KR102213991B1 - 개선된 자보플록사신의 제조방법 - Google Patents
개선된 자보플록사신의 제조방법 Download PDFInfo
- Publication number
- KR102213991B1 KR102213991B1 KR1020140060112A KR20140060112A KR102213991B1 KR 102213991 B1 KR102213991 B1 KR 102213991B1 KR 1020140060112 A KR1020140060112 A KR 1020140060112A KR 20140060112 A KR20140060112 A KR 20140060112A KR 102213991 B1 KR102213991 B1 KR 102213991B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- prepared
- reaction
- carboxylic acid
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
- ZNPOCLHDJCAZAH-UCQKPKSFSA-N zabofloxacin Chemical compound CO\N=C1\CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C2CC2)F)CC11CNC1 ZNPOCLHDJCAZAH-UCQKPKSFSA-N 0.000 title description 8
- 229950005850 zabofloxacin Drugs 0.000 title description 8
- 238000000034 method Methods 0.000 claims abstract description 35
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 132
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 23
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- -1 t-butyloxycarbonyl group Chemical group 0.000 claims description 20
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000002560 nitrile group Chemical group 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 239000008098 formaldehyde solution Substances 0.000 claims description 4
- 238000003328 mesylation reaction Methods 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000001384 succinic acid Substances 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims 4
- 230000000873 masking effect Effects 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- OBWXDHHUYKIHDV-USSIZITKSA-N (2R)-2-aminobutanedioic acid 1-cyclopropyl-6-fluoro-7-[(8Z)-8-methoxyimino-2,6-diazaspiro[3.4]octan-6-yl]-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound OC(=O)[C@H](N)CC(O)=O.CO\N=C1/CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C2CC2)F)CC11CNC1 OBWXDHHUYKIHDV-USSIZITKSA-N 0.000 abstract description 22
- 239000007858 starting material Substances 0.000 abstract description 9
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 7
- 238000006467 substitution reaction Methods 0.000 abstract description 6
- DFJILJPEHFSJGJ-UHFFFAOYSA-N methanesulfonic acid 2,2,2-trifluoro-1-(5-methoxyimino-2,7-diazaspiro[3.4]octan-2-yl)ethanone Chemical compound CS(=O)(=O)O.CON=C1CNCC12CN(C2)C(C(F)(F)F)=O DFJILJPEHFSJGJ-UHFFFAOYSA-N 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 23
- 239000008213 purified water Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000010410 layer Substances 0.000 description 20
- 239000000126 substance Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 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 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- OXNZWNNMJBOZQO-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical group C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 OXNZWNNMJBOZQO-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 5
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- VCRSBTDSKJGCNF-UHFFFAOYSA-N benzyl 3-(aminomethyl)-4-methoxyimino-3-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N1CC(C(C1)=NOC)(COS(=O)(=O)C)CN VCRSBTDSKJGCNF-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- BIAHACZTDYCPDX-UHFFFAOYSA-N 3-cyano-4-oxopyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CC(C#N)C(=O)C1 BIAHACZTDYCPDX-UHFFFAOYSA-N 0.000 description 2
- BSGNTBBTJGSUBP-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CC(C(C1)=NOC)(CO)C#N Chemical compound C(C1=CC=CC=C1)OC(=O)N1CC(C(C1)=NOC)(CO)C#N BSGNTBBTJGSUBP-UHFFFAOYSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 2
- WZOKTHSEPXSIRG-UHFFFAOYSA-N benzyl 8-methoxyimino-2,6-diazaspiro[3.4]octane-6-carboxylate phthalic acid Chemical compound C(C=1C(C(=O)O)=CC=CC1)(=O)O.C(C1=CC=CC=C1)OC(=O)N1CC2(CNC2)C(C1)=NOC WZOKTHSEPXSIRG-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- ZNPOCLHDJCAZAH-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diazaspiro[3.4]octan-6-yl)-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C2CC2)F)CC11CNC1 ZNPOCLHDJCAZAH-UHFFFAOYSA-N 0.000 description 1
- PTKWUEZHMCXDAM-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-7-[5-methoxyimino-2-[(2-methylpropan-2-yl)oxycarbonyl]-2,7-diazaspiro[3.4]octan-7-yl]-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C2CC2)F)CC11CN(C(=O)OC(C)(C)C)C1 PTKWUEZHMCXDAM-UHFFFAOYSA-N 0.000 description 1
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 1
- XOZQJQXLBAMVTH-UHFFFAOYSA-N 3-methoxyiminopyrrolidine-1-carboxylic acid Chemical compound CON=C1CCN(C1)C(=O)O XOZQJQXLBAMVTH-UHFFFAOYSA-N 0.000 description 1
- KBPHGYUXEIDPPV-UHFFFAOYSA-N 4-oxo-1h-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)=CNC2=N1 KBPHGYUXEIDPPV-UHFFFAOYSA-N 0.000 description 1
- UGFUGEXLYCNCIZ-UHFFFAOYSA-N 4-oxo-1h-1,8-naphthyridine-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C(=O)O)=CNC2=N1 UGFUGEXLYCNCIZ-UHFFFAOYSA-N 0.000 description 1
- XTVXJOZWVBIGMY-UHFFFAOYSA-N 8-methoxyimino-2,6-diazaspiro[3.4]octane-6-carboxylic acid Chemical compound CON=C1CN(CC11CNC1)C(=O)O XTVXJOZWVBIGMY-UHFFFAOYSA-N 0.000 description 1
- WNVPDUPCUWNXPA-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CC(C(C1)=NOC)(COS(=O)(=O)C)C#N Chemical compound C(C1=CC=CC=C1)OC(=O)N1CC(C(C1)=NOC)(COS(=O)(=O)C)C#N WNVPDUPCUWNXPA-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 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
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- TUUPQWMVTFXWOW-UHFFFAOYSA-N benzyl 3-cyano-4-oxopyrrolidine-1-carboxylate Chemical compound C1C(C#N)C(=O)CN1C(=O)OCC1=CC=CC=C1 TUUPQWMVTFXWOW-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 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
- 239000000047 product Substances 0.000 description 1
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
본 발명은 자보플록사신 D-아스파르트산염을 제조하기 위하여 사용하는 출발물질인 8-메톡시이미노-2,6-디아자-스피로[3,4]옥탄-2-카르복실산 t-부틸에스테르 숙신산염(TBDCS) 또는 2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥탄-8-온 O-메틸옥심 메탄설폰산염(TDMOS)의 신규한 제조방법을 제공한다.
본 발명에 따른 제조방법은 상기 출발물질을 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 제조할 수 있어, 대량생산에 적합하며, 치환반응시 TBDCS나 TDMOS를 1.0~1.1 당량을 사용하여 획기적으로 생산단가를 절감할 수 방법을 제공하기 때문에 자보플록사신 D-아스파르트산염의 대량생산에 유용하게 이용될 수 있다.
Description
Claims (16)
- 제 5 항에 있어서, 환원반응은 소디움보로하이드라이드와 리튬클로라이드를 사용하여 환원반응시키는 것인 방법.
- 제 1 항에 있어서, 화학식 5 화합물은 화학식 4 화합물을 1.0~1.1 당량 사용하여 상기 제1항에 기재된 화학식 3 화합물과 반응시킴을 특징으로 하는 방법.
- 제 11 항에 있어서, 환원반응은 소디움보로하이드라이드와 리튬클로라이드를 사용하여 환원반응시키는 것인 방법.
- 제 8 항에 있어서, 화학식 7 화합물은 화학식 6 화합물을 1.0~1.1 당량 사용하여 화학식 3 화합물과 반응시켜 제조함을 특징으로 하는 방법.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020140060112A KR102213991B1 (ko) | 2014-05-20 | 2014-05-20 | 개선된 자보플록사신의 제조방법 |
PCT/KR2015/005009 WO2015178663A1 (en) | 2014-05-20 | 2015-05-19 | An improved manufacturing method of zabofloxacin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020140060112A KR102213991B1 (ko) | 2014-05-20 | 2014-05-20 | 개선된 자보플록사신의 제조방법 |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20150133433A KR20150133433A (ko) | 2015-11-30 |
KR102213991B1 true KR102213991B1 (ko) | 2021-02-09 |
Family
ID=54554265
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020140060112A KR102213991B1 (ko) | 2014-05-20 | 2014-05-20 | 개선된 자보플록사신의 제조방법 |
Country Status (2)
Country | Link |
---|---|
KR (1) | KR102213991B1 (ko) |
WO (1) | WO2015178663A1 (ko) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108623608B (zh) * | 2018-08-06 | 2021-03-30 | 北京汇林思生物科技有限公司 | 扎布沙星中间体的制备方法 |
CN113278021B (zh) * | 2021-05-29 | 2022-09-23 | 天津全和诚科技有限责任公司 | 1,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯及其草酸盐的制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4822801A (en) | 1984-07-20 | 1989-04-18 | Warner-Lambert Company | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents |
US5633262A (en) | 1994-06-16 | 1997-05-27 | Lg Chemical Ltd. | Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof |
US6313299B1 (en) | 1997-06-26 | 2001-11-06 | Dong Wha Pharmaceutical Industrial Co., Ltd. | Quinolone carboxylic acid derivatives |
US20100184795A1 (en) | 2007-04-13 | 2010-07-22 | Dong Wha Pharmaceutical Ind. Co. Ltd | Aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, method for preparing the same, and antimicrobial pharmaceutical composition comprising the same |
-
2014
- 2014-05-20 KR KR1020140060112A patent/KR102213991B1/ko active IP Right Grant
-
2015
- 2015-05-19 WO PCT/KR2015/005009 patent/WO2015178663A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4822801A (en) | 1984-07-20 | 1989-04-18 | Warner-Lambert Company | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents |
US5633262A (en) | 1994-06-16 | 1997-05-27 | Lg Chemical Ltd. | Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof |
US6313299B1 (en) | 1997-06-26 | 2001-11-06 | Dong Wha Pharmaceutical Industrial Co., Ltd. | Quinolone carboxylic acid derivatives |
US20100184795A1 (en) | 2007-04-13 | 2010-07-22 | Dong Wha Pharmaceutical Ind. Co. Ltd | Aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, method for preparing the same, and antimicrobial pharmaceutical composition comprising the same |
Also Published As
Publication number | Publication date |
---|---|
WO2015178663A1 (en) | 2015-11-26 |
KR20150133433A (ko) | 2015-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4111431B2 (ja) | キノロン−およびナフチリドン−カルボン酸誘導体類 | |
KR910009330B1 (ko) | 항균작용을 갖는 퀴놀린계 화합물과 그의 제조방법 | |
CS246065B2 (en) | Method of new 7-substituted cyclic aminonaphthyridine-,quinoline-and benzoxazinecarboxylic acids production | |
US10336753B2 (en) | Process for the preparation of apixaban and intermediates thereof | |
CA2105923C (en) | 7-isoindolinyl-quinolone derivatives and 7-isoindolinyl-naphthyridone derivatives | |
US20040242556A1 (en) | Novel crystalline form of cefdinir | |
HUT62288A (en) | Process for producing 7-isoindolinylquinolone and naphthyridone-carboxylic acid derivatives, antibacterial agents and fodder additives comprising such compounds | |
JPH08169876A (ja) | 3−アルキル−3−ピロリジンメタンアミン類 | |
WO2006134491A2 (en) | New crystalline form of moxifloxacin hydrochloride and process for its preparation | |
NO168475B (no) | Fremgangsmaate for fremstilling av kinolin-3-karboksylsyre-forbindelser. | |
KR102213991B1 (ko) | 개선된 자보플록사신의 제조방법 | |
US6313299B1 (en) | Quinolone carboxylic acid derivatives | |
JPH04282384A (ja) | 7−(2,7−ジアザビシクロ〔3.3.0〕オクチル)−3−キノロン及びナフチリドンカルボン酸誘導体 | |
AU697608B2 (en) | Quinolone- and naphthyridonecarboxylic acid derivatives | |
CN102775425A (zh) | 一种头孢卡品二异丙胺盐的一锅煮制备方法 | |
KR100519158B1 (ko) | 퀴놀론 카르복실레이트 유도체의 제조방법 | |
KR100219327B1 (ko) | 퀴놀론 카르복실산 유도체 | |
KR100245982B1 (ko) | 신규한 퀴놀론카르복실산 유도체 | |
CA2679852A1 (en) | Method for producing quinolone carboxylic acid derivative | |
JPH1112278A (ja) | ピリドンカルボン酸誘導体、そのエステルまたはこれらの塩 | |
WO1997031919A1 (fr) | Derives d'acide pyridonecarboxylique et leur intermediaires de synthese | |
RU2641699C2 (ru) | Способ получения (1-циклопропил-6-фтор-1,4-дигидро-8-метокси-7-[(4as,7as)-октагидро-6н-пирроло[3,4-в]пиридин-6-ил]-4-оксо-3-хинолинкарбоновой кислоты | |
JPH0859656A (ja) | キノロン−及びナフチリドンカルボン酸誘導体 | |
JPH0348682A (ja) | ピリドンカルボン酸化合物 | |
KR940002954B1 (ko) | 퀴놀린 카르복실산 유도체와 그 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PA0109 | Patent application |
Patent event code: PA01091R01D Comment text: Patent Application Patent event date: 20140520 |
|
PG1501 | Laying open of application | ||
A201 | Request for examination | ||
PA0201 | Request for examination |
Patent event code: PA02012R01D Patent event date: 20190328 Comment text: Request for Examination of Application Patent event code: PA02011R01I Patent event date: 20140520 Comment text: Patent Application |
|
E902 | Notification of reason for refusal | ||
PE0902 | Notice of grounds for rejection |
Comment text: Notification of reason for refusal Patent event date: 20201026 Patent event code: PE09021S01D |
|
E701 | Decision to grant or registration of patent right | ||
PE0701 | Decision of registration |
Patent event code: PE07011S01D Comment text: Decision to Grant Registration Patent event date: 20210201 |
|
GRNT | Written decision to grant | ||
PR0701 | Registration of establishment |
Comment text: Registration of Establishment Patent event date: 20210203 Patent event code: PR07011E01D |
|
PR1002 | Payment of registration fee |
Payment date: 20210203 End annual number: 3 Start annual number: 1 |
|
PG1601 | Publication of registration | ||
PR1001 | Payment of annual fee |
Payment date: 20231214 Start annual number: 4 End annual number: 4 |
|
PR1001 | Payment of annual fee |
Payment date: 20241127 Start annual number: 5 End annual number: 5 |