LV10774B - Process for preparation of 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid, 6-fluoro-4-oxo-7-(4-carbethoxy-1-piperazinyl)-1,4-dihydroquinoline-3-ethylcarboxylate and method for preparing thereof - Google Patents

Process for preparation of 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid, 6-fluoro-4-oxo-7-(4-carbethoxy-1-piperazinyl)-1,4-dihydroquinoline-3-ethylcarboxylate and method for preparing thereof Download PDF

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LV10774B
LV10774B LV930828A LV930828A LV10774B LV 10774 B LV10774 B LV 10774B LV 930828 A LV930828 A LV 930828A LV 930828 A LV930828 A LV 930828A LV 10774 B LV10774 B LV 10774B
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Latvia
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piperazinyl
oxo
fluoro
dihydroquinoline
carboxylic acid
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LV930828A
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English (en)
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LV10774A (lv
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Natasa Zupancic
Boris Sket
Marko Zupan
Pavel Zupet
Marjeta Globokar
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Krka Tovarna Zdravil
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Publication of LV10774B publication Critical patent/LV10774B/lv

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Description

LV 10774
CnOCOE ΠΟΠΥΗΕΗΜΡ l-3AMELL|EHHOl/l 6-ΦΤΟΡ-4-ΟΚΟΟ-7-/Ι-ΠΜΠΕΡΑ31/1Η1/1Π/4,4-ΑΜΓΜΑΡΟΧΙ/1ΗΟΠΜΗ-3-ΚΑΡΕΟΗΟΒΟΙ/1 Kl/ICnOTbl Μ CJ10>KHblM STMJIOBblI/l 3ΦΜΡ I-3AMEHEHHOI/1 6-ΦΤΟΡ'4-ΟΚΟΟ-7-/4-ΚΑΡΕ3ΤΟΚΟΜ-Ι-Π1/1ΠΕΡΑ3ΜΗΜΠ/-Ι,4-ΠΜΓΜΠΡΟΧΜΗΟΠΜΗ-3-ΚΑΡΕΟΗΟΒΟΙ/1 KMCflOTbl 1/1 CnOCOE
ΕΓΟ ΠΟΠΥΗΕΗΙ/IR
HacTOflinee M3o6peieHne othocmtcji κ oGnacTM opraHunecKoro cnHTe3a n othocmtch κ cnoco6y nonyHeHHfl l-3aMemeHHoii 6-φτορ-4-οκοο-7-/Ι-nnnepa3MHMn/-lI4-fliirMflpoxMHonnH-3*Kap6oHOBoii κμοποτβι očmeM 0opwynbi I:
rfle R «Bn^eTCfl CH2CH3l αμκποπροπμπομ, CH2CH2OH, CH2OCH2CH2OH, ηοβογο οποχηογο 30npa l-3aMemeHHOM 6-φτορ-4-οκοο-7-/4-κΒρ63τοκοΜ-Ι-nnnepa3MHnn/-l,4-flnrnnpoxnHonnH-3-Kap6oHOBOM KMcnoTbi φopMyπbι II: 0
COOR1 COOCH2CH3 rfle R μμθθτ Te xe 3HaMeHM5i, hto m yKa3aHHbie paHee, a R1 αβπηθτοη stmhom, a Taxxe κ cnoco6y nonyHeHMfi coeflMHeHMfl φopMyπbl II, rfle R1 «BrifieTCfl BOflOpOflOM ΜΠΜ 3ΤΜΠ0Μ.
CoeflMHeHMe φopMyπbι I Mcnonb3yK>T b MeflMUMHe απη πθηθημα BOcnanMTenbHbix 3a6oneBaHMM. Ohm o6naflaioT ujmpokmm cneicrpoM aKTMBHocTeii προτΜΒ Kax rpaMnono>KMTenbHbix, TaK m rpaMOTpMqaTenbHbix čaKTepMM. -2 -
CymecTBOBana Heo6xoflHMocTb b hobom cnoco6e nonyHeHna coeflUHeHMfl φοριν^πω I, κοτορωρί 6bin 6bi caM no ce6e προοτ, οοθαιίηθημθ πθγκο 6bino 6bi Bbipen^Tb, c BbicoKMM BbixoflOM ueneBoro npoflyKTa, n stot cnoco6 βοπ>κθΗ 6bin 6bi omunaTbCJi ot yx<e 3aflBneHHbix cnoco6oB nonyHeHi/ifl yKa3aHHbix coeflUHeHnii. B naTeHTHoti nniepaiype pacKpbiT cnoco6 nonyHeHUfl οοθαηηθημα o6meii φopMyπbl I, HanpuMep, xax peaKLiM* xnop3aMeiueHHoro b ποποχθημμ 7- c nnnepa3HHOM b αποηοκομ naieHTHoii 3a?iBKe 66686/1979 n 33453/1980/ b Bbinox<eHHbix 3aflBKax ΦΡΓ flE 2840910 n 3308909, a Taoce xax peaxunfl rnAponn3a anKunoBoro οπο?κηογο 3φκρ3 b naTeHie Benbrnn 890223.
Cnoco6 HacTOfliuero μ3ο6ρθτθημη ocymecTBnaioT τθκμμ o6pa30M, hto l-3aMeiueHHyio 6^Top-4-oKco-7-/4-Kap6o3TOKcn-l-nnnepa3HHnn/-l,4-
Anri/iApoxnHonnH-3-Kap6oHOByio KMcnoTy nnn ee cno>KHbifi sTunoBbitf 3φΐ/ΐρ očiueii φοριν^Γ^ι II:
O
COOCH2CH3 γαθ R μμθθτ yKa3aHHbie paHee 3HaHeHMfl, a R1 αβπαθτοα boaopoaom nnn 3TnnoM, rnAponn3yioT b LuenoHHoii cpeAe ao nonyHeHnyi οοθακηθημα φορΜνπω I. ΓHAP0J1H3 npeAnoHTUTenbHo BeAyT b pacTBope KOH nnn aOH, m ripu TeMnepaType κμπθημα c očpambiM xonoAnnbHHKOM peaKLinoHHoii CMecn. rionyHeHHyK3 l-3aMeiueHHyio-6^Top-4-OKCo-7-/l-nMnepa3HHnn/-l,4-AnrnAPoxnHonnH-3-Kap6oHOByio Kncnoiy b φορΜθ conu HeūTpann3yioT, a 3aTeM nepeKpncTannn30BbiBai0T, HanpuMep, H3 cMecu Ν,Ν—ΑΜΜΘΤΙ/1ΠφθρΜ3ΜΙ/1ΑΘ m STaHona.
CoeAMHeHne φοριν^/^ι II, γαθ R1 αβπαθτοα stuhom, flBnaeTc* hobhm οοθα^ηθημθμ, m TaK>Ke ηβπαθτοα oahum H3 očteKTOB HacTOJuiļero n3o6peTeHna. HoBbiM sinnoBbiii cno>KHbiii 3φκρ nonynaK)T cnocočoM, KOTopbiii TaioKe ηβπαθτοα oahmm W3 ο61>θκτοβ Hacroflmero μ3ο6ρθτθημη, H3 3TnnoBoro cnox<Horo 3φι/ιρ3 l-3aMeiueHHoii 6-Φτορ-7-γ3πομα-4-οκοο-Ι,4-αιί™αροχμηοπμη- -3- LV 10774 3-Kap6oHOBoii KUcnoTbi. CoeflUHeHne φορινιγπΝ II, b κοτοροΜ R1 nenneTcn BOflopoflOM, nonyHaK)T τ3κ>κθ M3 l-3aMeLAeHHon-6^Top-7-ranonA-4-oKco-l,4-AnrnflpoxnHonnH-3-Kap6oHOBoii KMcnoTbi, hto BMflHo H3 npnB6ABHHon Aanee cxeMbi peaKijnn:
base ▼
O
COOR1
γαθ R = CH2CH3, UMKnonponi/inoM, CH2CH2OH, CH2OCH2CH2OH R1 = H, CH2CH3 X = TaKMM ranonAOM xax Cl, F
PeaKUUto βθαυτ b ποπηρΗωχ opraHHHecKnx pacTBopnTenax μπμ nx CMecax, Τ3ΚΜΧ xax Ν,Ν-αμμθτμπΦορμθμμα, βι-ιθτοη nTpnn, nnpnAnH, 2-μθτκπ- 5-3TMnnHpHAHH, Ι-ΜΘΤΜΠΠΜρρΟΠΜΑΟΗ, ΑΜΜΘΤΜΠΟγΠΒφΟΚΟΜΑ H T. Α·, Β npncyTCTBHn areHTa, CBfl3biBa»omero o6pa3y»omyK>cfl HX. Οπη θτογο mojkho ncnonb30BaTb TaKoiži peareHT xax l-Kap6o3TOKcnnnnepa3HH oahh nnn KaKoe-nnčo Apyroe ocHOBaHi/ie, HanpuMep, KapčoHaT HaTpna nnn Kanna.
Cnocoč HacTomuero n3o6peTeHna απα nonyHeHna οοθαμηθημμ φopMyπbι I aBnaeTca HOBbiM n ηθ onncaH b nnTepaiype. ΚροΜβ τογο, cnocoč nonyneHna n βηαθπθημα οοθαμηθημα φορινιγπΝ I προοτ, n npn stom AOCTnraKDT BblCOKHX BblXOAOB. flanee n3o6peieHne nnmocTpnpyeTca 6onee ποαρο6ηο cneAyK>mnMn npnMepaMn, KOTopbie, οαη3κο, ηθ οπθαυθτ paccMaipnBaTb xax orpaHHHntenbHbie. -4-
llpuMep I l-3Tnn-6^Top-4-oKco-7-/l-nnnepa3HHnn/-l,4-flnrnflpoxMHonMH-3-
KapčoHOBa^ KucnoTa l-3TMn-6^Top-4-OKCO-7-/4-Kap63TOKCM-l-nnnepa3MHMn/-l14-flnrnflpoxnHonnH-3-Kap6oHOBoii KidcnoTbi cno>KHbiii STunoBbiii 3φΜρ (0,838 r, 0,002 μοπη) cycneHanpyKDT b cMecu 3TaHona (12 μπ) m 10% βοαηογο pacTBopa KOH (18 μπ) m HarpeBaiOT b τθηθημθ 10 Hacoe npn TeMnepaType ΚΜΠΘΗΜΛ C OČpaTHbIM XOnOflMnbHMKOM peaKLļMOHHOii CMecu (3a XOflOM peaKLinn cneflflT c noMOiubio τοηκοοιομηομ χροΜ3τοφ3φΜΐ/ι: Si02, 3TaHon: aMMnaK = 72 : 20). Ilocne 3aBepiueHMH peaKunn pacTBopmenb οτγοηπιοτ b Bai<yyMe, 15% HCI (15 μπ) nočaBnaioT, pacTBop (^MnbTpoBbiBaiOT, a 3aTeM pH pacTBopa ycTaHaBnnBaiOT 7 10% KOH. nonyHeHHbiū ocaaoK φnπbτpy^oτ, npoMbieaioT Bofloii m cywaT. ΠρΜ stom BbiflenaioT Ι-3ΤΜΠ-6-φτορ-4-οκοο-7-(Ι-nnnepa3HHnn)-l,4-flnrnflpoxMHonMH-3-Kap6oHOByto KMcnoTy (0,478 r, 75%), t. nnaBnemia 216-220°C.
CneKTpanbHbie flaHHbie cooTBeTCTBy(OT nmepaTypHbiM aaHHbiM ΠρΜΜΘρ2 l-3TMn-6^Top-4-oKco-7-(l-nnnepa3HHnn/-1,4-flnrnflpoxMHonnH-3-
KapčoHOBan KucnoTa l-3Tnn-6^Top-4-oKco-7-/4-Kap6o3TOKCn-l-nnnepa3MHnn/-1,4-flnrnnpoxnHonnH-3-Kap6oHOByio xncnoTy (0,391 r, 0,001 μοππ) cycneHflnpyioT b CMecu STaHona (6 μπ) h 10% βοαηογο pacTBopa KOH (8 μπ), k HarpesatoT b TeMeHne 10 nacoB npn TeMnepaiype KuneHnn c očpambiM xonoannbHHKOM peaKLļnoHHoii cMecu (3a χοαομ peaKLinn cneaaT no aaHHbiM τοηκοοίομηομ χρ0Μ3Τ0Γρ3φΜΜ: Si02, 3TaHon: aMMuaK - 72:20). ilocne 3aBepiueHi/in peaKunn pacTBopmenb οτγοηπιοτ b BaKyyMe, aočaBnnioT 15% HCI (10 μπ), m MyTHbiū pacTBop φκπ^ρνιοτ m HeiiTpami3yK>T 10% KOH. rionyHeHHbiii ocaaoK φι^τρνιοτ c noacocoM, npoMbiBaKDT BOfloīi n cymaT. TaKMM očpa30M BblflenniOT Ι-3ΤΜΠ-6-φΤ0ρ-4-0Κ00-7-/Ι-ΠΜΠβρ33ΜΗΜΠ/-Ι,4-βΜΓΜηρ0ΧΜΗ0ΠΜΗ-3-Kap6oHOByto KucnoTy (0,240 r; 75%) t. nnaBneHUfl 216-220°C.
CneKTpanbHbie aaHHbie HaxoflflTcn b οοοτβθτοτβμμ c nnTepaTypHbiMM paHHblMU. -5- LV 10774 ΠρΜΜθρ 3 l-UMKnonponMn-6-0TOp-4-OKCO-7-/l-nnnepa3HHMn/-l14-flHrHflpOXHHOriMH-3-
KapčoHOBaa KucnoTa l-um<JionponMn-6-^Top-7-/4-Kap6o3TOKCM-l-nnnepa3MHMn/-4-oKco-l,4-flMrMflp0XMH0nMH-3-Kap60H0B0ii KMCnOTbl CnOJKHblti STMnOBbIM 3φΜρ ( 0,431 Γ, 0,001 μοππ) cycneHflnpyioT b siaHone (6 μπ) m 10% boahom pacTBope KOH (9 μπ), m HarpeBa»OT b τθηθημθ 8 nacoB npn TeMnepaType κμπθημπ c očpaTHbiM xonoflnnbHMKOM peaKUMOHHoti cMecM. 3aTeM pacTBopmenb οτγοηπιοτ b BaxyyMe κ cyxoMy ociaTKy AoāaBnnioT 5 μπ βοαν, μ pH ycTaHaBnnBaK)T I 15% BOflHbiM pacTBopoM HCI, MyTHbiti pacTBop φΐ/Η^τρνιοτ n HeūTpanM3y»OT 10% βοαηνμ pacTBopoM KOH no pH 7. l1onyHeHHbiii ocaAOK oτφnπbτpoBblBaιoτ, npoMbieaioT boaom w cymaT, rionyHaioT l-um<nonponnn-6-φΤθρ-4-ΟΚΟΟ-7-Ι-ΠΜΠβρ33ΜΗΜΠ/-Ι,4-ΑΜΓΜβρθΧΜΗΟΠΜΗ-3-Κ3ρ6θΗΟΒνΚ3 KMCnOTy (0,286 r, 86%), t. nnaBneHMfl 255-257°C. CneKTpanbHbie AaHHbie cooTBBTCTByioT nMTepaiypHbiM AaHHbiM.
[IpuMep 4 l-/2-rnApoKCH3Tnn/-6^Top-4-oKco-7-/l-nnnepa3HHnn-l,4-
AnrnApoxnHonnH-3-Kap6oHOBayi Kucnoia l-/2-rnAP0KCH3TMn/-6^T0p-4-0KC0-7-/4-Kap603T0KCH-l-nnnepa3HHMn/-l,4-AnrnApoxnHonnH-3-Kap6oHOByfo KHcnoiy (0,407 r, 0,001 μοππ) cycneHAnpyK)T b 3TaHone (6 μπ) h 10% boahom pacTBope KOH (9 μπ) h HarpeBaioT b τθηθημθ 14 nacoB m 45 MHHyT npn TeMnepaiype κμπθημπ c očpaTHbiM xonoAnnbHHKOM peaKunoHHOM cMecn. riocne 3aBepujeHnn peaKum/i pacTBopmenb οτγοηπιοτ b BaKyyMe, κ ocTan<y Ao6aBnntoT 5 μπ BOAbi n noAKucnnioT ao pH I I5% βοαηνμ pacTBopoM HCI. MyTHbiii pacTBop φι/^τρνιοτ, HeižiTpann3yiOT ao pH 7 10% βοαημμ pacTBopoM KOH, n nonyHeHHbiii ocaAOK οτφι/mbTpoBbiBaiOT. TaKUM o6pa30M nonyHaioT l-/2-rHAP0KCH3THn/-6^T0p-4-0KC0-7-/l-nMnepa3HHMn/-l,4-AMrMAP0XMH0nHH-3' Kap6oHOByio «ncnoTy (0,320 r, 96%), τ. ππθβπθηι/ιπ 6onee 300°C (nocne nepeKpncTannn3ai4HM H3 CMecu 3Τ3ηοπ-βοαα) · CneKTpanbHbie AaHHbie HaxoAHTcn b οοοτβθτοτβιιμ c nmepaTypHbiMH AaHHbiMH. flpuMep 5 - 6 -
CnO>KHblM 3THnOBblK 3φκρ l-3THn-6^TOp-4-OKCO-7-/4-Kap603TOKCH-l-nnnepa3MHMn/-l ,4-ΑΜΓΜΑρθΧΜΗΟΠΜΗ-3-Κ3ρ6θΗΟΒΟΜ KMCnOTbl Ι-3Τ1/ΙΠ-6,7-βΜφΤθρ-4-ΟΚΟΟ-Ι,4-ΑΜΓΜΑρθΧΜΗΟΠΜΗ-3-Κ3ρ6θΗΟΒθίί KMCHOTbl cno>KHbiii STnnoBbin 3φκρ (0,562 r, 0,0020 Mona), l-Kap6o3TOKCnnnnepa3HH (0,348 r, 0,0022 Mona) n xap6oHaT Kanna (0,303 r, 0,0022 Mona) cycneHflnpyK)T b Ν,Ν-αμμθτμπΦορμ3μι^αθ (6 μπ) n HarpeBaiOT b τθηθηκθ 4 nacoB npn TeMnepaiype κιλπθημπ c očpaTHbiM χοποαμπβημκομ peaKunoHHon CMecn. 3a peaKunen cnenaT c noMombio τοΗκοοηοήΗοη χροΜ3τοφ3φΐΊΐ/ΐ (Si02; 3TaHon: aMMnaK 72 : 20). Ilocne OKOHnaHna peaKLinn pacTBopnTenb OTroHatOT b BaKyyMe, Ao6aBnaioT BOfly (20 μπ) n 3KCTparnpyioT χποροφορΜΟΜ. ΧηοροφορΜΟΒοή cnon cyiuaT, pacTBopmenb οτγόηπιοτ b BaKyyMe, cyxon ocTaTOK eme pa3 npoMbiBaioT boaom n nepeKpncTannn30BbiBatoT H3 STaHona. B pe3ynbTaTe BbiflenaioT l-3Tnn-6^Top-4-OKco-7-/4-Kap6o3TOKcn-l-nnnepa3HHnn/-l,4-AnrnflpoxnHonnH-3-Kap6oHOBoii KncnoTbi STnnoBbiii cno>KHbin 3φκρ (0,448 r, 53%), t. nnaBneHna 198-202°C.
CneKTpanbHbie AanHbie: IH 9\MP (CflCI), TMC ): 5CH3= 1,20-1,33 μα (μ, 9H), 6H(nnnepa3HHnn) = 3,25 μα (μ, 4H), 3,67 μα (μ, 4H), 6CH2 = 4,00-4,60 μα (μ, 6H), 5Ha = 6,70 ma,
4yFH8 = 7 Γ14, IH δΗ5 = 7,95 μα (A, 3yFH5 = 13 Tu, IH), 5H2 = 8,32 ma (c, IH) 19F flMP (CflCl3, CCI3F): 6F =-123,00 ma (AA, \FHs = 13 Tu, 4yFH8 = 7 Tu)
SneMeHTHbiii aHann3: C21H26FN305
PaccMnTaHo: % 419,185635
HaiiAeHo: 419,1853
Macc-cneicrp μ/θ: 420 (M+ + 1,4%, 419 (M+, 16%), 348 (20), 347 (100), 245 (8), 318 (9), 56 (27),32(12). flpnMep 6 -7- LV 10774 l-3Tnn-6^Top-4-oKco-7V4-Kap6o3TOKCM-l-nMnepa3HHM/i/-l,4-flnrnflpoxnHonnH-3-Kap6oHOBafl KMcnoTa Ι-3ΤΜΠ-6-φΤ0ρ-7-ΧΠ0ρ-4-0Κ00-Ι,4-ΑΜΓΜβρ0Χ11Η0ΠΜΗ-3-Κ3ρ60Η0ΒγΚ) ΚΜοηοτγ (0,270 r, 0,001 Morm) n l-Kap603T0Kcnnnnepa3MH (0,632 r, 0,004 μοπβ) cycneHflnpyK)T b 2-μθτμπ-5-3ΤΜΓιπμρι/1Αμηθ (4 μπ) μ I—ΜΘΤΜΠΠΜρροηΐ/ΐβΟΗΘ (2 μπ) n HarpeBaioT Β ΤΘΗΘΗΚΘ 4 HacoB πρι/ι TeMnepaType κι/ιπθημπ peaKUMOHHoCi CMecu c o6paTHbiM χοποαμπι=ημκομ. Ilocne 3aBepiueHHfl peaKLļm/i Ao6aBnyuoT 10 μπ xnopo<ļiopMa, pacTBop npoMbieaioT 10% βοαηνμ pacTBopoM HCI n nocne βτογο βοαομ ao HeMTpann3aunn pacTBopa. ΧποροφορΜΟΒΗϋ cnoPi cyiuaT, a pacTBopwenb οτγοηπκ)τ b BaKyyMe. Cyxoii paccbinnaTbiM ocrraTOK npoMbieaioT βτβηοπομ h cyujaT. TaKMM o6pa30M nonysaioT l-3Tnn-6^Top-7-/4-Kap6o3TOKcn/-l-nnnepa3HHnn/-4-oKco-l,4-flnrnflpoxnHonnH-3-Kap6oHOByio KncnoTy (0,195 r, 50%). T. nnaBnem/m 270-273°C.
CneKTpanbHbie Aam-ibie: IH PMP (CFgCOOH, TMC): δΟΗ3=1,42 μπ^ΘΛ Tu (t, 3H), 5CH3=1,78 Μβ (τ, γ=6,4 Γα, 3H), 6H(m/inepa3UHnn)=3,88 μα (μ, 8H), 5CH2=4,41 ma (kb, 6,4 Tu, 2H), 6CH2=4,84 μα (kb, γ=6,4 Tu, 2H), δΗ8 - 7,40 μα (A, 4yFH8=6,5 Tu, IH), δΗ5=8,27 μα (A, 3yFH5=13 Tu, IH), δΗ2=9,28 ma (c, IH). 19F flMP (CF3COOH, CCI3F): 5F=-112,07 ma (AA, 3yFH5=13 Tu, 4yFH8=6,5 Tu)
Macc-cneKTp M/e: 392 (M+ + 1,3%), 391 (M+, 15%), 348 (15), 347 (100), 151 (14), 83 (12), 56 (10), 44 (15), 43 (11).
SneMeHTHbiū aHann3 απα Ci9H22FN305 PaccHHTaHo: 391,154
HaCiAeHo: 391,154 -8- llpuMep 7
CnO>KHbin 3THnOBblŪ 3φΜρ Ι-ΜΜΚΠΟΠρθΠΜΠ-6-φΤθρ-7-/4-Κ3ρ6θ3ΤΟΚΟΜ-Ι-nnnepa3HHnn/-4-oKco-l,4-flnrnflpoxMHonnH-3-Kap6oHOBoii KncnoTbi
Cno>KHbiii 3TnnoBbiii 3φι/ιρ Ι-141^ΚΠΟΠρθΠΜΠ-6,7-ΑΜφΤθρ-4-ΟΚΟΟ-Ι,4-flnrnflpoxnHonnH-3-Kap6oHOBoii KucnoTbi (0,439 r, 0,0015 Mona), l-Kap6o3TOKcnnunepa3HH (0,261 r, 0,00165 Mona) n KapčoHaT Kanna (0,228 r, 0,00165) cycneHflnpyK>T b Ν,Ν-ΑΜΜθτκπφορΜβΜΐ/ΐΑβ (5 μπ) n HarpeeaioT b TeHeHne 4 nacoB npn TeMnepaType KnneHna c očpaTHbiM xonoflnnbHHKOM peaKunoHHon CMecn. ilocne 3aBepweHnn peaKunn pacTBopmenb οτγοηλιοτ b BaKyyMe, Ao6aBna(OT 20 μπ eopbi n 3KCTparnpytoT χποροφορΜΟΜ. ΧποροφορΜΟΒΗή cnoii cyiuaT, n TBepayio nacTb οτγοη3ιοτ. Tbkum o6pa30M nonynaioT cnoKHbiii 3φΐΊρ STnnoBbiii Ι-ρηκποπροπηπ-6-φτορ-7-/4-κ3ρ6θ3Τθκοη-l-nnnepa3HHnn/-4-oKco-l,4-AnrnApoxnHonnH-3-Kap6oHOBoii KncnoTbi (0,529 r, 82%). nonyHeHHbin npoflyi<T nepeKpncTannn30BbiBaioT n3 siaHona, T.nnaBneHnn 225-229°C.
CneicrpanbHbie AaHHbie IH flMP (CflCIgTMC): 5CH3, CH3H (unKnonponnn)=1,45 (μ, IOH), 5H(nnnepa3HHnn), H(unKnonponnn)=3,32 μα (μ, 5H), 3,73 μα (μ, 4H), 6CH2CH2=4,32 μα (μ, 4H), 6H8=7,20 μα (A, 4yFHa=6,4 Tu, IH), 6H5 - 7,87 ma (A,3yFH5=13ru, IH), 5H2 - 8,43 ma (c, IH). 19F<RMP(CF3COOH, CCI3F): 5F=-112,57 ma (flfl, 3yFH5=13 Tu, 4yFM8=6,5 Tu)
Macc-cneKTp M/e: 432 (M+ + 1,6%), 431 (M+21%), 386 (8), 360 (21), 359 (100), 329 (6), 257 (6), 230 (6), 229 (5), 56 (26). ΠρΜΜβρ 8 l-UHKnonponnn-6^Top-7-/4-Kap6o3TOKCn-l-nnnepa3HHnn/-4-oKco-l,4-AnrnflpoxnHonnH-3-Kap6oHOBaa Kncncrra l-i4HKnonponnn-6,7-A^Top-4-OKCo-l,4-AnrnApoxnHonnH-3-Kap6oHOByio KncnoTy (0,265 r, 0,001 Mona), l-Kap6o3TOKCn-nnnepa3HH (0,174 r, -9- LV 10774 0,0011 μοππ) n KapčoHaT Kanna (0,152 r, 0,0011 Monen) cycneHflnpyioT b Ν,Ν—111ΊΜΘΤΙ/ΙΠφθρΜ3Μ11ΑΘ (10 ΜΠ) M HarpeBaiOT B ΤβΗβΗΙ/ΙΘ 2,5 MaCOB npn TeMnepaType KnneHna c o6paTHbiM xononnnbHHKOM peaKLinoHHon CMecn. ilocne 3aBepiueHna peaKunn pacTBopmenb οτγόηπιοτ b BaKyyMe, κ cyxoMy ocTaTKy AOČaBnaioT Bony (10 μπ), n pH cycneH3Hn ycTaHaBnnBafOT 15% HCI no HenTpanbHon. OcaflOK cm^nnbTpoBbiBaioT n cyiuaT. nonyMeHHbin npoAyKT nepeKpncTannn30BbiBaioT H3 ΑΜΜβτηπφορΜ3ΜηΑΒ. TaxnM o6pa30M nonyHatoT l-L4HKnonponnn-6^Top-7-/4-Kap6o3TOKCn-l-nnnepa3HHnn/-4-OKCo-l,4-flnrnApoxnHonnH-3-Kap6oHOByK) KHcnoTy (0,282 r, 70%), t. nnaBneHna 250°C. CneKTpanbHbie flaHHbie IH HMP (CF3COOH, TMC): 5CH3H (unKnonponnn)=1,50 ma/m, 7H/, 5H(nnnepa3HHnn), H(unKnonponnn)= 3,92 μα (μ, 9H), 5CH2=4,41 μα (κβ, γ=6,4 Γρ, 2H), δΗ8=7,88 μα (A, 4yFH8=6,5 Tu, IH), 5HS=8,27 ma (a, 3yFH5=13ru, IH), δΗ2= 9,32 (m.a. c, IH). 19 F 9\MP (CF3COOH, CFCI3): 5F=-112,40 μα (AA, 3yFH5=13 Tu, 4yFH8=6,5 Γρ)
Macc-cnetcrp M/e: 404 (M+ + 1,4%), 403 (M+, 21%), 360 (28), 359 (100), 347 (14), 289 (14), 287 (15), 257 (12), 245 (17), 57 (11), 56 (30), 44 (26). SneMeHTHbiii aHann3 αππ C2oHhhFN305 PaccnnTaHo: 403,154
HaiiAeHo: 403,150 npnMep 9 l-unKnonponnn-6^Top-7-/4-Kap6o3TOKCn-l-nnnepa3HHnn/-4-oKCO-l,4-AnrnApoxnHonnH-3-Kap6oHOBaa KncnoTa Ι-ΜΜΚΠΟΠρθΠΙ/1Π-6-φΤθρ-7-ΧΠθρ-4-ΟΚΟΟ-Ι,4-ΑΜΠ/1ΑρθΧΜΗΟΠΜΗ-3-Kap6oHOBy»o Kncnoiy (0,281 r, 0,001 μοππ) n l-Kap603T0Kcnnnnepa3nH (0,632 r, 0,004 Mona) cycneHAnpyraT b 2-MeTnn-5-3TnnnnpnAHHe (8 μπ) n 1-MeTnn-nnpponnAOHe (2 μπ) n HarpeeaiOT b Tenei-ine 4 sacoB npn TeMnepaiype κηπβΗηη c očpaTHbiM xonoAnnbHnKOM peaKunoHHon cMecn. Ilocne 3aBepiueHna peaKLjnn Ao6aBnaK)T 20 μπ χποροφορΜ3 κ xonoAHOMy pacTBopy, n nonyHeHHbin pacTBop npoMbiBatOT 15% BOAHbiM pacTBopoM HCI, -10- a nocne θτογο bohoū ao HeiiTpami3ai4W/i. ΧποροφορΜΟΒωίί cnofi cymaT, n pacTBopuTenb οτγόηηιοτ. Οοτβτοκ 3Τ3ηοπομ m cyuiaT.
TaKMM o6pa30M nonyHaK)T l-i4HKnonponnn-6-0Top-7-/4-Kap6o3TOKcn/4-OKCO-l,4-AMrnApoxMHonMH-3-Kap6oHOByro KncnoTy (0,222 r, 55%) t. nnaBneHMfl 6onee 250°C. nonyHeHHbiM 4 npoflyKT nepeKpncTanni/i30BbiBaK>T M3 Ν,Ν—ΑΜΜΘΤΜΠφθρΜΒΜ11Α3. -11 - LV 10774
ΦΟΡΜΥΠΑ M30EPETEHM5R
1. Cnocoč ποπγπθΗΜΛ l-3aMemeHHoPi 6^Top-4-oKco-7-/1-nnnepa3KHnn/-l,4-flMrMAp0XHH0nHH-3-Kap60H0B0ii KUCnOTbl φορΜγΠΝ I
ΓΑΘ R - 3THn, ΜΜΚΠΟΠρΟΠΜΠ Ι/ΙΠΜ Π/1ΑΡΟΚΟΜ3ΤΜΠ, ΟΤΠΜΗΘΙΟΙΑΜίίΟΑ ΤΘΜ, HTO l-3aMemeHHyK> 6^Top-4-OKCo-7-/4-Kap6o3TOKcn-l-nnnepa3HHnn/-l,4- AnrnflpoxMHonMH-3-Kap6oHOByKD ΚΜΟποτγ μπμ ee cno>KHbiii 3φκρ ο6ιαθμ φορΜγπω II:
rfle R μμθθτ x<e 3Η3ηθηι/ια, hto y«a3aHbi Bbiiue, a R1 ηβπαθτοη boaopoaom nnn 3TUriOM,
O noABepraiOT B03AeiicTBMfo menoHHoi/i cpeAbi. 2. Cnoco6 no nyHicry I, oinunaromnuicfl τθμ, hto b KanecTBe menoHHoii cpeAbi ncnonb3yioT cMecb aTaHona n βοαηογο pacTBopa ocHOBaHHa, τθκογο KaK KOH. 3. Cnoco6 no n. 1 h 2, omMHaKDLUniicfl τθμ, hto peatcunto βθαυγ npn TeMnepaType κιλπθημα peaKUnOHHoti CMecn. LV 10774 ΡΕΦΕΡΑΤ
CnOCo6 ΠΟΠγΗΘΗΙ/lfl 1 -33ΜΘ111ΘΗΗ0Μ 6-φΤθρ-4-ΟΚΟΟ-7-/1-ΠΜΠθρ33ΜΗΜΠ/-1,4-flHrHflp0XHH0nHH-3-Kap60H0B0M Kl/ICnOTbl
ΠρθβΠΟ>ΚΘΗ CI10C06 ΠΟΠγΗΘΗΜΑ 1-33ΜΘΙΜΘΗΗΟΜ-6-φΤθρ-4-ΟΚΟΟ-7-/1-ni/inepa3MHnn/-1^-AwrMflpoxiiHonviH-3-Kap6oHOBoii KucnoTbi očmeCi φopMyπbι I ο
rfle R = CH2CH3, 141/ικηοπροπνιπ, CH2CH2OH, CH2OCH2CH2OH u b κοτοροΜ 1-3aMemeHHyio 6-φτορ-4-οκοο-7-/4-κ3ρ6θ3τοκαι-1-nnnepa3MHnn/-1,4-flnrMflpoxMHonMH-3-Kap6oHOByK} κΜοποτγ μπμ ee cnox<Hbiii 3TI/inOBblii 3φΜρ o6meii φορΜγπΝ II Ο
COOCH2CH3 rne R HMeeT yKa3aHHbie paHee 3HaH©Hmi, a R1 ββπηθτοα BonopoAOM μπμ θτμπομ, rnflponM3yioT b menoHHoii cpefle no ποπυηθημη οοθακηθημα I. ΠρθΑΠθ>κθΗ TaK>Ke cocTae ηοβογο οπο>κηογο 3<$\λρά φορΜγπΜ II μ cnocoč ero ποπυηθημβ.

Claims (3)

  1. LV 10774 Izgudrojuma formula 1.6-F!uor-4-okso-7-(1 -piperazinil)-1,4-dihidrohinolin-3 vienaizvietotas karbonskābes ar formulu I iegūšanas paņēmiens:
    kur R - etil, ciklopropil, vai hidroksietilgrupa, atšķiras ar to, ka 6-fluor-4-okso-7-/4-karboetoksi-1 -piperazinil/-1,4-dihidrohinolin-3 vienaizvietoto karbonskābi vai tās esteri ar kopīgo formulu II 0
    COOCH2CH3 kur R ir tās pašas nozīmes, kā iepriekšminēts, bet R1 ir ūdeņraža atoms vai etiigrupa, pakļauj sārmainas vides iedarbībai.
  2. 2. Paņēmiens saskaņā ar 1. p., atšķiras ar to, ka kā sārmaino vidi izmanto maisījumu no etanola un tādas bāzes, kā KOH, ūdens šķīduma.
  3. 3. Paņēmiens saskaņā ar 1. vai 2. p., a t š ķ i r a s ar to, ka reakciju veic pie reakcijas maisījuma vārīšanās temperatūras.
LV930828A 1987-12-31 1993-06-30 Process for preparation of 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid, 6-fluoro-4-oxo-7-(4-carbethoxy-1-piperazinyl)-1,4-dihydroquinoline-3-ethylcarboxylate and method for preparing thereof LV10774B (en)

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YU244787A YU46099B (sh) 1987-12-31 1987-12-31 Postopek za pripravo 1-supstituirane 6-fluoro-4-okso-7- 1-piperazinil)-1

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LV10774B true LV10774B (en) 1996-08-20

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017622A (en) * 1972-12-18 1977-04-12 Dainippon Pharmaceutical Co., Ltd. Piperazine derivatives
SE444566B (sv) 1977-09-20 1986-04-21 Bellon Labor Sa Roger 7-dialkylamin-6-halogen-4-oxo-1,4-dihydrokinolin-3-karboxylsyra, forfarande for framstellning derav och farmaceutiskt preparat derav
JPS5845426B2 (ja) * 1978-09-29 1983-10-08 杏林製薬株式会社 置換キノリンカルボン酸誘導体
JPS5762259A (en) 1980-09-05 1982-04-15 Kyorin Pharmaceut Co Ltd Preparation of substituted quinolinecarboxylic acid derivative
DE3306771A1 (de) * 1983-02-25 1984-08-30 Bayer Ag, 5090 Leverkusen Chinoloncarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel
DE3308909A1 (de) 1983-03-12 1984-09-13 Bayer Ag, 5090 Leverkusen Bakterizide mittel auf chinoloncarbonsaeure-basis
DE3509546A1 (de) * 1985-03-16 1986-09-25 Bayer Ag, 5090 Leverkusen 7-amino-1-(subst.cyclopropyl)-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel
JPH06103891B2 (ja) 1989-05-31 1994-12-14 日本電信電話株式会社 パケット交換網用ルーチング方法
JPH066686A (ja) 1992-06-17 1994-01-14 Ricoh Co Ltd 撮像装置

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AT396105B (de) 1993-06-25
PT89359A (pt) 1989-12-29
CS903288A2 (en) 1990-12-13
LV10774A (lv) 1995-08-20
LTIP510A (en) 1994-11-25
SI8712447A8 (en) 1995-12-31
LT3274B (en) 1995-05-25
PL163337B1 (pl) 1994-03-31
HU200454B (en) 1990-06-28
NO885666D0 (no) 1988-12-21
ATA320688A (de) 1992-10-15
PT89359B (pt) 1993-08-31
CS274635B2 (en) 1991-09-15
NO885666L (no) 1989-07-03
PL276890A1 (en) 1989-10-16
HUT49129A (en) 1989-08-28
DD283386B5 (de) 1997-10-30
YU46099B (sh) 1992-12-21
YU244787A (en) 1990-06-30

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