Note: Descriptions are shown in the official language in which they were submitted.
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HOECHST AXTIENGESELLSCHAFT - HOE 92/F 051 Dr.BI/St
Description
Procass for the preparation of 2,4,5-trifluorobenzo-
nitrile
The present invention relates to a no~el, Lmproved pro-
cess for the preparation nf 2,4,5-trifluorobenzonitrile,
a valuable intermediate for the preparation of antibac-
terial agents from the fluoroquinolonecarboxylic acid
series via the hydrolysis product 2,4,5-trifluorobenzoic
acid.
To date, it was only possible to prepare 2,4,5-trifluoro-
benzonitrile, which can be converted by methods known
from the literature tEP 431 373, EP 433 124, H. Henecka
in Houben-Weyl-Muller, Methoden dex Organischen Chemie
[Methods of Organic Chemistry], Vol. 8 (1952), 427-433)
first into 2,4,5-trifluorobenzoic acid and then into the
active substances (J.P. Sanchez et al., J. Med. Chem. 31
(1988), 983-991; EP 227 088; DE 3 600 891; DE 3 420 743;
JP 60 072 885; EP 191 185), by economically unfavorable
processes which are unsatisfactory from the industrial
point of view.
Halex (chlorine/fluorine exchange) reaction of 2,4-
dichloro-5-fluorobenzonitrile (EP 431 373) in the solvent
dimethyl sulfoxide, which is undesirable from the indus-
trial point of view, with the use of spray-dried potas-
sium fluoride gives poor yields (43 ~) of 2,4,5-tri-
fluorobenzonitrile. Furthermore, 2,4,5-trifluoro-
benzonitrile is obtained as a by-product in yields of
approximately 20 % in the preparation of 2-chloro-4,5-
difluorobenzonitrile (EP 433 124) or by bromine/cyano
exchange of 2,4,5-trifluorobromobenzene by means of
alkali metal cyanides (EP 191 195).
2,4,5-Trifluorobenzoic acid can also be prepared ~ia
other routes, but some of these are unfavorable because
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they comprise several steps and entail poor total yields,
others because of their problems due to the materials and
reactions which are involved. These routes include the
fluorination of 2,5-difluoro-4-chlorobenzoyl fluoride
(PCT WO 90/12 780) and 2,4-dichloro-5-fluorobenzoyl
fluoride (JP 01/226 851; DE 3 420 7~6; EP 164 619) to
gi~e 2,4,5-trifluorobenzoyl fluoride, followed by hydro-
lysis. They also include the traditional fluorination of
4,5-difluoroanthranilic acid by the Schiemann reaction to
give 2,4,5-trifluorobenzoic acid (G.C. Finger et al.,
CA 50 (1955), 9312). Problems due to materials can be
found in dehalogenation reac~ions of tetrafluorophthalo-
dinitriles (EP 307 897, JP 01/160 944) or tetrafluoro-
ph~halate diesters. All these methods have a selective
decarboxylation of the resulting trifluoro(iso)phthalic
acids in common, frequently resulting in substantial
isomer residues which are difficult to remove
(US 4 935 541, JP 01/052 737; JP 01/025 737). Equally, it
is impossible to obtain 2,4,5-trifluorobenzoic acid by
complete selective decarboxylation of trifluorophthalic
acid obtained by fluorination of 3,4,6-trichlorophthalim-
ides (EP 431 294) followed by hydrolysis.
The acylation of 1,2,4-trifluorobenzene by means of
acetyl chlorides which are optionally chlorinated in the
aliphatic moiety followed by haloform reaction
(EP 411 252, DE 3 840 371, DE 3 840 375, JP 02 184 650)
is unfavorable from the economic point of view since
1,2,4-trifluorobenzene itself must be prepared, which
involves complicated steps as they are typical for the
Schiemann reaction.
It has now been found that 2,4,5-trifluorobenzonitrile
can be prepared in good yields by a novel, improved
process, in which 2,4-dichloro-5-fluorobenzonitrile is
reacted with approximately 100 to approximately
300 mol %, pref~rably approximately 105 to approximately
150 mol %, particularly preferably approximately 110 to
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approximately 120 mol %, of an alkali me~al fluoride ox
of a ~etraalkyl(Cl-Cla)ammonium fluoride per chlorine atom
to be exchanged, at temperatures from approximately 80 to
approximately 250C, preferably from approximately 140 to
approximately 200C, particularly preferably from
approximately 160 to approximately 190C, in the presence
of a phase transfer catalyst, if appropriate in a dipolar
aprotic solvent.
Suitable alkali metal fluorides are mainly potassium
fluoride, rubidium fluorlde and cesium fluoride, in
exceptional cases also lithium fluoride or sodium fluor-
ide. Potassium 1uoride, rubidium fluoride or cesium
fluoride, or mixtures of these, are pre~erably employed.
Mixtures o~ potassium fluoride and cesium fluoride are
preferred. Particularly preferred mixtures are those
which contain approximately 10 % by weight of cesium
fluoride.
It is also possible ~o employ spray-dried alkali metal
fluoride~ in the process according to the invention.
Suitable phase transfer catalysts are quaternary ammonium
or phosphonium compounds, such as tetraalkyl(Cl-Cl~)ammon-
ium chlorides, tetraalkyl(C1-C18)ammonium bromides or
tetraalkyl(Cl-Cl8)ammonium fluorides, tetraalkyl(Cl-Cl8)-
phosphonium chlorides or tetraalkyl(C1-C18)phosphonium
bromides, tetraphenylphosphonium chloride or tetraphenyl-
phosphonium bromide or (phenyl)m(alkyl(cl-cl8))n phosphon-
ium chlorides or (phenyl)~(alkyl(C1-C18))n-phosphonium
bromides, where m is 1 to 3, n is 3 to 1 and m+n is 4.
Preferred from amongst these are phosphonium salts,
particularly preferably tetraalkyl(C1-C18)phosphonium
bromides. These substances are employed in amounts of
approximately 0.01 to approximately 50 mol %, preferably
of approximately 0.5 to approximately 10 mol %, particu-
larly preferably of approximately 1 to approximately
5 mol %, based on 2,4-dichloro-5-fluorobenzonitrile. If
- 4 ~
a tetraalkyl(Cl-Cl~)ammonium fluoride is used as fluoride
salt, then the addition of other phase transfer catalysts
can be dispensed with since the fluoride salt itself
represents such a catalyst.
Oligo- or polyethylene glycol dimethyl ethers can also be
employed as phase transfer catalysks. The number of
glycol units in these compounds can be from approximate-
ly 4 (tetraethylene glycol dimethyl ether) to approxi-
mately 150; however, preferred polyethylene glycol
dimethyl ethers which are employed are those whose degree
of polymerization is between approximately 4 and approxi-
mately 25. The optLmum amount of these glycol ethers to
be employed is between approximately 0.5 % by weight and
approximately 200 % by weight, relative to the fluoride
employed. The glycol ethers are preferably used in
amounts of between approximately 5 and approximately
100 % by weight, particularly preferably between approxi-
mately 10 and approximately 50 % by weight, relative to
the fluoride employed. The particular advantage of the
use of these compounds is that, as a rule, less solvent
can be used relative to the amount of compounds employed
because the glycol ethers are always liquid at the
reaction temperature.
Surprisingly, the use of phase transfer catalysts allows
a virtually quantitative reaction, while without such an
addition reaction rates of more than 70 % can scarcely be
observed, but instead rapidly increasing decomposition
rates.
The process according to the invention can be carried out
in the complete absence of a solvent. However, it is also
possible to carry out the reaction in a dipolar aprotic
solvent, for example in sulfolane (tetramethylene sul-
fone), tetramethylene sulfoxide, N,N-diethylacetamide,
N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-
pyrrolidone, dimethyl sulfoxide, dimethyl sulfone,
5 2B~7~
diphenyl sulfoxide, diphenyl sulfone, tetramethylurea,tetra-n-butylurea, 1,3-dimethylLmidazolidin-2 one, or in
mixtures of these.
In general, the product mixture obtained by the process
according to the invention is obtained by fil~ering the
reaction salt and/ in particular when carried out on an
industrial scale, subsequent removal of the volatile
components by distillation and fractionation. Direct
fractionation of the filtrate is also possible. It is
equally possible to treat the crude mixture with water
and to remove the lighter top phase, which contains the
product. Extraction of the water allows complete separa-
tion of the product from the mother liquor. This can be
followed by purification by means of chromatography or
separation by distillation.
The process can be carried out under atmospheric pres-
sure, subatmospheric or superatmospheric pressure. It is
preferred to carry out the process under a slight super-
atmospheric pressure in a sealed vessel so as to avoid
loss of the volatile product, since the vapor pressure of
the latter at the reaction temperatures is already
considerable. This effect can be utilized for distilling
off the product continuously during the reaction, but
this requires a more complicated apparatus and control
~5 technology (uniform r0flux). In general, however, a
subsequent fine fractionation is still required. If
optimal reaction conditions are selected, such as
catalyst, concentration, temperature and amount of salt,
however, this additional process step is not reguired for
obtaining high yields and space-time yields.
An advantage of the process is a highly concentrated
reaction solution, which is required on an industrial
scale for reasons of economy. Moreover, the procedure
according to the invention allows very high reaction
rates to be achievedl which also results in high space-
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time yields, while the total yields still remain high ~overy high and are considerably improved compared with the
processes which have already been described. At ~he same
time, the process according to the invention has
5 advantages in terms of manipulation, since the use of
spray-dried salt is not necessarily required. The yields
are approximately 65 to approximately 85 % of theory,
depending on the choice of catalyst, reaction temperature
and concentration in the solvent.
10 The 2,4-dichloro-5-fluorobenzonitrile, which is employed
in the process according to the invention as starting
material, can be prepared from 2,4-dichloro-5-fluoro-
bromobenzene by processes known from the literature by
bromine/cyano exchange (EP 433 124), from 2,4-dichloro-
15 5-fluoroaniline by means of cyano Sandmeyer reaction
(CN 1 031 074) or from 2,4-dichloro-5-fluorobenzotri-
chloride (EP 431 373) by al[monolysis.
The examples which follow illustrate the process accord-
ing to the invention without restricting it thereto.
20 Use examples
In some examples, the course of the reaction was moni-
tored by gas chromatography by means of calibration with
the aid of an internal standard (inert under the reaction
conditions). This allows the amount of product formed,
25 which may be obtained by working-up as described in the
text of the description, which had been dispensed with in
these examples, to be determined exactly at any given
points in time. These batches may be carried out on a
larger scale ollowed by working-up (preferably fraction-
30 ation, but also extraction or chromatography), withoutproblems and without an addition of the internal stand-
ard, and in general even better results, such as shorter
reaction times, higher space-time yields and better
yields, are obtained by improving the stirring
_ 7 _~
conditions.
Boiling point
2,4,5-trifluorobenzonitrile 100 to~r/118~
torr/102C
26 torr/78~C
15 torr/72C
Example 1
13.6 g (0.22 mol) of potassium fluoridefcesium fluoride
(9:1) and 1.4 g of tetrabutylphosphonium bromide are
introduced into 50 g of sulfolane. After this, approxi-
mately 10 g of the solvent are distilled off in vacuo
(3 mbar/140C). 19.0 g (0.1 mol) of 2,4-dichloro-S-
fluorobenzonitrile are then added at 140C, and the
mixture is heated for 11 hours at 190C, with vigorous
stirring. 13.2 g ~84 %, 0.083g mol) of 2,4,5-trifluoro-
benzonitrile can subsequently be detected in the reaction
mixture by GC and can be removed from the mixture in
vacuo and then fractionated.
Example 2
11.3 g (0.103 mol) of rubidium fluoride and 1.7 g of
tetraoctylphosphonium bromide (3 mol %, 3 mmol) are
introduced into 20 g of N-methylpyrrolidone (NMP) with
stirring, and 13.6 g (0.1 mol) of 2,4-dichloro-5-fluoro-
benzonitrile are added to the resulting suspension at
100C. In an autoclave, the mixture is heated for
14 hours at 210C, after which it is analyzed by gas
chromatography. Calibration against the internal standard
allows lû.9 g (69 %, 0.0692 mol) of 2,4,5-trifluorobenzo-
nitrile to be detected.
Example 3
A reaction mixture of 95.0 g (0.5 mol) of 2~4-dichloro-
5-fluorobenzonitrile, 92.9 g (1.5 mol) of potassium
fluoride/cesium fluoride (9:1) and 20.3 g (8 mol ~6,
40 mmol) of hexadecyltributylphosphonium bromide is dried
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by incipient distillation with 40 g of toluene. After the
toluene has been removed completely, the mixture is
heated to 210C in a sealed apparatus (15 hours)~ The
reaction salt which has been filtered off is freed from
adhering product by washing with sulfolane. When the
reaction has ended, 52.2 g (66 ~, 0.332 mol) of 2,4,5-
trifluorobenzonitrile (degree of purity (GC): ~ 99.5 %)
are isolated from the reaction mixture by frac~iona~ion.
Example 4
136.2 g (2.2 mol) of potassium fluoride/cesium fluoride
(9:1) are treated with 6.0 g (1.5 mol %, 15 mmol) of n-
butyltriphenylphosphonium bromide and 300 g of sulfolane.
The mixture is subjected to incipient distillation,
190.0 g (1 mol) of 2,4-dichloro-5-fluorobenzonitrile are
subsequently added, and the mixture is heated at 200C.
After 9 hours, the reaction has ended. The reaction salt
is removed by filtration, and the mother liquor is
fractionated. This gives 118.8 g (0.756 mol, 76 ~) of
2,4,5-trifluorobenzonitrile, which distils over at
26 torr ~3.4 kPa)/78C. Small amounts of incompletely
reacted benzonitriles (intermediate cuts, boiling points
80-130C/3.4 kPa) are recycled together with the redis-
tilled solvent.
Example 5
Approximately 20 g of the solvent are removed from a
suspension of 38.3 g (0.618 mol) of potassium
fluoride/cesium fluoride (9:1) and 1.3 g (1 mol %;
3 mmol) of tetraphenylphosphonium bromide in 180 g of
N,N-dimethylacetamide by distillation. The mixture is
treated with 57.0 g (0.3 mol) of 2,4-dichloro-5-fluoro-
benzonitrile and heated in a glass autoclave for 8 hours
at 175~C, with vigorous stirring. After this, 33.7 g
(71 ~, 0.214 mol) of 2,4,5-trifluorobenzonitrile can be
detected in the reaction mixture by calibration against
the internal standard.
2~7~j
g
Example 6
52.0 g (0.84 mol) of potassium fluoride/cesium fluoride
(9:1) are introduced into 40 g of sulfolane, and 7.0 g of
octadecyltrimethylammonium chloride (5 mol %, 20 mmol)
are added. 2,4-Dichloro 5-fluorobenzonitrile (76.0 g,
0.4 mol) is added at 100C, and the reaction i5 conducted
for 5 hours at 205C. After this~ 41.4 g (66 %, 0.263 mol)
of 2,4,5-trifluorobenzonitrile can be d~tected by cali-
bration against the internal standard.
Example 7
30 ml of anhydrous N,N-dimethylacetamide and l9.0 g
(0.1 mol) of 2,4-dichloro-5-fluorobenzonitrile are added
to 23.3 g (O.25 mol) of tetramethylammonium fluoride
which has been dried in vacuo ~nd which is in the form of
a colorless oil. ~he reaction mi~ture is kept under argon
for 20 hours at 80C and then analyzed by GC. Calibration
against the internal standard indicates 12.6 g (80 %,
0.0803 mol) of 2,4,5-trifluorobenzonitrile in the pale
brown solution.
Example 8
Approximately 70 g of DMAc are distilled off from a
suspension of 100 g of N,N-dimethylacetamide (DMAc), 50 g
of polyethylene glycol dimethyl ether (n = 1000) and
38.7 g (0.625 mol) of potassium fluoride/cesium fluoride
(9:1), 47.5 g (0.25 mol) of 2,4-dichloro-5-fluoro-
benzonitrile are added, and the mixture is heated in a
glass autoclave for 10 hours at 200C, with vigorous
stirring. After this, the volatile components (product,
DMAc, secondary products) are distilled off from the
reaction mixture (30 torr/50C-130C), and the crude
mixture is subjected to fine fractionation. After the
solvent, 30.1 (28.3) g (72 %, 0.180 mol) of 2,4,5-tri-
fluorobenzonitrile (degree of purity (GC) : approximately
94 %) are obtained at 85 torr/102C. A purer product is
obtained when the batch size is increased.
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2 ~ 7 ~ $
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Example 9
19.4 g (C.3 mol) of potassium fluoxide/cesium fluoride(5:1) are added to 50 g of sulfolane, and approximately
20-25 g of solvent are di~illed off in vacuo. 7.9 g of
anhydrous te~raethylene glycol dime hyl ether and 19.0 g
(0.1 mol) of 2,4-dichloro-5-fluorobenzonitrile are added
to the bottom product, and the mixture is heated for
15 hours at 160C. Analysis by gas chromatography
(calibration against the internal standard) subsequently
demonstrates that ~he viscous reaction mixture contains
10.1 g (64 %, 0.0643 mol) of product.
Example 10 (Comparison Example)
13.6 g (0.22 mol) of potassium fluoride/cesium fluoride
(9:1) are suspended in 60 g of sulfolane, and 10 g of the
solvent are distilled off in vacuo. After 19.0 g
(0.1 mol) of 2,4-dichloro-5-fluorobenzonitrile have been
added, the mixture is heated for 20 hours at 200C. The
yields of 2,4,5-trifluorobenzonitrile which have been
determined by calibration against the internal standard
(GC) reach a maximum of approximately 50 % of theory
after 14-16 hours (in the further course of the reaction,
the yields decrease again). After the reaction time, the
reaction rate is approximately 85-90 %.
Example 11 (Hydrolysis Example)
~0 g (0.127 mol) of 2,4,5-trifluorobenzonitrile are added
dropwise at 180C in the course of 1 hour to 30 g of
75 percent sulfuric acid. The solution, which has a
temperature of 100C, is poured onto 50 g of ice, and the
mixture is subjected to filtration with suction at 0C.
The product is washed three times using 30 g of ice-water
and dried in vacuo at 50C. Extraction of the mother
liquors with dichloromethane, drying over magnesium
sulfate and removal of the solvent give 1.9 g (9 %,
0.011 mol) of pale yellowish crystals. The bulk is 19.3 g
of 2,4,5-trifluorobenzoic acid (86 %, 0.110 mol) in the
form of colorless crystals. The total yield is 95 %
(degree of purity (GC, HPL~) > 99 %; m~p. 98.3-99.5C)o
Recrystallization from water allows product of a melting
range of 100.6-101.8C to be obtained.
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