Title of Invention

"NOVEL METHOD OF PREPARING 3- FLUORINATED QUINOLINES"

Abstract The invention relates to a novel method of preparing 3-fluorinated quinolines having formula (I) The invention is characterised in that a compound having general formula (IV) is subjected to Hofmann degradation in order to produce a compound having general formula (III), which is treated in conditions such as to form the diazonium salt having general formula (II), which is in turn heated in an inert organic solvent.
Full Text The invention relates to a novel process for preparing 3-fluoroquinolines of general formula (I):
(Formula Removed)
wherein,
R1, R2, R3 and R4, which may be identical or different, represent:
- a hydrogen atom;
- a fluorine atom;
- a linear, branched or cyclic alkyl radical optionally substituted with one to three fluorine atoms, with a group OR5 in which R5 represents a linear or branched alkyl radical, a hydrogen atom or a hydroxyl radical- protecting group, or with a group NR' R" in which R' and R", which may identical or different, represent a linear or branched alkyl radical, a hydrogen atom or an amino radical-protecting group;
- a group OR6 in which R6 represents a hydrogen atom, a phenol-protecting group or a linear or branched alkyl radical optionally substituted with one to three fluorine atoms, with OR5 or with NR' R" as defined above;

- a group NR' R" in which R' 1 and R"1 have the values of R' and R" or represent a linear or branched alkyl radical substituted with one to three fluorine atoms, with a group OR5 as defined above or with a group NR' R" as defined above;
- a group CO2Ra, in which Ra represents a hydrogen atom,
a linear or branched alkyl radical or a carboxyl radical-protecting group;
- a phenyl radical or a heteroaryl radical, optionally substituted with one or more of the substituents
mentioned above.
In the general formula above, it is understood that the
alkyl radicals contain 1 to 10 carbon atoms in a linear or
branched chain and that the cycloalkyl radicals contain 3 to
6 carbon atoms.
When the compounds bear a heteroaryl substituent, the
latter contains 5 to 10 ring members and may be monocyclic or
bicyclic and chosen (in a nonlimiting manner), from thienyl,
furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,
thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrazinyl, pyrimidinyl, indolyl, benzothienyl, benzofuranyl,
indazolyl, benzothiazolyl, naphthyridinyl, quinolyl,
isoquinolyl, cinnolyl, quinazolyl, quinoxalyl, benzoxazolyl
and benzimidazolyl, which may be optionally substituted withthe substituents stated above.
According to the invention, the products of general
formula (I) are obtained by a process wherein a compound of
general formula (IV)
(Figure Removed)
in which RI, R2, R3 and R4 are as defined hereinabove, is
subjected to a Hofmann degradation, so as to obtain a
compound of general formula (III)
(Figure Removed)
in which Rlf R2, R3 and R4 are as defined hereinabove, which is
treated under conditions capable of forming the diazonium
salt of general formula (II)
(Figure Removed)
in which RI, R2, RS and R4 are as defined hereinabove, which is
heated in an inert organic solvent to a temperature of
between 35 and 120°C.
The Hofmann degradation is carried out with bromine and
sodium hydroxide, and also pyridine, in water, at a
temperature of approximately 60°C.
The conditions for preparing the diazonium salt consist,
for example, in carrying out the process in the presence of
an alkali metal salt or of an ester of nitrous acid, in
particular of sodium nitrite or of potassium nitrite or of
tert-butyl or isobutyl nitrite, and of fluoroboric acid, or
in the presence of boron trifluoride-ethyl ether complex, in
an appropriate solvent, in particular THF, water or an
alcohol, at a temperature between +15 and +20°C.
In order to convert the compound of formula (II) to a
compound of formula (I), the process is preferably carried
out in a solvent such as toluene, xylene, heptane, hexane, a
fluorinated solvent such as perfluorohexane, or else a
chlorinated solvent such as mono- or dichlorobenzene,
chlorobutane or methylene chloride.
The heating temperature is preferably between 60 and
100°C and depends, of course, on the solvent used.
A subject of the invention is also a process according
to the above, wherein the compound of general formula (IV) is
obtained by subjecting a compound of formula (V)
(Figure Removed)
in which Rl7 R2, R3 and R4 are as defined hereinabove, X
represents a chlorine atom or a bromine atom and alk
represents an alkyl radical containing from 1 to 6 carbon
atoms, to the action of a hydrogenolysis agent, and then to
that of aqueous ammonia, so as to obtain successively the
compound of formula (VI)
(Figure Removed)
which may or may not be isolated, and then the compound of
formula (IV).
According to the invention, the two reactions above may
be carried out in the reverse order, the compound
intermediately formed, and which may or may not be isolated,
then being the compound of formula (VII)
(Figure Removed)
The hydrogenolysis reaction is carried out in an
alcohol, in particular ethanol or methanol, in the presence
of triethylamine and of a catalyst such as palladium-oncharcoal,
by sparging hydrogen into the reaction medium.
It is also possible to carry out the process in
dimethylformamide, in the presence of sodium formate and of
tetrakis(triphenylphosphine)palladium.
A subject of the invention is also a process according
to the above, wherein the compound of formula (V) is obtained
by subjecting a compound of formula (VIII)
(Figure Removed)
in which R!, R2, R3 and R4 and alk are as defined hereinabove,
to the action of phosphorus oxychloride or phosphorus
oxybromide.
The, process is preferably carried out without a solvent,
at a temperature in the order of about 100°C.
A subject of the invention is also a process according
to the above, wherein the compound of formula (IV) is
obtained by treating a compound of formula (VIII), as defined
above, with a base, so as to obtain a corresponding acid of
formula (IX)
(Figure Removed)
in which Rx, R2, RS and R4 are as defined hereinabove, which is
subjected to the action of phosphorus oxychloride or of
phosphorus oxybromide, so as to obtain a compound of formula
(Figure Removed)
in which RI, R2/ RS, R4 and X are as defined hereinabove, which
is subjected to the action of ammonia so as to obtain a
compound of formula (VII) as defined above, which is
subjected to the action of a hydrogenolysis agent.
The saponification reaction is carried out under
conventional conditions known to those skilled in the art, in
particular by the action of sodium hydroxide or potassium
hydroxide in aqueous medium at reflux temperature.
The action of the phosphorus oxychloride or the
phosphorus oxybromide is preferably carried out at the reflux
temperature thereof, without solvent.
The hydrogenolysis agent is one of those which were
mentioned above.
A subject of the invention is also a process according
to the above, wherein the compound of formula (IV) is
obtained by heating a compound of formula (XI)
(Figure Removed)
in which Rl7 R2, RS, R4 and alk are as defined hereinabove, in
the presence of phosphorus pentoxide, so as to obtain a
compound of formula (IX) as defined above, and then pursuing
the synthesis as described above.
The reaction of the phosphorus pentoxide with the
compound of formula (XI) is preferably carried out in a
solvent such as nitrobenzene at a temperature in the order of
about 120-130°C.
The compound of formula (V) may also be obtained by
subjecting a compound of formula (XI) as defined above to the
action of phosphorus oxychloride or of phosphorus oxybromide.
The process is preferably carried out without solvent,
at a temperature in the order of about 100°C, starting with a
compound of formula (XI) in which the sensitive groups on R1;
R2, R3 and R4 are pre-protected.
The compound of formula (VIII) may be obtained by
heating a compound of formula (XI) as defined above, in a
solvent with a high boiling point.
The cyclization of the compound of formula (XI) is
preferably carried out in diphenyl ether, at reflux
temperature or at a temperature similar to the reflux of the
latter.
The compound of general formula (XI) is obtained by
reacting a compound of general formula (XII)
in which Rx, R2/ R3 and R4 are as defined hereinabove, with
compound of general formula (XIII)
(Figure Removed)
in which alk is as defined hereinabove and alkx represents a
linear or branched alkyl radical which may be. identical or
different to alk.
Under preferential conditions, the reaction is carried
out without the addition of a solvent, by heating to a
temperature of from about 80 to about 120°C.
According to the definitions of RI, R2/ R3 and R4, it may
be desirable, or even necessary, depending on the type of
reaction involved, to use compounds in which the substituents
are protected. These are in particular the alkyl
substituents substituted with OR5 or with NR'R", OR6, NRR'
and GO2Ra-
A subject of the invention is in particular a process as
defined above, wherein use is made of compounds in which the
possible sensitive substituents are protected, during the
preparation of the compounds of formula (X) from the
compounds of formula (IX) and also during the Hofmann
degradation producing the compounds of formula (III) from the
compounds of formula (IV). According to the invention, the
compounds involved are either protected from the beginning of
synthesis or just before the critical step is carried out.
The protective groups which may be used and also the use
thereof are known to those skilled in the art and described,
for example, by T.W. Greene and P.G.M. Nuts, "Protective
Groups in Organic Synthesis" (John Wiley & Sons, inc.).
A subject of the invention is in particular a process
according to the above, wherein use is made of compounds in
which RI, R2, Ra and R4, which may be identical or different,
represent a hydrogen atom, a fluorine atom, an optionally
substituted linear or branched alkyl radical as defined
above, or a radical ORe as defined above.
The subject of the invention is more particularly a
process wherein use is made of compounds in which Rl7 R2, RS
and R4, which may be identical or different, represent a
hydrogen atom, a fluorine atom or a radical OR6 as defined
above, and in particular an alkoxy radical.
Finally, a subject of the invention is a compound of
formula (II) as defined above.
The compounds of formula (I) are intermediate compounds
useful in particular in the preparation of compounds having
antibacterial activity, described, for example, in
applications WO 02/72572 and WO 02/40474.
The following examples illustrate the invention without,
however, limiting it.
Example 1: Preparation of 3 -f luoro-6-tnethoxyquinoline
A suspension of 1007 g of 6-methoxy-3-quinolinediazonium
fluoroborate taken in 9 1 of toluene is heated to 60°C in
85 minutes. A release of gas is observed at 60°C. The
reaction medium is then gradually heated further for 90
minutes to 70-72°C. After having been kept at 72°C for 90
minutes, the medium is then gradually heated again to 85°C.
After cooling and stirring overnight, 4 1 of ice-cold water
are added to the suspension. After having stirred for 15
minutes, 2.5 1 of ethyl acetate are added. After having
stirred for 45 minutes, the pH is adjusted to pH = 7-7.5 by
adding 47% sodium hydroxide (250 ml). The medium is stirred
for 30 minutes and then separated by settling out for 1 hour.
The lower aqueous phase is re-extracted with ethyl acetate.
The organic phases are combined together and washed with
water. The solution is filtered and then concentrated under
reduced pressure so as to give 655 g of crude 3-fluoro-
6-methoxyquinoline. The crude product is distilled under
reduced pressure. The distillation fractions (bp 103-110°C
under 1 mbar) containing the expected product are combined
together. 498.9 g of 3-fluoro-6-methoxyquinoline (76%) are
thus obtained in the form of a white solid which melts at
51-53°C.
Microanalysis: Ci0H8FNO calculated C 67.79; H 4.55; F 10.72;
N 7.91; O 9.03 found C 67.98; H 4.54; N 7.97
NMR spectrum: -H (300 MHz, (CD3)2SO d6, d in ppm) : 3.92 (s:
3H); 7.40 (mt: 2H); 7.97 (d, J = 10 Hz: 1H); 8.13 (dd, J =
and 3 Hz: 1H); 8.76 (d, J = 3 Hz: 1H).
Mass spectrum:
m = 177
El m/z = 177 M*' base peak
m/z = 134 [M - COCH3]+-
DCI m/z = 178 MH+ base peak
3-Diazoniumfluoroborate-6-methoxyquinoline:
3-Amino-6-methoxyquinoline (10 g) are suspended in 50 ml of
THF and stirred for 15 minutes at 20°C, before being cooled
to -15°C. 11.6 g of BF3-etherate are then added. The
temperature of the reaction mass is brought to -15°C. After
15 minutes at this temperature, 7.5 g of tert-butyl nitrite
at 90% in solution in 25 ml of THF are added over 10 minutes.
The suspension is stirred for 1 hour at -15°C, before being
brought to +15°C over a period of one hour. The precipitate
is filtered off, washed with hexane and then dried at 15-20°C
under constant pressure until a constant weight is obtained.
14.8 g (94.3%) of 3-diazoniumfluoroborate-6-methoxyquinoline
are obtained in the form of a yellow solid.
Decomposition temperature: 82°C
3-Amino-6-methoxyquinoline:
104 kg of a 32% sodium hydroxide solution are added to 341 kg
of water. The solution is cooled to 0°C and 22.0 kg of
bromine are introduced over 1.5 hours while maintaining the
temperature at 0°C. The solution is stirred at this
temperature for 1 hour, and then 409 kg of pyridine are
introduced over 3 hours at 0°C. 26.5 kg of 6-methoxyquinoline
-3 -carboxamide are then added over 50 minutes at
0°C. The reaction medium is kept at this temperature for
2 hours and then gradually heated to 60°C over 1 hour. After
maintaining the temperature at 60°C for 6 hours, the reaction
mass is cooled to 20°C and separated by settling out. The
aqueous phase (172 kg) is washed with pyridine (60 liters).
The organic phases are pooled (820 kg) and concentrated
dryness under reduced pressure (100-150 mbar) at a maximum of
84°C. The residue is then taken up with 425 1 of water
43 1 of ethanol. The suspension obtained is refluxed for
1 hour and then cooled. The product begins to precipitate
a temperature of 65°C. The medium is then cooled to 0-5°C,
and kept at this temperature for 2 hours. The precipitate is
filtered off, washed with cold water, and then dried at
50-55°C under reduced pressure. 16.5 kg (72.3%) of 3-amino-
6-methoxyquinoline are obtained in the form of a brown solid
(HPLC titer = 99.1%), having a melting point of 108-110°C.
A second crop of 3.7 kg (13.1%) is obtained from the mother
liquors (HPLC titer = 98%).
NMR__spectrum: ^E (300 MHz, (CD3)2SO d6, 8 in ppm) : 3.84 (s:
3H); 5.65 (s: 2H); 6.97 (dd, J = 9 and 3 Hz: 1H); 7.01 (d, J
= 3 Hz: 1H); 7.08 (d, J = 2.5 Hz: 1H); 7.67 (d, J = 9 Hz:
1H); 8.29 (d, J = 2.5 Hz: 1H).
12
IR spectrum: (KBr)
3454; 3312; 3204; 1630; 1619; 1607; 1504; 1383; 1251; 1239;
1216; 1167; 1027; 872; 827; 627 and 479 cm"1
Mass spectrum: m = 174
El m/z = 174 (M"1") - base peak m/z = 131 [M - COCH3]+.
6-Methoxyquinoline-3-carboxamide:
380 1 of ethanol are added to 49.2 kg of 4-chloro-3-ethoxycarbonyl-
6-methoxyquinoline. The suspension is heated at
45°C for 30 minutes and then cooled to 20°C. 18.65 kg of
triethylamine are added under nitrogen, followed by 1.91 kg
of palladium-on-charcoal at 5% (at 60% water content). A
stream of hydrogen is passed through under 0.5-0.8 bar at
33°C for 48 hours. At this time, an HPLC1 control shows that
the reaction is complete. The reactor is then vented with
nitrogen and the reaction medium is then filtered to remove
the catalyst. The filter is then rinsed with ethanol. The
filtrate is poured over 750 kg of an aqueous ammonia
solution. The reaction medium is then stirred at 25°C over a
period of 4 days. The ethanol is then removed by
distillation under reduced pressure at a temperature not
exceeding 40-45°C. The suspension thus obtained is cooled to
0-5°C and stirred for 3 hours at this temperature. The
precipitate is filtered off, washed with cold water, and then
dried at 60-65°C under reduced pressure until a constant
weight is obtained. 26.5 kg (71%) of 6-methoxyquinoline-3-
carboxamide are obtained in the form of a white solid which
melts at 93.7-95.7°C (HPLC%NIS= 98.3%).
NMR spectrum: iH (300 MHz, (CD3)2SO d6, 5 in ppm) : 3.94 (s:
3H) ; 7.45 (d, J = 3 Hz: 1H) ; 7.52 (dd, J = 9 and 3 Hz: 1H) ;
7.67 (broad s: 1H) ; 8.00 (d, J = 9 Hz: 1H) ; 8.29 (broad s:
1H); 8.74 (d, J = 2 Hz: 1H); 9.15 (d, J = 2 Hz: 1H).
IR spectrum: (KBr)
3408; -33-30; 3211; 1697; 1626; 1511; 1386; 1321; 1240; 1023-;
935; 826 and 693 cm"1
Mass spectrum: m = 202
El m/z = 202 [M+] - base peak
m/z = 186 [M -NH2] +
m/z = 158 [186 - CO]+
4 -Chioro-3 -ethoxycarbonyl-6-methoxyquinoline:
132 g of phosphoryl chloride are added, at 25°C, to 50 g
diethyl 2-[(4-methoxyphenylamino)methylene]malonate. The
reaction medium is stirred for 15 minutes at this
temperature, heated to 95-100°C over 45 minutes, and then
kept at this temperature for 4 hours. The excess phosphoryl
chloride is then removed by heating at 125°C for
approximately 2 hours. The mixture is then cooled to 25°C
and 125 ml of dichloromethane are added. The medium is then
stirred at 25°C for 1 hour, and then run into 900 ml of
water, over 30 minutes, while maintaining the temperature
below.30°G. The pH is then adjusted, to 7.5-8 by adding 172 g
of. a 47% -• sodium hydroxide solution, while maintaining the
temperature at 20-25°C. The 2 phases are sepa'rated and the
aqueous phase is extracted with dichloromethane. The organic
phases are pooled and washed with water. The dichloromethane
phase is half-concentrated and 190 ml of ethanol are added.
The concentration is continued until the temperature of the
reaction mass reaches 82°C and the vapor temperature reaches
78°C. The reaction mass is cooled to 0-5°C and then kept at
this temperature for 2 hours. The precipitate is filtered
off, washed with cold ethanol, and then dried at 50°C under
reduced pressure. 27.7 g (61%) of 4-chloro-3-ethoxycarbonyl-
6-methoxyguinoline are obtained in the form of a yellow solid
which melts at 93.7-95.7°C.
Titer (HPLC): 98.0%
Diethyl 2-[(4-methoxyphenylamino)methylene]malonate:
3.5 kg of p-anisidine are added to 6.25 kg of diethyl
ethoxymethylenemalonate at 14°C, over 85 minutes without
cooling of the reaction mass. At the end of addition, the
temperature has reached 59°C. The temperature is kept at
14
59°C for 30 minutes, and the reaction medium is then heated
to 90-95°C and kept at this temperature for 1 hour. The
ethanol formed is then removed by distillation at atmospheric
pressure and then under 250 mbar. After cooling to 45 °C,
8.4 kg of diethyl 2-[(4-methoxyphenylamino)methylenejmalonate
are recovered in the form of a brown viscous oil, with a
quantitative yield.
Titer (HPLC): 98.3%
References:
I/ Description of the analytical conditions:
Method: HPLC
Column: Hichrom 100 RP18 5jj. (250 x 4.6 mm)
Flow rate: 1 ml/min
Wavelength: 210 nm
Injection volume: 20 |ul
Eluent: 400 ml acetonitrile
600 ml 0.01M sodium dihydrogen phosphate
(pH 2.3)
2.88 g/1 sodium dodecyl sulfate.
Injection: 20 jal of 0.1 mg/ml solution.
Retention time:
p-anisidine 12.16 min
2-[(4-methoxyphenylamino)methylene]malonic
acid diethyl ester 25.0 min
3-ethoxycarbonyl-6-methoxy-4(1H)-quinolinone 4.15 min
4-chloro-6-methoxyquinoline-3-ethyl carboxylate 24.1 min
6-methoxyquinoline-3-ethyl carboxylate 16.5 min
6-methoxyquinoline-3-carboxamide 6.0 min
3-amino-6-methoxyquinoline 16.2 min
3-fluoro-6-methoxyquincline 10.0 min
Example 2: 3,7-Difluoro-6-methoxyquinoline
6.1 g of 3-amino-7-fluoro-6-methoxyquinoline are added, with
stirring at a temperature in the region of -5°C, to an
aqueous 40% fluoroboric acid solution, and a solution of
2.6 g of sodium nitrite in 5.2 cm3 of water is then added over
20 minutes. The reaction mixture is stirred at a temperature
in the region of +3°C for 40 minutes, and then filtered. The
solid is washed with an aqueous 40% fluoroboric acid solution
at -5°C, then with a mixture of isopropanol and of an aqueous
40% fluoroboric acid solution at -5°C, and then with ethyl
ether, spin-filtered to dryness and dried under reduced
pressure. 9.95 g of a solid are thus obtained, which are
dissolved in 80 cm3 of anhydrous toluene, and this solution is
brought to 92°C for 1 hour with vigorous stirring. After
cooling to ambient temperature, 50 cm3 of toluene are added,
followed by 80 cm3 of a saturated aqueous solution of sodium
hydrogen carbonate. The reaction medium is separated bysettling
out, the aqueous phase is extracted with toluene,
and the organic phases are pooled, washed with a saturated
aqueous solution of sodium chloride, and then dried oversodium
sulfate. After filtration and then evaporation to
dryness under reduced pressure of the toluene, the residue is
chromatographed on a silica column (100 g, particle size
20-46 /*m, eluent: dichloromethane). The fractions containing
the expected product are evaporated to dryness under reduced
pressure. 2.28 g of 3,7-difluoro-6-methoxyquinoline are
obtained, in the form of a white solid which melts at 98°C.
3-Amino-7-fluoro-6-methoxyquinoline:
2.4 cm3 of bromine are added dropwise, over 30 minutes, to solution of 133 cm3 of aqueous 2N sodium hydroxide solution
cooled to 0°C, followed by 111 cm3 of pyridine. 10.1 g of
7-fluoro-6-methoxyquinoline-3-carboxamide are then added to
this solution, still at 0°C, and the mixture is stirred at
0°C for 2 hours 30 min. The reaction medium is then allowed
to warm back up to ambient temperature, and is then heated
with stirring--to 60°C for 18 h. It is then allowed to cool
down again to ambient temperature, and 100 cm3 of water,
16
followed by 100 cm3 of ethyl acetate, are then added. The
reaction medium is separated by settling out, the aqueous
phase is extracted with ethyl acetate, and the aqueous phases
are pooled, washed with water and then dried over sodium
sulfate and evaporated to dryness under reduced pressure.
8.25 g of a solid residue are obtained, which residue is
triturated in 150 cm3 of isopropyl ether and filtered. The
solid is washed with isopropyl ether and then with pentane.
After drying, 6.20 g of 3-amino-7-fluoro-6-methoxyquinoline
are obtained, in the form of a light brown solid which melts
at 153°C.
7-Fluoro-6-methoxyquinoline-3-carboxamide:
5.58 g of sodium formate and 3.16 g of tetrakis-
(triphenylphosphine)palladium are added to a solution of
13.9 g of 4-chloro-7-fluoro-6-methoxyquinoline-3-carboxamide
in 278 cm3 of dimethylformamide, and this solution is heated
under an argon atmosphere at 100°C for 5 hours. After
cooling to ambient temperature, the reaction medium is
filtered. The filtrate is concentrated under reduced
pressure so as to obtain 200 cm3 of a solution, to which 600
cm3 of water are added. The precipitate formed is filtered
off, washed with water and then dried at 50°C under reduced
pressure. The solid obtained is washed with toluene, then
twice with ethyl ether, and then with pentane. 10.7 g of
fluoro-6-methoxyquinoline-3-carboxamide are obtained, in the
form of a beige solid which melts at 231°C.
4-Chloro-7-fluoro-6-methoxyquinoline-3-carboxamide:
A stirred solution of 15.83 g of 7-fluoro-4-hydroxy-6-
methoxyquinoline-3-carboxylic acid in 40 cm3 of phosphoryl
chloride is brought to 100°C for 3 hours. After cooling
ambient temperature, the reaction medium is distilled under
atmospheric pressure in order to remove the phosphoryl
chloride. The residue is dissolved in 70 cm3 of
dichloromethane, and then ammonia is sparged into this
solution-, -which is kept at ~2-3°C -with stirring for 5 hours.
The reaction medium is then filtered, and the solid obtained
is washed with dichloromethane and then dried at 50°C under
reduced pressure. 14.05 g of 4-chloro-7-fluoro-6-methoxyquinoline-
3-carboxamide are obtained, in the form of an offwhite
solid which melts at 228°C.
7-Fluoro-4-hydroxy-6-methoxyquinoline-3 -carboxylic acid:
A stirred solution of 23.57 g of ethyl 7-fluoro-4-hydroxy-6-
methoxyquinoline-3-carboxylate in 71 cm3 of an aqueous 5N
sodium hydroxide solution is brought to 100°C for 3 hours.
After cooling to ambient temperature, the reaction medium is
acidified by adding 32.5 cm3 of an aqueous 37% hydrochloric
acid solution. After addition of 150 cm3 of water, the
precipitate obtained is filtered off and the solid is washed
with water. After drying in the -open air, 22 g of 7-fluoro-
4-hydroxy-6-methoxyquinoline-3-carboxylic acid are obtained,
in the form of a cream solid which melts at 275°C.
Ethyl 7-fluoro-4-hydroxy-6-methoxyquinoline-3-carboxylate:
A stirred solution of 37.75 g of diethyl 2-[(3-fluoro-4-
methoxyphenylamino)methylene]malonate in 170 cm3 of diphenyl
ether is brought to 245°C for 3.5 hours. After cooling to
ambient temperature, 220 cm3 of cyclohexane are added, and the
precipitate thus obtained is filtered off and washed with
cyclohexane and then with pentane and is spin-filtered to
dryness. 24.10 g of ethyl 7-fluoro-4-hydroxy-6-methoxyquinoline-
3 -carboxylate are obtained, in the form of a solid
which melts at 280°C.
Diethyl 2-[(3-fluoro-4-methoxyphenylamino)methylene]malonate:
A stirred mixture of 15.61 g of 3-fluoro-4-methoxyaniline and
of 24.25 g of diethyl ethoxymethylenemalonate is brought to
100°C for 2.5 hours. After cooling to ambient temperature
and then evaporation to dryness at 50°C under reduced
pressure, 35 g of diethyl 2- [ (3-fluoro-4-
methoxyphenylamino)methylene]malonate are obtained, in the
-form-of a beige solid which melts at- 63°C. - - - - • ..
Example 3: 3,8-Difluoro-6-methoxyquinoline
By carrying out the process as described in Example 2, but
using 2.35 g of 3-amino-8-fluoro-6-methoxyquinoline, 1.35 g of 3,8-difluoro-6-methoxyquinoline are obtained, in the form
of a white solid which melts at 122°C
Characteristics of the synthesis intermediates:
3-Amino-8-fluoro-6-methoxyquinoline: brown solid which melts
at 135°C.
8-Fluoro-6-methoxyquinoline-3-carboxamide: beige solid which
melts at 248°C.
4-Chldro-8-fluoro-6-methoxyquinoline-3-carboxamide: light
brown solid which melts at 220°C.
8-Fluoro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid:
beige solid which melts at around 280°C.
Ethyl 8-fluoro-4-hydroxy-6-methoxyquinoline-3-carboxylate:
light brown solid which melts at 221°C.
Diethyl 2-t(2-fluoro-4-methoxyphenylamino)methylene]malonate:
mass spectrum El m/z = 311 (M"1") .
2-Fluoro-4-methoxyaniline is used at the start.
Example 4: 3,6-Difluoroquinoline
By carrying out the process as described in Example 2, but using 3-amino-6-fluoroquinoline, 3,6-difluoroquinoline is
obtained, mass spectrum El m/z = 165 (M+) .
Characteristics of the synthesis intermediates:
3-Amino-6-fluoroquinoline: mass spectrum El m/z = 162
6 -Fluoroquinoline- 3 -carboxamide : mass spectrum El m/z = 190
4-Chloro-6-f luoroquinoline- 3 -carboxamide : mass spectrum El
m/z = 224 (M+) .
4-Hydroxy-6-f luoroquinoline- 3 -carboxylic acid: mass spectrum
El m/z = 207 (M+) .
Ethyl 4-hydroxy-6-fluoroquinoline-3-carboxylate: mass
spectrum El m/z = 235 (M+) .
Diethyl 2- [ (2-f luoro-4-methoxyphenylamino) methylene]malonate :
mass spectrum El m/z = 281 (M+) .
4-Fluoroaniline is used at the start.









We claim:
1.A process for preparing 3-fluoroquinolines of formula (I):
(Formula Removed)
wherein,
R1, R2, R3 and R4, which may be identical or different, represent:
- a hydrogen atom;
- a fluorine atom;
- a linear, branched or cyclic alkyl radical optionally substituted with one to three fluorine atoms, with a group OR5 in which R5 represents a linear or branched alkyl radical, a hydrogen atom or a hydroxyl radical- protecting group, or with a group NR' R" in which R and R", which may identical or different, represent a linear or branched alkyl radical, a hydrogen atom or an amino radical-protecting group;
- a group OR6 in which R6 represents a hydrogen atom, a phenol-protecting group or a linear or branched alkyl radical optionally substituted with one to three fluorine atoms, with OR5 or with NR' R" as defined above;

- a group NR' R" in which R' 1 and R"1 have the values of R' and R" or represent a linear or branched alkyl radical substituted with one to three fluorine atoms, with a group OR5 as defined above or with a group NR' R" as defined above;
- a group CO2Ra, in which Ra represents a hydrogen atom,
a linear or branched alkyl radical or a carboxyl radical-protecting group;
- a phenyl radical or a heteroaryl radical, optionally substituted with one or more of the
substituents mentioned above,
wherein:
a compound of formula (IV):
(Formula Removed)
in which R1, R2, R3 and R4 are as defined above, is subjected to a Hofmann degradation, wherein the Hoffman degradation is carried out with bromine, sodium hydroxide, pyridine in water at a temperature of 60°C ; so as to obtain a compound of general formula (III),
(Formula Removed)
in which R1, R2, R3 and R4 are as defined above, which is treated under conditions capable of forming the diazonium salt of general formula (II):
(Formula Removed)
in which R1, R2, R3, and R4 are as defined above,
which is heated in an aromatic carbonated solvent as toluene or xylene, an alcane as heptane or hexane or a fluorinated or chlorinated solvent, by heating at a temperature between 60°C to 100°C .
2. The process as claimed in claim 1, wherein the condition for preparation of the diazonium salt are action of an alkali metal salt or of an alkyl ester of nitrous acid and of fluoroboric acid or of the boron trifluoride-ethyl ether complex at a temperature of 15°C to 20 °C.
3. The process as claimed in claims 1 to 2, wherein the sensitive substituents are protected.
4. The process as claimed in any one of claims 1 to 3, wherein R1, R2, R3 and R4, which may be identical or different, represent a hydrogen atom, a fluorine atom, an optionally substituted linear or branched alkyl radical as defined in claim 1, or a radical OR6 as defined in claim 1.
5. The process as claimed in claim 4, wherein R1, R2, R3 and R4, which may be identical or different, represent a hydrogen atom, a fluorine atom or a linear or branched alkoxy radical containing from 1 to 10 carbon atoms.

Documents:

2274-delnp-2006-abstract.pdf

2274-DELNP-2006-Claims-(02-05-2011).pdf

2274-DELNP-2006-Claims-(23-04-2010).pdf

2274-delnp-2006-claims.pdf

2274-DELNP-2006-Correspondence Others-(02-05-2011).pdf

2274-DELNP-2006-Correspondence-Others-(19-05-2010).pdf

2274-DELNP-2006-Correspondence-Others-(23-04-2010).pdf

2274-delnp-2006-correspondence-others-1.pdf

2274-delnp-2006-correspondence-others.pdf

2274-DELNP-2006-Description (Complete)-(23-04-2010).pdf

2274-delnp-2006-description (complete).pdf

2274-DELNP-2006-Form-1-(23-04-2010).pdf

2274-delnp-2006-form-1.pdf

2274-delnp-2006-form-18.pdf

2274-DELNP-2006-Form-2-(23-04-2010).pdf

2274-delnp-2006-form-2.pdf

2274-DELNP-2006-Form-3-(02-05-2011).pdf

2274-DELNP-2006-Form-3-(23-04-2010).pdf

2274-delnp-2006-form-3.pdf

2274-delnp-2006-form-5.pdf

2274-DELNP-2006-GPA-(23-04-2010).pdf

2274-delnp-2006-gpa.pdf

2274-delnp-2006-pct-210.pdf

2274-delnp-2006-pct-409.pdf

2274-DELNP-2006-Petition-137-(23-04-2010).pdf


Patent Number 260058
Indian Patent Application Number 2274/DELNP/2006
PG Journal Number 14/2014
Publication Date 04-Apr-2014
Grant Date 31-Mar-2014
Date of Filing 25-Apr-2006
Name of Patentee NOVEXEL
Applicant Address 102, Route de Noisy, F-93230 Romainville, France.
Inventors:
# Inventor's Name Inventor's Address
1 YOUSSEF EL-AHMAD 11, Avenue de Verdun, F-94000 Creteil, France.
2 JEAN-PIERRE; LECONTE, 17, Avenue Gallieni, F-91800 Brunoy France.
3 JOEL MALPART 77, Allee Arnoul Greban, Residence "Les Jardins d'Olivet", 45160 Olivet, France.
4 SERGE MIGNANI 14, Avenue de Robinson, 92290 Chatenay Malabry, France
5 STEPHANE MUTTI 122, Avenue du Marechal Joffre, 94170 Le Perreux Sur Marne, France.
6 MICHEL TABART 3, rue Paul Langevin, F-91290 La Norville, France.
PCT International Classification Number C07D 215/18
PCT International Application Number PCT/FR2004/002910
PCT International Filing date 2004-11-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03 13 384 2003-11-17 France