DK162637B - 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-CHLOR-QUINOLIN-3-CARBOXYLIC ACID FOR USE IN PREPARATION OF 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO 7-piperazino-quinoline-3-carboxylic acids - Google Patents
1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-CHLOR-QUINOLIN-3-CARBOXYLIC ACID FOR USE IN PREPARATION OF 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO 7-piperazino-quinoline-3-carboxylic acids Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
Description
DK 162637 BDK 162637 B
Den foreliggende opfindelse angår den hidtil ukendte l-cyclopropyl-6-fluor-l,4-dihydro-4-oxo-7-chlorquinolin-3--carboxylsyre til anvendelse som mellemprodukt ved fremstilling af l-cyclopropyl-6-fluor-l,4-dihydro-4-oxo-7-piperazi-5 no-quinolin-3-carboxylsyrer.The present invention relates to the novel 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloroquinoline-3-carboxylic acid for use as an intermediate in the preparation of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazi-5-quinoline-3-carboxylic acids.
Det er allerede kendt, at l-ethyl-6-fluor-l,4-dihy-dro-4-oxo-7-piperazino-quinolin-3-carboxylsyrer har antibak-terielle egenskaber, jfr. 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 has antibacterial properties, cf. J. Med. Chem. 23, 1358 (1980).
Det har nu vist sig, at l-cyclopropyl-6-fluor-l,4-di-10 hydro-4-oxo-7-piperazino-quinolin-3-carboxylsyrerne med formlen IIt has now been found that the 1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids of formula I
00
r-øAXTr-øAXT
hvori R betyder hydrogen, methyl eller ethyl, har en overlegen antibakteriel virkning i forhold til de kendte quino-20 Ion- og azaquinolon-carboxylsyrer.wherein R is hydrogen, methyl or ethyl, has a superior antibacterial effect over the known quinolone and azaquinolone carboxylic acids.
De her omhandlede forbindelser udviser deres overraskende antibakterielle virkning mod både grampositive og gramnegative bakterier, herunder Pseudomonas aeruginosa.The compounds of this invention exhibit their surprising antibacterial action against both gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa.
Det har endvidere vist sig, at l-cyclopropyl-6-fluor-25 -l,4-dihydro-4-oxo-7-piperazino-quinolin-3-carboxylsyrerneFurthermore, it has been found that the 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids
med formlen I fås, når 7-chlor-l-cyclopropyl-6-fluor-l,4-di-hydro-4-oxo-quinolin-3-carboxylsyre med formlen IIof formula I is obtained when 7-chloro-1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-quinoline-3-carboxylic acid of formula II
00
C00HC00H
30 TY Γ (11)30 TY Γ (11)
omsættes med piperazin eller piperazinderivater med formlen 35 IIIreacted with piperazine or piperazine derivatives of formula 35 III
22
DK 162637 BDK 162637 B
R-N ^ ^ NH m 5 hvori R har den ovenfor angivne betydning.R-N 4 NH m 5 wherein R is as defined above.
Omsætningen af II med III gennemføres fortrinsvis i et fortyndingsmiddel, såsom dimethyl sul f oxid, N,N-dimethyl-formamid, hexamethylphosphorsyretriamid, sulfolan, vand, en 10 alkohol eller pyridin ved temperaturer på 20-200°C, fortrinsvis 80-180°C. Omsætningen kan gennemføres ved normalt tryk, men også ved forhøjet tryk, især når der er tale om lavtko-gende fortyndingsmidler. I almindelighed arbejdes der ved tryk mellem ca. 1 og ca. 100 bar, fortrinsvis mellem 1 og 15 10 bar.The reaction of II with III is preferably carried out in a diluent such as dimethyl sulphoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, sulfolane, water, an alcohol or pyridine at temperatures of 20-200 ° C, preferably 80-180 ° C. The reaction can be carried out at normal pressure, but also at elevated pressure, especially in the case of low-boiling diluents. Generally, pressures are employed between approx. 1 and approx. 100 bar, preferably between 1 and 15 10 bar.
Ved gennemførelse af fremgangsmåden anvendes der pr. mol carboxylsyre II 1-5 mol alkylpiperazin (ved piperazin 1-15 mol), fortrinsvis 2-3 mol alkylpiperazin (ved piperazin 5-10 mol).In carrying out the method, per. moles of carboxylic acid II 1-5 moles of alkylpiperazine (for piperazine 1-15 moles), preferably 2-3 moles of alkylpiperazine (for piperazine 5-10 moles).
20 De fremstillede 7-piperazino-quinolon-3-carboxyl- syrer I kan eventuelt omdannes til salte med organiske eller uorganiske syrer. Syrer, der er egnede til saltdannelse, er f.eks. hydrogenhalogenidsyrer, såsom saltsyre, hydrogenbromidsyre, hydrogeniodidsyre, svovlsyre, eddikesyre, 25 citronsyre og benzensulfonsyre.The 7-piperazino-quinolone-3-carboxylic acids I produced can optionally be converted to salts with organic or inorganic acids. Acids suitable for salt formation are e.g. hydrogen halide acids such as hydrochloric acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid, acetic acid, citric acid and benzenesulfonic acid.
'Hvis der ved omsætningen af II med III f.eks. anvendes 7-chlor-l-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-quinolin--3-carboxylsyre og methylpiperazin som reaktanter, kan reaktionsforløbet gengives ved følgende reaktions-30 skema: 35'If in the reaction of II with III, e.g. If 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and methylpiperazine are used as reactants, the course of the reaction can be represented by the following reaction scheme:
DK 162637 BDK 162637 B
33
OISLAND
Fs^JyCOOHFs ^ JyCOOH
T| J \] + 2CH ι\τ NH - 5 Cl^^T 3 wT | J \] + 2CH ι \ τ NH - 5 Cl ^^ T 3 w
AA
F S.COOH Γ r-Λ " + CH3 «U®]3®31 CH3“1L/ ΛF S.COOH Γ r-Λ "+ CH3« U®] 3®31 CH3 "1L / Λ
ίο LAίο LA
Forbindelsen II ifølge opfindelsen kan fremstilles 15 via en malonestersyntese ifølge følgende reaktionsskema: 20 25 30 35The compound II of the invention can be prepared by a malone ester synthesis according to the following reaction scheme: 20 25 30 35
4 DK 162637 B4 DK 162637 B
„„„„ „ n _,COOC,H, '"" "" N ", COOC, H,"
K-X0C1 ^COOC.Hj F-^C-CHK-X0C1 ^ COOC.Hj F- ^ C-CH
10L + pXCnl C00C=^.10L + pXCnl C00C = ^.
Cl^^Xl ^cooc2H5Cl2 X1 ^ cooc2H5
IV VII VIIIIV VII VIII
i o o F-^^C-C-COOCgHg Fn^v^ C-CH2C00CaHg xr fn «- oiXXci C1 “ oc2h5i o o F - ^^ C-C-COOCgHg Fn ^ v ^ C-CH2C00CaHg xr fn «- oiXXci C1“ oc2h5
X IXX IX
0-nb20-NB2
VV
o 11 i^/^c-cooc^so 11 i ^ / ^ c-cooc ^ s
M;i -CHM; i -CH
ClCl
AA
1VI1VI
Ί/ 0 F nΊ / 0 F n
Fn^vVCOOC2H5 γ-ζν^^ΌΟΟΗ hydrolyse 1Fn ^ vVCOOC2H5 γ-ζν ^^ ΌΟΟΗ hydrolysis 1
„A"A
XXXX
55
DK 162637 BDK 162637 B
oisland
Herved acyleres malonsyrediethylester (VII) med IV i nærværelse af magnesiumalkoholat til dannelse af acylmalonesteren VIII (Organicum, 3. opl., 1964, s. 438).Thereby, malonic acid diethyl ester (VII) is acylated with IV in the presence of magnesium alcoholate to form the acyl malon ester VIII (Organicum, 3rd ed., 1964, p. 438).
Ved partiel forsæbning og decarboxylering af VIII 5 i vandigt medium med katalytiske mængder p-toluensulfonsyre får man i et godt udbytte aroyleddikesyreethylesteren IX, der med o-myresyretriethylester/acetanhydrid omdannes til 2- (2,4-dichlor-5-fluor-benzoyl)-3-ethoxy-acrylsyreethyl-esteren X. Omsætningen af X med cyclopropylamin i et opløs- 10 ningsmiddel, f.eks. methylenchlorid, alkohol, chloroform, cyclohexan eller toluen, fører ved en let eksoterm reaktion til det ønskede mellemprodukt VI.Partial saponification and decarboxylation of VIII 5 in aqueous medium with catalytic amounts of p-toluenesulfonic acid yields in good yield the aroyl acetic acid ethyl ester IX, which is converted into 2- (2,4-dichloro-5-fluoro-benzoyl) with o-formic acid triethyl ester / acetanhydride. The reaction of X with cyclopropylamine in a solvent, e.g. methylene chloride, alcohol, chloroform, cyclohexane or toluene leads to a desired exothermic reaction to the desired intermediate VI.
Ringslutningsreaktionen VI ——> XX gennemføres i et temperaturområde på ca. 60-280°C, fortrinsvis 80-180°C.The cyclization reaction VI - XX is carried out in a temperature range of approx. 60-280 ° C, preferably 80-180 ° C.
15 Som fortyndingsmidler kan der anvendes dioxan, dimethylsulfoxid, N-methylpyrrolidon, sulfolan, hexamethyl-phosphorsyretriamid og fortrinsvis Ν,Ν-dimethylformamid.As diluents, dioxane, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, hexamethylphosphoric acid triamide and preferably Ν, dim-dimethylformamide may be used.
I betragtning som syrebindende middel i dette reaktionstrin kommer kalium-tert.butanolat, butyllithium, 20 lithiumphenyl, phenylmagnesiumbromid, natriummethylat og især natriumhydrid eller kaliumcarbonat. Det kan være fordelagtigt at anvende et overskud af base på 10 mol-%.Considering as an acid binding agent in this reaction step come potassium tert.butanolate, butyllithium, lithium phenyl, phenylmagnesium bromide, sodium methylate and especially sodium hydride or potassium carbonate. It may be advantageous to use an excess base of 10 mole%.
Det som udgangsforbindelse til denne syntesevej anvendte 2,4-dichlor-5-fluor-benzoylchlorid IV og den tilsvarende 25 carboxylsyre samt det til fremstillingen af IV nødvendige 3- fluor-4,6-dichlortoluen XI er ikke kendt fra litteraturen.The 2,4-dichloro-5-fluoro-benzoyl chloride IV and the corresponding carboxylic acid used as the starting compound for this synthesis route and the 3-fluoro-4,6-dichlorotoluene XI required for the preparation of IV are not known in the literature.
Det efterfølgende reaktionsskema viser fremstillingen af disse udgangsforbindelser og mellemprodukter, idet der gås ud fra 2,4-dichlor-5-methyl-anilin XII.The following reaction scheme shows the preparation of these starting compounds and intermediates starting from 2,4-dichloro-5-methyl-aniline XII.
30 3530 35
6 DK 16263 7 B6 DK 16263 7 B
CH3 C1>|^ 1. NaN02, H30 ®CH3 C1> | ^ 1. NaN02, H30®
Ynh2 hn(ch3)2 Sr n=n-n(ch3)2Inh2 hn (ch3) 2 Sr n = n-n (ch3) 2
Cl Cl XI1 XllaCl Cl XI1 Xlla
HFHF
VV
CH-.CH-.
ClCl
XIXI
CC1, biCC1, bi
Ixmmicrons
c O OHc O OH
Cl i .Cl i.
Cl COC1 01Cl COC1 01
IVIV
77
DK 162637 BDK 162637 B
Herved diazoteres 2,4-dichlor-5-methylanilin (XII) ved hjælp af NaN02/ og det derved dannede diazoniumsalt omdannes med dimethylamin til triazenet Xlla.Thereby, 2,4-dichloro-5-methylaniline (XII) is diazotized by NaNO 2 / and the resulting diazonium salt is converted with dimethylamine to the triazene XIIa.
Triazenet Xlla opløses i et overskud af vandfrit HF.The triazenet XIIa is dissolved in an excess of anhydrous HF.
5 Derved spaltes triazenet til 2,4-dichlor-5-methyl-diazonium-fluorid og dimethylamin. Uden mellemisolering spaltes denne opløsning termisk ved 130-140°C under N2~fraspaltning til 3-fluor-4,6-dichlortoluen XI (udbytte 77,7% af det teoretiske).Thereby the triazene is cleaved to 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is thermally cleaved at 130-140 ° C under N 2 decomposition to 3-fluoro-4,6-dichlorotoluene XI (yield 77.7% of theory).
10 3-Fluor-4,6-dichlortoluen XI chloreres i et temperatur område på 110-160°C under UV-bestråling til dannelse af 2.4- dichlor-5-fluor-l-trichlormethylbenzen XIII.3-Fluoro-4,6-dichlorotoluene XI is chlorinated at a temperature range of 110-160 ° C under UV irradiation to give 2.4-dichloro-5-fluoro-1-trichloromethylbenzene XIII.
Ved forsæbning af XIII med 95%'s svovlsyre fås 2.4- dichlor-5-£luor-benzoesyre XV, der med thionylchlorid 15 omdannes til carboxylsyrechloridet IV.Saponification of XIII with 95% sulfuric acid gives 2.4-dichloro-5-fluoro-benzoic acid XV, which with thionyl chloride 15 is converted to the carboxylic acid chloride IV.
Forbindelserne med formlen I udmærker sig ved en særlig god antibakteriel virkning over for grampositive og gramnegative bakterier, især i forhold til forbindelserne ifølge DE patentansøgning P 30 33 157.8 og DE offentiiggørel-20 sesskrift nr. 28 04 097, som det fremgår af den følgende tabel.The compounds of formula I are characterized by a particularly good antibacterial effect against Gram-positive and Gram-negative bacteria, especially in relation to the compounds of DE Patent Application P 30 33 157.8 and DE Publication No. 28 04 097, as shown in the following table. .
25 30 35 825 30 35 8
DK 16263 7 BDK 16263 7 B
OISLAND
H oH o
^-=r\ S^ - = r \ S
0=( 0) \_/ tn «. in0 = (0) \ _ / tn «. in
/rr\ HH/ rr \ HH
/ \ Q) o/ \ Q) o
\\ // OG\\ // AND
r >-1 C QJ -—- Ir> -1 C QJ -—- I
fa 1 Η Η Mfa 1 Η Η M
0,0 g m io ia vo m Η Η II O O O O in oo - ~ ~0.0 g m io ia vo m Η Η II O O O O in oo - ~ ~
a Η Η fa O O O O O Oa Η Η fa O O O O O O
·*« >—r" 8 § -p y__ ^ m h /—λ “Jm M4 Ή C =\ 2·υ m \ / nj in in ia /-\ W W σι r- <N cn o / \ QCQO ^ V V 3J „ ** o o o o *- ® > / co cn Ό / ' Μ H o (0· * «> —R" 8 § -p y__ ^ mh / —λ “Jm M4 Ή C = \ 2 · υ m \ / nj in ia / - \ WW σι r- <N cn o / \ QCQO ^ VV 3J „** oooo * - ®> / co cn Ό / 'Μ H o (0
&-/ZN Ή Φ H& - / ZN Ή Φ H
Γ I }-) oo o, I J 4-> Ό CN \ 2^ Ό Cn gΓ I} -) oo o, I J 4-> Ό CN \ 2 ^ Ό Cn g
S C Cn . HS C Cn. H
OHM XOHM X
Μ H CΜ H C
—· r> o- · r> o
>H> H
= *= *
8 N8 N
C_> IC_> I
\ I iH\ I iH
/=\ W tP/ = \ W tP
°-< ?<] °-S« s° - <? <] ° -S «s
W -H c · GW -H c · G
/ \ Cnt~~ m H/ \ Cnt ~~ m H
\\ // n Sin v. Ό 2—f WHoO r-r-T-o H 2 * H C P5\\ // n Sin v. Ό 2 — f WHoO r-r-T-o H 2 * H C P5
Ooi un —.Ooi un -.
fa 4-1 H -Pfa 4-1 H -P
g fi Mg fi M
9) CIO 0) Ξ Cfl 4-1 H 4-> ^ (0 W fafa >i 4-1 •ri > Η 4-19) CIO 0) fl Cfl 4-1 H 4-> ^ (0 W fafa> i 4-1 • ri> Η 4-1
4-1 H4-1 H
οι οιοι οι
in (U Cin (U C
W 00 4J Φ 3 r- · © W 01 O id £ co t" 12 tnW 00 4J Φ 3 r- · © W 01 O id £ co t „12 tn
o <N 3 01 ^ C(Do <N 3 01 ° C (D
om <l) ns o co to 2 “om <l) ns o co to 2 “
OHriJ 2 Hr- c cd 'S POHriJ 2 Hr- c cd 'S P
Or- H O O E* HOr- H O O E * H
H HH <1)01 gg f*1 >l01H Η H 3 O-H f ^ Λ30 O Old) Ό tn £ ,2 faOJO O .0 4J 33 0Ό ns h uioaiLj 4J3 · · HH 01 3 £ -H HH <1) 01 gg f * 1> l01H Η H 3 O-H f ^ Λ30 O Old) Ό tn £, 2 faOJO O .0 4J 33 0Ό ns h uioaiLj 4J3 · · HH 01 3 £ -
WrtSH w «fa faio «gWrtSH w «fa faio« g
< Q<Q
99
DK 162637 BDK 162637 B
OISLAND
Opfindelsen illustreres ved de følgende eksempler. Eksempel 1The invention is illustrated by the following examples. Example 1
CH,NCH, N
w Δ 1°w Δ 1 °
En blanding af 20 g 7-chlor-l-cyclopropyl-6-fluor--l,4-dihydro-4-oxo-quinolin-3-carboxylsyre, 28,5 g N--methylpiperazin og 120 ml vandfrit dimethylsulfoxid opvarmes i 1,5 timer til 135-140°C. Opløsningsmidlet af-destilleres under højvakuum, og remanensen suspenderes i ca. 50 ml vand. Der fraskilles ved sugning, eftervaskes med vand, tørres i vakuumtørreskab ved 80°C over CaC^ og omkrystalliseres fra glycolmonomethylether. Der fås 14,5 g l-cyclopropyl-6-fluor-l,4-dihydro-7-(4-methylpipe-razino)-4-oxo-guinolin-3-carboxylsyre med et sønderdelingspunkt på 248-250°C.A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 28.5 g of N-methylpiperazine and 120 ml of anhydrous dimethyl sulfoxide is heated in 1 , 5 hours to 135-140 ° C. The solvent is distilled off under high vacuum and the residue is suspended for approx. 50 ml of water. It is separated by suction, washed with water, dried in a vacuum drying cabinet at 80 ° C over CaCl 2 and recrystallized from glycol monomethyl ether. 14.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methylpiperazino) -4-oxo-guinoline-3-carboxylic acid are obtained with a decomposition point of 248-250 ° C.
Eksempel 2 . o 25 ν^Ά^00Η w Δ 30 En blanding af 19,7 g 7-chlor-l-cyclopropyl-6- -fluor-1,4-dihydro-4-oxo-quinolin-3-carboxylsyre, 30,1 g vandfrit piperazin og 100 ml dimethylsulfoxid opvarmes i 2 timer til 135-140°C. Opløsningsmidlet af destilleres i højvakuum, og rananensen suspenderes i vand, fraskilles vel sugning og vaskes med vand. Til yderligere rensning opkoges 35 det fugtige råprodukt med 100 ml vand, hvorefter der fraskilles ved sugning, vaskes med vand og tørres indtil konstant 10Example 2. A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g anhydrous piperazine and 100 ml of dimethyl sulfoxide are heated to 135-140 ° C for 2 hours. The solvent is distilled off in high vacuum and the residue is suspended in water, well-suction separated and washed with water. For further purification, the moist crude product is boiled with 100 ml of water, then separated by suction, washed with water and dried until constant 10
DK 162637 BDK 162637 B
vægt i vakuumtørreskab over CaCl2 ved 100ec. Der fås 19,6 g l-cyclopropyl-6-fluor-l,4-dihydro-4-oxo-7-piperazino-quino-lin-3-carboxylsyre med et sønderdelingspunkt på 255-257°C.weight in vacuum drying cabinet over CaCl2 at 100ec. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid are obtained, with a decomposition point of 255-257 ° C.
Den fremstillede forbindelse opløses varmt i 50 ml 5 10%'s saltsyre. Der sættes 150 ml ethanol til den filtrerede opløsning, afkøles med is, fraskilles ved sugning, vaskes med alkohol og tørres i vakuum ved 100°C. Der fås 18,5 g l-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-piperazino-quino-lin-3-carboxylsyre-hydrochlorid som farveløse krystaller 10 med et sønderdelingspunkt på 308-310°C.The compound obtained is dissolved hot in 50 ml of 10% hydrochloric acid. 150 ml of ethanol are added to the filtered solution, cooled with ice, separated by suction, washed with alcohol and dried in vacuo at 100 ° C. 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloride are obtained as colorless crystals 10, with a decomposition point of 308-310 ° C .
Eksempel 3 Δ,Example 3 Δ,
En blanding af 1,2 g l-cyclopropyl-6-fluor-1,4--d ihydro-4-oxo-7-pipera zino-quino1in-3-carboxy1syre, 1,13 g ethyliodid, 0,73 g triethylamin og 20 ml N,N--dimethylformamid opvarmes i 2,5 timer til 70-80°C. Opløsningsmidlet afdestilleres i vakuum, og remanensen suspenderes i vand. Der fraskilles ved sugning, eftervaskes med vand og trykkes mod ler. Der fås 1,15 g 1-cyclopropyl--6-fluor-7-(ethylpiperazino)-l,4-dihydro-4-oxo-quinolin-3--carboxylsyre-hydroiodid med et sønderdelingspunkt på 306°C.A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of N, N - dimethylformamide are heated for 2.5 hours to 70-80 ° C. The solvent is distilled off in vacuo and the residue is suspended in water. It is separated by suction, washed with water and pressed against clay. 1.15 g of 1-cyclopropyl-6-fluoro-7- (ethylpiperazino) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydroiodide are obtained with a decomposition point of 306 ° C.
Den som udgangsforbindelse anvendte 7-chlor-l--cyclopropyl-6-fluor-1,4-dihydro-4-oxo-quinolin-3-carboxylsyre II fremstilles som følger: 30 24,3 g magnesiumspåner suspenderes i 50 ml vandfri ethanol. Der tilsættes 5 ml carbontetrachlorid, og når reaktionen er kommet i gang tilsættes der dråbevis en blanding af 160 g malonsyrediethylester VII, 100 ml absolut ethanol og 400 ml vandfri ether, hvorved der 35 iagttages en kraftig tilbagesvaling. Efter at reaktionen er klinget af, opvarmes der yderligere 2 timer til kogning, 11The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II used as the starting compound is prepared as follows: 24.3 g of magnesium chips are suspended in 50 ml of anhydrous ethanol. Carbon tetrachloride (5 ml) is added and, when the reaction is started, a mixture of 160 g of malonic acid diethyl ester VII, 100 ml of absolute ethanol and 400 ml of anhydrous ether is added dropwise, giving a strong reflux. After the reaction is quenched, add another 2 hours to boil, 11
DK 162637 BDK 162637 B
0 afkøles med tøris/acetone til -5 til -10°C, og ved denne temperatur tilsættes der langsomt dråbevis en opløsning af 227,5 g 2,4-dichlor~5-fluor-benzoylchlorid IV i 100 ml absolut ether. Der omrøres 1 time ved 0 til -5°C, blandingen får lov at komme op på stuetemperatur natten over, og der 5 tilsættes under isafkøling en blanding af 400 ml isvand og 25 ml koncentreret svovlsyre. Faserne adskilles, og der efterekstraheres to gange med ether. De forenede etheropløsninger vaskes med mættet NaCl-opløsning, tørres med natriumsulfat, og opløsningsmidlet afdrives i vakuum.0 is cooled with dry ice / acetone to -5 to -10 ° C and at this temperature a solution of 227.5 g of 2,4-dichloro-5-fluoro-benzoyl chloride IV in 100 ml of absolute ether is slowly added dropwise. Stir for 1 hour at 0 to -5 ° C, allow the mixture to come to room temperature overnight and add 5 ml of ice-water cooling under ice-cooling to 25 ml of concentrated sulfuric acid. The phases are separated and extracted twice with ether. The combined ether solutions are washed with saturated NaCl solution, dried over sodium sulfate and the solvent is evaporated in vacuo.
1010
Der fås 349,5 g 2,4-dichlor-5-fluor-benzoyl-malonsyrediethyl-ester VIII som råprodukt.349.5 g of 2,4-dichloro-5-fluoro-benzoyl-malonic acid diethyl ester VIII is obtained as crude product.
Til en emulsion af 34,9 g råt 2,4-dichlor-5-fluor--benzoyl-malonsyrediethylester VIII i 50 ml vand sættes 0,15 g p-toluensulfonsyre. Der opvarmes under god omrøring 15 til kogning i 3 timer, den afkølede emulsion ekstraheres flere gange med methylenehlorid, de forenede methylenchlorid-opløsninger vaskes 1 gang med mættet natriumchloridopløsning og tørres med natriumsulfat, og opløsningsmidlet afde-stilleres i vakuum. Ved fraktionering af remanensen i 20 højvakuum fas 21,8 g 2,4-dichlor-5-fluor-benzoyl-eddikesyre- ethylester IX med kogepunktet 127-142 °C/0,09 mbar.To an emulsion of 34.9 g of crude 2,4-dichloro-5-fluoro-benzoyl-malonic acid diethyl ester VIII in 50 ml of water is added 0.15 g of p-toluenesulfonic acid. With good stirring, it is heated to boiling for 3 hours, the cooled emulsion is extracted several times with methylene chloride, the combined methylene chloride solutions are washed once with saturated sodium chloride solution and dried with sodium sulfate, and the solvent is distilled off in vacuo. By fractionation of the residue in high vacuum, 21.8 g of 2,4-dichloro-5-fluoro-benzoyl-acetic acid ethyl ester IX are boiled at boiling point 127-142 ° C / 0.09 mbar.
En blanding af 21,1 g 2,4-dichlor-5-fluor-benzoyl- -eddikesyreethylester IX, 16.,65 g o-myresyreethylester og 18,55 g acetanhydrid opvarmes i 2 timer til 150°C. Derefter 25 afdestilleres de flygtige bestanddele i vandstralevakuum og til sidst i højvakuum ved en badtemperatur på 120°C.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 acetanic anhydride is heated at 150 ° C for 2 hours. Then, the volatiles are distilled off in water jet vacuum and finally in high vacuum at a bath temperature of 120 ° C.
Tilbage bliver 25,2 g rå 2-(2,4-dichlor-5-fluor-benzoyl)-3- -ethoxy-acrylsyreethylester X. Den er tilstrækkelig ren til de videre omsætninger.25.2 g of crude 2- (2,4-dichloro-5-fluoro-benzoyl) -3- -ethoxy-acrylic acid ethyl ester X remains. It is sufficiently pure for the further reactions.
3030
Til en opløsning af 24,9 g 2-(2,4-dichlor-5-fluor- -benzoyl)-3-ethoxy-acrylsyreethylester X i 80 ml ethanol sættes under isafkøling og omrøring dråbevis 4,3 g cyclo- propylamin. Når den eksoterme reaktion er klinget af, efteromrøres der endnu 1 time ved stuetemperatur, opløs-35 ningsmidlet afdrives i vakuum, og remanensen omkrystalli- 12To a solution of 24.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester X in 80 ml of ethanol is added under ice-cooling and stirred dropwise 4.3 g of cyclopropylamine. When the exothermic reaction is quenched, stir for another hour at room temperature, the solvent is evaporated in vacuo and the residue recrystallized.
DK 162637 BDK 162637 B
seres fra cyclohexan/petroleumsether. Der fås 22f9 g 2-(2,4-dichlor-5-fluor-benzoyl)-3-cyclopropylamino--acrylsyreethylester VI med smp. 89-90°C.is cyclohexane / petroleum ether. 22 g of g of 2- (2,4-dichloro-5-fluoro-benzoyl) -3-cyclopropylamino-acrylic acid ethyl ester VI are obtained, m.p. 89-90 ° C.
Til en opløsning af 31,9 g 2-(2,4-dichlor-5-5 -fluor-benzoyl)-3-cyclopropylamino-acrylsyre-ethylester VI i 100 ml vandfrit dioxan sættes der portionsvis under isafkøling og omrøring 3,44 g 80%'s natriumhydrid. Derefter omrøres der 30 minutter ved stuetemperatur og 2 timer under tilbagesvaling, og dioxanet fjernes i vakuum. Remanensen 10 (40,3 g) suspenderes i 150 ml vand, og der tilsættes 6,65 g ætskali og tilbagesvales i 1,5 timer. Den varme opløsning filtreres og eftervaskes med vand. Derefter gøres blandingen sur til en pH-værdi på 1-2 med halvkoncentreret saltsyre under isafkøling, og bundfaldet fraskilles ved sugning, 15 vaskes med vand og tørres i vakuum ved 100°C. Der fås på denne måde 27,7 g 7-chlor-l-cyclopropyl-6-fluor-l,4-dihy-dro-4-oxo-quinolin-3-carboxylsyre II med smp. 234-237"C.To a solution of 31.9 g of 2- (2,4-dichloro-5-5-fluoro-benzoyl) -3-cyclopropylamino-acrylic acid ethyl ester VI in 100 ml of anhydrous dioxane is added portionwise under ice-cooling and stirring 3.44 g 80% sodium hydride. Then, 30 minutes at room temperature and 2 hours under reflux, the mixture is stirred and the dioxane removed in vacuo. The residue 10 (40.3 g) is suspended in 150 ml of water and 6.65 g of ethanol are added and refluxed for 1.5 hours. The hot solution is filtered and washed with water. Then the mixture is acidified to a pH of 1-2 with semi-concentrated hydrochloric acid under ice-cooling and the precipitate is separated by suction, washed with water and dried in vacuo at 100 ° C. There is thus obtained 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II, m.p. 234-237 "C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3142854 | 1981-10-29 | ||
| 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 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK190890A DK190890A (en) | 1990-08-10 |
| DK190890D0 DK190890D0 (en) | 1990-08-10 |
| DK162637B true DK162637B (en) | 1991-11-25 |
| DK162637C DK162637C (en) | 1992-04-13 |
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ID=6145081
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| Application Number | Title | Priority Date | Filing Date |
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| DK306082A DK160491C (en) | 1981-10-29 | 1982-07-07 | METHOD OF ANALOGUE FOR THE PREPARATION OF 1-CYCLO-PROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7- (4-BETA-HYDROXYETHYL-PIPERAZINO) -QUINOLINE-3-CARBOXYLIC ACID ACRODUCTIVE ACID ACRODUCTIVE ACID DRUGE |
| DK190890A DK162637C (en) | 1981-10-29 | 1990-08-10 | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-CHLOR-QUINOLIN-3-CARBOXYLIC ACID FOR USE IN PREPARATION OF 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO 7-piperazino-quinoline-3-carboxylic acids |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK306082A DK160491C (en) | 1981-10-29 | 1982-07-07 | METHOD OF ANALOGUE FOR THE PREPARATION OF 1-CYCLO-PROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7- (4-BETA-HYDROXYETHYL-PIPERAZINO) -QUINOLINE-3-CARBOXYLIC ACID ACRODUCTIVE ACID ACRODUCTIVE ACID DRUGE |
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| Country | Link |
|---|---|
| EP (1) | EP0078362B1 (en) |
| JP (5) | JPS5874667A (en) |
| KR (1) | KR870000895B1 (en) |
| AT (1) | ATE23040T1 (en) |
| AU (3) | AU561103B2 (en) |
| CA (1) | CA1218067A (en) |
| DD (1) | DD202560A5 (en) |
| DE (2) | DE3142854A1 (en) |
| DK (2) | DK160491C (en) |
| ES (1) | ES8307787A1 (en) |
| FI (1) | FI78689C (en) |
| GR (1) | GR77707B (en) |
| HU (1) | HU187580B (en) |
| IE (1) | IE53709B1 (en) |
| IL (1) | IL66243A (en) |
| LU (1) | LU88325I2 (en) |
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| CN113912539B (en) * | 2021-12-13 | 2022-03-11 | 山东国邦药业有限公司 | Synthesis method of cyclopropanecarboxylic acid |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5188973A (en) * | 1975-01-29 | 1976-08-04 | SHINKINAKINORONKARUBONSAN JUDOTAINOSEIHO | |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| CA1175836A (en) * | 1977-09-20 | 1984-10-09 | Marcel Pesson | Production of 1,4-dihydroquinoline-3-carboxylic acid derivatives |
| JPS5466686A (en) * | 1977-09-20 | 1979-05-29 | Dainippon Pharmaceut Co Ltd | Quinoline-3-carboxylic acid derivative, its preparation, and pharmaceutical composition containig the same |
| DE2808070A1 (en) * | 1978-02-24 | 1979-08-30 | Bayer Ag | PROCESS FOR THE PRODUCTION OF 4-PYRIDONE-3-CARBONIC ACIDS AND / OR DERIVATIVES |
| DE3033157A1 (en) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| JPS5762259A (en) * | 1980-09-05 | 1982-04-15 | Kyorin Pharmaceut Co Ltd | Preparation of substituted quinolinecarboxylic acid derivative |
| IE52125B1 (en) * | 1980-10-02 | 1987-06-24 | Fox Charles L Jun | 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quino-line carboxylic acid and metal salts thereof useful in burn therapy |
| US4788320A (en) * | 1986-01-20 | 1988-11-29 | Kyorin Pharmaceutical Co., Ltd. | Benzoylacetic acid ester derivatives and process for their preparations |
| US4689423A (en) * | 1986-04-01 | 1987-08-25 | Warner-Lambert Company | Process for the preparation of 2,3,4,5-tetrafluorobenzoyl acetates |
| JPS6356224A (en) * | 1986-08-27 | 1988-03-10 | 株式会社クボタ | Soil covering apparatus of mulching work machine |
| CA2017090A1 (en) * | 1990-05-17 | 1991-11-17 | Stephen Dunn | Coating composition |
-
1981
- 1981-10-29 DE DE19813142854 patent/DE3142854A1/en not_active Withdrawn
-
1982
- 1982-07-01 IE IE1606/82A patent/IE53709B1/en not_active IP Right Cessation
- 1982-07-05 NO NO822346A patent/NO158018C/en not_active IP Right Cessation
- 1982-07-06 IL IL66243A patent/IL66243A/en not_active IP Right Cessation
- 1982-07-07 ZA ZA824829A patent/ZA824829B/en unknown
- 1982-07-07 DK DK306082A patent/DK160491C/en not_active IP Right Cessation
- 1982-07-08 FI FI822442A patent/FI78689C/en not_active IP Right Cessation
- 1982-07-09 AU AU85768/82A patent/AU561103B2/en not_active Expired
- 1982-07-16 DD DD82241728A patent/DD202560A5/en unknown
- 1982-07-19 EP EP82106472A patent/EP0078362B1/en not_active Expired
- 1982-07-19 AT AT82106472T patent/ATE23040T1/en not_active IP Right Cessation
- 1982-07-19 DE DE8282106472T patent/DE3273892D1/en not_active Expired
- 1982-07-19 KR KR8203203A patent/KR870000895B1/en active IP Right Grant
- 1982-07-29 JP JP57131346A patent/JPS5874667A/en active Granted
- 1982-08-13 CA CA000409435A patent/CA1218067A/en not_active Expired
- 1982-10-25 GR GR69612A patent/GR77707B/el unknown
- 1982-10-26 NZ NZ202278A patent/NZ202278A/en unknown
- 1982-10-28 HU HU823457A patent/HU187580B/en unknown
- 1982-10-28 ES ES516921A patent/ES8307787A1/en not_active Expired
- 1982-10-28 PH PH28052A patent/PH18803A/en unknown
-
1987
- 1987-04-09 AU AU71406/87A patent/AU573126B2/en not_active Expired
- 1987-04-09 AU AU71405/87A patent/AU573125B2/en not_active Expired
- 1987-05-25 JP JP62127877A patent/JPS6322076A/en active Granted
- 1987-05-25 JP JP62127876A patent/JPS6322075A/en active Granted
- 1987-05-25 JP JP62127878A patent/JPS6322057A/en active Granted
-
1990
- 1990-08-10 DK DK190890A patent/DK162637C/en not_active IP Right Cessation
-
1991
- 1991-05-27 JP JP3151073A patent/JPH0824536B2/en not_active Expired - Lifetime
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1993
- 1993-06-24 LU LU88325C patent/LU88325I2/en unknown
-
1994
- 1994-12-30 NO NO1994030C patent/NO1994030I1/en unknown
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| PUP | Patent expired |