SI9200377A - Process for the preparation of 1-substituted 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxilic acid, novel intermediate used in this process and process for its preparation - Google Patents

Description

Translated fromSlovenian

Postopek za pripravo l-subst-6-fluoro-4-okso-7-(l-piperazinil)-X,4-dihidrokinoIin3-karboksilne kisline, nov intermediat, uporaben v tem postopku, in postopek za pripravo tega intermediataA process for the preparation of 1-subst-6-fluoro-4-oxo-7- (1-piperazinyl) -X, 4-dihydroquinoline-3-carboxylic acid, a new intermediate useful in this process, and a process for the preparation of this intermediate

Področje tehnike, v katero spada izumFIELD OF THE INVENTION

Predloženi izum je s področja organske kemije in se nanaša na postopek za pripravo bioaktivne spojine l-subst.-6-fluoro-4-okso-7-(l-piperazinil)-l,4-dihidrokinolin-3karboksilne kisline s splošno formulo IIThe present invention relates to the field of organic chemistry and relates to a process for the preparation of the bioactive compound 1-subst.-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid of general formula II

COOH kjer pomeni R_x nižji alkil, nižji cikloalkil ali 2,4-difluorofenil, na nov intermediat l-subst.-6-fluoro-4-okso-7-(4-subst.-l-piperazinil)-l,4-dihidrokinolin-3-karboksilat borov diacetat s splošno formulo ICOOH where R_{x is} lower alkyl, lower cycloalkyl or 2,4-difluorophenyl, to a new intermediate 1-subst-6-fluoro-4-oxo-7- (4-subst-1-piperazinyl) -1, 4- dihydroquinoline-3-carboxylate boron diacetate of general formula I

AeO OAc \ /AeO OAc \ /

c=oc = o

COOR2 kjer imaCOOR2 where it has

R_x preje navedeni pomen in R₂ pomeni nižji alkil ali v danem primeru substituiran fenil, ter na postopek za njegovo pripravo.R_{x is the} aforesaid meaning and R₂ is lower alkyl or optionally substituted phenyl, and a process for preparing it.

Spojine s formulo II se uporabljajo v medicini za zdravljenje vnetnih obolenj. Spekter njihovega delovanja je širok, saj delujejo na gram-pozitivne in gram-negativne bakterije.The compounds of formula II are used in medicine for the treatment of inflammatory diseases. Their spectrum of activity is broad, as they act on both gram-positive and gram-negative bacteria.

Tehnični problemA technical problem

Obstajala je potreba po novem postopku za pripravo bioaktivnih spojin s splošno formulo II, kjer bi lahko izvedli nukleofilno substitucijo atoma halogena na mestu 7 v izhodni spojini 1-substituiranem 6-fluoro-7-halo-4-okso-l,4-dihidrokinolin-3karboksilatu borovem diacetatu s splošno formulo IIIThere was a need for a new process for the preparation of bioactive compounds of general formula II, where nucleophilic substitution of the halogen atom at site 7 in the starting compound 1-substituted 6-fluoro-7-halo-4-oxo-1,4-dihydroquinoline- 3carboxylate of boron diacetate of general formula III

kjer je X F ali CI ter ima R₁ preje navedeni pomen, s sekundarnim aminom ob milejših reakcijskih pogojih, kar bi zmanjšalo delež nastalega substitucijskega produkta na mestu 6.wherein XF or CI and R_{1 of the} yarn has the indicated meaning, with a secondary amine under milder reaction conditions, which would reduce the proportion of the resulting substitution product at site 6.

Stanje tehnikeThe state of the art

Sinteza spojin s splošno formulo II je opisana v številnih patentnih dokumentih, npr. kot substitucija klora na mestu 7 l-alkil-6-fluoro-7-halo-4-okso-l,4-dihidrokinolin-3karboksilne kisline s piperazinom v JP št. 66686/1979 in JP št. 33453/1980, v DE 2840910 in DE 3308909 ter kot reakcija hidrolize alkilestra na mestu 3 l-alkil-6fluoro-7-(l-piperazinil)-4-okso-l,4-dihidrokinolin-3-karboksilne kisline v BE 890223.The synthesis of compounds of general formula II is described in a number of patent documents, e.g. as the substitution of chlorine at the site of 7-alkyl-6-fluoro-7-halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid by piperazine in JP no. 66686/1979 and JP Nos. 33453/1980, in DE 2840910 and DE 3308909, and as the reaction of hydrolysis of alkyl ester at the site of 3-alkyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid in BE 890223.

Za vse te postopke je značilno, da substitucijska reakcija poteka učinkovito le pri temperaturah nad 100 °C, kar ima za posledico velik odstotek konkurenčne reakcije na mestu 6.All of these processes are characterized by the fact that the substitution reaction proceeds efficiently only at temperatures above 100 ° C, resulting in a large percentage of the competitive reaction at site 6.

V ES 9001782 je opisana nukleofilna substitucija na borovih, aluminijevih in silicijevih kelatih, vendar pa nastalega substitucijskega produkta niso izolirali, temveč so takoj izvedli hidrolizo do bioaktivne spojine. V HU 1505/87 je tudi opisana nukleofilna substitucija atoma halogena na mestu 7 v borovem kelatnem kompleksu, ki poteka pri temperaturah nad 100 °C. Tudi v tem primeru nastalega substitucijskeg produkta niso izolirali, temveč so takoj izvedli hidrolizo.ES 9001782 describes nucleophilic substitution on boron, aluminum and silicon chelates, but did not isolate the resulting substitution product but performed hydrolysis immediately to the bioactive compound. HU 1505/87 also describes the nucleophilic substitution of a halogen atom at site 7 in a boron chelate complex that takes place at temperatures above 100 ° C. Even in this case, the resulting substitution product was not isolated but hydrolyzed immediately.

Opis rešitve tehničnega problemaDescription of solution to a technical problem

Prvi predmet izuma je postopek za pripravo l-subst.-6-fluoro-4-okso-7-(lpiperazinil)-l,4-dihidrokinolin-3-karboksilne kisline s splošno formulo IIThe first object of the invention is a process for the preparation of 1-subst.-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid of general formula II

kjer pomeni Rj nižji alkil, nižji cikloalkil ali 2,4-difluorofenil, ali njene farmacevtsko sprejemljive kislinske adicijske soli, kot hidroklorida ali laktata, in hidratov, ki ga izvedemo tako, da spojino s splošno formulo Iwherein R1 represents lower alkyl, lower cycloalkyl or 2,4-difluorophenyl, or pharmaceutically acceptable acid addition salts thereof, such as hydrochloride or lactate, and hydrates, which are carried out by the compound of general formula I

kjer imawhere it has

R₂ preje navedeni pomen in R₂ pomeni nižji alkil ali v danem primeru substituiran fenil, podvržemo alkalni hidrolizi ter po želji dobljeno spojino s splošno formulo II prevedemo v njeno farmacevtsko sprejemljivo kislinsko adicijsko sol, kot hidroklorid ali laktat, ali v hidrate.R_{2 is} given the above meaning and R₂ is lower alkyl or optionally substituted phenyl, subjected to alkaline hydrolysis, and optionally the resulting compound of general formula II is converted into its pharmaceutically acceptable acid addition salt, such as hydrochloride or lactate, or hydrates.

Alkalno hidrolizo izvedemo v vodnem ali vodno-etanolnem mediju npr. z raztopino alkalijskega hidroksida, kot 10%-nega KOH ali 10%-nega NaOH, pri temperaturi odAlkaline hydrolysis is carried out in an aqueous or aqueous-ethanol medium, e.g. with a solution of alkali hydroxide, such as 10% KOH or 10% NaOH, at a temperature of

50°C do temperature refluksa, prednostno pri temperaturi refluksa reakcijske zmesi.50 ° C to reflux temperature, preferably at reflux temperature of the reaction mixture.

Po nevtralizaciji s kislino, prednostno ocetno kislino, se izloči produkt, ki vsebuje brez dodatnega čiščenja pod 0,5% skupnih nečistot.After neutralization with an acid, preferably acetic acid, a product is eliminated which contains, without further purification, less than 0.5% of the total impurities.

Drugi predmet izuma je nov intermediat, t.j. l-subst.-6-fluoro-4-okso-7-(4-subst.-lpiperazinil)-l,4-dihidrokinolin-3-karboksilat borov diacetat s splošno formulo I, uporaben kot izhodna snov v gornjem postopku za pripravo bioaktivne spojine s splošno formulo II.Another object of the invention is a novel intermediate, i.e. 1-subst.-6-fluoro-4-oxo-7- (4-subst.-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate of general formula I, useful as a starting material in the above process for the preparation of bioactive compounds of general formula II.

Še nadaljnji predmet izuma je postopek za pripravo novega intermediata s splošno formulo I, pri katerem v 1-substituiranem 6-fluoro-4-okso-7-halo-l,4-dihidrokinolin3-karboksilatu borovem diacetatu s splošno formulo III izvedemo nukleofilno substitucijo atoma halogena na mestu 7 z 1-substituiranim piperazinom s formuloA further object of the invention is a process for the preparation of a novel intermediate of general formula I in which nucleophilic atom substitution is carried out in 1-substituted 6-fluoro-4-oxo-7-halo-1,4-dihydroquinoline-3-carboxylate boron diacetate of halogen at site 7 with 1-substituted piperazine of formula

coor₂ kjer ima R₂ preje navedeni pomen.coor₂ where R₂ yarn has the indicated meaning.

Reakcijo izvajamo v organskem topilu, kot piridinu, dimetilsulfoksidu, dimetilformamidu, l-metil-2-pirolidonu, prednostno l-metil-2-pirolidonu, pri temperaturah od 0 °C do 40 °C, prednostno od 25 °C do 30 °C. Pri tej temperaturi v l-metil-2pirolidonu kot topilu poteče reakcija v času od 10 do 15 ur, pri čemer ne nastanejo nobeni stranski produkti in tudi hidroliza borove soli pri tej temperaturi ne poteče. Pri reakcijskih temperaturah nad 40 °C je namreč razgradnja borove soli zaznavna in s povišano temperaturo zelo hitro narašča. Nastala 3-karboksilna kislina kot posledica te razgradnje je mnogo manj reaktivna, saj poteče nukleofilna substitucija pri temperaturah nad 100 °C.The reaction is carried out in an organic solvent such as pyridine, dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably 1-methyl-2-pyrrolidone, at temperatures from 0 ° C to 40 ° C, preferably from 25 ° C to 30 ° C. . At this temperature, the reaction in l-methyl-2-pyrrolidone as a solvent proceeds for 10 to 15 hours, with no by-products produced and no hydrolysis of the boron salt at this temperature. For reaction temperatures above 40 ° C, the decomposition of boron salt is noticeable and increases rapidly with increasing temperature. The resulting 3-carboxylic acid as a result of this degradation is much less reactive as nucleophilic substitution expires at temperatures above 100 ° C.

Izolacija nastale spojine s formulo I je zelo enostavna , saj se pri obaijanju z alkoholom izloči v čisti obliki in dodatno čiščenje ni potrebno.The isolation of the resultant compound of Formula I is very straightforward, since it is eliminated in pure form when treated with alcohol and no further purification is necessary.

Spojino s splošno formulo I uporabimo kot izhodno snov pri pripravi spojine s splošno formulo II, in sicer v izolirani obliki ali pa in situ.The compound of general formula I is used as a starting material in the preparation of the compound of general formula II, either in isolated form or in situ.

Vsi reaktanti so bodisi tržno dostopni ali pa jih lahko dobimo na tukaj opisani način.All reactants are either commercially available or can be obtained as described herein.

Oba postopka v smislu izuma sta pregledno podana z naslednjo reakcijsko shemo, kjer imajo X, Rj in R₂ preje navedeni pomen.Both of the processes of the invention are illustrated transparently by the following reaction scheme, wherein X, R 1 and R_{2 have the} indicated meaning.

AeO OAcAeO OAcH0' N ··coor₂H 0 'N ·· coor₂FsFsAeO OAcy °^- ?1 H IIAeO OAc y °^- ? 1 H II0'*χΥ0 '*χΥ0.0=00.0 = 0HimHimCOOR2COOR2^RiI^R and I

“V R,_ttVR,_tt

Izum natančneje opisujemo, nikakor pa ne omejujemo z naslednjimi primeri.The invention is described in more detail, but in no way limited by the following examples.

Primer 1 l-ciklopropil-6-fluoro-4-okso-7-(4-karboetoksi-l-piperazinil)-l,4-dihidrokinolin-3-karboksilat borov diacetat g (0,0244· molov) l-ciklopropil-6-fluoro-4-okso-7-kloro-l,4-dihidrokinolin-3karboksilata borovega diacetata in 15,44 g (0,0977 molov) l-karboetoksipiperazina suspendiramo v 40 ml l-metil-2-pirolidona in mešamo pri temperaturi 30 °C 12 ur. Po končani reakciji dodamo k reakcijski zmesi 60 ml absolutnega etanola in mešamo pri sobni temperaturi 2 uri. Izločeno oborino odnučamo, speremo z etanolom in posušimo v vakuumu pri 80 °C. Filtrat ohladimo na 0 do 5 °C in izločeno oborino odnučamo, suspendiramo v zmes l-metil-2-pirolidona/etanola (2:1) in maceriramo 2 uri, odnučamo in posušimo. Produkta združimo. Tako dobimo 10,75 g (83%) kromatografsko čistega l-ciklopropil-6-fluoro-4-okso-7-(4-karboetoksi- 1piperazinil)-l,4-dihidrokinolin-3-karboksilata borovega diacetata s tal. 235 do 240°C.Example 1 1-Cyclopropyl-6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate g (0.0244 · mol) 1-cyclopropyl-6 -fluoro-4-oxo-7-chloro-1,4-dihydroquinoline-3-carboxylate of boron diacetate and 15.44 g (0.0977 mol) of 1-carboethoxypiperazine were suspended in 40 ml of 1-methyl-2-pyrrolidone and stirred at 30 ° C 12 hours After completion of the reaction, 60 ml of absolute ethanol was added to the reaction mixture and stirred at room temperature for 2 hours. The precipitated precipitate was filtered off, washed with ethanol and dried in vacuo at 80 ° C. The filtrate was cooled to 0 to 5 ° C and the precipitated precipitate was filtered off, suspended in 1-methyl-2-pyrrolidone / ethanol (2: 1) and macerated for 2 hours, filtered off and dried. We combine products. There was thus obtained 10.75 g (83%) of chromatographically pure 1-cyclopropyl-6-fluoro-4-oxo-7- (4-carboethoxy-1piperazinyl) -1,4-dihydroquinoline-3-carboxylate pine diacetate from m.p. 235 to 240 ° C.

Spektroskopski podatki:Spectroscopic data:

*H NMR spekter (CF₃COOH, TMS) (posneto na 300 MHz instrumentu):* H NMR spectrum (CF₃ COOH, TMS) (recorded on a 300 MHz instrument):

^cH2(cikio_Propii) ~ (^m> J⁼8Hz, 2H), 5_CH3 = 1.30 (t, J=8Hz, 3H), 5_CH2^_ciklopropi])=^ cH2 (cyclo_P ropii) ~ (^m > J⁼ 8Hz, 2H), 5_CH3 = 1.30 (t, J = 8Hz, 3H), 5_CH2 ^_cyclopropes] ) =

1.52 (m, J=8Hz, 2H), 5_CH3 = 2.03 (s, 6H), 6_{CH2(piperazinil}^ = 3.42 (m, 4H), ^_CH2(._piperazinilj = 3.74 (m, 4H), §_{CH(ciklopropil)} = 3.73 (m, J=8Hz, IH), S_0CH2 = 4.2 (q, J=8Hz, 2H),^δΗ8⁼ 7-48 PP^m J⁼8Hz, IH), δ_Η5 = 8.08 (d, J=14.3Hz, IH), δ_Η2= 9.0 ppm (s, IH).1.52 (m, J = 8Hz, 2H), 5_CH3 = 2.03 (s, 6H), 6_{CH2 (piperazinyl} = 3.42 (m, 4H), ^_{CH2 (} ._Piperazinyl j = 3.74 (m, 4H),_{§CH (cyclopropyl)} = 3.73 (m, J = 8Hz, 1H), S_0CH2 = 4.2 (q, J = 8Hz, 2H),^δ Η8⁼ 7-48 PP^m J⁼ 8Hz, 1H), δ_Η5 = 8.08 (d , J = 14.3Hz, 1H), δ_{Η 2} = 9.0 ppm (s, 1H).

IR spekter:IR spectrum:

1700,1630,1480,1370,1275,1240,1060,960 cm’¹.1700,1630,1480,1370,1275,1240,1060,960 cm '¹ .

Primer 2 l-etiI-6-fluoro-4-okso-7-(4-karboetoksi-l-piperazmil)-l,4-dihidrokinolin-3-karboksilat borov diacetatExample 2 1-Ethyl-6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate

2,37 g (0,006 molov) l-etil-6-fluoro-4-okso-7-kloro-l,4-dihidrokinolin-3-karboksilata borovega diacetata in 3,78 g (0,024 molov) l-karboetoksipiperazina suspendiramo v2.37 g (0.006 mol) of 1-ethyl-6-fluoro-4-oxo-7-chloro-1,4-dihydroquinoline-3-carboxylate of boron diacetate and 3.78 g (0.024 mol) of 1-carboethoxypiperazine were suspended in

9,5 ml l-metil-2-pirolidona in mešamo 9 ur pri 30 °C. Po končani reakciji dodamo reakcijski zmesi 19 ml absolutnega etanola in mešamo 2 uri pri sobni temperaturi.9.5 ml of 1-methyl-2-pyrrolidone and stirred at 30 ° C for 9 hours. After completion of the reaction, 19 mL of absolute ethanol was added to the reaction mixture and stirred at room temperature for 2 hours.

Izločeni produkt odnučamo, speremo z etanolom in posušimo v vakuumu pri 80 °C. Tako dobimo 2,7 g (87%) l-etil-6-fluoro-4-okso-7-(4-karboetoksi-l-piperazinil)-l,4dihidrokinolin-3-karboksilata borovega diacetata s tal. 235 do 238 °C.The separated product was filtered off, washed with ethanol and dried in vacuo at 80 ° C. 2.7 g (87%) of 1-ethyl-6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate of boron diacetate were obtained from m.p. 235 to 238 ° C.

Spektroskopski podatki:Spectroscopic data:

Ή NMR spekter (CF₃COOH, TMS) (posneto na 60 MHz instrumentu):Ή NMR spectrum (CF₃ COOH, TMS) (recorded on a 60 MHz instrument):

5_CH3 = 1.53 (t, J=7Hz, 3H), 5_CH3 = 1.97 (t, J=7Hz, 3H), 5_CH3 = 2.4 (s, 6H), ^CH2(piperazinil) ~ ^NCH2 ~ fa’ J⁼7Hz, 2H), 5_QCH2 = 5.03 (q, J=7Hz,5_CH3 = 1.53 (t, J = 7Hz, 3H), 5_CH3 = 1.97 (t, J = 7Hz, 3H), 5_CH3 = 2.4 (s, 6H), ^ CH2 (piperazinyl) ~ ^ NCH2 ~ fa 'J⁼ 7Hz, 2H), 5_QCH2 = 5.03 (q, J = 7Hz,

2H), δ_Η8 = 7.7 (d, J=6Hz, IH), δ_Η5 = 8.4 (d, J=12Hz, IH), δ_Η2 = 9.6 ppm (s, IH).2H), δ_Η8 = 7.7 (d, J = 6Hz, 1H), δ_Η5 = 8.4 (d, J = 12Hz, 1H), δ_Η2 = 9.6 ppm (s, 1H).

¹⁹F NMR spekter (CF₃COOH, CFC1₃) (posneto na 60 MHz instrumentu): δ_ρ= -114.0 ppm (dd, J=12Hz; 6Hz).¹⁹ F NMR spectrum (CF₃ COOH, CFC1₃ ) (recorded on a 60 MHz instrument): δ_ρ = -114.0 ppm (dd, J = 12Hz; 6Hz).

IR spekter:IR spectrum:

1700,1635,1490,1375,1285,1240,1060,970 cm⁴.1700,1635,1490,1375,1285,1240,1060,970 cm⁴ .

Primer 3 l-ciklopropil-6-fluoro-4-okso-7-(l-piperazinil)-l,4-dihidrokinolin-3-karboksilna kislina g (0,0188 molov) l-ciklopropil-6-fluoro-4-okso-7-(4-karboetoksi-l-piperazinil)l,4-dihidrokinolin-3-karboksilata borovega diacetata suspendiramo v 187 ml 10%nega KOH in segrevamo pri temperaturi refluksa 1,5 ure. Nato reakcijsko zmes ohladimo na sobno temperaturo in z ocetno kislino uravnamo pH na 7,2 do 7,4. Reakcijsko zmes mešamo še 30 minut, oborino odnučamo, speremo z vodo in posušimo. Tako dobimo 5,95 g (96%) l-ciklopropil-6-fluoro-4-okso-7-(l-piperazinil)-l,4dihidrokinolin-3-karboksilne kisline s tal. 258 do 263 °C.Example 3 1-Cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid g (0.0188 mol) 1-cyclopropyl-6-fluoro-4-oxo -7- (4-Carboethoxy-1-piperazinyl) 1,4-dihydroquinoline-3-carboxylate boron diacetate was suspended in 187 ml of 10% KOH and heated at reflux for 1.5 hours. The reaction mixture was then cooled to room temperature and the pH adjusted to 7.2 to 7.4 with acetic acid. The reaction mixture was stirred for another 30 minutes, the precipitate was filtered off, washed with water and dried. 5.95 g (96%) of 1-cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid are thus obtained, m.p. 258 to 263 ° C.

Primer 4 l-ciklopropil-6-fluoro-4-okso-7-(l-piperazinil)-l,4-dihidrokinolin-3-karboksilna kislina hidroklorid monohidrat g (0,0056 molov) l-ciklopropil-6-fluoro-4-okso-7-(4-karboetoksi-l-piperazinil)-l,4dihidrokinolin-3-karboksilata borovega diacetata suspendiramo v 56 ml 10%-negaExample 4 1-Cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid hydrochloride monohydrate g (0.0056 mol) 1-cyclopropyl-6-fluoro-4 -oxo-7- (4-carboethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate of boron diacetate was suspended in 56 ml of 10%

KOH in segrevamo pri temperaturi refluksa 1,5 ure. Po končani reakciji dodamo 8 ml koncentrirane HC1 in segrevamo 30 minut pri temperaturi 80 °C. Nato reakcijsko zmes ohladimo na sobno temperaturo, dodamo 14 ml etanola, mešamo še 30 minut, izločeno oborino odnučamo in izperemo z vodo ter posušimo do konstantne mase. Tako dobimo 1,98 g (92%) l-ciklopropil-6-fluoro-4-okso-7-(l-piperazinil)-l,4dihidrokinolin-3-karboksilna kisline hidroklorida monohidrata s tal. 282 do 288 °C.KOH and heated at reflux temperature for 1.5 hours. After completion of the reaction, 8 ml of concentrated HCl was added and heated at 80 ° C for 30 minutes. The reaction mixture was then cooled to room temperature, 14 ml of ethanol was added, stirred for a further 30 minutes, the precipitate was filtered off and washed with water and dried to constant weight. 1.98 g (92%) of 1-cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid hydrochloride monohydrate are thus obtained from m.p. 282 to 288 ° C.

Primer 5 l-etil-6-fluoro-4-okso-7-(l-piperazinil)-l,4-dihidrokinolin-3-karboksilna kislinaExample 5 1-Ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid

1,04 g (0,002 mola) l-etil-6-fluoro-4-okso-7-(4-karboetoksi-l-piperazinil)-l,4dihidrokinolin-3-karboksilata borovega diacetata suspendiramo v 16 ml 10%-nega KOH in 12 ml etanola ter segrevamo pri temperaturi refluksa zmesi 11 ur. Nato zmes ohladimo na 15 °C in uravnamo pH na 7,2 do 7,4 s 15% HC1 in mešamo pri omenjeni temperaturi še 30 minut. Izločeno oborino odnučamo, speremo z vodo in posušimo do konstantne mase v vakuumskem sušilniku pri 100 °C. Tako dobimo 0,6 g (93%) l-etil-6-fluoro-4-okso-7-(l-piperazinil)-l,4-dihidrokinolin-3-karboksilne kisline s tal. 218 do 221 °C.1.04 g (0.002 mol) of 1-ethyl-6-fluoro-4-oxo-7- (4-carboethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate of boron diacetate were suspended in 16 ml of 10% KOH and 12 ml of ethanol and heated at reflux temperature for 11 hours. The mixture was then cooled to 15 ° C and the pH adjusted to 7.2 to 7.4 with 15% HCl and stirred at this temperature for another 30 minutes. The precipitated precipitate was filtered off, washed with water and dried to constant weight in a vacuum oven at 100 ° C. 0.6 g (93%) of 1-ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid are obtained from m.p. 218 to 221 ° C.

Claims (7)

Translated fromSlovenian

PATENTNI ZAHTEVKIPATENT APPLICATIONS1. Postopek za pripravo l-subst.-6-fluoro-4-okso-7-(l-piperazinil)-l,4dihidrokinolin-3-karboksilne kisline s splošno formulo II kjer pomeni Rj nižji alkil, nižji cikloalkil ali 2,4-difluorofenil, ali njene farmacevtsko sprejemljive kislinske adicijske soli, kot hidroklorida ali laktata, in hidratov, označen s tem, da spojino s splošno formulo IA process for the preparation of 1-subst.-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid of the general formula II wherein R 1 is lower alkyl, lower cycloalkyl or 2,4 -difluorophenyl, or its pharmaceutically acceptable acid addition salts, such as hydrochloride or lactate, and hydrates, characterized in that the compound of general formula ICOOEt, kjer ima R_t preje navedeni pomen in R₂ pomeni nižji alkil ali v danem primeru substituiran fenil, podvržemo alkalni hidrolizi in po želji dobljeno spojino s splošno formulo II pretvorimo v njeno farmacevtsko sprejemljivo kislinsko adicijsko sol, kot hidroklorid ali laktat, in hidrate.COOEt, wherein R_{t is of the} foregoing meaning and R₂ is lower alkyl or optionally substituted phenyl, is subjected to alkaline hydrolysis and optionally converted to a pharmaceutically acceptable acid addition salt thereof, such as hydrochloride or lactate, and hydrates .2. l-subst.-6-fluoro-4-okso-7-(4-subst.-l-piperazinil)-l,4-dihidrokinolin-3-karboksilat borov diacetat s splošno formulo I kjer pomeni R₁ nižji alkil, nižji cikloalkil ali 2,4-difluorofenil in R2 nižji alkil ali v danem primeru substituiran fenil.2. 1-Subst-6-fluoro-4-oxo-7- (4-subst-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate of general formula I wherein R_{1 is} lower alkyl, lower cycloalkyl or 2,4-difluorophenyl and R2 lower alkyl or optionally substituted phenyl.3. Postopek za pripravo l-subst.-6-fluoro-4-okso-7-(4-subst.-l-piperazinil)-l,4dihidrokinolin-3-karboksilata borovega diacetata s splošno formulo I kjer pomeni R_x nižji alkil, nižji cikloalkil ali 2,4-difluorofenil in R₂ nižji alkil ali v danem primeru substituiran fenil, označen s tem, da v 1-substituiranem 6-fluoro-4-okso-7-halo-l,4-dihidrokinolin-3karboksilatu borovem diacetatu s splošno formulo III kjer je X F ali Cl ter ima Rj preje navedeni pomen, izvedemo nukleofilno substitucijo atoma halogena na mestu 7 z 1-substituiranim piperazinom s formuloA process for the preparation of 1-subst.-6-fluoro-4-oxo-7- (4-subst-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate of boron diacetate of the general formula I wherein R_{x is} lower alkyl , lower cycloalkyl or 2,4-difluorophenyl and R₂ lower alkyl or optionally substituted phenyl, characterized in that in 1-substituted 6-fluoro-4-oxo-7-halo-1,4-dihydroquinoline-3-carboxylate boron diacetate of general formula III wherein XF or Cl and Rj having the foregoing meaning, nucleophilic substitution of the halogen atom at site 7 with 1-substituted piperazine of formulaΗ kjer ima R₂ preje navedeni pomen.Η where R₂ yarn has the indicated meaning.4. Postopek po zahtevku 1, označen s tem, da ga izvajamo v vodnem ali etanolnovodnem mediju.A process according to claim 1, characterized in that it is carried out in aqueous or ethanol-water medium.5. Postopek po zahtevku 1, označen s tem, da ga izvajamo pri temperaturi od 50°C do temperature refluksa reakcijske zmesi.A process according to claim 1, characterized in that it is carried out at a temperature from 50 ° C to the reflux temperature of the reaction mixture.6. Postopek po zahtevku 3, označen s tem, da ga izvedemo v organskem topilu, kot piridinu, dimetilsulfoksidu, dimetilformamidu, l-metil-2-pirolidonu, prednostno l-metil-2-pirolidonu.Process according to claim 3, characterized in that it is carried out in an organic solvent such as pyridine, dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably 1-methyl-2-pyrrolidone.7. Postopek po zahtevku 3, označen s tem, da ga izvajamo pri temperaturah od 0 °C do 40 °C, prednostno od 20 do 30 °C.The method of claim 3, characterized in that it is carried out at temperatures from 0 ° C to 40 ° C, preferably from 20 to 30 ° C.