CZ97496A3 - Process for preparing 1-cyclopropyl-6-fluoro-1, 4-dihydro-7-£(1s, 4s)|-5-methyl-2,5-diazabicyclo £2.2.1|hept-2-yl|-4-oxo-3-quinolinecarboxylic acid and salts thereof - Google Patents
Process for preparing 1-cyclopropyl-6-fluoro-1, 4-dihydro-7-£(1s, 4s)|-5-methyl-2,5-diazabicyclo £2.2.1|hept-2-yl|-4-oxo-3-quinolinecarboxylic acid and salts thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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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
- C07D215/18—Halogen atoms or nitro radicals
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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
Abstract
Description
Způsob přípravy l-cyklopropyl-6-fluoř^ ro-7-[(1S,Process for the preparation of 1-cyclopropyl-6-fluoro-7 - [(1S,
5-methyl-2,5-diazabicyklo[2.2.l]hept-2-yl]-4-oxo-3-chinolin-------------------------karboxylové kyseliny a jejích solí5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3-quinoline ---------------------- --- carboxylic acids and their salts
Oblast technikyTechnical field
Vynález se týká způsobu přípravy l-cyklopropyl-6-fluor1,4-dihydro-7-[(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]hept2- yl]-4-oxo-3-chinolinkarboxylové kyseliny a jejích solí, což je syntetická sloučenina s výhodnými farmaceutickými vlastnostmi a která patří mezi skupinu fluorchinolonů vykazujících antibakteriální účinky a která se používá ve veterinární medicíně.The present invention relates to a process for the preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3 quinolinecarboxylic acid and its salts, which is a synthetic compound with advantageous pharmaceutical properties and which belongs to the group of fluoroquinolones exhibiting antibacterial effects and which is used in veterinary medicine.
Dosavadní stav technikyBACKGROUND OF THE INVENTION
V patentu EP 215 650 a v jeho ES analogu č. 2 001 428 se popisuje postup přípravy výše uvedeného produktu reakcí mezi 6,7-difluor-l-cyklopropyl-1,4-dihydro-4-oxo-3-chinolinkarboxylovou kyselinou a vhodným (lS,4S)-2,5-diazabicyklo[2.2.1]heptanovým derivátem. Předmětem tohoto vynálezu je nový a zlepšený postup přípravy uvedeného produktu.EP 215 650 and its EC analogue No. 2 001 428 disclose a process for preparing the above product by reaction between 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and a suitable (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane derivative. The present invention provides a new and improved process for preparing said product.
Kromě toho, v literatuře je popsána řada postupů pro přípravu některých fluorchinolonů, jako jsou ofloxacin a ciprofloxacin (ES patent č. 516 608 a 2 006 882), reakcí mezi některými cheláty boru odvozených od odpovídajících 4-oxo-3chinolinkarboxylových kyselin a vhodných aminů.In addition, a number of processes for the preparation of certain fluoroquinolones such as ofloxacin and ciprofloxacin (EC Patent Nos. 516,608 and 2,006,882) are described in the literature by reaction between some boron chelates derived from the corresponding 4-oxo-3-quinolinecarboxylic acids and suitable amines.
Podstata vynálezuSUMMARY OF THE INVENTION
Způsob přípravy l-cyklopropyl-6-fluor-1,4-dihydro-7[(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1Jhept-2-yl]-4-oxo3- chinolinkarboxylové kyseliny a jejích solí, který je předmětem tohoto vynálezu spočívá v reakci alkyl l-cyklopropyl-6-fluor-7-chlor-l,4-dihydro-4-oxo-3-chino2 linkarboxylátu s kyselinou boritou v přítomnosti anhydridu ky se líný octové a katalytického množství zinečnaťé soli, přičemž vznikne (l-cyklopropyl-6-fluor-7-chlor-l,4-dihydro4-oxo-3-chinolinkarboxyláto-03,O4)bís(acetáto-0)boran. Tento produkt reaguje s (1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]heptanem nebo s jeho adiční solí, popřípadě v přítomnosti acidobázického akceptoru za vzniku meziproduktu, (1-cyklopropyl-6-fluor-1,4-dihydro-7-[(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.l]hept-2-yl]-4-oxo-3-chinolinkarboxyláto-03,04)bis(acetáto-O)boranu. Po hydrolýze se získá žádaný produkt, který se izoluje z reakční směsi konvenčními způsoby.A process for the preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-7 [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3-quinolinecarboxylic acid and salts of the present invention are the reaction of alkyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quino2 linkarboxylate with boric acid in the presence of lactic acid anhydride and catalytic amount of zinc salt, to give (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylate-0 3, O 4) bis (acetato-0) borane. This product is reacted with (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane or an addition salt thereof, optionally in the presence of an acid-base acceptor to form the intermediate, (1-cyclopropyl-6-fluoro-1). , 4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2] hept-2-yl] -4-oxo-3-quinolinecarboxylate-0 3, 0 4) bis (acetato-O) borane. After hydrolysis, the desired product is obtained, which is isolated from the reaction mixture by conventional means.
Chemická reakce uvedeného postupu se znázorní následovně:The chemical reaction of the process is illustrated as follows:
CH-CCO ^OCOCHj o-SCH-CCO4OCOCH3 -S
oO
CHCH
COOKCOOK
Tento postup je nový a nebyl dosud popsán pro přípravu fluorchinolonů substituovaných v poloze' 7- skupinami---diazabicykloalkylového typu majících lipofilní povahu, jako je to v případě l-cyklopropyl-6-fluor-1,4-dihydro-7-[(1S,4S)This procedure is new and has not been described yet for the preparation of 7-position substituted diazabicycloalkyl-type fluoroquinolones having a lipophilic nature, such as 1-cyclopropyl-6-fluoro-1,4-dihydro-7 - [( 1S, 4S)
5-methyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-chinolinkarboxylové kyseliny.5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-quinolinecarboxylic acid.
Navíc, tento způsob umožňuje získat žádanou sloučeninu ve vysokém výtěžku a ve vysoké čistotě a postupem, který je snadný při praktickém použití.In addition, this process makes it possible to obtain the desired compound in high yield and high purity and by a process that is easy to use in practice.
Příprava výchozí sloučeniny, alkyl l-cyklopropyl-6fluor-7-chlor-l,4-dihydro-4-oxo-3-chinolinkarboxylátu, je popsána v ES patentu č. 516 921.The preparation of the starting compound, alkyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, is described in EC Patent No. 516 921.
Kromě toho, konverze alkyl l-cyklopropyl-6-fluor-7chlor-1,4-dihydro-4-oxo-3-chinolinkarboxylátu na (1-cyklopropyl-6-fluor-7-chlor-l,4-dihydro-4-oxo-3-chinolinkarboxyláto-O3,04)bis(acetáto-0)boran je popsána v ES 2 006 881.In addition, the conversion of alkyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylate to (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-3-quinolinecarboxylate a-3 0 4), bis (acetato-0) borane is disclosed in ES 2,006,881.
(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1Jheptan a jeho soli, společně s příbuznými sloučeninami a jejich příprava jsou popsány v různých publikacích, jako je J. Med. Chem., 1974, 17, 481, J. Orq. Chem, 1990, 55, 1684 a J. Orq. Chem., 1966, 31, 1059.(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane and its salts, together with related compounds, and their preparation are described in various publications such as J. Med. Chem., 1974, 17,481, J. Orq. Chem., 1990, 55, 1684 and J. Orq. Chem., 1966,31,1059.
Postup se výhodně provádí s izolací meziproduktu, (l-cyklopropyl-6-fluor-7-chlor-l,4-dihydro-4-oxo-3-chinolinkarboxyláto-O3,O4)bís(acetáto-0)boranu. Tento produkt reaguj s (1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]heptanem nebo s jeho adiční kyselou solí, popřípadě v přítomnosti báze za vzniku meziproduktu, (l-cyklopropyl-6-fluor-1,4-dihydro-7[(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo3-chinolinkarboxyláto-O3,O4)bis-(acetáto-0)boranu, který se hydrolyzuje na žádaný produkt.The process is preferably carried out with isolation of the intermediate (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylate-O 3, O 4) bis (acetato-0) borane. This product is reacted with (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane or an acid addition salt thereof, optionally in the presence of a base to form the intermediate, (1-cyclopropyl-6-fluoro-1). 4-dihydro-7 [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo- 3 -quinolinecarboxylate-O, 3,4- bis (acetate) -O) borane, which is hydrolyzed to the desired product.
Postup se výhodné provádí tak, že se boranový derivát, (l-cyklopropyl-6-fluor-l,4-dihydro-7-[(lS,4S)-5-methyl-2,5diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolinkarboxyláto-O3,O4)bis-(acetáto-0)boran, převede na žádaný produkt bez izolace.The process is preferably carried out by the borane derivative, (1-cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2). yl] -4-oxo-3-quinolinecarboxylate-O 3, O 4) bis (acetato-0) borane is converted to the desired product without isolation.
Boranový derivát, (l-cyklopropyl-6-fluor-7-chlor-l,4dihydro-4-oxo-3-chinolinkarboxyláto-03,O4)bis-(acetáto-0)boran a (lS,4S)-5-methyl-2,5-diazabicyklo[2.2.l]heptan nebo jeho adiční kyselá sůl mohou reagovat za zahřívání na poměrně krátkou dobu v přítomnosti vhodného inertního organického rozpouštědla a případně v přítomnosti acidobázického akceptoru.Borane derivative, (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylate-0 3, O 4) bis (acetato-0) borane and (S, 4S) -5 -methyl-2,5-diazabicyclo [2.2.1] heptane or its acid addition salt may react with heating for a relatively short time in the presence of a suitable inert organic solvent and optionally in the presence of an acid-base acceptor.
Jako organická rozpouštědla, která jsou inertní vůči reakčnímu prostředí se výhodné používají N-methyl-2-pyrrolidon, dimethylacetamid, dimethylformamid, dimethylsulfoxid, sulfolan nebo pyridin.Preferred organic solvents which are inert to the reaction medium are N-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, sulfolane or pyridine.
Jako (1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]heptanové soli se použijí soli odvozené od halogenvodíkových kyselin, jako jsou dihydrochloridy a dihydrobromidy.As (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane salts, salts derived from hydrohalic acids such as dihydrochlorides and dihydrobromides are used.
Jako zinečnaté soli se použijí chlorid zinečnatý a acetát zinečnatý.The zinc salts used are zinc chloride and zinc acetate.
Jako akceptor kyseliny se použije bud přebytek stejného (1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]heptanu nebo organické nebo anorganické báze, například více nebo méně bráněné terciární aminy (triethylamin, tributylamin, pyridin,The acid acceptor used is either an excess of the same (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane or an organic or inorganic base, for example, more or less hindered tertiary amines (triethylamine, tributylamine, pyridine,
1,5-diazabicyklo[ 4.3.0 ]non-5-en (DBN), 1,4-diazabicyklo· [2.2.2]oktan (TDE), 1,8-diazabicyklo[5.4.0]undek-7-en (DBU) nebo uhličitan nebo hydrogenuhličitan alkalických kovů nebo kovů alkalických zemin.1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (TDE), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or an alkali or alkaline earth metal carbonate or bicarbonate.
Teplota reakce mezi boranovým derivátem, (1-cyklopropyl5Reaction temperature between borane derivative, (1-cyclopropyl)
6-fluor-7-chlor-l,4-dihydro-4-oxo-3-chinolinkarboxylátoO3,O4) bis- (acetáťo-0) -bóránem á '(1Š, 4S) -5-methýl-2,5-diaza-— bicyklof2.2.1]heptanem nebo jeho adiční kyselou solí se pohybuje v intervalu 20 ’C až 200 ‘C, v závislosti na použitém rozpouštědle. Podobně, reakční doba se pohybuje v intervalu 30 minut až 6 hodin, v závislosti na reakční teplotě a použitém rozpouštědle.6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-chinolinkarboxylátoO 3, O 4) bis (acetato-0) borane A '(1S, 4S) -5-methyl-2,5 The diaza-bicyclo [2.2.1] heptane or acid addition salt thereof ranges from 20 ° C to 200 ° C, depending on the solvent used. Similarly, the reaction time ranges from 30 minutes to 6 hours, depending on the reaction temperature and the solvent used.
Postup konverze boranového derivátu, (1-cyklopropyl6- fluor-1,4-dihydro-7-[(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.l]hept-2-yl]-4-oxo-3-chinolinkarboxyláto-03,04)bis(acetáto-O)-boranu na l-cyklopropyl-6-fluor-1,4-dihydro7- [(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4oxo-3-chinolinkarboxylovou kyselinu se výhodně provádí hydrolýzou za kyselých nebo zásaditých podmínek.Borane derivative conversion procedure, (1-cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4- oxo-3-quinolinecarboxylate-0 3, 0 4), bis (acetato-O) borane to l-cyclopropyl-6-fluoro-1,4-dihydro-7- [(1S, 4S) -5-methyl-2,5- diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3-quinolinecarboxylic acid is preferably carried out by hydrolysis under acidic or basic conditions.
Bázická hydrolýza se provádí zahříváním reakční směsi v přítomnosti vodného roztoku uhličitanu nebo hydroxidu alkalického kovu nebo kovu alkalických zemin.The basic hydrolysis is carried out by heating the reaction mixture in the presence of an aqueous solution of an alkali or alkaline earth metal carbonate or hydroxide.
Kyselá hydrolýza se provádí výhodně za použití vodného roztoku anorganických kyselin, jako je kyselina chlorovodíková, kyselina sírová nebo kyselina fosforečná.The acid hydrolysis is preferably carried out using an aqueous solution of inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid.
Výhodně se hydrolýza provádí ve vodném prostředí v přítomnosti ve vodě misitelného organického rozouštědla. Tak se alkalická nebo kyselá hydrolýza provádí ve směsích vody a N-methyl-2-pyrrolidonu, dimethylacetamidu, dimethylformamidu, dimethylsulfoxidu nebo sulfolanu.Preferably, the hydrolysis is carried out in an aqueous medium in the presence of a water-miscible organic solvent. Thus, the alkaline or acid hydrolysis is carried out in mixtures of water and N-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide or sulfolane.
Po skončení hydrolýzy se žádaný produkt izoluje za použití konvenčních způsobů a rekrystalizuje se z organických rozpouštědel nebo jejich směsí.Upon completion of the hydrolysis, the desired product is isolated using conventional methods and recrystallized from organic solvents or mixtures thereof.
Je-li to žádoucí, l-cyklopropyl-6-fluor-l,4-dihydro7-[(1S,4S)-5-methyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-46 oxo-3-chinolinkarboxylová kyselina se izoluje ve formě adičních solí s organickými- nebch-anorganickými kyselinami standartním zpracováním volné báze se stechiometrickým množstvím odpovídající kyseliny ve vhodném rozpouštědle.If desired, 1-cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -46-oxo The 3-quinolinecarboxylic acid is isolated in the form of addition salts with organic or non-inorganic acids by standard treatment of the free base with a stoichiometric amount of the corresponding acid in a suitable solvent.
Vynález je blíže objasněn v následujících příkladech provedení. Tyto příklady mají výhradně ilustrativní charakter a rozsah vynálezu nijak neomezují.The invention is illustrated by the following examples. These examples are illustrative only and are not intended to limit the scope of the invention in any way.
Příklady provedení vynálezuDETAILED DESCRIPTION OF THE INVENTION
Příklad 1 (l-cyklopropyl-6-fluor-7-chlor-l,4-dihydro-4-oxo-3chinolinkarboxyláto-O3, O4)bis(acetáto-0)-boran g (1,5 mol) kyseliny borité se přidá po částech ke směsi 480 g (440 ml, 4,7 mol) anhydridu kyseliny octové a 1,4 g (0,01 mol) bezvodého chloridu zinečnatého. Reakční směs se zahřeje na teplotu 110 ’C, ochladí se a za míchání se přidá 295,5 g (1,0 mol) methyl l-cyklopropyl-6-fluor-7-chlor-l,4dihydro-4-oxo-3-chinolinkarboxylátu. Reakční směs se udržuje na teplotě 80 °C po dobu 1 hodiny a potom se nechá zchladnout na teplotu místnosti. Vysražená pevná látka se odfiltruje a promyje studenou vodou. Suchý produkt se rozkládá při teplotě 254-256 °C.EXAMPLE 1 (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylate-O 3, O 4) bis (acetato-0) borane g (1.5 moles) of boric acid was added portionwise to a mixture of 480 g (440 mL, 4.7 mol) of acetic anhydride and 1.4 g (0.01 mol) of anhydrous zinc chloride. The reaction mixture was heated to 110 ° C, cooled and methyl 5-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3- (295.5 g, 1.0 mol) was added with stirring. quinolinecarboxylate. The reaction mixture is maintained at 80 ° C for 1 hour and then allowed to cool to room temperature. The precipitated solid was filtered off and washed with cold water. The dry product decomposes at 254-256 ° C.
Elementární analýza pro C17H14O7NBC1F:Elemental analysis for C 17 H 14 O 7 NBC1F:
Vypočteno: C = 49,86 %, H = 3,45 %, N = 3,42 %Calculated: C = 49.86%, H = 3.45%, N = 3.42%
Nalezeno C = 49,80 %, H = 3,50 % N = 3,48 %Found C = 49.80%, H = 3.50% N = 3.48%
Příklad 2 l-cyklopropyl-6-fluor-1,4-dihydro-7-[(1S,4S)-5-methyl2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolinkarboxylová kyselinaExample 2 1-Cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3- quinolinecarboxylic acid
Směs (l-cyklopropyl-6-fluor-7-chlor-l,4-dihydro-4-oxo-3chinoiinkarboxyláto-O3,O4)bis(acetato-0J-boránu (40,9 g, o , 1 mol) a dihydrochloridu (lS,4S)-5-methyl-2,5-diazabicyklo[2.2.1]heptanu (22 g, 0,12 mol) v 300 ml bezvodéhoA mixture of (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo- 3 -quinolinecarboxylate-O, 3,4 ) bis (acetato-O-borane) (40.9 g, 0.1 mol) and (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane dihydrochloride (22 g, 0.12 mol) in 300 mL anhydrous
N-methyl-2-pyrrolidonu se zpracuje s 1,8-diazabicyklo[5.4.0]undek-7-enem (36,4 g, 0,24 mol). Směs se zahřívá na teplotu 85 ’C po dobu 4 hodin a potom se ochladí na 10 °C. Vysražená vN-methyl-2-pyrrolidone was treated with 1,8-diazabicyclo [5.4.0] undec-7-ene (36.4 g, 0.24 mol). Heat the mixture at 85 ° C for 4 hours and then cool to 10 ° C. Precipitated in
pevná látka se odfiltruje a suspenduje se ve vodě. Přidáním 30% hydroxidu sodného, případně zahříváním se dosáhne úplného rozpuštění. Roztok se ochladí a přidáním koncentrované kyseliny chlorovodíkové se upraví pH na neutrální hodnotu. Vysražená pevná látka se odfiltruje, promyje vodou a suší se. Získá se 33,7 g (94% výtěžek) sloučeniny uvedené v názvu.the solid is filtered off and suspended in water. Addition of 30% sodium hydroxide or heating to achieve complete dissolution. The solution was cooled and the pH was adjusted to neutral by addition of concentrated hydrochloric acid. The precipitated solid was filtered off, washed with water and dried. This gave 33.7 g (94% yield) of the title compound.
Produkt rekrystalovaný z ethanolu má teplotu tání 275-276,5 ’C. Mesylátová sůl se získá zpracováním báze slabým přebytkem methansulfonové kyseliny ve směsi ethanolu a vody. Teplota tání: 336,5-339 °C.The product recrystallized from ethanol has a melting point of 275-276.5 ° C. The mesylate salt is obtained by treating the base with a slight excess of methanesulfonic acid in a mixture of ethanol and water. Melting point: 336.5-339 ° C.
Příklad 3 l-cyklopropyl-6-fluor-1,4-dihydro-7-[(1S,4S)-5-methyl2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolinkarboxylová kyselinaExample 3 1-Cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3- quinolinecarboxylic acid
Směs (l-cyklopropyl-6-fluor-7-chlor-l,4-dihydro-4-oxo-3chinolinkarboxyláto-O3,04)bis(acetáto-0)-boranu (40,9 g, 0,1 mol) a dihydrochloridu (lS,4S)-5-methyl-2,5-diazabicyklo[2.2.1Jheptanu (22 g, 0,12 mol) v 300 ml bezvodéhoA mixture of (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo- 3 -quinolinecarboxylate-0, 4 ) bis (acetato-O) -borane (40.9 g, 0.1 mol) ) and (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane (22 g, 0.12 mol) in 300 mL anhydrous
N-methyl-2-pyrrolidonu se zpracuje s 1,8-diazabicyklo[5.4.0]undek-7-enem (36,4 g, 0,24 mol). Směs se zahřívá na teplotu 85 °C po dobu 4 hodin a potom se ochladí. Část rozpouštědla se odstraní vakuovou destilací a ke zbytku se přidá voda a 30% roztok hydroxidu sodného. Směs se ochladí a přidáním * koncentrované kyseliny chlorovodíkové se upraví pH na neutrální hodnotu. Vysražená pevná látka se odfiltruje, promyje se vodou a po vysušení se získá 33,0 g (92% výtěžek) il sloučeniny uvedené v názvu. Získaný produkt má stejné vlastnosti- jako produkt získaný v příkladu-2 .-------------N-methyl-2-pyrrolidone was treated with 1,8-diazabicyclo [5.4.0] undec-7-ene (36.4 g, 0.24 mol). The mixture was heated at 85 ° C for 4 hours and then cooled. Some of the solvent was removed by vacuum distillation and water and 30% sodium hydroxide solution were added to the residue. The mixture was cooled and the pH was adjusted to neutral by addition of concentrated hydrochloric acid. The precipitated solid was filtered off, washed with water and dried to give 33.0 g (92% yield) of the title compound. The product obtained has the same properties as the product obtained in Example-2 .-------------
Claims (5)
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Application Number | Priority Date | Filing Date | Title |
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ES09500782A ES2092963B1 (en) | 1995-04-12 | 1995-04-12 | PROCEDURE FOR THE PREPARATION OF ACID 1-CICLOPROPIL-6-FLUORO-1, 4-DIHIDRO-7- (1S, 4S) -5-METHYL-2,5-DIAZABICICLO (2.2.1) HEPT-2-IL) -4 -OXO-3-QUINOLINCARBOXILICO AND ITS SALTS. |
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CZ97496A3 true CZ97496A3 (en) | 1996-10-16 |
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CZ96974A CZ97496A3 (en) | 1995-04-12 | 1996-04-03 | Process for preparing 1-cyclopropyl-6-fluoro-1, 4-dihydro-7-£(1s, 4s)|-5-methyl-2,5-diazabicyclo £2.2.1|hept-2-yl|-4-oxo-3-quinolinecarboxylic acid and salts thereof |
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KR (1) | KR960037676A (en) |
AR (1) | AR001560A1 (en) |
AT (1) | ATA65396A (en) |
CZ (1) | CZ97496A3 (en) |
ES (1) | ES2092963B1 (en) |
FI (1) | FI961583A (en) |
GR (1) | GR960100116A (en) |
HU (1) | HUP9600941A3 (en) |
MX (1) | MX9601351A (en) |
NO (1) | NO961442L (en) |
PL (1) | PL313697A1 (en) |
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IN166416B (en) * | 1985-09-18 | 1990-05-05 | Pfizer | |
HU196218B (en) * | 1985-12-09 | 1988-10-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing quinoline carboxylic acid boric acid anhydrides |
CA1306750C (en) * | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
ATE58538T1 (en) * | 1986-07-04 | 1990-12-15 | Chemie Linz Gmbh | 4-QUINOLONE-3-CARBONIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. |
NZ224150A (en) * | 1987-04-08 | 1990-11-27 | Chinoin Gyogyszer Es Vegyeszet | Preparation of piperazinyl-substituted quinoline derivatives |
HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
SI8810667A8 (en) * | 1987-04-08 | 1996-04-30 | Chinoin Gyogyszer Es Vegyeszet | Anhydride of quinoline carboxylic acid of boron acid and process for their production. |
JP2693988B2 (en) * | 1987-06-24 | 1997-12-24 | キノイン ギオギスゼル エス ベギエスゼチ テルメケク ギヤラ アールティー. | Method for producing quinoline carboxylic acid derivative |
HU203746B (en) * | 1988-12-22 | 1991-09-30 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
JPH0778065B2 (en) * | 1990-07-06 | 1995-08-23 | 杏林製薬株式会社 | (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O ▲ above 3 ▼, O ▲ above 4) bis (acyloxy-O) Boron compound, salt thereof, and method for producing the same |
-
1995
- 1995-04-12 ES ES09500782A patent/ES2092963B1/en not_active Expired - Fee Related
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- 1996-04-10 KR KR1019960010690A patent/KR960037676A/en not_active Application Discontinuation
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KR960037676A (en) | 1996-11-19 |
NO961442L (en) | 1996-10-14 |
HU9600941D0 (en) | 1996-06-28 |
PT101864B (en) | 1997-12-31 |
ES2092963A1 (en) | 1996-12-01 |
AR001560A1 (en) | 1997-11-26 |
ATA65396A (en) | 1998-09-15 |
MX9601351A (en) | 1997-04-30 |
FI961583A (en) | 1996-10-13 |
FI961583A0 (en) | 1996-04-11 |
PL313697A1 (en) | 1996-10-14 |
SK46896A3 (en) | 1997-07-09 |
PT101864A (en) | 1997-01-31 |
HUP9600941A3 (en) | 1998-01-28 |
ES2092963B1 (en) | 1997-12-16 |
GR960100116A (en) | 1996-12-31 |
HUP9600941A2 (en) | 1997-06-30 |
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