CN1025616C - 喹啉羧酸的制备方法 - Google Patents
喹啉羧酸的制备方法 Download PDFInfo
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- CN1025616C CN1025616C CN88101907A CN88101907A CN1025616C CN 1025616 C CN1025616 C CN 1025616C CN 88101907 A CN88101907 A CN 88101907A CN 88101907 A CN88101907 A CN 88101907A CN 1025616 C CN1025616 C CN 1025616C
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- piperazinyl
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- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- -1 4-methyl-piperazinyl 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 claims description 3
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000001408 amides Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 229960002646 scopolamine Drugs 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 150000004885 piperazines Chemical class 0.000 claims 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 claims 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims 1
- 230000035484 reaction time Effects 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 229940088710 antibiotic agent Drugs 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- ISPVACVJFUIDPD-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ISPVACVJFUIDPD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 3
- LACQPOBCQQPVIT-SEYKEWMNSA-N scopolamine hydrobromide trihydrate Chemical class O.O.O.Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 LACQPOBCQQPVIT-SEYKEWMNSA-N 0.000 description 3
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 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
- 239000011230 binding agent Substances 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 150000001638 boron Chemical class 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
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-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
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 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
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000005968 1-Decanol Substances 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-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
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 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
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 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
- 239000002585 base Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 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
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 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 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 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
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
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- 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)
Abstract
本发明涉及制备已知抗菌素通式I的化合物及其可供药用的盐的新方法。
式中各符号所表示的意义，说明书中都有解释。
本方法的优点是简单，收率高和反应时间短。
Description
本发明涉及制备1-环丙基-7-取代基-6-氟-4-氧代-1，4-二氢-喹啉-3-羧酸衍生物及其可供药用盐的新方法。
众所周知，通式Ⅰ的1-环丙基-7-取代基-6-氟-4-氧代-1，4-二氢-喹啉-3-羧酸衍生物
（其中R代表哌嗪基、4-甲基-哌嗪基或4-乙基-哌嗪基）具有很高的抗菌活性（Eur.J.Clin.Microbiol.1983，2，Page lll;J.Clin.Pharmacol.1985，25，Page 82;Drugs Exptl.Clin.Res.1985，5，Page 317）。
在溶剂存在下，1-环丙基-6-氟-7氯-4-氧代-1，4-二氢-喹啉-3-羧酸和环胺于135-140℃反应2小时可得通式Ⅰ的喹啉羧酸（Germam off.3.033.157;German Off.3.142.854）。
本发明提供一种制备通式Ⅰ的1-环丙基-7-取代基-6-氟-4-氧代-1，4-二氢-喹啉-3-羧酸衍生物（其中R同上述定义）的新方法，包括把通式Ⅱ的
（Ⅱ）
（其中R1和R2相同或不同，并代表卤素、被卤素任意取代含2到6个碳原子的脂肪酰氧基或含
7到11个碳原子的芳香酰氧基）与通式Ⅲ的环胺
（其中R3代表氢、甲基或乙基）或它的盐反应，并将所得的通式Ⅳ的
（Ⅱ）
（其中R、R1和R2如上所述）水解。
本发明方法的优点是使期望的通式Ⅰ化合物的制备方法简单，收率高且反应时间短。
按照本发明首选的具体方法可以不经分离，直接将通式Ⅳ的硼酸酯衍生物（其中R、R1和R2如上所述）转化为期望的通式Ⅰ的喹啉-3-羧酸。
通式Ⅳ的硼酸酯衍生物是新化合物。
在惰性有机溶剂和酸性结合剂存在下，通式Ⅱ的硼酸酯衍生物和通式Ⅲ的环胺可以各种方式反应。
最好用酰胺（如二甲基甲酰胺、二甲基乙酰胺）、酮（如丙酮、甲乙酮）、醚（如二噁烷、四氢呋喃、乙醚）、酯（如乙酸乙酯、乙酸甲酯、丙酸乙酯）、亚砜（如二甲亚砜）、醇（如甲醇、乙醇、1-癸醇、丁醇）作惰性有机溶剂。
可用有机碱或无机碱作酸结合剂。有机碱类是三烷基胺（如三乙胺、三丁胺）、环胺（如吡啶，1，5-二氮杂二环[5，4，0]十一-5-烯、1，5-二氮杂二环[4，3，0]壬-5-烯、1，4-二氮杂二环[2，2，2]辛烷，无机碱最好是碱金属或碱土金属的氢氧化物或碳酸盐。因此，最好用碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钙等或过量的通式Ⅲ的胺为酸结合剂。
通式Ⅱ的硼衍生物和通式Ⅲ的环胺的反应温度取决于所用的溶剂，根据反应温度，反应时间可以在半小时到10小时之间。如果反应温度较高，则反应时间可以缩短。以上仅是较佳反应条件，也可使用其它条件。
通式Ⅳ的硼酸酯（其中R、R1和R2如上所述）可事先分离或不分离，在酸性或碱性条件下水解成所要的通式Ⅰ的喹啉-3-羧酸。如果需要，通式Ⅳ的化合物（其中R如上所述）可经冷却从反应混合物中沉淀出来，也可用过滤或离心分离。
碱性水解最好是将碱金属的氢氧化物、碳酸盐或碱土金属的氢氧化物的水溶液加热。最好用氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、氢氧化钙、碳酸氢钾水溶液。也可用有机胺（如三乙基胺）进行水解。
酸性水解最好用无机酸水溶液完成。可与同样的盐酸、溴化氢、硫酸或磷酸水溶液一起加热，将通式Ⅳ的硼酸酯水解。也可以用有机酸（如乙酸、丙酸等）进行水解。
通式Ⅳ化合物的水解也可在水可溶有机溶剂存在下在含水的介质中进行。为此目的，可用诸如醇（如甲醇、乙醇）、酮（如丙酮）、醚（如二噁烷），酰胺（如甲酰胺、二甲基甲酰胺）、亚砜（如二甲基亚砜）、或吡啶。
调节水溶液的PH值到合适的值，将所得的通式Ⅰ喹啉-3-羧酸游离，再用诸如过滤或离心将沉淀的结晶分出，或经含水反应混合物亲脂化分离产物。
用已知的方法可将通式Ⅰ的化合物转化成可供药用的盐。这样，最好用卤化氢、磺酸、硫酸或有机酸形成酸加成盐，可生成盐酸盐、氢溴酸盐、4-甲基-苯磺酸盐、甲磺酸盐、马来酸盐、丁二烯二酸盐、苯甲酸盐等。通式Ⅰ化合物也可用碱金属、碱土金属或其它金属离子成盐。从而可以制备钠、钾、镁、银和铜等盐。
通式Ⅰ的化合物及其可供药用的盐可用已知的方法转化成水合物（如半水合物、三水合物等）。
本发明还提供通式Ⅳ的新化合物（其中R、R1和R2如上所述）。
可用某些方法制备通式Ⅱ的起始物，如将1-环丙基-6-氟-7-氯-4-氧代-1，4-二氢-喹啉-3-羧酸（German off.3，141，854）与硼衍生物（例如通式Ⅴ的化合物）反应
（其中R1、R2和R5代表卤素、被卤素任意取代的含2到6个碳原子的脂酰氧基或含7到11个碳原子的芳香酰氧基），也可在水或有机介质中与氟硼化物反应。
本发明进一步的详述由下列实施例提供，但保护范围不受所述实施例的限制。
实施例1
4.1克（1-环丙基-6-氟-7-氯-1，4-二氢-4-氧代-喹啉-3-羧酸酯-03，04）-双（乙酰基-0）-硼和2.8克无水哌嗪于16毫升二甲基亚砜中搅拌加热至110℃，在棕红色溶液中加入40毫升3%（w/v）氢氧化钠水溶液，反应混合物在回流下煮沸1小时。将浅黄色溶液趁热过滤，加入1.8毫升96%乙酸调节PH值至7。将反应混合物冷却至室温，过滤沉淀的白色结晶，用水和甲醇洗涤，干燥。在10毫升水中煮沸以提纯粗品。得2.99克1-环丙基-6-氟-7-（1-哌嗪基）-1，4-二氢-4-氧代-喹啉-3-羧酸。产品分解温度为255℃。
分子式C17H18FN3OH3的分析：
计算值：C＝61.62% H＝5.48% N＝12.68%
实测值：C＝61.58% H＝5.50% N＝12.61%
实施例2
根据实施例1将（1-环丙基-6-氟-7-氯-1，4-二氢-4-氧代-喹啉-3-羧酸酯-03，04）-双（乙酰-0）-硼和N-甲基-哌嗪反应，制得1-环丙基-6-氟-7-（4-甲基-哌嗪）-1，4-二氢-4-氧代-喹啉-3-羧酸。产品分解温度为248-250℃。
实施例3
4.1克（1-环丙基-6-氟-7-氯-1，4-二氢-4-氧代-喹啉-3-羧酸酯-03，04）-双-（乙酰-0）-硼和3.7gN-乙基-哌嗪于16毫升二甲亚砜中搅拌且升温至90℃。10分钟后加入40毫升3%（w/w）氢氧化钠水溶液，反应混合物加热回流1小时，趁热过滤，用96%醋酸调节PH值到7，将反应混合物冷却，过滤沉淀的结晶，用水洗涤，得3.3克1-环丙基-7-（4-乙基-哌嗪基）-6-氟-1，4-二氢-4-氧代-喹啉-3-羧酸。熔点：183-185℃。
分子式：C19H22FN3O3的分析：
计算值：C＝63.35 H＝6.17 N＝11.69
实测值：C＝63.31 H＝6.21 N＝11.70
实施例4：
根据实施例3将3.3克（1-环丙基-6-氟-7-氯-1，4-二氢-4-氧代-喹啉）-3-羧酸酯-03，04）-二氟硼和3.7克N-乙基-哌嗪反应，得3.4克1-环丙基-7-（4-乙基-1-哌嗪基）-6-氟-1，4-二氢-4-氧代-喹啉-3-羧酸，以任何比例与实施例3的产品掺和，其熔点不下降。
Claims (10)
1、通式Ⅰ的化合物及其可供药用的盐的制备方法
其中R代表哌嗪基、4-甲基-哌嗪基或4-乙基-哌嗪基，该方法包括通式Ⅱ的化合物
其中R1和R2代表被卤素任意取代的含2到6个碳原子的脂肪酰氧基，在酸性结合剂存在下，于有机溶剂中，和通式Ⅲ的哌嗪衍生物或其盐
其中R3代表氢、甲基或乙基，进行反应，在分离后或不经分离，将所得通式Ⅳ的化合物，其中R、R1、R2如上所述，水解。
如果需要，将所得通式Ⅰ的化合物转化成其盐或从它的盐中将酸游离出来。
2、权利要求1的方法，其中有机溶剂为酰胺、亚砜、酮、醇、醚或酯。
3、权利要求2的方法，其中用二甲基亚砜作有机溶剂。
4、权利要求1的方法，其中用胺或过量的通式Ⅲ的化合物作酸性结合剂。
5、权利要求1的方法，包括在酸性介质中进行水解。
6、权利要求5的方法，包括以有机或无机酸为酸性介质进行反应。
7、权利要求1的方法，包括在碱性介质中进行水解。
8、权利要求7的方法，包括以碱金属氢氧化物、碱土金属氢氧化物或有机碱为碱。
9、权利要求6的方法，其中所述的酸性介质为盐酸、硫酸或乙酸。
10、权利要求8的方法，其中所述有机碱为三乙胺水溶液。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU871505A HU198709B (en) | 1987-04-08 | 1987-04-08 | Process for producing quinoline-carboxylic acid derivatives |
| HU1505/87 | 1988-02-26 |
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| Publication Number | Publication Date |
|---|---|
| CN88101907A CN88101907A (zh) | 1988-10-26 |
| CN1025616C true CN1025616C (zh) | 1994-08-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN88101907A Expired - Lifetime CN1025616C (zh) | 1987-04-08 | 1988-04-07 | 喹啉羧酸的制备方法 |
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| Country | Link |
|---|---|
| US (2) | US5091530A (zh) |
| EP (1) | EP0309537B1 (zh) |
| JP (1) | JP2693987B2 (zh) |
| CN (1) | CN1025616C (zh) |
| AT (1) | ATE124687T1 (zh) |
| AU (1) | AU612648B2 (zh) |
| CS (1) | CS274460B2 (zh) |
| DD (1) | DD269848A5 (zh) |
| DE (1) | DE3854109T2 (zh) |
| DK (1) | DK175037B1 (zh) |
| HU (1) | HU198709B (zh) |
| SU (1) | SU1701110A3 (zh) |
| WO (1) | WO1988007993A1 (zh) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| HU203746B (en) * | 1988-12-22 | 1991-09-30 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| JPH0778065B2 (ja) * | 1990-07-06 | 1995-08-23 | 杏林製薬株式会社 | （６，７―置換―８―アルコキシ―１―シクロプロピル―１，４―ジヒドロ―４―オキソ―３―キノリンカルボン酸―ｏ▲上３▼，ｏ▲上４▼）ビス（アシルオキシ―ｏ）ホウ素化合物及びその塩並びにその製造方法 |
| GB9118183D0 (en) * | 1991-08-23 | 1991-10-09 | Solanki Kishor K | Imaging of infections |
| US5440061A (en) * | 1994-03-29 | 1995-08-08 | The Procter & Gamble Company | Hydrolysis of methyl esters in dimethylsulfoxide for production of fatty acids |
| NZ260530A (en) * | 1994-05-16 | 1997-06-24 | Nigel Paul Maynard | Organoborate complexes of divalent metal; use as timber treament agents |
| ES2092963B1 (es) * | 1995-04-12 | 1997-12-16 | Sint Quimica Sa | Procedimiento para la preparacion del acido 1-ciclopropil-6-fluoro-1, 4-dihidro-7-(1s,4s)-5-metil-2,5-diazabiciclo(2.2.1) hept-2-il)-4-oxo-3-quinolincarboxilico y sus sales. |
| ES2095809B1 (es) * | 1995-07-27 | 1997-12-16 | Sint Quimica Sa | Procedimiento para la preparacion de acidos naftiridin carboxilicos y sus sales. |
| CN101195614B (zh) * | 2006-12-04 | 2011-10-26 | 河南康泰制药集团公司 | 一种巴洛沙星的制备及纯化方法 |
| CN101671302B (zh) * | 2008-12-30 | 2011-03-30 | 广东海康兽药有限公司 | 禽畜用抗菌药恩诺沙星的生产工艺 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3142854A1 (de) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-piperazino-chinolin-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| US4670444B1 (en) * | 1980-09-03 | 1999-02-09 | Bayer Ag | and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds |
| DE3033157A1 (de) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| JPS5980683A (ja) * | 1982-10-30 | 1984-05-10 | Koei Chem Co Ltd | ６−フルオロ−１，８−ナフチリジン誘導体およびその製造法 |
| JPS59122470A (ja) * | 1982-12-27 | 1984-07-14 | Dai Ichi Seiyaku Co Ltd | キノリン−３−カルボン酸誘導体の製造法 |
| JPS6075489A (ja) * | 1983-10-03 | 1985-04-27 | Dai Ichi Seiyaku Co Ltd | ホウ素キレ−ト化合物 |
| JPS6078986A (ja) * | 1983-10-07 | 1985-05-04 | Dai Ichi Seiyaku Co Ltd | オキサジン誘導体の製法 |
| JPS60126290A (ja) * | 1983-12-13 | 1985-07-05 | Dai Ichi Seiyaku Co Ltd | ホウ素キレ−ト化合物の製造法 |
| HU196782B (en) * | 1985-12-09 | 1989-01-30 | Chinoin Gyogyszer Es Vegyeszet | Process for production of quinoline carbonic acid |
| HU196415B (en) * | 1985-12-09 | 1988-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing quinoline carboxylic acid boric acid anhydrides |
| HU196218B (en) * | 1985-12-09 | 1988-10-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing quinoline carboxylic acid boric acid anhydrides |
| US4940710A (en) * | 1986-01-17 | 1990-07-10 | American Cyanamid Company | 7-(substituted)piperazinyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| YU46451B (sh) * | 1987-04-08 | 1993-10-20 | Chinoin Gyogyszer Es Vegyeszeti Ter Mekek Gyara Rt. | Postupak za dobivanje mešovitih anhidrida hinolin-karboksilne i borne kiseline |
| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| KR970005911B1 (ko) * | 1987-06-24 | 1997-04-22 | 치노인 교기스져 에스 베게스제티 테르메케크 기야라 알티 | 퀴놀린 카복실산 유도체를 제조하는 제조방법 |
| JPS6419069A (en) * | 1987-07-14 | 1989-01-23 | Dainippon Pharmaceutical Co | Production of polyhalogenoquinoline derivative |
-
1987
- 1987-04-08 HU HU871505A patent/HU198709B/hu unknown
-
1988
- 1988-04-07 DD DD88314509A patent/DD269848A5/de not_active IP Right Cessation
- 1988-04-07 CN CN88101907A patent/CN1025616C/zh not_active Expired - Lifetime
- 1988-04-08 DE DE3854109T patent/DE3854109T2/de not_active Expired - Lifetime
- 1988-04-08 AU AU15721/88A patent/AU612648B2/en not_active Expired
- 1988-04-08 AT AT88903335T patent/ATE124687T1/de not_active IP Right Cessation
- 1988-04-08 US US07/290,105 patent/US5091530A/en not_active Expired - Lifetime
- 1988-04-08 CS CS242088A patent/CS274460B2/cs not_active IP Right Cessation
- 1988-04-08 JP JP63503085A patent/JP2693987B2/ja not_active Expired - Lifetime
- 1988-04-08 EP EP88903335A patent/EP0309537B1/en not_active Expired - Lifetime
- 1988-04-08 WO PCT/HU1988/000019 patent/WO1988007993A1/en active IP Right Grant
- 1988-12-07 SU SU884613033A patent/SU1701110A3/ru active
- 1988-12-07 DK DK198806822A patent/DK175037B1/da not_active IP Right Cessation
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1991
- 1991-09-06 US US07/756,345 patent/US5300644A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE3854109T2 (de) | 1995-11-30 |
| SU1701110A3 (ru) | 1991-12-23 |
| DK682288D0 (da) | 1988-12-07 |
| ATE124687T1 (de) | 1995-07-15 |
| EP0309537B1 (en) | 1995-07-05 |
| JP2693987B2 (ja) | 1997-12-24 |
| US5300644A (en) | 1994-04-05 |
| DE3854109D1 (de) | 1995-08-10 |
| DK682288A (da) | 1988-12-07 |
| DK175037B1 (da) | 2004-05-10 |
| AU612648B2 (en) | 1991-07-18 |
| WO1988007993A1 (en) | 1988-10-20 |
| JPH01503301A (ja) | 1989-11-09 |
| CN88101907A (zh) | 1988-10-26 |
| DD269848A5 (de) | 1989-07-12 |
| AU1572188A (en) | 1988-11-04 |
| HUT46686A (en) | 1988-11-28 |
| CS242088A2 (en) | 1990-09-12 |
| HU198709B (en) | 1989-11-28 |
| EP0309537A1 (en) | 1989-04-05 |
| CS274460B2 (en) | 1991-04-11 |
| US5091530A (en) | 1992-02-25 |
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