Note: Descriptions are shown in the official language in which they were submitted.
W~91/17138 2 0 8 U ~ 9 ~ PCT/US91/02~0
PROCESS FOR PREPARING 3.4-D~LUOROAN~ E
sackqround of the invention
The present invention relates to a novel method for
praparing 3,4-difluoroaniline. This compound is useful in
the preparation of quinolone antibacterials as described in
United States Patent 4,833,270.
United States Patent 4,145~364 refers to the prepara-
tion of monofluoroanilines via a Bamberger rearrangement or
an arylhydroxylamine route. The patent indicates that the
arylhydroxylamine route "suffers from the disadvantage of
concomitant formation of corresponding unfluorinated
aniline, as well as the sym~etrioal azo and azoxy com-
pounds" and that "considerable tar is formed making product
isolation difficult." The patent also refers to tha
preparation of monofluoroanilines and difluoroanilines by
treating aromatic azid~s with anhydrous hydroge~ fluoride.
T.J. Broxton et al., J. Org. Chem., 42, 643-649 (1977)
refer to the effect of oxygen and nitrogen atmospher~s on
thermolysis of arenediazonium salts.
The process of the present invention is advantageous
in that it uses hydroxyla~ines which ar~ relatively stable
compared to aromatic azid~s. The latter are used as
starting materials in the process of U.S. Patent 4,145,364~
Azides, on the other hand, are not 5table and tend to
decompose whsn warmed or when left for a long period cf
time at room temperature. Furthermore, hydroxylamines are,
in most cases, ~rystalline and can be conveniently purified
should the need aris~
~h~ process of the present invention does not result
in the formation of a significant amount of unfluorina~ed
~aterial or tar. I have found that the use of anhydrous
condikions and the exclusion of oxygen avoid such undesir-
able results~
.
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WO91/17138 2 0 8 0 ~ .9 6 PCT/US91/02540
Summary of the Invention
The present invention relates to a process for pre
paring 3,4-fluoroaniline comprising reactin~ l-hydroxyl-
amine-3-fluorobenzene with anhydrous hydrogen fluoride in
S the absence of oxygen. Preferably, oxygen is excluded by
conducting the reaction under an inert atmosphere such as
nitrogen or argon. The solvent for the foregoing reaction
is preferably pyridine.
In one embodiment of the invention, l-hydroxylamine-3-
fluorobenzene is prepared by hydrogenating 3-fluoro-l-nitro-
benzene. The hydrogenation is preferably accomplished by
reacting the latter compound with hydrazine hydrate in the
presence of platinum on carbon in an alcoholic solvent such
as ethanol.
Deta~ Descri~tion of the Invention
The presant invention also relates to the novel
compound 3-fluoro-l-hydroxylamine.
The reaction of l-hydroxylamine-3-fluorobenzene with
hydrogen fluoride should be conducted in an inert solvent.
Suitable solvents include acetonitrile and pyridine.
Pyridine is a preferred solvent. The reaction will
generally be conducted at a temperature from about 0C to
about 50C, preferably from about 20C to 25OC. The
temperature is most preferably 25C.
The hydrogenation of 3-fluoro-l-nitrobenzene is
preferably accomplished by reacting the compound with
hydrazine in the presence of platinum on carbon. Othex
sources of hydrogen such a-~ ammonium formate and other
hydrogenation catalysts such as Raney Nickel may also be
used. Suitable solvents for the hydrogenation reaction
include most alcohols. The preferred solvent is ethanol.
The reaction temperature will generally be from about -20C
to about 50C, preferably from about 0C to about ~C. The
temperature is most preferably 0C.
The prqssures of the foregoing react.ions are not
critical. The reactions will generally be conducted at a
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WO 91/17138 PCr/US91/02540
pressure of about 0.5 to about 2 atmospheres, preferably at
ambient pressure (generally about one atmosphere).
3,4-Difluoroaniline may be reacted as described in
United States Patent 4,833,270 to provide 1-cyclopropyl-
6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
which may be used to prepare various quinolone antibiotics,
including danofloxacin. As discussed in that patent, an
aqueous solution of 3,4-difluoroaniline and hydroxylamine
hydrochloride containing hydrochloric acid is reacted with
an aqueous solution of chloral hydrate and sodium sulfate
at the reflux temperature, then filtered while hot, giving
N-(3,4-difluorophenyl)-2-(hydroxyimino)-acetamide. The
latter compound is reacted with concentrated sulfuric acid
with heat, then added to cracked ice, giving 5,6-difluoro-
lH-indole-2,3-dione. A basic aqueous solution o~ the dione
is treated with hydrogen peroxide and heat, and then cooled
and acidified, giving 2-amino-4,5-difluorobenzoic acid. The
2-amino-4,5-difluorobenzoic acid is added to a mixture o
anhydrous copper at 0-5C, and then added to a dilute
mineral acid, giving 2-chloro-4,5-difluorobenzoic acid.
A solution o~ 2-chloro-4,5-difluorobenzoic acid in
acetonitrile containing a catalytic amount of dimethyl-
formamide is reacted under an inert atmosphere with the
dropwise addition of oxalyl chloride, giving 2-chloro-
4,5-difluorobenzoic acid chloride, which is dissolved in
diethyl ether and slowly added to a cold solution of
magnesium diethylmalonate, which is then added to ice water
and acidified to pH 2.5, giving (2-chloro-4,5-difluoro-
benzoyl)propanedioic acid diethyl ester. A solution o~ the
diethyl ester in p-dioxane and water is heated at refiux,
and then evaporated and distilled, gi~ing 2 chloro-4~5-
di~luoro-B-oxobenzenepropanoic acid ethyl ester. A
solution of the ethyl ester and triethyl ortho~ormate in
acetic anhydride is heated at 150C for 2 hours, giving
2-chloro-a-(ethoxymethylene)-4,5-difluoro-B-oxobenzenepro-
panoic acid ethyl ester. Cyclopropylamine is added to a
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WO91/17138 2 0 8 0 ~ ~ 6 PCT/US91/02~0 ~
solution of the latter ethyl ester in ethanol, giviny
2-chloro-~-[(cyclopropylamino)methylene]-4,5-difluoro-B-
oxobenzenepropanoic acid ethyl ester, which is reacted with
sodium hydride in dxy dimethylformamide under an inert
atmosphere with heat, gi~ing l-cyclopropyl-6,7-difluoro-
l,4-dihydro-4-oxo-3-quinol`lnecarboxylic acid ethyl ester,
which is t~en refluxed with acid, giving l-cyclopropyl-
6,7-difluoro-l,4-dihydro 4-oxo-3-quinolinecarboxylic acidO
Danofloxacin may be prepared by reacting the acid thus
prepared with (S,S)-2-methyl-2,5-diazabicyclo[2.2.l]heptane
and an amine base.
Quinolone antibacterials such as danofloxacin (dis-
closed in U.S. Patent 4,861,779) and the pharmaceutically
acceptable acid addition salts thereof are useful in the
treatment of bacterial infections of broad spectrum,
particularly the treatment of gram-positive bacterial
strains.
Th~ quinolone antibacterials of U.S. Patent 4,861,779
may be administered alone, but will generally be adminis-
tered in admixture with a phar~aceutical carrier selectedwith regard to the intended route of administration and
standard pharmaceutical practice. For example, they can be
administered orally or in the form of tablets containing
such excipients as starch or lactose, or in capsules either
alone or in admixture with excipients, or in the form of
elixirs or suspensions containing flavoring or coloring
agents. In the case of animals, they are advantageously
contained in an animal feed or drinking water in a concen-
tration of 5-5000 ppm, preferably 25-500 ppm. They can be
injected parenterally, for exampl~, intramuscularly,
intravenously or subcutaneouslyO For parenteral adminis-
tration, they ar best used in the ~orm of a sterile aqueous
solution which can contain other solutes, for example,
enough salt or glucose to made the solution isotonic. In
the case of animals, compounds can be administered intra-
muscularly or subcutaneously at dosage levels of about
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WO 91/17138 PCT/US91/02540
-5-
0.1-50 mg/kg/day, advantageously 0.2-10 mg/kg/day given in
a single daily dose or up to 3 divided doses.
The quinolone antibacterials can be administered to
humans for the treatment of bacterial diseases by either
the oral or parenteral routes, and may be administered
advantageously 0.1-50 mg/kg/day given in a single dose or
up to 3 divided doses. For intramuscular or intravenous
administration, dosage levels are about 0.1-200 mg/kg/day,
advantageously 0.5-50 mg/kg/day. While intramuscular
administration may be single dose or up to 3 divided
doses, intravenous administration can include a continuous
drip. Variations will necessarily occur depending on the
particular route of administration chosen as will be known
to those skilled in the art.
Example 1
1-Hydeoxlamine-3-fluorobenzene
3-Fluoro-1-nitrobenzene (20 g, 0.14 mol) was dissolved
weight %) was added. The mixture was then cooled with an
ice bath to 0°C and hydrazine hydrate (1308 ml, 0.25 mmol)
was added dropwise over a period of 45 minutes. After an
additional stirring period of 30 minutes, the reaction
mixture was filtered through diatomaceous earth (Celite
(trademark)) and the solvent was evaporated under vacuo.
The residual oil was suspended in 400 ml of water and
extracted with 3x500 ml of methylene chloride. The com-
bined organic solvents were dried (MgSO4) and evaporated to
produce 12.84 g of an off white solid in 71% yeild, m.p.
58-59°C Anal. calc'd for C6H6NF: C, 56.69; H, 4.76; n,
11.02; Found: C. 56.73; H, 4.80; N, 11.14.
Example 2
3,4-Difluoroaniline
A plastic bottle was charged with 75 ml of HF -
pyridine under an inert atmosphere at 0°C and to that
WO91/17138 2 0 ~ 0 ~ 9 G PCT/US91/025~0
-6-
1-hydroxylamine-3-fluoro~enzene (5.0 g, 39.4 mmol) was
added carefully. The reaction mixture was allowed to warm
to room temperature and was stirred for 48 hours. The
reaction mixture was carefully quenched with 2 1 of sat-
urated aqueous NaHCO3 solution and extracted with 5 x 500 mlportions of methylene chloride. The combined organic
solvents were washed with saturated CuS04 solution (3x),
dried (MgSO4) and evaporated to produce 4.6 g of an oil in
90% yield. NMR(CDCl3): ~ 6.95 (q, lH~, 6.55 (m, lH), 6.34
(m, lH), 3.6 (broad, 2H).
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