Field of the Invention
[0001.] The present invention relates to a process for industrial production of a-
fluoroaldehydes.
Background Art
[0002.] α-Fluoroaldehydes can be produced by reduction of corresponding a-
fluoroesters. For such reduction reactions, it is often the case to use stoichiometric
amounts of hydride reducing agents e.g. sodium borohydride, lithium aluminum
hydride etc. (see Patent Document 1 and Non-Patent Document 1). However, the
processes for production of a-fluoroaldehydes using the stoichiometric amounts of
hydride reducing agents are not suitable for large-scale production applications in
view of the facts that: the hydride reducing agents are expensive and need to be
handled with great caution; and the post treatments of the resulting reaction products
require complicated operations and cause large amounts of wastes.
[0003.] On the other hand, there have been proposed, as relevant techniques,
process for production of fluoral hydrates by reaction of trifluoroacetic acids
(including corresponding esters) with hydrogen gas (H2) in the presence of
ruthenium/tin bimetal catalysts in vapor phases (see Patent Documents 2 and 3).
Prior Art Documents
Patent Documents
[0004.] Patent Document 1: Japanese Laid-Open Patent Publication No. H05-
170693
Patent Document 2: Japanese Laid-Open Patent Publication No. H05-
294882
Patent Document 3: International Publication No. WO 97/017134
Non-Patent Documents
[0005.] Non-Patent Document 1: Journal of the American Chemical Society
(U.S.), 1954, vol. 76, p. 300

Summary of the Invention
Problems to be Solved by the Invention
[0006.] The production process using the hydrogen gas in the presence of the
bimetal catalysts provides solutions to all problems raised in the production process
using the stoichiometric amount of hydride reducing agent, but lead to high
industrial manufacturing cost due to the need for special production equipment to
perform the reaction in the vapor phase under high-temperature conditions.
[0007.] It is therefore an object of the present invention to provide a process for
industrially producing an a-fluoroaldehyde by hydrogen reduction of an a-
fluoroester without the need for special production equipment. As far as the present
inventors know, there has been no specific report about the hydrogen reduction of a-
fluoroesters and particularly about the production of a-fluoroaldehydes by hydrogen
reduction of a-fluoroesters with the use of homogeneous catalysts. In the present
specification, the term "homogeneous catalyst" is a catalyst as defined in Kagaku
Daijiten (Tokyo Kagaku Dojin, edited by Michinori Ohki, Toshiaki Osawa,
Motoharu Tanaka and Hideaki Chihara) and the like.
Means for Solving the Problems
[0008.] As a result of extensive researches, the present inventors have found that
a ruthenium complex of the following general formula [2], especially a ruthenium
complex of the following general formula [4], can be used as a catalyst or precursor
thereof for hydrogen reduction of an α-fluoroester without the need for special
production equipment. This ruthenium complex functions as a homogeneous
ruthenium catalyst, which is different from the supported-type (heterogeneous)
ruthenium/tin bimetal catalysts of Patent Documents 2 and 3.


In the general formula [2], R each independently represents a hydrogen atom, an
alkyl group, a substituted alkyl group, an aromatic ring group or a substituted
aromatic ring group; Ar each independently represents an aromatic ring group or a
substituted aromatic ring group; X each independently represents a ligand with a
formal charge of -1 or 0 (with the proviso that the sum of the formal charges of three
X is -2); and n each independently represents an integer of 1 or 2.

In the general formula [4], Ph each independently represent a phenyl group.
[0009.] The present applicant has filed, as a technique relevant to the present
invention, an application for a process for industrial production of a p-fluoroalcohol
by reduction of an a-fluoroester with a dramatic reduction in hydrogen pressure
(hereinafter referred to as "relevant application"). The disclosure of the relevant
application is summarized as follows. In the relevant application, the [5-
fluoroalcohol is produced by reaction of the a-fluoroester of the general formula [1]
with hydrogen gas in the presence of a specific ruthenium complex (as
corresponding to the ruthenium complex of the following general formula [2],
especially the ruthenium complex of the following general formula [4], of the

present invention). In the production process of the relevant application, there is no
need to use a high-pressure gas production facility as the hydrogen pressure can
preferably be set to 1 MPa or lower. Further, the amount of the catalyst used can be
reduced to a significantly low level (e.g. a substrate/catalyst ratio of 20,000) in the
production process of the relevant application as compared to the substrate/catalyst
ratio (e.g. 1,000) in the conventional reduction processes of a-fluoroalcohols. It is
possible by these reductions in hydrogen pressure and catalyst amount to largely
reduce the production cost of the p-fluoroalcohol. In addition, the reduction reaction
is inert to unsaturated bonds (such as carbon-carbon double bond) in the production
process of the relevant application so that it is a preferred embodiment of the
relevant application to carry out the reduction reaction in a functional-group-
selective manner (see Comparative Examples 1,2, 3 and 4 as explained later in the
present specification).
[0010.] The a-fluoroester as the raw substrate material of the relevant
application is represented by the following formula.

In the above formula, R1 and R2 each independently represent a hydrogen atom, a
halogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a
substituted aromatic ring group; and R3 represents an alkyl group or a substituted
alkyl group.
Further, the p-fluoroalcohol as the target product of the relevant
application is represented by the following formula.


In the above formula, R1 and R2 have the same meanings as those of the a-
fluoroester.
The present invention and the relevant application are similar to each
other in that: the halogen atom used as R1 and R2 in the a-fluoroester of the relevant
application can be the same as the halogen atom used as R1 in the a-fluoroester of
the general formula [1] of the present invention; the alkyl or substituted alkyl group
used as R1 and R2 in the a-fluoroester of the relevant application can be the same as
the alkyl or substituted alkyl group used as R2 in the a-fluoroester of the general
formula [1] of the present invention; the aromatic ring or substituted aromatic ring
group used as R1 and R2 in the a-fluoroester of the relevant application can be the
same as the aromatic ring or substituted aromatic ring group used as R in the
ruthenium complex of the general formula [2] of the present invention; and the alkyl
or substituted alkyl group used as R in the a-fluoroester of the relevant application
can be the same as the alkyl or substituted alkyl group used as R in the a-
fluoroester of the general formula [1] of the present invention.
[0011.] The present invention is however clearly different from the relevant
application in the kind of the raw substrate material. The raw material substrate of
the present invention corresponds to those in which one of R1 and R of the α-
fluoroester as the raw material of the relevant application is a fluorine atom and the
other is a halogen atom or a haloalkyl group. It has been found that the a-
fluoroaldehyde can be selectively obtained as a hydrogen reduction intermediate
from the raw material substrate of the present invention. Although the raw substrate
material of the present invention is included in the raw substrate material of the
relevant application, not only the α-fluoroaldehyde but also a β-fluoroalcohol as a
by-product are obtained in the present invention. There is thus no limitation
imposed by the present invention on the relevant application. In the present
invention, the by-produced β-fluoroalcohol can be easily separated by purification
from the target a-fluoroaldehyde because of the large difference between the

physical properties of the α-fiuoroaldehyde and the β-fluoroalcohol. There is thus
no limitation imposed by the relevant application onto the production process of the
a-fluoroaldehyde according to the present invention.
[0012.] In this way, the present inventors have found the useful techniques for
industrial production of the a-fluoroaldehyde. The present invention is based on
these findings.
[0013.] The present invention thus provides a production process of an a-
fluoroaldehyde as defined by the following aspects 1 to 9.
[0014.] [Inventive Aspect 1]
A process for producing an a-fluoroaldehyde of the general formula [3],
comprising: reaction of an a-fluoroester of the general formula [1] with hydrogen
gas (H2) in the presence of a ruthenium complex of the general formula [2]

where R1 represents a halogen atom or a haloalkyl group; and R2 represents an alkyl
group or a substituted alkyl group,

where R each independently represents a hydrogen atom, an alkyl group, a
substituted alkyl group, an aromatic ring group or a substituted aromatic ring group;
Ar each independently represents an aromatic ring group or a substituted aromatic

ring group; X each independently represents a ligand with a formal charge of-1 or 0
(with the proviso that the sum of the formal charges of three X is -2); and n each
independently represents an integer of 1 or 2,

where R1 has the same meaning as in the general formula [1].
[0015.] [Inventive Aspect 2]
The process according to Inventive Aspect 1, wherein the reaction is
performed in the presence of a base.
[0016.] [Inventive Aspect 3]
A process for producing an a-fluoroaldehyde of the general formula [3],
comprising: reaction of an a-fluoroester of the general formula [1] with hydrogen
gas (H2) in the presence of a ruthenium complex of the general formula [4]

where R1 represents a halogen atom or a haloalkyl group; and R2 represents an alkyl
group or a substituted alkyl group,

where Ph represents a phenyl group,


where R1 has the same meaning as in the general formula [1].
[0017.] [Inventive Aspect 4]
The process according to any one of Inventive Aspects 1 to 3, wherein
the α-fluoroester of the general formula [1] is an a-fluoroester of the general
formula [5]; and the α-fluoroaldehyde of the general formula [3] is an a-
fluoroaldehyde of the general formula [6]

where R3 is an alkyl group,

[0018.] [Inventive Aspect 5]
The process according to any one of Inventive Aspects 1 to 4, wherein
the reaction is performed at a hydrogen pressure of 2 MPa or lower.
[0019.] [Inventive Aspect 6]
The process according to any one of Inventive Aspects 1 to 4, wherein
the reaction is performed at a hydrogen pressure of 1 MPa or lower.
[0020.] [Inventive Aspect 7]
The process according to any one of Inventive Aspects 1 to 4, wherein
the reaction is performed at a hydrogen pressure of 0.5 MPa or lower.

[0021.] [Inventive Aspect 8]
A process for producing an α-fluoroaldehyde of the general formula [3],
comprising: reaction of an α-fluoroester of the general formula [1] with hydrogen
gas (H2) in the presence of a ruthenium catalyst

where R1 represents a halogen atom or a haloalkyl group; and R2 represents an alkyl
group or a substituted alkyl group,

where R1 has the same meaning as in the general formula [1].
[0022.] [Inventive Aspect 9]
The process according to Inventive Aspect 8, wherein the ruthenium
catalyst is a homogeneous catalyst.
[0023.] In the present invention, there is no need to use special production
equipment for hydrogen reduction of the α-fluoroester. There is also no need to use
a high-pressure gas production facility by adoption of the preferable hydrogen
pressure condition (1 MPa or lower) in the present invention. It is therefore possible
to allow relatively easy industrial production of the α-fluoroaldehyde. Further, it is
possible to directly obtain, as stable synthetic equivalents of the α-fluoroaldehyde
(as explained later), not only a hydrate (as obtained by conventional techniques) but
also a hemiacetal that is easy to purify and is of high value in synthetic applications.

[0024.] As mentioned above, the present invention provides solutions to all
problems in the conventional techniques and establishes the significantly useful
process for production of the α-fluoroaldehyde.
Detailed Description of the Invention
[0025.] The production process of the α-fluoroaldehyde according to the present
invention will be described below in detail. It should be noted that: the scope of the
present invention is not limited to the following examples; and various changes and
modifications can be made as appropriate without impairing the scope of the present
invention. All of the publications cited in the present specification, such as prior art
documents and patent documents e.g. published patents and patent applications, are
herein incorporated by reference. In the following description, the structures of the
general formulas [1] to [6] are as defined above.
[0026.] In the present invention, the α-fluoroaldehyde of the general formula [3]
is produced by reaction of the α-fluoroester of the general formula [1] with
hydrogen gas (H2) in the presence of the ruthenium complex of the general formula
[2].
[0027.] In the α-fluoroester of the general formula [1], R1 represents a halogen
atom or a haloalkyl group. Examples of the halogen atom are fluorine, chlorine,
bromine and iodine. Examples of the haloalkyl group are those obtained by
substitution of any number of and any combination of the above halogen atoms onto
any of carbon atoms of alkyl groups having 1 to 18 carbon atoms in the form of a
straight-chain structure, a branched structure or a cyclic structure (in the case of 3 or
more carbons). Among others, preferred is a fluorine atom.
[0028.] In the α-fluoroester of the general formula [1], R2 represents an alkyl
group or a substituted alkyl group. Examples of the alkyl group are those having 1
to 18 carbon atoms in the form of a straight-chain structure, a branched structure or a
cyclic structure (in the case of 3 or more carbons). Examples of the substituted alkyl
group are those obtained by substitution of any number of and any combination of

substituents onto any of carbon or nitrogen atoms of the above alkyl groups. As
such substituents, there can be used: halogen atoms such as fluorine, chlorine and
bromine; lower alkyl groups such as methyl, ethyl and propyl; lower haloalkyl
groups such as fluoromethyl, chloromethyl and bromomethyl; lower alkoxy groups
such as methoxy, ethoxy and propoxy; lower haloalkoxy groups such as
fluoromethoxy, chloromethoxy and bromomethoxy; cyano group; lower
alkoxycarbonyl groups such as methoxycarbonylmethyl, ethoxycarbonylethyl and
propoxycarbonylpropyl; aromatic-ring groups such as phenyl, naphthyl, anthryl,
pyrrolyl (including nitrogen-protected form), pyridyl, furyl, thienyl, indolyl
(including nitrogen-protected form), quinolyl, benzofuryl and benzothienyl;
carboxyl group; protected carboxyl groups; amino group; protected amino groups;
hydroxyl group; and protected hydroxyl groups. In the substituted alkyl group, an
arbitrary carbon-carbon single bond or bonds may be replaced by any number of and
any combination of carbon-carbon double bonds and carbon-carbon triple bonds.
(As a matter of course, the alkyl group with such an unsaturated bond or bonds may
have any of the above substituent groups.) Depending on the kind of the substituent
group, the substituent group itself may be involved in a side reaction. However, the
side reaction can be minimized by the adoption of suitable reaction conditions. In
the present specification, the term "lower" means that the group to which the term is
attached is a group having 1 to 6 carbon atoms in the form of a straight-chain
structure, a branched structure or a cyclic structure (in the case of 3 or more
carbons). The aromatic ring groups described above as "such substituent groups"
may further be substituted with a halogen atom, a lower alkyl group, a lower
haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a cyano group, a
lower alkoxycarbonyl group, a carboxyl group, a protected carboxyl group, an
amino group, a protected amino group, a hydroxyl group, a protected hydroxyl
group etc. As the protecting groups of the pyrrolyl, indolyl, carboxyl, amino and

hydroxyl groups, there can be used those described in "Protective Groups in Organic
Synthesis", Third Edition, 1999, John Wiley & Sons, Inc.
[0029.] Among the α-fluoroester of the general formula [1], the α-fluoroester of
the general formula [5] is preferred because it is easily available on a large scale. In
this case, the resulting α-fluoroaldehyde of the general formula [6] is important as
an intermediate for pharmaceutical and agrichemical products.
[0030.] In the ruthenium complex of the general formula [2], R each
independently represent a hydrogen atom, an alkyl group, a substituted alkyl group,
an aromatic ring group or a substituted aromatic ring group. Examples of the alkyl
and substituted alkyl groups as R are the same as those of R2 in the α-fluoroester of
the general formula [1]. Examples of the aromatic ring group are those having 1 to
18 carbon atoms, such as: aromatic hydrocarbon groups as typified by phenyl,
naphthyl and anthryl; and aromatic heterocyclic groups containing heteroatoms e.g.
as nitrogen, oxygen or sulfur as typified by pyrrolyl (including nitrogen-protected
form), pyridyl, furyl, thienyl, indolyl (including nitrogen-protected form), quinolyl,
benzofuryl and benzothienyl. Examples of the substituted aromatic ring group are
those obtained by substitution of any number of and any combination of substituents
onto any of carbon or nitrogen atoms of the above aromatic ring groups. As such
substituents, there can be used the same substituents as mentioned above. Two
vicinal R (except hydrogen atoms) may form a cyclic structure by covalent bond of
carbon atoms with or without a nitrogen atom, an oxygen atom or a sulfur atom. In
particular, it is preferable that all of eight R are hydrogen (in the case where each of
two n is 1).
[0031.] Ar each independently represent an aromatic ring group or a substituted
aromatic ring group in the ruthenium complex of the general formula [2]. Examples
of the aromatic ring and substituted aromatic ring groups as Ar are the same as those
of Rin the ruthenium complex of the general formula [2]. In particular, it is
preferable that all of four Ar are phenyl.

[0032.] X each independently represent a ligand having a formal charge of -1 or
0 with the proviso that the sum of the formal charges of three X is -2 (the formal
charge of Ru is +2) in the ruthenium complex of the general formula [2]. Examples
of the ligand having a formal charge of-1 or 0 are: ligands described in "Hegedus:
Transition Metals in the Synthesis of Complex Organic Molecules (written by L.
S. Hegedus, Second Edition, translated by Shinji Murai, p. 4-9, Tokyo Kagaku
Dojin, 2001)" and in "Organic Chemistry for Graduate Students Vol. II: Molecular
Structure & Reaction/Organic Metal Chemistry (Ryoji Noyori et al., p. 389-390,
Tokyo Kagaku Dojin, 1999)" etc.; BH4; and R4CO2-. (Herein, R4 represents a
hydrogen atom, an alkyl group or a substituted alkyl group. Examples of the alkyl
and substituted alkyl groups as R4 are the same as those of R2 in the α-fluoroester of
the general formula [1].) In particular, it is preferable that the three ligands are
hydrogen, chlorine and carbon monoxide, respectively.
[0033.] The reaction can be performed in the absence of the base in the case
where at least one of three X ligands is BH4 in the ruthenium complex of the general
formula [2]. (As a matter of course, it is alternatively feasible to perform the
reaction in the presence of the base). Among others, it is preferable to use the
ruthenium complex of the general formula [4] in which the Cl ligand has been
replaced by BH4(H-BH3) (see International Application Publication No.
2011/048727).
[0034.] Further, n each independently represent an integer of 1 or 2 in the
ruthenium complex of the general formula [2]. In the case where n is 1, a nitrogen
atom and a phosphorus atom are bonded to each other via two carbon atoms in the
ruthenium complex. In the case where n is 2, a nitrogen atom and a phosphorus
atom are bonded to each other via three carbon atoms in the ruthenium complex. It
is preferable that each of two n is 2.
[0035.] In the ruthenium complex of the general formula [4], Ph represents a
phenyl group.

[0036.] Among the ruthenium complex of the general formula [2], the ruthenium
complex of the general formula [4] is preferred. There can be used, as the
ruthenium complex of the general formula [4], a commercially available complex
Ru-MACHO™ (manufactured by Takasago International Corporation).
[0037.] The ruthenium complex of the general formula [2] can be prepared in a
similar manner with reference to the preparation process of the above complex Ru-
MACHO™. Further, the ruthenium complex of the general formula [2] can be used
even when water or organic solvent such as toluene is contained in the ruthenium
complex. It suffices that the purity of the ruthenium complex is 70% or higher. The
purity of the ruthenium complex is preferably 80% or higher, more preferably 90%
or higher.
[0038.] It suffices to use the ruthenium complex of the general formula [2] in an
amount of 0.000001 mol or more per 1 mol of the α-fluoroester of the general
formula [1]. The amount of the ruthenium complex of the general formula [2] is
preferably 0.00001 to 0.005 mol, more preferably 0.00002 to 0.002 mol, per 1 mol
of the α-fluoroester of the general formula [1].
[0039.] Examples of the base usable in the reaction are: alkali metal
hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate
and potassium hydrogencarbonate; alkali metal carbonates such as lithium
carbonate, sodium carbonate and potassium carbonate; alkali metal hydroxides such
as lithium hydroxide, sodium hydroxide and potassium hydroxide; tetraalkyl
ammonium hydroxides such as tetramethyl ammonium hydroxide, tetraethyl
ammonium hydroxide, tetrα-n-propyl ammonium hydroxide and tetrα-n-butyl
ammonium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium
methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium
ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide,
lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide; organic
bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and

l,8-diazabicyclo[5.4.0]undec-7-ene; alkali metal bis(trialkylsilyl)amides such as
lithium bis(trialkylsilyl)amide, sodium bis(trialkylsilyl)amide and potassium
bis(trialkylsilyl)amide; and alkali metal borohydrides such as lithium borohydride,
sodium borohydride and potassium borohydrode. Among others, alkali metal
alkoxides are preferred. Particularly preferred are lithium methoxide, sodium
methoxide and potassium methoxide.
[0040.] It suffices to use the base in an amount of 0.001 mol or more per 1 mol
of the α-fluoroester of the general formula [1]. The amount of the base is preferably
0.005 to 5 mol, more preferably 0.01 to 3 mol, per 1 mol of the α-fluoroester of the
general formula [1].
[0041.] As it is assumed that the true catalytic active species is derived from the
ruthenium catalyst of the general formula [2] optionally in the presence of the base,
the case where the catalytic active species (including isolated form) is prepared in
advance and used in the reduction reaction is included in the scope of the present
invention.
[0042.] It suffices to use the hydrogen gas in an amount of 1 mol or more per 1
mol of the α-fluoroester of the general formula [1]. The hydrogen gas is preferably
used in a large excessive amount, more preferably in a large excessive amount under
the following pressurized conditions.
[0043.] There is no particular limitation on the hydrogen pressure. The
hydrogen pressure is preferably 2 to 0.001 MPa, more preferably 1 to 0.01 MPa. It
is particularly preferred that the hydrogen pressure is 0.05 MPa or lower in order to
maximize the effects of the present invention.
[0044.] Examples of the reaction solvent usable in the reaction are: aliphatic
hydrocarbon solvents such as n-hexane and n-heptane; aromatic hydrocarbon
solvents such as toluene and xylene; halogenated solvents such as methylene
chloride and 1,2-dichloroethane; ether solvents such as diethyl ether, 1,2-
dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl

methyl ether, diisopropyl ether, diethylene glycol dimethyl ether and anisole;
alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-
butanol, n-pentanol, n-hexanol and cyclohexanol; amide solvents such as N,N-
dimethylformamide and l,3-dimethyl-2-imidazolidinone; nitrile solvents such as
acetonitrile and propionitrile; dimethyl sulfoxide; and water. Among others, ether
solvents and alcohol solvents are preferred. Alcohol solvents are more preferred as
the reaction solvent. These reaction solvents can be used solely or in combination of
two or more thereof. It is particularly preferable to use methanol, ethanol or
propanol, each of which is easy to separate by fractional distillation, for production
of the α-fluoroaldehyde of the general formula [6] (or the after-mentioned synthetic
equivalent thereof) as the preferred target compound.
[0045.] It suffices to use the reaction solvent in an amount of 0.01 L (liter) or
more per 1 mol of the α-fluoroester of the general formula [1]. The amount of the
reaction solvent is preferably 0.03 to 10 L, more preferably 0.05 to 7 L, per 1 mol of
the α-fluoroester of the general formula [1]. The reaction can alternatively be
performed under neat conditions without the use of the reaction solvent.
[0046.] It suffices that the reaction temperature is +150°C or lower. The
reaction temperature is preferably +125 to -50°C, more preferably +100 to -25°C.
[0047.] Further, it suffices that the reaction time is 72 hours or less. As the
reaction time varies depending on the raw substrate material and reaction conditions,
it is preferable to determine the time at which there is seen almost no decrease of the
raw substrate material as the end of the reaction while monitoring the progress of the
reaction by any analytical means such as gas chromatography, liquid
chromatography or nuclear magnetic resonance.
[0048.] The α-fluoroaldehyde of the general formula [3] can be obtained by any
ordinary post treatment operation for organic synthesis.
[0049.] As the α-fluoroaldehyde of the general formula [3] is an aldehyde
having directly bonded thereto a strong electron-attracting group, it is often the case

that the α-fluoroaldehyde of the general formula [3] is obtained as stable synthetic
equivalents such as a self-polymerization product, hydrate and hemiacetal. (As a
matter of course, the α-fluoroaldehyde of the general formula [3] can be obtained in
the form of an aldehyde.) These synthetic equivalents are thus included in the oc-
fluoroaldehyde of the general formula [3] as the scope of the present invention.
(The same applies to that of the general formula [6].) Herein, the alcohol function
of the hemiacetal is derived from the alkali metal alkoxide used as the base, the
alcohol used as the reaction solvent (see Example 6), the ester moiety of the raw
material substrate (i.e. OR2 in the α-fluoroester of the general formula [1]) or the
like. It is feasible to replace the alcohol function of the hemiacetal with an arbitrary
alcohol function by shifting the equilibrium of the reaction system upon the addition
of the arbitrary alcohol during post treatment (see Example 8). (The "arbitrary
alcohol function" refers to those having 1 to 18 carbon atoms in the form of a
straight-chain structure, a branched structure or a cyclic structure (in the case of 3 or
more carbons).) Similarly, the hydrate can be obtained upon the addition of water.
Further, the crude product can be purified to a high purity, as needed, by
activated carbon treatment, fractional distillation, recrystallization, column
chromatography or the like. It is convenient to recover the target compound by
directly subjecting the reaction completed solution to recovery distillation in the
case where the target compound has a low boiling point. In the case where the
reaction is performed in the presence of the base, the relatively highly acidic target
compound (such as self-polymerization product, hydrate, hemicacetal etc.) tends to
form a salt or complex with the base and remain in the residue of distillation. In
such a case, it is feasible to obtain the target compound with high yield by
neutralizing the reaction completed solution with an organic acid such as formic
acid, acetic acid, citric acid, oxalic acid, benzoic acid, methanesulfonic acid or
paratoluenesulfonic acid or an inorganic acid such as hydrogen chloride, hydrogen
bromide, nitric acid or sulfuric acid in advance, and then, subjecting the neutralized

reaction completed solution to recovery distillation (including recovery by washing
the distillation residue with an organic solvent such as diisopropyl ether).
Examples
[0050.] The present invention will be described in more detail below by way of
the following examples. It should be noted that the following examples are
illustrative and are not intended to limit the present invention thereto. In the
following description, the abbreviations "Me", "Ph", and "Et" refer to methyl,
phenyl and ethyl, respectively.
[0051.] [Example 1]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 2.6 g (20 mmol, 1 eq) of α-fluoroester of the following formula, 6.1 mg (purity:
94.2%; 9.5 μmol, 0.0005 eq) of ruthenium complex of the following formula, 270
mg (5.0 mmol, 0.25 eq) of sodium methoxide and 10 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by
F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of α-fluoroaldehyde equivalent of the following formula
were 96% and 62.3%, respectively.


It was also confirmed that the selectivity of β-fluoroalcohol of the following formula
as an excessive reduction product was 37.7%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.

[0052.] [Example 2]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 2.6 g (20 mmol, 1 eq) of α-fluoroester of the following formula, 6.1 mg (purity:
94.2%; 9.5 μmol, 0.0005 eq) of ruthenium complex of the following formula, 270
mg (5.0 mmol, 0.25 eq) of sodium methoxide and 10 mL (0.5 L/mol) of methanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 0.5 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by
19F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of α-fluoroaldehyde equivalent of the following formula
were 97% and 72.4%, respectively.

It was also confirmed that the selectivity of β-fluoroalcohol of the following formula
as an excessive reduction product was 27.6%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.


[0053.] [Example 3]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 5.8 g (40 mmol, 1 eq) of α-fluoroester of the following formula, 13 mg (purity:
94.2%; 20 μmol, 0.0005 eq) of ruthenium complex of the following formula, 540
mg (10.0 mmol, 0.25 eq) of sodium methoxide and 20 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by
19F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of α-fluoroaldehyde equivalent of the following formula
were 83% and 89.4%, respectively.


It was also confirmed that the selectivity of P-fluoroalcohol of the following formula
as an excessive reduction product was 10.6%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.

[0054.] [Example 4]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 14 g (100 mmol, 1 eq) of α-fluoroester of the following formula, 6.4 mg
(purity: 94.2%; 10 μmol, 0.0001 eq) of ruthenium complex of the following
formula, 840 mg (10.0 mmol, 0.1 eq) of potassium ethoxide and 44 mL (0.4 L/mol)
of ethanol.


The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 0.8 MPa. The resulting
solution inside the reaction vessel was stirred all night at 38°C. It was confirmed by
19F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of α-fluoroaldehyde equivalent of the following formula
were 91% and 83.0%, respectively.

It was also confirmed that the selectivity of P-fluoroalcohol of the following formula
as an excessive reduction product was 17.0%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.


[0055.] [Example 5]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 8.9 g (50 mmol, 1 eq) of α-fluoroester of the following formula, 6.4 mg (purity:
94.2%; 10 μmol, 0.0002 eq) of ruthenium complex of the following formula, 270
mg (5.0 mmol, 0.1 eq) of sodium methoxide and 25 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 0.5 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by
1 F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of α-fluoroaldehyde equivalent of the following formula
were 84% and 80.0%, respectively.


It was also confirmed that the selectivity of β-fluoroalcohol of the following formula
as an excessive reduction product was 20.0%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.

[0056.] [Example 6]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 61 g (480 mmol, 1 eq) of α-fluoroester of the following formula, 62 mg (purity:
94.2%; 96 μmol, 0.0002 eq) of ruthenium complex of the following formula, 3.3 g
(48 mmol, 0.1 eq) of sodium ethoxide and 220 mL (0.5 L/mol) of ethanol.



The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 0.9 MPa. The resulting
solution inside the reaction vessel was stirred all night at 38°C. It was confirmed by
19F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction, the selectivity of α-fluoroaldehyde equivalent (ethyl hemiacetal) of the
following formula and the selectivity of α-fluoroaldehyde equivalent (methyl
hemiacetal) of the following formula were 95%, 60.9% and 7.9%, respectively.

It was also confirmed that the selectivity of β-fluoroalcohol of the following formula
as an excessive reduction product was 31.2%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalents (ethyl hemiacetal and methyl hemiacetal) was in
agreement with those of the reference standards. For reference purposes, the
reaction procedure and reaction results of the present example are summarized in the
following scheme.


[0057.] [Example 7]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 130 g (1.0 mol, 1 eq) of α-fluoroester of the following formula, 32 mg (purity:
94.2%; 50 μmol, 0.00005 eq) of ruthenium complex of the following formula, 11 g
(200 mmol, 0.2 eq) of sodium methoxide and 500 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 0.9 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by
19F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of α-fluoroaldehyde equivalent of the following formula
were 89% and 96.0%, respectively.


It was also confirmed that the selectivity of β-fluoroalcohol of the following formula
as an excessive reduction product was 4.0%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.

To the reaction completed solution, 4.5 g (75 mmol, 0.075 eq) of acetic acid was
added. The resulting solution was directly subjected to recovery distillation (oil bath
temperature: ~63°C, vacuum degree: ~1.6 kPa) so that the target compound was
recovered in the form of a methanol solution thereof. The methanol solution was
then subjected to fractional distillation (theoretical plate number: 20, distillation
temperature: 93°C, atmospheric pressure). By this, 93 g of α-fluoroaldehyde
equivalent of the above formula was obtained. The yield of α-fluoroaldehyde
equivalent was 67% as determined by internal standard method (internal standard

material: a,a,α-trifluorotoluene, quantitative value: 87 g). The 19F-NMR purity of
α-fluoroaldehyde equivalent was 98.0% or higher. The contents of methanol
content and water were 7.0% or lower and 0.05% or lower, respectively.
[0058.] [Example 8]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 154 g (1.2 mol, 1 eq) of α-fluoroester of the following formula, 150 mg (purity:
94.2%; 240 μmol, 0.0002 eq) of ruthenium complex of the following formula, 6.5 g
(120 mmol, 0.1 eq) of sodium methoxide and 530 mL (0.4 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 0.9 MPa. The resulting
solution inside the reaction vessel was stirred for 8 hours at 38°C. It was confirmed
by 19F-NMR analysis of the reaction completed solution that the conversion rate of
the reaction and the selectivity of α-fluoroaldehyde equivalent (methyl hemiacetal)
of the following formula were 92% and 91.2%, respectively.

It was also confirmed that the selectivity of P-fluoroalcohol of the following formula
as an excessive reduction product was 8.8%.


The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.

To the reaction completed solution, 6.5 g (110 mmol, 0.09 eq) of acetic acid was
added. The resulting solution was directly subjected to recovery distillation (oil bath
temperature: ~80°C, vacuum degree: ~1.8 kPa) so that the target compound was
recovered in the form of a methanol solution thereof. The methanol solution was
then subjected to fractional distillation (theoretical plate number: 10, distillation
temperature: 106°C, atmospheric pressure). (The distillation was continued with the
addition of 120 g (2.6 mol, 2.2 eq) of ethanol to the distillation still (i.e. the
distillation residue containing the target compound) at the time the major portion of
methanol was distilled.) By this, 97 g of α-fluoroaldehyde equivalent (ethyl
hemiacetal) of the following formula was obtained.


The contents of methanol, ethanol, α-fluoroaldehyde equivalent (methyl hemiacetal)
of the above formula and α-fluoroaldehyde equivalent (ethyl hemiacetal) of the
above formula were determined by gas chromatographic analysis to be < 0.1%,
14.8%, 0.1% and 84.5%, respectively. The yield of α-fluoroaldehyde equivalent
(ethyl hemiacetal) was 48% in view of the gas chromatographic purity.
[0059.] [Example 9]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 1.6 g (10 mmol, 1 eq) of α-fluoroester of the following formula, 0.9 mg (purity:
94.2%; 1.4 μmol, 0.00014 eq) of ruthenium complex of the following formula, 54
mg (1.0 mmol, 0.10 eq) of sodium methoxide and 10 mL (1.0 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 0.5 MPa. The resulting
solution inside the reaction vessel was stirred all night at 36°C. It was confirmed by
19F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of α-fluoroaldehyde equivalent of the following formula
were 24% and 90.0%, respectively.


It was also confirmed that the selectivity of P-fluoroalcohol of the following formula
as an excessive reduction product was 10.0%.

The 1H- and 19F-NMR data and gas chromatographic data of the obtained α-
fluoroaldehyde equivalent was in agreement with those of the reference standard.
For reference purposes, the reaction procedure and reaction results of the present
example are summarized in the following scheme.

[0060.] [Comparative Example 1]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 53 g (480 mmol, 1 eq) of α-fluoroester of the following formula, 15 mg (purity:
94.2%; 24 μmol, 0.00005 eq) of ruthenium complex of the following formula, 8.4 g
(120 mmol, 0.25 eq) of potassium methoxide and 240 mL (0.5 L/mol) of methanol.



The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 40°C. It was confirmed by
gas chromatographic analysis of the reaction completed solution that the conversion
rate of the reaction and the selectivity of β-fluoroalcohol of the following formula
were 100% and 97.6%, respectively.

For reference purposes, the reaction procedure and reaction results of the present
example are indicated in the following scheme.

The above reaction operation was repeated five times to obtain the reaction
completed solution equivalent to 2.4 mol of α-fluoroester. Then, 36 g (600 mmol,
0.25 eq) of acetic acid was added to the reaction completed solution. The resulting
solution was directly subjected to recovery distillation (oil bath temperature: 55°C,

vacuum degree: ~1.5 kPa) so that the target compound was recovered in the form of
a methanol solution thereof. The distillation residue (i.e. the solid matter containing
the target compound and potassium acetate) was washed by stirring with 200 mL of
diisopropyl ether and filtered out. The thus-obtained solid matter was further
washed with 200 mL of diisopropyl ether. In each of these washing operations, the
target compound was recovered in the form of a diisopropyl ether solution thereof.
The recovered solutions were combined and subjected to fractional distillation
(theoretical plate number: 20, distillation temperature: 92°C, atmospheric pressure).
By this, 158 g of P-fluoroalcohol of the above formula was obtained. The yield of
(3-fluoroalcohol was 80%. The gas chromatographic purity of P-fluoroalcohol was
99.6%. The content of water was 0.05%.
[0061.] [Comparative Example 2]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 5.0 g (40 mmol, 1 eq) of α-fluoroester of the following formula, 10 mg (purity:
94.2%; 16 μmol, 0.0004 eq) of ruthenium complex of the following formula, 700
mg (10 mmol, 0.25 eq) of potassium methoxide and 20 mL (0.5 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 37°C. It was confirmed by
gas chromatographic analysis of the reaction completed solution that the conversion

rate of the reaction and the selectivity of β-fiuoroalcohol of the following formula
were 92% and 98.9%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0062.] [Comparative Example 3]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 4.0 g (20 mmol, 1 eq) of α-fluoroester of the following formula, 4.3 mg (purity:
94.2%; 6.7 μmol, 0.0003 eq) of ruthenium complex of the following formula, 270
mg (5.0 mmol, 0.25 eq) of sodium methoxide and 10 mL (0.5 L/mol) of methanol.



The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 40°C. It was confirmed by
gas chromatographic analysis of the reaction completed solution that the conversion
rate of the reaction and the selectivity of β-fluoroalcohol of the following formula
were 100% and 98.2%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.

[0063.] [Comparative Example 4]
A pressure-proof reaction vessel of stainless steel (SUS) was charged
with 38 g (250 mmol, 1 eq) of α-fiuoroester of the following formula, 64 mg (purity:

94.2%; 100 μmol, 0.0004 eq) of ruthenium complex of the following formula, 3.4 g
(63 mmol, 0.25 eq) of sodium methoxide and 250 mL (1.0 L/mol) of methanol.

The inside of the reaction vessel was replaced five times with hydrogen gas. The
hydrogen pressure inside the reaction vessel was then set to 1.0 MPa. The resulting
solution inside the reaction vessel was stirred all night at 35°C. It was confirmed by
19F-NMR analysis of the reaction completed solution that the conversion rate of the
reaction and the selectivity of (3-fluoroalcohol of the following formula were 100%
and 98.0%, respectively.

The reaction procedure and reaction results of the present example are indicated in
the following scheme for reference purposes.


The above reaction operation was repeated twice to obtain the reaction completed
solution equivalent to 470 mmol of α-fluoroester. Then, 7.1 g (120 mmol, 0.25 eq)
of acetic acid and an appropriate amount of methoquinone (polymerization inhibitor)
were added to the reaction completed solution. The resulting solution was directly
subjected to recovery distillation (oil bath temperature: ~63°C, vacuum degree: ~7.9
kPa) so that the target compound was recovered in the form of a methanol solution
thereof. The distillation residue (i.e. the solid matter containing the target
compound and sodium acetate) was washed by stirring with 400 mL of diisopropyl
ether and filtered out. The thus-obtained solid matter was further washed with a
small amount of diisopropyl ether. In each of these washing operations, the target
compound was recovered in the form of a diisopropyl ether solution thereof. The
recovered solutions were combined and subjected to fractional distillation
(theoretical plate number: 4, distillation temperature: 57 to 62°C, 13 to 12 kPa). By
this, 40 g of P-fluoroalcohol of the above formula was obtained. The yield of P-
fluoroalcohol was 78%. The gas chromatographic purity of P-fluoroalcohol was
98.9%. The 1H- and 19F-NMR measurement results of P-fluoroalcohol are indicated
below.
1H-NMR (reference material: Me4Si, deuterated solvent: CDCl3) δ ppm; 2.21 (br,
1H), 3.81 (t, 2H), 5.55 (d, 1H), 5.74 (m, 1H), 5.97 (m, 1H).

19F-NMR (reference material: C6F6, deuterated solvent: CD3OD) δ ppm; 55.44 (m,
2F).
[0064.] As described above, there is no need to use special production
equipment for hydrogen reduction of the α-fluoroester in the present invention.
There is also no need to use a high-pressure gas production facility by adoption of
the preferable hydrogen pressure condition (1 MPa or lower) in the present
invention. It is therefore possible to allow relatively easy industrial production of
the α-fluoroaldehyde. Further, it is possible to directly obtain, as stable synthetic
equivalents of the α-fluoroaldehyde, not only a hydrate (as by conventional
techniques) but also a hemiacetal that is easy to purify and is of high value in
synthetic applications.
Industrial Applicability
[0065.] The α-fluoroaldehydes produced by the production method according to
the present invention are usable as intermediates for pharmaceutical and
agrichemical products.

WE CLAIM:
1. A process for producing an α-fluoroaldehyde of the general formula [3],
comprising: reaction of an α-fluoroester of the general formula [1] with hydrogen
gas (H2) in the presence of a ruthenium complex of the general formula [2]

where Rl represents a halogen atom or a haloalkyl group; and R2 represents an alkyl
group or a substituted alkyl group,

where R each independently represents a hydrogen atom, an alkyl group, a
substituted alkyl group, an aromatic ring group or a substituted aromatic ring group;
Ar each independently represents an aromatic ring group or a substituted aromatic
ring group; X each independently represents a ligand with a formal charge of-1 or 0
(with the proviso that the sum of the formal charges of three X is -2); and n each
independently represents an integer of 1 or 2,


where R1 has the same meaning as in the general formula [1].
2. The process as claimed in claim 1, wherein the reaction is performed in the
presence of abase.
3. A process for producing an α-fluoroaldehyde of the general formula [3],
comprising: reaction of an α-fluoroester of the general formula [1] with hydrogen
gas (H2) in the presence of a ruthenium complex of the general formula [4]

where R represents a halogen atom or a haloalkyl group; and R represents an alkyl
group or a substituted alkyl group,

where Ph represents a phenyl group,

where R1 has the same meaning as in the general formula [1].
4. The process as claimed in any one of claims 1 to 3, wherein the α-fluoroester
of the general formula [1] is an α-fluoroester of the general formula [5]; and the α-

fluoroaldehyde of the general formula [3] is an α-fluoroaldehyde of the general
formula [6]

where R3 is an alkyl group,

5. The process as claimed in any one of claims 1 to 4, wherein the reaction is
performed at a hydrogen pressure of 2 MPa or lower.
6. The process as claimed in any one of claims 1 to 4, wherein the reaction is
performed at a hydrogen pressure of 1 MPa or lower.
7. The process as claimed in any one of claims 1 to 4, wherein the reaction is
performed at a hydrogen pressure of 0.5 MPa or lower.
8. A process for producing an α-fluoroaldehyde of the general formula [3],
comprising: reaction of an α-fluoroester of the general formula [1] with hydrogen
gas (H2) in the presence of a ruthenium catalyst


where R1 represents a halogen atom or a haloalkyl group; and R2 represents an alkyl
group or a substituted alkyl group,

where R1 has the same meaning as in the general formula [1].
9. The process as claimed in claim 8, wherein the ruthenium catalyst is a
homogeneous catalyst.