Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1 3250 1 0
-1- 23305-1129
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PROCESS FOR THE PREPARATION OF QUINOLINE CARBOXYLIC ACID
DERIVATIVES
This invention relates to a new process for the
preparation of 1-substituted-7-(optionally substit~ted
piperazine)-6-fluoro-8-(optionally fluoro-substituted)-4-oxo-1,4-
dihydro-quinoline-3-carboxylic acid derivatives of the general
Formula I O
F ~ COOH
R2 ~ N /
R3 R1
and pharmaceutically acceptable salts thereof.
In the general Formula I ~
R1 stands for phenyl being optlonally subatituted by 1 or 2 ; -
halogen atoms, or a group of the general Formula -
--CH2CR6R7R8 (whereln R6, R7 and R8 stand for hydrogen or
halogen);
R stands for piperazinyl or 4-methyl-piperazlnyl;
~3 stands for hydrogen or fluorine, provided that either
R con~ains a halogen atom or R3 is fluorine. ; ;
It is known that a group of the 7-substituted- -
carhoxylic derivatives of the general ~ormula I (wherein R2 stands
for piperazinyl, 4-methyl-piperazinyl, R1 stands for a group of
the general Formula -CH~CR6R7R3 (wherein R6, R7 and R8 stand for
hydrogen or halogen) and R3 stands for fluorine) possesses high
antibacterial activity (J.~ed. Chem. 1986, 29,
~ . .
- 2 - 13~01~
445; Dru3s of Fut. 1984, 9, 246; 23rd Intersci. Conf. Anti-
microb. Agents Chemother. 1983, Abst. 658, 7th Int. Symp. Fut.
Trends Chemother. 1986, 86). These compounds can be prepared
by reacting 6,7,~-trifluoro-4-cxo-1,4-dihydro-quinoline-3-
c~rboxylic acid and cyclic amines (Belgian patent specifica-
tion 887a74, Ga patent specification 2057444, Austrian patent
specification 537813 and European patent specification
10644E9~.
Another group of the 7-substituted-quinolinz-3-
carboxylic acids of the general Formula I (wherein Rl stands ~ -
Eor phenyl optionally substituted by 1 or 2 halogen atoms, R2 ~ ~ -
stands for piperazinyl or 4-methyl-piperazinyl and R3 stands
for hydrogen) has also high antibacterial activity (24th
Intersci. Conf. Antimicrob. ~ents Chemother, 1984, Abst. 72-
78., Amtimicrob. Agents Chemother. 1987., 619, Antimicrob.
Agents Chemother. 1986., 192-208). These compounds can be pre-
pared by reacting l-substituted phenyl-6-fluoro-7-chloro-4-
oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amines -
in the presence of a solvent at a temperature of 100 C for 20
hours (European patent specification 131839, J. Med. Chem. -
1985, 1558., J. Med. Chem. 1987. 504.). ~-
According to the present invention there is provided a -
ne" process for the preparation of quinoline-3-carboxylic acid ~ ~
derivatives of the general Formula I (wherein Rl stands for ~ -
phenyl optionally substituted by 1 or 2 halogen atoms, or a
group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and
R8 stand for hydrogen or halogen), R2 stands for piperazinyl,
~-methyl-piperaizinyl and R3 stands for hydrogen or fluorine) ~ -
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. ' , ', ., .' ' ' .
- 3 - 1325010 - ~
and pharmaceutically acceptable salts thereof which comprises
reactin~ a compound of the general Formula II
R \ / R
, B~
F O (II)
R4 ~ N . ;:: .
'.
R3 R1 :-
(~Jherein R stands for halogen, an aliphatic acyloxy group - ~:
containing 2 to 6 carbon atoms or aromatic acyloxy group
containing 7 to ll carbon atoms, R4 stands for fluorine or
chlorine, Rl and R2 are as stated above) with an amine of the
general Formula III
5 A
R N NH (III) ~
(~nerein R5 stands for hydrogen or methyl) or a salt thereof ~:
and subjecting the compound of the general Formula IV ::
1 3250 1 0
-- 4
R / R
B
O 0~
¦¦ l (IV)
~2
R3 R1 ~-
. ::
thus obtained (wherein R, R1, R2 and R3 are as stated above)
to hydrolysis after or without isolation and if desired con-
verting the compound of the general Formula I thus obtained -
into a salt thereof or setting free the same from its salt. ~-
The advantage of the process of the present invention
is that it enables the preparation of the compounds of the
general Formula I in a simple manner, with very high yields
and in a short reaction time. - ;
The boron derivatives o~ the general Formula IV are ~
,: .
new compounds.
According to a preferred form of realization of the ~-
process of the present invention the boron derivative of the ;
general Formula IV is converted into the desired quinoline-3-
carboxylic acid of the ~eneral Formula I without isolation.
The boron derivatives of the general Formula II can be -- -
reacted with the amine of the general Formula III if desired
in the presence of an inert organic solvent and an acid
. ~ .
binding agent.
As inert organic solvent preferably an acid amide - -;
(e.g. dimethyl formamide, dimethyl acetamide), a ketone (e.g. ~
.' ~ ' .
. ,. . - . . ~ J . . .: ~
5 1 3250 1 0 ~
acetone, methyl ethyl l<etone), an ether (e.g. dioxane, tetra-
hydrofuran, diethyl ether), an ester (e.g. ethyl acetate,
methyl acetate, ethyl propionate), a sulfoxide (e.g. dimethyl
sulfoxide), an alcohol (e.g. methanol, ethanol, l-decanol,
butanol) may be used.
As acid binding agent an organic or inorganic base may `~
be used. From the group of organic bases trialkyl amines (e.g.
triethyl amine, tributyl amine), cyclic amines (e.g. pyridine,
1,5-diazabicyclo/5,4,û/undec-5-ene, 1,5-diazabicyclo/4.3.0/-
non-5-ene, 1,4-diazabicyclo/2.2.2/octane) can be mentioned,
while as inorganic base preferably hydroxides or carbonates of ~
alkali or alkaline earth metals can be applied. Thus as acid -
binding agent zdvantageously potassium carbonate, potassium
hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc.
or an excess of the amine of the general Formula III can be
used.
The boron derivative of the general Formula II and the
amine of the general Formula III can be reacted at a tempera-
ture between 0 and 200 C, depending on the solvent used. The ~ -
reaction time may vary between half an hour and 10 hours. The
reaction time depends on the reaction temperature, too. If the
reaction is carried out at higher temperature, the reaction
time can be shortened. The above reaction conditions are - ;
.:- ..
preferable values and other conditions may be used as well.
The compounds of the general Formula IV can be hydro-
lysed LO the desired quinoline-3-carboxylic acids of the
general Formula I, after or without isolation, under acidic or
basiG conditions. The compound of the general Formula IV pre-
- 6 _ 1325010
; ~ '
cipi-tates from the reaction mixture e.g. on cooling and can be
scparated e.g. by filtration or centrifuging, if desired.
Basic hydrolysis may be preferably carried out by
heating, with the aid of a hydroxide or carbonate of an alkali
.:
metal or an alkaline earth metal hydroxide, used as aqueous ~
solution. One may preferably use an aqueous solution of sodium ~-
hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate, calcium hydroxide. However, organic amines (e.g. -
triethyl amine) may also be applied in the hydrolysis step.
Acidic hydrolysis may preferably be accomplished by ~
using an aqueous mineral acid. One may preferably proceed by `
hydrolysing a compound of the general Formula IV by heating
ith an aqueous solution of hydrochloric acid, hydrogen, ; -
bromide, sulfuric acid or phosphoric acid. Hydrolysis may also ~ -
., i ., . :
be accomplished with the aid or an organic acid (e.g. acetic
acid, propionic acid, etc.).
Hydrolysis of the compounds o~ the general Formula IV ~-
-: .
may also be carried out in aqueous medium in the presence of a
water-miscible organic solvent. For this purpose e.g. alcoholsi -
(e.g. methanol, ethanol), a ketone (e.g. acetone), an ether
. . .
(e.g. dioxane), an acid amide (e.g. dimethyl formamide), a
sulfoxide ~e.g. dimethyl sulfoxide), or pyridine may be used.
The quinoline-3-carboxylic acid of the general Formula -
I thus obtained may be isolated e.g. adjusting the pH value of
the aqueous solution to a suitable value and separating the `
precipitated crystals e.g. by filtration or centrifuging or by
liophyli2ing the aqueous reaction mixture. - -
The compounds of the general Formula I can be con-
. ~ : : ::: :~ : : .. :: : : :
_ 7 _ 1325010
verted into pharmaceutically acceptable salts thereof in a
known manner. Thus preferably acid addition salts can be
formed, e.g. salts formed ~ith hydrogen halides, sulfonic
acids, sulfuric acid or organic acids. One may form preferably
chlorides, bromides, aryl sulfonates, methane sulfonates,
maleates, fumarates, benzoates, etc. The compounds of the
general Formula I form salts with alkali or alkaline earth
metals or nther metal ions as well. Accordingly the sodium,
potassium, magnesium, silver, copper salts, etc. may be pre-
pared.
The compounds of the general Formula I and pharma-
ceutically acceptable salts thereof can be converted into
hydrates (e.g. hemihydrates, trihydrates, etc.) by methods
known per se.
According to a further aspect of the present invention
there are provided new compounds of the general Formula IV
(wherein R, Rl, R2 and R3 are as stated~above). -~
The starting materials of the general formula II can -~
be prepared by reacting l-phenyl-6-fluoro-7-chloro-4-oxo-1,4-
dihydro-quinoline-3-carboxylic acid (European patent speci-
fication 131.839) or 1-ethyl-6,7,8-triiluoro-4-oxo-1,4-di- ~-
hydro-quinoline-3-carboxylic acid (G8 patent speciiication
2.057.440) with a boron derivative (e.g. with a compound of
the general Formula V R
B - R (V)
\ R
(wherein R is halogen or an aliphatic acyloxy group containing
-a - 1325010 ~: ~
. .
. ,::.~. ,.
2 to 6 carbon atoms or an aromatic acyloxy 0roup containing 7
to 11 carbon a-toms) cr with fluoroborate in aqueous or in
organic mcdium.
Further details of the present invention are to be
found in the following Examples without limit~ng the scope of
protection to the said Examples. ~u
':.:`. :'
Example 1 -
,.. ,:, ::
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1.59 9 of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-
. . .
quinoline-7-carboxylate-03,04)-difluoro-boron are reacted with
1.29 9 of piperazine in 8 ml of dimethyl sulfoxide at 100 C
.: :~
for 3 hours. A 6 W/v% aqueous solution of 12.6 ml of sodium -
,~:.: .:
hydroxide are added and hydrolysis is carried out by heating ~
for 2 nours. The reaction mixture is filtered, the pH value is -
.",.~:, .~ ,.
adjusted to 7 ~Jith 96 W/v% acetic acid and diluted with 15 ml ~ :
of water. The crystalline reaction mixture is cooled overnight
and the precipitated crystals are filtered, washed with water
and dried. Thus 1.61 9 of 1-ethyl-6,8-difluoro-1,4-dihydro-4-
oxo-7-pipera~ino-quinoline-3-carboxylic acid are obtained.
.p. is ~34-236 C.
Analysis for the For~ula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45% -
Found: C=56.75% H=5.02% N=12.4d%.
.,,,:,
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1325010
Example 2
1.99 9 of (1-ethyl-6,7,~-trifluoro-1,4-dihydro-4-oxo-
quinoline-3-carboxylate-03,D4)-bis(diacetate-0)-boron are re-
acted with 1.29 9 of piperazine in 8 ml of dimethyl sulfoxide
at 110 C for 2 hours. A 3 W/v% aqueous solution of 20 ml of 3
W/v% sodium hydroxide are added. The reaction mixture is re-
fluxed Ior an hour whereupon filtered and the pH value is
adjusted to 7 with 96 W/v% acetic acid. After cooling and ~--
diluting with 10 ml of water the precipitated crystals are ;
filtered and dried. Thus 1.59 9 of ochre coloured 1-ethyl-6,~-
difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic
acid are obtained. M.p. is 234 C.
Analysis for the Formula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45%
Found: C=57.03% H=5.11% rJ=12.51%.
Exame~
According to Example 2 1.06 9 of (1-ethyl-6,7,~-tri-
fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- ~ -
(propionato-0)-boron are reacted with 0.64 9 of piperazine in
~, ml of dimethyl sulfoxide. A 6 W/v% of aqueous solution of -
6.3 ml of scdium hydroxide are added and the reaction mixture
is refluxed for an hour. After filtration the pH value is
adjusted to 7 with 96 W/v% acetic acid, 10 ml of water are
added and the reaction mixture is cooled overnight. The pre-
cipitated crystals are filtered, washed with water and dried.
- lO - 1 3 2 5 0 1 0 ~:
Thus 0.74 9 of 1-etbyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
piperazino-quinoline-3-carboxylic acid are obtained. M.p. is ~ ~
232-236 C. - -
Analysis for the formula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45%
Found: C=56.85% H=5.00% N=12.39%.
. '- .
Example 4
According to Example 1 1.59 9 of (1-ethyl-6,7,8-tri-
fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-di-
fluoro-boron are reacted with 1.5 9 of l-methyl-piperazine in
8 ml of dimethyl sulfoxide. Thus 1.54 9 of 1-ethyl-6,8-di- ~ -
fluoro-l,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinoline-3-' ' ,.
carboxylic acid are obtained. M.p. is 237-240 C.
Analysis for the Formula C17H19F2N3û3: -
Calculated: C=58.10% H=5.45% N=11.91%
Found: C=58.00% H=5.46% N=11.95%.
....
Example 5
According to Example 2 1.99 9 of (1-ethyl-6,7,8-tri-
fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- , ' '
(acetato-0)-boron are reacted with 1.5 9 of l-methyl-pipera-
. . -, . .
zine. Thus 1.5 9 of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(l-methyl-piperazino)-quinoline-3-carboxylic acid are
obtained. M.p. is 238-240 C. ;
... :..
Analysis for the formula C17HlgF2N303:
Calculated: C=58.1û% H=5.45% ~I=11.91%
8~und: C=58.19% H=5.53% N=11.87%. ~-
;''~'.'-,
1325010 - ~
- 11 - 23305-1129
Example 6
According to Example 3 1.06 9 oi (1-ethyl-6,7,8-trl-- ~
fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- `;
~propionato-0)-boron are reacted with 0.75 g oi l-methyl-plpe-
razine. Thus 0.79 9 oi 1-ethyl-6,8-diiluoro-1,4-dihydro-4-oxo-
7-(1-methyl-piperazino)-quinollne-3-carboxylic acid are ob-
tained. M.p. is 239-24û C.
Analysis for the Formula C17H19F2N303:
Calculated: C=58.10% H=5.45% N=11.91%
Found: C=57.95% H=5.37% N=11.90%.
"~".'
Examole 7
0.46 9 oi 1-(4'-iluoro-phenyl)-6-iluoro-7-chloro-1,4-
dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis(acetato-0)-
boron are reacted with 0.6 9 oi N-methyl-piperazine in 5 ml of
dimethyl sulfoxide at 110 C ior an hour. 10 ml O~ 5 w/v~ ;
aqueous sodium hydrogen carbonate solution are added, the re-
action mixture is reiluxed ior 2 hours whereupon the pH value
is adjusted to 7 with 96 W/v% acetic acid. The reaction -- ~
mixture is cooled and the precipitated crystals are iiltered : -
and ~ashed with cold water. Thus 0.359 oi 1-~4'-fluoro-
phenyl)-6-fluoro-7-(N-methyl-piperazinyl)-1,4-dihydro-4-oxo-
quinoline-3-carboxylic acid are obtained. M.p. is 2a2-284 C. ~-
The carboxylic acid thus obtained is dissolved in a weak
solution of hydrochloride acid under heating, the solution is
evaporated in V3CUO and thus the hydrochloric salt oi 1-(4'-
{, ~ "'. '
' ~ !, i, -: .. : ' '~ '
- 12 - 1325010 :~:
fluoro-phenyl)-6-fluorn-7-(N-methyl-piperazinyl)-1,4-dihydro- :. :
.. -: . - .
4-cxo-~uinoline-3-carboxylic acid is obtained.
The proouct decomposes over 270 C.
, ~ - ., . ~. . .
Analysis for the Formula C21H19F2N303~
Calculated: C=63.15% H=~.79% N=10.52% .:
Found: C=63.27% H=4.89%N=10.35~..................................... .
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