYSA-N ethyl 1-cyclopropyl-6-fluoro-8-methyl-4-oxo-7-tributylstannylquinoline-3-carboxylate Chemical compound CC=1C([Sn](CCCC)(CCCC)CCCC)=C(F)C=C(C(C(C(=O)OCC)=C2)=O)C=1N2C1CC1 VXRBGAFSKVCCPM-UHFFFAOYSA-N 0.000 description 1
• ZKVISDWFQBXDBQ-UHFFFAOYSA-N ethyl 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-7-[2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]-4-oxoquinoline-3-carboxylate Chemical compound C12=C(OC(F)F)C(C=3C=C4CN(CC4=CC=3)S(=O)(=O)C=3C=CC(C)=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 ZKVISDWFQBXDBQ-UHFFFAOYSA-N 0.000 description 1
• LEMAOLKAGZTUPM-UHFFFAOYSA-N ethyl 2,4,5-trifluoro-3-(hydroxymethyl)benzoate Chemical compound CCOC(=O)C1=CC(F)=C(F)C(CO)=C1F LEMAOLKAGZTUPM-UHFFFAOYSA-N 0.000 description 1
• CNLWICAPVKYJDJ-UHFFFAOYSA-N ethyl 2,4,5-trifluoro-3-methylbenzoate Chemical compound CCOC(=O)C1=CC(F)=C(F)C(C)=C1F CNLWICAPVKYJDJ-UHFFFAOYSA-N 0.000 description 1
• CEPLJQDPAZORNG-UHFFFAOYSA-N ethyl 3-(difluoromethoxy)-2,4,5-trifluorobenzoate Chemical compound CCOC(=O)C1=CC(F)=C(F)C(OC(F)F)=C1F CEPLJQDPAZORNG-UHFFFAOYSA-N 0.000 description 1
• KGYBWHCJEKZOGW-UHFFFAOYSA-N ethyl 3-ethenyl-2,4,5-trifluorobenzoate Chemical compound CCOC(=O)C1=CC(F)=C(F)C(C=C)=C1F KGYBWHCJEKZOGW-UHFFFAOYSA-N 0.000 description 1
• OFHNDDHZXUJUNT-UHFFFAOYSA-N ethyl 6-fluoro-1-(2-fluoroethyl)-7-[2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]-4-oxoquinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=CN(CCF)C2=CC=1C(C=C1C2)=CC=C1CN2S(=O)(=O)C1=CC=C(C)C=C1 OFHNDDHZXUJUNT-UHFFFAOYSA-N 0.000 description 1
• GJYVCONENKJLIF-UHFFFAOYSA-N ethyl 7-bromo-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(Br)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 GJYVCONENKJLIF-UHFFFAOYSA-N 0.000 description 1
• SRINWXKXKOGNLK-UHFFFAOYSA-N ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-(fluoromethyl)-4-oxoquinoline-3-carboxylate Chemical compound C12=C(CF)C(Br)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 SRINWXKXKOGNLK-UHFFFAOYSA-N 0.000 description 1
• ACQPPJRQHYJLOZ-UHFFFAOYSA-N ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methyl-4-oxoquinoline-3-carboxylate Chemical compound C12=C(C)C(Br)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 ACQPPJRQHYJLOZ-UHFFFAOYSA-N 0.000 description 1
• PKHWSGHCWRUQAY-UHFFFAOYSA-N ethyl 8-(acetyloxymethyl)-7-bromo-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(COC(C)=O)C(Br)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 PKHWSGHCWRUQAY-UHFFFAOYSA-N 0.000 description 1
• NGBNERNKQCSRHM-UHFFFAOYSA-N ethyl 8-chloro-1-cyclopropyl-6-fluoro-7-[2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Cl)C(C=3C=C4CN(CC4=CC=3)S(=O)(=O)C=3C=CC(C)=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 NGBNERNKQCSRHM-UHFFFAOYSA-N 0.000 description 1
• CAJGLPNJTCNSIA-UKILVPOCSA-N ethyl 8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxo-7-(2-phenylmethoxycarbonyl-1,3-dihydroisoindol-5-yl)quinoline-3-carboxylate Chemical compound C12=C(Cl)C(C=3C=C4CN(CC4=CC=3)C(=O)OCC=3C=CC=CC=3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1[C@@H]1C[C@@H]1F CAJGLPNJTCNSIA-UKILVPOCSA-N 0.000 description 1
• 125000004494 ethyl ester group Chemical group 0.000 description 1
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• 238000005755 formation reaction Methods 0.000 description 1
• 238000009472 formulation Methods 0.000 description 1
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• 230000002140 halogenating effect Effects 0.000 description 1
• 150000004678 hydrides Chemical class 0.000 description 1
• 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
• 239000011261 inert gas Substances 0.000 description 1
• 238000001802 infusion Methods 0.000 description 1
• 230000002401 inhibitory effect Effects 0.000 description 1
• 229910052500 inorganic mineral Inorganic materials 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
• 238000002955 isolation Methods 0.000 description 1
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 239000011976 maleic acid Substances 0.000 description 1
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• 239000011707 mineral Substances 0.000 description 1
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• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
• 125000001624 naphthyl group Chemical group 0.000 description 1
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• 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
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• 210000000056 organ Anatomy 0.000 description 1
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• UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 230000036961 partial effect Effects 0.000 description 1
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• 239000011591 potassium Substances 0.000 description 1
• 229910052700 potassium Inorganic materials 0.000 description 1
• 239000011698 potassium fluoride Substances 0.000 description 1
• 235000003270 potassium fluoride Nutrition 0.000 description 1
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
• 230000003389 potentiating effect Effects 0.000 description 1
• 239000000843 powder Substances 0.000 description 1
• MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
• 229960004919 procaine Drugs 0.000 description 1
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• 238000000746 purification Methods 0.000 description 1
• PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 229910001923 silver oxide Inorganic materials 0.000 description 1
• VFWRGKJLLYDFBY-UHFFFAOYSA-N silver;hydrate Chemical compound O.[Ag].[Ag] VFWRGKJLLYDFBY-UHFFFAOYSA-N 0.000 description 1
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• 239000012279 sodium borohydride Substances 0.000 description 1
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• 235000013024 sodium fluoride Nutrition 0.000 description 1
• 235000010288 sodium nitrite Nutrition 0.000 description 1
• KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
• 229910000080 stannane Inorganic materials 0.000 description 1
• 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
• 239000000126 substance Substances 0.000 description 1
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• 239000013589 supplement Substances 0.000 description 1
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• 208000024891 symptom Diseases 0.000 description 1
• 238000010189 synthetic method Methods 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
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• 235000002906 tartaric acid Nutrition 0.000 description 1
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 238000010998 test method Methods 0.000 description 1
• JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
• LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
• QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
• CYCNUTJNTFCXKJ-UHFFFAOYSA-N tributyl-[1-methyl-2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]stannane Chemical compound C1C2=CC([Sn](CCCC)(CCCC)CCCC)=CC=C2C(C)N1S(=O)(=O)C1=CC=C(C)C=C1 CYCNUTJNTFCXKJ-UHFFFAOYSA-N 0.000 description 1
• ZYIICCXNHGLNPV-UHFFFAOYSA-N tributyl-[3-methyl-2-(4-methylphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]stannane Chemical compound CC1C2=CC([Sn](CCCC)(CCCC)CCCC)=CC=C2CN1S(=O)(=O)C1=CC=C(C)C=C1 ZYIICCXNHGLNPV-UHFFFAOYSA-N 0.000 description 1
• IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
• TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
• YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1