CN1031710C - 喹啉羧酸硼酸酐的制法 - Google Patents
喹啉羧酸硼酸酐的制法 Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title abstract 3
- KXWNUUOZJUFUHG-UHFFFAOYSA-N C1=CC=CC2=NC(C(=O)OB(O)O)=CC=C21 Chemical compound C1=CC=CC2=NC(C(=O)OB(O)O)=CC=C21 KXWNUUOZJUFUHG-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- -1 acyloxy boron derivatives Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 2
- 150000007513 acids Chemical class 0.000 abstract 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract 1
- LZMKGWAXQRCLAL-UHFFFAOYSA-N quinoline-3-carbonyl quinoline-3-carboxylate Chemical compound C1=CC=CC2=CC(C(OC(=O)C=3C=C4C=CC=CC4=NC=3)=O)=CN=C21 LZMKGWAXQRCLAL-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000013078 crystal Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229910052796 boron Inorganic materials 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000004327 boric acid Substances 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 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 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- HJZQMXIVAIMIQA-UHFFFAOYSA-N 1-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)=CN(F)C2=C1 HJZQMXIVAIMIQA-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- OKZIUSOJQLYFSE-UHFFFAOYSA-N difluoroboron Chemical compound F[B]F OKZIUSOJQLYFSE-UHFFFAOYSA-N 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 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 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
- 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- LKIBSJCOAXOWJY-UHFFFAOYSA-N ethyl 4-oxo-3h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)C=NC2=C1 LKIBSJCOAXOWJY-UHFFFAOYSA-N 0.000 description 2
- JLDJEPINTWDIOY-UHFFFAOYSA-N ethyl 7-chloro-6-fluoro-1-(4-fluorophenyl)-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(Cl)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1=CC=C(F)C=C1 JLDJEPINTWDIOY-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- GQKLTNAIFDFUDN-UHFFFAOYSA-N n-(2-hydroxyethyl)propanamide Chemical compound CCC(=O)NCCO GQKLTNAIFDFUDN-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DTYLXDLAOLOTKT-UHFFFAOYSA-N 1,4-dihydroquinoline-3-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)=CNC2=C1 DTYLXDLAOLOTKT-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N Ciprofloxacin Natural products C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ACXQCLCOXPDOQV-UHFFFAOYSA-N ethyl 1-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CN(F)C2=C1 ACXQCLCOXPDOQV-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
-
- 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
- C07F5/04—Esters of boric acids
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
本发明涉及通式I的新的喹啉-3-羧酸酐及其制备方法。式I中各符号含义及该制备方法详见说明书。式I化合物是制备具有抗菌作用的已知喹啉-3-羧酸类化合物的新的中间体。
Description
本发明涉及通式I的新(1-取代-6-氟-7-取代-8-可氟代*-4-氧代-1，4-二氢-喹啉-3-羧酸-硼酸)酸酐衍生物及其制法。(*指8位可以用氟取代，也可以不取代)
在通式I中
R代表环丙基、通式-CH2CR5R6R7(其中R5、R6、R7代表氢或卤素)的基团或可被一或两个卤原子取代的苯基；
R1和R2相同或不相同，代表囟素、含2—6个碳原子且可卤代的脂肪族酰氧基或含7—11个碳原子的芳香族酰氧基；
R3代表氯或氟；
R4代表氢或氟。
1-对氟苯基-6-氟-7-氯-4-氧代-1，4-二氢-喹啉-3-羧酸乙酯是制备具有抗菌作用的1-对氟苯基-6-氟-1，4-二氢-4-氧代-7-(4-甲基-1-哌嗪基)-3-喹啉羧酸的中间体(见24th Intersci.Conf.Antimicrob.Agents.Chemother.1984.Abst.72-78)。后一化合物可由1-对氟苯基-6-氟-7-氯-4-氧代-1，4-二氢喹啉-3-羧酸乙酯经两步反应而制得。1-对氟苯基-6-氟-1，4-二氢-4-氧代-7-(4-甲基-1-哌嗪基)-3-喹啉羧酸可以这样制备：在100℃温度下，使1-对氟苯基-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸(由水解相应酯而得)与1-甲基哌嗪在有溶剂存在的情况下反应20小时(见第131839号欧洲专利说明书)。
1-环丙基-6-氟-7-氯-4-氧代-1，4-二氢喹啉-3-羧酸乙酯是制备1-环丙基-6-氟-1，4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸(也具有抗菌作用)的中间体(Eur.J.Clin.Microbiol.1983.，2.，111)。后一化合物可由(1-环丙基-6-氟-7-氯-4-氧代-1，4-二氢喹啉-3-羧酸乙酯经两步反应制得。将该酯水解后，使所得到的1-环丙基-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸与哌嗪在有溶剂存在的情况下，在135—140℃温度下反应2小时，由此可制得1-环丙基-6-氟-1，4-二氢-4-氧代-7-(1-哌嗪基)喹啉-3-羧酸(见German Off.No.3033157和German Off.No.3142854)。
1-取代-6，7，3-三氟-4-氧代-1，4-二氢喹啉-3-羧酸衍生物(英国专利说明书2057440、比利时专利说明书887574、欧洲专利说明书106489及15049、德国专利说明书3433924、日本专利说明书60006684及61085381、葡萄牙专利说明书80187)是制备7-取代-6，8-二氟-1，4-二氢-4-氧代喹啉-3-羧酸衍生物的中间体(J.Med，Chem，1986，29，445；DrugsFut.1984.9，246；23rd Intersci，Conf.Ant imicrob.Agents Chemother.1983.Abstr.658；7th Int.Symp.Fut.Trends Chemother.1986.80)。
依照本发明，以下三类衍生物可按简单方法，以通式I的新化合物作为原料来制备，它们是1-(可囟代的)乙基-6，8-二氟-1，4-二氢-4-氧代-7-取代喹啉-3-羧酸衍生物、1-环丙基-6-氟-1，4-二氢-4-氧代-7-(可带有取代基的哌嗪基)喹啉-3-羧酸衍生物和1-取代-6-氟-1，4-二氢-4-氧代-7-(可带有取代基的哌嗪基)喹啉-3-羧酸衍生物。
R、R1、R2、R3、R4同上所述的通式I化合物可按下述制得：使通式II的化合物
(式中R、R3、R4同上所述，R8代表氢或含1—4个碳原子的烷基)与式III的氟硼酸
HBF4 (III)或与通式IV的三囟化硼或它的醚配合物
BX (IV)(式中X代表氟、氯或溴)或与通式V的三酰氧基硼衍生物
B(OCOR9)3(式中R9代表含1—5个碳原子且可被卤代的烷基或含6—10个碳原子的芳基)进行反应。
三氟化硼、三溴化硼、三氯化硼，这些化合物的配合物或水溶液可用作通式IV化合物。最好采用醚或醇的配合物(例如三氟化硼与四氢呋喃、乙醚、甲醇或丙醇的配合物)。如果需要，可使用三囟化硼在脂肪烃(例如己烷)或卤代烃(例如二氯甲烷)或羧酸(例如乙酸、三氟乙酸、丙酸)中的溶液。
式III的氟硼酸、通式IV的三卤化硼及其配合物以及通式V的三酰氧基硼衍生物与通式II化合物之间的摩尔比可以是50∶1，最好是5∶1。但需要时，摩尔比也可以取其它值。
该反应也可以在有溶剂存在的情况下进行。溶剂可采用水、酮(例如丙酮、甲乙酮)、烃(例如己烷、苯、甲苯)、醚(例如乙醚、二氧杂环己烷、四氢呋喃)或有机酸(例如乙酸、丙酸、三氟乙酸)。
需要时，该反应可以在室温下进行。若反应在较高温度下进行，反应时间可缩短。反应温度最好在20—150℃范围内，但它取决于所用的溶剂。
通式I化合物可从反应混合物中自动析出或经冷却而析出，因而可用例如过滤法予以分离。
以下实例进一步说明本发明的细节，但本发明的保护范围并不受其限制。
实例1
把4.6g克乙酸加到0.93g酸硼酸和1.5mg(毫克)氯化锌的混合物中，所得悬浮液在搅拌下缓慢加热。在80℃形成一清溶液。在100℃于此清溶液内滴入3.1g1-环丙基-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸乙酯在5ml(毫升)热乙酸(96w/v％)中的溶液。反应混合物在110℃搅拌2小时，然后冷至10℃，用10ml水稀释。所得悬浮液在10℃搅拌2小时。滤出析出的雪花膏色的晶体，用水及乙醇洗，干燥之。得4.02g(1-环丙基-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸根-O3，O4)双(乙酸-O)硼[(1-cyclopropyl-6-fluoro-7-chloro-1，4-dihydro-4-oxo-quinoline-3-carboxy late-O3，O4)bis(acetato-O)-borone]。此产物在254—256℃分解。
元素分析(C17H14O7NBClF)：
计算：C＝49.86％ H＝3.45％ N＝3.42％
实测：C＝50.03％ H＝3.41％ N＝3.50％
实例2
在80-90℃搅拌3.0g1-乙基-6，7，8-三氟-1，4-二氢-4-氧代喹啉-3-羧酸乙酯与15ml50w/v％的氟硼酸水溶液的混合物2.5小时。半小时后从清溶液中析出晶体，由此得一稠厚悬浮液。把反应混合物冷至室温，在冰冷却下结晶过夜。过滤收集析出的晶体，用水及甲醇洗涤。干燥后，得3.1g(1-乙基-6，7，8-三氟-1，4-二氢-4-氧代喹啉-3-羧酸根-O3，O4)二氟化硼。此产物在289℃分解。
元素分析(C12H7BF5NO3)：
计算：C＝45.18％ H＝2.21％ N＝4.40％
实测：C＝45.26％ H＝2.18％ N＝4.32％
实例3
在95—100℃搅拌0.93g硼酸与6.9g丙酸酐的混合物30分钟。在稳定加热的条件下，向反应混合物中加入3.0g在12ml温热丙酸中的3.0g1-乙基-6，7，8-三氟-1，4-二氢-4-氧代喹啉-3-羧酸乙酯。所得红色溶液在110℃搅拌5小时，然后冷至室温，用150ml水稀释。过滤收集析出的晶体；用水及甲醇洗涤，干燥之。得4.1g(1-乙基-6，7，8-三氟-1，4-二氢-4-氧代喹啉-3-羧酸根-O3，O4)双(丙酸-O)硼。此产物在195-196℃分解。
元素分析(C18H17BF3NO7)：
计算：C＝50.61％ H＝4.01％ N＝3.29％
实测：C＝50.72％ H＝4.11％ N＝3.31％
实例4
将10ml乙酐加到1.85g硼酸与20mg氯化锌的混合物中。搅拌悬浮液；在搅拌过程中混合物温度升至80℃，随后下降。在110℃继续搅拌1小时，然后滴加6.0g1-乙基-6，7，8-三氟-1，4-二氢-4-氧代喹啉-3-羧酸乙酯在20ml温热的96w/v％乙酸中的溶液。反应混合物在110℃搅拌2小时，再冷至室温。向反应混合物中加入150ml水，所得悬浮液在冷却下搅拌3小时。过滤收集析出的晶体，用水、甲醇洗涤，干燥。得7.7g(1-乙基-6，7，8-三氟-1，4-二氢-4-氧代喹啉-3-羧酸根-O3，O4)双(乙酸-O)硼。此产物在211℃分解。
元素分析(C16H13BF3NO7)：
计算：C＝48.15％ H＝3.28％ N＝3.52％
实测：C＝48.12％ H＝3.28％ N＝3.54％
实例5
在搅拌下，把3.64g(0.01ml(摩尔))1-(4-氟苯基)-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸乙酯加到30ml 50w/v％氟硼酸水溶液中，然后把反应混合物加热到110℃。所得溶液在110℃搅拌2小时，此过程中有沉淀物析出。将反应混合物冷却，在冰冷却下结晶过夜。过滤收集析出的晶体，用5ml水、5ml甲醇洗。得3.66g[1-(4-氟苯基)-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸根-O3，O4)二氟化硼白色晶体，熔点324-326℃。
元素分析(C16H7NO3BF4Cl)：
计算：C＝50.11％ H＝1.84％ N＝3.65％
实测：C＝50.21％ H＝1.92％ N＝3.68％
实例6
把4.5g乙酸加到0.93g硼酸与1.5mg氯化锌的混合物中，然后在搅拌下缓慢加热悬浮液。在80℃得一清溶液。在100℃向此清溶液中滴加3.64g(0.0lmol)1-(4-氟苯基)-6-氟-7-氯-l，4-二氢-4-氧代喹啉-3-羧酸乙酯在20ml热的96w/v％乙酸中的溶液。反应混合物在110℃搅拌3小时，冷却，用10ml水稀释。混合物在冰冷却下结品过夜。过滤收集析出的晶体，用5ml水、5ml乙醇洗。得4.54g晶形[1-(4’-氟苯基)-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸根-O3，O4)双(乙酸-O)硼。此产物在248—250℃分解。
元素分析(C20H13NO7BF2Cl)：
计算：C＝51.82％ H＝2.83％ N＝3.02％
实测：C＝52.01％ H＝2.91％ N＝3.07％
实例7
把5.3g97w/v％丙酐加到0.93g硼酸与1.5mg氯化锌的混合物中，然后在搅拌下缓慢加热悬浮液。在90℃得一清溶液。向此溶液中加入3.64g(0.01mol)1-(4-氟苯基)-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸乙酯，反应混合物在10℃搅拌半小时，然后冷却，用6ml水稀释。混合物在冰冷却下结晶过夜。过滤收集析出的晶体，用5ml水、5ml乙醇洗。得4.72g晶形[1-(4-氟苯基)-6-氟-7-氯-1，4-二氢-4-氧代喹啉-3-羧酸根-O3，O4)二氟化硼。此产物在278-280℃分解。
元素分析(C22H17NO7BF2Cl)：
计算：C＝53.75％ H＝3.40％ N＝2.85％
实测：C＝53.71％ H＝3.39％ N＝2.79％
Claims (2)
1.制备通式I化合物的方法，
式中R代表环丙基、通式—CH2CR5R6R7，其中R5、R6、R7代表氢或卤素，条件是R5，R6，R7不能同时为氢，或由1—2个卤原子取代的苯基，R1、R2代表含2—6个碳原子的酰氧基，R3代表氯或氟，R4代表氢或氟该方法包括：使通式II的化合物
式中R、R3、R4定义同上述，R8代表氢或含1—4个碳原子的烷基，与通式V的三酰氧基硼衍生物
B(OCOR9)3 (V)式中R9代表含1—5个碳原子且可被卤代的烷基或含6—10个碳原子的芳基，进行反应。
2.按照权利要求1的方法，该方法包括：使通式II化合物与通式V化合物在有溶剂存在的情况下反应。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1504/87 | 1987-04-08 | ||
| HU871504A HU198728B (hu) | 1987-04-08 | 1987-04-08 | Eljárás kinolinkarbonsavszármazékok előállítására |
| HU872857A HU200464B (en) | 1987-06-24 | 1987-06-24 | Process for producing dihydroquinolinecarboxylic acid derivatives |
| HU2857/87 | 1987-06-24 | ||
| HU873147A HU200187B (en) | 1987-07-10 | 1987-07-10 | Process for producing (1-substituted-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid-boric) anhydrides |
| HU3147/87 | 1987-07-10 |
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| Publication Number | Publication Date |
|---|---|
| CN88101941A CN88101941A (zh) | 1988-10-26 |
| CN1031710C true CN1031710C (zh) | 1996-05-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN88101941A Expired - Fee Related CN1031710C (zh) | 1987-04-08 | 1988-04-07 | 喹啉羧酸硼酸酐的制法 |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4940794A (zh) |
| EP (1) | EP0310647B1 (zh) |
| JP (1) | JPH0826041B2 (zh) |
| KR (1) | KR970004204B1 (zh) |
| CN (1) | CN1031710C (zh) |
| AT (1) | ATE83235T1 (zh) |
| CA (1) | CA1294968C (zh) |
| CZ (1) | CZ279045B6 (zh) |
| DD (1) | DD268474A5 (zh) |
| DE (1) | DE3876583T2 (zh) |
| DK (1) | DK682488A (zh) |
| ES (1) | ES2006881A6 (zh) |
| FI (1) | FI90874C (zh) |
| GE (1) | GEP19971008B (zh) |
| GR (1) | GR1001109B (zh) |
| HR (1) | HRP930554B1 (zh) |
| LV (1) | LV10254B (zh) |
| NO (1) | NO171019C (zh) |
| NZ (1) | NZ224152A (zh) |
| RU (1) | RU1838302C (zh) |
| SI (1) | SI8810667A8 (zh) |
| SK (1) | SK278618B6 (zh) |
| WO (1) | WO1988007998A1 (zh) |
| YU (1) | YU46451B (zh) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| US5591744A (en) * | 1987-04-16 | 1997-01-07 | Otsuka Pharmaceutical Company, Limited | Benzoheterocyclic compounds |
| US5290934A (en) * | 1987-04-16 | 1994-03-01 | Otsuka Pharmaceutical Company, Limited | Benzoheterocyclic compounds |
| 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 |
| GR910100517A (el) * | 1991-12-30 | 1993-08-31 | Kyorin Seiyaku Kk | Δις(ακυλοξυ-ο) βορικος εστερας του (6,7-υποκατεστημενου-8-αλκοξυ-1- κυκλοπροπυλ-1,4,-διυδρο-4-οξο-3-κινολινοκαρβοξυλικου οξεως-ο3,ο4)και αλας αυτου, και μεθοδος παρασκευης αυτου. |
| ES2049636B1 (es) * | 1992-04-15 | 1994-12-16 | Genesis Para La Investigacion | Procedimiento para la preparacion de derivados de acidos quinolincarboxilicos. |
| ES2077490B1 (es) * | 1992-11-18 | 1996-10-16 | Marga Investigacion | Esteres trimetilsililicos y solvatos de quelatos de acidos quinolin-3-carboxilicos. preparacion y aplicacion al proceso de quinolonas. |
| 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. |
| US7691793B2 (en) * | 2004-07-21 | 2010-04-06 | Chemtura Corporation | Lubricant additive containing alkyl hydroxy carboxylic acid boron esters |
| US7365201B2 (en) * | 2006-03-02 | 2008-04-29 | Apotex Pharmachem Inc. | Process for the preparation of the boron difluoride chelate of quinolone-3-carboxylic acid |
| US8124623B2 (en) | 2006-11-10 | 2012-02-28 | Actelion Pharmaceuticals Ltd. | 5-hydroxymethyl-oxazolidin-2-one-derivatives and their uses as antibacterials |
| KR101539561B1 (ko) * | 2006-11-13 | 2015-07-27 | 씨아이피엘에이 엘티디. | 목시플록사신 염산염의 합성방법 |
| 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 |
| CN103073570B (zh) * | 2013-02-06 | 2016-03-02 | 北大国际医院集团西南合成制药股份有限公司 | 一种莫西沙星和其盐中间体及其制备方法 |
| US10087171B2 (en) | 2016-12-19 | 2018-10-02 | Actelion Pharmaceuticals Ltd | Crystalline forms of cadazolid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CA1306750C (en) * | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
| HU196218B (en) * | 1985-12-09 | 1988-10-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing quinoline carboxylic acid boric acid anhydrides |
| HU196415B (en) * | 1985-12-09 | 1988-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing quinoline carboxylic acid boric acid anhydrides |
| HU196782B (en) * | 1985-12-09 | 1989-01-30 | Chinoin Gyogyszer Es Vegyeszet | Process for production of quinoline carbonic acid |
| EP0230053A3 (en) * | 1986-01-17 | 1988-03-30 | American Cyanamid Company | 7-(substituted)piperazinyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| EP0251308B1 (de) * | 1986-07-04 | 1990-11-22 | Chemie Linz Gesellschaft m.b.H. | 4-Chinolon-3-carbonsäurederivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate |
| JPS62294689A (ja) * | 1987-05-29 | 1987-12-22 | Dai Ichi Seiyaku Co Ltd | キノリン−３−カルボン酸誘導体 |
| JPH0742299A (ja) * | 1993-08-02 | 1995-02-10 | Nippon Kagaku Sangyo Kk | 天井の換気構造 |
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