NO167800B - INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-QUINOLIN-3-CARBOXYLIC ACID. - Google Patents
INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-QUINOLIN-3-CARBOXYLIC ACID. Download PDFInfo
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- NO167800B NO167800B NO871195A NO871195A NO167800B NO 167800 B NO167800 B NO 167800B NO 871195 A NO871195 A NO 871195A NO 871195 A NO871195 A NO 871195A NO 167800 B NO167800 B NO 167800B
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- Prior art keywords
- dihydro
- oxo
- fluoro
- cyclopropyl
- carboxylic acid
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title 1
- ISPVACVJFUIDPD-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical group C12=CC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ISPVACVJFUIDPD-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- JXWCOCIEGOAZOG-UHFFFAOYSA-N 1,5-dichloro-2-fluoro-4-methylbenzene Chemical compound CC1=CC(F)=C(Cl)C=C1Cl JXWCOCIEGOAZOG-UHFFFAOYSA-N 0.000 description 3
- IGSFOXNHUBLZHU-UHFFFAOYSA-N 2,4-dichloro-5-methylaniline Chemical compound CC1=CC(N)=C(Cl)C=C1Cl IGSFOXNHUBLZHU-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 3
- RPZXUSJCSDQNTE-UHFFFAOYSA-N 2,4-dichloro-5-fluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(Cl)C=C1Cl RPZXUSJCSDQNTE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- -1 acyl malonic ester Chemical compound 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- DYRSCZBWQXEMNL-UHFFFAOYSA-N diethyl 2-(2,4-dichloro-5-fluorobenzoyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C(=O)C1=CC(F)=C(Cl)C=C1Cl DYRSCZBWQXEMNL-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- POKPUCWXUHWGMX-UHFFFAOYSA-N ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(Cl)C=C1Cl POKPUCWXUHWGMX-UHFFFAOYSA-N 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WZWNFRQEMDEWEO-UHFFFAOYSA-N 1,5-dichloro-2-fluoro-4-(trichloromethyl)benzene Chemical compound FC1=CC(C(Cl)(Cl)Cl)=C(Cl)C=C1Cl WZWNFRQEMDEWEO-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- KZCWJHUTTSVCRO-UHFFFAOYSA-N 2,4-dichloro-5-fluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(Cl)C=C1Cl KZCWJHUTTSVCRO-UHFFFAOYSA-N 0.000 description 1
- WJWWAIRPNRIXJW-UHFFFAOYSA-N 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyprop-2-enoic acid Chemical compound CCOC=C(C(O)=O)C(=O)C1=CC(F)=C(Cl)C=C1Cl WJWWAIRPNRIXJW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LYOAKSDOTROZEF-UHFFFAOYSA-N ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=CC(F)=C(Cl)C=C1Cl LYOAKSDOTROZEF-UHFFFAOYSA-N 0.000 description 1
- UYJWKMILOGUYTL-UHFFFAOYSA-N ethyl 3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)prop-2-enoate Chemical compound C=1C(F)=C(Cl)C=C(Cl)C=1C(=O)C(C(=O)OCC)=CNC1CC1 UYJWKMILOGUYTL-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical class C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
Description
Foreliggende oppfinnelse angår et mellomprodukt for fremstilling av l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-piperazino-kinolin-3-karboksylsyre. The present invention relates to an intermediate for the production of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid.
Nærmere bestemt angår oppfinnelsen et mellomprodukt som karakteriseres ved at det er l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-klor-kinolin-3-karboksylsyre. More specifically, the invention relates to an intermediate product characterized by the fact that it is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloro-quinoline-3-carboxylic acid.
Det er allerede kjent at l-etyl-6-fluor-1,4-dihydro-4-okso-7-piperazino-kinolin-3-karboksylsyrer har antibakterielle egenskaper. ["J.Med.Chem." 23, 1358 (1980)]. It is already known that 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids have antibacterial properties. ["J.Med.Chem." 23, 1358 (1980)].
NO-PS 158 018 beskriver nye l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-piperazino-kinolin-3-karboksylsyrer med formel I NO-PS 158 018 describes new 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids of formula I
der R betyr hydrogen, metyl, etyl eller p<->hydroksyetyl, og deres farmasøytisk godtagbare syreaddisjonssalter og hydrater har en antibakteriell virkning, som er overlegne kjente kinolin- og azakinolin-karboksylsyrer. Forbindelsene med formel I viser overlegen antibakteriell virkning såvel mot grampositive som mot gramnegative bakterier, deri blandet Pseudonomas aeruglnosa. where R means hydrogen, methyl, ethyl or p<->hydroxyethyl, and their pharmaceutically acceptable acid addition salts and hydrates have an antibacterial effect, which is superior to known quinoline and azaquinoline carboxylic acids. The compounds of formula I show superior antibacterial activity both against gram-positive and against gram-negative bacteria, including Pseudonomas aeruglnosa.
Videre beskrives det at l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-piperazino-kinolin-3-karboksylsyre med formel (I) fåes når 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-kinolin-3-karboksylsyre med formel II omsettes med piperazin eller piperazlnderlvater med formel Furthermore, it is described that 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid of formula (I) is obtained when 7-chloro-1-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid of formula II is reacted with piperazine or piperazine derivatives of formula
III III
der R har overnevnte betydning. where R has the above meaning.
Forbindelsen med formel II er ny og er som nevnt ovenfor gjenstanden for foreliggende oppfinnelse. The compound with formula II is new and, as mentioned above, is the subject of the present invention.
Omsetningen av II med III foretas fortrinnsvis i et for-tynnlngsmiddel som dimetylsulfoksyd, N,N-dimetylformamid, heksametylfosforsyre-trisamid, sulfolan, vann, en alkohol eller pyridin ved temperaturer på 20-200"C, fortrinnsvis 80-180°C. Omsetningen kan gjennomføres ved normaltrykk, men også ved forhøyet trykk, spesielt ved lavtkokende fortynnings-midler. Vanligvis arbeider man ved trykk mellom ca. 1 og ca. 100 bar, fortrinnsvis mellom.„1 og 10 bar. The reaction of II with III is preferably carried out in a diluent such as dimethylsulfoxide, N,N-dimethylformamide, hexamethylphosphoric trisamide, sulfolane, water, an alcohol or pyridine at temperatures of 20-200°C, preferably 80-180°C. can be carried out at normal pressure, but also at elevated pressure, especially with low-boiling diluents. Generally, one works at a pressure between about 1 and about 100 bar, preferably between 1 and 10 bar.
Ved gjennomføring av fremgangsmåten anvender man på 1 mol karboksylsyrer II 1-5 mol alkylpiperazin (ved piperazin 1-15 mol), fortrinnsvis 2-3 mol alkylpiperazin (ved piperazin 5-10 mol). When carrying out the method, 1-5 mol of alkylpiperazine (in the case of piperazine 1-15 mol), preferably 2-3 mol of alkylpiperazine (in the case of piperazine 5-10 mol) are used for 1 mol of carboxylic acids II.
Anvender man ved omsetningen for eksempel metylpiperazin som reaksjonsdeltaker med formel III kan reaksjonsforløpet gjengis ved følgende formelskjema: If, for example, methylpiperazine is used in the reaction as a reaction participant with formula III, the course of the reaction can be reproduced by the following formula:
Oppfinnelsens mellomprodukter II kan fremstilles over en malonestersyntese ifølge reaksjonskjerna I. The intermediate products II of the invention can be prepared via a malonester synthesis according to reaction core I.
I henhold til dette reaksjonsskjema acyleres malonsyredietyl-esteren VII med IV i nærvær av magnesiumalkoholat til acylmalonester VIII ("Organicum" 3, opplag 1964, side 438). According to this reaction scheme, the malonic acid diethyl ester VII is acylated with IV in the presence of magnesium alcoholate to acyl malonic ester VIII ("Organicum" 3, edition 1964, page 438).
Ved partiell forsåpnlng ved dekarboksylering av VIII 1 vandig medium med katalytiske mengder p-toluensulfonsyre får man i godt utbytte aryleddiksyreetylesteren IX som med o-maur-syretrietylester/acetanhydrid går over til 2-(2,4-diklor-5-fluor-benzoyl)-3-etoksy-akrylsyreetylester. Omsetningen av X med cyklopropylamin i en oppløsning som for eksempel metylenklorid, alkohol, kloroform, cykloheksan eller toluen fører i svakt eksoterm reaksjon til det ønskede mellomprodukt By partial saponification by decarboxylation of VIII 1 in an aqueous medium with catalytic amounts of p-toluenesulfonic acid, the arylacetic acid ethyl ester IX is obtained in good yield, which with o-formic acid triethyl ester/acetic anhydride converts to 2-(2,4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester. The reaction of X with cyclopropylamine in a solution such as methylene chloride, alcohol, chloroform, cyclohexane or toluene leads to a slightly exothermic reaction to the desired intermediate
VI. WE.
Ringslutningsreaksjon VI II (R<1> = alkyl) gjennomføres i et temperaturområde på ca. 60 til 280°C, fortrinnsvis 80 til 180°C. Ring closure reaction VI II (R<1> = alkyl) is carried out in a temperature range of approx. 60 to 280°C, preferably 80 to 180°C.
Som fortynningsmiddel kan det anvendes dioksan, dlmetyl-sulfoksyd, N-metylpyrrolidon, sulfolan, heksametylfosfor-syretriamid og fortrinnsvis N,N-dimetylformamid. As a diluent, dioxane, dlmethylsulfoxide, N-methylpyrrolidone, sulfolane, hexamethylphosphoric acid triamide and preferably N,N-dimethylformamide can be used.
Som syrebindere kommer for dette reaksjonstrinn i betraktning kalium-t-butanolat, butyl-litium, litium-fenyl, fenyl-magnesiumbromid, natriumetylat og spesielt foretrukket natriumhydrid eller kaliumkarbonat. Det kan være fordelaktig å anvende et overskudd på 10 mol-# av basen. As acid binders for this reaction step potassium t-butanol, butyl lithium, lithium phenyl, phenyl magnesium bromide, sodium ethylate and particularly preferred sodium hydride or potassium carbonate come into consideration. It may be advantageous to use an excess of 10 mol-# of the base.
Det som utgangsmaterial for denne syntesemåte anvendte 2,4-diklor-5-fluor-benzoylklorid IV og den tilsvarende karboksyl-syre samt det for fremstillingen av IV nødvendige 3-fluor-4,6-dlklortoluen XI var ennå ikke omtalt i litteraturen. The 2,4-dichloro-5-fluoro-benzoyl chloride IV and the corresponding carboxylic acid used as starting material for this method of synthesis, as well as the 3-fluoro-4,6-dichlorotoluene XI required for the production of IV, had not yet been described in the literature.
Reaksjonsskjerna II viser fremstilling av disse for- resp. mellomprodukter idet det gåes ut fra 2,4-diklor-5-metyl-anilin XII. Reaction nucleus II shows the production of these precursors and intermediates starting from 2,4-dichloro-5-methylaniline XII.
Derefter diazoteres 2,4-diklor-5-metyl-anilin (XII) ved hjelp av NaN02 og det derved dannede diazonlumsalt overføres med dimetylamin til triazen (Xlla). Then 2,4-dichloro-5-methylaniline (XII) is diazotized with the aid of NaN02 and the resulting diazonium salt is transferred with dimethylamine to the triazene (Xlla).
Triazen (Xlla) oppløses -i overskytende vannfri HF. Derved spaltes triazen i 2,4-diklor-5-metyl-diazoniumfluorid og dimetylamin. Uten mellomisolering spaltes denne oppløsning termisk ved 130-140°C under N2-avspaltning til 3-fluor-4,6-diklortoluen XI utbytte 77,7 % av det teoretiske. The triazene (Xlla) is dissolved in excess anhydrous HF. Thereby, the triazene is split into 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is thermally decomposed at 130-140°C under N2 decomposition to 3-fluoro-4,6-dichlorotoluene XI yield 77.7% of the theoretical.
3-fluor-4,6-diklortoluen XI kloreres i et temperaturområde fra 110 til 160°C under UV-bestråling til 2,4-diklor-5-fluor-1-trlklormetylbenzen XIII. 3-fluoro-4,6-dichlorotoluene XI is chlorinated in a temperature range from 110 to 160°C under UV irradiation to 2,4-dichloro-5-fluoro-1-trichloromethylbenzene XIII.
Forsåpningene av XIII med 95 1o svovelsyre fører til 2,4-diklor-5-fluor-benzosyre XV som med tionylklorid går over i karboksylsyreklorid IV. The saponification of XIII with 95 10 sulfuric acid leads to 2,4-dichloro-5-fluoro-benzoic acid XV which with thionyl chloride passes into carboxylic acid chloride IV.
7-klor-l-cyklopropyl - 6-f luor-1,4-dihydro-4-okso-kinolin-3-karboksylsyre II fremstilles som følger: 24,3 g magnesiumspon suspenderes i 50 ml vannfri etanol. Derefter blandes dette med 5 ml karbontetraklorid og efter at reaksjonen er kommet igang dryppes det til en blanding av 160 g malonsyre dietylester VII, 100 ml absolutt etanol og 400 ml vannfri eter hvorved det iakktas et heftig tilbakeløp. Efter avslutning av reaksjonen oppvarmes det hele I ytterligere 2 timer til koking hvorefter det hele avkjøles med tørris/aceton til -5 til. -10°C og det ved denne temperatur langsomt dryppes til en oppløsning av 227,5 g 2,4-diklor-5-f luorbenzoylklorid IV I 100 ml absolutt eter. Det hele omrøres i 1 time til 0 til -5"C, lar reaksjonsblandingen innta romtemperatur ved henstand over natten hvorefter man ved isavkjøling setter til en blanding av 400 ml isvann og 25 ml konsentrert svovelsyre. Fasene separeres og ekstraheres to ganger med eter. De forenede eteroppløsninger vaskes med mettet NaCl-oppløsning, tørkes med Na2S04 og fjerner oppløsningsmidlet under vakuum. Man oppnår 349,5 g 2,4-diklor-5-fluor-benzoyl-malonsyre-dietylester VIII som råprodukt. 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II is prepared as follows: 24.3 g of magnesium shavings are suspended in 50 ml of anhydrous ethanol. This is then mixed with 5 ml of carbon tetrachloride and, after the reaction has started, it is added dropwise to a mixture of 160 g of malonic acid diethyl ester VII, 100 ml of absolute ethanol and 400 ml of anhydrous ether, whereby a vigorous reflux is observed. After completion of the reaction, the whole is heated for a further 2 hours until boiling, after which the whole is cooled with dry ice/acetone to -5 to. -10°C and at this temperature it is slowly added dropwise to a solution of 227.5 g of 2,4-dichloro-5-fluorobenzoyl chloride IV in 100 ml of absolute ether. The whole is stirred for 1 hour at 0 to -5"C, the reaction mixture is allowed to reach room temperature by standing overnight, after which a mixture of 400 ml of ice water and 25 ml of concentrated sulfuric acid is added to it with ice-cooling. The phases are separated and extracted twice with ether. The combined ether solutions are washed with saturated NaCl solution, dried with Na 2 SO 4 and the solvent is removed under vacuum.349.5 g of 2,4-dichloro-5-fluoro-benzoyl-malonic acid diethyl ester VIII are obtained as crude product.
En emulsjon av 34,9 g uren 2,4-diklor-5-fluor-benzoylmalon-syre-dietylester VIII i 50 ml vann blandes med 0,15 g p-toluensulfonsyre. Det hele oppvarmes under god omrøring tre timer til koking, ekstraherer den avkjølte emulsjon flere ganger med metylenklorid, vasker de forente CH2Cl2-oppløs-ninger en gang med mettet NaCl-oppløsning, tørker med Na2S04 og destillerer av oppløsningsmidlet under vakuum. En fraksjonering av resten under høyvakuum gir 21,8 g 2,4-diklor-5-fluor-benzoyl-eddiksyreetylester IX med kokepunkt 127-142°C/0,09 mbar. An emulsion of 34.9 g of impure 2,4-dichloro-5-fluoro-benzoylmalonic acid diethyl ester VIII in 50 ml of water is mixed with 0.15 g of p-toluenesulfonic acid. The whole is heated with good stirring for three hours until boiling, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution, dried with Na2SO4 and the solvent is distilled off under vacuum. A fractionation of the residue under high vacuum gives 21.8 g of 2,4-dichloro-5-fluoro-benzoyl-acetic acid ethyl ester IX with boiling point 127-142°C/0.09 mbar.
En blanding av 21,1 g 2,4-diklor-5-fluor-benzoyl-eddiksyre-etylester IX, 16,65 g o-maursyreetylester og 18,55 g acetanhydrid oppvarmes i 2 timer til 150°C. Derefter av-destilleres flyktige bestanddeler først i vannstrålevakuum og derefter i høyvakuum ved en badtemperatur på 120°C. Det blir tibake en rest på 25,2 g uren 2,(2,4-diklor-5-benzoyl-3-etoksy-akrylsyreetylester X. Dette produkt er tilstrekkelig rent for videre opparbeiding. A mixture of 21.1 g of 2,4-dichloro-5-fluoro-benzoyl-acetic acid ethyl ester IX, 16.65 g of o-formic acid ethyl ester and 18.55 g of acetic anhydride is heated for 2 hours at 150°C. Volatile components are then distilled off first in a water jet vacuum and then in a high vacuum at a bath temperature of 120°C. A residue of 25.2 g of impure 2,(2,4-dichloro-5-benzoyl-3-ethoxy-acrylic acid ethyl ester X is left behind. This product is sufficiently pure for further processing.
En oppløsning av 24,9 g 2-(2,4-diklor-5-fluorbenzoyl)-3-etoksy-akrylsyreester X i 80 ml etanol blandes under isavkjøling og omrøring dråpevis med 4,3 g cyklopropylamin. Efter at den eksoterme reaksjon er til ende, omrøres reaksjonsblandingen ytterligere en time ved romtemperatur hvorefter oppløsningsmidlet fjernes under vakuum og resten omkrystaliseres fra cykloheksan/petroleter. Man oppnår 22,9 g 2- ( 2 , 5-diklor-5-f luor-benzoyl )-3-cyklopropylaminoakrylsyre-etylester VI (R<1> = C2H5) med smeltepunkt 89-90°C. A solution of 24.9 g of 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-acrylic acid ester X in 80 ml of ethanol is mixed dropwise with 4.3 g of cyclopropylamine under ice-cooling and stirring. After the exothermic reaction has come to an end, the reaction mixture is stirred for a further hour at room temperature, after which the solvent is removed under vacuum and the residue is recrystallized from cyclohexane/petroleum ether. 22.9 g of 2-(2,5-dichloro-5-fluoro-benzoyl)-3-cyclopropylaminoacrylic acid ethyl ester VI (R<1> = C2H5) with melting point 89-90°C is obtained.
En oppløsning av 31,9 g 2-(2,4-diklor-5-fluor-benzoyl)-3-cyklopropylamino-akrylsyre-etylester VI (R<1> - C2H5) I 100 ml vannfri dioksan blandes under isavkjøling og omrøring porsjonsvis med 3,44 g 80 #-ig natriumhydrid. Derefter omrøres blandingen i 30 minutter ved romtemperatur og 2 timer under tilbakeløp hvorefter dioksanet fjernes under vakuum. Resten, 40,3 g, suspenderes i 150 ml vann, blandes med 6,65 g KOH og kokes under tilbakeløp i 1 time. Derefter filtreres den varme oppløsning og vaskes med H2O. Reaksjonsblandningen surgjøres med halvkonsentrert HC1 under isavkjøling til pH = 1 til 2 hvorefter utfellingen suges fra, vaskes med vann og tørkes under vakuum ved 100°C. A solution of 31.9 g of 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylic acid ethyl ester VI (R<1> - C2H5) in 100 ml of anhydrous dioxane is mixed under ice-cooling and stirring in portions with 3.44 g of 80 #-ig sodium hydride. The mixture is then stirred for 30 minutes at room temperature and 2 hours under reflux, after which the dioxane is removed under vacuum. The residue, 40.3 g, is suspended in 150 ml of water, mixed with 6.65 g of KOH and refluxed for 1 hour. The hot solution is then filtered and washed with H2O. The reaction mixture is acidified with semi-concentrated HC1 under ice-cooling to pH = 1 to 2, after which the precipitate is suctioned off, washed with water and dried under vacuum at 100°C.
På denne måte oppnås 27,7 g 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-kinolin-3-karboksylsyre II med smeltepunkt 234-237<0>C. In this way, 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II with melting point 234-237<0>C are obtained.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO871195A NO167800C (en) | 1981-10-29 | 1987-03-23 | INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-QUINOLIN-3-CARBOXYLIC ACID. |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813142854 DE3142854A1 (en) | 1981-10-29 | 1981-10-29 | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-CHINOLINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| NO822346A NO158018C (en) | 1981-10-29 | 1982-07-05 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-QUINOLIN-3-CARBOXYL ACID. |
| NO871195A NO167800C (en) | 1981-10-29 | 1987-03-23 | INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-QUINOLIN-3-CARBOXYLIC ACID. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO871195L NO871195L (en) | 1983-05-02 |
| NO871195D0 NO871195D0 (en) | 1987-03-23 |
| NO167800B true NO167800B (en) | 1991-09-02 |
| NO167800C NO167800C (en) | 1991-12-11 |
Family
ID=27189653
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO871195A NO167800C (en) | 1981-10-29 | 1987-03-23 | INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-QUINOLIN-3-CARBOXYLIC ACID. |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO167800C (en) |
-
1987
- 1987-03-23 NO NO871195A patent/NO167800C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO871195D0 (en) | 1987-03-23 |
| NO871195L (en) | 1983-05-02 |
| NO167800C (en) | 1991-12-11 |
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