Note: Descriptions are shown in the official language in which they were submitted.
~2~2~
--1--
CHLORINE EXCHANGE FOR FLUORINE IN
2-FLUORO-P~RIDINE COMPOUNDS
The present invention relates to a method of
exchanging chlorine atoms for fluorine atoms in 2-fluoro-
-pyridine compounds.
2-Chloro-5-(trifluoromethyl)pyridine compounds
are commercially valuable chemical in-termediates useful
in the preparation of medicinal agents and agricultural
chemicals. 2-Chloro-5-(trifluoromethyl)pyridine compounds
are generally prepared by fluorinating a (trichloromethyl)-
pyridine compound.
Problems associated with the preparation of
2-chloro-5-(trifluoromethyl)pyridine compounds include
~1) an over fluorinated end product, i.e., 2-fluoro-5-
-~trifluoromethyl)pyridines, and (2) the formation of a
2-1uoro isomer of the desired (trifluoromethyl)pyridine
product generally described as a 2-fluoro-5-(chloro-
difluoromethyl)pyridine compound. These 2~fluoro-
-pyridine by-products reduce the yield of the desired
(trifluoromethyl)pyridines and nec~ssitate additional
separatory procedures which are both bothersome
30,863-F
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and expensive. The 2-fluoro isomer is a particularly
annoying by-product because of the difficulty in
separating it from the desired (trifluoromethyl~pyridine
product.
In accordance with the present invention,
a 2-fluoro pyridine compound is reacted with a
chlorinating agent at superatmospheric pressures to
replace the fluorine atom in the 2-position of the
pyridine ring with a chlorine atom. The chlorina-ted
products of this method are useful as intermediates in
the synthesis of biologically active compounds, such
as, medicinals and herbicides.
Of particular interest in the practice of
this invention is a method of replacing the fluorine
atom at the 2-ring position of 3-chloro-2-fluoro-5-
-(trifluoromethyl)pyridine with a chlorine atom
yielding 2,3-dichloro-5-(trifluoromethyl)pyridine, an
intermediate in the manufacture of agricultural chemicals.
Also of interest are methods of replacing the
fluorine atoms at the 2-position of 2-fluoro-5-(trifluoro-
methyl)pyridine; 3-chloro-2-fluoro-5-(chlorodifluoro-
mPthyl~pyridine; and 2-fluoro-5-(chlorodifluoromethyl)-
pyridine with a chlorine atom yielding 2-chloro-5-
-(trifluoromethyl)- or (chlorodifluoromethyl)-pyridine .
compounds.
In conducting the present reaction, a 2-fluoro-
pyridine compound is contacted with a chlorinating
agent at a superatmospheric pressure usually in the
range of from 25 to 400 pounds per square inch guage
(psig) advantageously a~ a temperature in the range
of from 50C to 200C.
30,863-F -2
-3~
2-Fluoro-pyridine compounds include
3 chloro-2~fluoro-5-(trifluoromethyl)pyridine; 2-fluoro-
-5-(-trifluoromethyl)pyridine; and the above compounds
wherein Ichlorodifluoromethyl or -dichlorofluoromethyl
groups are substituted for the trifluoromethyl groups.
The 2-fluoro-pyridine compounds can be reacted separately
or as a mixture con-taining more than one 2-fluoro-pyridine
compound.
In a preferred embodiment, a mixture containing
chlorinated~(trifluoromethyl)pyridines and one or more
2 fluoro-pyridine compounds is reacted according to the
present invention whereby a chlorine atom is exchanged
for the fluorine atom attached to the 2-position of the
pyridine ring. The above mixtures are advantageously
obtained from the reaction products in the preparation of
(trifluoromethyl)pyridine compounds such as, for example,
2,3-dichLoro-5-~trifluoromethyl)pyridine and 2-chloro-
-S-(trifluoromethyl)pyridine, whereby the 2-fluoro-
-pyridine compounds are undesirable by-products.
The employment of a chlorinating agent is a
critical component of the present invention and HCl is
suitably employed. Suitable chlorinating agents are pre-
ferably supplied in amounts to provide at least about
one mole of chlorine atoms per mole of fluorine atoms
to be displaced on the 2-fluoro-pyridine compounds. An
excess of chlorinating agent is preferably employed and
is not detrimental to the present process.
Generally, the present reaction is conducted
neat or in the absence of a solvent.
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-4- ~ ~ ~ ~ ~ 0
In practicing -~he present invention,
superatmospheric pressures are employed. The present
reaction is conduc-ted at a pressure of at least 5 psig
and usually at a pressure of from 25 to 400 psig,
while 20~ psig represents a preferred pressure. The
upper pressure limit, i.e., 400 psig, is not meant to
be a limitation of the present invention but is only
set forth as an economical consideration. Conducting
the present reaction at a superatmospheric pressure
provides conversion of the 2-fluoro-pyridines to their
corresponding 2-chloro analogs at an accelerated rate
when compared to conducting the reaction at atmospheric
pressure. Furthermore, the excellent yield of the
desired products (about 98 percent of theoretical~
avoids the use of a catalyst and provides a cleaner
reaction eliminating the costs, material handling,
recovery and/or disposal eforts associated with the
use of catalys-ts.
The present reaction is a~vantageously con-
ducted in the liquid phase at a temperature of between50C and 200C and preferably between 100C and 125C.
A particularly preferred -temperature to conduct the
present reac-tion is 110C. The present reaction is
typically conducted in the presence of agitation
sufficient to disperse the HCl in the liquid phase.
In conducting the present reaction, neither
the rate of addition of the chlorinating agent nor the
order of addition of the reactants is critical. Pre-
ferably, the suitable chlorinating agent is added in
gaseous form to the 2-fluoro-pyridine compounds. A
typical reaction according to the present invention
generally requires from 1/2 to 24 hours to be substan-
tially complete.
30,863-F _4-
_5~
In a preferred embodiment of the present
invention, the reaction product in the preparation
of 2-chloro-5-(trifluoromethyl)pyridine, which con-
tains 2-fluoro-pyridines, such as, 2-fluoro-5-ttri-
fluoromethyl)pyridine and 2-fluoro-5-(chlorodifluoro-
methyl~pyridine, in addition to the desired 2-chloro-
-5-(trifluoromethyl)pyridine, is contacted with HCl
at superatmospheric pressures and elevated tempera-
tures as described herein to convert the 2-fluoro-
-pyridines to their corresponding 2-chloro analo~s.
The desired 2 chloro-5-(trifluoromethyl)pyridine is
then readily separa~le from the reaction mixture by
distillation since the 2-fluoro isomer, i.e. 2-fluoro-
-5-~chlorodifluoromethyl)pyridine, is converted to
2-chloro-5-(chlorodifluoromethyl)pyridine which has
a boiling point different from the desired product.
In an especially preferred embodiment of the
present invention, the reaction product in the prepara-
tion of 2,3-dichloro-5-(trifluoromethyl~pyridine,
which contains 2-fluoro-pyridines, such as, 3 chloro-
-2~fluoro-5-(trifluoromethyl)pyridine and 3-chloro
-2-fluoro-5-(chlorodifluoromethyl)pyridine, in adddition
to the desired 2,3~dichloro-5-(trifluoromethyl)pyridine,
is contacted with HC1 at supera-tmospheric pressures
and elevated temperatures as described herein to con-
vert the 2-fluoro-pyridines to their corresponding
2-chloro analogs. The desired 2,3-dichloro-5-(tri-
fluoromethyl)pyridine is then readily separable from
the reaction mi~ture by distillation since the 2-fluoro
isomer, i.e., 3-chloro-2-fluoro-5-(chlorodifluoromethyl)-
pyridine, is converted to 2,3-dichloro-5-(chlorodi-
fluoromethyl)pyridine which has a boiling point dif-
ferent from the desired product.
30,863-F -5-
~6--
The following example illustrates the practice
of the present invention.
Example 1 - Preparation of 2,3-Dichloro-5-(trifluoro-
methyl~pyridine
A 45 milliliter (ml) Teflon~-lined Parr bomb,
which was equipped with a pressure gauge, rupture disk
and needle valve, was charged with 2 grams (g) of
3-chloro-2-fluoro-5-trifluoromethylpyridine and then
pressurized with anhydrous HCl to 200 psig. The bomb
was placed in a heated rocker and kept at 110C for
20 hours. The maximum pressure was 220 psig. The bomb
was removed from the heater and allowed to cool to
room temperature, at which time it was placed in an
ice bath. The bomb was vented to a caustic scrubber
and 2.5 g of a light tan liquid consisting of HF and
84.3% 2,3-dichloro-5-trifluoromethylpyridine (by wt.).
This represents a 97.7% yield of 2,3-dichloro-5-
-trifluoromethylpyridine (by wt.) with 0.4% of
3~chloro~2-fluoro-5 trifluoromethylpyridine r~ai ni ng.
No additional products were observed by analysis with
gas chromatography.
On repeating the above procedures using
other substituted ring-fluorinated pyridine compounds,
described herein as starting materials, substantially
the same results are obtained, i.e., chloro displaces
the ring-fluoro. Additionally, the present reaction
may be conducted as a continuous process whereby similar
results are obtained.
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