FI91749C - Process for the preparation of quinoline carboxylic acid derivatives - Google Patents
Process for the preparation of quinoline carboxylic acid derivatives Download PDFInfo
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- FI91749C FI91749C FI882326A FI882326A FI91749C FI 91749 C FI91749 C FI 91749C FI 882326 A FI882326 A FI 882326A FI 882326 A FI882326 A FI 882326A FI 91749 C FI91749 C FI 91749C
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- 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
91 '74991 '749
Menetelma kinoliini-karboksyylihappojohdannaisten valmis-tamiseksiProcess for the preparation of quinoline carboxylic acid derivatives
Keksinttt koskee uutta ja yksinkertaista menetelmaa 5 kaavan I mukaisten kinoliinikarboksyylihappojen ja niiden hydraattien ja suolojen valmistamiseksi, 0 rji· 15 jossa kaavassa R on vety tai formyyli, R1 on vety tal suoraketjulnen tai syklinen alkyyliryhma, jossa on 1 - 4 hiiliatomia, tai R1 on CH3-NH- ja R2 on vety tai alempi 20 alkyyli.The invention relates to a novel and simple process for the preparation of quinolinecarboxylic acids of the formula I and their hydrates and salts, in which R is hydrogen or formyl, R 1 is hydrogen or a straight-chain or cyclic alkyl group having 1 to 4 carbon atoms, or R 1 is CH 3 -NH- and R 2 is hydrogen or lower alkyl.
Yhdisteita, joiden kaava on 0 25 I I (III) N. J r1Compounds of formula 0 25 I I (III) N. J r1
OHCOHC
30 on aikaisemmin valmistettu siten, etta kinoliinikarbok-syylihappojohdannainen, jonka kaava on • · « 91 749 230 has previously been prepared such that a quinolinecarboxylic acid derivative having the formula • · «91 749 2
OO
5 XXX ni> Ål saatetaan reagoimaan formyyli-piperatsiinin kanssa dime-10 tyyllsulfoksidllluottlmessa (BE-patenttijulkaisu nro 870576). Edelleen eraan tunnetun valmistusmenetelman mu-kaan formyloidaan formyyliton johdannainen muurahaisha-polla, jolloin saanto on 50 % (J. Med. Chem. 23 1358,5 XXX ni> Ål is reacted with formyl-piperazine in dime-10 ethyl sulfoxide (BE Patent No. 870576). Furthermore, according to a known preparation method, a formyl-free derivative is formylated with formic acid in a yield of 50% (J. Med. Chem. 23,135,
[1980]). Jaiklmmainen menetelma on erittain syOvyttava, 15 koska siina kaytetaan muurahalshappoa.[1980]). This method is very corrosive, because formic acid is used.
FI-patenttijulkaisusta 79 702 tunnetaan menetelma formyyllplperatslnokinolllnlyhdlsteen valmistamiseksi kahdessa valheessa. MenetelmSn mukaan piperatsiini ja ki-noliinijohdannainen saatetaan reagoimaan DMS0:ssa ja sit-20 ten suoritetaan erillinen formylointi kayttaen muurahais-happo-etikkahappoanhydidia. Kokonaissaanto on kuitenkin alhainen, noin 45 %.FI patent publication 79 702 discloses a process for the preparation of a formylpiperazine quinol compound in two lies. According to the method, the piperazine and the quinoline derivative are reacted in DMSO and then subjected to separate formylation using formic acid-anhydride. However, the overall yield is low, about 45%.
Julkaisusta Chemical Abstracts vol. 79, 1973, 91540w (=Synthesis 6, 361 - 2, 1972) ilmenee, etta pipe-25 ridiinin (analoginen piperatsiinin kanssa) formylointi vaatii 90 tuntia.Chemical Abstracts vol. 79, 1973, 91540w (= Synthesis 6, 361-2, 1972) shows that formylation of pipe-25 ridine (analogous to piperazine) requires 90 hours.
Julkaisusta Chemical Abstracts vol. 104, 1986, 88605a tunnetaan menetelma, jossa piperatsiini saatetaan reagoimaan DMF:n ja formyylipiperatsiinin kanssa, jolloin 30 sivutuotteena saadaan Ν,Ν-dimetyylipiperatsiinia. Ilmoi-tetut arvot osoittavat, etta paafraktion saanto on pieni. Tama on ymmarrettavaa ottaen huomioon se tosiasia, etta tyydyttyneiden, heterosyklisten sekundaaristen amiinien, kuten piperatsiinin, formylointi DMFrlla on vaikeaa.Chemical Abstracts vol. 104, 1986, 88605a discloses a process in which piperazine is reacted with DMF and formylpiperazine to give Ν, Ν-dimethylpiperazine as a by-product. The reported values indicate that the yield of the toast fraction is low. This is understandable given the fact that formylation of saturated, heterocyclic secondary amines such as piperazine with DMF is difficult.
35 FI-patenttihakemuksen 842 687 mukaisessa menetel- massa taas lopputuotteen saaminen edellyttaa 3 vaihetta.In the method according to 35 FI patent application 842 687, on the other hand, obtaining the final product requires 3 steps.
91/49 391/49 3
Epåedullista nSisså menetelmissS on se, etta ne suoritetaan monien vaiheiden kautta ja kalliissa liuotti-missa, kuten pyridiinissa, dimetyylisulfoksidissa jne.The disadvantage of these methods is that they are carried out in many steps and in expensive solvents such as pyridine, dimethyl sulfoxide, etc.
Lisaksi saannot ovat hyvin alhaisia.In addition, the yields are very low.
5 Esilia oleva keksintO koskee menetelmaa kaavan IThe present invention relates to a process of formula I.
mukaisten kinoliinikarboksyylihappojen ja niiden hydraat-tien ja suolojen valmistamiseksi. Menetelmålle on tunnus-omaista, etta yhdiste, jonka kaava on 10 0 I jT (id pifor the preparation of quinolinecarboxylic acids and their hydrates and salts according to The process is characterized in that the compound of formula 10 0 I jT (id pi
15 R15 R
jossa R1 ja R2 tarkoittavat samaa kuin edelia, tai sen happoadditiosuola saatetaan reagoimaan dimetyyliformami-dissa piperatsiinin kanssa ja, haluttuaessa, saadulle yh- 20 disteeelle, jonka kaava on 0 .__. [ I (III) klwherein R 1 and R 2 are as defined above, or an acid addition salt thereof is reacted in dimethylformamide with piperazine and, if desired, to give the obtained compound of formula 0 .__. [I (III) class
OHCOHC
30 jossa R1 ja R2 tarkoittavat samaa kuin edelia, suoritetaan happo- tai emaskasittely, tai sita kasiteliaan edul-lisesti hyratsiinin, erityisesti hydratsiinihydraatin kanssa.Wherein R1 and R2 are as defined above, the acid or base treatment is carried out, or it is preferably treated with a hydrazine, in particular hydrazine hydrate.
Esilia olevan keksinnOn mukaan formylointi tulisi 35 suorittaa edullisesti kuumentamalla. Korkeammat 1ampOti- 91749 4 lat (120 - 153 eC) johtavat lyhyempåån reaktioaikaan. Reaktiosaantoa voldaan suurentaa kåyttåmållå hapanta vå-llalnetta, ja reaktloalkaa voldaan vastaavasti lyhentåå. Hapan våliaine voldaan varmlstaa siten, ettå kåytetåån 5 ylelsen kaavan (II) mukalsen yhdlsteen happoaddltlosuo-laa tal edulllsesti reaktio tullsl suorlttaa hapon låsnå ollessa, edulllsesti suola- tal rikklhapon låsna ollessa.According to the present invention, the formylation should preferably be performed by heating. Higher 1 ampOti- 91749 4 lat (120 - 153 eC) results in a shorter reaction time. The reaction yield is increased by using an acidic medium, and the reaction time is reduced accordingly. The acidic medium is ensured by using an acid addition salt of the compound of formula (II) above, preferably the reaction is carried out in the presence of an acid, preferably in the presence of a salt in the presence of sulfuric acid.
Reaktioseoksen kåsittely, tuotteen talteenotto on erittåin vaivatonta. Lluottlmena kåytettåvå dimetyyli-10 formamldl ja reagenssi polstetaan alennetussa palneessa, ja nlltå voldaan kåyttåå uudelleen. Jåånndkseen lisåtåån vettå, ja saostuma otetaan talteen suodattamalla.The handling of the reaction mixture, the recovery of the product is very effortless. Dimethyl-10 formamide and the reagent are burned under reduced pressure and re-used. To the residue, water is added and the precipitate is collected by filtration.
Kaavan I mukaisista yhdisteistå l-etyyli-6-fluori- 7- (4-formyyli)-piperatsinyyli-1,4-dihydro-4-okso-kinolii-15 ni-3-karboksyylihapolla on erittåin huomattava antibak-teerinen vaikutus. Inhibitiokonsentraationa, joka on 0,25 pg/ml, se on tehokas Pasteurella multocidaa vastaan, erilaisia Bacillus-kantoja vastaan (esim. Bac. subtilis,Of the compounds of formula I, 1-ethyl-6-fluoro-7- (4-formyl) -piperazinyl-1,4-dihydro-4-oxoquinoline-15-3-carboxylic acid has a very remarkable antibacterial effect. At an inhibitory concentration of 0.25 pg / ml, it is effective against Pasteurella multocida, against various Bacillus strains (e.g. Bac. Subtilis,
Bac. licheniform) hyvin pienenå inhibitio-konsentraatio-20 na, joka on 0,5 - 0,75 pg/ml, ja vastaavasti mybs hyvin pienenå inhibitio-konsentraationa, joka on 0,75 pg/ml. Shigella sonnei ja salmonella cholerae-suis -kantoja vastaan.Bac. licheniform) as a very low inhibitory concentration of 0.5 to 0.75 pg / ml and mybs as a very low inhibitory concentration of 0.75 pg / ml. Against Shigella sonnei and Salmonella cholerae-suis strains.
Ylelsen kaavan (I) muakisista yhdisteistå niillå, 25 joilla on yleinen kaava (IV), 0 Γτ:;ίΓΝγ^^αοοκ2 30 (IV) I I h HN,^^ R1 on my5s erittåin arvokas antibakteerinen vaikutus (esim.Of the other compounds of formula (I) in those of general formula (IV), H1, R1 is also a very valuable antibacterial effect (e.g.
35 Antimicrob. Agents Chemother. 1985 581 - 586). Nåmå voi- • · i 5 9 Ί '7 4 9 daan valmistaa yhdisteista, joilla on yleinen kaava (III) ja jotka sisaitavat formyyliryhman, happo- tai emaskasit-telylia, tai edullisesti kasittelemaiia hydratsiinin, edullisesti hydratsiinihydraatin kanssa, valinnaisesti 5 hapon lasna ollessa (esim. etikkahappo).35 Antimicrob. Agents Chemother. 1985 581 - 586). These can be prepared from compounds of general formula (III) which contain a formyl group, an acid or female treatment, or preferably treated with hydrazine, preferably hydrazine hydrate, optionally in the form of a glass of 5 acids. (e.g. acetic acid).
Happoina kaytetaan ensisijaisesti mineraalihappo-ja, esim. suolahappoa, rikkihappoa, fosforihappoa jne., ja niita kaytetaan sopivina laimennuksina. Emaksina kaytetaan alkali- ja maa-alkalimetallien hydroksideja ja 10 karbonaatteja. Formyyliryhman poisto suoritetaan orgaa-nisessa liuottimessa ja/tai vedessa, edullisesti alkoho-li-vesiseoksessa. Edullisin on seos, jossa on 3:1 isopro-pyylialkoholia ja vetta. Reaktio suoritetaan lampOtilas-sa, joka on 25 - 100 °C, edullisesti kiehumispisteessa; 15 korkeampi låmpOtila johtaa reaktioajan lyhenemiseen.The acids used are preferably mineral acids, e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc., and are used as suitable dilutions. Alkali and alkaline earth metal hydroxides and carbonates are used as emas. The removal of the formyl group is carried out in an organic solvent and / or water, preferably in an alcohol-water mixture. Most preferred is a mixture of 3: 1 isopropyl alcohol and water. The reaction is carried out at a temperature of 25 to 100 ° C, preferably at the boiling point; A higher temperature leads to a shortening of the reaction time.
Tuote saadaan edullisesti reaktioseoksen happo-tai emasylimaaran neutraloimisen jaikeen, ja talteenotto tapahtuu suodattamalla. Haluttaessa tuote voidaan puhdis-taa uudelleenkiteyttamaiia.The product is preferably obtained by neutralizing the acid or mother liquor of the reaction mixture, and the recovery takes place by filtration. If desired, the product can be recrystallized.
20 Yleisen kaavan (I) mukaisia yhdisteita voidaan valmistaa hydraattien muodossa, tai hydraatit voidaan muodostaa, ne voidaan vapauttaa suoloistaan, kukin erik-seen, tai voidaan muodostaa yhdisteiden terapeuttisesti hyvaksyttavia suoloja.The compounds of general formula (I) may be prepared in the form of hydrates, or the hydrates may be formed, they may be liberated from their salts, each into Erik, or therapeutically acceptable salts of the compounds may be formed.
• 25 Merkittava seikka keksinnOn mukaisessa menetelmås- så on se, etta yleisen kaavan (III) mukaisesta yhdistees-ta voidaan poistaa formyyliryhmå saattamalla yhdiste rea-goimaan hydratsiinin kanssa. Tama johtaa uudentyyppiseen menetelmåån, jonka avulla saadaan yhtenaisempi ja puh-30 taampi tuote hydrolyysimenetelmiin verrattuna.An important aspect of the process of the invention is that the formyl group can be removed from the compound of general formula (III) by reacting the compound with hydrazine. This leads to a new type of process which gives a more uniform and cleaner product compared to hydrolysis processes.
Seuraavat esimerkit valaisevat keksintOå.The following examples illustrate the invention.
Esimerkki 1 5,4 g (0,02 mol) l-etyyli-6-fluori-7-kloori-l,4-dihydro-4-okso-kinoliini-3-karboksyylihappoa ja 10,4 g 35 (0,12 mol) piperatsiinia 120 ml:ssa dimetyyliformamidia 91 749 6 kuumennetaan 6 tuntia 145 °C:ssa. Taman jaikeen liuotin poistetaan redusoldussa paineessa ja jaanndkseen lisataan 300 ml vetta. Saostuma saadaan suodattamalla. Nain saadaan 4,6 g l-etyyli-6-fluori-7-(4-formyyli)piperatsi-5 nyyli-1,4-dihydro-4-okso-kinoliini-3-karboksyylihappoa, joka sulaa 270 °C:ssa. Kun tuote uudelleenklteytettiln dlmetyyllformamldlsta, sen sulamispiste nousl 285 -286 °C:een.Example 1 5.4 g (0.02 mol) of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 10.4 g (0.12 mol) of ) piperazine in 120 ml of dimethylformamide 91 749 6 is heated for 6 hours at 145 ° C. The solvent of this fraction is removed under reduced pressure and 300 ml of water are added to the residue. The precipitate is obtained by filtration. 4.6 g of 1-ethyl-6-fluoro-7- (4-formyl) piperazin-5-yl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, melting at 270 ° C. When the product was recrystallized from dimethylformamide, its melting point rose to 285-286 ° C.
Esimerkkl 2 10 1,0 g (0,0029 mol) l-etyyli-6-fluori-7-(4-formyy- li)piperatsinyyli-l,4-dihydro-4-okso-kinoliini-3-karbok-syylihappoa suspendoldaan 40 ml:an seosta, jossa on 3:1 isopropyylialkoholia ja vetta, ja lisataan 10 ml 1 N suo-lahappoa. Reaktloseosta keitetaan 5 tuntia. Jaahdyttami-15 sen jaikeen tuote klteytyy suolahapposuolan muotoon, ja se voldaan polstaa suodattamalla, tal 1 N natriumhydrok-sldlliuoksella neutralolmlsen jaikeen saostunut tuote suodatetaan. Kulvaamlsen jaikeen saadaan 0,58 g 1-etyyli- 6-fluori-7-piperatsinyyli-l,4-dihydro-4-oksokinoliini-3-20 karboksyylihappoa; sulamispiste 222 °C.Example 2 1.0 g (0.0029 mol) of 1-ethyl-6-fluoro-7- (4-formyl) piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are suspended To 40 ml of a mixture of 3: 1 isopropyl alcohol and water and 10 ml of 1N hydrochloric acid are added. The reaction mixture is boiled for 5 hours. The product of the cooled fraction is cleaved in the form of the hydrochloric acid salt and is quenched by filtration, and the precipitated product is filtered off with 1 N sodium hydroxide solution. 0.58 g of 1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-20 carboxylic acid are obtained; melting point 222 ° C.
Esimerkki 3 1.0 g (0,0029 mol) l-etyyli-6-fluori-7-(4-formyy-li)piperatsinyyli-l,4-dihydro-4-okso-kinolilni-3-karboksyylihappoa suspendoldaan 40 ml:an seosta, jossa on 3:1 25 isopropyylialkoholia ja vetta, ja lisataan 5 ml 1 N nat-riumhydroksidin vesiliuosta. Reaktloseosta keitetaan 8 tuntia. jaahdyttamisen jaikeen liuos neutraloidaan lai-mealla suolahappoliuoksella. Saostunut tuote suodatetaan.Example 3 1.0 g (0.0029 mol) of 1-ethyl-6-fluoro-7- (4-formyl) piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are suspended in 40 ml of the mixture. , with 3: 1 isopropyl alcohol and water, and 5 ml of 1N aqueous sodium hydroxide solution are added. The reaction mixture is boiled for 8 hours. the solution of the cooling fraction is neutralized with a dilute hydrochloric acid solution. The precipitated product is filtered off.
Syntynyt l-etyyli-6-fluori-7-piperatsinyyli-l,4-dihydro-30 4-okso-kinoliini-3-karboksyylihappo sulaa 218 °C:ssa.The resulting 1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-30-oxo-quinoline-3-carboxylic acid melts at 218 ° C.
Esimerkki 4 1.0 g (0,0029 mol) l-etyyli-6-fluori-7-(4-formyy-li)piperatsinyyli-l,4-dihydro-4-okso-kinoliini-3-karbok-syylihappoa suspendoldaan 50 ml:an seosta, jossa on 3:1 35 isopropyylialkoholia ja vetta, ja lisataan 0,5 ml (0,010 i, 91749 7 mol) 98 % hydratsiinihydraattia ja 0,6 ml (0,010 mol) etlkkahappoa. Reaktloseosta kuumennetaan 100 °C:ssa 6 tuntia. Jååhtyneestå 1luoksesta klteytynyt tuote saadaan suodattamalla. Nain saadaan 0,827 g l-etyyli-6-fluori-7-5 piperatsinyyli-1,4-dihydro-4-okso-kinoliini-3-karboksyy- llhappoa, joka sulaa 222 °C:ssa.Example 4 1.0 g (0.0029 mol) of 1-ethyl-6-fluoro-7- (4-formyl) piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are suspended in 50 ml of: a mixture of 3: 1 isopropyl alcohol and water and 0.5 ml (0.010 l, 91749 7 mol) of 98% hydrazine hydrate and 0.6 ml (0.010 mol) of acetic acid are added. The reaction mixture is heated at 100 ° C for 6 hours. The product which has cooled from the cooled solution is obtained by filtration. 0.827 g of 1-ethyl-6-fluoro-7-5 piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained, melting at 222 ° C.
Eslmerkki 5 1,35 g (0,005 mol) l-etyyli-6-fluori-7-kloori-l,4-dihydro-4-okso-kinoliini-3-karboksyylihappoa, 2,6 g 10 (0,03 mol) piperatsiinia ja 1 ml vdkevaa suolahappoa kuu mennetaan kiehumisiampdtilassa 30 ml:ssa dimetyyliform-amidia 4 tuntia. Lluotln polstetaan redusoidussa painees-sa ja jaanndkseen lisåtåån 80 ml vetta. Saostunut tuote suodatetaan ja pestaan vedellå. Kulvaamlsen jålkeen saa-15 daan 1,42 g (82 %) l-etyyli-6-fluori-7-(4-formyyllpipe-ratsinyyll)-l,4-dihydro-4-okso-kinoliini-3-karboksyyli-happoa, joka sulaa 288 °C:ssa.Example 5 1.35 g (0.005 mol) of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 2.6 g of 10 (0.03 mol) of piperazine and 1 ml of concentrated hydrochloric acid is boiled in a boiling atmosphere in 30 ml of dimethylformamide for 4 hours. The solution is incubated under reduced pressure and 80 ml of water are added to give. The precipitated product is filtered off and washed with water. After working up, 1.42 g (82%) of 1-ethyl-6-fluoro-7- (4-formylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, melting at 288 ° C.
Esimerkkl 6Example 6
Esimerkin 4 mukainen menetelmå tolstetaan paltsl, 20 ettå låhtOaineena kåytetåån l-metyyliamino-6-fluori-7-(4- formyylipiperatsinyyli)-l,4-dihydro-4-okso-kinoliini-3-karboksyylihappoa. Saadaan 0,8 g l-metyyliamino-6-fluori- 7-piperatsinyyli-l,4-dihydro-4-okso-kinoliini-3-karbok-syylihappoa, sp. 288 - 290 °C.The process of Example 4 is carried out using 1-methylamino-6-fluoro-7- (4-formylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid as starting material. 0.8 g of 1-methylamino-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained, m.p. 288-290 ° C.
25 Esimerkkl 725 Example 7
Esimerkin 4 mukainen menetelmå tolstetaan paitsi ettå lahtOaineena kåytetåån l-syklopropyyli-6-fluori-7-(4-formyylipiperatsinyyli)-l,4-dihydro-4-okso-kinoliini- 3-karboksyylihappoa. Saadaan l-syklopropyyli-6-fluori-7-30 piperatsinyyli-1,4-dihydro-4-okso-kinoliini-3-karboksyy- lihappo, sp. 255 - 257 “C.The process of Example 4 is carried out except that 1-cyclopropyl-6-fluoro-7- (4-formylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid is used as the starting material. 1-Cyclopropyl-6-fluoro-7-30 piperazinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained, m.p. 255 - 257 “C.
Esimerkkl 8 5,4 g (0,02 moolia) l-metyyliamino-6-fluori-7-kloori-1,4-dihydro-4-okso-kinoliini-3-karboksyylihappoa 35 ja 10,4 g (0,12 moolia) piperatsiinia 120 ml:ssa dimetyy-liformamidissa kuumennetaan 6 tuntia 145 eC:ssa. Tåmån 91749 8 jSlkeen liuotin poistetaan alennetussa paineessa ja jaan-nttkseen lisataan 300 ml vetta. Suodattamalla saadaan saostuma. Nain saadaan 4,5 g l-metyyliamino-6-fluori-7-(4-formyyli)-piperatsinyyli-1,4-dihydro-4-okso-kinoliini-5 3-karboksyylihappoa, sp. > 300 eC.Example 8 5.4 g (0.02 mol) of 1-methylamino-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 35 and 10.4 g (0.12 mol) ) piperazine in 120 ml of dimethylformamide is heated for 6 hours at 145 ° C. 91749 8 The solvent is then removed under reduced pressure and 300 ml of water are added to the mixture. Filtration gives a precipitate. 4.5 g of 1-methylamino-6-fluoro-7- (4-formyl) -piperazinyl-1,4-dihydro-4-oxoquinoline-5-carboxylic acid are thus obtained, m.p. > 300 eC.
Esimerkkl 9 5,66 g (0,02 moolia) l-syklopropyyli-6-fluori-7-kloori-1,4-dihydro-4-okso-kinoliini-3-karboksyylihappoa ja 10,4 g (0,12 moolia) piperatsiinia 120 ml:ssa dimetyy-10 liformamidia kuumennetaan 6 tuntia 145 °C:ssa. Taman jai-keen liuotin poistetaan alennetussa paineessa ja jaannOk-seen lisataan 300 ml vetta. Suodattamalla saadaan saostuma. Nain saadaan 4,7 g l-syklopropyyli-6-fluori-7-(4-for-myyli)-piperatsinyyli-1,4-dihydro-4-okso-7-(4-formyyli)-15 piperatsinyyli-1,4-dihydro-4-okso-kinoliini-3-karboksyy- lihappoa, sp. > 300 eC.Example 9 5.66 g (0.02 mol) of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 10.4 g (0.12 mol) piperazine in 120 ml of dimethyl-10-formoform is heated for 6 hours at 145 ° C. The solvent of this fraction is removed under reduced pressure and 300 ml of water are added to the mixture. Filtration gives a precipitate. 4.7 g of 1-cyclopropyl-6-fluoro-7- (4-formyl) -piperazinyl-1,4-dihydro-4-oxo-7- (4-formyl) -15-piperazinyl-1,4 -dihydro-4-oxo-quinoline-3-carboxylic acid, m.p. > 300 eC.
**
Claims (4)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU864292A HU196987B (en) | 1986-10-15 | 1986-10-15 | Process for producing quinoline-carboxylic acid derivatives |
| HU429287 | 1987-10-01 | ||
| HU429287 | 1987-10-01 | ||
| HU429286 | 1987-10-01 | ||
| PCT/HU1987/000044 WO1988002748A1 (en) | 1986-10-15 | 1987-10-14 | Process for the preparation of quinoline-carboxylic acid derivatives |
| HU8700044 | 1987-10-14 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI882326A0 FI882326A0 (en) | 1988-05-18 |
| FI882326A FI882326A (en) | 1988-05-18 |
| FI91749B FI91749B (en) | 1994-04-29 |
| FI91749C true FI91749C (en) | 1994-08-10 |
Family
ID=26317755
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI882326A FI91749C (en) | 1986-10-15 | 1988-05-18 | Process for the preparation of quinoline carboxylic acid derivatives |
Country Status (7)
| Country | Link |
|---|---|
| KR (1) | KR880701712A (en) |
| CA (1) | CA1312603C (en) |
| CS (1) | CS269995B2 (en) |
| DK (1) | DK322888A (en) |
| ES (1) | ES2005432A6 (en) |
| FI (1) | FI91749C (en) |
| NO (1) | NO169389C (en) |
-
1987
- 1987-10-14 CA CA000549293A patent/CA1312603C/en not_active Expired - Fee Related
- 1987-10-15 CS CS877469A patent/CS269995B2/en unknown
- 1987-10-15 ES ES8703122A patent/ES2005432A6/en not_active Expired
-
1988
- 1988-05-18 FI FI882326A patent/FI91749C/en not_active IP Right Cessation
- 1988-06-06 NO NO882493A patent/NO169389C/en unknown
- 1988-06-09 KR KR1019880700653A patent/KR880701712A/en not_active Application Discontinuation
- 1988-06-14 DK DK322888A patent/DK322888A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI882326A0 (en) | 1988-05-18 |
| NO882493D0 (en) | 1988-06-06 |
| NO882493L (en) | 1988-06-06 |
| KR880701712A (en) | 1988-11-04 |
| CA1312603C (en) | 1993-01-12 |
| NO169389C (en) | 1992-06-17 |
| DK322888D0 (en) | 1988-06-14 |
| DK322888A (en) | 1988-06-14 |
| CS269995B2 (en) | 1990-05-14 |
| ES2005432A6 (en) | 1989-03-01 |
| FI91749B (en) | 1994-04-29 |
| CS746987A2 (en) | 1989-09-12 |
| NO169389B (en) | 1992-03-09 |
| FI882326A (en) | 1988-05-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| BB | Publication of examined application | ||
| MM | Patent lapsed | ||
| MM | Patent lapsed |
Owner name: CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT. |