LT3274B - Process for preparing 1-substituted 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid - Google Patents
Process for preparing 1-substituted 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid Download PDFInfo
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- LT3274B LT3274B LTIP510A LTIP510A LT3274B LT 3274 B LT3274 B LT 3274B LT IP510 A LTIP510 A LT IP510A LT IP510 A LTIP510 A LT IP510A LT 3274 B LT3274 B LT 3274B
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Abstract
Description
Šis išradimas priklauso organinės sintezės sričiai ir liečia 1-pakeistos 6-fluor-4-okso-7-(1-piperazinil)1,4-dihidrochinolin-3-karboksirūgšties gavimo būdą, turinčios I formulę:The present invention relates to the field of organic synthesis and relates to a process for the preparation of 1-substituted 6-fluoro-4-oxo-7- (1-piperazinyl) 1,4-dihydroquinoline-3-carboxylic acid of formula I:
GOOH kurioje R=etilas, ciklopropilas arba hidroksietilas.GOOH wherein R = ethyl, cyclopropyl or hydroxyethyl.
I formulės junginiai yra naudojami medicinoje uždegiminių procesų gydymui. Jie pasižymi plačiu aktyvumų spektru kaip prieš gramteigiamas, taip ir prieš gramneigiamas bakterijas.The compounds of formula I are used in medicine for the treatment of inflammatory processes. They exhibit a broad spectrum of activity against both gram-positive and gram-negative bacteria.
Patentinėje literatūroje yra atskleistas junginių, turinčių bendrą I formulę, gavimo būdas, kaip, pavyzdžiui, chloropakeisto darinio padėtyje 7 reakcija su piperazinu Japonijos patentinėse paraiškose Nr. 66686/1979 ir Nr. 33453/1980, eksponuotose VFR paraiškose Nr. 2840910 ir Nr. 3308909, o taip pat kaip alkileterio hidrolizės reakcija Belgijos patente Nr. 890223.The patent literature discloses a process for the preparation of compounds of general formula I, such as the reaction of the chloro-substituted derivative at position 7 with piperazine in Japanese Patent Application Ser. No. 66686/1979 and no. 33453/1980, Exhibited VFR Application Nos. 2840910 and no. No. 3308909, as well as the reaction of hydrolysis of an alkyl ether in Belgian patent no. 890223.
Belgijos patente Nr. 890223 aprašyta sintezė, kurios paskutinė stadija yra Rx-6-fluor-4-okso-7-(1-piperazinil) -1,4-dihidrochinolin-3-karboksirūgšties (Rx=etilas, vinilas) molekulės 3 padėtyje esančios esterinės grupės hidrolizė ir atitinkamai analogiškame 4-chinoline esterinės grupės hidrolizė, kur piperazino grupės, sujungtos chinolono 7 padėtyje, 4 padėtyje yra žemesnio alkilo grupė.The Belgian patent no. No. 890223 describes the synthesis of the ester group at the 3-position of the molecule R x -6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (R x = ethyl, vinyl). hydrolysis, and hydrolysis of the corresponding 4-quinoline ester group, respectively, wherein the piperazine group linked at the 7-position of the quinolone is a lower alkyl group.
Reikėjo junginių, turinčių I formulę, naujo gavimo būdo, kuris būtų paprastas, junginį būtų lengva išskirti, su norimo produkto didele išeiga, ir šis būdas turi skirtis nuo jau esamų minėtų junginių gavimo būdų.There was a need for a novel process for the preparation of compounds of Formula I which was simple, easy to isolate, with high yields of the desired product, and should be different from those already available for the preparation of said compounds.
Šio išradimo būdas realizuojamas taip, kad 1-pakeistąThe method of the present invention is carried out in such a way that 1-substituted
6-fluor-4-okso-7-(4-karboetoksi-l-piperazinil)-1,4-dihidrochinolin-3-karboksirūgštį arba jos etilo esterį, turinčius bendrą formulę II6-Fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid or its ethyl ester having the general formula II
COOR1 COOR 1
II kurioje R turi anksčiau nurodytas reikšmes, o R1 yra vandenilio atomas arba etilo grupė, hidrolizuoja šarminėje terpėje iki I junginio gavimo.Wherein R 1 has the meanings given above and R 1 is a hydrogen atom or an ethyl group hydrolyzed in an alkaline medium to give compound I.
Hidrolizė geriausiai atliekama vandeniniame etanolio ir KOH tirpale ir reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu.Hydrolysis is best performed in aqueous ethanol and KOH and at reflux temperature of the reaction mixture.
Gauta 1-pakeista 6-fluor-4-okso-7-(1-piperazinil)-1,4dihidro-chinolin-3-karboksirūgštis druskos pavidale neutralizuojama, ir po to perkristalinama, pavyzdžiui, iš N,N-dimetilformamido ir etanolio mišinio.The resulting 1-substituted 6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid is neutralized in the form of a salt and then recrystallized, for example, from a mixture of N, N-dimethylformamide and ethanol.
Junginys, turintis II formulę, kurioje R1 yra etilo grupė, yra naujas junginys. Naujas etilo esteris gaunamas iš 1-pakeistos 6-fluor-7-halogen-4-okso-l,4dihidrochinolin-3-karboksirūgšties etilo esterio. Junginys, turintis II formulę, kurioje R1 yra vandenilio atomas, gaunamas taip pat iš 1-pakeistos 6LT 3274 B fluor-7-halogen-4-okso-l,4-dihidrochinolin-3-karboksirūgšties, kaip pateiktoje žemiau reakcijos schemoje:A compound of formula II wherein R 1 is ethyl is a novel compound. The new ethyl ester is obtained from the 1-substituted 6-fluoro-7-halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. The compound of formula II wherein R 1 is a hydrogen atom is also prepared from the 1-substituted 6LT 3274B fluoro-7-halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as shown in the reaction scheme below:
COCRCOCR
4ΙΆ4ΙΆ
COO R* kurioje R=CH2CH3, ciklopropilas, CH2CH2OHCOO R * wherein R = CH 2 CH 3 , cyclopropyl, CH 2 CH 2 OH
R1=H, CH2CH3 R 1 = H, CH 2 CH 3
X = toks halogenas, kaip Cl, FX = a halogen such as Cl, F
Reakcija atliekama pūliniuose organiniuose tirpikliuose arba jų mišiniuose tokiuose, kaip N,N-dimetilformamidas, acetonitrilas, piridinas, 2-metil-5-etilpiridinas, 1-metilpirolidonas, dimetilsulfoksidas ir t. t., esant agento, surišančio susidariusi HX. Šiam tikslui galima naudoti tokį reagentą, kaip 1-karboetoksipiperaziną arba kokią nors kitą bazę, pavyzdžiui, natrio arba kalio karbonatą.The reaction is carried out in purulent organic solvents or mixtures thereof such as N, N-dimethylformamide, acetonitrile, pyridine, 2-methyl-5-ethylpyridine, 1-methylpyrrolidone, dimethylsulfoxide and the like. i.e., in the presence of an agent binding HX formed. A reagent such as 1-carboethoxypiperazine or any other base such as sodium or potassium carbonate can be used for this purpose.
Junginys, turintis II formulę, yra lengvai prieinamas ir gaunasi aukšto grynumo laipsnio pagal aprašytą, bet ne pareikštą šioje paraiškoje gavimo būdą.The compound of formula II is readily available and obtains a high degree of purity according to the method of preparation described but not claimed herein.
Šiame procese piperazino darinys, būtent 1-karboetoksipiperazinas, naudojamas tik 10% pertekliuje ir baze naudojamas pigus kalio karbonatas, kas supaprastina išskyrimo procesą ir išsprendžia nutekamųjų vandenų apdorojimo problemą, kuriuose pagal būdą, aprašytą VFR patente Nr. 2840910, yra nesureagavęs piperazinas, kadangi tame metode piperazinas naudojamas dideliame pertekliuje.In this process, the piperazine derivative, namely 1-carboethoxypiperazine, is used in an excess of only 10% and uses cheap potassium carbonate as a base, which simplifies the isolation process and solves the wastewater treatment problem. 2840910, is unreacted piperazine, since piperazine is used in high excess in this method.
Be to, pagal žinomą techniką esterio hidrolizė atliekama atskiroje stadijoje, tuo tarpu siūlomame būde esterio hidrolizė ir dekarboksilinimas atliekamas vienos stadijos metu.In addition, the prior art hydrolysis of the ester is carried out in a separate step, whereas in the proposed process the hydrolysis of the ester and the decarboxylation are carried out in a single step.
Iki šiol niekur literatūroje nebuvo atskleistas junginių, turinčių I formulę, gavimas paraiškoje siūlomos sintezės keliu; tai susiję su l-alkil-6fluoro-7-(4-karboetoksi-l-piperazinil)-4-okso-l,4-dihidrochinolin-3-karboksirūgšties kaip pradinio junginio panaudojimu. Pagal šį išradimą junginys hidrolizuoj amas ir dekarboksilinamas šarminės terpės sąlygomis.To date, no literature has disclosed the preparation of compounds of Formula I by the synthesis route proposed in the application; this relates to the use of 1-alkyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a starting compound. The compound of the present invention is hydrolyzed and decarboxylated under alkaline conditions.
Būde pagal išradimą, charakterizuojamame išradimo apibrėžties 1-3 punktais, pradinėmis medžiagomis naudojami labai gryni ir turintys naujumą (išskyrus vieną) junginiai, o galutiniai produktai yra pakankamai gero grynumo laipsnio. Išankstinis azoto atomo funkcionalizavimas piperazine karboetoksi grupe inhibuoja įvairias pašalines reakcijas, kurios galimos I junginio sintezės eigoje. Priemaišų kiekis galutiniame produkte, susintetintame pagal būdą sutinkamai su išradimu, esminiai mažesnis, negu produkte, susintetintame pagal žinomą technikos lygį (produkte pagal išradimą priemaišų kiekis, išmatuotas plonasluoksnės chromatografijos metodu, yra mažesnis negu 0,5%, o produkte pagal žinomą technikos lygį - apie 1%) . Tokia charakteristika, kaip pagerintas grynumo laipsnis, yra pakankamai svarbi junginiams, naudojamiems farmakopėjoje, kur pastebima užteršiančių priemaišų kiekio apatinės ribos mažinimo tendencija.In the process of the invention characterized by the claims 1-3 of the invention, the starting materials used are very pure and novel (except one) compounds and the final products are of sufficiently good purity. Pre-functionalization of the nitrogen atom with a piperazine carboethoxy group inhibits various side reactions that may occur during the synthesis of Compound I. The amount of impurities in the final product synthesized according to the invention is substantially lower than in the product synthesized according to the state of the art (the impurity content of the product according to the invention measured by thin layer chromatography is less than 0.5%; about 1%). Such a characteristic as improved purity is sufficiently important for compounds used in the pharmacopoeia, where there is a tendency to lower the lower limit of contaminating impurities.
Čia aprašytas junginio, atvaizduoto I formule, gavimo ir išskyrimo būdas yra paprastas, ir tuo pačiu pasiekiamos aukštos išeigos.The process for the preparation and isolation of the compound represented by Formula I described herein is simple, and high yields are achieved.
Toliau išradimas smulkiau iliustruojamas tokiais pavyzdžiais, kuriuos, tačiau, nereikia suprasti kaip apriboj ančius.The invention is further illustrated by the following examples which, however, are not to be construed as limitations.
I pavyzdys l-Etil-6-fluor-4-okso-7-(1-piperazinil)-1,4dihidrochinolin-3-karboksirūgštis.Example I 1-Ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid.
l-Etil-6-fluor-4-okso-7-(4-karboetoksi-l-piperazinil)1,4-dihidrochinolin-3-karboksirūgšties etilo esteris (0,838 g, 0,002 mol) suspenduojamas etanolio (12 ml) ir 10% vandeninio KOH tirpalo (18 ml) mišinyje ir kaitinamas 10 vai. reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu (reakcijos eiga sekama plonasluoksnės chromatografijos pagalba: SiO2; etanolis :amoniakas=72 : 20) . Pasibaigus reakcijai, tirpiklis nudistiliuoj amas vakuume, pridedama 15% HCl (15 ml), tirpalas filtruojamas, po to tirpalo pH padaromas lygus 7, naudojant 10% KOH. Susidarę nuosėdos filtruojamos, praplaunamos vandeniu ir džiovinamos. Taip išskiriama l-etil-6-fluor-4-okso-7-(1-piperazi-nil)-1,4-dihidrochinolin-3-karboksirūgštis (0,478 g, 75%), lyd. t. 216220°C.1-Ethyl-6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) 1,4-dihydroquinoline-3-carboxylic acid ethyl ester (0.838 g, 0.002 mol) is suspended in ethanol (12 mL) and 10% aqueous KOH (18 mL) in the mixture and heated for 10 h. the reaction mixture was refluxed (followed by thin layer chromatography: SiO 2 ; ethanol: ammonia = 72:20). After completion of the reaction, the solvent was distilled off in vacuo, 15% HCl (15 mL) was added, the solution was filtered, and then the pH of the solution was adjusted to 7 using 10% KOH. The precipitate formed is filtered off, washed with water and dried. This affords 1-ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (0.478 g, 75%), m.p. t. 216220 ° C.
Spektriniai duomenys atitinka literatūrinius duomenis.Spectral data are consistent with literature data.
pavyzdys l-Etil-6-fluor -4-okso-(1-piperazinil)-1, 4dihidrochinolin-3-karboksirūgštis l-Etil-6-fluor-4-okso-7-(4-karboetoksi-l-piperazinil)1,4-dihidrochinolin-3-karboksirūgštis (0,391 g, 0,001 mol) suspenduojama etanolio (6 ml) ir 10% vandeninio KOH tirpalo (8 ml) mišinyje, ir kaitinama 10 vai. reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu (reakcijos eiga sekama pagal plonasluoksnės chromatografijos duomenis: SiO2; etanolis:amoniakas = 72:20). Pasibaigus reakcijai, tirpiklis nudistiliuojamas vakuume, pridedama 15% HCl (10 ml), ir neskaidrus tirpalas filtruojamas ir neutralizuojamas 10% KOH. Gautos nuosėdos filtruojamos nusiurbiant, praplaunamos vandeniu ir džiovinamos.Example 1 1-Ethyl-6-fluoro -4-oxo (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid 1-Ethyl-6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) 1 , 4-Dihydroquinoline-3-carboxylic acid (0.391 g, 0.001 mol) was suspended in a mixture of ethanol (6 mL) and 10% aqueous KOH solution (8 mL) and heated for 10 h. the reaction mixture was refluxed (followed by thin layer chromatography: SiO 2 ; ethanol: ammonia = 72:20). After completion of the reaction, the solvent is distilled off in vacuo, 15% HCl (10 mL) is added and the opaque solution is filtered and neutralized with 10% KOH. The resulting precipitate is filtered off with suction, rinsed with water and dried.
Taip išskiriama l-etil-6-fluor-4-okso-7-(1-piperazinil) -1,4-dihidrochinolin-3-karboksirūgštis (0,240 g; 75%), lyd.t. 216-220°C.There was thus isolated 1-ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (0.240 g, 75%), m.p. 216-220 ° C.
Spektriniai duomenys atitinka literatūrinius duomenis.Spectral data are consistent with literature data.
pavyzdys l-Ciklopropil-6-fluor-4-okso-7-(1-piperazinil)-1,4dihidrochinolin-3-karboksirūgštis.Example 1 1-Cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid.
l-Ciklopropil-6-fluor-7-(4-karboetoksi-l-piperazinil)4-okso-l,4-dihidrochinolin-3-karboksirūgšties etilo esteris (0,431 g, 0,001 mol) suspenduojama etanolyje (6 ml) ir 10% vandeniniame KOH tirpale (9 ml), ir kaitinama 8 vai. reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu. Po to tirpiklis nudistiliuojamas vakuume, į sausą liekaną pripilama 5 ml vandens, ir pH padaromas lygus 1 su 15% HCl vandeniniu tirpalu, neskaidrus tirpalas filtruojamas ir neutralizuojamas 10% KOH vandeniniu tirpalu iki pH 7. Gautos nuosėdos filtruojamos, praplaunamos vandeniu ir džiovinamos. Gaunama l-ciklopropil-6-fluor-4-okso-7-(15 piperazinil)-1,4-dihidrochinolin-3-karboksirūgštis (0,286 g,, 86%), lyd. t. 255-257°C. Spektriniai duomenys atitinka literatūrinius duomenis.1-Cyclopropyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (0.431 g, 0.001 mol) is suspended in ethanol (6 ml) and 10%. aqueous KOH solution (9 mL) and heated for 8 h. of the reaction mixture at reflux. The solvent is then distilled off in vacuo, 5 ml of water are added to the dry residue and the pH is adjusted to 1 with 15% aqueous HCl, the opaque solution is filtered and neutralized with 10% aqueous KOH to pH 7. The resulting precipitate is filtered, washed with water and dried. 1-Cyclopropyl-6-fluoro-4-oxo-7- (15-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (0.286 g, 86%), m.p. t. 255-257 ° C. Spectral data are consistent with literature data.
pavyzdysexample
1-(2-Hidroksietil)-6-fluor-4-okso-7-(1-piperazinil)1.4- dihidrochinolin-3-karboksirūgštis.1- (2-Hydroxyethyl) -6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid.
1-(2-Hidroksietil)-6-fluoro-4-okso-7-(4-karboetoksi-l15 piperazinil)-1,4-dihidrochinolin-3-karboksirūgštis (0,407 g, 0,001 mol) suspenduojama etanolyje (6 ml) ir 10% KOH vandeniniame tirpale (9 ml) ir kaitinama 14 vai ir 45 min. reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu. Pasibaigus reakcijai, tirpiklis nudistiliuoj amas vakuume, į liekaną pripilama 5 ml vandens ir parūgštinama iki pH 1 15% vandeniniu HCl tirpalu. Neskaidrus tirpalas filtruojamas, neutralizuojamas iki pH 7 10% vandeniniu KOH tirpalu, ir gautos nuosėdos filtruojamos. Taip gaunama 1-(2-hidroksietil)25 6-fluoro-4-okso-7-(1-piperazinil)-1, 4-dihidrochinolin3-karboksirūgštis (0,320 g, 96%, lyd. t. virš 300°C) po perkristalinimo iš etanolio-vandens mišinio.1- (2-Hydroxyethyl) -6-fluoro-4-oxo-7- (4-carboethoxy-11β-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (0.407 g, 0.001 mol) is suspended in ethanol (6 ml) and 10% KOH in aqueous solution (9 mL) and heated for 14 h and 45 min. of the reaction mixture at reflux. After completion of the reaction, the solvent is distilled off in vacuo, the residue is taken up in 5 ml of water and acidified to pH 1 with 15% aqueous HCl. The clear solution is filtered, neutralized to pH 7 with 10% aqueous KOH, and the resulting precipitate is filtered. There was thus obtained 1- (2-hydroxyethyl) -6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (0.320 g, 96%, m.p.> 300 ° C). recrystallization from ethanol-water mixture.
Spektriniai duomenys atitinka literatūrinius duomenis.Spectral data are consistent with literature data.
pavyzdys l-Etil-6-fluor-4-okso-7-(4-karbetoksi-l-piperazinil)1.4- dihidrochinolin-3-karboksirūgšties etilo esteris.Example 1 1-Ethyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid ethyl ester.
l-Etil-6,7-difluoro-4-okso-l,4-dihidrochinolin-3karboksirūgšties etilo esteris (0,562 g, 0,0020 mol),1-Ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (0.562 g, 0.0020 mol),
1-karbetoksipiperazinas (0,348 g, 0,0022 mol) ir kalio karbonatas (0,303 g, 0,0022 mol) suspenduojama N,Ndimetilformamide (6 ml) ir kaitinama 4 vai. reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu. Reakcija sekama plonasluoksnės chromatografijos pagalba (SiO2, etanolis:amoniakas=72:20). Pasibaigus reakcijai, tirpiklis nudistiliuoj amas vakuume, pripilama vandens (20 ml) ir ekstrahuojama chloroformu. Chloroforminis sluoksnis džiovinamas, tirpiklis nudistiliuoj amas vakuume, sausa liekana dar kartą praplaunama vandeniu ir perkristalinama iš etanolio. Taip išskiriama 1-etil6-fluoro-4-okso-7-(4-karboetoksi-l-piperazinil)-1,4dihidrochinolin-3-karboksirūgšties etilo esteris (0,448 g, 53%), lyd. t. 198-202°C.1-Carbethoxypiperazine (0.348 g, 0.0022 mol) and potassium carbonate (0.303 g, 0.0022 mol) were suspended in N, N-dimethylformamide (6 ml) and heated for 4 hours. of the reaction mixture at reflux. The reaction is followed by thin layer chromatography (SiO 2 , ethanol: ammonia = 72:20). After completion of the reaction, the solvent was distilled off in vacuo, water (20 ml) was added and the mixture was extracted with chloroform. The chloroform layer is dried, the solvent is distilled off in vacuo, the dry residue is rinsed again with water and recrystallized from ethanol. This gives 1-ethyl6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid ethyl ester (0.448 g, 53%), m.p. t. 198-202 ° C.
Spektriniai duomenys:Spectral data:
ΧΗ BMR (CDC13), TMS) : δ0Η =1,20-1,33 m.d. (m, 9H) , (piperazinil) =3,25 m.d. (m, 4H), 3,67 m.d. (m, 4H), Χ Η NMR (CDCl 3 ), TMS: δ 0Η = 1.20-1.33 md (m, 9H), (piperazinyl) = 3.25 md (m, 4H), 3.67 md (m, 4H) ),
5ch2 =4,00-4, 60 m.d. (m, 6H), δ^θ=6,70 m.d., 40JFH8 = 75ch 2 = 4.00-4, 60 md (m, 6H), δ ^ θ = 6.70 md, 40 JFH 8 = 7
Hz, 1H δΗ5 = 7,95 m.d. (d,3JFH5 = 13 Hz, 1H) , δΗ =8,32 m.d. (s, 1H) 19F BMR (CDC13, CC13F) : δΕ= -123, 00 m.d. (dd, 3JFH5=13 Hz, 4JFH8=7 Hz).Hz, 1H δ Η5 = 7.95 ppm (d, 3 5 JFH = 13 Hz, 1H), δ Η = 8.32 ppm (s, 1H) 19 F NMR (CDC13, CC13F) δΕ = -123, 00 md (dd, 3 JFH5 = 13 Hz, 4 JFH 8 = 7 Hz).
Elementinė analizė: C21H26FH3O5: apskaičiuota: 419, 185635 rasta: 419,1853Elemental Analysis: C 21 H 26 FH 3 O 5 : Calculated: 419, 185635 Found: 419.1853
Masių spektras: m/z: 420 (Μ++δ1,4%), 419 (M+, 16%), 348 (20), 347 (100), 245 (8), 318 (9), 56 (27), 32 (12).Mass Spectrum: m / z: 420 (Μ + + δ1.4%), 419 (M + , 16%), 348 (20), 347 (100), 245 (8), 318 (9), 56 (27 ), 32 (12).
pavyzdys l-Etil-6-fluor-4-okso-7-(4-karboetoksi-l-piperazinil)1,4-dihidrochinolin-3-karboksirūgštis l-Etil-6-fluor-4-okso-7-chloro-l,4-dihidrochinolin-3karboksirūgštis (0,270 g, 0,001 mol) ir 1-karbetoksipiperazinas (0,632 g, 0,004 mol) suspenduojama 2-metil5-etilpiridine (4 ml) ir 1-metilpirolidone (2 ml) ir kaitinama 4 vai. reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu. Pasibaigus reakcijai, pripilama 10 ml chloroformo, tirpalas praplaunamas 10% vandeniniu HCl tirpalu ir po to vandeniu iki tirpalo neutralios reakcijos. Chloroforminis sluoksnis džiovinamas, o tirpiklis nudistiliuoj amas vakuume. Sausa biri liekana praplaunama etanoliu ir džiovinama. Taip gaunama l-etil-6-fluoro -7-(4-karbetoksi-l-piperazinil)-4-okso-l,4-dihidrochinolin-3-karboksirūgštis (0,195 g, 50%), lyd. t. 270-273°C.Example 1 1-Ethyl-6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) 1,4-dihydroquinoline-3-carboxylic acid 1-Ethyl-6-fluoro-4-oxo-7-chloro-1 , 4-Dihydroquinoline-3-carboxylic acid (0.270 g, 0.001 mol) and 1-carbethoxypiperazine (0.632 g, 0.004 mol) were suspended in 2-methyl-5-ethylpyridine (4 ml) and 1-methylpyrrolidone (2 ml) and heated for 4 hours. of the reaction mixture at reflux. At the end of the reaction, add 10 ml of chloroform, wash the solution with 10% aqueous HCl and then with water until the solution is neutral. The chloroform layer was dried and the solvent was distilled off in vacuo. The dry bulk residue is washed with ethanol and dried. There was thus obtained 1-ethyl-6-fluoro-7- (4-carbethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.195 g, 50%), m.p. t. 270-273 ° C.
Spektriniai duomenys:Spectral data:
4H BMR (CF3COOH, TMS): 5CH = 42 m.d. (3 = 6,4 Hz, t, 3H), δ0Η3 = 1,78 m.d. (t, J = 6,4 Hz, 3H), δΗ(piperazinil) = 3,88 m.d. (m, 8H) , 6Cjį2 = 4,41 m.d.(k, 4 H NMR (CF 3 COOH, TMS): δCH = 42 md ( 3 = 6.4 Hz, t, 3H), δ0Η3 = 1.78 md (t, J = 6.4 Hz, 3H), δ Η (piperazinyl) = 3.88 md (m, 8H), 6 C it 2 = 4.41 md (k,
6,4 Hz, 2H) , SCn2 = 4,84 m.d. (k, J=6,4 Hz, 2H), δΗθ=7,40 m.d. (d, 4JFH8=6,5 Hz, 1H), δΗ5=8,27 m.d. (d, 3JFH5=13Hz, 1H), δΗζ=9,28 m.d. (c, 1H) .6.4 Hz, 2H), S C n 2 = 4.84 md (k, J = 6.4 Hz, 2H), δ Η θ = 7.40 md (d, 4 J F H 8 = 6.5 Hz, 1H), δ Η5 = 8.27 ppm (d, 3 = 5 JFH 13Hz, 1H), δ Ηζ = 9.28 ppm (c, 1H).
19F BMR (CF3COOH, CC13F) :δΓ=-112,07 m.d. (dd, 3JFH5 = 13 Hz, 4JFH8 = 6,5 Hz) 19 F NMR (CF 3 COOH, CC 13 F): δΓ = -112.07 md (dd, 3 J F H 5 = 13 Hz, 4 J J H 8 = 6.5 Hz)
Masių spektras m/z: 392 (M++l, 3%), 391 (M+, 15%), 348 (15), 347 (100), 151 (14), 83 (12), 56 (19), 44 (15), 43 (11) .Mass spectrum m / z: 392 (M + + 1.3%), 391 (M + , 15%), 348 (15), 347 (100), 151 (14), 83 (12), 56 (19). , 44 (15), 43 (11).
Elementinė analizė C19H22FN3O5: apskaičiuota: 391, 154, rasta:Elemental analysis for C 19 H 22 FN 3 O 5 : Calculated: 391, 154, Found:
391,154.391,154.
io pavyzdys l-Ciklopropil-6-fluoro-7-(4-karboetoksi-l-piperazinil)4-okso-l,4-dihidrochinolin-3-karboksirūgšties etilo esteris l-Ciklopropil-6,7-difluor-4-okso-l,4-dihidrochinolin-3karboksirūgšties etilo esteris (0,439 g, 0,0015 mol), 1-karboetoksi-piperazinas (0,26 g, 0,00165 mol ir kalio karbonatas (0,228 g, 0,00165 mol) suspenduojama N,Ndimetilformamide ir kaitinama 4 vai. reakcijos mišinio virimo temperatūroje. Pasibaigus reakcijai, tirpiklis nudistiliuojamas vakuume, pripilama 20 ml vandens ir ekstranuojama chloroformu.Example 1 1-Cyclopropyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 1-Cyclopropyl-6,7-difluoro-4-oxo- 1,4-Dihydroquinoline-3-carboxylic acid ethyl ester (0.439 g, 0.0015 mol), 1-carboethoxy-piperazine (0.26 g, 0.00165 mol) and potassium carbonate (0.228 g, 0.00165 mol) are suspended in N, N-dimethylformamide After heating the reaction mixture, the solvent is distilled off in vacuo, 20 ml of water are added and the mixture is extracted with chloroform.
Chloroforminis sluoksnis džiovinamas ir kieta fazė pašalinama. Taip gaunama l-ciklopropil-6-fluoro-7-(4karboetoksi-l-piperazinil)-4-okso-l,4-dihidrochinolin-3 karboksirūgšties etilo esteris. (0,529 g, 82%). Gautas produktas perkristalinamas iš etanolio, lyd. t. 225229°C.The chloroform layer is dried and the solid phase is removed. This gives 1-cyclopropyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3 carboxylic acid ethyl ester. (0.529 g, 82%). The resulting product is recrystallized from ethanol, m.p. t. 225229 ° C.
Spektriniai duomenys:Spectral data:
XH BMR (CDC13, TMS) : 5CH , CH , H (ciklopropil) =1,45 (m, 10H), δΗ (piperazinil), H(ciklopropil) = 3,32 m.d. (m, 5H) 3,73 m.d. (m, 4H) , δς^ς^ = 4,32 m.d. (m, 4H) , δ^θ = 7,20 m.d. (d, 4JFH8 = 6,4 Hz, 1H), δΗ = 7,87 m.d. (d, 3JFH5 = 13 Hz, 1H), δΗ = 8,43 m.d. (c, 1H) . 1 H NMR (CDCl 3, TMS): δCH, CH, H (cyclopropyl) = 1.45 (m, 10H), δΗ (piperazinyl), H (cyclopropyl) = 3.32 md (m, 5H) 3.73 md (m, 4H), δς ^ ς ^ = 4.32 md (m, 4H), δ ^ θ = 7.20 md (d, 4 JFH8 = 6.4 Hz, 1H), δ Η = 7.87 md (d, 3 5 JFH = 13 Hz, 1H), δ Η = 8.43 ppm (c, 1H).
19F BMR (CF3 COOH, CC13F) : δ? = -112,57 m.d. (dd, 3JFH5 = 13 Hz, 4JFH8 =6,5 Hz) 19 F NMR (CF3 COOH, CC13F): δ? = -112.57 md (dd, 3 JFH5 = 13 Hz, 4 JFH 8 = 6.5 Hz)
Masių spektras: m/z: 432 (M++ 1, 6%), 431 (M+, 21%), 386 (8), 360 (21), 359 (100), 329 (6), 257 (6), 230 (6), 229 (5) ,56 (26) .Mass Spectrum: m / z: 432 (M + + 1.6%), 431 (M + , 21%), 386 (8), 360 (21), 359 (100), 329 (6), 257 (6) ), 230 (6), 229 (5), 56 (26).
pavyzdys l-Ciklopropil-6-fluoro-7-(4-karboetoksi-l-piperazinil)4-okso-l,4-dihidrochinolin-3-karboksirūgštis l-Ciklopropil-6,7-difluoro-4-okso-l,4-dihidrochinolin3-karboksirūgštis (0,265 g, 0,001 mol), 1-karboetoksipiperazinas (0,174 g, 0,0011 mol) ir kalio karbonatas (0,152 g, 0,0011 mol) suspenduojama N,lydime t ii f ormamide (10 ml) ir kaitinama 2,5 vai.Example 1 1-Cyclopropyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-Cyclopropyl-6,7-difluoro-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid (0.265 g, 0.001 mol), 1-carboethoxypiperazine (0.174 g, 0.0011 mol) and potassium carbonate (0.152 g, 0.0011 mol) are suspended in N, melted in tii f ormamide (10 ml) and heated 2.5 or.
reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu. Pasibaigus reakcijai, tirpiklis nudistiliuojamas vakuume, į sausą liekaną pripilama vandens (10 ml) , ir neutralizuojama iki pH neutralaus su 15% HCl. Nuosėdos filtruojamos ir džiovinamos. Gautas produktas perkristalinamas iš dimetilformamido.of the reaction mixture at reflux. At the end of the reaction, the solvent was distilled off in vacuo, water (10 mL) was added to the dry residue and neutralized to pH neutral with 15% HCl. The precipitate is filtered off and dried. The product is recrystallized from dimethylformamide.
Taip gaunama l-ciklopropil-6-fluoro-7-(4-karboetoksi-lpiperazinil) -4-okso-l,4-dihidrochinolin-3karboksirūgštis (0,282 g, 70%), lyd. t. 250oC.There was thus obtained 1-cyclopropyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.282 g, 70%), m.p. t. 250 ° C.
Spektriniai duomenys:Spectral data:
XH BMR (CF3COOH, TMS) : δ0Η,H(ciklopropil) = 1,50 m.d. (m, 7H), δΗ (piperazinil), H (ciklopropil) = 3,92 m.d. (m, 9H), δΟπ2 = 4,41 m.d. (k, J =6,4 Hz, 2H) , 6Hg = 7,88 m.d. (d, 4JFH8 = 6,5 Hz), δΗ = 8,27 m.d. (d, 3JFH5 = 13 Hz, IH), δΗ2 = 9,32 m.d. (s, IH). 1 H NMR (CF 3 COOH, TMS): δ0Η, H (cyclopropyl) = 1.50 md (m, 7H), δΗ (piperazinyl), H (cyclopropyl) = 3.92 md (m, 9H), δΟπ2 = 4, 41 ppm (q, J = 6.4 Hz, 2H), 7.88 6HG = md (d, 4 JFH8 = 6.5 Hz), δ Η = 8.27 ppm (d, 3 5 JFH = 13 Hz, 1H ), δ Η2 = 9.32 md (s, 1H ).
19F BMR (CFgCOOH, CFC13) : δρ = -112, 40 m.d. (dd, 3JFH5 = 13 Hz, 4JFH8 =6,5 Hz). 19 F NMR (CF 8 COOH, CFCl 3): δρ = -112, 40 md (dd, 3 J F H 5 = 13 Hz, 4 J F H 8 = 6.5 Hz).
Elementinė analizė C20H22FN3O5: apskaičiuota: 403, 154 rasta: 403,150 pavyzdys l-Ciklopropil-6-fluor-7-(4-karboetoksi-l-piperazinil)4-okso-l,4-dihidrochinolin-3-karboksirūgštis l-Ciklopropil-6-fluor-7-chlor-4-okso-l,4-dihidrochinolin-3-karboksirūgštis (0,281 g, 0,001 mol) ir 1karboetoksipiperazinas (0,632 g, 0,004 mol) suspenduojama 2-metil-5-etilpiridine (8 ml) ir 1metilpirolidone (2 ml) ir kaitinama 4 vai, reakcijos mišinio virimo temperatūroje su grįžtamuoju šaldytuvu. Pasibaigus reakcijai, pripilama 20 ml chloroformo į šaltą tirpalą, ir gautas tirpalas praplaunamas 15% vandeniniu HCI tirpalu, o po to vandeniu iki neutralios reakcijos. Chloroforminis sluoksnis džiovinamas, ir tirpiklis nudistiliuojamas. Liekana praplaunama etanoliu ir džiovinama.Elemental Analysis for C 20 H 22 FN 3 O 5 : Calculated: 403, 154 Found: Example 403,150 1-Cyclopropyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) 4-oxo-1,4-dihydroquinoline-3 -Carboxylic acid l-Cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.281 g, 0.001 mol) and 1-carboethoxypiperazine (0.632 g, 0.004 mol) are suspended in 2-methyl-5- ethyl pyridine (8 mL) and 1-methylpyrrolidone (2 mL) and heated at reflux for 4 hours. At the end of the reaction, add 20 mL of chloroform to the cold solution and wash the resulting solution with 15% aqueous HCl and then with water until neutral. The chloroform layer is dried and the solvent is distilled off. The residue is washed with ethanol and dried.
Taip gaunama l-ciklopropil-6-fluoro-7-(4-karboetoksi-lpiperazinil) -4-okso-l,4-dihidrochinolin-3-karboksirūgštis (0,222 g, 55%), lyd.t. virš 250°C.There was thus obtained 1-cyclopropyl-6-fluoro-7- (4-carboethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.222 g, 55%), m.p. above 250 ° C.
Gautas produktas perkristalinamas iš Ν,Ν-dimetilformamido.The resulting product is recrystallized from Ν, Ν-dimethylformamide.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU244787A YU46099B (en) | 1987-12-31 | 1987-12-31 | PROCESS FOR PREPARING 1-SUBSTITUTED 6-FLUORO-4-OXO-7- 1-PIPERAZINYL) -1 |
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| LTIP510A LTIP510A (en) | 1994-11-25 |
| LT3274B true LT3274B (en) | 1995-05-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| LTIP510A LT3274B (en) | 1987-12-31 | 1993-05-05 | Process for preparing 1-substituted 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid |
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| Country | Link |
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| AT (1) | AT396105B (en) |
| CS (1) | CS274635B2 (en) |
| DD (1) | DD283386B5 (en) |
| HU (1) | HU200454B (en) |
| LT (1) | LT3274B (en) |
| LV (1) | LV10774B (en) |
| NO (1) | NO885666L (en) |
| PL (1) | PL163337B1 (en) |
| PT (1) | PT89359B (en) |
| RU (1) | RU2002744C1 (en) |
| SI (1) | SI8712447A8 (en) |
| YU (1) | YU46099B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2840910A1 (en) | 1977-09-20 | 1979-04-05 | Bellon Labor Sa Roger | 7-DIALKYLAMINO-6-HALOGEN-4-OXO-1,4-DIHYDRO-3-QUINOLINECARBONIC ACIDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL AGENTS CONTAINING THEM |
| BE890223A (en) | 1980-09-05 | 1982-01-04 | Kyorin Seiyaku Kk | PROCESS FOR THE PREPARATION OF QUINOLEINE-CARBOXYLIC ACID DERIVATIVES |
| DE3308909A1 (en) | 1983-03-12 | 1984-09-13 | Bayer Ag, 5090 Leverkusen | BACTERICIDALS BASED ON CHINOLONIC CARBONIC ACID |
| JPH033453A (en) | 1989-05-31 | 1991-01-09 | Nippon Telegr & Teleph Corp <Ntt> | Routing method for packet switching network |
| JPH066686A (en) | 1992-06-17 | 1994-01-14 | Ricoh Co Ltd | Image pickup device |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4017622A (en) * | 1972-12-18 | 1977-04-12 | Dainippon Pharmaceutical Co., Ltd. | Piperazine derivatives |
| JPS5845426B2 (en) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | Substituted quinoline carboxylic acid derivatives |
| DE3306771A1 (en) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | CHINOLONIC CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| DE3509546A1 (en) * | 1985-03-16 | 1986-09-25 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1- (SUBST.CYCLOPROPYL) -1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
-
1987
- 1987-12-31 YU YU244787A patent/YU46099B/en unknown
- 1987-12-31 SI SI8712447A patent/SI8712447A8/en unknown
-
1988
- 1988-12-21 NO NO88885666A patent/NO885666L/en unknown
- 1988-12-28 PT PT8935988A patent/PT89359B/en not_active IP Right Cessation
- 1988-12-29 CS CS903288A patent/CS274635B2/en unknown
- 1988-12-30 AT AT320688A patent/AT396105B/en not_active IP Right Cessation
- 1988-12-30 DD DD32470388A patent/DD283386B5/en active IP Right Maintenance
- 1988-12-30 PL PL27689088A patent/PL163337B1/en unknown
- 1988-12-30 HU HU667788A patent/HU200454B/en not_active IP Right Cessation
- 1988-12-30 RU SU4613227 patent/RU2002744C1/en active
-
1993
- 1993-05-05 LT LTIP510A patent/LT3274B/en not_active IP Right Cessation
- 1993-06-30 LV LV930828A patent/LV10774B/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2840910A1 (en) | 1977-09-20 | 1979-04-05 | Bellon Labor Sa Roger | 7-DIALKYLAMINO-6-HALOGEN-4-OXO-1,4-DIHYDRO-3-QUINOLINECARBONIC ACIDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL AGENTS CONTAINING THEM |
| BE890223A (en) | 1980-09-05 | 1982-01-04 | Kyorin Seiyaku Kk | PROCESS FOR THE PREPARATION OF QUINOLEINE-CARBOXYLIC ACID DERIVATIVES |
| DE3308909A1 (en) | 1983-03-12 | 1984-09-13 | Bayer Ag, 5090 Leverkusen | BACTERICIDALS BASED ON CHINOLONIC CARBONIC ACID |
| JPH033453A (en) | 1989-05-31 | 1991-01-09 | Nippon Telegr & Teleph Corp <Ntt> | Routing method for packet switching network |
| JPH066686A (en) | 1992-06-17 | 1994-01-14 | Ricoh Co Ltd | Image pickup device |
Also Published As
| Publication number | Publication date |
|---|---|
| YU46099B (en) | 1992-12-21 |
| LTIP510A (en) | 1994-11-25 |
| PT89359A (en) | 1989-12-29 |
| NO885666D0 (en) | 1988-12-21 |
| PL163337B1 (en) | 1994-03-31 |
| HU200454B (en) | 1990-06-28 |
| DD283386B5 (en) | 1997-10-30 |
| NO885666L (en) | 1989-07-03 |
| LV10774A (en) | 1995-08-20 |
| PL276890A1 (en) | 1989-10-16 |
| HUT49129A (en) | 1989-08-28 |
| PT89359B (en) | 1993-08-31 |
| ATA320688A (en) | 1992-10-15 |
| CS903288A2 (en) | 1990-12-13 |
| YU244787A (en) | 1990-06-30 |
| RU2002744C1 (en) | 1993-11-15 |
| AT396105B (en) | 1993-06-25 |
| CS274635B2 (en) | 1991-09-15 |
| SI8712447A8 (en) | 1995-12-31 |
| LV10774B (en) | 1996-08-20 |
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