CN1043712A - The preparation method of quinoline carboxylic acid derivative - Google Patents
The preparation method of quinoline carboxylic acid derivative Download PDFInfo
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- CN1043712A CN1043712A CN89109448A CN89109448A CN1043712A CN 1043712 A CN1043712 A CN 1043712A CN 89109448 A CN89109448 A CN 89109448A CN 89109448 A CN89109448 A CN 89109448A CN 1043712 A CN1043712 A CN 1043712A
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- Prior art keywords
- logical formula
- compound
- described method
- hydrolyzed
- acid
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 150000004885 piperazines Chemical class 0.000 claims 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims 1
- 230000035484 reaction time Effects 0.000 abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 150000001638 boron Chemical class 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical class C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BVBRZOLXXOIMQG-UHFFFAOYSA-N fluoroborane Chemical compound FB BVBRZOLXXOIMQG-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- DTYLXDLAOLOTKT-UHFFFAOYSA-N 1,4-dihydroquinoline-3-carboxylic acid Chemical class C1=CC=C2CC(C(=O)O)=CNC2=C1 DTYLXDLAOLOTKT-UHFFFAOYSA-N 0.000 description 1
- 239000005968 1-Decanol Substances 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- -1 cyclic amine Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000012971 dimethylpiperazine Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000005451 methyl sulfates Chemical class 0.000 description 1
- 229950000081 metilsulfate Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 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
-
- 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
-
- 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
- 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
- C07F5/022—Boron compounds without C-boron linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a kind of new preparation general formula (I) compound (R
1And R
2Represent hydrogen or C
1-4Alkyl, R
2Represent C
1-4Alkyl, R
4, R
5And R
6Represent hydrogen or halogen) and the method for pharmaceutical salts.General formula (I) compound is known antiseptic-germicide.The advantage of this method is that preparation process is simple, the productive rate height, and the reaction times is short.
Description
But the present invention relates to the 1-(halo that a kind of new preparation has logical formula I)-ethyl-7-(3,4, the piperazine that 5-replaces)-6,8-two fluoro-4-oxygen-1, the method for 4-dihydro-quinoline-3-carboxylic acid derivative and pharmaceutical salts thereof.
In logical formula I, R
1And R
3Represent hydrogen or C1-4 alkyl, R
2Represent the C1-4 alkyl, R
4, R
5And R
6Represent hydrogen or halogen.
A known class has the 7-(3 of logical formula I, 4, the piperazine that 5-replaces)-quinoline-3-carboxylic acid derivative has high anti-microbial activity and (sees Antimicrob.Agents Chemother 1987,31,854; Drugs of Fut.1986,11,578 26th Interscci.Conf.Antimicrob.Agents Chemother.1986, Abst.430-431; 25th Intersci.Conf.Antimicrob.Agents Chemother.1985,567).Can be by making 6,7,8-three fluoro-4-oxygen-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amine reaction prepare these compounds (seeing German patent specification 3 433 924, Japanese patent specification 60 142 980,61 85 381 and 61 65 882).
The invention provides a kind of new preparation and have logical formula I (R wherein
1And R
3Represent hydrogen or C1-4 alkyl, R
2Represent the C1-4 alkyl, R
4, R
5And R
6Represent hydrogen or halogen) the quinoline-3-carboxylic acid derivative and the method for pharmaceutical salts, this method comprises makes the compound with logical formula II:
(wherein R represents halogen, contains the aliphatic acyloxy of 2-6 carbon atom or contains the aromatics acyloxy of 7-11 carbon atom, R
4, R
5And R
6Definition same as described above) with have the amine of logical formula III:
(R wherein
1, R
2And R
3Definition same as described above) or its reactant salt, and at after separating (or not separating), the logical formula IV compound that reaction is obtained:
(wherein R, R
1, R
2, R
3, R
4, R
5And R
6Definition same as described above) hydrolysis, if desired, the logical formula I compound that obtains thus is converted into its salt, perhaps be not converted into salt.
The advantage of the inventive method is to make the preparation of logical formula I compound to simplify, and productive rate height and reaction times are short.
Boron derivative with logical formula IV is new compound.
According to the embodiment of preferred the inventive method, directly will lead to the formula IV boron derivative and be converted into required logical formula I quinoline-3-carboxylic acid and need not separation.
If desired, can in the presence of inert organic solvents and acid binding agent, make the reaction of logical formula II boron derivative and logical formula III amine.
Inert organic solvents preferred amide (for example dimethyl formamide, N,N-DIMETHYLACETAMIDE), ketone (for example acetone, methylethylketone), ether (for example diox, tetrahydrofuran (THF), ether), ester (for example ethyl acetate, methyl acetate, ethyl propionate), sulfoxide (for example dimethyl sulfoxide (DMSO)), alcohol (for example methyl alcohol, ethanol, 1-decanol, butanols), nitrile (for example acetonitrile) and halogenated organic solvent (for example chloroform, ethylene dichloride).
Organic or inorganic alkali can be used as acid binding agent.In organic bases, can enumerate trialkylamine (for example triethylamine, Tributylamine), cyclammonium (pyridine, 1 for example, 5-diaza-bicyclo [5.4.0] 11 carbon-5-alkene, 1,5-diaza-bicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diaza-bicyclo [2.2.2] octane); The oxyhydroxide of mineral alkali preferred as alkali or alkaline-earth metal or carbonate.Therefore, can advantageously adopt salt of wormwood, saleratus, sodium hydroxide, calcium hydroxide etc. or excessive logical formula III amine as acid binding agent.
According to used solvent, the reaction of logical formula II boron derivative and logical formula III amine can be carried out under 10-200 ℃.Reaction times is in 0.1-10 hour scope.Reaction times is also depended on temperature of reaction.Carry out if be reflected under the higher temperature, can shorten the reaction times.Above-mentioned reaction conditions is preferred value, also can adopt other reaction conditions.
Can be after separating (also can without separate), will lead to the formula IV compound hydrolysis under acidity or alkaline condition is required logical formula I quinoline-3-carboxylic acid.If desired, can logical formula IV compound be precipitated out from reaction mixture by for example cooling, and can be by for example filtering or centrifugal it being separated.
Can be by carrying out alkaline hydrolysis in the heated in water solution of basic metal or alkaline earth metal hydroxides or carbonate.The preferred aqueous solution that uses sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, calcium hydroxide.But, in hydrolysing step, also can use organic amine (for example diethylamine).
Can in inorganic acid aqueous solution, carry out acidic hydrolysis.A kind of preferable methods is to heat in hydrochloric acid, hydrogen bromide, sulfuric acid or phosphate aqueous solution, makes logical formula IV compound hydrolysis.Also can in organic acid (for example acetate, propionic acid etc.), be hydrolyzed.
The hydrolysis of logical formula IV compound also can with the miscible organic solvent of water in the presence of in aqueous medium, carry out.For example alcohol (for example methyl alcohol, ethanol), ketone (for example acetone), ether (for example diox), acid amides (for example dimethyl formamide), sulfoxide (for example dimethyl sulfoxide (DMSO)) or pyridine can be used for this purpose.
Can be by for example pH value of aqueous solution being adjusted to a suitable value and, perhaps, the logical formula I quinoline-3-carboxylic acid that obtains thus being separated by the lyophilize of aqueous reaction mixture by the crystallization of for example filtering or centrifugation is separated out.
Available known method will be led to the formula I compound and will be converted into its pharmaceutical salts.Be preferably formed acid salt, for example the salt that forms with halocarbon, sulfonic acid, sulfuric acid or organic acid.Can form muriate, bromide, arylsulphonate, metilsulfate, maleate, fumarate, benzoate etc.Logical formula I compound can form salt with basic metal or alkaline-earth metal or other metal ion etc.Therefore, can prepare sodium salt, sylvite, magnesium salts, silver salt and mantoquita etc.
Available currently known methods will lead to the formula I compound and pharmaceutical salts is converted into hydrate (for example semihydrate, trihydrate etc.).
The present invention further provides a kind of have logical formula IV (wherein R, R
1, R
2, R
3, R
4, R
5And R
6Definition same as described above) new compound.
Raw material with logical formula II can prepare according to following method: make 1-ethyl-6, and 7-8-three fluoro-4-oxygen-1,4-dihydro-quinoline-3-carboxylic acid (british patent specification 2,057,440) and a kind of boron derivative (compound that for example has general formula (V):
(wherein R is halogen, contains the aliphatic acyloxy of 2-6 carbon atom or contain the aromatics acyloxy of 7-11 carbon atom)] or fluoroboric acid in water or organic medium, react.
Provided other details of the present invention in the following embodiments, but these embodiment can not limit protection scope of the present invention.
Embodiment 1
Make 31.9g(1-ethyl-6,7,8-three fluoro-1,4-dihydro-4-oxygen-quinoline-3-carboxylic ion-O
3, O
4)-two fluoro-boron and 57.1g2,6-dimethyl-piperazine reacted 3 hours down at 100 ℃ in the 150ml dimethyl sulfoxide (DMSO).Add 400ml 3%(w/v) aqueous sodium hydroxide solution, heat and be hydrolyzed in 2 hours.Filter reaction mixture is used 96%(w/v) acetate transfers to 7 with the pH value.With the logical clouds cooling of crystalline reaction mixture, leach the crystal of separating out, wash with water and drying.Obtain 29.9g 7-[3,5-dimethyl-Piperazino] 1-ethyl-6,8-two fluoro-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid.M.p.=232-234℃。
Molecular formula C
17H
19F
2N
3O
3Ultimate analysis:
Calculated value: C=59.17% H=5.80% N=11.49%
Measured value: C=59.05% H=5.91% N=11.45%
Embodiment 2
According to embodiment 1 described method, make 31.9g(1-ethyl-6,7,8-three fluoro-1,4-dihydro-4-oxygen-quinoline-3-carboxylic ion-O
3, O
4)-two fluoro-boron and 50.1g 2-methyl-piperazine react in the 150ml dimethyl sulfoxide (DMSO).Obtain 30.6g 1-ethyl-6,8-two fluoro-1,4-dihydro-4-oxygen-7-(3-methyl-Piperazino)-quinoline-3-carboxylic acid.M.p.=238-240℃。
Molecular formula C
17H
19F
2N
3O
3Ultimate analysis:
Calculated value: C=58.11% H=5.45% N=11.96%
Measured value: C=58.01% H=5.55% N=12.07%
Embodiment 3
According to embodiment 1 described method, make 39.9g(1-ethyl-6,7,8-three fluoro-1,4-dihydro-4-oxygen-quinoline-3-carboxylic ion-O
3, O
4)-two-(acetato--O)-boron and 50.1g 2-methyl-piperazine react in the 150ml dimethyl sulfoxide (DMSO).Obtain 30.2g 1-ethyl-6,8-two fluoro-1,4-dihydro-4-oxygen-7-(3-methyl-Piperazino)-quinoline-3-carboxylic acid.M.p.=237-239℃。
Molecular formula C
17H
19F
2N
3O
3Ultimate analysis:
Calculated value: C=50.11% H=5.45% N=11.96%
Measured value: C=57.97% H=5.53% N=11.90%
Embodiment 4
According to embodiment 1 described method, make 42.7g(1-ethyl-6,7,8-three fluoro-1,4-dihydro-4-oxygen-quinoline-3-carboxylic ion-O
3, O
4)-two-(the propionic acid ion-O)-boron and 50.1g 2-methyl-piperazine reaction.Obtain 28.7g 1-ethyl-6,8-two fluoro-1,4-dihydro-4-oxygen-7-(3-methyl-Piperazino)-quinoline-3-carboxylic acid.M.p.=237-239℃。
Molecular formula C
17H
19F
2N
3O
3Ultimate analysis:
Calculated value: C=58.11% H=5.45% N=11.96%
Measured value: C=57.99% H=5.52% N=12.10%
Claims (10)
1, the logical formula I compound of a kind of preparation
(R wherein
1And R
3Represent hydrogen or C1-4 alkyl, R
2Represent the C1-4 alkyl, R
4, R
5And R
6Represent hydrogen or halogen) and the method for pharmaceutical salts, this method comprises makes logical formula II compound
(wherein R represents halogen, contains the aliphatic acyloxy of 2-6 carbon atom or contains the aromatics acyloxy of 7-11 carbon atom, R
4, R
5And R
6Definition same as described above) with logical formula III bridged piperazine derivatives
(R wherein
1, R
2And R
3Definition same as described above) or its reactant salt, and in after separating (or without separating), the logical formula IV compound that reaction is obtained
(wherein R, R
1, R
2And R
3Definition same as described above) be hydrolyzed, if desired, the logical formula I compound that obtains thus is converted into its salt, perhaps be not translated into salt.
2, the described method of claim 1, this method is included under the existence of organic solvent (preferred amide, sulfoxide, ketone, alcohol, ether, ester or nitrile), makes the reaction of logical formula II compound and logical formula III amine.
3, the described method of claim 2, this method comprise with the dimethyl sulfoxide (DMSO) being organic solvent.
4, the described method of claim 1, this method are included in the reaction of leading to formula II compound and logical formula III compound under the existence of acid binding agent.
5, the described method of claim 4, this method comprise that with amine or excessive logical formula VI compound be acid binding agent.
6, the described method of claim 1, this method is included in the acidic medium and is hydrolyzed.
7, the described method of claim 6, this method are included under the existence of organic acid or mineral acid (preferred hydrochloric acid, sulfuric acid or acetate) and are hydrolyzed.
8, the described method of claim 1, this method is included in the alkaline medium and is hydrolyzed.
9, the described method of claim 8, this method are included under the existence of alkali metal hydroxide, alkaline earth metal hydroxides or organic bases (preferred triethylamine aqueous solution) and are hydrolyzed.
10, logical formula IV compound
(R wherein
1And R
3Represent hydrogen or C1-4 alkyl, R
2Represent the C1-4 alkyl, R
4, R
5And R
6Represent hydrogen or halogen).
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU6560/88 | 1988-12-22 | ||
HU886560A HU203746B (en) | 1988-12-22 | 1988-12-22 | Process for producing quinoline-carboxylic acid derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1043712A true CN1043712A (en) | 1990-07-11 |
CN1031190C CN1031190C (en) | 1996-03-06 |
Family
ID=10971814
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN89109448A Expired - Fee Related CN1031190C (en) | 1988-12-22 | 1989-12-22 | Process for preparation of quinoline carboxylic acid derivatives |
Country Status (11)
Country | Link |
---|---|
JP (1) | JP2825641B2 (en) |
KR (1) | KR0146335B1 (en) |
CN (1) | CN1031190C (en) |
AT (1) | AT397385B (en) |
AU (1) | AU622256B2 (en) |
FR (1) | FR2640974B1 (en) |
GB (1) | GB2245562B (en) |
HU (1) | HU203746B (en) |
IL (1) | IL92821A0 (en) |
WO (1) | WO1990006922A1 (en) |
YU (1) | YU47215B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2077490B1 (en) * | 1992-11-18 | 1996-10-16 | Marga Investigacion | TRIMETILSILILIC ESTERS AND SOLVATES OF CHELATES OF QUINOLIN-3-CARBOXYL ACIDS. PREPARATION AND APPLICATION TO THE QUINOLON PROCESS. |
NZ260530A (en) * | 1994-05-16 | 1997-06-24 | Nigel Paul Maynard | Organoborate complexes of divalent metal; use as timber treament agents |
ES2092963B1 (en) * | 1995-04-12 | 1997-12-16 | Sint Quimica Sa | PROCEDURE FOR THE PREPARATION OF ACID 1-CICLOPROPIL-6-FLUORO-1, 4-DIHIDRO-7- (1S, 4S) -5-METHYL-2,5-DIAZABICICLO (2.2.1) HEPT-2-IL) -4 -OXO-3-QUINOLINCARBOXILICO AND ITS SALTS. |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59122470A (en) * | 1982-12-27 | 1984-07-14 | Dai Ichi Seiyaku Co Ltd | Preparation of quinoline-3-carboxylic acid derivative |
US4550167A (en) * | 1983-05-23 | 1985-10-29 | Ethyl Corporation | Preparation of 1-alkyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinoline carboxylic acid |
JPS6078986A (en) * | 1983-10-07 | 1985-05-04 | Dai Ichi Seiyaku Co Ltd | Preparation of oxazine derivative |
JPS6165882A (en) * | 1984-09-06 | 1986-04-04 | Hokuriku Seiyaku Co Ltd | 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazinyquinoline-3-carboxylic ester derivative and its preparation |
JPS6185381A (en) * | 1984-10-04 | 1986-04-30 | Hokuriku Seiyaku Co Ltd | Preparation of 1-ethyl-6, 8-difluoro-1, 4-dihydro-4-oxo-7-piperazinylquinoline-3-carboxylic acid derivative |
CA1306750C (en) * | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
HU196782B (en) * | 1985-12-09 | 1989-01-30 | Chinoin Gyogyszer Es Vegyeszet | Process for production of quinoline carbonic acid |
US4738800A (en) * | 1986-03-26 | 1988-04-19 | Ciba-Geigy Corporation | Process for the preparation of 1,4-diamino-2,3-dicyanoanthraquinones |
HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
JPS6419069A (en) * | 1987-07-14 | 1989-01-23 | Dainippon Pharmaceutical Co | Production of polyhalogenoquinoline derivative |
-
1988
- 1988-12-22 HU HU886560A patent/HU203746B/en not_active IP Right Cessation
-
1989
- 1989-12-15 JP JP2500847A patent/JP2825641B2/en not_active Expired - Lifetime
- 1989-12-15 KR KR1019900701858A patent/KR0146335B1/en not_active IP Right Cessation
- 1989-12-15 AT AT0902489A patent/AT397385B/en not_active IP Right Cessation
- 1989-12-15 GB GB9018360A patent/GB2245562B/en not_active Expired - Lifetime
- 1989-12-15 AU AU47480/90A patent/AU622256B2/en not_active Ceased
- 1989-12-15 WO PCT/HU1989/000063 patent/WO1990006922A1/en unknown
- 1989-12-20 IL IL92821A patent/IL92821A0/en not_active IP Right Cessation
- 1989-12-22 YU YU243789A patent/YU47215B/en unknown
- 1989-12-22 CN CN89109448A patent/CN1031190C/en not_active Expired - Fee Related
- 1989-12-22 FR FR8917102A patent/FR2640974B1/fr not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
GB2245562A (en) | 1992-01-08 |
GB2245562B (en) | 1992-12-23 |
HU203746B (en) | 1991-09-30 |
JP2825641B2 (en) | 1998-11-18 |
WO1990006922A1 (en) | 1990-06-28 |
AT397385B (en) | 1994-03-25 |
GB9018360D0 (en) | 1990-10-24 |
AU622256B2 (en) | 1992-04-02 |
CN1031190C (en) | 1996-03-06 |
ATA902489A (en) | 1993-08-15 |
IL92821A0 (en) | 1990-09-17 |
JPH03502803A (en) | 1991-06-27 |
KR910700245A (en) | 1991-03-14 |
YU243789A (en) | 1991-02-28 |
KR0146335B1 (en) | 1998-08-17 |
FR2640974A1 (en) | 1990-06-29 |
YU47215B (en) | 1995-01-31 |
AU4748090A (en) | 1990-07-10 |
HUT52086A (en) | 1990-06-28 |
FR2640974B1 (en) | 1994-02-18 |
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