SK46896A3 - Preperation method of 1-cyclopropyl-6-fluor-1,4-dihydro-7- -£(1s,4s)-5-methyl-2,5-diazabicyclo-£2.2.1.|hept-2-yl|-4-oxo-3- -quinoline-carboxylic acid and its salts - Google Patents
Preperation method of 1-cyclopropyl-6-fluor-1,4-dihydro-7- -£(1s,4s)-5-methyl-2,5-diazabicyclo-£2.2.1.|hept-2-yl|-4-oxo-3- -quinoline-carboxylic acid and its salts 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
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Abstract
Description
Spôsob prípravy l-cyklopropyl-6-fluór-l,4-dihydro-7~[(lS,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxylovej kyseliny a jej solíProcess 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
Oblasť technikyTechnical field
Vynález sa týka spôsobu prípravy l-cyklopropyl-6-fluór-l,4-dihydro-7-[(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxylovej kyseliny a jej solí, čo je syntetická zlúčenina s výhodnými farmaceutickými vlastnosťami a ktorá patrí medzi skupinu fluórchinolínov vykazujúcich antibakteriálne účinky a ktorá sa používa vo veterinárnej medicíne.The 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 a group of fluoroquinolines having antibacterial effects and which is used in veterinary medicine.
Doterajší stav technikyBACKGROUND OF THE INVENTION
V patente EP 215 650 a jeho ES analógu č. 2 001 428 sa popisuje postup prípravy vyššie uvedeného produktu reakciou medzi 6,7-di fluór-1-cyklopropy1-1,4-dihydro-4-oxo-3-chinolínkarboxýlovou kyselinou a vhodným (1S,4S)-2,5-diazabicyklo[2.2.l]heptánovým derivátom. Predmetom tohto vynálezu je nový a zlepšený postup prípravy uvedeného produktu.In EP 215 650 and its ES analogue no. No. 2,001,428 describes 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. It is an object of the present invention to provide a new and improved process for preparing said product.
Okrem toho, v literatúre je popísané množstvo postupov na prípravu niektorých fluórchinolínov, ako sú ofloxacín a ciprofloxacín (ES patent č. 516 608 a 2 006 882), reakciou medzi niektorými chelátmi boru odvodených od príslušnýchIn addition, a number of processes for the preparation of certain fluoroquinolines, 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 respective
4-oxo-3-chinolínkarboxylových kyselín a vhodných amínov.4-oxo-3-quinolinecarboxylic acids and suitable amines.
Podstata vynálezuSUMMARY OF THE INVENTION
Spôsob prípravy l-cyklopropyl-6-fluór-l,4-dihydro-7- [ (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinol ínkarboxyl ovej kyseliny a jej solí, ktorý je predmetom tohto vynálezu, spočíva v reakcii C alkyl l-cyklopropyl-6-fluór-7-chlór-1,4-dihydro-4-oxo-3-chinolínkarboxylátu s kyselinou boritou v prítomnosti anhydridu kyseliny octovej a katalytického množstva zinočnatej soli, pričom vznikne (l-cyklopropyl-6-fluór-7-chlór-1,4-dihydro-4-oxo-3 -chinolínkarboxyláto-O3,Q4)bis(acetáto-0)bóran. Tento produkt reaguje s (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptánom alebo s jeho adičnou, soľou, poprípade v prítomnosti acidobázického akceptora za vzniku medziprodutku, (l-cyklopropyl-6-fluór-l, 4-dihydro-7-[(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxyláto-O3,O4)bis(acetáto-O)bóranu. Po hydrolýze sa získa požadovaný produkt, ktorý sa izoluje z reakčnej zmesi konvenčnými spôsobmi.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- The object of the present invention is to react 3-quinolinecarboxylic acid and its salts by reacting C1 alkyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylate with boric acid in presence of acetic anhydride and a catalytic amount of a zinc salt to form (l-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-H -chinolínkarboxyláto 3, Q 4) of bis (acetato-0 ) borane. This product is reacted with (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane or its addition salt, optionally in the presence of an acid-base acceptor to form the intermediate, (1-cyclopropyl-6-fluoro- l, 4-dihydro-7 - [(1 S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3-quinolinecarboxylato-O 3, O 4) bis (acetato-O) borate. After hydrolysis, the desired product is obtained, which is isolated from the reaction mixture by conventional means.
Chemická reakcia uvedeného postupu sa znázorní takto:The chemical reaction of this procedure is shown as follows:
Tento postup je nový a nebol doteraz popísaný pre prípravu fluórchinolínov substituovaných v polohe 7 skupinami diazabicykloalkylového typu majúcich lipofilnú povahu, ako je to v prípade l-cyklopropyl-6-fluór-1,4-dihydro-7-[ (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxylovej kyseliny.This procedure is novel and has not been described to date for the preparation of fluoroquinolines substituted in the 7-position by diazabicycloalkyl-type groups having a lipophilic nature, as is the case with 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.
Navyše, tento spôsob umožňuje získať požadovanú zlúčeninu vo vysokom výťažku a vo vysokej čistote a pomocou postupu, ktorý je ľahký pri praktickom použití.Moreover, this process makes it possible to obtain the desired compound in high yield and in high purity and by a process that is easy to use in practice.
Príprava východiskovej zlúčeniny, alkyl l-cyklopropyl-6-fluór-7-1,4-dihydro-4-oxo-3-chinolínkarboxylátu, je popísaná v ES patente č. 516 921.The preparation of the starting compound, alkyl 1-cyclopropyl-6-fluoro-7-1,4-dihydro-4-oxo-3-quinolinecarboxylate, is described in EC patent no. 516 921.
Okrem toho, konverzia alkyl l-cyklopropyl-6-fluór-7-chlór -1,4-dihydro-4-oxo-3-chinolínkarboxylátu na (1-cyklopropyl-6 -fluór-7-chlór-l,4-dihydro-4-oxo-3-chinolínkarboxyláto-03,O4)bis(acetáto-Q)bóran je popísaná 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-quinolinecarboxylato-0 3, O 4) bis (acetato-Q) borane is disclosed in ES 2006881st
(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptán a jeho soli, spoločne s príbuznými zlúčeninami a ich príprava sú popísané v rôznych publikáciách, ako je J. Med. Chem.. 1974, 17, 481, J.(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.
Org. Chem.. 1990, 55, 1684 a J. Org, Chem,. 1966, 31, 1059.Org. Chem., 1990, 55, 1684 and J. Org, Chem. 1966, 31, 1059.
Postup sa výhodne uskutočňuje s izoláciou medziproduktu, (1-(1-cyklopropy1-6-fluór-7-chlór-1,4-dihydro-4-oxo-3 -chinolínkarboxyláto-03,04)bis(acetáto-O)bóranu. Tento produkt reaguje s (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptánom alebo s jeho adičnou kyslou soľou, poprípade v prítomnosti bázy za vzniku medziproduktu, (l-cyklopropyl-6-fluór-1,4-dihydro-7-[(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxyláto-Q3,24)bis-(acetáto-O)bóranu, ktorý sa hydrolyzuje na požadovaný produkt.The process is preferably carried out with isolation of the intermediate, (1- (1-cyklopropy1-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3--chinolínkarboxyláto 0 3, 0 4) of bis (acetato-O) This product is reacted with (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane or its acid addition salt, optionally in the presence of a base to form the intermediate, (1-cyclopropyl-6-fluoro). -1,4-dihydro-7 - [(1 S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3-quinolinecarboxylato-Q 3 2 4 of bis (acetato-O) borane, which is hydrolyzed to the desired product.
Postup sa výhodne uskutočňuje tak, že sa boránový derivát, (l-cyklopropyl-6-fluór-l,4-dihydro-7-[(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxyláto-03,04)bis-(acetáto-O)bóran, prevedie na požadovaný produkt bez izolácie.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-quinolinecarboxylato-0 3, 0 4) of bis (acetato-O) borane, is converted to the title compound without isolation.
Bóranový derivát, (l-cyklopropyl-6-fluór-7-chlór-l,4-dihydro-4-oxo-3-chinolínkarboxyláto-03,04)bis(acetáto-O)bóran a (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptán alebo jeho adičná kyslá soľ môžu reagovať pri zahrievaní za pomerne krátky čas v prítomnosti vhodného inertného organického rozpúšťadla a prípadne v prítomnosti acidobázického akceptora.A borane derivative, (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylato-0 3, 0 4) of bis (acetato-O) borane and (1 S, 4 S) - The 5-methyl-2,5-diazabicyclo [2.2.1] heptane or its acid addition salt may react under 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.
Ako organické rozpúšťadlá, ktoré sú inertné voči reakčnému prostrediu sa výhodne používa N-metyl-2-pyrolidón, dimetylacetamid, dimetylformamid, dimetylsulfoxid, sulfolan alebo pyridín.The organic solvents which are inert to the reaction medium are preferably N-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, sulfolane or pyridine.
Ako (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptánové soli sa použijú soli odvodené od halogénvodíkových kyselín, ako sú dihydrochloridy a dihydrobromidy.The (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane salts used are those derived from hydrohalogenic acids such as dihydrochlorides and dihydrobromides.
Ako zinočnaté soli sa použije chlorid zinočnatý a acetát zinočnatý.The zinc salts used are zinc chloride and zinc acetate.
Ako akceptor kyseliny sa použije buď prebytok rovnakého (1S, 4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptánu alebo organickej alebo anorganickej bázy, napríklad viac alebo menej bránené terciáme amíny (trietylamín, tributylamín, pyridín,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-diazabicklo[4.3.0]non-5-én (DBN, 1,4-diazabicklo[2.2.2]oktán (TDE), 1,8-diazabicyklo[5.4.0]undek-7-én (DBU) alebo uhličitan alebo hydrogenuhličitan alkalických kovov alebo kovov alkalických zemín.1,5-diazabicyclo [4.3.0] non-5-ene (DBN, 1,4-diazabiclo [2.2.2] octane (TDE), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) ) or an alkali metal or alkaline earth metal carbonate or bicarbonate.
Teplota reakcie medzi boránovým derivátom, (l-cyklopropyl-6-fluór-7-chlór-1,4-dihydro-4-oxo-3 -chinolínkarboxyláto-O3,O4)bis(acetáto-O)bóranom a (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptánom alebo jeho adičnou soľou sa pohybuje v intervale 20 °C ažThe temperature of the reaction between a borane derivative, (l-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3 -chinolínkarboxyláto-O 3, O 4) bis (acetato-O) and borane (1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane or its addition salt ranges from 20 ° C to
200 °C, v závislosti od použitého rozpúšťadla. Podobne, reakčná doba sa pohybuje v intervale 30 minút až 6 hodín, v závislosti od reakčnej teploty a použitého rozpúšťadla.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 konverzie boránového derivátu, (1-cyklopropy1-6-fluór-1,4-dihydro-7-[(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hep t - 2 - y 1 ] - 4 - oxo - 3 - chinolínkarboxyláto-O3 , ) bi s - (acetáto-Q) bóra nu na l-cyklopropyl-6-fluór-l,4-dihydro-7-[(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxylovú kyselinu sa výhodne uskutočňuje pri kyslých alebo zásaditých podmienkach.Conversion procedure of borane derivative, (1-cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hep t-2-yl) ] - 4 - oxo - 3 - quinolinecarboxylato O 3) Bis - (acetato-Q) borate n the l-cyclopropyl-6-fluoro-l, 4-dihydro-7 - [(1 s, 4 s) -5- methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3-quinolinecarboxylic acid is preferably carried out under acidic or basic conditions.
Bázická hydrolýza sa uskutočňuje pomocou zahrievania reakčnej zmesi v prítomnosti vodného roztoku uhličitanu alebo hydroxidu alkalického kovu alebo kovu alkalických zemín.The basic hydrolysis is carried out by heating the reaction mixture in the presence of an aqueous solution of an alkali metal or alkaline earth metal carbonate or hydroxide.
Kyslá hydrolýza sa uskutočňuje výhodne použitím vodného roztoku anorganických kyselín, ako je kyselina chlorovodíková, kyselina sírová alebo 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.
Výhodne sa hydrolýza uskutočňuje vo vodnom prostredí v prítomnosti vo vode miešateľného organického rozpúšťadla. Tak sa alkalická alebo kyslá hydrolýza uskutočňuje v zmesiach vody a N-metyl-2-pyrolidónu, dimetylacetamidu, dimetylformamidu, dimetylsulfoxidu alebo sulfolánu.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 sa požadovaný produkt izoluje použitím konvenčných spôsobov a rekryštalizuje sa z organických rozpúšťadiel alebo ich zmesí.Upon completion of the hydrolysis, the desired product is isolated using conventional methods and recrystallized from organic solvents or mixtures thereof.
Ak to je žiadúce, (l-cyklopropyl-6-fluór-1,4-dihydro-7- [ (1S, 4S) -5--metyl-2,5-diazabicyklo [2.2.1] hept-2-yl] -4-oxo-3-chinolínkarboxylová kyselina sa izoluje vo forme adičných solí s organickými alebo anorganickými kyselinami štandardným spracovaním voľnej bázy so stechiometrickým množstvom zodpovedajúcej kyseliny vo vhodnom rozpúšťadle.If desired, (1-cyclopropyl-6-fluoro-1,4-dihydro-7 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] The 4-oxo-3-quinolinecarboxylic acid is isolated in the form of addition salts with organic or inorganic acids by standard treatment of the free base with a stoichiometric amount of the corresponding acid in a suitable solvent.
Vynález je bližšie objasnený v nasledujúcich príkladoch realizácie. Tieto príklady majú výlučne ilustratívny charakter a rozsah vynálezu nijako neobmedzujú.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.
Príklady realizácie vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1 (l-cyklopŕopyl-6-fluór-7-chlór-l,4-dihydro-4-oxo-3-chinolínkarboxyláto-Q3,Q4)bis (acetáto-<>) -bóran g (1,5 mol) kyseliny boritej sa pridá po častiach k zmesi 480 g (440 ml, 4,7 mol) anhydridu kyseliny octovej a 1,4 g (0,01 mol) bezvodého chloridu zinočnatého. Reakčná zmes sa zahreje na teplotu 110 °C, ochladí sa a pri miešaní sa pridá 295,5 g (1,0 mol) metyl 1-cyklopropyl- 6 -fluór-7-chlór-1,4-dihydro-4-oxo-3 -chinolínkarboxylátu. Reakčná zmes sa udržuje na teplote 80 °C počas 1 hodiny a potom sa nechá schladiť na teplotu miestnosti. Vyzrážaná látka sa odfiltruje a premyje studenou vodou. Suchý produkt sa rozkladá pri teplote 254-256 °C.EXAMPLE 1 (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylato-Q 3, Q 4) of bis (acetato - <>) borane g (1.5 mol 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 is heated to 110 ° C, cooled and 295.5 g (1.0 mol) of methyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo- 3-quinolinecarboxylate. The reaction mixture is maintained at 80 ° C for 1 hour and then allowed to cool to room temperature. The precipitated substance was filtered off and washed with cold water. The dry product decomposes at 254-256 ° C.
Elementárna analýza pre C^H^O^NBCIF:Elemental analysis for C ^ H ^ O ^ NBCIF:
Vypočítané: C = 49,86 %, H = 3,45 %, N = 3,42 %Calculated: C = 49.86%, H = 3.45%, N = 3.42%
Zistené: C = 49,80 %, H = 3,50 %, N = 3,48 %Found: C = 49.80%, H = 3.50%, N = 3.48%
Príklad 2 (l-cyklopropyl-6-f luór-1,4-dihydro-7- [ (1S, 4S) -5-metyl-2,5-diazabicyklo [2. 2 .1]hept-2-yl]-4-oxo-3-chinolínkarboxylová 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
Zmes (l-cyklopropyl-6-fluór-7-chlór-l,4-dihydro-4-oxo-3-chinolínkarboxyláto-03,£)4)bis (acetáto-O) -bóranu (40,9 g, 0,1 mol) a dihydrochloridu (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptánu (22 g, 0,12 mol) v 300 ml bezvodého N-metyl-2-pyrolidónu sa spracuje s 1,8-diazabicyklo[5.4.0]-undek-7-énom (36,4 g, 0,24 mol) . Zmes sa zahrieva na teplotu 85 °C počas 4 hodín a potom sa ochladí na 10 °C. Vyzrazana pevná latka s odfiltruje a suspenduje sa vo vode. Pridaním 30% hydroxidu sodného, prípadne zahrievaním sa dosiahne úplné rozpustenie. Roztok sa ochladí a pridaním koncentrovanej kyseliny chlorovodíkovej sa upraví pH na neutrálnu hodnotu. Vyzrážaná pevná látka sa odfiltruje, premyje vodou a suší sa. Získa sa 33,7 g (94% názve.A mixture of (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylato-0 3, £) 4) of bis (acetato-O) borane (40.9 g, 0 (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane (22 g, 0.12 mol) in 300 mL of anhydrous 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 to 10 ° C. The precipitated solid was filtered off and suspended in water. Addition of 30% sodium hydroxide, optionally by heating, results in complete dissolution. The solution is cooled and the pH is adjusted to neutral by addition of concentrated hydrochloric acid. The precipitated solid is filtered off, washed with water and dried. 33.7 g (94% of the title) are obtained.
Produkt rekryštalizovaný z 275-276,5 °C. Mezylová soľ sa prebytkom metánsulfónovej kyseliny Teplota topenia: 336,5-339 °C.Product recrystallized from 275-276.5 ° C. The mesyl salt with an excess of methanesulfonic acid Melting point: 336.5-339 ° C.
Príklad 3 výťažok) zlúčeniny uvedenej v etanolu má teplotu topenia získa spracovaním bázy slabým v zmesi etanolu a vody.Example 3 Yield) of the compound mentioned in ethanol has a melting point obtained by treating a base weak in a mixture of ethanol and water.
(l-cyklopropyl-6-fluór-l,4-dihydro-7-[(1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]hept-2-yl]-4-oxo-3-chinolínkarboxylová kyselina(L-cyclopropyl-6-fluoro-l, 4-dihydro-7 - [(1 S, 4 S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -4-oxo-3 quinolinecarboxylic acid
Zmes (l-cyklopropyl-6-fluór-7-chlór-l,4-dihydro-4-oxo-3-chinolínkarboxyláto-Q3,0*)bis(acetáto-O)-bóranu (40,9 g, 0,1 mol) a dihydrochloridu (1S,4S)-5-metyl-2,5-diazabicyklo[2.2.1]heptánu (22 g, 0,12 mol) v 300 ml bezvodého N-metyl-2-pyrolidónu sa spracuje s 1,8-diazabicyklo[5.4.0]-undek-7-énom (36,4 g, 0,24 mol) . Zmes sa zahrieva na teplotu 85 °C počas 4 hodín a potom sa ochladí. Časť rozpúšťadla sa odstráni vákuovou destiláciou a k zvyšku sa pridá voda a 30% roztok hydroxidu sodného. Zmes sa ochladí a pridaním koncentrovanej kyseliny sa upraví pH na neutrálnu hodnotu. Vyzrážaná pevná látka sa odfiltruje, premyje sa vodou a po vysušení sa získa 33,0 g (92% výťažok) zlúčeniny uvedenej v názve. Získaný produkt má rovnaké vlastnosti ako produkt získaný v príklade 2.A mixture of (l-cyclopropyl-6-fluoro-7-chloro-l, 4-dihydro-4-oxo-3-quinolinecarboxylato-Q 3, 0 *) of 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 of anhydrous N-methyl-2-pyrrolidone are treated with 1 N 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 adjusted to neutral by addition of concentrated 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)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| SK46896A3 true SK46896A3 (en) | 1997-07-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK468-96A SK46896A3 (en) | 1995-04-12 | 1996-04-12 | Preperation method of 1-cyclopropyl-6-fluor-1,4-dihydro-7- -£(1s,4s)-5-methyl-2,5-diazabicyclo-£2.2.1.|hept-2-yl|-4-oxo-3- -quinoline-carboxylic acid and its salts |
Country Status (13)
| Country | Link |
|---|---|
| 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) |
| PT (1) | PT101864B (en) |
| SK (1) | SK46896A3 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN166416B (en) * | 1985-09-18 | 1990-05-05 | Pfizer | |
| CA1306750C (en) * | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
| HU196218B (en) * | 1985-12-09 | 1988-10-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing quinoline carboxylic acid boric acid anhydrides |
| DE3766299D1 (en) * | 1986-07-04 | 1991-01-03 | Chemie Linz Gmbh | 4-CHINOLON-3-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. |
| 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. |
| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| NZ224150A (en) * | 1987-04-08 | 1990-11-27 | Chinoin Gyogyszer Es Vegyeszet | Preparation of piperazinyl-substituted quinoline derivatives |
| 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
- 1996-04-03 CZ CZ96974A patent/CZ97496A3/en unknown
- 1996-04-03 GR GR960100116A patent/GR960100116A/en unknown
- 1996-04-08 AR AR33607596A patent/AR001560A1/en unknown
- 1996-04-10 KR KR1019960010690A patent/KR960037676A/en not_active Application Discontinuation
- 1996-04-10 PT PT101864A patent/PT101864B/en not_active IP Right Cessation
- 1996-04-11 AT AT0065396A patent/ATA65396A/en not_active Application Discontinuation
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| Publication number | Publication date |
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| PL313697A1 (en) | 1996-10-14 |
| PT101864B (en) | 1997-12-31 |
| ES2092963B1 (en) | 1997-12-16 |
| ATA65396A (en) | 1998-09-15 |
| FI961583A (en) | 1996-10-13 |
| KR960037676A (en) | 1996-11-19 |
| FI961583A0 (en) | 1996-04-11 |
| ES2092963A1 (en) | 1996-12-01 |
| GR960100116A (en) | 1996-12-31 |
| HU9600941D0 (en) | 1996-06-28 |
| HUP9600941A2 (en) | 1997-06-30 |
| AR001560A1 (en) | 1997-11-26 |
| NO961442L (en) | 1996-10-14 |
| PT101864A (en) | 1997-01-31 |
| HUP9600941A3 (en) | 1998-01-28 |
| NO961442D0 (en) | 1996-04-11 |
| CZ97496A3 (en) | 1996-10-16 |
| MX9601351A (en) | 1997-04-30 |
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