KR20010031474A - 7-이소인돌린-퀴놀론 카복실산 유도체 및 그 중간체의제조방법 및 7-이소인돌린-퀴놀론 카복실산 유도체의 염,그 수화물 및 이들을 활성 성분으로 함유하는 조성물 - Google Patents
7-이소인돌린-퀴놀론 카복실산 유도체 및 그 중간체의제조방법 및 7-이소인돌린-퀴놀론 카복실산 유도체의 염,그 수화물 및 이들을 활성 성분으로 함유하는 조성물 Download PDFInfo
- Publication number
- KR20010031474A KR20010031474A KR1020007004509A KR20007004509A KR20010031474A KR 20010031474 A KR20010031474 A KR 20010031474A KR 1020007004509 A KR1020007004509 A KR 1020007004509A KR 20007004509 A KR20007004509 A KR 20007004509A KR 20010031474 A KR20010031474 A KR 20010031474A
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- group
- salt
- compound
- substituted
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 277
- 239000000203 mixture Substances 0.000 title claims abstract description 46
- 239000004480 active ingredient Substances 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 39
- 239000002253 acid Substances 0.000 title claims description 8
- 150000004677 hydrates Chemical class 0.000 title abstract description 8
- 239000000543 intermediate Substances 0.000 title abstract description 8
- 150000007513 acids Chemical class 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 88
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 45
- 125000006239 protecting group Chemical group 0.000 claims abstract description 42
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 41
- 125000005843 halogen group Chemical group 0.000 claims abstract description 34
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims description 226
- -1 halogenated formic acid ester Chemical class 0.000 claims description 185
- 238000006243 chemical reaction Methods 0.000 claims description 121
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 76
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 46
- 229910052763 palladium Inorganic materials 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 229910052751 metal Inorganic materials 0.000 claims description 27
- 239000002184 metal Substances 0.000 claims description 27
- 125000003277 amino group Chemical group 0.000 claims description 24
- 125000002252 acyl group Chemical group 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 150000002940 palladium Chemical class 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 18
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 17
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 claims description 16
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- 150000004682 monohydrates Chemical class 0.000 claims description 12
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- 150000001298 alcohols Chemical class 0.000 claims description 9
- PFCRRGCZGUSSFY-UHFFFAOYSA-N 2,3-dihydro-1h-isoindol-5-ylboronic acid Chemical class OB(O)C1=CC=C2CNCC2=C1 PFCRRGCZGUSSFY-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 238000005885 boration reaction Methods 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000001569 carbon dioxide Substances 0.000 claims description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- GLXLQCKTUSWCDP-UHFFFAOYSA-N 7-bromo-2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=C(Br)C=C2NC(=O)C(C(=O)O)=CC2=C1 GLXLQCKTUSWCDP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000005414 inactive ingredient Substances 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000005658 halogenation reaction Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 150000002905 orthoesters Chemical class 0.000 claims description 3
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims 2
- CEROEJJKQHMTSL-UHFFFAOYSA-N 2,3-dihydro-1h-indol-5-ylboronic acid Chemical class OB(O)C1=CC=C2NCCC2=C1 CEROEJJKQHMTSL-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 241000283690 Bos taurus Species 0.000 claims 1
- 229930194542 Keto Natural products 0.000 claims 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 125000000468 ketone group Chemical group 0.000 claims 1
- 239000004599 antimicrobial Substances 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000002904 solvent Substances 0.000 description 72
- 239000012044 organic layer Substances 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 51
- 239000013078 crystal Substances 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 50
- 238000002360 preparation method Methods 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- 239000002585 base Substances 0.000 description 32
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- NJDRXTDGYFKORP-LLVKDONJSA-N garenoxacin Chemical compound N([C@@H](C1=CC=2)C)CC1=CC=2C(C=1OC(F)F)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 NJDRXTDGYFKORP-LLVKDONJSA-N 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000001816 cooling Methods 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 230000002411 adverse Effects 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000012046 mixed solvent Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 150000001408 amides Chemical class 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 16
- 150000002170 ethers Chemical class 0.000 description 16
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 229940098779 methanesulfonic acid Drugs 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 150000003462 sulfoxides Chemical class 0.000 description 12
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 11
- 150000008282 halocarbons Chemical class 0.000 description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 description 11
- 235000017550 sodium carbonate Nutrition 0.000 description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000012456 homogeneous solution Substances 0.000 description 10
- 150000002825 nitriles Chemical class 0.000 description 10
- 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 10
- 239000002244 precipitate Substances 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 239000008096 xylene Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 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 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 8
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 238000002955 isolation Methods 0.000 description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 8
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 8
- 230000000704 physical effect Effects 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- 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 7
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 7
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 6
- QDTAWQSYHADTLC-UHFFFAOYSA-N 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound C=1C=C2C(C)NCC2=CC=1B1OC(C)(C)C(C)(C)O1 QDTAWQSYHADTLC-UHFFFAOYSA-N 0.000 description 6
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 6
- 230000002140 halogenating effect Effects 0.000 description 6
- 239000011261 inert gas Substances 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 229930040373 Paraformaldehyde Natural products 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 150000001735 carboxylic acids Chemical class 0.000 description 5
- 235000015165 citric acid Nutrition 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- ZVUUANRFLJIZGV-UHFFFAOYSA-N ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxoquinoline-3-carboxylate Chemical compound C12=C(OC(F)F)C(Br)=CC=C2C(=O)C(C(=O)OCC)=CN1C1CC1 ZVUUANRFLJIZGV-UHFFFAOYSA-N 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
- ZLUNJWQJXQFSAM-SECBINFHSA-N n-[(1r)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)N[C@H](C)C1=CC=C(Br)C=C1 ZLUNJWQJXQFSAM-SECBINFHSA-N 0.000 description 5
- 229920002866 paraformaldehyde Polymers 0.000 description 5
- 239000003444 phase transfer catalyst Substances 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- LXFQSRIDYRFTJW-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonic acid Chemical compound CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- 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 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical class C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- IPJALOIDFYMFEI-OAQYLSRUSA-N [(1r)-1-methyl-2-trityl-1,3-dihydroisoindol-5-yl]boronic acid Chemical compound N1([C@@H](C2=CC=C(C=C2C1)B(O)O)C)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 IPJALOIDFYMFEI-OAQYLSRUSA-N 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 150000001342 alkaline earth metals Chemical class 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 description 4
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- WJYHCYBNUJVCEH-UHFFFAOYSA-N cyclohexane;ethoxyethane Chemical compound CCOCC.C1CCCCC1 WJYHCYBNUJVCEH-UHFFFAOYSA-N 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 235000014655 lactic acid Nutrition 0.000 description 4
- 238000006138 lithiation reaction Methods 0.000 description 4
- 159000000003 magnesium salts Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 150000002739 metals Chemical class 0.000 description 4
- 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 4
- 230000003287 optical effect Effects 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 150000003460 sulfonic acids Chemical class 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 4
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 4
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 4
- 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 4
- HUWRJTHKCYGECM-OAQYLSRUSA-N (1r)-5-bromo-1-methyl-2-trityl-1,3-dihydroisoindole Chemical compound N1([C@@H](C2=CC=C(Br)C=C2C1)C)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HUWRJTHKCYGECM-OAQYLSRUSA-N 0.000 description 3
- KWHZYHLFMXRMKD-SECBINFHSA-N 1-[(1r)-5-bromo-1-methyl-1,3-dihydroisoindol-2-yl]-2,2-dimethylpropan-1-one Chemical compound BrC1=CC=C2[C@@H](C)N(C(=O)C(C)(C)C)CC2=C1 KWHZYHLFMXRMKD-SECBINFHSA-N 0.000 description 3
- NJDRXTDGYFKORP-UHFFFAOYSA-N 1-cyclopropyl-8-(difluoromethoxy)-7-(1-methyl-2,3-dihydro-1h-isoindol-2-ium-5-yl)-4-oxoquinoline-3-carboxylate Chemical compound C=1C=C2C(C)NCC2=CC=1C(C=1OC(F)F)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 NJDRXTDGYFKORP-UHFFFAOYSA-N 0.000 description 3
- LWJLLBOVJVEMCG-UHFFFAOYSA-N 1-cyclopropyl-8-methoxy-7-(1-methyl-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C=C3CNC(C)C3=CC=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 LWJLLBOVJVEMCG-UHFFFAOYSA-N 0.000 description 3
- YVJTUBPLRNUTCJ-UHFFFAOYSA-N 1-cyclopropyl-8-methyl-7-(1-methyl-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C=1C=C2C(C)NCC2=CC=1C(C=1C)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 YVJTUBPLRNUTCJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 3
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 3
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- ZDKRMIJRCHPKLW-UHFFFAOYSA-N benzyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=CC=CC=C1 ZDKRMIJRCHPKLW-UHFFFAOYSA-N 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- WZICLKPREVGMFK-UHFFFAOYSA-N ethyl 2,4-dibromo-3-hydroxybenzoate Chemical compound CCOC(=O)C1=CC=C(Br)C(O)=C1Br WZICLKPREVGMFK-UHFFFAOYSA-N 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- OIXMUQLVDNPHNS-UHFFFAOYSA-N methanesulfonic acid;hydrate Chemical compound O.CS(O)(=O)=O OIXMUQLVDNPHNS-UHFFFAOYSA-N 0.000 description 3
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 3
- 229960004919 procaine Drugs 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- KTUCROBKAQWWPX-ZCFIWIBFSA-N (1r)-5-bromo-1-methyl-2,3-dihydro-1h-isoindole Chemical compound BrC1=CC=C2[C@@H](C)NCC2=C1 KTUCROBKAQWWPX-ZCFIWIBFSA-N 0.000 description 2
- TWYJGRVECRRQTM-FYZOBXCZSA-N (1r)-5-bromo-1-methyl-2,3-dihydro-1h-isoindole;hydrochloride Chemical compound Cl.BrC1=CC=C2[C@@H](C)NCC2=C1 TWYJGRVECRRQTM-FYZOBXCZSA-N 0.000 description 2
- JVCAVLWZRHPLJI-RXMQYKEDSA-N (3r)-6-bromo-3-methyl-2,3-dihydroisoindol-1-one Chemical compound BrC1=CC=C2[C@@H](C)NC(=O)C2=C1 JVCAVLWZRHPLJI-RXMQYKEDSA-N 0.000 description 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 2
- HBBKPRZFGXDWHG-SNVBAGLBSA-N 2,2-dimethyl-n-[(1r)-1-phenylethyl]propanamide Chemical compound CC(C)(C)C(=O)N[C@H](C)C1=CC=CC=C1 HBBKPRZFGXDWHG-SNVBAGLBSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- WGLLSSPDPJPLOR-UHFFFAOYSA-N 2,3-dimethylbut-2-ene Chemical group CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 description 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- 229910021536 Zeolite Inorganic materials 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 229940022663 acetate Drugs 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- 229940007550 benzyl acetate Drugs 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 229910010277 boron hydride Inorganic materials 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical group [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 2
- XEEDFGKSFOYCAN-UHFFFAOYSA-N ethyl 2,4-dibromo-3-(difluoromethoxy)benzoate Chemical compound CCOC(=O)C1=CC=C(Br)C(OC(F)F)=C1Br XEEDFGKSFOYCAN-UHFFFAOYSA-N 0.000 description 2
- CNMVLPVSDHLZTF-UHFFFAOYSA-N ethyl 3-[2,4-dibromo-3-(difluoromethoxy)phenyl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(Br)C(OC(F)F)=C1Br CNMVLPVSDHLZTF-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001012 protector Effects 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 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 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 239000010457 zeolite Substances 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- GBVSONMCEKNESD-UHFFFAOYSA-N 1,1'-biphenyl;lithium Chemical compound [Li].C1=CC=CC=C1C1=CC=CC=C1 GBVSONMCEKNESD-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 1
- 125000006033 1,1-dimethyl-2-propenyl group Chemical group 0.000 description 1
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 1
- WUYQAYADHXKJTF-UHFFFAOYSA-N 1,3,2-dioxaborinane Chemical compound B1OCCCO1 WUYQAYADHXKJTF-UHFFFAOYSA-N 0.000 description 1
- NCWDBNBNYVVARF-UHFFFAOYSA-N 1,3,2-dioxaborolane Chemical compound B1OCCO1 NCWDBNBNYVVARF-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- VTESXCPJVXOXLJ-UHFFFAOYSA-N 1,3,6,2-dioxazaborocane Chemical compound B1OCCNCCO1 VTESXCPJVXOXLJ-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- DTYLXDLAOLOTKT-UHFFFAOYSA-N 1,4-dihydroquinoline-3-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)=CNC2=C1 DTYLXDLAOLOTKT-UHFFFAOYSA-N 0.000 description 1
- GYKKCYNVGMAQMO-UHFFFAOYSA-N 1-cyclopropyl-7-(1-methyl-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C=1C=C2C(C)NCC2=CC=1C(C=1)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 GYKKCYNVGMAQMO-UHFFFAOYSA-N 0.000 description 1
- FDWMJYDRNDWGIB-UHFFFAOYSA-N 1-cyclopropyl-7-(2,3-dihydro-1h-isoindol-5-yl)-4-oxo-8-(trifluoromethyl)quinoline-3-carboxylic acid Chemical compound C12=C(C(F)(F)F)C(C=3C=C4CNCC4=CC=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 FDWMJYDRNDWGIB-UHFFFAOYSA-N 0.000 description 1
- KMBHNDQXCHIBAA-UHFFFAOYSA-N 1-cyclopropyl-7-(2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(C=3C=C4CNCC4=CC=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 KMBHNDQXCHIBAA-UHFFFAOYSA-N 0.000 description 1
- GFMRHTLUAIUNSO-UHFFFAOYSA-N 1-cyclopropyl-7-(2,3-dihydro-1h-isoindol-5-yl)-8-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(C=3C=C4CNCC4=CC=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 GFMRHTLUAIUNSO-UHFFFAOYSA-N 0.000 description 1
- IBGWUWYVISOKHY-UHFFFAOYSA-N 1-cyclopropyl-7-(2,3-dihydro-1h-isoindol-5-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C=C3CNCC3=CC=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IBGWUWYVISOKHY-UHFFFAOYSA-N 0.000 description 1
- INAFBRKSIUWFII-UHFFFAOYSA-N 1-cyclopropyl-7-(2,3-dihydro-1h-isoindol-5-yl)-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound CC1=C(C=2C=C3CNCC3=CC=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 INAFBRKSIUWFII-UHFFFAOYSA-N 0.000 description 1
- FBLSLRDHGHOMTF-UHFFFAOYSA-N 1-cyclopropyl-7-(2-methyl-1,3-dihydroisoindol-5-yl)-4-oxo-8-(trifluoromethyl)quinoline-3-carboxylic acid Chemical compound C1=C2CN(C)CC2=CC=C1C(C=1C(F)(F)F)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 FBLSLRDHGHOMTF-UHFFFAOYSA-N 0.000 description 1
- GLZVXKQPBSSPFV-UHFFFAOYSA-N 1-cyclopropyl-7-(2-methyl-1,3-dihydroisoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2CN(C)CC2=CC=C1C(C=1)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 GLZVXKQPBSSPFV-UHFFFAOYSA-N 0.000 description 1
- BUOUDMCIVURDGI-UHFFFAOYSA-N 1-cyclopropyl-7-(4,7-difluoro-2,3-dihydro-1H-isoindol-5-yl)-8-(difluoromethyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1(CC1)N1C=C(C(C2=CC=C(C(=C12)C(F)F)C=1C(=C2CNCC2=C(C1)F)F)=O)C(=O)O BUOUDMCIVURDGI-UHFFFAOYSA-N 0.000 description 1
- HMDAJTUWHRTCBT-UHFFFAOYSA-N 1-cyclopropyl-7-(4,7-difluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(C=3C(=C4CNCC4=C(F)C=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 HMDAJTUWHRTCBT-UHFFFAOYSA-N 0.000 description 1
- VMHGHUZEVLDKDJ-UHFFFAOYSA-N 1-cyclopropyl-7-(4,7-difluoro-2,3-dihydro-1h-isoindol-5-yl)-8-(difluoromethoxy)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(OC(F)F)C(C=3C(=C4CNCC4=C(F)C=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 VMHGHUZEVLDKDJ-UHFFFAOYSA-N 0.000 description 1
- QNSQIOJLKVVILO-UHFFFAOYSA-N 1-cyclopropyl-7-(4,7-difluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C(=C3CNCC3=C(F)C=2)F)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 QNSQIOJLKVVILO-UHFFFAOYSA-N 0.000 description 1
- OSPMYLDZQVGQBG-UHFFFAOYSA-N 1-cyclopropyl-7-(4,7-difluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound CC1=C(C=2C(=C3CNCC3=C(F)C=2)F)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 OSPMYLDZQVGQBG-UHFFFAOYSA-N 0.000 description 1
- ADCMFHSVVJSLTG-UHFFFAOYSA-N 1-cyclopropyl-7-(4-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxo-8-(trifluoromethyl)quinoline-3-carboxylic acid Chemical compound C12=C(C(F)(F)F)C(C=3C(=C4CNCC4=CC=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 ADCMFHSVVJSLTG-UHFFFAOYSA-N 0.000 description 1
- KXERDEDUKPXDDG-UHFFFAOYSA-N 1-cyclopropyl-7-(4-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(C=3C(=C4CNCC4=CC=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 KXERDEDUKPXDDG-UHFFFAOYSA-N 0.000 description 1
- DTPDIPJIXOLSPM-UHFFFAOYSA-N 1-cyclopropyl-7-(4-fluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C(=C3CNCC3=CC=2)F)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 DTPDIPJIXOLSPM-UHFFFAOYSA-N 0.000 description 1
- UDIREVODORZFGM-UHFFFAOYSA-N 1-cyclopropyl-7-(4-fluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound CC1=C(C=2C(=C3CNCC3=CC=2)F)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 UDIREVODORZFGM-UHFFFAOYSA-N 0.000 description 1
- CVNWWRQTRHZTKZ-UHFFFAOYSA-N 1-cyclopropyl-7-(6-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxo-8-(trifluoromethyl)quinoline-3-carboxylic acid Chemical compound C12=C(C(F)(F)F)C(C=3C(=CC=4CNCC=4C=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 CVNWWRQTRHZTKZ-UHFFFAOYSA-N 0.000 description 1
- NTKHJQLUIKUKML-UHFFFAOYSA-N 1-cyclopropyl-7-(6-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(C=3C(=CC=4CNCC=4C=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 NTKHJQLUIKUKML-UHFFFAOYSA-N 0.000 description 1
- BJUXIHXVQWFAHB-UHFFFAOYSA-N 1-cyclopropyl-7-(6-fluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C(=CC=3CNCC=3C=2)F)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 BJUXIHXVQWFAHB-UHFFFAOYSA-N 0.000 description 1
- RRERXURTGRCXDV-UHFFFAOYSA-N 1-cyclopropyl-7-(6-fluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound CC1=C(C=2C(=CC=3CNCC=3C=2)F)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 RRERXURTGRCXDV-UHFFFAOYSA-N 0.000 description 1
- VVCLRRMOJJNUMH-UHFFFAOYSA-N 1-cyclopropyl-7-(7-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxo-8-(trifluoromethyl)quinoline-3-carboxylic acid Chemical compound C12=C(C(F)(F)F)C(C=3C=C(F)C=4CNCC=4C=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 VVCLRRMOJJNUMH-UHFFFAOYSA-N 0.000 description 1
- VHXVMCVMJSKJRE-UHFFFAOYSA-N 1-cyclopropyl-7-(7-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(C=3C=C(F)C=4CNCC=4C=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 VHXVMCVMJSKJRE-UHFFFAOYSA-N 0.000 description 1
- DBKLLRRNCRZSOE-UHFFFAOYSA-N 1-cyclopropyl-7-(7-fluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C=C(F)C=3CNCC=3C=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 DBKLLRRNCRZSOE-UHFFFAOYSA-N 0.000 description 1
- PKJZMQDLXLFPMJ-UHFFFAOYSA-N 1-cyclopropyl-7-(7-fluoro-2,3-dihydro-1h-isoindol-5-yl)-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound CC1=C(C=2C=C(F)C=3CNCC=3C=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 PKJZMQDLXLFPMJ-UHFFFAOYSA-N 0.000 description 1
- RATIWBOHUIFHIJ-UHFFFAOYSA-N 1-cyclopropyl-8-(difluoromethoxy)-7-(2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(OC(F)F)C(C=3C=C4CNCC4=CC=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 RATIWBOHUIFHIJ-UHFFFAOYSA-N 0.000 description 1
- NBPVDGXTPQMTRT-UHFFFAOYSA-N 1-cyclopropyl-8-(difluoromethoxy)-7-(2-methyl-1,3-dihydroisoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2CN(C)CC2=CC=C1C(C=1OC(F)F)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 NBPVDGXTPQMTRT-UHFFFAOYSA-N 0.000 description 1
- UWQYMIKAWZEGPX-UHFFFAOYSA-N 1-cyclopropyl-8-(difluoromethoxy)-7-(4-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(OC(F)F)C(C=3C(=C4CNCC4=CC=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 UWQYMIKAWZEGPX-UHFFFAOYSA-N 0.000 description 1
- TVWCPWGAFDYEHC-UHFFFAOYSA-N 1-cyclopropyl-8-(difluoromethoxy)-7-(6-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(OC(F)F)C(C=3C(=CC=4CNCC=4C=3)F)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 TVWCPWGAFDYEHC-UHFFFAOYSA-N 0.000 description 1
- KOGXAHZNANLRJB-UHFFFAOYSA-N 1-cyclopropyl-8-(difluoromethoxy)-7-(7-fluoro-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(OC(F)F)C(C=3C=C(F)C=4CNCC=4C=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 KOGXAHZNANLRJB-UHFFFAOYSA-N 0.000 description 1
- WSHHAIYKQTYWNU-UHFFFAOYSA-N 1-cyclopropyl-8-methoxy-7-(2-methyl-1,3-dihydroisoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C=C3CN(C)CC3=CC=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 WSHHAIYKQTYWNU-UHFFFAOYSA-N 0.000 description 1
- RHOVYNIDTZYUPB-UHFFFAOYSA-N 1-cyclopropyl-8-methoxy-7-(7-methyl-2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(C=2C=C(C)C=3CNCC=3C=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 RHOVYNIDTZYUPB-UHFFFAOYSA-N 0.000 description 1
- QUMBMVPLUOPMBQ-UHFFFAOYSA-N 1-cyclopropyl-8-methyl-7-(2-methyl-1,3-dihydroisoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2CN(C)CC2=CC=C1C(C=1C)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 QUMBMVPLUOPMBQ-UHFFFAOYSA-N 0.000 description 1
- NJUXYACRTVWQDU-UHFFFAOYSA-N 1-methoxy-7-(1-methyl-2,3-dihydro-1H-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound CON1C=C(C(C2=CC=C(C=C12)C=1C=C2CNC(C2=CC=1)C)=O)C(=O)O NJUXYACRTVWQDU-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- CELLHQBVSVSMOD-UHFFFAOYSA-N 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisoindole Chemical compound C1=C2CN(C)CC2=CC=C1B1OC(C)(C)C(C)(C)O1 CELLHQBVSVSMOD-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- 125000006032 3-methyl-3-butenyl group Chemical group 0.000 description 1
- WLICPIFMVDESHT-UHFFFAOYSA-N 4,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=C(CNC2)C2=C1F WLICPIFMVDESHT-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- NZVJHVOSVGSULX-UHFFFAOYSA-N 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound O1C(C)(C)C(C)(C)OB1C(C=C1Cl)=CC2=C1CNC2 NZVJHVOSVGSULX-UHFFFAOYSA-N 0.000 description 1
- FIATYVAEKXDNJN-UHFFFAOYSA-N 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(CNC2)C2=C1F FIATYVAEKXDNJN-UHFFFAOYSA-N 0.000 description 1
- XWXZKPXACUAAHU-UHFFFAOYSA-N 4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound O1C(C)(C)C(C)(C)OB1C(C=C1F)=CC2=C1CNC2 XWXZKPXACUAAHU-UHFFFAOYSA-N 0.000 description 1
- SESCQXHHDAFNBD-UHFFFAOYSA-N 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound C=1C=2CNCC=2C(C)=CC=1B1OC(C)(C)C(C)(C)O1 SESCQXHHDAFNBD-UHFFFAOYSA-N 0.000 description 1
- PYNZSPXHQFJJOJ-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(CNC2)C2=C1 PYNZSPXHQFJJOJ-UHFFFAOYSA-N 0.000 description 1
- JOOVYNWWHGUGHN-UHFFFAOYSA-N 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1h-isoindole Chemical compound O1C(C)(C)C(C)(C)OB1C(C(=C1)F)=CC2=C1CNC2 JOOVYNWWHGUGHN-UHFFFAOYSA-N 0.000 description 1
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 description 1
- NRIBZVXWHUTWKM-UHFFFAOYSA-N 7-(7-chloro-2,3-dihydro-1h-isoindol-5-yl)-1-cyclopropyl-8-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound CC1=C(C=2C=C(Cl)C=3CNCC=3C=2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 NRIBZVXWHUTWKM-UHFFFAOYSA-N 0.000 description 1
- ADETUNJFZXVQQU-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-7-(2,3-dihydro-1h-isoindol-5-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(Cl)C(C=3C=C4CNCC4=CC=3)=CC=C2C(=O)C(C(=O)O)=CN1C1CC1 ADETUNJFZXVQQU-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- QTZLDNIAPHSZEX-UHFFFAOYSA-N B1OCCOCCO1 Chemical compound B1OCCOCCO1 QTZLDNIAPHSZEX-UHFFFAOYSA-N 0.000 description 1
- KIEGNJYQCARKBO-UHFFFAOYSA-N B1OCOCO1 Chemical compound B1OCOCO1 KIEGNJYQCARKBO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical class FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 1
- SSUFDOMYCBCHML-UHFFFAOYSA-N CCCCC[S](=O)=O Chemical group CCCCC[S](=O)=O SSUFDOMYCBCHML-UHFFFAOYSA-N 0.000 description 1
- ZFAGXQVYYWOLNK-UHFFFAOYSA-N CCO[Mg] Chemical compound CCO[Mg] ZFAGXQVYYWOLNK-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- JAGZUIGGHGTFHO-UHFFFAOYSA-N Ethyl 3-phenylpropanoate Chemical compound CCOC(=O)CCC1=CC=CC=C1 JAGZUIGGHGTFHO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- OUEUIIJTNCEBTO-UHFFFAOYSA-N FCON1C=C(C(C2=CC=C(C=C12)C=1C=C2CNC(C2=CC1)C)=O)C(=O)O Chemical compound FCON1C=C(C(C2=CC=C(C=C12)C=1C=C2CNC(C2=CC1)C)=O)C(=O)O OUEUIIJTNCEBTO-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920003114 HPC-L Polymers 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- RZKYEQDPDZUERB-UHFFFAOYSA-N Pindone Chemical compound C1=CC=C2C(=O)C(C(=O)C(C)(C)C)C(=O)C2=C1 RZKYEQDPDZUERB-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- BQCAANUXMMQVAY-FYZOBXCZSA-N [(1r)-1-(4-bromophenyl)ethyl]azanium;chloride Chemical compound Cl.C[C@@H](N)C1=CC=C(Br)C=C1 BQCAANUXMMQVAY-FYZOBXCZSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000001980 alanyl 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
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-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
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical compound C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- DLUMWCMYRMIKEG-UHFFFAOYSA-N ethyl 3-(cyclopropylamino)-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]prop-2-enoate Chemical compound C=1C=C(Br)C(OC(F)F)=C(Br)C=1C(=O)C(C(=O)OCC)=CNC1CC1 DLUMWCMYRMIKEG-UHFFFAOYSA-N 0.000 description 1
- MWSMNBYIEBRXAL-UHFFFAOYSA-N ethyl 3-hydroxybenzoate Chemical compound CCOC(=O)C1=CC=CC(O)=C1 MWSMNBYIEBRXAL-UHFFFAOYSA-N 0.000 description 1
- YBEOYBKKSWUSBR-UHFFFAOYSA-N ethyl 4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1 YBEOYBKKSWUSBR-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- URYCLRKRSNDVMD-UHFFFAOYSA-N ethyl chlorate Chemical compound CCOCl(=O)=O URYCLRKRSNDVMD-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- PWOYTBYNBYNZCO-UHFFFAOYSA-N ethyl quinoline-2-carboxylate Chemical compound C1=CC=CC2=NC(C(=O)OCC)=CC=C21 PWOYTBYNBYNZCO-UHFFFAOYSA-N 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-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
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000013622 meat product Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- NHNMRJSHULPMIM-UHFFFAOYSA-N methyl chlorate Chemical compound COCl(=O)=O NHNMRJSHULPMIM-UHFFFAOYSA-N 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 125000006126 n-butyl sulfonyl group Chemical group 0.000 description 1
- 125000006124 n-propyl sulfonyl group Chemical group 0.000 description 1
- 125000005185 naphthylcarbonyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002896 organic halogen compounds Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- QJPQVXSHYBGQGM-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 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 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
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- RNMAVYVRUNMYCN-UHFFFAOYSA-N quinoline-3-carboxylic acid hydrate Chemical compound O.N1=CC(=CC2=CC=CC=C12)C(=O)O RNMAVYVRUNMYCN-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical class [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([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
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000006177 thiolation reaction Methods 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
T-3811의 염 | pH | 용해도(㎍/㎖) |
메탄설폰산염 | 3.66 | 16510 |
인산염 | 3.29 | 8520 |
L-락트산염 | 4.40 | 1980 |
나트륨염 | 10.11 | 2340 |
시트르산염 | 3.90 | 420 |
아세트산염 | 4.22 | 6230 |
염산염 | 3.99 | 5450 |
마그네슘 염 | 7.58 | 60 |
황산염 | 3.46 | 1170 |
Claims (21)
- (i) 금속 팔라듐의 존재하에, 하기 화학식 2의 이소인돌린-5-붕소산 유도체 또는 그의 염을 하기 화학식 3의 7-이탈기-치환된-퀴놀론 카복실산 또는 그의 염과 반응시키는 단계, 또는(ii) 금속 팔라듐, 팔라듐 염 및 팔라듐 착체로부터 선택된 팔라듐 촉매의 존재하에, 하기 화학식 4의 5-할로게노이소인돌린 유도체 또는 그의 염을 하기 화학식 5a의 디알콕시보란 또는 하기 화학식 5b의 알콕시디보란과 반응시켜 하기 화학식 2a의 이소인돌린-5-붕소산 유도체 또는 그의 염을 생성한 후, 이들을 단리시켜 하기 화학식 3의 7-이탈기-치환된-퀴놀론 카복실산 또는 그의 염과 반응시키는 단계를 특징으로 하는, 하기 화학식 1의 7-이소인돌린-퀴놀론 카복실산 유도체 또는 그의 염의 제조방법:화학식 1화학식 2화학식 2a화학식 3화학식 4상기 식에서,R1은 수소 원자 또는 카복실 보호기이고;R2는 치환되거나 비치환된 알킬, 알케닐, 사이클로알킬, 아릴 또는 헤테로환 기이고;R3은 수소 원자, 할로겐 원자, 치환되거나 비치환된 알킬, 알케닐, 사이클로알킬, 아릴, 알콕시 또는 알킬티오기, 니트로기, 시아노기, 아실기, 보호되거나 비보호된 하이드록실기 및 보호되거나 비보호되고 치환되거나 비치환된 아미노기에서 선택된 하나 이상의 기이고;R4는 수소 원자, 할로겐 원자, 치환되거나 비치환된 알킬, 알케닐, 사이클로알킬, 아르알킬, 아릴, 알콕시 또는 알킬티오기, 보호되거나 비보호된 하이드록실 또는 이미노기, 보호되거나 비보호되고 치환되거나 비치환된 아미노기, 알킬리덴기, 옥소기 및 R4가 결합하는 탄소 원자와 함께 사이클로알칸환을 형성하는 기에서 선택된 하나 이상의 기이고;R5는 수소 원자, 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;R6은 수소 원자, 할로겐 원자, 치환되거나 비치환된 알킬, 알콕시 또는 알킬티오기, 보호되거나 비보호된 하이드록실 또는 아미노기 또는 니트로기이고;A는 CH 또는 C-R7이고;상기 R7은 할로겐 원자, 치환되거나 비치환된 알킬, 알콕시 또는 알킬티오기 또는 보호되거나 비보호된 하이드록실기이고;R8및 R9는 수소 원자 또는 저급 알킬기이거나, 또는 함께 불소 원자를 함유하는 환을 형성하고;X1는 할로겐 원자이고;X2는 이탈기이고;Z는 알킬렌기이다.
- 제 1 항에 있어서,R5가 수소 원자, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기인 제조방법.
- 금속 팔라듐, 팔라듐 염 및 팔라듐 착체에서 선택된 팔라듐 촉매의 존재하에, 하기 화학식 4의 5-할로게노이소인돌린 유도체 또는 그의 염을 화학식 5a의 디알콕시보란 또는 하기 화학식 5b의 알콕시디보란과 반응시킴을 특징으로 하는, 하기 화학식 2a의 이소인돌린-5-붕소산 유도체 또는 그의 염의 제조방법:화학식 2a화학식 4화학식 5a화학식 5b상기 식에서,R3은 수소 원자, 할로겐 원자, 치환되거나 비치환된 알킬, 알케닐, 사이클로알킬, 아릴, 알콕시 또는 알킬티오기, 니트로기, 시아노기, 아실기, 보호되거나 비보호된 하이드록실기 및 보호되거나 비보호되고 치환되거나 비치환된 아미노기에서 선택된 하나 이상의 기이고;R4는 수소 원자, 할로겐 원자, 치환되거나 비치환된 알킬, 알케닐, 사이클로알킬, 아르알킬, 아릴, 알콕시 또는 알킬티오기, 보호되거나 비보호된 하이드록실 또는 이미노기, 보호되거나 비보호되고 치환되거나 비치환된 아미노기, 알킬리덴기, 옥소기 및 R4가 결합하는 탄소 원자와 함께 사이클로알칸환을 형성하는 기에서 선택된 하나 이상의 기이고;R5는 수소 원자, 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;X1은 할로겐 원자이고;Z는 알킬렌기이다.
- 제 3 항에 있어서,R5가 수소 원자, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기인 제조방법.
- 하기 화학식 10의 페닐알킬아민 유도체 또는 그의 염을 염기의 존재하에 이산화탄소, 할로겐화 포름산 에스테르 또는 탄산 에스테르와 반응시켜 하기 화학식 9의 2-아미노알킬 벤조산 유도체 또는 그의 염을 수득한 후, 할로겐화 반응에 도입하여 하기 화학식 8의 2-아미노알킬-5-할로게노벤조산 유도체 또는 그의 염을 수득한 후, 환원반응에 도입하여 하기 화학식 6의 2-아미노알킬-5-할로게노벤질알콜 유도체 또는 그의 염을 수득한 후, 폐환반응에 도입하여 하기 화학식 4a의 1-알킬-5-할로게노이소인돌린 유도체 또는 그의 염을 수득한 후 요오드 붕산화반응에 도입함을 특징으로 하는, 하기 화학식 2b의 1-알킬이소인돌린-5-붕소산 유도체 또는 그의 염의 제조방법:화학식 2b화학식 4a상기 식에서,R4a는 알킬기이고;R5a는 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;R5는 수소 원자, 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;R10은 수소 원자 또는 카복실 보호기이고;X1은 할로겐 원자이고;R8및 R9는 수소 원자 또는 저급 알킬기이거나, 또는 함께 불소 원자를 함유하는 환을 형성한다.
- 제 5 항에 있어서,R4a가 저급 알킬기이고, R5a가 아미노 보호기이고, R5가 수소 원자 또는 아미노 보호기인 제조방법.
- 하기 화학식 10의 페닐알킬아민 유도체 또는 그의 염을 염기의 존재하에 이산화탄소, 할로겐화 포름산 에스테르 또는 탄산 에스테르와 반응시켜 하기 화학식 9의 2-아미노알킬 벤조산 유도체 또는 그의 염을 수득한 후, 할로겐화 반응에 도입하여 하기 화학식 8의 2-아미노알킬-5-할로게노벤조산 유도체 또는 그의 염을 수득한 후, 폐환반응에 도입하여 하기 화학식 7의 1-알킬-3-옥소-5-할로게노이소인돌린 유도체 또는 그의 염을 수득한 후, 환원반응에 도입하여 하기 화학식 4a의 1-알킬-5-할로게노이소인돌린 유도체 또는 그의 염을 수득한 후, 붕산화반응에 도입함을 특징으로 하는, 하기 화학식 2b의 1-알킬이소인돌린-5-붕소산 유도체 또는 그의 염의 제조방법:화학식 2b화학식 4a화학식 8화학식 9화학식 10상기 식에서,R4a는 알킬기이고;R5a는 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;R5는 수소 원자, 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;R10은 수소 원자 또는 카복실 보호기이고;X1은 할로겐 원자이고;R8및 R9는 수소 원자 또는 저급 알킬기이거나, 또는 함께 불소 원자를 함유하는 환을 형성한다.
- 제 7 항에 있어서,R4a가 저급 알킬기이고, R5a가 아미노 보호기이고, R5가 수소 원자 또는 아미노 보호기인 제조방법.
- 하기 화학식 12의 4-할로게노벤질아민 유도체 또는 그의 염을 아릴리튬의 존재하에, 포름알데히드 또는 그 유도체와 반응시켜 하기 화학식 6의 2-아미노알킬-5-할로게노벤질 알콜 유도체 또는 그의 염을 수득한 후, 이탈기를 도입하여 하기 화학식 11의 2-아미노알킬-5-할로게노벤질 유도체 또는 그의 염을 수득한 후, 염기의 존재하에 폐환반응에 도입함을 특징으로 하는, 하기 화학식 4a의 1-알킬-5-할로게노이소인돌린 유도체 또는 그의 염의 제조방법:화학식 4a화학식 6상기 식에서,R4a는 알킬기이고;R5b, R5c및 R5d는 동일하거나 상이한 알킬기이고;X1은 할로겐 원자이고;R5는 수소 원자, 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;Y는 이탈기이다.
- 제 9 항에 있어서,R5가 수소 원자 또는 아미노 보호기인 제조방법.
- 하기 화학식 13의 2,4-디브로모-3-하이드록시벤조산 에스테르 또는 그의 염을 하기 화학식 14의 화합물과 반응시켜 하기 화학식 15의 3-알콕시-2,4-디브로모벤조산 에스테르 또는 그의 염을 수득한 후, 카복실 보호기의 이탈반응에 도입하여 하기 화학식 16의 3-알콕시-2,4-디브로모벤조산 또는 그의 염을 수득한 후, 케토에스테르화 반응에 도입하여 하기 화학식 17의 3-알콕시-2,4-디브로모벤조일아세트산 에스테르 또는 그의 염을 수득하고 이어서 오르토에스테르류 또는 아세탈과 반응시킨 후, 하기 화학식 18의 화합물 또는 그의 염과 반응시켜 하기 화학식 19의 2-(3-알콕시-2,4-디브로모벤조일)-3-치환된-아미노아크릴산 에스테르 또는 그의 염을 수득한 후, 폐환반응에 도입함을 특징으로 하는, 하기 화학식 3a의 7-브로모퀴놀론 카복실산 유도체 또는 그의 염의 제조방법:화학식 3a
R7a-X R2a-NH2 상기 식에서,R1a는 카복실산 보호기이고;R7a는 치환되거나 비치환된 알킬기이고;X는 할로겐 원자이고;R1b는 카복실산 보호기이고;R2a는 치환되거나 비치환된 알킬, 사이클로알킬, 아릴 또는 헤테로환 기이다. - (R)-1-사이클로프로필-8-디플루오로메톡시-7-(1-메틸-2,3-디하이드로-1H-5-이소인돌릴)-4-옥소-1,4-디하이드로-3-퀴놀린카복실산의 메탄설폰산 염.
- (R)-1-사이클로프로필-8-디플루오로메톡시-7-(1-메틸-2,3-디하이드로-1H-5-이소인돌릴)-4-옥소-1,4-디하이드로-3-퀴놀린카복실산의 메탄설폰산 염·일수화물.
- (R)-1-사이클로프로필-8-디플루오로메톡시-7-(1-메틸-2,3-디하이드로-1H-5-이소인돌릴)-4-옥소-1,4-디하이드로-3-퀴놀린카복실산의 메탄설폰산 염 및 (R)-1-사이클로프로필-8-디플루오로메톡시-7-(1-메틸-2,3-디하이드로-1H-5-이소인돌릴)-4-옥소-1,4-디하이드로-3-퀴놀린카복실산의 메탄설폰산 염·일수화물로 이루어진 군에서 선택된 활성성분, 및 불활성성분을 포함하는 조성물.
- 제 14 항에 있어서,불활성성분이 제제로서 허용되는 담체인 조성물.
- 하기 화학식 2a의 이소인돌린-5-일 붕소산 유도체 또는 그의 염:화학식 2a상기 식에서,R3는 수소 원자, 할로겐 원자, 치환되거나 비치환된 알킬, 알케닐, 사이클로알킬, 아릴, 알콕시 또는 알킬티오기, 니트로기, 시아노기, 아실기, 보호되거나 비보호된 하이드록실기, 보호되거나 비보호되고 치환되거나 비치환된 아미노기에서 선택된 하나 이상의 기이고;R4는 수소 원자, 할로겐 원자, 치환되거나 비치환된 알킬, 알케닐, 사이클로알킬, 아르알킬, 아릴, 알콕시 또는 알킬티오기, 보호되거나 비보호된 하이드록실 또는 이미노기, 보호되거나 비보호되고 치환되거나 비치환된 아미노기, 알킬리덴기, 옥소기 및 R4가 결합하는 탄소 원자와 동시에 사이클로알칸환을 형성하는 기에서 선택된 하나 이상의 기이고;R5는 수소 원자, 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;Z는 알킬렌기이다.
- 하기 화학식 6의 2-아미노알킬-5-할로게노벤질 알콜 유도체 또는 그의 염:화학식 6상기 식에서,R4a는 알킬기이고;R5는 수소 원자, 아미노 보호기, 치환되거나 비치환된 알킬, 사이클로알킬, 알킬설포닐, 아릴설포닐, 아실 또는 아릴기이고;X1은 할로겐 원자이다.
- 제 1 항에 있어서,화학식 2의 화합물 또는 그의 염이 제 5 항에 따르는 방법에 의해서 수득된 화학식 2b의 화합물 또는 그의 염이고, 화학식 3의 화합물 또는 그의 염이 화학식 3b의 화합물 또는 그의 염이고, 화학식 1의 화합물 또는 그의 염이 화학식 1a의 화합물 또는 그의 염인 제조방법.
- 제 1 항에 있어서,화학식 2의 화합물 또는 그의 염이 제 7 항에 따르는 방법에 의해서 수득된 화학식 2b의 화합물 또는 그의 염이고, 화학식 3의 화합물 또는 그의 염이 화학식 3b의 화합물 또는 그의 염이고, 화학식 1의 화합물 또는 그의 염이 화학식 1a의 화합물 또는 그의 염인 제조방법.
- 제 1 항에 있어서,화학식 2의 화합물 또는 그의 염이 제 9 항에 따르는 방법에 의해서 수득된 화학식 4a의 화합물 또는 그의 염을 붕산화반응에 도입함으로써 수득된 화학식 2b의 화합물 또는 그의 염이고, 화학식 1의 화합물 또는 그의 염이 화학식 1a의 화합물 또는 그의 염인 제조방법.
- 제 1 항에 있어서,화학식 3의 화합물 또는 그의 염이 제 11 항에 따르는 방법에 의해서 수득된 화학식 3a의 화합물 또는 그의 염이고, 화학식 1의 화합물 또는 그의 염이 화학식 1b의 의 화합물 또는 그의 염인 제조방법.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020057009280A KR100611869B1 (ko) | 1997-10-27 | 1998-10-27 | 7-이소인돌린-퀴놀론 카복실산 유도체 및 그 중간체의제조방법 및 7-이소인돌린-퀴놀론 카복실산 유도체의 염,그의 수화물 및 이들을 활성성분으로 함유하는 조성물 |
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP31137697 | 1997-10-27 | ||
JP97-311376 | 1997-10-27 | ||
JP98-92807 | 1998-03-20 | ||
JP9280798 | 1998-03-20 | ||
JP98-140586 | 1998-05-07 | ||
JP14058698 | 1998-05-07 | ||
JP24482898 | 1998-08-31 | ||
JP98-244828 | 1998-08-31 | ||
JP98-253656 | 1998-09-08 | ||
JP25365698 | 1998-09-08 | ||
PCT/JP1998/004854 WO1999021849A1 (fr) | 1997-10-27 | 1998-10-27 | Procedes servant a preparer des derives 7-isoindolinequinolonecarboxyliques et leurs intermediaires, sels d'acides 7-isoindolinequinolonecarboxyliques, leurs hydrates, compositions les contenant en tant qu'ingredients actifs |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020057009280A Division KR100611869B1 (ko) | 1997-10-27 | 1998-10-27 | 7-이소인돌린-퀴놀론 카복실산 유도체 및 그 중간체의제조방법 및 7-이소인돌린-퀴놀론 카복실산 유도체의 염,그의 수화물 및 이들을 활성성분으로 함유하는 조성물 |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20010031474A true KR20010031474A (ko) | 2001-04-16 |
KR100565362B1 KR100565362B1 (ko) | 2006-03-30 |
Family
ID=27525611
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020007004509A KR100565362B1 (ko) | 1997-10-27 | 1998-10-27 | 7-이소인돌린-퀴놀론 카복실산 유도체 및 그 중간체의 제조방법 및 7-이소인돌린-퀴놀론 카복실산 유도체의 염, 그의 수화물 및 이들을 활성성분으로 함유하는 조성물 |
KR1020057009280A KR100611869B1 (ko) | 1997-10-27 | 1998-10-27 | 7-이소인돌린-퀴놀론 카복실산 유도체 및 그 중간체의제조방법 및 7-이소인돌린-퀴놀론 카복실산 유도체의 염,그의 수화물 및 이들을 활성성분으로 함유하는 조성물 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020057009280A KR100611869B1 (ko) | 1997-10-27 | 1998-10-27 | 7-이소인돌린-퀴놀론 카복실산 유도체 및 그 중간체의제조방법 및 7-이소인돌린-퀴놀론 카복실산 유도체의 염,그의 수화물 및 이들을 활성성분으로 함유하는 조성물 |
Country Status (19)
Country | Link |
---|---|
US (4) | US6337399B1 (ko) |
EP (1) | EP1031569B1 (ko) |
KR (2) | KR100565362B1 (ko) |
CN (3) | CN1515555A (ko) |
AT (1) | ATE461186T1 (ko) |
AU (1) | AU750760B2 (ko) |
CA (3) | CA2307824C (ko) |
CY (1) | CY1110242T1 (ko) |
DE (1) | DE69841563D1 (ko) |
DK (1) | DK1031569T3 (ko) |
ES (1) | ES2341509T3 (ko) |
HK (1) | HK1030779A1 (ko) |
HU (1) | HU229995B1 (ko) |
IL (2) | IL135406A0 (ko) |
NO (2) | NO318813B1 (ko) |
NZ (1) | NZ504084A (ko) |
PT (1) | PT1031569E (ko) |
TW (2) | TW593308B (ko) |
WO (1) | WO1999021849A1 (ko) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9067887B2 (en) | 2011-08-31 | 2015-06-30 | Otsuka Pharmaceutical Co., Ltd | Quinolone compound |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE364036T1 (de) * | 2000-03-07 | 2007-06-15 | Ranbaxy Lab Ltd | Eintopfsynthese von 3-cyclopropylamino-2- 2,4- dibromo-3-(difluoromethoxy)benzoylö-2-propensäu e alkylester als nützliches zwischenprodukt für antibakterielle quinolon-arzneistoffe |
DE10111262A1 (de) * | 2001-03-09 | 2002-09-12 | Studiengesellschaft Kohle Mbh | Verfahren zur Herstellung von Vinyl- Aryl- und Heteroarylessigsäuren und ihrer Devivate |
US6777420B2 (en) | 2001-06-15 | 2004-08-17 | Microbiotix, Inc. | Heterocyclic antibacterial compounds |
JP2006151808A (ja) * | 2002-12-24 | 2006-06-15 | Dai Ichi Seiyaku Co Ltd | 抗菌性水性製剤 |
US20090156577A1 (en) * | 2004-09-09 | 2009-06-18 | Benjamin Davis | 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones |
CA2629935C (en) * | 2005-11-24 | 2016-01-19 | Dompe S.P.A. | (r)-arylalkylamino derivatives and pharmaceutical compositions containing them |
US7902227B2 (en) * | 2007-07-27 | 2011-03-08 | Janssen Pharmaceutica Nv. | C-7 isoxazolinyl quinolone / naphthyridine derivatives useful as antibacterial agents |
CN101298418B (zh) * | 2008-06-13 | 2010-12-15 | 江苏康鹏农化有限公司 | 3-氧代-3-(2,4-二卤代-3-二氟甲氧基苯基)丙酸乙酯的制备方法 |
JP5921826B2 (ja) * | 2010-06-30 | 2016-05-24 | 富山化学工業株式会社 | 5−ブロモ−2−(1−置換エチル)安息香酸エステルの新規製造法 |
WO2013121439A2 (en) * | 2012-02-15 | 2013-08-22 | Glenmark Generics Limited | Process for garenoxacin mesylate |
CN105837555B (zh) * | 2016-03-31 | 2019-01-25 | 南京华威医药科技集团有限公司 | 加雷沙星及其中间体制备方法 |
CN105801482B (zh) * | 2016-04-18 | 2018-06-22 | 浙江中欣氟材股份有限公司 | 一种1-环丙基-4-氧代-7-溴-8-二氟甲氧基-1,4-二氢喹啉-3-羧酸乙酯的制备方法 |
CN105777631B (zh) * | 2016-04-18 | 2018-06-29 | 浙江中欣氟材股份有限公司 | 一种1-环丙基-4-氧代-7-溴-8-二氟甲氧基-1,4-二氢喹啉-3-羧酸乙酯的合成方法 |
CN106957255B (zh) * | 2017-03-28 | 2018-01-09 | 上海馨远医药科技有限公司 | 一种(R)‑N‑Boc‑5‑溴‑1‑甲基异吲哚啉及其制备方法和应用 |
CN112028816B (zh) * | 2020-09-11 | 2022-10-14 | 江阴迈康升华医药科技有限公司 | 一种取代异吲哚啉的合成方法 |
CN114105790A (zh) * | 2021-12-14 | 2022-03-01 | 无锡捷化医药科技有限公司 | 一种3-氨基-4,5-二溴苯甲酸甲酯的制备方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0775702T3 (da) * | 1994-08-12 | 2003-08-18 | Toyama Chemical Co Ltd | Hidtil ukendte quinolon- eller naphthylidoncarboxylsyrederivater eller salt deraf |
DE4431821A1 (de) * | 1994-09-07 | 1996-03-14 | Bayer Ag | Verfahren zur Herstellung von N-Arylaminoacrylsäurederivaten und die Verwendung so hergestellter N-Arylaminoacrylsäurederivate zur Herstellung von 4-Chinolon-3-carbonsäurederivaten |
CA2242242C (en) * | 1996-02-09 | 2001-08-07 | Toyama Chemical Co., Ltd. | Quinolonecarboxylic acid derivatives or salts thereof |
JP4252282B2 (ja) * | 2001-11-06 | 2009-04-08 | 富山化学工業株式会社 | 2−[(1r)−1−メチル−2−トリチル−2,3−ジヒドロ−1h−5−イソインドリル]−1,3,6,2−ジオキサアザボロカンの非溶媒和物およびその製造法 |
-
1998
- 1998-10-27 CN CNA031603793A patent/CN1515555A/zh active Pending
- 1998-10-27 NZ NZ504084A patent/NZ504084A/xx not_active IP Right Cessation
- 1998-10-27 IL IL13540698A patent/IL135406A0/xx active IP Right Grant
- 1998-10-27 CN CNB2004100797208A patent/CN1296369C/zh not_active Expired - Lifetime
- 1998-10-27 DK DK98950405.5T patent/DK1031569T3/da active
- 1998-10-27 PT PT98950405T patent/PT1031569E/pt unknown
- 1998-10-27 ES ES98950405T patent/ES2341509T3/es not_active Expired - Lifetime
- 1998-10-27 CA CA002307824A patent/CA2307824C/en not_active Expired - Lifetime
- 1998-10-27 CA CA2593381A patent/CA2593381C/en not_active Expired - Lifetime
- 1998-10-27 TW TW087117800A patent/TW593308B/zh not_active IP Right Cessation
- 1998-10-27 US US09/529,407 patent/US6337399B1/en not_active Expired - Lifetime
- 1998-10-27 CN CNB988106272A patent/CN1195752C/zh not_active Expired - Lifetime
- 1998-10-27 WO PCT/JP1998/004854 patent/WO1999021849A1/ja not_active Application Discontinuation
- 1998-10-27 KR KR1020007004509A patent/KR100565362B1/ko not_active IP Right Cessation
- 1998-10-27 TW TW093113303A patent/TWI242012B/zh not_active IP Right Cessation
- 1998-10-27 AU AU96486/98A patent/AU750760B2/en not_active Expired
- 1998-10-27 DE DE69841563T patent/DE69841563D1/de not_active Expired - Lifetime
- 1998-10-27 KR KR1020057009280A patent/KR100611869B1/ko not_active IP Right Cessation
- 1998-10-27 AT AT98950405T patent/ATE461186T1/de active
- 1998-10-27 CA CA002568251A patent/CA2568251A1/en not_active Abandoned
- 1998-10-27 HU HU0101766A patent/HU229995B1/hu unknown
- 1998-10-27 EP EP98950405A patent/EP1031569B1/en not_active Expired - Lifetime
-
2000
- 2000-03-31 IL IL135406A patent/IL135406A/en not_active IP Right Cessation
- 2000-04-26 NO NO20002125A patent/NO318813B1/no not_active IP Right Cessation
-
2001
- 2001-03-12 HK HK01101736A patent/HK1030779A1/xx not_active IP Right Cessation
- 2001-09-25 US US09/961,364 patent/US6482835B2/en not_active Expired - Lifetime
-
2002
- 2002-08-01 US US10/209,078 patent/US20050203301A1/en not_active Abandoned
-
2004
- 2004-05-21 NO NO20042109A patent/NO20042109L/no not_active Application Discontinuation
-
2007
- 2007-03-27 US US11/691,740 patent/US7371868B2/en not_active Expired - Fee Related
-
2010
- 2010-06-11 CY CY20101100540T patent/CY1110242T1/el unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9067887B2 (en) | 2011-08-31 | 2015-06-30 | Otsuka Pharmaceutical Co., Ltd | Quinolone compound |
US9440951B2 (en) | 2011-08-31 | 2016-09-13 | Otsuka Pharmaceutical Co., Ltd | Quinolone compound |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7371868B2 (en) | Processes for producing 7-isoindoline-quinolonecarboxylic acid derivative and its intermediate, as well as salt of 7-isoindoline-quinolonecarboxylic acid derivative, its hydrate and composition comprising the same as active ingredient | |
JP5232233B2 (ja) | 抗癌剤としてのキノリン誘導体を製造および投与する方法 | |
CN111094243A (zh) | 用于治疗与nlrp活性相关的病症的化合物和组合物 | |
HU228979B1 (en) | Pyrrole substituted 2-indolinone protein kinase inhibitors | |
KR100276477B1 (ko) | 퀴놀론카복실산유도체또는그의염 | |
AU2014294866B2 (en) | Novel derivatives of indole and pyrrole, method for the production thereof and pharmaceutical compositions containing same | |
WO2018133826A1 (zh) | 用于抑制蛋白激酶活性的(杂)芳基酰胺类化合物 | |
PT1070713E (pt) | Derivados de ácido quinolonocarboxílico ou seus sais | |
WO2004091605A1 (ja) | アルキルエーテル誘導体またはその塩を含有する網膜神経疾患の予防・治療剤 | |
JPH06508372A (ja) | 抗生物性化合物 | |
JP4370002B2 (ja) | キノロンカルボン酸誘導体またはその塩 | |
JP4061194B2 (ja) | 6−置換アルキルアミノ−3−ピリジルホウ酸誘導体またはその塩およびそれらの製造法 | |
KR20190122764A (ko) | 피라졸로[3,4-d]피리미딘 화합물을 사용한 항종양 효과 증강제 | |
JPH0899957A (ja) | 新規なキノロンまたはナフチリドン化合物もしくはそれらの塩、それらからなる抗ヘルペスウイルス剤 | |
JP3542165B2 (ja) | 新規なキノロンカルボン酸誘導体またはその塩 | |
JP4499846B2 (ja) | 7−イソインドリン−キノロンカルボン酸誘導体の製造法並びにイソインドリン−5−ボロン酸誘導体の製造法 | |
JP2000229946A (ja) | キノロンカルボン酸の製造法およびその中間体 | |
CN101967123B (zh) | 2-环丙基-4-(n-甲基取代苯胺基)喹啉类化合物及其中间体、制备方法和应用 | |
JP3031722B2 (ja) | キノロンカルボン酸誘導体またはその塩 | |
WO2007102368A1 (ja) | 新規3-(1-アミノアルキリデン)フラン-2,4 (3h, 5h)-ジオン誘導体、その製造方法、および、これを有効成分とする医薬組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
AMND | Amendment | ||
E902 | Notification of reason for refusal | ||
A107 | Divisional application of patent | ||
AMND | Amendment | ||
E902 | Notification of reason for refusal | ||
AMND | Amendment | ||
E601 | Decision to refuse application | ||
AMND | Amendment | ||
J201 | Request for trial against refusal decision | ||
B701 | Decision to grant | ||
GRNT | Written decision to grant | ||
A101 | Application to extend term of patent right by permit | ||
FPAY | Annual fee payment |
Payment date: 20130304 Year of fee payment: 8 |
|
FPAY | Annual fee payment |
Payment date: 20140228 Year of fee payment: 9 |
|
FPAY | Annual fee payment |
Payment date: 20150224 Year of fee payment: 10 |
|
FPAY | Annual fee payment |
Payment date: 20160219 Year of fee payment: 11 |
|
FPAY | Annual fee payment |
Payment date: 20170221 Year of fee payment: 12 |
|
FPAY | Annual fee payment |
Payment date: 20180302 Year of fee payment: 13 |
|
FPAY | Annual fee payment |
Payment date: 20190306 Year of fee payment: 14 |
|
EXPY | Expiration of term |