CN101619068A - Novel method for preparing marbofloxacin - Google Patents
Novel method for preparing marbofloxacin Download PDFInfo
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- CN101619068A CN101619068A CN200910101707A CN200910101707A CN101619068A CN 101619068 A CN101619068 A CN 101619068A CN 200910101707 A CN200910101707 A CN 200910101707A CN 200910101707 A CN200910101707 A CN 200910101707A CN 101619068 A CN101619068 A CN 101619068A
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- marbofloxacin
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Links
- 238000000034 method Methods 0.000 title claims abstract description 36
- BPFYOAJNDMUVBL-UHFFFAOYSA-N LSM-5799 Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3N(C)COC1=C32 BPFYOAJNDMUVBL-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960002531 marbofloxacin Drugs 0.000 title claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000002253 acid Substances 0.000 claims abstract description 16
- -1 piperazine compound Chemical class 0.000 claims abstract description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 150000002081 enamines Chemical class 0.000 claims abstract description 9
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 7
- 238000005815 base catalysis Methods 0.000 claims abstract description 5
- 239000011230 binding agent Substances 0.000 claims abstract description 5
- 150000007524 organic acids Chemical class 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 150000002500 ions Chemical class 0.000 claims abstract description 4
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 15
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 15
- 238000009835 boiling Methods 0.000 claims description 15
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 13
- 238000010792 warming Methods 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 8
- 230000005494 condensation Effects 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 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 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
- 229910001948 sodium oxide Inorganic materials 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002585 base Substances 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000000413 hydrolysate Substances 0.000 abstract 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 150000002466 imines Chemical class 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- 239000008367 deionised water Substances 0.000 description 24
- 229910021641 deionized water Inorganic materials 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- 238000009413 insulation Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 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 3
- QMEQBOSUJUOXMX-UHFFFAOYSA-N 2h-oxadiazine Chemical group N1OC=CC=N1 QMEQBOSUJUOXMX-UHFFFAOYSA-N 0.000 description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000012209 synthetic fiber Substances 0.000 description 2
- 229920002994 synthetic fiber Polymers 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- YNXURHRFIMQACJ-UHFFFAOYSA-N lithium;methanidylbenzene Chemical compound [Li+].[CH2-]C1=CC=CC=C1 YNXURHRFIMQACJ-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention mainly discloses a novel method for preparing marbofloxacin, which comprises the steps of forming negative ions by 2, 3, 4, 5-tetrafluorobenzoyl alkyl ester and strong base in an inert organic solvent under the protection of inert gas, condensing with imines to obtain N-dimethyl substituted enamine derivatives, and reacting with N-methylhydrazide in organic acid to obtain the N-methyl-N-acyl substituted enamine derivatives. Under the reflux state, the quinoline carboxylic ester is obtained by the base catalysis of the N-methyl-N-acyl substituted enamine derivative. The quinoline carboxylic ester takes water as a solvent, and is catalyzed by alkali at a proper temperature to be neutralized to obtain quinoline carboxylic acid. Quinoline carboxylic acid is condensed with N-methyl piperazine under the action of an acid-binding agent to obtain piperazine condensate. Heating the piperazine compound in an aqueous solution of alkali metal hydroxide to a proper temperature, preserving the temperature, and neutralizing to obtain a hydrolysate. The hydrolysate is reacted with dialkoxy methane or methylene dihalide under the catalysis of catalyst with water as solvent to obtain marbofloxacin. The method has high yield and is beneficial to industrial large-scale production.
Description
Technical field
The invention belongs to chemical field, provided a kind of novel method for preparing marbofloxacin specifically, with 2,3,4,5-tetra fluoro benzene carbamoyl ester is a raw material, obtains target compound through series of chemical.
Background technology
Marbofloxacin (Marbofloxacin is to call Compound I in the following text) is the novel fluoroquinolone antibacterial agent of animal specific.By the development of Luo Shi (Roche) company,, successively go on the market the earliest in English, method in nineteen ninety-five after Ve ' toquinol company further develops.Its structural formula is:
Advantages such as marbofloxacin has has a broad antifungal spectrum, and sterilizing power is strong, absorbs soon, and is widely distributed in the body, easy to use with other antibiotic no cross resistances, and untoward reaction is little.Pharmacokinetic studies shows that marbofloxacin is removed long half time in animal body, and bioavailability is near 100%, does not almost have residually in blood, ight soil and the tissue of animal, is well suited for clinically to antibiotic requirement for animals.
Marbofloxacin is a tricyclic compound, comprises Yi oxadiazine ring.The synthetic method of document mainly contains following several:
One, US4801584 has reported two kinds of synthetic routes (square method one, method two) of marbofloxacin.
Method one
Method one is basic identical with method two; all be with 2; 3-two fluoro-6-nitrophenolss are starting raw material, through reduction, contract and, series of chemical such as cyclization, alkylation, amido protecting obtain target compound, difference only is the order difference protected on the phenolic hydroxyl group.
These two kinds of method routes are longer, wherein need to use the reagent of price costlinesses such as EMME, alkylating reagent, easy contaminate environment, are unfavorable for large-scale industrial production.
Two, ZL94190968.9 has reported three kinds of synthetic routes (square method three, method four, method five) of marbofloxacin
Method three
Wherein R represents the alkyl of 1 to 4 carbon atom, preferable methyl or ethyl; M is the positively charged ion of alkali metal hydroxide.
This method is starting raw material with the tetrafluorobenzoic aid, behind the formation monoesters, obtains target compound through reactions such as etherificate, amination, cyclization, the piperazine that contracts, hydrolysis.This method route is moderate, reacts comparatively simple, and overall yield has 32%, but during the potassium hydroxide hydrolysis because the existence of alkoxyl group is arranged, under the effect of potassium hydroxide, be easy to form the by-product that alkoxyl group replaces.
Method four
Still be starting raw material, obtain target compound through reactions such as amine exchange, cyclization, the piperazines that contracts again with XII with the tetrafluorobenzoic aid.The difficult point of this method is the preparation of compounds X II and the reaction of tetrafluorobenzoic aid and XII condensation, has limited its industrial applications.
Method five
Still be starting raw material with the tetrafluorobenzoic aid, direct and XIII condensation, reaction obtains target compound through the number step again.Though this method route is shorter, the preparation of compounds X III is difficulty more, and the tetrafluorobenzoic aid and the productive rate in one step of XIII condensation be the end more, does not have industrial value substantially.
Three, document (Dax SL; Wei CC, Quinolone antibacterials:Ahydroxymethylation-intra-molecular cychzation route to pyrio[3,2,1-ij]-1,3,4-benzoxadiazines[J] .J Org Chem, 1992,57 (2): 744-766.) provide a kind of synthetic fiber crops to protect the novel method of Sha Xing oxadiazine ring.
This method is closed ring to adopt the catalysis of tetrabutyl fluoride amine, and with the N methyl piperazine condensation, hydrolysis gets target compound more again.But because the tetrabutyl fluoride amine that uses costs an arm and a leg, and reaction needed carries out under the anhydrous condition of strictness, therefore do not have industrial value.
In sum, in the existing marbofloxacin synthetic route, there are various deficiencies, more or the like as severe reaction conditions, chemical reagent costliness, long, the indivedual reactions steps impurity of reaction scheme.In view of the defective that above-mentioned the whole bag of tricks exists, the inventor has done research trial, invents out a kind of new method for preparing marbofloxacin, and this case produces thus.
Summary of the invention
The structural formula of involved compound is as follows in below describing:
Technical characterictic of the present invention is as follows:
1,2,3,4; 5-tetra fluoro benzene formyl radical alkyl ester (formula II) at inert organic solvents, forms negative ion with the highly basic effect in the preferred toluene under protection of inert gas; with inferior amine salt (formula III) condensation, make the enamine derivates (formula IV) that the N-dimethyl replaces again, need not to separate and purify.
Wherein said alkyl R is the alkyl of 1 to 4 carbon atom, preferred ethyl or methyl; Rare gas element can be argon gas or nitrogen, preferred nitrogen; Inert organic solvents can be acetonitrile, oil of mirbane, chlorobenzene, dimethylbenzene, toluene, preferred toluene; Used highly basic comprises alkalimetal hydrides such as sodium hydride, potassium hydride KH; Alkali-metal lower alkyl oxide compounds such as sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert.-butoxide; Organo-metallic such as magnesium methylate, magnesium ethylate magnesium compound; And organo-metallic lithium compounds such as butyllithium, di-isopropyl ammonia lithium, benzyl lithium, preferred sodium hydride or sodium ethylate.
2, formula IV and N-methylhydrazide (formula V), with in the feed liquid of step gained, under organic acid catalysis, reaction makes the enamine derivates (compound VI) of N-methyl-N-acyl substituted.
Wherein said R ' can be formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, ethoxycarbonyl, 2,2,2-trichlorine ethoxycarbonyl, benzene oxygen formyl radical, carbobenzoxy, uncle's fourth oxygen formyl radical etc., preferred formyl radical; Described organic acid is acetate, trifluoroacetic acid, Phenylsulfonic acid, tosic acid etc., preferred acetate.
3, formula VI under the preferred reflux state, at base catalysis ShiShimonoseki ring, makes quinoline carboxylic ester (formula VII) in the feed liquid of last step gained.
Described in alkali be the oxyhydroxide of alkaline-earth metal, the carbonate of alkaline-earth metal, the supercarbonate or the lower trialkyl amine of alkaline-earth metal, as sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, triethylamine etc., preferred yellow soda ash or salt of wormwood.
4, formula VII is solvent with water, at a certain temperature, with an amount of base catalysis, hydrolysis reaction takes place, and with an amount of acid neutralization, filters again, and drying under reduced pressure makes quinoline carboxylic acid (formula VIII).
Wherein said temperature of reaction is 30-100 ℃, preferred 70 ℃; The alkali that is used for catalyzed reaction can be the oxyhydroxide of alkaline-earth metal or the carbonate of alkaline-earth metal, preferred sodium hydroxide; Be used for neutral acid and can be protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetate, Phenylsulfonic acid, tosic acid, preferred hydrochloric acid.
5, formula VIII rises to certain temperature in organic solvent, under the effect of acid binding agent, with the N methyl piperazine condensation, makes the piperazine thing (formula IX) that contracts.
Wherein said organic solvent can be methyl alcohol, ethanol, Virahol, primary isoamyl alcohol, acetonitrile, toluene, DMSO, DMF, pyridine etc., preferred pyridine; Described acid binding agent can be the carbonate of alkaline-earth metal or rudimentary tri-alkoxy amine such as yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, triethylamine etc., preferred triethylamine.The temperature of reaction is 30 ℃ of boiling points to solvent, preferred 60 ℃.
6, formula IX rises to certain temperature in certain density alkali metal hydroxide aqueous solution, is incubated to the regular hour, with the acid neutralization, makes hydrolyzate (formula X) again.
Wherein said alkali metal hydroxide is sodium hydroxide or potassium hydroxide, preferred potassium hydroxide; Concentration is 20-40% (weight concentration), preferred 30%; The temperature of reaction is 50-120 ℃, preferred reflux temperature; Reaction times is 10-60 hour, preferred 20 hours; The consumption of alkali metal hydroxide is more than 10 equivalents.
7, formula X is solvent with water, under the catalysis of acid or alkali, reacts with dialkoxy methane or methylene halide (formula XI), is neutralized to pH value=7.0-8.0 with an amount of alkali or acid again, makes Compound I.
Wherein said R " be the lower alkoxy or the halogen atom of carbonatoms 1 to 4, preferred methoxyl group or bromine atoms; If " be lower alkoxy, described to be used for catalytic acid be acetate, hydrochloric acid, sulfuric acid, Phenylsulfonic acid, tosic acid etc., preferably hydrochloric acid R; If R " be halogen atom, described oxyhydroxide or carbonate or the supercarbonate that catalytic alkali is alkaline-earth metal, the preferred sodium hydroxide of being used for; Comparatively the consumption of Shi Yi catalyzer (comprising bronsted lowry acids and bases bronsted lowry) is the 2.0-3.0 equivalent, preferred 2.5 equivalents.
The invention provides a kind of synthetic route of new preparation marbofloxacin, compare, have following characteristics with existing various synthetic routes:
1, total recovery of the present invention is more than 50%, and simple to operate, side reaction is few, reaction conditions gentleness, suitable industrial scale operation.
2, after the present invention sloughs ester group and amino protecting group again with N methyl piperazine generation condensation reaction; because lone-pair electron delocalized influence on carboxyl ionization and the amino in solvent; increase cloud density on the phenyl ring, strengthened the piperazine reactive activity that contracts, improved yield.
3, the present invention reacts in potassium hydroxide aqueous solution after ester group and amino protecting group are sloughed again, has both increased the activity of 8 fluorine atoms, can effectively avoid the existence of alkoxyl group again and the side reaction that causes, has therefore shortened the reaction times, and has improved yield.
4, the invention provides a kind of method of the husky star oxadiazine ring of synthetic fiber crops guarantor of novelty, is cyclizing agent with dialkoxy methane or methylene halide, reacts under the catalysis of acid or alkali, makes marbofloxacin.
5, except that midbody compound VIII need take out, all the other intermediates all can not take out, and directly carry out the next step, are very beneficial for mass preparation.
Embodiment
With 2,3,4, the 5-tetrafluorobenzoyl ethyl is that starting raw material prepares marbofloxacin, and synthetic route chart is as follows:
In order to set forth conveniently, each step of the present invention is called an embodiment, wherein embodiment 1 is the synthetic of 3-(dimethylamino)-2-(2,3,4,5-tetra fluoro benzene formyl radical) ethyl acetate; Embodiment 2 be 3-(2-formyl radical-2-methyl diazanyl)-2-(2,3,4,5-tetra fluoro benzene formyl radical ethyl propenoate synthetic; Embodiment 3 is 6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester synthetic; Embodiment 4, embodiment 5 and embodiment 6 are 6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic; Embodiment 7, embodiment 8 and embodiment 9 are 6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic; Embodiment 10, embodiment 11 and embodiment 12 are 6-fluoro-8-hydroxyl-1-(methylamino) 7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic; Embodiment 13, embodiment 14 and embodiment 15 are the synthetic of marbofloxacin.
Synthesizing of embodiment 1,3-(dimethylamino)-2-(2,3,4,5-tetra fluoro benzene formyl radical) ethyl acetate
Input 4g sodium hydride in the 500ml four-hole boiling flask that is full of nitrogen (60%, 0.10mol), about 0 ℃, drip 2,3,4, the toluene solution of 5-tetrafluoro ethyl benzoylacetate (26.42g is dissolved in 60ml toluene) with 200ml toluene.Dripped off in about 2-3 hour, and be incubated 8 hours down in 0 ℃.Other gets 39.85g1, and 1-dimethyl-2-methoxyl group imines mesylate (0.20mol) is added dropwise under 0 ℃ in the above-mentioned solution, drip to finish 0-5 ℃ of following insulation reaction 15 hours.Reaction is finished, decompress filter, and filter cake is bleached with an amount of toluene.Merging filtrate, with deionized water wash twice, each deionized water 40ml uses anhydrous sodium sulfate drying again; the filtering siccative promptly gets 3-(dimethylamino)-2-(2,3; 4,5-tetra fluoro benzene formyl radical) the toluene feed liquid of ethyl acetate need not purifying and is directly used in the next step.
Embodiment 2,3-(2-formyl radical-2-methyl diazanyl)-2-(2,3,4,5-tetra fluoro benzene formyl radical ethyl propenoate synthetic
Upwards go on foot adding 8.6ml glacial acetic acid (0.15mol) in the gained feed liquid, stirred 10 minutes, drip 8.81gN-amino-N-methylformamide (0.10mol) down in 5 ℃.Drip and finish, 5-10 ℃ was reacted 6 hours down.Reaction is finished, and regulates pH value to 6 with an amount of sodium hydroxide solution.Again with frozen water washing three times, 40ml frozen water at every turn.The organic layer anhydrous sodium sulfate drying, the filtering siccative, (2,3,4, the toluene feed liquid of 5-tetra fluoro benzene formyl radical ethyl propenoate need not purifying and is directly used in the next step to get 3-(2-formyl radical-2-methyl diazanyl)-2-.
Embodiment 3,6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester synthetic
Upwards go on foot adding 6.36g yellow soda ash (0.06mol) in the gained feed liquid, be warming up to backflow, reaction is 4 hours under reflux state.There is product to separate out in the reaction process gradually.Reaction is finished, suction filtration.To neutral, 60 ℃ of following vacuum-dryings again get faint yellow to yellow powder 29.54g (yield 90.0%), fusing point 188-191 ℃ filter cake with rinsed with deionized water.
Embodiment 4,6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 32.82g6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester (0.10mol) and 100ml2N sodium hydroxide solution (0.2mol) are warming up to 70 ℃, react 4 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7 with the 2N hydrochloric acid soln.Transfer and finish, stirred 30 minutes.Decompress filter, filter cake 100ml deionized water rinsing at twice, 60 ℃ of following vacuum-dryings get pale yellow powder 26.10g (yield 95.9%), fusing point 236-239 ℃.
Embodiment 5,6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 32.82g6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester (0.10mol) and 10.60g yellow soda ash (0.10mol) are warming up to 100 ℃, react 4 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7 with the 2N hydrochloric acid soln.Transfer and finish, stirred 30 minutes.Decompress filter, filter cake 100ml deionized water rinsing at twice, 60 ℃ of following vacuum-dryings get pale yellow powder 24.50g (yield 90.0%), fusing point 236-239 ℃.
Embodiment 6,6,7,8-three fluoro-1-(methylamino) 4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 31.42g6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylate methyl ester (0.10mol) and 8g sodium hydroxide (0.20mol) are warming up to 30 ℃, react 8 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7 with the 2N hydrochloric acid soln.Transfer and finish, stirred 30 minutes.Decompress filter, filter cake 100ml deionized water rinsing at twice, 60 ℃ of following vacuum-dryings get pale yellow powder 25.04g (yield 92.0%), fusing point 236-239 ℃.
Embodiment 7,6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 27.22g6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol), 10.12g triethylamine (0.10mol), 11.01g N methyl piperazine (0.11mol) and 150ml pyridine, be warming up to 60 ℃, insulation reaction 4 hours.Reaction is finished, and the evaporated under reduced pressure solvent adds 150ml methylene dichloride and 100ml deionized water, stirs standing demix 30 minutes.Water layer dichloromethane extraction three times, each 40ml.Merge organic layer, deionized water wash twice, each 40ml.Organic layer is used anhydrous sodium sulfate drying again, the filtering siccative, and the filtrate decompression evaporate to dryness gets faint yellow to yellow solid 32.82g (yield 93.1%), fusing point 225-228 ℃.
Embodiment 8,6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 27.22g6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol), 5.3g yellow soda ash (0.05mol), 11.01g N methyl piperazine (0.11mol) and 150ml Virahol, be warming up to backflow, insulation reaction 6 hours.Reaction is finished, and the evaporated under reduced pressure solvent adds 150ml methylene dichloride and 100ml deionized water, stirs standing demix 30 minutes.Water layer dichloromethane extraction three times, each 40ml.Merge organic layer, deionized water wash twice, each 40ml.Organic layer is used anhydrous sodium sulfate drying again, the filtering siccative, and the filtrate decompression evaporate to dryness gets faint yellow to yellow solid 31.82g (yield 90.3%), fusing point 225-228 ℃.
Embodiment 9,6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 27.22g6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol), 10.12g triethylamine (0.10mol), 15.02g N methyl piperazine (0.15mol) and 150mlDMF, 30 ℃ of following insulation reaction 6 hours.Reaction is finished, and the evaporated under reduced pressure solvent adds 150ml methylene dichloride and 100ml deionized water, stirs standing demix 30 minutes.Water layer dichloromethane extraction three times, each 40ml.Merge organic layer, deionized water wash twice, each 40ml.Organic layer is used anhydrous sodium sulfate drying again, the filtering siccative, and the filtrate decompression evaporate to dryness gets faint yellow to yellow solid 31.50g (yield 89.4%), fusing point 225-228 ℃.
Embodiment 10,6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 56.11g potassium hydroxide (1.0mol), add the 130.9ml deionized water, after stirring makes dissolving, be chilled to room temperature.Again to wherein adding 35.23g 6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol) is warming up to backflow, and reaction is 20 hours under reflux state.Reaction is finished, and is chilled to room temperature, and Dropwise 5 N hydrochloric acid soln is regulated pH value=7-7.5.Transfer and finish, stirred 30 minutes, decompress filter, filter cake 100ml rinsed with deionized water rinsing at twice, 60 ℃ of following vacuum-dryings again get pale powder 29.32g (yield 83.7%).
Embodiment 11,6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 60.00g sodium hydroxide (1.5mol), add the 240ml deionized water, after stirring makes dissolving, be chilled to room temperature.Again to wherein adding 35.23g 6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol) is warming up to 120 ℃, insulation reaction 60 hours.Reaction is finished, and is chilled to room temperature, and Dropwise 5 N hydrochloric acid soln is regulated pH value=7-7.5.Transfer and finish, stirred 30 minutes, decompress filter, filter cake 100ml rinsed with deionized water rinsing at twice, 60 ℃ of following vacuum-dryings again get pale powder 29.88g (yield 85.3%).
Embodiment 12,6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 112.22g potassium hydroxide (2.0mol), add the 168.33ml deionized water, after stirring makes dissolving, be chilled to room temperature.Again to wherein adding 35.23g6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol) is warming up to 50 ℃, insulation reaction 10 hours.Reaction is finished, and is chilled to room temperature, and Dropwise 5 N hydrochloric acid soln is regulated pH value=7-7.5.Transfer and finish, stirred 30 minutes, decompress filter, filter cake 100ml rinsed with deionized water rinsing at twice, 60 ℃ of following vacuum-dryings again get pale powder 23.56g (yield 67.25%).
Synthesizing of embodiment 13, marbofloxacin
In the 500ml four-hole boiling flask, successively drop into 35.03g6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1, the 5N hydrochloric acid soln (0.20mol) of 4-dihydroquinoline-3 carboxylic acid (0.10mol), 240ml deionized water and 40ml, restir add 7.60g formaldehyde dimethyl acetal (0.10mol) down.Be warming up to 50 ℃, reacted 6 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7.0-8.0 with the 3N sodium hydroxide solution, and ice-water bath is chilled to 0-5 ℃, close stirring, left standstill crystallization 12 hours, suction filtration, the 100ml rinsed with deionized water rinsing at twice of gained filter cake filter cake, 60 ℃ of following drying under reduced pressure get marbofloxacin 33.60g.Yield 92.7%, fusing point 265-268 ℃.
Synthesizing of embodiment 14, marbofloxacin
In the 500ml four-hole boiling flask, successively drop into 35.03g6-fluoro-8-hydroxyl-1-(methylamino base)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1, the 5N hydrochloric acid soln (0.30mol) of 4-dihydroquinoline-3 carboxylic acid (0.10mol), 240ml deionized water and 60ml, restir add 10.42g ethylal (0.10mol) down.Be warming up to 90 ℃, reacted 2 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7.0-8.0 with the 3N sodium hydroxide solution, and ice-water bath is chilled to 0-5 ℃, close stirring, left standstill crystallization 12 hours, suction filtration, the 100ml rinsed with deionized water rinsing at twice of gained filter cake, 60 ℃ of following drying under reduced pressure get marbofloxacin 32.55g.Yield 89.8%, fusing point 265-268 ℃.
Synthesizing of embodiment 15, marbofloxacin
In the 500ml four-hole boiling flask, successively drop into 35.03g6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1, the 5N sodium hydroxide solution (0.25mol) of 4-dihydroquinoline-3 carboxylic acid (0.10mol), 240ml deionized water and 50ml, restir add 17.38g methylene bromide (0.10mol) down.Be warming up to 100 ℃, reacted 4 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7.0-8.0 with the 3N hydrochloric acid soln, and ice-water bath is chilled to 0-5 ℃, close stirring, left standstill crystallization 12 hours, suction filtration, the 100ml rinsed with deionized water rinsing at twice of gained filter cake, 60 ℃ of following drying under reduced pressure get marbofloxacin 33.10g.Yield 91.3%, fusing point 265-268 ℃.
Claims (10)
1, a kind of new method for preparing marbofloxacin is characterized in that:
Step 1,2,3,4,5-tetra fluoro benzene formyl radical alkyl ester (formula II) forms negative ion with the highly basic effect in inert organic solvents under protection of inert gas, with inferior amine salt (formula III) condensation, make the enamine derivates (formula IV) that the N-dimethyl replaces again, need not to separate and purify;
(R is the alkyl of 1 to 4 carbon atom)
Step 2, in the feed liquid of last step gained, the enamine derivates (formula IV) that the N-dimethyl replaces is (formula V) with the N-methylhydrazide, under organic acid catalysis, reaction makes the enamine derivates (formula VI) of N-methyl-N-acyl substituted;
(R ' be formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, ethoxycarbonyl, 2,2, any one in 2-trichlorine ethoxycarbonyl, benzene oxygen formyl radical, carbobenzoxy, the uncle's fourth oxygen formyl radical)
Step 3, in the feed liquid of last step gained, the enamine derivates (formula VI) of N-methyl-N-acyl substituted at base catalysis ShiShimonoseki ring, makes quinoline carboxylic ester (formula VII) under reflux state;
Step 4, the quinoline carboxylic ester (formula VII) that step 3 is made is solvent with water, under 30 ℃ of-100 ℃ of temperature, uses base catalysis, and hydrolysis reaction takes place, and with the acid neutralization, filters again, drying under reduced pressure makes quinoline carboxylic acid (formula VIII);
Step 5 makes quinoline carboxylic acid (formula VIII) in organic solvent with step 4, heat up, 30 ℃ to the temperature range of organic solvent boiling point, under the effect of acid binding agent,, make the piperazine thing (formula IX) that contracts with the N methyl piperazine condensation;
Step 6 contracts piperazine thing (formula IX) to what step 5 made in the alkali metal hydroxide aqueous solution of 20%-40% weight concentration, is warming up to 50 ℃-120 ℃, is incubated 10 hours-60 hours, with the acid neutralization, makes hydrolyzate (formula X) again;
Step 7 is solvent with water with the hydrolyzate of step 6 gained, and under the catalysis of catalyzer, XI reacts with formula, is neutralized to pH value=7.0-8.0 again, makes marbofloxacin.
R″(CH)
2R″
XI (R " be the lower alkoxy or the halogen atom of carbonatoms 1 to 4)
2, a kind of new method for preparing marbofloxacin as claimed in claim 1, it is characterized in that: the inert organic solvents described in the step 1 is a toluene; Rare gas element is a nitrogen; The alkyl R of formula II is ethyl or methyl; Used highly basic is alkalimetal hydride, preferred sodium hydride, or be alkali-metal lower alkyl oxide compound, preferred alcohol sodium, or be the organo-metallic magnesium compound, or be the organo-metallic lithium compound.
3, a kind of new method for preparing marbofloxacin as claimed in claim 1 is characterized in that: organic acid is the wherein a kind of of acetate, trifluoroacetic acid, Phenylsulfonic acid, tosic acid in the described step 2.
4, a kind of new method for preparing marbofloxacin as claimed in claim 1, it is characterized in that: the alkali described in the step 3 is the oxyhydroxide of alkaline-earth metal, or is the carbonate of alkaline-earth metal, preferred yellow soda ash or salt of wormwood, or be the supercarbonate of alkaline-earth metal, or be lower trialkyl amine.
5, a kind of new method for preparing marbofloxacin as claimed in claim 1 is characterized in that: preferred 70 ℃ of the temperature of reaction described in the step 4; The alkali that is used for catalyzed reaction is the oxyhydroxide of alkaline-earth metal, preferred sodium hydroxide, or be the carbonate of alkaline-earth metal, and it is wherein a kind of to be used for neutral acid and to be hydrochloric acid, sulfuric acid, phosphoric acid, acetate, Phenylsulfonic acid, tosic acid.
6, a kind of new method for preparing marbofloxacin as claimed in claim 1, it is characterized in that: the organic solvent described in the step 5 is that methyl alcohol, ethanol, Virahol, primary isoamyl alcohol, acetonitrile, toluene, DMSO, DMF, pyridine are wherein a kind of; Described acid binding agent is the carbonate of alkaline-earth metal, or rudimentary tri-alkoxy amine, preferred triethylamine, and the temperature of reaction is 60 ℃.
7, a kind of new method for preparing marbofloxacin as claimed in claim 6 is characterized in that: the carbonate of described alkaline-earth metal is the wherein a kind of of yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus.
8, a kind of new method for preparing marbofloxacin as claimed in claim 1, it is characterized in that: the alkali metal hydroxide described in the step 6 is sodium hydroxide or potassium hydroxide, preferred potassium hydroxide; Weight concentration is 30%; Temperature of reaction is a reflux temperature; Reaction times is 20 hours; The consumption of alkali metal hydroxide is more than 10 equivalents.
9, a kind of new method for preparing marbofloxacin as claimed in claim 1 is characterized in that: R in the step 7 " is lower alkoxy, preferred methoxyl group; The described catalyzer that is used for is that acetate, hydrochloric acid, sulfuric acid, Phenylsulfonic acid, tosic acid are wherein a kind of.
10, a kind of new method for preparing marbofloxacin as claimed in claim 1 is characterized in that: R in the step 7 " is halogen atom, preferred bromine atoms; Describedly be used for oxyhydroxide or carbonate or the supercarbonate that catalyzer is an alkaline-earth metal, consumption is the 2.0-3.0 equivalent, preferred sodium oxide, and consumption is 2.5 equivalents.
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