NO179517B - Process for the preparation of 8-chloroquinolone derivatives - Google Patents
Process for the preparation of 8-chloroquinolone derivatives Download PDFInfo
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- NO179517B NO179517B NO914053A NO914053A NO179517B NO 179517 B NO179517 B NO 179517B NO 914053 A NO914053 A NO 914053A NO 914053 A NO914053 A NO 914053A NO 179517 B NO179517 B NO 179517B
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- Prior art keywords
- group
- formula
- amino
- chlorinating agent
- compound
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 13
- JNXUGJMCFLONJN-UHFFFAOYSA-N 8-chloroquinolin-2(1H)-one Chemical class C1=CC(=O)NC2=C1C=CC=C2Cl JNXUGJMCFLONJN-UHFFFAOYSA-N 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 quinolone compound Chemical class 0.000 claims description 52
- 125000003277 amino group Chemical group 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000012320 chlorinating reagent Substances 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical group ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000005660 chlorination reaction Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- KBESHLYCSZINAJ-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(Cl)=C1F KBESHLYCSZINAJ-UHFFFAOYSA-N 0.000 description 2
- FZIUFWGYMHTWKY-KFKAGJAMSA-N 6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-7-[(7s)-7-[(2-methylpropan-2-yl)oxycarbonylamino]-5-azaspiro[2.4]heptan-5-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound C([C@H]1NC(=O)OC(C)(C)C)N(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3C=2)[C@H]2[C@H](C2)F)F)CC11CC1 FZIUFWGYMHTWKY-KFKAGJAMSA-N 0.000 description 2
- DVCFPCHNBNBXPN-VEVZXVCZSA-N 7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid hydrochloride Chemical compound Cl.N[C@@H]1CN(CC12CC2)C2=C(C=C1C(C(=CN(C1=C2)[C@H]2[C@H](C2)F)C(=O)O)=O)F DVCFPCHNBNBXPN-VEVZXVCZSA-N 0.000 description 2
- ZIIBRZUXPHJMLW-NUEKZKHPSA-N C([C@H]1NC(=O)OC(C)(C)C)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 Chemical compound C([C@H]1NC(=O)OC(C)(C)C)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 ZIIBRZUXPHJMLW-NUEKZKHPSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YJMPDZLZEKRKFR-ZJIMSODOSA-N (7s)-5-azaspiro[2.4]heptan-7-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CNCC11CC1 YJMPDZLZEKRKFR-ZJIMSODOSA-N 0.000 description 1
- PGEGEJNTABPWJH-GFCCVEGCSA-N (7s)-5-benzyl-5-azaspiro[2.4]heptan-7-amine Chemical compound C([C@H](C1(CC1)C1)N)N1CC1=CC=CC=C1 PGEGEJNTABPWJH-GFCCVEGCSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ONUWJJIRDXEMLU-UHFFFAOYSA-N 2-methylpropyl hypochlorite Chemical compound CC(C)COCl ONUWJJIRDXEMLU-UHFFFAOYSA-N 0.000 description 1
- TVOYMYXRLULSCE-GXSJLCMTSA-N 6,7-difluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1[C@@H]1C[C@@H]1F TVOYMYXRLULSCE-GXSJLCMTSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001334 alicyclic compounds Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- GGUKKWVQUROSDV-UHFFFAOYSA-N butan-2-yl hypochlorite Chemical compound CCC(C)OCl GGUKKWVQUROSDV-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GUGRBFQNXVKOGR-UHFFFAOYSA-N butyl hypochlorite Chemical compound CCCCOCl GUGRBFQNXVKOGR-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- NOAADQGAIOTYSP-UHFFFAOYSA-N heptane;dihydrochloride Chemical compound Cl.Cl.CCCCCCC NOAADQGAIOTYSP-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical class Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- BIZGMTWBKDPTLH-UHFFFAOYSA-N propan-2-yl hypochlorite Chemical compound CC(C)OCl BIZGMTWBKDPTLH-UHFFFAOYSA-N 0.000 description 1
- PMYRRVREJIBUQU-UHFFFAOYSA-N propyl hypochlorite Chemical compound CCCOCl PMYRRVREJIBUQU-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av 8-klorkinolonderivater med potensiell antimikrobe-aktivitet og med høy sikkerhet, og som er lovende som et syntetisk antimikrobemiddel. The present invention relates to a method for the production of 8-chloroquinolone derivatives with potential antimicrobial activity and with high safety, and which are promising as a synthetic antimicrobial agent.
8-klor-7-substituert-l-(2-fluorsyklopropyl)-4-kinolonderivater med formel (II) eller (III) som beskrevet i det etterfølgende, kan anvendes som potente antimikrobemidler som -omtalt i EP-A-0341493 og JP-A-Hei-2-231475. 8-Chloro-7-substituted-1-(2-fluorocyclopropyl)-4-quinolone derivatives of formula (II) or (III) as described in the following, can be used as potent antimicrobial agents as mentioned in EP-A-0341493 and JP -A-Hello-2-231475.
Disse forbindelser er fremstilt ved å gå ut fra 3-klor-2,4,5-trifluorbenzosyre. Da det imidlertid er nokså vanskelig å oppnå 3-klor-2,4,5-trifluorbenzosyre med høy renhet på grunn av vanskeligheter i forbindelse med syntesen derav, er fremgangsmåten hvor disse forbindelser anvendes som utgangs-material ikke særlig fordelaktig sett ut fra et økonomisk synspunkt. These compounds are prepared starting from 3-chloro-2,4,5-trifluorobenzoic acid. However, since it is quite difficult to obtain 3-chloro-2,4,5-trifluorobenzoic acid with high purity due to difficulties in connection with its synthesis, the process in which these compounds are used as starting material is not particularly advantageous from an economic point of view point of view.
Et formål for den foreliggende oppfinnelse er å tilveiebringe en fremgangsmåte for fremstilling av 8-klorkinolonderivater ved hjelp av enkle og lette operasjoner og som er økonomisk fordelaktig. An object of the present invention is to provide a method for the production of 8-chloroquinolone derivatives by means of simple and easy operations and which is economically advantageous.
Som et resultat av inngående studier har man etablert en fremgangsmåte hvor et 8-klorkinolonderivat kan oppnås både enkelt og lettvint mens man samtidig oppnår tilfredsstillende utbytte og renhet. As a result of in-depth studies, a method has been established in which an 8-chloroquinolone derivative can be obtained both simply and easily while at the same time achieving satisfactory yield and purity.
Den foreliggende oppfinnelse tilveiebringer således en fremgangsmåte for fremstilling av et 8-klorkinolonderivat med formel (III) The present invention thus provides a method for the preparation of an 8-chloroquinolone derivative of formula (III)
hvor X representerer et halogenatom og R<3> representerer en syklisk aminogruppe valgt fra hvor R<5>, R<6>, R<7>, R<8>, R<9>, R10, R11, R12, R13, R14 og R1<5> hver representerer et hydrogenatom eller en alkylgruppe med 1 til 6 karbona tome r, og hvor R14 og R<15> kan være forbundet med hverandre til å gi en metylenkjede for dannelse av en 3- til 6-leddet ring som er kjennetegnet ved at en kinolonforbindelse med formel (I) hvor R<2> har den for R<3> ovenfor angitte betydning og hvor en amino subst i tuen t på den cykliske aminogruppe eventuelt er beskyttet, og X er som angitt i det foregående, reageres med et kloreringsmiddel, og idet den oppnådde forbindelse med formel (II) where X represents a halogen atom and R<3> represents a cyclic amino group selected from where R<5>, R<6>, R<7>, R<8>, R<9>, R10, R11, R12, R13, R14 and R1<5> each represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, and where R14 and R<15> may be joined together to give a methylene chain to form a 3- to 6-membered ring which is characterized by a quinolone compound of formula (I) where R<2> has the meaning given for R<3> above and where an amino subst in tuen t on the cyclic amino group is optionally protected, and X is as indicated in preceding, is reacted with a chlorinating agent, and as the obtained compound of formula (II)
hvor X og R<2> er som definert i det foregående, deretter eventuelt underkastes fjerning av beskyttelsesgruppen. where X and R<2> are as defined above, then possibly subjected to removal of the protecting group.
De kloreringsmidler som kan anvendes i forbindelse med den foreliggende oppfinnelse kan velges fra sulfurylklorid, natriumhypokloritt, N-klorsuccinimid, klor og en underklorsyrlingester som er representert ved formelen (IV): The chlorinating agents that can be used in connection with the present invention can be selected from sulphuryl chloride, sodium hypochlorite, N-chlorosuccinimide, chlorine and a hypochlorous acid ester represented by the formula (IV):
hvori R<4> er en alkylgruppe med fra 1 til 6 karbonatomer, en fenylalkylgruppe eller en klorfenylalkylgruppe. wherein R<4> is an alkyl group with from 1 to 6 carbon atoms, a phenylalkyl group or a chlorophenylalkyl group.
Som kloreringsmiddel er det foretrukket å anvende sulfurylklorid, klor eller underklorsyrlingesteren med formel (IV) hvor R<4> er en alkylgruppe med 1 til 6 karbonatomer. As a chlorinating agent, it is preferred to use sulphuryl chloride, chlorine or the hypochlorous acid ester of formula (IV) where R<4> is an alkyl group with 1 to 6 carbon atoms.
Blant kloreringsmidlene som er vist i det foregående, er underklorsyrlingesteren særlig foretrukket i henhold til det som er angitt i det etterfølgende. Among the chlorinating agents shown above, the hypochlorous acid ester is particularly preferred according to what is indicated below.
Klorer ing av en forbindelse med formel (I) med en aminogruppe på den heterosykliske gruppe R<2> er tilbøyelig til å være ledsaget av bireaksjoner, noe som resulterer i reduksjon i utbytte og produktrenhet, med mindre aminogruppen er beskyttet. Ved anvendelse av en forbindelse (I) hvor dens aminogruppe er beskyttet, kreves det to ytterligere trinn; innføring av en beskyttelsesgruppe og fjerning av beskyttelsesgruppen. Ved siden av en økning i antall trinn, har innføring og fjerning av en beskyttelsesgruppe en tendens til å gi uønskede bireaksjoner, noe som fører til ytterligere reduksjoner i utbytte og renhet. Chlorination of a compound of formula (I) with an amino group on the heterocyclic group R<2> tends to be accompanied by side reactions, resulting in a reduction in yield and product purity, unless the amino group is protected. When using a compound (I) where its amino group is protected, two additional steps are required; introduction of a protection group and removal of the protection group. Beside an increase in the number of steps, the introduction and removal of a protecting group tends to produce undesirable side reactions, leading to further reductions in yield and purity.
I forbindelse med undersøkelser vedrørende en økonomisk og enkel syntese av 8-klorkinolonderivater, har man nå funnet at dette kan løses ved anvendelse av særlig underklorsyrlingesteren med formel (IV) som et kloreringsmiddel. Anvendelse av denne ester med formel (IV) som kloreringsmiddel gjør det mulig å fremme klorineringen av forbindelsen med formel (I) som har en aminogruppe på dens heterosykliske gruppe R<2>, til å gi den klorerte forbindelse med formel (II) i høyt utbytte og med høy renhet, uavhengig av om aminogruppen er beskyttet eller ikke. In connection with investigations concerning an economical and simple synthesis of 8-chloroquinolone derivatives, it has now been found that this can be solved by using, in particular, the hypochlorous acid ester of formula (IV) as a chlorinating agent. Use of this ester of formula (IV) as a chlorinating agent makes it possible to promote the chlorination of the compound of formula (I) having an amino group on its heterocyclic group R<2>, to give the chlorinated compound of formula (II) in high yield and with high purity, regardless of whether the amino group is protected or not.
Underklorsyrlingesteren med formel (IV) inkluderer alkyl-estere, f.eks. propylestere (f.eks. n-propylhypokloritt og isopropylhypokloritt), butylestere (f.eks. n-butylhypokloritt, isobutylhypokloritt, sec-butylhypokloritt og t-butylhypokloritt) og en benzylester, idet t-butylhypokloritt er foretrukket. The hypochlorous acid ester of formula (IV) includes alkyl esters, e.g. propyl esters (eg n-propyl hypochlorite and isopropyl hypochlorite), butyl esters (eg n-butyl hypochlorite, isobutyl hypochlorite, sec-butyl hypochlorite and t-butyl hypochlorite) and a benzyl ester, with t-butyl hypochlorite being preferred.
Disse hypokloritter syntetiseres på vanlig måte, dvs. ved at en alkohol reageres med et salt av en underklorsyrling eller ved at en blanding av en alkohol og et alkalihydroksyd (f.eks. natriumhydroksyd) reageres med klor. These hypochlorites are synthesized in the usual way, i.e. by reacting an alcohol with a salt of hypochlorous acid or by reacting a mixture of an alcohol and an alkali hydroxide (e.g. sodium hydroxide) with chlorine.
I det tilfellet hvor substituenten R<2> er ytterligere substituert med en aminogruppe, kan denne aminogruppe være beskyttet av en beskyttelsesgruppe. Beskyttelsesgrupper som kan anvendes for aminogruppen på R<2> inkluderer en alkylkarbonyl-gruppe, en alkyloksykarbonylgruppe, en halogenalkylkarbonyl-gruppe, en halogenalkyloksykarbonylgruppe, en fenylalkyl-oksykarbonylgruppe og en nitro- eller klorfenylalkyloksy-karbonylgruppe. Spesifikke eksempler på beskyttelsesgrupper er acetyl, kloracetyl, 2,2,2-trikloretyloksykarbonyl, p-nitrobenzyloksykarbonyl og p-klorbenzyloksykarbonyl. In the case where the substituent R<2> is further substituted with an amino group, this amino group can be protected by a protecting group. Protecting groups that can be used for the amino group of R<2> include an alkylcarbonyl group, an alkyloxycarbonyl group, a haloalkylcarbonyl group, a haloalkyloxycarbonyl group, a phenylalkyloxycarbonyl group and a nitro or chlorophenylalkyloxycarbonyl group. Specific examples of protecting groups are acetyl, chloroacetyl, 2,2,2-trichloroethyloxycarbonyl, p-nitrobenzyloxycarbonyl and p-chlorobenzyloxycarbonyl.
I formlene (I), (II) og (III), er den heterosykliske gruppe som representert ved R<2> eller R<3> som nevnt en syklisk aminogruppe som er avledet fra et syklisk amin. Et syklisk amin er en forbindelse som er avledet fra en alisyklisk forbindelse ved at ringkarbonatomet er erstattet med et nitrogenatom. In formulas (I), (II) and (III), the heterocyclic group represented by R<2> or R<3> as mentioned is a cyclic amino group derived from a cyclic amine. A cyclic amine is a compound derived from an alicyclic compound by replacing the ring carbon atom with a nitrogen atom.
Som vist i det foregående kan den sykliske aminogruppe inneholde en eller flere substituenter, slik som polare grupper (f.eks. en substituert eller usubstituert aminogruppe eller en substituert eller usubstituert aminoalkylgruppe) og en rettkjedet, forgrenet eller syklisk alkylgruppe med fra 1 til 6 karbonatomer. De polare grupper inkluderer foretrukket en usubstituert aminogruppe, en aminometylgruppe og en 1-aminoetylgruppe. Alkylgruppen som substituent på den sykliske aminogruppe inkluderer foretrukket metyl, etyl, propyl, gem-dimetyl og gem-dietyl. Det er også foretrukket at en slik alkylsubstituent danner en syklopropanring eller en syklo-butanring for å danne en spiroring sammen med den sykliske aminogruppe. As shown above, the cyclic amino group may contain one or more substituents, such as polar groups (e.g. a substituted or unsubstituted amino group or a substituted or unsubstituted aminoalkyl group) and a straight-chain, branched or cyclic alkyl group of from 1 to 6 carbon atoms . The polar groups preferably include an unsubstituted amino group, an aminomethyl group and a 1-aminoethyl group. The alkyl group as a substituent on the cyclic amino group preferably includes methyl, ethyl, propyl, gem-dimethyl and gem-diethyl. It is also preferred that such an alkyl substituent forms a cyclopropane ring or a cyclobutane ring to form a spiro ring together with the cyclic amino group.
Spesifikke eksempler på disse sykliske aminogruppene omfatter 3-aminopyrrolidinyl, 3-metylaminopyrrolidinyl, 3-dimetylaminopyrrolidinyl, 3-etylaminopyrrolidinyl, 3-propylaminopyrrolidinyl, 3-isopropylaminopyrrolidinyl, 3- amino-4-metylpyrrolidinyl, 4-amino-2-metylpyrrolidinyl, 4- amino-2,3-dimetylpyrrolidinyl, 3-metylamino-4-metylpyrro-lidinyl, 4-metylamino-2-metylpyrrolidinyl, 4-metylamino-2,3-dimetylpyrrolidinyl, 3-dimetylamino-4-metylpyrrolidinyl, 4-dimetylamino-2-metylpyrrolidinyl, 4-dimetylamino-2,3-dimetylpyrrolidinyl, 3-metylpiperazinyl, 4-metylpiperazinyl, 3,4-dimetylpiperazinyl, 3,5-dimetylpiperazinyl, 3,4,5-trimetylpiperazinyl, 4-etyl-3,5-dimetylpiperazinyl, 4-isopropyl-3,5-dimetylpiperazinyl, 3-aminometylpyrrolidinyl, 3-metylaminometylpyrrolidinyl, 3-(1-amino)etylpyrrolidinyl, 3-(1-metylamino)etylpyrrolidinyl, 3-(1-etylamino)etylpyrro-lidinyl, 3-(1-amino)propylpyrrolidinyl, 3-(1-metylamino)pro-pylpyrrolidinyl, 3-aminopyrrolidinyl, 4-amino-3,3-dimetyl-pyrrolidinyl, 7-amino-5-azaspiro[2,4]heptan-5-yl, 8-amino-6-azaspiro[3,4]oktan-6-yl, 1,4-diazabisyklo[3.2.1]oktan-4-yl, 3,8-diazabisyklo[3.2.1]oktan-3-yl, 8-metyl-3,8-diazabisyklo-[3.2.1]oktan-3-yl og 8-etyl-3,8-diazabisyklo[3.2.1]oktan-3-yl. Specific examples of these cyclic amino groups include 3-aminopyrrolidinyl, 3-methylaminopyrrolidinyl, 3-dimethylaminopyrrolidinyl, 3-ethylaminopyrrolidinyl, 3-propylaminopyrrolidinyl, 3-isopropylaminopyrrolidinyl, 3-amino-4-methylpyrrolidinyl, 4-amino-2-methylpyrrolidinyl, 4-amino -2,3-dimethylpyrrolidinyl, 3-methylamino-4-methylpyrrolidinyl, 4-methylamino-2-methylpyrrolidinyl, 4-methylamino-2,3-dimethylpyrrolidinyl, 3-dimethylamino-4-methylpyrrolidinyl, 4-dimethylamino-2-methylpyrrolidinyl , 4-dimethylamino-2,3-dimethylpyrrolidinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3,5-dimethylpiperazinyl, 3,4,5-trimethylpiperazinyl, 4-ethyl-3,5-dimethylpiperazinyl, 4 -isopropyl-3,5-dimethylpiperazinyl, 3-aminomethylpyrrolidinyl, 3-methylaminomethylpyrrolidinyl, 3-(1-amino)ethylpyrrolidinyl, 3-(1-methylamino)ethylpyrrolidinyl, 3-(1-ethylamino)ethylpyrrolidinyl, 3-(1 -amino)propylpyrrolidinyl, 3-(1-methylamino)propylpyrrolidinyl, 3-aminopyrrolidinyl, 4-amino-3,3-dimethyl-pyrrolidinyl, 7-amino-5- azaspiro[2,4]heptan-5-yl, 8-amino-6-azaspiro[3,4]octan-6-yl, 1,4-diazabicyclo[3.2.1]octan-4-yl, 3,8- diazabicyclo[3.2.1]octan-3-yl, 8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl and 8-ethyl-3,8-diazabicyclo[3.2.1]octan-3 - howl.
Klorering av forbindelsen som er representert ved formelen (I) kan vanligvis gjennomføres ved at forbindelsen (I) oppløses i et løsningsmiddel hvorpå kloreringsmidlet tilsettes til oppløsningen under avkjøling. Chlorination of the compound represented by the formula (I) can usually be carried out by dissolving the compound (I) in a solvent whereupon the chlorinating agent is added to the solution while cooling.
Løsningsmidler som kan anvendes for klorering er ikke spesielt begrenset så lenge de er i stand til å oppløse utgangsforbindelsen og være inaktive overfor kloreringsmidlet. Slike løsningsmidler inkluderer halogenerte hydrokarboner, f.eks. metylenklorid, kloroform, karbontetraklorid og 1,2-dikloretan, alkylkarboksylsyrer, f.eks. eddiksyre, og maursyre. I tillegg kan klorsulfonsyre, alkoholer (f.eks. metanol, etanol og propanol), acetonitril, N,N-dimetylformamid og -etylacetat også anvendes. På bakgrunn av oppløsningsegenskaper og reaksjons-akselererende effekt, er maursyre og eddiksyre foretrukne. Solvents which can be used for chlorination are not particularly limited as long as they are capable of dissolving the starting compound and are inactive towards the chlorinating agent. Such solvents include halogenated hydrocarbons, e.g. methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane, alkyl carboxylic acids, e.g. acetic acid, and formic acid. In addition, chlorosulfonic acid, alcohols (e.g. methanol, ethanol and propanol), acetonitrile, N,N-dimethylformamide and -ethyl acetate can also be used. On the basis of dissolution properties and reaction-accelerating effect, formic acid and acetic acid are preferred.
Klorering av forbindelsen med formel (I) gjennomføres enten i en oppløsning eller en suspensjon av forbindelse (I) i et løsningsmiddel, og foretrukket i en oppløsning. Reaksjonen gjennomføres ved en temperatur opp til tilbakeløpstemperaturen for det anvendte løsningsmiddel, vanligvis ved avkjøling med is eller ved romtemperatur (dvs. fra 0°C til 30°C). Chlorination of the compound of formula (I) is carried out either in a solution or a suspension of compound (I) in a solvent, and preferably in a solution. The reaction is carried out at a temperature up to the reflux temperature of the solvent used, usually by cooling with ice or at room temperature (ie from 0°C to 30°C).
Kloreringsmidlet anvendes vanligvis i en mengde fra 1 til 2 molekvivalenter i forhold til utgangsforbindelsen (I). Når klor anvendes som et kloreringsmiddel, kan det vanligvis anvendes i overskudd. The chlorinating agent is usually used in an amount of from 1 to 2 molar equivalents in relation to the starting compound (I). When chlorine is used as a chlorinating agent, it can usually be used in excess.
Kloreringsreaksjonen i henhold til den foreliggende oppfinnelse skjer raskt og er fullstendig innen 5 minutter til 10 timer og vanligvis innen 5 minutter til 2 timer med avkjøling på is. The chlorination reaction according to the present invention is rapid and is complete within 5 minutes to 10 hours and usually within 5 minutes to 2 hours with cooling on ice.
Når R<2> i den klorerte forbindelse med formel (II) har en beskyttet aminogruppe, kan beskyttelsesgruppen fjernes ved hjelp av kjente metoder som katalytisk reduksjon eller ved sur eller alkalisk hydrolyse. When R<2> in the chlorinated compound of formula (II) has a protected amino group, the protective group can be removed using known methods such as catalytic reduction or by acid or alkaline hydrolysis.
Det ønskede 8-klorkinolonderivat med formel (III) kan deretter isoleres fra reaksjonsblandingen ved hjelp av vanlig anvendte kjemiske metoder som ekstraksjon, vasking av ekstraktet, separasjon ved silikagelkolonnekromatografi, rekrystallisering og represipitering. The desired 8-chloroquinolone derivative of formula (III) can then be isolated from the reaction mixture using commonly used chemical methods such as extraction, washing of the extract, separation by silica gel column chromatography, recrystallization and precipitation.
Den foreliggende oppfinnelse skal nå illustreres nærmere ved hjelp av undereksempler og eksempler. Alle prosentandeler er i vektprosent dersom annet ikke er indikert. The present invention will now be illustrated in more detail by means of sub-examples and examples. All percentages are by weight unless otherwise indicated.
Undereksempel 1 Subexample 1
7-( S) - amino- 5- azaspiro[ 2. 4] heptandihvdroklorid 7-( S )- amino- 5- azaspiro[ 2. 4] heptane dihydrochloride
En blanding av 6,07 g 7-(S)-amino-5-benzyl-5-azaspiro-[2.4]heptan, 7,5 ml konsentrert saltsyre og 2,4 g 5 % palladium-på-karbon (fuktighet 50 %) i 2 00 ml metanol ble rystet under en hydrogenatmosfære i 20 timer. Katalysatoren ble fjernet ved filtrering og filtratet ble konsentrert til tørrhet under redusert trykk til å gi 5,13 g av tittelforbindelsen i form av et pulver. A mixture of 6.07 g of 7-(S)-amino-5-benzyl-5-azaspiro-[2.4]heptane, 7.5 ml of concentrated hydrochloric acid and 2.4 g of 5% palladium-on-carbon (moisture 50% ) in 200 ml of methanol was shaken under a hydrogen atmosphere for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness under reduced pressure to give 5.13 g of the title compound as a powder.
Smp.: 222-238°C (spalting) Melting point: 222-238°C (decomposition)
[<X]D: -43,27° (c=0,537, H20) [<X]D: -43.27° (c=0.537, H 2 O)
Elementanalyser for C6H12N2'2HC1:Elemental analyzes for C6H12N2'2HC1:
Beregnet (%): C 38,93; H 7,62; N 15,13 Calculated (%): C 38.93; H 7.62; N 15,13
Funnet (%): C 38,83; H 7,88; N 14,67 Found (%): C 38.83; H 7.88; N 14.67
<1>H-NMR (D20) 8: 0,9-1,3 (4H, m) , 3,25 og 3,72 (1H, d, <1>H-NMR (D2O) δ: 0.9-1.3 (4H, m), 3.25 and 3.72 (1H, d,
J=12,2Hz, hver), 3,68 og 3,82 (1H, dd, J=12,2, 2,9Hz, hver), 4,10 (1H, dd, J=7,3, 6,4Hz) J=12.2Hz, each), 3.68 and 3.82 (1H, dd, J=12.2, 2.9Hz, each), 4.10 (1H, dd, J=7.3, 6, 4Hz)
Undereksempel 2 Subexample 2
7-[7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluor-1-[(IR,2S)-2-fluor-l-syklopropyl]-1,4-dihvdro- 4- oksokinolin- 3- karboksvlsvremonohvdroklorid 7-[7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl]-1,4- dihydro- 4- oxoquinoline- 3- carboxylic acid monohydrochloride
Til 85 ml acetonitril ble det tilsatt 4,25 g 6,7-difluor-1-[ (IR, 2S) -2-f luor-l-syklopropyl] -1,4-dihydro-4-oksokinolin-3-karboksylsyre, 3,33 g 7-(S)-amino-5-azaspiro[2.4]heptan-dihydroklorid og 10,5 ml trietylamin, og blandingen ble oppvarmet med tilbakeløp i 2,5 time. Etter avkjøling ble det dannede presipitat samlet ved filtrering og suspendert i 30 ml vann. Til denne suspensjonen ble det tilsatt 2,5 ml konsentrert saltsyre og blandingen ble omrørt ved romtempe-råtur i 1 time. En krystall i suspensjonen ble samlet ved filtrering, vasket med vann og tørket til å gi 5,81 g av tittelforbindelsen. To 85 ml of acetonitrile was added 4.25 g of 6,7-difluoro-1-[(IR, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3.33 g of 7-(S)-amino-5-azaspiro[2.4]heptane dihydrochloride and 10.5 ml of triethylamine, and the mixture was heated under reflux for 2.5 hours. After cooling, the precipitate formed was collected by filtration and suspended in 30 ml of water. To this suspension was added 2.5 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 1 hour. A crystal in the suspension was collected by filtration, washed with water and dried to give 5.81 g of the title compound.
Smp.: 228-233°C (spalting) Melting point: 228-233°C (decomposition)
[<X]D: -23,93° (c=0,449, IN NaOH) [<X]D: -23.93° (c=0.449, 1N NaOH)
Elementanalyser for C19H19N3F203* HC1-1/2H20: Elemental analyzes for C19H19N3F203* HC1-1/2H20:
Beregnet (%): C 54,22; H 5,03; N 9,98 Calculated (%): C 54.22; H 5.03; N 9.98
Funnet (%): C 53,88; H 5,24; N 9,64 Found (%): C 53.88; H 5.24; N 9.64
<1>H-NMR (NaOD) 8: 0,4-0,8 (4H, m), 1,4-1,7 (2H, m), 2,97 <1>H-NMR (NaOD) δ: 0.4-0.8 (4H, m), 1.4-1.7 (2H, m), 2.97
(1H, br s), 3,10 og 3,53 (1H, d, J=10,3Hz, hver), 3,15-3,3 (2H, m), 3,71 (1H, br s), 5,05 (1H, br d, J=64,0Hz), 6,40 (1H, d, J=7,3Hz), 7,51 (1H, d, J=15,lHz), 8,28 (1H, br s), 3.10 and 3.53 (1H, d, J=10.3Hz, each), 3.15-3.3 (2H, m), 3.71 (1H, br s) , 5.05 (1H, br d, J=64.0Hz), 6.40 (1H, d, J=7.3Hz), 7.51 (1H, d, J=15.1Hz), 8.28
(1H, s) (1H, s)
Eksempel 1 Example 1
7-[7-(S)-t-butoksykarbonylamino-5-azaspiro[2.4]heptan-5-yl]-8-klor-6-fluor-1-[(IR,2S)-2-fluor-l-syklopropyl]- 1, 4- dihydro- 4- oksokinolin- 3- karboksylsvre 7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl ]- 1, 4- dihydro- 4- oxoquinoline- 3- carboxylic acid
I 20 ml diklormetan ble det oppløst 120 mg 7-[7-(S)-t-butoksykarbonylamino-5-azaspiro[2.4]heptan-5-yl]-6-fluor-1-[(IR,2 S)-2-fluor-1-syklopropy1]-1,4-dihydro-4-oksokino1in-3-karboksylsyre, og en oppløsning av 40 mg sulfurylklorid i 5 ml diklormetan ble tilsatt dråpevis dertil over en periode på 5 minutter under omrøring og med avkjøling på is. Etter den dråpevise tilsetning ble omrøringen fortsatt i ytterligere 10 minutter. Etter at man hadde bekreftet at utgangsmaterialet var forsvunnet ved hjelp av tynnsjiktkromatografi, ble reaksjonsblandingen vasket påfølgende med en mettet vandig oppløsning av natriumhydrogenkarbonat og vann, og deretter tørket over vannfri natriumsulfat. Diklormetan ble fjernet fra blandingen under redusert trykk. Resten ble renset i en kolonne som var pakket med 10 g silikagel ved anvendelse av et elueringsmiddel bestående av en blanding av kloroform og metanol (9:1, i volumdeler) til å gi 101 mg av tittelforbindelsen. 120 mg of 7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(IR,2 S)-2 were dissolved in 20 ml of dichloromethane -fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and a solution of 40 mg of sulfuryl chloride in 5 ml of dichloromethane was added dropwise thereto over a period of 5 minutes with stirring and cooling on ice . After the dropwise addition, stirring was continued for a further 10 minutes. After confirming the disappearance of the starting material by thin layer chromatography, the reaction mixture was subsequently washed with a saturated aqueous solution of sodium bicarbonate and water, and then dried over anhydrous sodium sulfate. Dichloromethane was removed from the mixture under reduced pressure. The residue was purified on a column packed with 10 g of silica gel using an eluent consisting of a mixture of chloroform and methanol (9:1, by volume) to give 101 mg of the title compound.
Smp.: 223-226°C M.p.: 223-226°C
[cc]D: -211,15° (c=0,771, kloroform) [cc]D: -211.15° (c=0.771, chloroform)
Elementanalyser for Cj^^lFj^C^: Elemental analyzes for Cj^^lFj^C^:
Beregnet (%): C 56,53; H 5,14; N 8,24 Calculated (%): C 56.53; H 5.14; N 8.24
Funnet (%): C 56,67; H 4,95; N 8,14 Found (%): C 56.67; H 4.95; N 8,14
%-NMR-spektret for produktet var identisk med spektret i de rapporterte data. The % NMR spectrum of the product was identical to the spectrum in the reported data.
Eksempel 2 Example 2
7-(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl)-8-klor-6-fluor-1-[(IR,2S)-2-fluor-l-syklopropyl]-1, 4- dihvdro- 4- oksokinolin- 3- karboksvlsvre 7-(7-(S)-amino-5-azaspiro[2.4]heptan-5-yl)-8-chloro-6-fluoro-1-[(IR,2S)-2-fluoro-1-cyclopropyl]- 1, 4- dihydro- 4- oxoquinoline- 3- carboxylic acid
Til klorsulfonsyre ble det tilsatt 120 mg 7-(7-(S)-t-butoksykarbonylamino-5-azaspiro[2.4]heptan-5-yl)-6-fluor-1-[(IR,2S)-2-fluor-l-syklopropyl]-1,4-dihydro-4-oksokinolin-3-karboksylsyre under omrøring og med avkjøling på is, og en spormengde jod ble deretter tilsatt. Klorgass ble innført i oppløsningen i 10 minutter og blandingen ble omrørt i 1 time. Reaksjonsblandingen ble helt over i isvann. Blandingen ble først gjort alkalisk med en IN vandig oppløsning av natriumhydroksyd og deretter ble pH justert til 7 med en vandig oppløsning av sitronsyre. Blandingen ble ekstrahert med tre 50 ml porsjoner kloroform og ekstraktet ble tørket over vannfri natriumsulfat. Oppløsningsmidlet ble fjernet under redusert trykk og resten ble rekrystallisert fra vandig etanol til å gi 45 mg av tittelforbindelsen. To chlorosulfonic acid was added 120 mg of 7-(7-(S)-t-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl)-6-fluoro-1-[(IR,2S)-2-fluoro- 1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with stirring and cooling on ice, and a trace amount of iodine was then added. Chlorine gas was introduced into the solution for 10 minutes and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water. The mixture was first made alkaline with a 1N aqueous solution of sodium hydroxide and then the pH was adjusted to 7 with an aqueous solution of citric acid. The mixture was extracted with three 50 ml portions of chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from aqueous ethanol to give 45 mg of the title compound.
Smp.: 127,3-135,5°C M.p.: 127.3-135.5°C
[CC]D: -179° (c=l,12, IN NaOH) [CC]D: -179° (c=1.12, 1N NaOH)
Elementanalyser for C19H18C1F2N303- 3/2H20: Elemental analyzes for C19H18C1F2N303- 3/2H20:
Beregnet (%): C 52,24; H 4,85; N 9,61 Calculated (%): C 52.24; H 4.85; N 9.61
Funnet (%): C 52,16; H 4,70; N 9,53 Found (%): C 52.16; H 4.70; N 9.53
Eksempel 3 Example 3
7-[7-(S)-amino-5-azaspiro[2.4]heptan-5-yl)-8-klor-6-fluor-1-[(1R,2S)-2-fluor-l-syklopropyl]-1, 4- dihvdro- 4- oksokinolin- 3- karboksvlsyre 7-[7-(S)-amino-5-azaspiro[2.4]heptan-5-yl)-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]- 1, 4- dihydro- 4- oxoquinoline- 3- carboxylic acid
I 15 ml maursyre ble det oppløst 3,09 g 7-[7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluor-1-[(IR,2S)-2-fluor-l-syklopropyl] -1, 4-dihydro-4-oksokinolin-3-karboksylsyre-hydroklorid, og oppløsningen ble avkjølt slik at temperaturen i oppløsningen var i området fra 5 til 10°C. Til oppløsningen ble det dråpevis og sakte tilsatt 1,25 g t-butylhypokloritt ved denne temperatur. Etter tilsetningen ble reaksjonsblandingen ytterligere omrørt i 5 minutter, helt over i kaldt vann og nøytralisert med en 20 % vandig natriumhydroksyd-oppløsning. En utfelt krystall ble samlet ved filtrering, vasket med vann og tørket til å gi 3,02 g av tittelforbindelsen som en lysegul krystall. In 15 ml of formic acid, 3.09 g of 7-[7-(S)-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(IR,2S)-2- fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, and the solution was cooled so that the temperature of the solution was in the range of 5 to 10°C. 1.25 g of t-butyl hypochlorite was added dropwise and slowly to the solution at this temperature. After the addition, the reaction mixture was further stirred for 5 minutes, poured into cold water and neutralized with a 20% aqueous sodium hydroxide solution. A precipitated crystal was collected by filtration, washed with water and dried to give 3.02 g of the title compound as a pale yellow crystal.
Smp.: 221-226°C (spalting) Melting point: 221-226°C (decomposition)
[a]D: -209,7° (c=0,631, IN NaOH) [α]D: -209.7° (c=0.631, 1N NaOH)
Elementanalyser for C19<H>18C1F2N305-3/2H20: Elemental analyzes for C19<H>18C1F2N305-3/2H20:
Beregnet (%): C 52,24; H 4,85; N 9,61 Calculated (%): C 52.24; H 4.85; N 9.61
Funnet (%): C 52,31; H 4,52; N 9,60 <1>H-NMR-spektret for produktet var identisk med det som er angitt i rapporterte data. Found (%): C 52.31; H 4.52; N 9.60 <1>H-NMR spectrum of the product was identical to that indicated in the reported data.
Eksempel 4 Example 4
7-[7-(S)-t-butoksykarbonylamino-5-azaspiro[2.4]-heptan-5-yl]-8-klor-6-fluor-1-[(IR,2S)-2-fluor-1-cvklopropyl]- 1, 4- dihvdro- 4- oksokinolin- 3- karboksvlsvre 7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-6-fluoro-1-[(IR,2S)-2-fluoro-1- cyclopropyl]- 1, 4- dihydro- 4- oxoquinoline- 3- carboxylic acid
I 5 ml metylenklorid ble det oppløst 238 mg 7-[7-(S)-t-butoksykarbonylamino-5-azaspiro[2.4]heptan-5-yl]-6-fluor-1-[(IR,2S)-2-fluor-l-syklopropyl]-1,4-dihydro-4-oksokinolin-3-karboksylsyre, og 80 mg t-butylhypokloritt ble dråpevis og sakte tilsatt til blandingen under avkjøling med is. Etter tilsetningen ble blandingen ytterligere omrørt ved denne temperatur i 2 timer. Reaksjonsblandingen ble vasket påfølgende med en 5 % vandig oppløsning av sitronsyre og vann, og oppløsningsmidlet ble fjernet under redusert trykk til å gi 217 mg av tittelforbindelsen i form av et lysegult pulver. In 5 ml of methylene chloride, 238 mg of 7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(IR,2S)-2- fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and 80 mg of t-butyl hypochlorite were added dropwise and slowly to the mixture while cooling with ice. After the addition, the mixture was further stirred at this temperature for 2 hours. The reaction mixture was washed subsequently with a 5% aqueous solution of citric acid and water, and the solvent was removed under reduced pressure to give 217 mg of the title compound as a pale yellow powder.
Smp.: 220-224°C M.p.: 220-224°C
[<X]D: -208,31° (c=0,693, kloroform) [<X]D: -208.31° (c=0.693, chloroform)
Elementanalyser for C24H26C1F2N305: Elemental analyzes for C24H26C1F2N305:
Beregnet (%): C 56,53; H 5,14; N 8,24 Calculated (%): C 56.53; H 5.14; N 8.24
Funnet (%): C 56,21; H 5,04; N 8,31 Found (%): C 56.21; H 5.04; N 8.31
H<->NMR-spektret for produktet var identisk med det som er The H<->NMR spectrum of the product was identical to what is
angitt i rapporterte data. indicated in reported data.
I henhold til fremgangsmåten for den foreliggende oppfinnelse According to the method of the present invention
kan 8-klorkinolonderivater oppnås i tilfredsstillende utbytte og med høy renhet ved hjelp av enkle operasjoner. Når utgangskinolonderivatet har en aminogruppe som en substituent i sitt molekyl, vil spesielt anvendelse av en underklorsyrlingester som et kloreringsmiddel gjøre det mulig å oppnå klorering av en slik forbindelse uten nødvendig beskyttelse av aminogruppen og med samtidig oppnåelse av tilfredsstillende utbytte og produktrenhet. 8-chloroquinolone derivatives can be obtained in satisfactory yield and with high purity by means of simple operations. When the starting quinolone derivative has an amino group as a substituent in its molecule, in particular the use of a hypochlorous acid ester as a chlorinating agent will make it possible to achieve chlorination of such a compound without the necessary protection of the amino group and with the simultaneous achievement of a satisfactory yield and product purity.
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27977890 | 1990-10-18 | ||
| JP22815391 | 1991-05-30 |
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| Publication Number | Publication Date |
|---|---|
| NO914053D0 NO914053D0 (en) | 1991-10-16 |
| NO914053L NO914053L (en) | 1992-04-21 |
| NO179517B true NO179517B (en) | 1996-07-15 |
| NO179517C NO179517C (en) | 1996-10-23 |
Family
ID=26528079
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO914053A NO179517C (en) | 1990-10-18 | 1991-10-16 | Process for the preparation of 8-chloroquinolone derivatives |
Country Status (16)
| Country | Link |
|---|---|
| KR (1) | KR100253047B1 (en) |
| CN (1) | CN1038509C (en) |
| AR (1) | AR247884A1 (en) |
| AT (1) | AT402501B (en) |
| EE (1) | EE03027B1 (en) |
| ES (1) | ES2039300B1 (en) |
| FI (1) | FI100531B (en) |
| GR (1) | GR1000997B (en) |
| HU (1) | HU221195B1 (en) |
| MX (1) | MX9101668A (en) |
| MY (1) | MY109714A (en) |
| NO (1) | NO179517C (en) |
| PL (1) | PL168831B1 (en) |
| PT (1) | PT99268B (en) |
| RU (1) | RU2049778C1 (en) |
| YU (1) | YU48819B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0593766T3 (en) * | 1991-05-28 | 2000-10-09 | Daiichi Seiyaku Co | pyridonecarboxylic |
| ZA946853B (en) * | 1993-09-10 | 1995-04-24 | Daiichi Seiyaku Co | Crystals of antimicrobial compound. |
| CN1184221C (en) * | 2001-08-08 | 2005-01-12 | 中国医学科学院医药生物技术研究所 | New quinaldinic acid derivative with 7-(7-aminomethyl-5-azaspiro [2,4] heplane) substituent and its preparation method |
| CN103483315B (en) * | 2013-09-18 | 2015-07-01 | 浙江司太立制药股份有限公司 | 7-(3-aminomethyl-4-alkoxyimino-1-piperidyl)-1-[(1R,2S)-2-fluorocyclopropyl] quinolone carboxylic acid compounds and preparation method thereof |
| CN103709100A (en) * | 2013-12-31 | 2014-04-09 | 南京工业大学 | Preparation method of 8-chloroquinolone derivatives |
| CN104892600B (en) * | 2015-06-04 | 2017-02-01 | 浙江司太立制药股份有限公司 | 7-(3-aminomethyl-4-substituted-benzyloxyimino-1-pyrrolidinyl)naphthyridinone carboxylic acid compounds |
| CN107513053A (en) * | 2015-08-10 | 2017-12-26 | 江苏吴中医药集团有限公司 | A kind of preparation method of sitafloxacin hydrate |
| CN105669646B (en) * | 2016-02-26 | 2018-03-09 | 济川药业集团有限公司 | A kind of synthetic method of sitafloxacin |
| CN113527200B (en) * | 2021-05-27 | 2022-12-02 | 北京斯利安药业有限公司 | Preparation method of cloquinadol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2840437A1 (en) * | 1978-09-16 | 1980-04-03 | Hoechst Ag | 8-CHLORINE-5,6,7,8-TETRAHYDRO-2-CHINOLONE AND 8-CHROME-5,6,7,8-TETRAHYDRO-2-CHINOLONE, THEIR HYDROCHLORIDE OR. HYDROBROMIDE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3576335D1 (en) * | 1984-12-14 | 1990-04-12 | Daiichi Seiyaku Co | CHINOLINE CARBONIC ACID DERIVATIVES. |
| JPH0635457B2 (en) * | 1985-06-28 | 1994-05-11 | 杏林製薬株式会社 | Pyridonecarboxylic acid derivative and method for producing the same |
| DE3635218A1 (en) * | 1986-10-16 | 1988-04-21 | Bayer Ag | 7-AMINO-1-CYCLOPROPYL-8-CHLORINE-6-FLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR ANTIBACTERIAL AGENTS CONTAINING THEM |
| JPS6490183A (en) * | 1987-09-30 | 1989-04-06 | Kyorin Seiyaku Kk | Production of quinolonecarboxylic acid derivative |
| JPH0196786A (en) * | 1987-10-09 | 1989-04-14 | Toshiba Corp | Data totalization processing system for ticket checker |
| MY105136A (en) * | 1988-04-27 | 1994-08-30 | Daiichi Seiyaku Co | Optically active pyridonecarboxylic acid derivatives. |
| CA1336090C (en) * | 1988-08-31 | 1995-06-27 | Isao Hayakawa | Spiro-substituted cyclic amines of quinolone derivatives |
-
1991
- 1991-10-12 MY MYPI91001865A patent/MY109714A/en unknown
- 1991-10-14 YU YU165791A patent/YU48819B/en unknown
- 1991-10-16 FI FI914875A patent/FI100531B/en active
- 1991-10-16 NO NO914053A patent/NO179517C/en unknown
- 1991-10-17 PL PL91292087A patent/PL168831B1/en not_active IP Right Cessation
- 1991-10-17 PT PT99268A patent/PT99268B/en not_active IP Right Cessation
- 1991-10-17 GR GR910100427A patent/GR1000997B/en not_active IP Right Cessation
- 1991-10-17 ES ES09102304A patent/ES2039300B1/en not_active Expired - Fee Related
- 1991-10-17 RU SU915010041A patent/RU2049778C1/en not_active IP Right Cessation
- 1991-10-17 AT AT0206691A patent/AT402501B/en not_active IP Right Cessation
- 1991-10-17 AR AR91320942A patent/AR247884A1/en active
- 1991-10-17 HU HU280/91A patent/HU221195B1/en not_active IP Right Cessation
- 1991-10-18 KR KR1019910018376A patent/KR100253047B1/en not_active IP Right Cessation
- 1991-10-18 CN CN91110833A patent/CN1038509C/en not_active Expired - Lifetime
- 1991-10-18 MX MX9101668A patent/MX9101668A/en unknown
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- 1994-11-22 EE EE9400253A patent/EE03027B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| YU165791A (en) | 1994-05-10 |
| KR920008007A (en) | 1992-05-27 |
| PL168831B1 (en) | 1996-04-30 |
| FI914875A0 (en) | 1991-10-16 |
| NO914053D0 (en) | 1991-10-16 |
| NO179517C (en) | 1996-10-23 |
| ES2039300B1 (en) | 1994-05-16 |
| HU221195B1 (en) | 2002-08-28 |
| PT99268B (en) | 1999-04-30 |
| PL292087A1 (en) | 1992-11-16 |
| RU2049778C1 (en) | 1995-12-10 |
| HU913280D0 (en) | 1992-01-28 |
| YU48819B (en) | 2001-12-26 |
| GR910100427A (en) | 1992-09-25 |
| CN1062906A (en) | 1992-07-22 |
| GR1000997B (en) | 1993-03-31 |
| AT402501B (en) | 1997-06-25 |
| MX9101668A (en) | 1992-06-05 |
| ATA206691A (en) | 1996-10-15 |
| FI914875A (en) | 1992-04-19 |
| MY109714A (en) | 1997-04-30 |
| HUT59388A (en) | 1992-05-28 |
| CN1038509C (en) | 1998-05-27 |
| NO914053L (en) | 1992-04-21 |
| ES2039300A1 (en) | 1993-09-16 |
| EE03027B1 (en) | 1997-08-15 |
| KR100253047B1 (en) | 2000-05-01 |
| AR247884A1 (en) | 1995-04-28 |
| PT99268A (en) | 1992-08-31 |
| FI100531B (en) | 1997-12-31 |
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