TECHNICAL FIELD
[0001] The present invention relates to a process for producing
α,α-difluoroaromatic compounds.
BACKGROUND OF THE INVENTION
[0002] α,α-difluoroaromatic compounds are important as intermediates
of medicines and agricultural chemicals (Patent Publication 1). As
typical processes for producing such compounds, it is possible to mention
deoxodifluorination reactions of aromatic carbonyl compounds using
DAST or Deoxo-Fluor (Non-patent Publications 1 and 2).
[0003] As a technique relating to the present invention, there is
disclosed a process for producing an α,α-difluoroethylbenzene by a
reaction (addition or substitution) of hydrogen fluoride to vinyl chloride
moiety of an a-chlorostyrene (Non-patent Publication 3).
PRIOR ART PUBLICATIONS
PATENT PUBLICATIONS
[0004] Patent Publication V International Publication 2011/154298
NON-PATENT PUBLICATIONS
[0005] Non-patent Publication 1: J. Org. Chem. (US), 1975, Vol. 40, p.
574
Non-patent Publication 2: J. Org. Chem. (US), 1999, Vol. 64, p. 7048
Non-patent Publication 3: J. Org. Chem. (US), 1962, Vol. 27, p. 4015
SUMMARY OF THE INVENTION
[0006] The processes of Non-patent Publications 1 and 2 are unsuitable
for an industrial production due to the use of high-price fluorination
agents.

[0007] The process of Non-patent Publication 3 is low in yield in both
liquid phase method (28 %) and gas phase method (11 %). The gas phase
method requires a catalyst having highly toxic mercury oxide supported
on activated carbon. Furthermore, the reaction apparatus is complicated,
and the operation is cumbersome.
[0008] In general, it is known in the production of geminal difluoro
compounds that yield is greatly affected by whether or not
difluoromethylene (CF2) group in the target compound is directly bonded
to the aromatic ring. For example, there are reports (J. Org. Chem. (US),
1979, Vol. 44, p. 3872 and Non-patent Publication 3) of a process for
producing geminal difluoro compounds by adding two molecules of
hydrogen fluoride to the triple bond of acetylene compounds. In this
process, yield is high in the cases of 2,2-difluorohexane (70 %) and
3,3-difluorohexane (75 %), but is low in the cases of
α,α-difluoroethylbenzene (18 % in liquid phase method) and 1-bromo-4-(1,1-difluoroethyl)benzene (less than 5 % as shown in
Comparative Example 1 of this specification). Furthermore, there are
reports (J. Fluorine Chem. (the Netherlands), 2010, Vol. 131, p. 29 and
Japanese Patent Application Publication Heisei 1-199922) of a
deoxodifluorination reaction of a carbonyl compound via an acylal having
two trifluoromethylcarbonyloxy groups (CF3CO2). As to this
deoxodifluorination reaction, it is possible to reproduce a high yield (91 %)
of the publication in the case of 1,1-difluorocyclohexane, but it is not
possible at all to reproduce a high yield (90 %) of the publication in the
case of α,α-difluoroethylbenzene. In fact, in Comparative Example 2 of

this specification, yield of α,α-difluoroethylbenzene was less than 10 %,
and that of 1-bromo-4-(1,1-difluoroethyl)benzene was also low to be
around 15 %. Furthermore, Japanese Patent Application Publication
2013-028569 by the present applicant discloses a process for producing a
geminal difluoro compound comprising the step of reacting a
fluorine-containing enol sulfate with a fluorination agent. In this
process too, yield lowered significantly in case that a CF2 group was
directly bonded to an aromatic ring in the target substance (see the result
of Comparative Example 3 relative to that of Comparative Example 4 in
this specification).
[0009] As mentioned above, in the production of an α,α-difluoroaromatic
compound (having a CF2 group directly bonded to the aromatic ring),
which has been difficult to expect a high yield, there has been a strong
demand for a new process in which a highly toxic catalyst is not necessary,
the reaction apparatus is simple, the operation is easy, and the target
compound can industrially be produced with a low cost and a good yield.
[0010] There are two patent applications (Japanese Patent Application
No. 2012-045360 and Japanese Patent Application No. 2012-045361) by
the present applicant. Since they will not yet been published at the time
of filing the present invention, they are briefly mentioned. The former
patent application is a process for producing an α,α-difluoroaromatic
compound comprising the step of reacting 1-chloro-1-aromatic ring
substituted ethene with a salt or complex of an organic base and hydrogen
fluoride. The latter patent application is a process for producing an α,α. difluoroaromatic compound comprising the step of reacting

1-fluoro-1-aromatic ring substituted ethene with a fluorination agent.
These patent applications are very useful as industrial production
processes, but it is necessary to use a salt or complex of an organic base
and hydrogen fluoride, or 1-fluoro-1-aromatic ring substituted ethene,
which causes a high cost as compared with the present invention.
[0011] As a result of an eager study, the present inventors have found
that a desired reaction proceed well by replacing an ether used as the
reaction solvent in the liquid phase method of Non-patent Publication 3
with an aromatic-series or halogen-series reaction solvent, thereby
reaching the present invention. Furthermore, we have clarified a
preferable raw material substrate, the reaction conditions (the method of
adding hydrogen fluoride, the usage of hydrogen fluoride, and the reaction
temperature), and the method for removing by-products in the present
invention.
[0012] Specifically, 1-chloro-1-aromatic ring substituted ethene is
reacted with hydrogen fluoride using an aromatic-series or halogen-series
reaction solvent. With this, it is possible to produce an
α,α-difluoroaromatic compound with a good yield. The
1-chloro-1-aromatic ring substituted ethene is preferably one in which the
aromatic ring moiety at C1 is an aromatic hydrocarbon group or
substituted aromatic hydrocarbon group, and in which two substituents at
C2 are each hydrogen atoms. The resulting product is particularly
important as an intermediate of medicines and agricultural chemicals.
Furthermore, it is possible to obtain an a,ordifluoroaromatic compound
with a particularly high selectivity by using a single one or an arbitrary

combination of the following specific reaction conditions. As the specific
reaction conditions, it is possible to mention that 1-chloro-1-aromatic ring
substituted ethene is diluted with an aromatic-series or halogen-series
reaction solvent, and then hydrogen fluoride is bubbled in a gas condition
into this solution, that the usage of hydrogen fluoride is 2.0-10 mols
relative to 1 mol of 1-chloro-1-aromatic ring substituted ethene, and that
the reaction temperature is 0-50 °C.
[0013] Finally, it is possible to obtain an α,α-difluoroaromatic compound
with a particularly high purity by converting an aromatic carboxylic acid
fluoride contained as a by-product in the aimed α,α-difluoroaromatic
compound into an aromatic carboxylic acid or aromatic carboxylic acid
amide to remove the same.
[0014] That is, the present invention contains [Invention 1] to [Invention
6] and provides a process for producing an α,α-difluoroaromatic compound.
The production process disclosed in the present invention has never been
reported up to now and therefore new.
[0015]
[Invention 1]
A process for producing an α,α-difluoroaromatic compound
represented by the general formula [2],

wherein Ar1 represents an aromatic ring group or a substituted
aromatic ring group, and each of R1 and R2 independently represents a

hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic
ring groups, or a substituted aromatic ring group, and Ar1 and R1, Ar1 and
R2, or R1 and R2 optionally forms a ring structure by a covalent bond
therebetween,
the process comprising the step of reacting 1-chloro-1-aromatic
ring substituted ethene represented by the general formula [1],

wherein Ar1, R1 and R2 are defined as in the general formula [2],
with hydrogen fluoride using an aromatic-series or halogen-series
reaction solvent.
[0016]
[Invention 2]
The process as described in Invention 1, wherein the
1-chloro-1-aromatic ring substituted ethene represented by the general
formula [1] is 1-chloro-1-aromatic ring substituted ethene represented by
the general formula [3],

wherein Ar2 represents an aromatic hydrocarbon group or a
substituted aromatic hydrocarbon group, and the α,α-difluoroaromatic
compound represented by the general formula [2] is an
α,α-difluoroaromatic compound represented by the general formula [4],


wherein Ar2 is defined as in the general formula [3].
[0017]
[Invention 3]
The process as described in Invention 1 or Invention 2, which is
characterized by that the reaction is conducted by the steps of
diluting the 1-chloro-1-aromatic ring substituted ethene with the
aromatic-series or halogen-series reaction solvent to form a solution; and
bubbling hydrogen fluoride in a gas condition into the solution.
[0018]
[Invention 4]
The process as described in any of Invention 1 to Invention 3,
which is characterized by that usage of the hydrogen fluoride is 2.0-10
mols relative to 1 mol of the 1-chloro-1-aromatic ring substituted ethene.
[0019]
[Invention 5]
The process as described in any of Invention 1 to Invention 4,
which is characterized by that the reaction is conducted at a temperature
of from 0 to 50°C.
[0020]
[Invention 6]
The process as described in any of Invention 1 to Invention 5,
which is characterized by that a purification of the α,α-difluoroaromatic

compound is conducted by converting an aromatic carboxylic acid fluoride
contained as a by-product in the α,α-difluoroaromatic compound into an
aromatic carboxylic acid or an aromatic carboxylic acid amide to remove
the aromatic carboxylic acid fluoride from the α,α-difluoroaromatic
compound.
ADVANTAGEOUS EFFECT OF THE INVENTION
[0021] It is possible to get 1-chloro-1-aromatic ring substituted ethene
and hydrogen fluoride, which are used in the invention, with low prices
and in large amounts. Since the reaction conditions are mild, selectivity
is high, and yield is also good. It is possible to obtain the target product
of a high purity by the purification step, which can easily be conducted.
Furthermore, it is not necessary to use a highly toxic catalyst, the reaction
apparatus is simple, and the operation is also easy. Thus, the present
invention is extremely useful as a process for industrially producing an
α,α-difluoroaromatic compound.
[0022] It is possible by the present invention to obtain the target product
with a remarkably high yield, as compared with Non-patent Publication 3.
In fact, in case that 1-bromo-4-(1,1-difluoroethyl)benzene is similarly
produced by using ether as the reaction solvent with reference to the
liquid phase method of Non-patent Publication 3, the target product is
produced by only a very small amount (Comparative Example 7 of this
specification), as compared with that of Examples 1 and 2 of the present
invention respectively using chloroform and toluene as the reaction
solvents. Furthermore, since the target product is produced by only very
small amounts even under neat condition using no reaction solvent

(Comparative Examples 5 and 6 of this specification), the necessity of
using a reaction solvent and the importance of using an aromatic-series or
halogen-series reaction solvent, not an ether-series reaction, are clear.
DETAILED DESCRIPTION
[0023] The α,α-difluoroaromatic compound production process of the
present invention is explained in detail.
[0024] The scope of the present invention is not limited to these
explanations. Besides the following exemplary description, it is possible
to implement the invention with a suitable modification to the extent of
not deviating from the gist of the present invention. All the publications
cited in the present specification, such as prior art publications, patent
publications like patent application publications and patent applications,
and other non-patent publications and books, are incorporated by
reference into the present specification.
[0025] Each of R1 and R2 of the 1-chloro-1-aromatic ring substituted
ethene represented by the general formula [1] independently represents a
hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic
ring group, or a substituted aromatic ring group. In particular, it is
preferable that both R1 and R2 are hydrogen atoms. The alkyl group is of
C1-18 straight-chain or branched chain or cyclic (in case that the number of
carbon atoms is at least three). The aromatic ring groups are CMS
aromatic hydrocarbons, such as phenyl group, naphthyl group and
anthryl group, or hetero atom (e.g., nitrogen atom, oxygen atom or sulfur
atom) containing, aromatic heterocyclic groups, such as pyrrolyl group
(containing its nitrogen-protecting groups), pyridyl group, furyl group,

thienyl group, indolyl group (containing its nitrogen-protecting groups),
quinolyl group, benzofuryl group and benzothienyl group. The
substituted alkyl group and the substituted aromatic ring group have
substituents by an arbitrary number and an arbitrary combination on
arbitrary carbon atoms or nitrogen atoms of their alkyl group and
aromatic ring group. Such substituents are halogen atoms of fluorine,
chlorine, bromine and iodine, nitro group, lower alkyl groups such as
methyl group, ethyl group and propyl group, lower haloalkyl groups such
as fluoromethyl group, chloromethyl group and bromomethyl group, lower
alkoxy groups such as methoxy group, ethoxy group and propoxy group,
lower haloalkoxy groups such as fluoromethoxy group, chloromethoxy
group and bromomethoxy group, lower acyloxy groups such as formyloxy
group, acetyloxy group, propionyloxy group and butyryloxy group, cyano
group, lower alkoxycarbonyl groups such as methoxycarbonyl group,
ethoxycarbonyl group and propoxycarbonyl group, aromatic ring groups
such as phenyl group, naphthyl group, anthryl group, pyrrolyl group
(containing its nitrogen-protecting groups), pyridyl group, furyl group,
thienyl group, indolyl group (containing its nitrogen-protecting groups),
quinolyl group, benzofuryl group and benzothienyl group, carboxyl group,
carboxyl-protecting groups, amino group, amino-protecting groups,
hydroxyl group, hydroxyl-protecting groups, etc. Furthermore, in the
substituted alkyl group, arbitrary carbon-carbon single bonds of the alkyl
group can also be replaced with carbon-carbon double bonds or
carbon-carbon triple bonds by an arbitrary number and an arbitrary
combination (It is natural that the alkyl groups having these unsaturated

bonds partially substituted can also similarly have the substituents.
Furthermore, there is also a possibility that hydrogen fluoride is added to
these unsaturated bonds, but it is possible to selectively conduct only a
desired reaction by choosing preferable reaction conditions of the present
invention.). In the present specification, "lower" means one being Ci-e,
straight-chain or branched chain or cyclic (in the case of having at least
three carbon atoms). The aromatic ring groups of the above-mentioned
"such substituents" can also be replaced with halogen atoms, nitro group,
lower alkyl groups, lower haloalkyl groups, lower alkoxy groups, lower
haloalkoxy groups, formyloxy group, lower acyloxy groups, cyano group,
lower alkoxycarbonyl groups, carboxyl group, carboxyl-protecting groups,
amino group, amino-protecting groups, hydroxyl group,
hydroxyl-protecting groups, etc. Furthermore, the protective groups of
the pyrrolyl group, the indolyl group, the carboxyl group, the amino group,
and the hydroxyl group are protective groups described in Protective
Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons,
Inc., etc.
[0026] Ar1 of the 1-chloro-1-aromatic ring substituted ethene
represented by the general formula [1] represents an aromatic ring group
or a substituted aromatic ring group. The aromatic ring group and the
substituted aromatic ring group are the same as those described for R1
and R2 of the 1-chloro-1-aromatic ring substituted ethene represented by
the general formula [1]. In particular, an aromatic hydrocarbon group or
a substituted aromatic hydrocarbon group is preferable.

[0027] Ar1 and R1, Ar1 and R2, or R1 and R2 of the 1-chloro-1-aromatic
ring substituted ethene represented by the general formula [1] can also
form a ring structure by a covalent bond. Specifically, between Ar1 and
R1, Ar1 and R2, or R1 and R2, a ring structure (e.g., monocyclic, condensed
polycyclic, crosslinked, spiro-ring, ring assembly, etc.) can also be formed
by a covalent bond by arbitrary carbon atoms (it is also possible to
interpose a hetero atom, such as nitrogen atom, oxygen atom or sulfur
atom, etc.) by an arbitrary number and an arbitrary combination
[excluding a substituent (hydrogen atom) that is not capable of being
involved with the covalent bond].
[0028] The 1-chloro-1-aromatic ring substituted ethene represented by
the general formula [1] is preferably one in which Ar1 is an aromatic
hydrocarbon group or a substituted aromatic hydrocarbon group, and both
R1 and R2 are hydrogen atoms (corresponding to the 1-chloro-1-aromatic
ring substituted ethene represented by the general formula [3]).
[0029] The 1-chloro-1-aromatic ring substituted ethene represented by
the general formula [1] can similarly be produced with reference to 4th
edition, Jikken Kagaku Koza 19, Organic Synthesis I, hydrocarbons and
halogen compounds, edited by the Chemical Society of Japan, MARUZEN
Co., Ltd., p. 416-460, and 5th edition, Jikken Kagaku Koza 13, Syntheses
of Organic Compounds I, hydrocarbons and halides, MARUZEN Co., Ltd.,
p. 374-443, etc. Depending on the process for preparing the raw material
substrate, in some cases, an α,α-dichloroaromatic compound represented
by the general formula [5],


[in the formula, Ar1 represents an aromatic ring group or a substituted
aromatic ring group, and each of R1 and R2 independently represents a
hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic
ring group, or a substituted aromatic ring group, and Ar1 and R1, Ar1 and
R2, or R1 and R2 can also form a ring structure by a covalent bond
therebetween. The alkyl group, the substituted alkyl group, the
aromatic ring group, and the substituted aromatic ring group are the
same as those described for the 1-chloro-1-aromatic ring substituted
ethene represented by the general formula [1]]
may be contained as a by-product. From this by-product too, the target
substance of the present invention, an α,α-difluoroaromatic compound,
may be obtained with a relatively good yield. Therefore, even when the
1-chloro-1-aromatic ring substituted ethene represented by the general
formula [1] contains the α,α-dichloroaromatic compound represented by
the general formula [5] as a minor component (a relation of
1-chloro-1-aromatic ring substituted ethene > α,α-dichloroaromatic
compound), it is treated as the raw material substrate described in the
claims of the present invention.
[0030] The aromatic-series reaction solvent is a C6-12 aromatic
hydrocarbon, such as benzene, toluene, ethylbenzene, xylene, mesitylene,
etc. This aromatic hydrocarbon can have substituents, such as halogen
atoms of fluorine, chlorine, bromine and iodine, nitro group, cyano group,

lower alkoxycarbonyl groups such as methoxycarbonyl group,
ethoxycarbonyl group and propoxycarbonyl group, etc., on arbitrary
carbon atoms by an arbitrary number and an arbitrary combination.
Specifically, it is possible to mention chlorobenzene, dichlorobenzene,
α,α,α-trifluorotoluene, nitrobenzene, benzonitrile, ethyl benzoate, etc.
[0031] The halogen-series reaction solvent is a C1-8 halogenated alkane
or alkene, such as methylene chloride, chloroform, carbon tetrachloride,
1,2-dichloroethane, trichloroethylene, tetrachloroethylene, etc. As the
halogen atom, besides chlorine, it is possible to choose fluorine, bromine
and iodine, too. It can have halogen atoms by an arbitrary number and
an arbitrary combination on arbitrary carbon atoms.
[0032] As the reaction solvent, in particular, toluene, chlorobenzene,
a,α,α-trifluorotoluene, methylene chloride, chloroform and
1,2-dichloroethane are preferable, and a,α,α-trifluorotoluene, methylene
chloride, chloroform and 1,2-dichloroethane are particularly preferable.
The aromatic-series and halogen-series reaction solvents can be used
singly or in combination. Furthermore, it is also possible to use a
combination of a reaction solvent, such as aliphatic hydrocarbon series
like n-hexane and n-heptane, ether series like diethyl ether and
tetrahydrofuran, ester series like ethyl acetate and n-butyl acetate, amide
series like N,N-dimethylformamide and l,3-dimethyl-2-imidazolidinone,
nitrile series like acetonitrile and propionitrile, dimethylsulfoxide, etc.,
and the aromatic-series and/or halogen-series reaction solvent.
[0033] Usage of the reaction solvent is not particularly limited. It
suffices to use the same by at least 0.05 L (liter), preferably 0.1-10 L,

particularly preferably 0.2-5 L, relative to 1 mol of the 1-chloro-1-aromatic
ring substituted ethene represented by the general formula [1].
[0034] Usage of hydrogen fluoride is not particularly limited. It suffices
to use the same by at least 1.6 mols, preferably 1.8-15 mols, particularly
preferably 2.0-10 mols, relative to 1 mol of the 1-chloro-1-aromatic ring
substituted ethene represented by the general formula [1]. Even its use
by a large excess is not particularly problematic (Example 2), but it is
economically not preferable in the case of assuming an industrial
production process. Furthermore, depending on the method of adding
hydrogen fluoride (Example 7 vs. Example 8), its excessive use may lower
selectivity of the target product (naturally, selectivity is almost not
lowered by choosing a preferable method for the addition, even if it is
excessively used). Furthermore, it is possible to obtain a sufficient
conversion by using the theoretically necessary minimum amount (two
equivalents) (Examples 3 and 7). From these findings, a preferable
usage of hydrogen fluoride is considered to be 2.0-10 mols relative to 1 mol
of the 1-chloro-1-aromatic ring substituted ethene represented by the
general formula [1] (Table 1).
[0035] The method of adding hydrogen fluoride is not particularly
limited, but it is possible to obtain good results on the whole by diluting
the 1-chloro-1-aromatic ring substituted ethene represented by the
general formula [1] with the aromatic-series or halogen-series reaction
solvent and then bubbling hydrogen fluoride in a gas condition into this
solution (Examples 1-3 and 10). It is possible to confirm usefulness of
this addition method even by a comparison between Examples (10 vs. 6

and 7) in which the raw material substrate, the reaction solvent, usage of
hydrogen fluoride and the reaction temperature have been made uniform
(Table 1).
[0036] The reaction temperature is not particularly limited, but it
suffices to conduct that in a range of-50 to +100 °C, preferably -25 to +75
°C, particularly preferably 0 to +50 °C. If the reaction temperature is
high, conversion may lower on the contrary due to that the contact with
hydrogen fluoride (boiling point: 20 °C) does not go well (Example 4). On
the other hand, it is possible to obtain a sufficient conversion even at 0 °C
(Examples 5 and 9). In the case of assuming an industrial production
process, the burden of equipment to conduct that at a lower temperature
(lower than 0 °C) is economically not preferable. Therefore, a preferable
reaction temperature is considered to be 0 to +50 °C (Table 1).
[0037] The reaction time is not particularly limited, but it suffices to
conduct that in a range of 48 hours or less. Since it is different
depending on the raw material substrate, the reaction solvent and the
reaction conditions, it is preferable to monitor the condition of the reaction
progress by analytical means such as gas chromatography, liquid
chromatography, or nuclear magnetic resonance and judge the time when
the decrease of the raw material substrate has become almost not found
as being the end point.
[0038] In the present invention, the target product may be obtained with
a remarkably good yield by conducting the reaction in the presence of an
acid catalyst. It is, however, possible to smoothly conduct the desired
reaction in the absence of an acid catalyst by choosing preferable reaction

conditions of the present invention (acid catalyst is not essential for the
present invention). As such acid catalyst, it is possible to mention
inorganic acids, such as hydrogen chloride, hydrogen bromide, sulfuric
acid, nitric acid, perchloric acid, fluorosulfuric acid, tetrafluoroboric acid,
hexafluorophosphoric acid, hexafluoroantimonic acid, boron trifluoride,
antimony trifluoride, antimony pentafluoride, antimony trichloride,
antimony pentachloride, antimony trifluorodichloride, iodine
pentafluoride, iodine heptafluoride, etc., and organic acids, such as
2,2,2-trifluoroethanol, l,l,l,3,3,3-hexafluoro-2-propanol, formic acid,
acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, oxalic
acid, methanesulfonic acid, p-toluenesulfonic acid,
trifluoromethanesulfonic acid, etc. These acid catalysts can be used
singly or in combination.
[0039] It is possible to obtain the α,α-difluoroaromatic compound
represented by the general formula [2] by choosing a general operation in
organic syntheses as a post-treatment. According to need, a crude
product can be purified to have a high purity by activated carbon
treatment, fractional distillation, recrystallization, column
chromatography, or the like.
[0040] In the present invention, depending on the raw material
substrate, the reaction solvent and the reaction conditions to be chosen,
an aromatic carboxylic acid fluoride represented by the general formula
[6],


[in the formula, Ar3 represents an aromatic ring group or a substituted
aromatic ring group. The aromatic ring group and the substituted
aromatic ring group are the same as those described for the
1-chloro-1-aromatic ring substituted ethene represented by the general
formula [1]]
may be produced as a byproduct. Since the aromatic carboxylic acid
fluoride is very close to the target product, α,α-difluoroaromatic
compound, in boiling point {the difference of retention time in gas
chromatography of Example 1 was 0.1 minutes [the target product
1-bromo-4-(1,1-difluoroethyl)benzene vs. by-product 4-bromobenzoyl
fluoride], and the difference of retention time in gas chromatography of
Example 3 was 0.2 minutes [the target product 1,1-difluoroethylbenzene
vs. by-product benzoyl fluoride]}, it is not possible to effectively separate
them even by fractional distillation [it is difficult to say that the target
product is a thermally stable compound (Non-Patent Publication 3), and
therefore a fractional distillation to be conducted under high temperature
by spending long hours is originally not a preferable purification method].
[0041] Thus, it has been found that a purification method by selectively
converting an aromatic carboxylic acid fluoride contained as a by-product
into an aromatic carboxylic acid or aromatic carboxylic acid amide, which
is greatly different in properties (solubility, boiling point, etc.) to remove
the same is very effective for obtaining a high-purity product of the target
product. Specifically, the target product (the reaction-terminated liquid,
the recovered organic layer, a crude product, a distilled product, etc.)
containing by-products is subjected to hydrolysis or amidation

(aminolysis) to selectively convert only the by-products while the target
product is in an unreacted condition. Thus, it is possible to easily obtain
a high-purity product by a simple liquid separation operation, a simple
distillation, which is small in thermal load, or the like. Based on the
conversion conditions of aliphatic or aromatic carboxylic acid chlorides
frequently used in organic syntheses, it is possible to similarly choose the
conversion conditions of the hydrolysis and the amidation. It is possible
to similarly choose them, based on, for example, Shin Jikken Kagaku
Koza 14, Syntheses and Reactions of Organic Compounds [II], edited by
the Chemical Society of Japan, MARUZEN Co., Ltd., p. 921-1000 and
1134-1189, 4th Edition, Jikken Kagaku Koza 22, Organic Syntheses VI,
Amino Acids and Peptides, MARUZEN Co., Ltd., p. 1-43 and 137-173, 5th
Edition, Jikken Kagaku Koza 16, Syntheses of Organic Compounds IV,
Carboxylic Acids, Amino Acids and Peptides, MARUZEN Co., Ltd., p. 1-34
and 118-154, or Protective Groups in Organic Synthesis, Third Edition,
1999, John Wiley & Sons, Inc., etc.
[0042] Specific conversion examples of the hydrolysis and the amidation
are described in the following, but they are not limited to these.
[0043] As the hydrolysis, it is easy and effective to conduct an operation
by washing the reaction-terminated liquid or the recovered organic layer,
etc. with an 0.1-50 % alkaline aqueous solution such as lithium hydroxide,
sodium hydroxide, potassium hydroxide or cesium hydroxide, etc. Usage
of these alkaline aqueous solutions is not particularly limited. It suffices
that the aqueous layer after the washing has a pH of 9 or higher.

[0044] By choosing such conversion condition, the hydrolyzed aromatic
carboxylic acid takes a form of the corresponding alkali metal salt. Such
condition is also treated as being contained in "by converting into an
aromatic carboxylic acid" mentioned in the claim.
[0045] The amidation is conducted by using ammonia or a C1-18 aliphatic
or aromatic amine, such as methylamine, dimethylamine, ethylamine,
diethylamine, n-propylamine, di-n-propylamine, isopropylamine,
diisopropylamine, n-butylamine, di-n-butylamine, aniline, o-toluidine,
nrtoluidine, p-toluidine, etc. Usage of these ammonia or the aliphatic or
aromatic amines, etc. is not particularly limited. It suffices to use the
amount at which free ammonia or the aliphatic or aromatic amine, etc.
remain, even after the conversion of by-products.
[0046] The reaction temperature of the hydrolysis or amidation is not
particularly limited. It suffices to conduct that in a range of-30 to +100
°C, preferably -20 to +75 °C, particularly preferably -10 to +50 °C.
[0047] The reaction time of the hydrolysis or amidation is not
particularly limited. It suffices to conduct that in a range of 24 hours or
less. It is different depending on the content and the conversion
conditions of the by-product, it is preferable to monitor the condition of the
conversion progress by analytical means such as gas chromatography,
liquid chromatography, or nuclear magnetic resonance and judge the time
when the decrease of the by-product has become almost not found as being
the end point.
[0048] Since the aromatic carboxylic acid (containing the corresponding
alkali metal salt) converted by the hydrolysis has been transferred into an

alkali aqueous solution, it can be removed by an easy liquid separation
operation. Furthermore, since the aromatic carboxylic acid amide
converted by the amidation becomes remarkably high in boiling point, it
can be removed as still residue by a simple distillation (containing flush
distillation), which is small in thermal load.
[0049]
[Examples]
In the following, embodiments of the present invention are
explained in detail by examples, but the present invention is not limited
to these examples.
[Example 1]
[0050] A fluororesin-lined reaction container was charged with 77.4 g of
1-chloro-1-aromatic ring substituted ethene (gas chromatography purity:
74.6 %', α,α-dichloroaromatic compound: 21.2 %, the total: 330 mmol, 1.00
eq) represented by the following formula,

and 294 mL (0.891 L/mol) of chloroform. Into this solution, at 20 °C, 52.3
g (2.61 mol, 7.91 eq) of hydrogen fluoride was bubbled in a gas condition
by spending 4 hours and 20 minutes while accompanied by nitrogen gas (a
purge line was installed to avoid a pressurized condition, and the purge
line was cooled at 0 °C to prevent scattering of chloroform), followed by
stirring for 1 hour and 30 minutes at the same temperature. Nitrogen
gas was bubbled into the reaction-terminated liquid for 1 hour (to purge

the remaining hydrogen chloride and hydrogen fluoride), followed by
washing with 300 mL of 5 % sodium hydrogencarbonate aqueous solution
(the aqueous solution: pH 8) and then drying with anhydrous magnesium
sulfate. By gas chromatography of the recovered organic layer,
conversion and purity of α,α-difluoroaromatic compound represented by
the following formula,

were respectively 100 % and 89.3 % (4-bromoacetophenone: 4.7 %). The
recovered organic layer was concentrated under reduced pressure to
obtain 94.0 g of a crude product of α,α-difluoroaromatic compound. The
total of the crude product was subjected to a fractional distillation (boiling
point: 64-71 °C; the degree of decompression: 0.6-0.5 kPa) to obtain 55.4 g
of a purified product. The purified product had a gas chromatography
purity of 98.6 % (4-bromoacetophenone: 0.3 %). The purity-converted
yield was 75 %. In the purified product, an aromatic carboxylic acid
fluoride represented by the following formula,

was contained by 0.9 %. The difference of retention time between the
α,α-difluoroaromatic compound and the aromatic carboxylic acid fluoride
in gas chromatography was 0.1 minutes. 1H and 19F-NMR of the purified
product are shown in the following.

[0051] 1H-NMR (standard substance: Me4Si; deuterated solvent: CDCl3),
5 ppm; 1.89 (t, 3H), 7.46 (Ar-H, 4H).
[0052] 19F-NMR (standard substance: C6F6; deuterated solvent: CDCl3),
5 ppm; 73.93 (q, 2F).
[Example 2]
[0053] A fluorore sin-lined reaction container was charged with 3.00 g of
1-chloro-l'aromatic ring substituted ethene (gas chromatography purity:
86.4 %', α,α-dichloroaromatic compound: 10.8 %, the total: 13.2 mmol, 1.00
eq) represented by the following formula,

and 31.2 mL (2.36 L/mol) of toluene. Into this solution, at 20 °C, 18.9 g
(945 mmol, 71.6 eq) of hydrogen fluoride was bubbled in a gas condition by
spending 1 hour and 10 minutes while accompanied by nitrogen gas (a
purge line was installed to avoid a pressurized condition, and the purge
line was cooled at 0 °C to prevent scattering of toluene), followed by
stirring for 2 hours and 25 minutes at the same temperature. The same
post-treatment operation as that of Example 1 was conducted. By gas
chromatography of the recovered organic layer, conversion and purity of
α,α-difluoroaromatic compound represented by the following formula,


were respectively 100 % and 81.8 % (4-bromoacetophenone: 3.5 %). In
the recovered organic layer, an aromatic carboxylic acid fluoride
represented by the following formula,

was contained by 1.6 %. 1H and 19F-NMR of the α,α-difluoroaromatic
compound contained in the recovered organic layer were the same as
those in Example 1.
[Example 3]
[0054] A fluororesin-lined reaction container was charged with 100 g of
1-chloro-1-aromatic ring substituted ethene (gas chromatography purity:
99.3 %; α,α-dichloroaromatic compound: 0.3 %, the total: 718 mmol, 1.00
eq) represented by the following formula,

and 380 mL (0.529 L/mol) of chloroform. Into this solution, at 20 °C, 51.9
g (2.59 mol, 3.61 eq) of hydrogen fluoride was bubbled in a gas condition
by spending 4 hours while accompanied by nitrogen gas (a purge line was
installed to avoid a pressurized condition, and the purge line was cooled at
0 °C to prevent scattering of chloroform), followed by stirring for 1 hour
and 5 minutes at the same temperature. Nitrogen gas was bubbled into
the reaction-terminated liquid for 1 hour and 5 minutes (to purge the
remaining hydrogen chloride and hydrogen fluoride), followed by washing

with 300 mL of 5 % sodium hydrogencarbonate aqueous solution (the
aqueous solution: pH 8). By gas chromatography of the recovered
organic layer, conversion and purity of α,α-difluoroaromatic compound
represented by the following formula,

were respectively 100 % and 92.6 % (acetophenone: 1.0 %). The
recovered organic layer was concentrated under reduced pressure to
obtain 230 g of a crude product of α,α-difluoroaromatic compound. The
total of the crude product was subjected to a fractional distillation (boiling
point: 40-61 °C; the degree of decompression: 5.2-1.8 kPa) to obtain 77.5 g
of a purified product. The purified product had a gas chromatography
purity of 99.5 % (acetophenone: less than 0.1 %). The purity-converted
yield was 76 %. In the purified product, an aromatic carboxylic acid
fluoride represented by the following formula,

was contained by 0.2 %. The difference of retention time between the
α,α-difluoroaromatic compound and the aromatic carboxylic acid fluoride
in gas chromatography was 0.2 minutes. 1H and 19F-NMR of the purified
product are shown in the following.
[0055] 1H-NMR (standard substance-- Me4Si; deuterated solvent: CDC13),
δ ppm; 1.92 (t, 3H), 7.47 (Ar-H, 5H).

[0056] 19F-NMR (standard substance: C6F6; deuterated solvent: CDCl3),
δ ppm; 74.02 (q, 2F).
[Example 4]
[0057] A fluororesin-lined reaction container was charged with 10.0 g of
1-chloro-1-aromatic ring substituted ethene (gas chromatography purity:
100 %; 46.0 mmol, 1.00 eq) represented by the following formula,

and 38.0 mL (0.826 L/mol) of chloroform. Into this solution, at 50 °C,
12.2 g (610 mmol, 13.3 eq) of hydrogen fluoride was bubbled in a gas
condition by spending 5 hours while accompanied by nitrogen gas (a purge
line was installed to avoid a pressurized condition, and the purge line was
cooled at 0 °C to prevent scattering of chloroform), followed by stirring for
2 hours and 55 minutes at the same temperature. The same
post-treatment operation as that of Example 1 was conducted. By gas
chromatography of the recovered organic layer, conversion and purity of
α,α-difluoroaromatic compound represented by the following formula,

were respectively 41 % and 24.8 % (4-bromoacetophenone: 0.9 %). In the
recovered organic layer, an aromatic carboxylic acid fluoride represented
by the following formula,


was contained by 0.9 %. 1H and 19F-NMR of the α,α-difluoroaromatic
compound contained in the recovered organic layer were the same as
those in Example 1.
[Example 5]
[0058] A fluororesin-lined reaction container was charged with 10.0 g of
1-chloro-1-aromatic ring substituted ethene (gas chromatography purity:
100 %; 46.0 mmol, 1.00 eq) represented by the following formula,

and 38.0 mL (0.826 L/mol) of chloroform. Into this solution, at 0 °C, 4.00
g (200 mmol, 4.35 eq) of hydrogen fluoride was added in parts in a liquid
condition, followed by stirring for 6 hours and 20 minutes at the same
temperature. The same post-treatment operation as that of Example 1
was conducted. By gas chromatography of the recovered organic layer,
conversion and purity of α,α-difluoroaromatic compound represented by
the following formula,

were respectively 100 % and 50.2 % (4-bromoacetophenone: 18.6 %). In
the recovered organic layer, an aromatic carboxylic acid fluoride
represented by the following formula,


was contained by 1.6 %. 1H and 19F-NMR of the a,ordifluoroaromatic
compound contained in the recovered organic layer were the same as
those in Example 1.
[Example 6]
[0059] A fluororesin-lined, pressure-resistant, reaction container was
charged with 10.0 g of 1-chloro-1-aromatic ring substituted ethene (gas
chromatography purity: 100 %; 46.0 mmol, 1.00 eq) represented by the
following formula,

and 38.0 mL (0.826 L/mol) of chloroform. Into this solution, at 0 °C, 3.65
g (182 mmol, 3.96 eq) of hydrogen fluoride was added in parts in a liquid
condition, followed by stirring for 3 hours and 25 minutes at 20 °C. The
same post-treatment operation as that of Example 1 was conducted. By
gas chromatography of the recovered organic layer, conversion and purity
of α,α-difluoroaromatic compound represented by the following formula,

were respectively 100 % and 65.9 % (4-bromoacetophenone: 14.0 %). In
the recovered organic layer, an aromatic carboxylic acid fluoride
represented by the following formula,


was contained by 1.1 %. Yield of the recovered organic layer according to
internal standard method (19F-NMR, standard substance^
hexafluorobenzene) was 54 %. 1H and 19F-NMR of the
α,α-difluoroaromatic compound contained in the recovered organic layer
were the same as those in Example 1.
[Example 7]
[0060] A fluororesin-lined, pressure-resistant, reaction container was
cooled in an iced bath and charged with 2.92 g (146 mmol, 3.17 eq) of
hydrogen fluoride in a liquid condition. To the hydrogen fluoride, there
was added a chloroform solution [usage of the solvent: 38.0 mL (0.826
L/mol)] of 1-chloro-1-aromatic ring substituted ethene amounting to 10.0 g
(gas chromatography purity: 100%, 46.0 mmol, 1.00 eq) and represented
by the following formula,

followed by stirring at 20 °C for 3 hours. The same post-treatment
operation as that of Example 1 was conducted. By gas chromatography
of the recovered organic layer, conversion and purity of
α.α-difluoroaromatic compound represented by the following formula,


were respectively 99 % and 60.8 % (4-bromoacetophenone: 19.4 %). In
the recovered organic layer, an aromatic carboxylic acid fluoride
represented by the following formula,

was contained by 1.1 %. Yield of the recovered organic layer according to
internal standard method (19F-NMR, standard substance:
hexafluorobenzene) was 44 %. 1H and 19F-NMR of the
α,α-difluoroaromatic compound contained in the recovered organic layer
were the same as those in Example 1.
[Example 8]
[0061] A fluororesin-lined, pressure-resistant, reaction container was
cooled in an iced bath and charged with 9.20 g (460 mmol, 10.0 eq) of
hydrogen fluoride in a liquid condition. To the hydrogen fluoride, there
was added a chloroform solution [usage of the solvent: 38.0 mL (0.826
L/mol)] of 1-chloro-1-aromatic ring substituted ethene amounting to 10.0 g
(gas chromatography purity: 100%, 46.0 mmol, 1.00 eq) and represented
by the following formula,


followed by stirring at 20 °C for 3 hours. The same post-treatment
operation as that of Example 1 was conducted. By gas chromatography
of the recovered organic layer, conversion and purity of
α,α-difluoroaromatic compound represented by the following formula,

were respectively 100 % and 41.0 % (4-bromoacetophenone: 44.4 %). In
the recovered organic layer, an aromatic carboxylic acid fluoride
represented by the following formula,

was contained by 2.4 %. 1H and 19F-NMR of the α,α-difluoroaromatic
compound contained in the recovered organic layer were the same as
those in Example 1.
[Example 9]
[0062] A fluororesin-lined reaction container was cooled in an iced bath
and charged with a chloroform solution [usage of the solvent: 38.0 mL
(0.846 L/mol)] of hydrogen fluoride amounting to 3.60 g (180 mmol, 4.01
eq). To this solution, at 0-3 °C, there was 9.77 g (gas chromatography
purity: 100 %, 44.9 mmol, 1.00 eq) of 1-chloro-1-aromatic ring substituted
ethene represented by the following formula,


by spending 36 minutes, followed by stirring at the same temperature for
5 minutes. The same post-treatment operation as that of Example 1 was
conducted. By gas chromatography of the recovered organic layer,
conversion and purity of α,α-difluoroaromatic compound represented by
the following formula,

were respectively 91 % and 58.8 % (4-bromoacetophenone: 18.1 %). In
the recovered organic layer, an aromatic carboxylic acid fluoride
represented by the following formula,

was contained by 1.9 %. Yield of the recovered organic layer according to
internal standard method (19F-NMR, standard substance:
hexafluorobenzene) was 46 %. 1H and 19F-NMR of the
α,α-difluoroaromatic compound contained in the recovered organic layer
were the same as those in Example 1.
[Example 10]
[0063] A fluororesin-lined reaction container was charged with 50.0 g
(gas chromatography purity: 100 %, 230 mmol, 1.00 eq) of
1-chloro-1-aromatic ring substituted ethene represented by the following
formula,


and 190 mL (0.826 L/mol) of chloroform. Into this solution, at 20 °C, 17.6
g (880 mmol, 3.83 eq) of hydrogen fluoride was bubbled in a gas condition
by spending 2 hours while accompanied by nitrogen gas (a purge line was
installed to avoid a pressurized condition, and the purge line was cooled at
0 °C to prevent scattering of chloroform), followed by stirring for 1 hour
and 20 minutes at the same temperature. Nitrogen gas was bubbled into
the reaction-terminated liquid (to purge the remaining hydrogen chloride
and hydrogen fluoride), followed by adding 300 mL of 5 % sodium
hydroxide aqueous solution, then stirring and washing at 20 °C for 1 hour
(pH of the aqueous layer: 11 corresponding to a hydrolysis of an aromatic
carboxylic acid fluoride by a two-phase system), then drying with
anhydrous magnesium sulfate, and then concentration under reduced
pressure, thereby obtaining 111 g of a crude product of
α,α-difluoroaromatic compound represented by the following formula.

The total of the crude product was subjected to a simple distillation
(boiling point: 52-53 °C; the degree of decompression: 0.4 kPa) to obtain
26.2 g of a purified product. The purified product had a gas
chromatography purity of 99.7 % (4-bromoacetophenone: 0.1 %). The

δ ppm; 5.54 (d, 1H), 5.77 (d, 1H), 7.52 (Ar-H, 2H), 7.62 (Ar-H, 2H).
[Reference Example 2]
[0068] 1.84 g (11.2 mmol, 0.00560 eq) of 2,2'-azobisisobutyronitrile was
added to 212 g (2.00 mmol, 1.00 eq) of ethylbenzene represented by the
following formula.

purity-converted yield was 51 %. In the purified product, an aromatic
carboxylic acid fluoride represented by the following formula,

was not contained at all (no detection).
[0064] Incidentally, by gas chromatography of the reaction-terminated
liquid, conversion and purities of the α,α-difluoroaromatic compound and
the aromatic carboxylic acid fluoride were respectively 99 %, 74.4 %
(4-bromoacetophenone: 16.5 %) and 0.7 %.
[Reference Example 1]
[0065] To 289 mL (0.576 L/mol) of toluene, there were added 131 g (629
mmol, 1.25 eq) of phosphorus pentachloride and 100 g (502 mmol, 1.00 eq)
of 4-bromoacetophenone represented by the following formula.

While the oil bath temperature was set at 73 °C, stirring was conducted
for 3 hours (hydrogen chloride was generated). To the
reaction-terminated liquid, 116 mL of toluene was added, followed by
pouring into 300 mL of iced water. The recovered organic layer was
washed with 200 mL of water, then washed with 200 mL of 10 % brine,
and then concentration under reduced pressure, thereby obtaining 154 g
of a crude product of 1-chloro-1-aromatic ring substituted ethene
represented by the following formula.

purity-converted yield was 51 %. In the purified product, an aromatic
carboxylic acid fluoride represented by the following formula,

was not contained at all (no detection).
[0064] Incidentally, by gas chromatography of the reaction-terminated
liquid, conversion and purities of the α,α-difluoroaromatic compound and
the aromatic carboxylic acid fluoride were respectively 99 %, 74.4 %
(4-bromoacetophenone: 16.5 %) and 0.7 %.
[Reference Example 1]
[0065] To 289 mL (0.576 L/mol) of toluene, there were added 131 g (629
mmol, 1.25 eq) of phosphorus pentachloride and 100 g (502 mmol, 1.00 eq)
of 4-bromoacetophenone represented by the following formula.

While the oil bath temperature was set at 73 °C, stirring was conducted
for 3 hours (hydrogen chloride was generated). To the
reaction-terminated liquid, 116 mL of toluene was added, followed by
pouring into 300 mL of iced water. The recovered organic layer was
washed with 200 mL of water, then washed with 200 mL of 10 % brine,
and then concentration under reduced pressure, thereby obtaining 154 g
of a crude product of 1-chloro-1-aromatic ring substituted ethene
represented by the following formula.


[0066] The total of the crude product of the above-obtained
1-chloro-1-aromatic ring substituted ethene was subjected to a fractional
distillation (boiling point: 92-104 °C; and the degree of decompression: 0.3
kPa) to obtain 77.4 g of a purified product. Gas chromatography purity
of the purified product was 74.6 %, and α,α-dichloroaromatic compound
represented by the following formula,

and 4-bromoacetophenone were contained by 21.2 % and 1.7 %,
respectively. The purity-converted yield (including the
α,α-dichloroaromatic compound, too) was 66 %. 1H-NMR of the purified
product is shown in the following.
[0067] 1H-NMR (standard substance:. Me4Si; deuterated solvent: CDC13),
δ ppm; 5.54 (d, 1H), 5.77 (d, 1H), 7.52 (Ar-H, 2H), 7.62 (Ar-H, 2H).
[Reference Example 2]
[0068] 1.84 g (11.2 mmol, 0.00560 eq) of 2,2'-azobisisobutyronitrile was
added to 212 g (2.00 mmol, 1.00 eq) of ethylbenzene represented by the
following formula.


While it was stirred at an internal temperature of 20-50 °C, chlorine (Cl2)
gas was bubbled thereinto at 1.00 mol/hour for 4 hours and 30 minutes
(4.50 mol in total, 2.25 eq; α,α-dichlorination), followed by stirring at an
internal temperature of 113-134 °C for 2 hours and 30 minutes
(dehydrochlorination). The same reaction was repeated, and the
reaction-terminated liquids were brought together, followed by a
fractional distillation (boiling point: 86 °C, the degree of decompression:
3.5 kPa), thereby obtaining 288 g of a purified product of
1-chloro-1-aromatic ring substituted ethene represented by the following
formula.

Gas chromatography purity of the purified product was 99.5 %
(α,α-dichloroaromatic compound was not contained). Purity-converted
yield was 52 %. 1H-NMR of the purified product is shown in the
following.
[0069] 1H-NMR (standard substance: Me4Si; deuterated solvent: CDCl3),
δ ppm; 5.52 (m, 1H), 5.76 (m, 1H), 7.36 (ArH, 3H), 7.63 (Ar-H, 2H).
[Comparative Example 1]
[0070] A fluororesin-lined reaction container was charged with 220 mg
(11.0 mmol, 19.9 eq) of hydrogen fluoride and 0.300 mL (0.543 L/mol) of
methylene chloride, followed by cooling at 5 °C, adding 100 mg (0.552
mmol, 1.00 eq) of 1-bromo-4-ethynylbenzene (a two-phase system)
represented by the following formula,


and then a vigorous stirring at the same temperature for 2 hours. The
reaction-terminated liquid was diluted with 5 mL of chloroform, washed
with 5 mL of water, and then washed with 5 mL of 5 % potassium
carbonate aqueous solution. As a result of a quantitative determination
of the recovered organic layer with an internal standard method (internal
standard substance: a,α,α-trifluorotoluene) by 19F-NMR,
1-bromo-4-(1,1-difluoroethyl)benzene represented by the following
formula,

was contained by only less than 27.6 µmol. Yield by the internal
standard method was less than 5 %. By gas chromatography of the
recovered organic layer, conversion and purity were respectively 100 %
and 0.6 % (4-bromoacetophenone: 87.5 %).
[Comparative Example 2]
[0071] To 1.00 g (8.32 mmol, 1.00 eq) of acetophenone represented by the
following formula,

4.37 g (20.8 mmol, 2.50 eq) of trifluoroacetic anhydride was added,
followed by stirring at 35 °C for four days. By gas chromatography of the

reaction-terminated liquid, conversion and purities of an acylal having
two of CF3CO2 groups represented by the following formula,

and an enol trifluoroacetate represented by the following formula,

were respectively 52 %, 15.2 %, and 16.4 %. The reaction-terminated
liquid was subjected to a post-treatment that was the same as that of
Example 1 of Japanese Patent Application Publication Heisei 1-199922
and then the same fluorination step, but α,α-difluoroethylbenzene
represented by the following formula,

was contained by only less than 0.832 mmol. Yield by the internal
standard method was less than 10 %.
[0072] Apart from the above, the same acylal preparation and
fluorination step were conducted by using 4-bromoacetophenone as a raw
material substrate, but yield of the corresponding
1-bromo-4-(1,1-difluoroethyl)benzene was around 15 %.
[0073] On the other hand, cyclohexanone provided
1,1-difluorocyclohexane with a yield of 87 %.
[Comparative Example 3]

[0074] A fluororesin-lined reaction container was immersed in a coolant
bath of-5 °C and then charged with 3.45 g (172 mmol, 20.0 eq) of
hydrogen fluoride, 2.00 g (8.61 mmol, 1.00 eq) of a fluorine-containing enol
sulfate represented by the following formula,

0.200 mL (0.0232 L/mol) of chloroform and 196 mg (1.72 mmol, 0.200 eq)
of trifluoroacetic acid, followed by stirring at -5 °C for 3 hours and 15
minutes. The reaction-terminated liquid was diluted with 10 mL of
chloroform, followed by washing two times with 10 mL and 5 mL of water,
washing with 10 mL of 10 % potassium carbonate aqueous solution, and
then washing with 5 mL of 10 % brine. As a result of a quantitative
determination of the recovered organic layer with an internal standard
method (internal standard substance: hexafluorobenzene) by 19F-NMR, a
gem-difluoro compound represented by the following formula,

was contained by 6.59 mmol. Yield by the internal standard method was
77 %. 19F-NMR is shown in the following.
[0075] 19F-NMR (standard substance: C6F6, deuterated solvent: CDC13),
δ ppm; 71.45 (m, 2F).
[Comparative Example 4]

[0076] A fluororesin-lined reaction container was immersed in a coolant
bath of-5 °C and then charged with 1.56 g (78.0 mmol, 19.7 eq) of
hydrogen fluoride, 1.00 g (3.96 mmol, 1.00 eq) of a fluorine-containing enol
sulfate represented by the following formula,

0.100 mL (0.0253 L/mol) of chloroform and 90.3 mg (0.792 mmol, 0.200 eq)
of trifluoroacetic acid, followed by stirring at -5 °C for 3 hours. The
reaction-terminated liquid was diluted with 5 mL of chloroform, followed
by washing two times with 5 mL and 2.5 mL of water, washing with 5 mL
of 10 % potassium carbonate aqueous solution, and then washing with 2.5
mL of 10 % brine. As a result of a quantitative determination of the
recovered organic layer with an internal standard method (internal
standard substance: hexafluorobenzene) by 19F-NMR, a gem-difluoro
compound represented by the following formula,

was contained by only less than 0.396 mmol. Yield by the internal
standard method was less than 10 %.
[Comparative Example 5]
[0077] A fluororesin-lined reaction container was charged with 1.84 g
(92.0 mmol, 20.4 eq) of hydrogen fluoride, followed by cooling at -5 °C ,
adding 1.06 g (gas chromatography purity: 74.6 %; α,α-dichloroaromatic

compound: 21.2 %, the total: 4.52 mmol, 1.00 eq) of 1-chloro-1-aromatic
ring substituted ethene (a two-phase system) represented by the following
formula,

and stirring at the same temperature for 30 minutes and at 5 °C for 1
hour. The reaction-terminated liquid was diluted with chloroform,
followed by conducting the same post-treatment as that of Example 1.
By gas chromatography of the recovered organic layer, conversion and
purity of α,α-difluoroaromatic compound represented by the following
formula,

were respectively 100 % and less than 10.0 % (4-bromoacetophenone:
63.5 %).
[Comparative Example 6]
[0078] A fluororesin-lined, pressure-resistant reaction container was
charged with 10.0 g (gas chromatography purity: 100 %, 46.0 mmol, 1.00
eq) of 1-chloro-1-aromatic ring substituted ethene represented by the
following formula.


To the raw material substrate, 2.92 g (146 mmol, 3.17 eq) of hydrogen
fluoride was added at 0 °C in parts in a liquid condition, followed by
stirring at 20 °C for 3 hours. The reaction-terminated liquid was diluted
with chloroform, followed by conducting the same post-treatment as that
of Example 1. By gas chromatography of the recovered organic layer,
conversion and purity of α,α-difluoroaromatic compound represented by
the following formula,

were respectively 100 % and 5.1 % (4-bromoacetophenone: 24.5 %). In
the recovered organic layer, an aromatic carboxylic acid fluoride
represented by the following formula,

was contained by 14.4 %. Yield of the recovered organic layer by an
internal standard method (19F-NMR, standard substance:
hexafluorobenzene) was less than 5 %.
[Comparative Example 7]
[0079] A fluororesin-lined, pressure-resistant reaction container was
cooled in an iced bath, followed by adding an ether solution [usage of the
solvent: 23.5 mL (0.568 L/mol)] of hydrogen fluoride of 9.14 g (457 mmol,
11.0 eq). To this solution, 9.00 g (gas chromatography purity: 100 %, 41.4

mmol, 1.00 eq) of 1-chlorco-aromatic ring substituted ethene represented
by the following formula,

was added at 0 °C by spending 30 minutes, followed by stirring at the
same temperature for 5 hours and 30 minutes and at 20 °C throughout
the night. The same post-treatment operation as that of Example 1 was
conducted. By gas chromatography of the recovered organic layer,
conversion and purity of α,α-difluoroaromatic compound represented by
the following formula,

were respectively 48 % and 7.7 % (4-bromoacetophenone: 29.1 %). In the
recovered organic layer, an aromatic carboxylic acid fluoride represented
by the following formula,

was contained by 1.9 %.
[0080] The results of Examples 1-10 and Comparative Examples 5-7 are
summarized in Table 1.


*A: Hydrogen fluoride is bubbled in a gas condition into a solution of the raw material
substrate.
B: Hydrogen fluoride is added in a liquid condition to a solution of the raw material
substrate.
C: A solution of the raw material substrate is added to hydrogen fluoride in a liquid
condition.
D: The raw material substrate is added to a solution of hydrogen fluoride.
E: The raw material substrate is added to hydrogen fluoride in a liquid condition (neat).
F: Hydrogen fluoride is added in a liquid condition to the raw material substrate (neat).

INDUSTRIAL APPLICABILITY
[0084] α,α-difiuoroaromatic compound, which is the target of the present
invention, can be used as an intermediate of medicines and agricultural
chemicals.

WE CLAIM:
1. A process for producing an α,α-difluoroaromatic compound
represented by the general formula [2],

wherein Ar1 represents an aromatic ring group or a substituted
aromatic ring group, and each of R1 and R2 independently represents a
hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic
ring group, or a substituted aromatic ring group, and Ar1 and R1, Ar1 and
R2, or R1 and R2 optionally forms a ring structure by a covalent bond
therebetween,
the process comprising the step of reacting 1-chloro-1-aromatic
ring substituted ethene represented by the general formula [1],

wherein Ar1, R1 and R2 are defined as in the general formula [2],
with hydrogen fluoride using an aromatic-series or halogen-series
reaction solvent.
2. The process as claimed in claim 1, wherein the
1-chloro-1-aromatic ring substituted ethene represented by the general
formula [1] is 1-chloro-1-aromatic ring substituted ethene represented by
the general formula [3],


wherein Ar2 represents an aromatic hydrocarbon group or a
substituted aromatic hydrocarbon group, and the α,α-difluoroaromatic
compound represented by the general formula [2] is an
α,α-difluoroaromatic compound represented by the general formula [4],

wherein Ar2 is defined as in the general formula [3].
3. The process as claimed in claim 1 or claim 2, which is
characterized by that the reaction is conducted by the steps of:
diluting the 1-chloro-1-aromatic ring substituted ethene with the
aromatic-series or halogen-series reaction solvent to form a solution; and
bubbling hydrogen fluoride in a gas condition into the solution.
4. The process as claimed in any one of claim 1 to claim 3, which is
characterized by that usage of the hydrogen fluoride is 2.0-10 mols
relative to 1 mol of the 1-chloro-1-aromatic ring substituted ethene.
5. The process as claimed in any one of claim 1 to claim 4, which is
characterized by that the reaction is conducted at a temperature of from 0
to 50 °C.

6. The process as claimed in any one of claim 1 to claim 5, which is
characterized by that a purification of the α,α-difluoroaromatic compound
is conducted by converting an aromatic carboxylic acid fluoride contained
as a by-product in the α,α-difluoroaromatic compound into an aromatic
carboxylic acid or an aromatic carboxylic acid amide to remove the
aromatic carboxylic acid fluoride from the α,α-difluoroaromatic
compound.