TECHNICAL FIELD
The present invention relates to a novel method for producing a geminal difluoro
compound using an oxime compound as the starting material.
BACKGROUND ART
10 A geminal difluoro compound having, as a partial structure, a group having two
fluorine atoms substituted on one carbon atom, is a compound useful as a
pharmaceutical or agricultural chemical, or as an intermediate thereof (Patent
Document 1), and as the method for producing such a compound, many reactions have
been developed. As a typical one, a difluorination reaction of an oxime compound may
15 be mentioned (Non-Patent Documents 1 to 3).
As the difluorination reaction using an oxime compound as the starting material, a
method of using iodine monofluoride (Non-Patent Document 2) has been reported.
However, iodine monofluoride to be used can be present only at a low temperature, and
in the reaction, in order to generate iodine monofluoride in situ, it is required to put
20 crushed iodine to the reaction solution, and to blow fluorine/nitrogen gas thereto at
-78 C. Therefore, the use of iodine monofluoride involves a problem that it is required
to use special reaction conditions and reaction apparatus (Non-Patent Documents 2
and 4).
Further, a method of using nitrosyl tetrafluoroborate and a hydrogen fluoride25
pyridine complex (Non-Patent Document 3) has also been reported. However, in the
example of its application to the synthesis of 1-phenyl-1,1-difluoroethane derivative, the
target compound is obtained only in low yield (Patent Document 2). Nitrosyl
tetrafluoroborate has a strong hygroscopic property, and therefore, at the time of
conducting the difluorination reaction, it is required to handle it in a dried inert gas, and
30 further, there is a problem such that it is expensive (Non-Patent Documents 5 and 6).
Therefore, a novel method for producing a geminal difluoro compound has been
desired which presents high yield and which is useful also as an industrial production
2
method, without using these reagents.
PRIOR ART DOCUMENTS
PATENT DOCUMENTS
Patent Document 1: WO 2011/154298
5 Patent Document 2: WO 2012/139775
NON-PATENT DOCUMENTS
Non-Patent Document 1: Science of Synthesis, 2007, Vol. 29, pp. 13-61
Non-Patent Document 2: Journal of Organic Chemistry, 1991, Vol. 56, pp. 4695-
4700
10 Non-Patent Document 3: Synlett, 1994, pp. 425-426
Non-Patent Document 4: Chemische Berichte, 1970, Vol. 103, pp. 590-593, pp.
880-884
Non-Patent Document 5: Inorganic Synthesis, 2004, Vol. 33, pp. 75-82
Non-Patent Document 6: Encyclopedia of Reagents for Organic Synthesis, 1995,
15 Vol. 6, pp. 3768-3770
DISCLOSURE OF INVENTION
TECHNICAL PROBLEM
The purpose of the present invention is to provide a method for producing a
20 geminal difluoro compound in high yield, which does not require a special reaction
apparatus or reaction conditions.
SOLUTION TO PROBLEM
As a result of extensive studies, the present inventors have found a novel method
25 for producing a geminal difluoro compound in high yield, by reacting a fluorinating agent
and an oxime compound in the presence of an N-chloroimide compound, and have
accomplished the present invention. That is, the present invention is characterized by
the following.
[1] A method for producing a geminal difluoro compound represented by the formula
30 (2), which is characterized by reacting an oxime compound represented by the formula
(1) with a fluorinating agent, in the presence of an N-chloroimide compound:
3
wherein R1 is C1-4 alkyl, and X is a halogen atom,
wherein R1 and X are as defined above.
[2] The method for producing a geminal difluoro compound according to the above [1],
wherein the N-chloroimide compound is N-chlorosuccinimide, N-chlorophthalimide, 1,3-
dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate or 5 trichloroisocyanuric acid.
[3] The method for producing a geminal difluoro compound according to the above [2],
wherein the N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-
dimethylhydantoin or trichloroisocyanuric acid.
[4] The method for producing a geminal difluoro compound according to any one of
10 the above [1] to [3], wherein the amount of the N-chloroimide compound present, is from
0.1 equivalent to 100 equivalents, to 1 equivalent of the oxime compound of the formula
(1).
[5] The method for producing a geminal difluoro compound according to any one of
the above [1] to [4], wherein the amount of the fluorinating agent used, is from 2 to
15 1,000 equivalents, to 1 equivalent of the oxime compound of the formula (1).
[6] The method for producing a geminal difluoro compound according to any one of
the above [1] to [5], wherein the fluorinating agent is a hydrogen fluoride-pyridine
complex or a poly[4-vinyl pyridinium poly(hydrogen fluoride)].
[7] The method for producing a geminal difluoro compound according to the above [6],
20 wherein the fluorinating agent is a hydrogen fluoride-pyridine complex.
[8] The method for producing a geminal difluoro compound according to the above [7],
wherein the weight ratio of hydrogen fluoride to pyridine in the hydrogen fluoridepyridine
complex is from 70:30 to 20:80.
[9] The method for producing a geminal difluoro compound according to any one of
the above [1] to [5], wherein the fluorinating agent is hydrogen fluoride.
[10] The method for producing a geminal difluoro compound according to any one of
the above [1] to [9], wherein R1 is methyl.
[11] The method for producing a geminal difluoro 5 compound according to any one of
the above [1] to [10], wherein X is a chlorine atom or a bromine atom.
[12] The method for producing a geminal difluoro compound according to the above
[11], wherein X is a bromine atom.
[13] The method for producing a geminal difluoro compound according to any one of
10 the above [1] to [12], wherein the reaction is conducted in the presence of a solvent.
[14] The method for producing a geminal difluoro compound according to the above
[13], wherein the solvent is a halogenated hydrocarbon.
ADVANTAGEOUS EFFECTS OF INVENTION
15 According to the present invention, it is possible to provide a novel production
method whereby a geminal difluoro compound useful as e.g. an intermediate for
medicines or agricultural chemicals, can be obtained in high yield.
DESCRIPTION OF EMBODIMENTS
20 Hereinafter, the present invention will be described in detail.
In this specification, “n-“ means normal, "s-" means secondary, and "t-" means
tertiary.
Further, as used in the description of chemical structures, "(E)" means an E
isomer, and "(Z)" means a Z isomer.
25 "C1-4 alkyl" means a straight or branched chain alkyl having from 1 to 4 carbon
atoms. Specifically, it means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl
or t-butyl.
A "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an
iodine atom.
30 (Method for producing geminal difluoro compound)
5
By reacting an oxime compound represented by the formula (1) (compound (1))
with a fluorinating agent in the presence of an N-chloroimide compound, it is possible to
produce a geminal difluoro compound represented by the formula (2) (compound (2)).
In this specification, the N-chloroimide compound means an imide compound
having a nitrogen atom chlorinated. The N-chloroimide co 5 mpound to be used in the
present invention may, for example, be N-chlorosuccinimide, N-chlorophthalimide, 1,3-
dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate, trichloroisocyanuric acid,
etc. A preferred N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-
dimethylhydantoin or trichloroisocyanuric acid, and more preferred N-chloroimide
10 compound is trichloroisocyanuric acid.
One of these N-chloroimide compounds may be used alone, or two or more of
them may be used as mixed.
Among the N-chloroimide compounds to be used in the present invention,
trichloroisocyanuric acid is known to be used as a fungicide for a pool, a deodorant, etc.
15 Further, trichloroisocyanuric acid is known to be a reagent which has high stability and
is inexpensive (Organic Process Research and Development, 2002, Vol. 6, pp. 384-
393).
The amount of the N-chloroimide compound used, is preferably from 0.1
equivalent to 100 equivalents, more preferably from 0.5 equivalent to 30 equivalents,
20 further preferably from 1 equivalent to 15 equivalents, to the compound (1).
The fluorinating agent to be used in the present invention may, for example, be a
hydrogen fluoride-pyridine complex, a poly[4-vinyl pyridinium poly(hydrogen fluoride)],
etc. A preferred fluorinating agent is a hydrogen fluoride-pyridine complex.
As the fluorinating agent, it is also possible to use hydrogen fluoride.
25 The hydrogen fluoride-pyridine complex having a weight ratio of hydrogen fluoride:
pyridine = 70:30 is known as an Olah reagent (Encyclopedia of Reagents for Organic
Synthesis, 1995, Vol. 6, pp. 4373-4375). The Olah reagent is known to act as
hydrogen fluoride which is stabilized with a low volatility, and thus, it is suitable for
6
industrial use.
The poly[4-vinyl pyridinium poly(hydrogen fluoride)] is a compound composed of a
polymer of a pyridine derivative and hydrogen fluoride (Synlett, 1990, pp 267-269).
With respect to the hydrogen fluoride-pyridine complex to be used in the present
invention, for example, an Olah reagent having 5 a weight ratio of hydrogen fluoride:
pyridine = 70:30, is available from Aldrich, Fluorochem Ltd., etc. Further, one with a
composition having a weight ratio of hydrogen fluoride: pyridine = 60:40, 50:50, 40:60 or
20:80 is, for example, available from Manchester Organics, Inc., and one with a
composition having a weight ratio of hydrogen fluoride: pyridine = 55:45 is, for example,
10 available from Apollo Scientific.
The hydrogen fluoride-pyridine complex to be used in the present invention
preferably has a weight ratio of hydrogen fluoride:pyridine = 70:30 to 20:80. A more
preferred weight ratio is hydrogen fluoride:pyridine = 70:30 to 50:50, and a further
preferred weight ratio is hydrogen fluoride:pyridine = 68:32 to 63:37.
15 The amount of the fluorinating agent to be used in the present invention, is from 2
equivalents to 1,000 equivalents, to 1 equivalent of the oxime compound of the formula
(1), and the preferred amount is from 2 equivalents to 500 equivalents, and the more
preferred amount is from 5 equivalents to 200 equivalents.
The compound (1) to be used in the present invention is meant to be either one
20 oxime compound represented by the formula (1a) or the formula (1b), or a mixture of
compounds of the formula (1a) and the formula (1b).
R1
N
HO
( 1 )
X
(E) (Z)
R1
HO N
R1
N OH
( 1a ) ( 1b )
X X
According to ranking rule, an oxime compound represented by the formula (1a)
has a stereochemical structure of (E), and an oxime compound represented by the
25 formula (1b) has a stereochemical structure of (Z).
A compound having a stereochemical structure of (E) and a compound having a
stereochemical structure of (Z), are geometric isomers to each other, and in many cases,
they can be isolated. In order to obtain one of the isomers, it is also possible to carry
7
out isomerization to a thermodynamically stable isomer by e.g. fractional crystallization,
hydrochloric acid treatment, or the like. In the present invention, it is possible to use
only one isomer of the oxime compounds, or it is also possible to use a mixture of the
oxime compounds of (E) and (Z).
As a usual method for producing 5 an oxime compound, for example, a
condensation reaction of a carbonyl compound with a hydroxylamine may be mentioned,
and the oxime compound can be prepared in accordance with a known method
disclosed in a literature (Comprehensive Organic Functional Group Transformations II,
2005, Vol. 3, pp. 451-467).
10 The solvent to be used in the present invention is not particularly limited so long
as it does not interfere with the reaction, and, as examples thereof, the following may be
mentioned. An alcohol solvent (e.g. methanol, ethanol, 2-propanol), a halogenated
hydrocarbon solvent (e.g. dichloromethane, chloroform, carbon tetrachloride, 1,2-
dichloroethane, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene), an
15 aromatic halogenated hydrocarbon solvent (e.g. chlorobenzene, dichlorobenzene), an
aromatic hydrocarbon solvent (e.g. benzene, toluene, xylene), an aliphatic hydrocarbon
solvent (e.g. hexane, heptane), an amine-type solvent (e.g. triethylamine, N,N-dibutylbutane-
1-amine, 2-methyl-N,N-bis(2-methylbutyl)-1-butanamine, N,N-dimethylaniline), a
pyridine-type solvent (e.g. pyridine, picoline) , an ether solvent (e.g. dimethyl ether,
20 diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl
ether, 1-methoxy-2-(2-methoxyethoxy)ethane), etc.
Preferred is a halogenated hydrocarbon solvent, an amine-type solvent, a
pyridine-type solvent or an ether solvent, more preferred is a halogenated hydrocarbon
solvent, and further preferred is dichloromethane or chloroform.
25 One of these solvents may be used alone, or two or more of them may be used as
mixed.
The amount of the solvent which can be used in the production method of the
present invention, is preferably from 0 time by weight to 1,000 times by weight, more
preferably from 1 time by weight to 100 times by weight, further preferably from 5 times
30 by weight to 50 times by weight, to the oxime compound represented by the formula (1).
The reaction temperature is not particularly limited and is preferably from -78 C to
the reflux temperature of the reaction mixture, more preferably from -60 C to 50 C, and
8
further preferably from -40 C to 30 C. Here, as another embodiment of a preferred
reaction, from the beginning of the reaction to about 7 hours, the temperature is 0 C,
and then, from 3 to 21 hours, the temperature is from 20 C to 30 C.
The total reaction time is within about 28 hours, preferably from 3 to 21 hours.
Further, when using hydrogen fluoride as the fluorinating 5 agent, it is within about 20
hours, preferably from 1 to 5 hours.
EXAMPLES
Now, the present invention will be described in more detail with reference to
10 Reference Synthesis Example and Synthesis Examples, but the present invention is not
limited to these Examples.
In Examples (Synthesis Examples), the proton nuclear magnetic resonance (1H
NMR) was measured in a deuterated chloroform solvent by using JNM-ECP300
manufactured by JEOL, or JNM-ECX300 manufactured by JEOL, and the chemical shift
15 was represented by a δ value (ppm) when tetramethylsilane was used as an internal
standard (0.0 ppm).
In Examples, the fluorine nuclear magnetic resonance (19F NMR) was measured
in a deuterated chloroform solvent by using JNM-ECX300 manufactured by JEOL, and
the chemical shift was represented by a δ value (ppm) when hexafluorobenzene was
20 used as an internal standard (-162.2 ppm).
In the description of the NMR spectra, "s" means singlet, "d" means doublet, "t"
means triplet, "q" means quartet, "m" means multiplet, "br" means broad, "J" means
coupling constant , "Hz" means hertz, and "CDCl3" means deuterated chloroform.
SYNTHESIS EXAMPLE 1
25 Production of 1-(1,1-difluoroethyl)-4-bromobenzene
After replacing inside of a reaction container made of a resin of a
tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (abbreviated as PFA) with
nitrogen gas, a hydrogen fluoride-pyridine complex (10.0 g, weight ratio of [63.8%
9
(hydrogen fluoride):36.2% (pyridine)], 318.8 mmol as hydrogen fluoride, manufactured
by Aldrich) was added to the reaction container and cooled to 0 C. Then, to the
reaction container, trichloroisocyanuric acid (2.70 g, 11.62 mmol) and a
dichloromethane (30.0 g) solution of 1-(4-bromophenyl)ethanone oxime (1.00 g, 4.67
mmol) were sequentially added, and the reaction mi 5 xture was stirred at 0 C for 7 hours.
Further, after the reaction temperature was raised to 20 C, the mixture was stirred at the
same temperature for 3 hours. Then, the reaction was stopped by the addition of
water to the reaction mixture. Then, chloroform was added to the reaction mixture, and
the organic layer was separated. The obtained organic layer was washed with a
10 saturated aqueous solution of sodium hydrogen carbonate and water, and then, the
solvent was distilled off under reduced pressure. The obtained crude product was
purified by silica gel chromatography (eluent: n-hexane) to obtain the desired compound
(0.93 g, yield: 90%) as a colorless liquid.
1H NMR (CDCl3): δ7.56(d, J=8.6Hz, 1H), 7.37(d, J=8.6Hz, 1H), 1.90(t, J=18.3Hz, 3H).
15 19F NMR (CDCl3): δ-88.3(2F, q, J=18.3Hz).
SYNTHESIS EXAMPLE 2
Production of 1-(1,1-difluoroethyl)-4-bromobenzene
After replacing inside of a reaction container made of a resin of PFA with nitrogen
gas, a hydrogen fluoride-pyridine complex (10.0 g, weight ratio of [63.8% (hydrogen
20 fluoride):36.2% (pyridine)], 318.8 mmol as hydrogen fluoride, manufactured by Aldrich)
was added to the reaction container, and cooled to 0 C. Then, to the reaction
container, N-chlorosuccinimide (5.01 g, 37.52 mmol) and a dichloromethane (30.0 g)
solution of 1-(4-bromophenyl)ethanone oxime (1.00 g, 4.67 mmol) were sequentially
added, and the reaction mixture was stirred at 0 C for 3 hours. Further, after the
25 reaction temperature was raised to from, 25 C to 30 C, the mixture was stirred for 21
hours at the same temperature. Then, the reaction was stopped by the addition of
water to the reaction mixture. Then, chloroform was added to the reaction mixture, and
the organic layer was separated. The obtained organic layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and water, and the solvent
30 was distilled off under reduced pressure. The obtained crude product was purified by
silica gel chromatography (eluent: n-hexane) to obtain the desired compound (0.94 g,
yield: 88%) as a colorless liquid.
10
1H NMR (CDCl3): δ7.55 (d, J=8.7Hz, 1H), 7.37(d, J=8.7Hz, 1H), 1.90(t, J=18.2Hz, 3H).
SYNTHESIS EXAMPLE 3
Production of 1-(1,1-difluoroethyl)-4-bromobenzene
After replacing inside of a reaction container made of a resin of PFA with nitrogen
gas, a hydrogen fluoride-pyridine complex (10.0 g, weight r 5 atio of [63.8% (hydrogen
fluoride):36.2% (pyridine)], 318.8 mmol as hydrogen fluoride, manufactured by Aldrich)
was added to the reaction container, and cooled to 0 C. Then, to the reaction
container, 1,3-dichloro-5,5-dimethylhydantoin (4.60 g, 23.35 mmol) and a
dichloromethane (30.0 g) solution of 1-(4-bromophenyl)ethanone oxime (1.00 g, 4.67
10 mmol) were sequentially added, and the reaction mixture was stirred at 0 C for 7 hours.
Further, after the reaction temperature was raised to 20 C, the mixture was stirred at the
same temperature for 3 hours. Then, the reaction was stopped by the addition of
water to the reaction mixture. Then, chloroform was added to the reaction mixture, and
the organic layer was separated. The obtained organic layer was washed with a
15 saturated aqueous solution of sodium hydrogen carbonate and water, and the solvent
was distilled off under reduced pressure. The obtained crude product was purified by
silica gel chromatography (eluent: n-hexane) to obtain the desired compound (0.96 g,
yield: 93%) as a colorless liquid.
1H NMR (CDCl3): δ7.55 (d, J=8.6Hz, 1H), 7.37(d, J=8.6Hz, 1H), 1.90(t, J=18.1Hz, 3H).
20 In the following Synthesis Example 4 to Synthesis Example 6, by using isolated
and purified 1-(1,1-difluoroethyl)-4-bromobenzene as a standard substance, and methyl
4-hydroxybenzoate as an internal standard substance, the reaction yield was calculated
by a quantitative analysis method using a ultra-high performance liquid chromatography.
Ultra-high-performance liquid chromatography: ACQUITY UPLC H-Class, manufactured
25 by Waters Corp.
Column: Waters Acquity UPLC BEH C18 (1.7 μm, 2.1×50 mm) column
Column oven temperature: 40 C
Eluent: acetonitrile: 10 mM aqueous ammonium acetate solution/acetonitrile=100/5 (v/v),
30:70 (0-1 min), 30:70-95:5 (1-3 min), 95:5 (3-5 min), (v/v)
30 Eluent velocity: 0.5 mL/min
Detection wavelength: 230 nm
SYNTHESIS EXAMPLE 4
11
Production of 1-(1,1-difluoroethyl)-4-bromobenzene
After replacing inside of a reaction container made of a resin of PFA with nitrogen
gas, a hydrogen fluoride pyridine complex (1.00 g, weight ratio of [63.8% (hydrogen
fluoride):36.2% (pyridine)], 31.9 mmol as hydrogen fluoride, manufactured by Aldrich)
was added to the reaction container and cooled to 0 C. 5 Then, to the reaction container,
trichloroisocyanuric acid (0.24 g, 1.03 mmol) was added, and then a chloroform (2.01 g)
solution of 1-(4-bromophenyl)ethanone oxime (103.5 mg, 0.484 mmol) was added,
whereupon the reaction mixture was stirred at 0 C for 3 hours. Then, the reaction was
stopped by the addition of chloroform and water to the reaction mixture, and after liquid
10 separation, the organic layer was washed with a saturated aqueous solution of sodium
hydrogen carbonate. The obtained organic layer was quantified, whereby the
quantitative yield of 1-(1,1-difluoroethyl)-4-bromobenzene (desired compound) was 97%.
SYNTHESIS EXAMPLE 5
Production of 1-(1,1-difluoroethyl)-4-bromobenzene
15 After replacing inside of a reaction container made of a resin of PFA with nitrogen
gas, a hydrogen fluoride-pyridine complex (1.00 g, weight ratio of [63.8% (hydrogen
fluoride):36.2% (pyridine)], 31.9 mmol as hydrogen fluoride, manufactured by Aldrich)
was added to the reaction container and cooled to 0 C. Then, to the reaction container,
trichloroisocyanuric acid (0.23 g, 0.99 mmol) was added, and then 1-(4-
20 bromophenyl)ethanone oxime (104.3 mg, 0.487 mmol) was added, whereupon the
reaction mixture was stirred at 0 C for 3 hours and 30 minutes. Then, the reaction was
stopped by the addition of chloroform and water, and after liquid separation, the organic
layer was washed with a saturated aqueous solution of sodium hydrogen carbonate.
The obtained organic layer was quantified, whereby the quantitative yield of 1-(1,1-
25 difluoroethyl)-4-bromobenzene (desired compound) was 94%.
SYNTHESIS EXAMPLE 6
To a reaction container made of a trifluorochloroethylene copolymer resin, 1-(4-
bromophenyl)ethanone oxime (1.00 g, 4.67 mmol) and trichloroisocyanuric acid (2.40 g,
10.33 mmol) were sequentially added. Then, the reaction container was cooled by a
30 dry ice-methanol bath, and under reduced pressure, hydrogen fluoride (11 mL, 551
mmol) was introduced. Then, while maintaining the external temperature of the
reaction container at from -38 to -35 C, the mixture was stirred for 3 hours. Then, the
12
reaction container was cooled by a dry ice-methanol-water bath, and hydrogen fluoride
was distilled off under reduced pressure. Then, to the reaction container, chloroform
and water were added, followed by stirring, whereupon liquid separation was conducted,
and the organic layer was washed with a saturated aqueous solution of sodium
hydrogen carbonate. The obtained organic l 5 ayer was quantified, whereby the
quantitative yield of 1-(1,1-difluoroethyl)-4-bromobenzene (desired compound) was 51%.
REFERENCE SYNTHESIS EXAMPLE 1
Production of 1-(4-bromophenyl)ethanone oxime
After replacing inside of a glass reaction container with nitrogen gas, 4'-
10 bromoacetophenone (50.0 g, 251.31 mmol), ethanol (100 g) and hydroxylamine
hydrochloride (19.6 g, 282.05 mmol) were added to the reaction container, and the
reaction mixture was heated to 72 C. Then, the reaction mixture was stirred at from
72 C to 80 C for 3 hours. Then, the reaction was stopped by cooling the reaction
mixture to 5 C. Then, to the reaction mixture, water (100 g) was added to precipitate a
15 solid, and after filtration, the obtained solid was washed with a mixed solution of ethanol
(50 g) and water (100 g). Further, the obtained solid and ethanol (100 g) were added
to the reaction container, and the mixture was heated to 65 C, whereupon the reaction
mixture was cooled to 4 C, to precipitate a solid again, followed by filtration. The
obtained solid was washed with ethanol (50 g) cooled to 0 C and dried under reduced
20 pressure at 50 C for 3 hours, to obtain the desired compound (26.15 g, yield: 49%) as a
white solid.
1H NMR (CDCl3): δ8.59(s, 1H), 7.50(s, 4H), 2.27(s, 3H).
INDUSTRIAL APPLICABILITY
25 The geminal difluoro compound obtainable by the present invention is useful in a
wide range of fields as e.g. an intermediate for production of medicines, agricultural
chemicals, etc.
The entire disclosure of Japanese Patent Application No. 2014-199055 filed on
N
HO
Br
13
September 29, 2014 including specification, claims and summary is incorporated herein
by reference in its entirety.

CLAIMS
1. A method for producing a geminal difluoro compound represented by the formula
(2), which is characterized by reacting an oxime compound represented by the formula
(1) with a fluorinating agent, in the presence of an N-chloroimide compound:
wherein R 5 1 is C1-4 alkyl, and X is a halogen atom,
wherein R1 and X are as defined above.
2. The method for producing a geminal difluoro compound according to Claim 1,
wherein the N-chloroimide compound is N-chlorosuccinimide, N-chlorophthalimide, 1,3-
dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate or trichloroisocyanuric acid.
10 3. The method for producing a geminal difluoro compound according to Claim 2,
wherein the N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-
dimethylhydantoin or trichloroisocyanuric acid.
4. The method for producing a geminal difluoro compound according to any one of
Claims 1 to 3, wherein the amount of the N-chloroimide compound present, is from 0.1
15 equivalent to 100 equivalents, to 1 equivalent of the oxime compound of the formula (1).
5. The method for producing a geminal difluoro compound according to any one of
Claims 1 to 4, wherein the amount of the fluorinating agent used, is from 2 to 1,000
equivalents, to 1 equivalent of the oxime compound of the formula (1).
6. The method for producing a geminal difluoro compound according to any one of
20 Claims 1 to 5, wherein the fluorinating agent is a hydrogen fluoride-pyridine complex or
a poly[4-vinyl pyridinium poly(hydrogen fluoride)].
7. The method for producing a geminal difluoro compound according to Claim 6,
wherein the fluorinating agent is a hydrogen fluoride-pyridine complex. 8. The method for producing a geminal difluoro compound according to Claim 7,
wherein the weight ratio of hydrogen fluoride to pyridine in the hydrogen fluoridepyridine
complex is from 70:30 to 20:80.
9. The method for producing a geminal difluoro compound according to any one of
Claims 1 to 5, wherein the fluorinating agent is hydrogen fluoride.
10. The method for producing a geminal difluoro compound according to any one of
Claims 1 to 9, wherein R1 is methyl.
11. The method for producing a geminal difluoro compound according to any one of
Claims 1 to 10, wherein X is a chlorine atom or a bromine atom.
12. The method for producing a geminal difluoro compound according to Claim 11,
wherein X is a bromine atom.
13. The method for producing a geminal difluoro compound according to any one of
Claims 1 to 12, wherein the reaction is conducted in the presence of a solvent.
14. The method for producing a geminal difluoro compound according to Claim 13,
wherein the solvent is a halogenated hydrocarbon.