Note: Descriptions are shown in the official language in which they were submitted.
1333715
The invention relates to a new process for the
preparation of 4-oxo-3-quinoline-carboxylic acids which
are used as intermediates for the preparation of known
quinolonecarboxylic acids having pharmaceutical activity.
It is known that 1-cyclopropyl-7-chloro-6-fluoro-
1,4-dihydro-4-oxo-3-quinoline-carboxylic acids are ob-
tained in the following way:
1st stage:
F~ eH_ COOR ~ ~ ~ ,COOR
Cl CH-N(CH3)2 ll
Cl Cl Cl CH-N(CH3)2
(1) (2) ~3)
2nd stage:
( 3 ) ~ D~H2 F~C COOR
- ~CH3 )2NH Cl Cl CH-NH--<¦
3rd stage:
( 5 ) ~ K2C3 ~COOR
Cl J~
~6)
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4th stage:
(6) hydrolysis F~COOH
Cl
~\
~7)
It has also been disclosed to prepare (7) in the
follo~ing way:
1st stage:
C ~ COzR C ~ ;CH~CO2R)2
2nd stage:
decarboxylation ~ C~ ,~02R
~ CH2
Cl Cl
3rd stage:
~C02R
CH(OEt.)3 ' J.~ IC
C 1 C 1 CH- Oc2H5
4th stage:
D--NH2 , ~C~ ~C02R
C I CH-NH--<]
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5th stage:
K2C3 C~f 02R
6th stage:
hydrolysis ~ OOH
CI
S However, all the known processes have the disad-
vantage that the target compound is prepared via many
intermediate stages.
Moreover, elaborate separation and drying opera-
tions must be carried out.
The washing procedures which become necessary
thereby mean that large amounts of solvents must be in-
cinerated or reprocessed.
It is necessary to apply elaborate analytical meth-
ods for the characterization of the intermediate stages.
The invention relates to a process for the pre-
paration of quinolonecarboxylic acids of the general for-
mula I
X~OOH ( I )
R
in ~hich
Z0 R1 represents propyl, cyclopropyl, isopropyl
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or vinyl,
x1 denotes fluorine, chlorine, Br, CN, N02 or
hydrogen, and
X2, X3 and X4 represent fluorine, chlorine, N02
S or hydrogen,
which is characterized in that a compound of the formula
II
X~OCl (II)
X 1
in which
x1 to X4 have the abovementioned meaning, and
XS represents halogen, in particular chlorine
or fluorine,
is reacted, without isolation of intermediate stages in
a so-called one-pot reaction, with a compound of the for-
mula (III)
IlH-cooR2
CH-tJR3R3 (III)
in which
R2 and R3 are identical or different and rep-
resent C1-C4-alkyl,
in the presence of a solvent and of a base, where approp-
riate heating to SûC to 150C, to give the compounds
of the formula IV
X~ O O
1 li 11
X3~:-C-C-OR2 ( I V )
5CHNR3R3
X
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these compounds IV are subjected to an amine exchange at
temperatures of 50C to 120C in the presence of the
abovementioned solvents and in the presence of an amine
of the formula R1NH2 in which R1 has the abovementioned
meaning, resulting in the compounds of the formula
X~C_C_oR2 ( V )
X2 Xl CH-NH-Rl
having the abovementioned radical meanings, and sub-
sequently the compounds V are cyclized and hydrolysed at
temperatures between 80C and 180C in the presence of a
base, and the compounds of the formula I are precipitated
by addition of acid.
The compounds which are prepared according to the
invention, in particular, are those in which R1 in formula
I represents a cyclopropyl radical.5 Preferably: X1 and X4 = hydrogen,
x2 = chlorine and
X3 = fluorine.
Additionally preferred compounds of the formula
I are those in which R1 denotes cyclopropyl, x2 repre-
sents chlorine, and X1 and X3 denote fluorine, while X4
represents hydrogen.
Compounds which are furthermore preferred are
those in which X3 represents fluorine, and X1 and x2
represent chlorine, while X4 denotes hydrogen.
Given the complicated course of the reaction, it
has to be designated extremely surprising that the com-
pound 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-
3-quinoline-carboxylic acid can be prepared without iso-
lation of intermediates in a "one-pot" reaction in excel-
lent yields by the following route:
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a) acylation
C ~ OCl CH-COOR2
tert. org. BASE~ ~COOR2
inert org. solvent l CH-NR3R3
Suitable org. solvents are:
toluene,
xylene,
cyclohexane,
open-chain hydrocarbons (mixtures),
DMF, and
DMS0.
Bases which can be used are:
tert. org. amines such as
R3N with R = C1-C4-alkyl, benzyl, cycl. amines
R-N N-R
r--~ R
O~__~N-R
pyridine, etc., with R = C1-C4-alkyl.
The temperatures for the acylation of the dimethyl-
am;noacrylic ester are between 50C and 150C, preferably
at 80C to 120C.
Hydrochloride, which precipitates out during the
reaction, of the auxiliary base can be separated out via
a filter or be removed by extraction by stirring with
water.
The org. phase with the aroylacrylic ester is fur-
ther reacted with cyclopropylamine.
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This reaction can be carried out in the same sol-
vent or, after evaporation (in vacuo or under atmospheric
pressure), in another solvent.
b)amine exchange:
1l~ ~COOR2
C ~ ll ¦>~H2
Cl CH-N(CH3 )2
1l
~ C~ ~COOR
C ~ Cl CH-N
Suitable solvents are:
toluene,
xylene,
cyclohexane,
open-chain hydrocarbons (mixtures),
alcohols,
DMF,
DMS0 and
butylglycol.
The temperatures for the amine exchange are at
50C to 120C, preferably at 65C to 85C.
The reaction mixture is maintained further at the
elevated temperature until the evolution of gas (dimethyl-
amine) ceases.
If the amine exchange is carried out in a low-
boiling diluent such as, for example, cyclohexane, the
solvent is evaporated off before the cyclization (in vacuo
or under atmospheric pressure) and replaced by a higher-
boiling diluent such as, for example, butylglycol.
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c) cyclization:
F~C~ ~COOR
C~ CH Nl~a o
~ OOR
Suitable solvents are:
higher alcohols such as
butylglycol i-propyl alcohol,
ethylene glycol butanol,
triethylene glycol,
polyethylene glycol,
amino alcohols such as diethylaminoethanol,
DMF,
DMS0,
dioxane and
N-methylpyrrolidone.
The cyclization to give the quinolone system is
carried out at temperatures bet~een 80C and 180C, pre-
ferably at 130C to 160C, in the presence of a base.
~ases which can be used are:
Na tert.-butylate,
NaH and
K2C03 .
The base is used in an equimolar amount or up to
an excess of 3 ~ole-equ;valents, preferably in an excess
of 0.1 to 0.5 mole-equivalents.
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d) hydrolysis and precipitation
O . O
2R ~OOH
For the hydrolysis, the reaction mixture is cooled
to about 100C, and water is added.
Owing to the excess of base in the cyclization,
the hydrolysis is complete within a short time at tempera-
tures of 50C to 100C.
The quinolone carboxylic acid is precipitated by ad-
dition of a mineral acid or an org. acid and is isolated.
Suitable and preferred acids are:
sulphuric acid,
hydrochloric acid and
acetic acid.
Example 1
28.8 9 of ethyl N,N-dimethylamino-acrylate and
26 9 of N,N-dimethylbenzylamine in 71 ml of toluene are
heated to 90C and, at this temperature, 40 9 of 2,4-di-
chloro-5-fluorobenzoyl chloride are added dropwise in 60
min.
The mixture is then stirred for 15 min, and the
precipitated N,N-dimethylbenzylamine hydrochloride is
separated off through a suction filter funnel.
The filtrate is substantially evaporated in vacuo,
and 80 ml of butylglycol are added to the residue.
13 9 of cyclopropylam;ne are added dropwise at
70-75C in 30 min and, after addition is complete, the
mixture is maintained at 100C for 1 hour until the evo-
lution of gas ceases.
27.9 9 of potassium carbonate and 100 ml of butyl-
glycol are added to the reaction mixture, which is thenLe A 25 272
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slowly heated to 135-145C.
During this, about 40 ml of low-boiling constitu-
ents distil out.
The temperature is maintained for 1.5 h.
It is then cooled to 100-120C, and 130 ml of
water are added to the reaction mixture.
The mixture is stirred at 90C for 15 min and,
at this temperature, 27 ml of acetic acid are added drop-
wise in 15 min. The contents of the flask are cooled,
and the solid is separated off through a suction filter
funnel.
The product is washed with 27 ml of water and 5û ml
of methanol, sucked thoroughly dry and dried at 70C in
vacuo for 24 h.
Yield: 37 9 = 74.9% of theory.
Example 2
43.2 9 of ethyl N,N-dimethylamino-acrylate in
84 mL of toluene are heated to 100C, and 40 ml of tri-
ethylamine are added.
At the reflux temperature, 60 9 of 2,4-dichloro-5-
fluorobenzoyl chloride are added dropwise in 30 min, and
then the precipitated triethylamine hydrochloride is
separated off through a suction filter funnel.
After washing with 65 ml of toluene, 16.2 9 of
cyclopropylamine are added dropwise to the filtrate at
70C in Z0 min.
The mixture is heated at 100C until evolution of
gas ceases.
Then 42 9 of potassium carbonate and 270 ml of
butylglycol are added, and the mixture is slowly heated
to 135-145C. During this, about 180 ml of toluene and
low-boiling constituents distil out.
135-145C are maintained for 1.5 h and, after
the reaction mixture has been cooled to 100C, 200 ml of
water are added.
After 15 min, 40.5 ml of acetic acid are added
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dropwise at 90C, and the precipitated solid is fil-
tered off with suction through a suction filter funnel.
The product is then washed with 140 ml of water
and 75 ml of methanol, thoroughly sucked dry and dried
S at 70C in vacuo for 24 h.
Yield: 58.5 9 = 79X of theory.
Example 3
44.7 9 of ethyl N,N-dimethylaminoacrylate and
17.1 9 of N,N~-dimethylpiperazine in 95 ml of cyclohexane
are heated to reflux.
62 9 of 2,4-dichloro-5-fluoro-benzoyl chloride
are added dropwise in 1 h.
The precipitated dimethylbenzylamine hydrochloride
is separated off through a suction filter funnel, and the
filtrate is evaporated to dryness in vacuo.
The residue is dissolved in 125 ml of butylglycol
and, at 90C, 20.2 9 of cyclopropylamine are added drop-
wise to the solution.
After the evolution of gas ceases, 43.4 9 of pot-
Z0 assium carbonate and 165 ml of butylglycol are added, andthe mixture is heated at 145C for 1.5 h. Initially
during this small amounts of low-boiling constituents dis-
til out.
After 1.5 h, the mixture is cooled to 100C, 205 ml
of water are added, and the mixture is then stirred at
95C for 15 min.
Then 42 9 of acetic acid are added dropwise in
15 min, the temperature is reduced to 30C, and the pre-
cipitated solid is separated off on a suction filter fun-
nel.
The filter cake is washed with 180 ml of waterand 80 ml of 80~ strength ;sopropanol and is dried at 70C
in vacuo overnight.
Yield: 60.1 9 = 78.1Z of theory.
Example 4
33.7 9 of methyl N,N-dimethylamino-acrylate are
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heated with 40 5 9 of N,N-dimethylbenzylamine in 95 ml of toluene
at 110C.
At the reflux temperature, 62 9 of 2,4-dichloro-5-
fluorobenzoyl chloride are added dropwise in 1 h, and then
S the precipitated dimethylbenzylamine hydrochloride is re-
moved through a suction filter funnel.
The solvent is distilled off in vacuo, 130 ml of
butylglycol are added and, at 90C, 20.2 9 of cyclopropyl-
amine are added dropwise in 20 min.
After the evolution of gas ceases, 43.4 9 of
potassium carbonate and 150 ml of butylglycol are added
to the reaction mixture which is then slowly heated to
140C. During this, small amounts of low-boiling solvent
distil out.
The mixture is then stirred at 140C for 1.5 h.
After cooling to 100C, 205 ml of water are added to the
reaction mixture and it is then stirred at 90C for 15
min.
While cooling slightly, 100 ml of 30% strength
sulphuric acid are added, and the solid is filtered off
with suction on a suction filter funnel and is washed with
200 ml of uater and 200 ml of isopropanol.
The solid is dried in vacuo at 70C overnight.
Yield: 59.4 9 = 77.2X of theory.
Example 5
55.6 9 of tributylamine are added to 44.7 9 of
ethyl N,N-dimethylamino-acrylate in 95 ml of cyclohexane
and, at 85-95C, 62 9 of 2,4-dichloro-5-fluorobenzoyl
chloride are added dropwise in 1 h.
Then 250 ml of water are added to the reaction
mixture, and the aqueous salt phase is separated off.
The aqueous phase is extracted 1 x more by stir-
ring with 50 ml of cyclohexane, and the combined org.
phases are evaporated to dryness under water pump vacuum.
The residue is taken up in 125 ml of butylglycol,
and the mixture is heated to 70C and 20.2 9 of
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cyclopropylamine are added dropwise in 15 min.
After the evolution of gas ceases, a further 160 ml
of butylglycol and 44 9 of potassium carbonate are added,
and the mixture is slowly heated to 140C.
After the mixture has reached 140C, it is stirred
for 1.5 h and then cooled to 100C, and 205 ml of water
are added.
After 15 min, 42 9 of acetic acid are added drop-
wise in 10 min, and the mixture is cooled to room tempera-
ture.
The precipitate is isolated through a suction fil-
ter funnel and is washed ~ith water and isopropanol.
The yield obtained after drying at 50C in vacuo
overnight is 54.6 9 = 71% of theory.
Example 6
105 9 of tributylamine and 86 9 of methyl N,N-
dimethylamino-acrylate in 148 ml of toluene are heated to
105C, and 124 9 of 2,4-dichloro-S-fluoro-benzoyl chlor-
ide are added dropwise in 1 h.
After the reaction mixture has been cooled to 50C,
it is extracted 2 x with 250 ml of water each time.
The organic phase is substantially concentrated
under water pump vacuum, and 37.5 9 of cyclopropylamine
are added dropwise to the residue at an internal tempera-
ture of 70-75C. This results in gaseous dimethylamine
escaping until the reaction is complete.
86.8 9 of potassium carbonate and 500 ml of butyl-
glycol are added to the reaction mixture which is then
slowly heated to 135 - 145C. During this, small amounts
of low-boiling solvents distil out.
135 - 145C are maintained for 1.5 h, and then
the mixture is cooled to 100C, and 535 ml of a 10% strength
acetic acid are added dropwise.
The resulting suspension is cooled to room tem-
perature, and the sol;d is separated off through a suctionfilter funnel and washed with 175 ml of water and 200 ml
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of 80X strength isopropanol.
The product is dried in vacuo at 70C overnight.
Yield: 220 9 = 78.1% of theory.
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